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Furans and their Benzo Derivatives: (ii) Reactivity
3.11 Furans and their Benzo Derivatives: (ii) Reactivity M. V. SARGENT University of Western Australia
and F. M. DEAN University of Liverpool 3.11.1 INTRODUCTION 3.11.2 FULLY CONJUGATED RINGS: REACTIVITY AT RING ATOMS 3.11.2.1 Thermal and Photochemical Reactions involving No Other Species 3.11.2.2 Reactions with Electrophiles 3.11.2.2.1 Reactivity and directive effects 3.11.2.2.2 Protonation 3.11.2.2.3 Nitration 3.11.2:2.4 Sulfonation 3.11.2.2.5 Halogenation 3.11.2.2.6 Acylation 3.11.2.2.7 Alkylation 3.11.2.2.8 Reactions with aldehydes and ketones 3/il.2.2.9 Mercuration /3.11.2.2.10 Reactions with diazonium salts 3.11.2.3 Reactions with Oxidants 3.11.2.4 Reactions with Nucleophiles 3.11.2.5 Reactions with Reducing Agents 3.11.2.6 Reactions with Free Radicals and Other Electron Deficient Species 3.11.2.7 Cycloaddition Reactions 3.11.2.7.1 Thermal reactions 3.11.2.7.2 Photochemical reactions 3.11.3 FULLY CONJUGATED RINGS: REACTIVITY OF SUBSTITUENTS 3.11.3.1 Fused Benzene Rings 3.11.3.2 Alkyl and Substituted Alkyl Substituents 3.11.3.3 Carboxylic Acids 3.11.3.4 Acyl Substituents 3.11.3.5 N-Linked Substituents 3.11.3.6 O-Linked Substituents 3.11.3.7 S-Linked Substituents 3.11.3.8 Halogen Substituents 3.11.3.9 Metal Substituents 3.11.4 SATURATED AND PARTIALLY SATURATED RINGS 3.11.4.1 2,3-Dih ydrofurans 3.11.4.2 2,3-Dihydrobenzo[b]furans 3.11.4.3 2,5-Dihydrofurans 3.11.4.4 Tetrahydrofurans
599 600 600 601 601 602 603 604 604 606 607 607 608 608 609 611 614 615 619 619 636 642
642 644 646 646 647 648 650 650 650 653 653 654 654 655
3.11.1 INTRODUCTION The chemistry of furan (1) has been fully reviewed from time to time. The text by Dunlop and Peters (B-53MI31100) covers the literature exhaustively up to 1953. Bosshard and Eugster <66AHC(7)377) and Dean <82AHC(3O)167, 82AHC(3l)237> have updated the treatment to the end
599
Furans and their Benzo Derivatives: (ii) Reactivity
600
of 1979. A text is available on benzo[& ]furan (2) (74HC(29)l) and the chemistry of benzofc]furan (3) has been reviewed by Friedrichsen (80AHC(26)l35). The chemistry of dibenzofuran (4) has received scant attention and the last full review was published in 1951 (B-51MI31100). The treatment in the present chapter is of necessity somewhat selective and to some degree idiosyncratic, but an attempt has been made to reflect the more modern developments in the subject. Where no reference is given in the text the appropriate monograph mentioned above should be consulted.
O 1
(2)
(1)
(4)
(3)
3.11.2 FULLY CONJUGATED RINGS: REACTIVITY AT RING ATOMS 3.11.2.1 Thermal and Photochemical Reactions involving No Other Species The thermal reactions of furans merit only brief mention. Ligularone (5) is isomerized to isoligularone (6) without a catalyst at 260 °C and diradical intermediates have been postulated (73TL3999). The double bond of furan can be forced to participate in electrocyclic
O
(6)
(5)
reactions. Thus the 2-methylbuta-l,3-dienyl ethers (7) of both furan-2-methanol (Scheme 1) and furan-3-methanol undergo thermal rearrangement, as does the vinyl ether of furan-2-methanol. The intermediate (8) undergoes both 1,3-hydrogen shift producing (9) and Cope rearrangement producing (10) (70HCA605). Gas phase pyrolysis of l-(2'furyl)buta-l,3-diene produces 4,5-dihydrobenzo[&]furan; there is no scrambling of deuterium when the 4,4-dideutero derivative is pyrolyzed and a mechanism involving trans-cis isomerization, thermally allowed disrotatory cyclization and 1,5-sigmatropic hydrogen shift has been proposed (77TL151). CHO
CHO
heat
CHO (7)
(9)
(8)
(10)
Scheme 1
The photorearrangement of furans has been extensively studied (B-80MI31100) and involves fission of the weaker C—O bond in the lowest excited state. The intermediate diradical recloses to a cyclopropane carbonyl derivative or to the original furan. The cyclopropane can sometimes be isolated but its fate on absorption of a further photon varies. Irradiation of 2,5-di-f-butylfuran (Scheme 2) in pentane yields (11; 3%), (13; 4%) and (16; 6%). The initial product is (12) which can open by photolysis of the 2,3-bond leading to (13) via the diradical (14), or by breaking of the 1,3-bond to yield (16) via hydrogen migration in the intermediate diradical (15). In the case of 2,3,5-tri-f-butylfuran (Scheme 3) the products are (21; 90%) and (20; 5%). The alternative modes of cleavage afford the intermediates (17) and (18) which close to the cyclopropenes (20) and (19). Cyclopropene (19) is photolabile and intramolecular hydrogen abstraction gives the diradical (22) which cyclizes to the ketone (21). In certain cases the intermediate cyclopropenes may be trapped; amines ultimately afford N- alkylpyrroles. Methanol traps the cyclopropene (24) from furan-2carbonitrile as a stereoisomeric mixture of cyclopropenes (25; Scheme 4). In the case of
Furans and their Benzo Derivatives', (ii) Reactivity
V
%.
o
O
iBu1
Bu1 O (12)
(11)
Bu 1
Bu l
601
O 1
Bu
o
o
(13)
(14)
Bu1
(15)
(16)
Scheme 2 Bu1
Bu1
Bu1
Bu l / : . ;>Bu
Bu1
o
O
O Bu1 (19)
(18)
Bu1
Bu1
/ARM1
Bu1
Bu1
o
(20) (22)
(21) Scheme 3
o
hv MeOH
V
CN"
OHC
L CHO (24) Scheme 4
(23)
V
OMe
CN (25)
2-nitrofuran the initial product is thought to be the nitrite (26) which on thermolysis or photolysis yields nitric oxide and furyloxyl radical (27). Recombination then affords the hydroxyiminolactone (28; 79%) (Scheme 5) <72JCS(P1)2527>. NOH hv
NO,
Me2CO
+ NO
ONO (27)
Scheme 5
The cyclophane (29) on irradiation with a low-pressure mercury lamp at 20 °C or —190 °C undergoes opening to aflEord relatively stable solutions of (30; Scheme 6) which was detected by its UV spectrum (76AG(E)442>.
O O
"-Q-
(29)
(30) Scheme 6
3.11.2.2 Reactions with Electrophiles 3.11.2.2,1 Reactivity and directive effects Furan exhibits great reactivity towards electrophiles (71PMH(4)55, 71AHC(13)235> and the conditions under which these reactions are carried out require to be carefully controlled.
602
Furans and their Benzo Derivatives: (//) Reactivity
Furans substituted with electron releasing groups usually undergo polymerization with mineral acids due to facile protonation at the 2-position. Aluminum chloride also causes resiniflcation of furan but benzo[& ]furan and compounds with electron withdrawing groups are, however, more stable. The reversion to type so characteristic of the electrophilic substitution of benzene is by no means prevalent in the chemistry of furan and benzo[& ]furan and many apparent electrophilic substitutions in reality proceed by addition. The reactivity order of five-membered heterocycles has already been treated (Section 3.02.2.3) and it can merely be noted that furan lies between pyrrole and thiophene. Furan is estimated to be 4.8-3.3 x 102 times more reactive than benzo[&]furan in a number of acylation reactions. Substitution at the 2- or 5-positions in furan is paramount unless these positions are blocked and this position is estimated to be 6 x 1011 times more reactive than a benzene position. The a : /3 ratios for acylation of furan under various conditions are in the range 8 x 102 to 6.8 x 103 but the 3- or 4-position is still much more reactive than a benzene position. The isomer distribution in the acetylation of benzo[£ ]furan has been studied under a range of conditions and here the preference for 2-substitution is less marked since the 2:3 ratio varies between 1.7 to 8.4 and there is a significant temperature dependence, lower values being obtained at higher temperature. The reactivity of furan and benzo[6 ]furan has also been considered from the standpoint of linear free energy relationships and transmission effects. Empirical correlations can readily be made on the directing effects of substituents from the large body of data available. Furans with a + / or a —I/+M substituent at the 2-position invariably give 5-substituted products. For a —I/—M substituent at the 2-position the substituent mesomeric effect will deactivate the 5-position but this is usually outweighed by the powerful orientational effect of the ring oxygen and 5-substitution usually ensues in the absence of Lewis acids. Lewis acids enhance the —M effect of a 2-carbonyl substituent (the 'swamping catalyst effect') and electrophilic substitution then occurs at the 4-position although 4,5-disubstituted compounds are also isolated (68AG(E)519). For a + / substituent at the 3-position the 2-position is more activated by electronic effects than the 5-position but the 5-position is unhindered and mixtures of 2- and 5-substituted isomers are usually obtained, the composition of which depends on the size of both the 3-substituent and the electrophile. A —I/—M substituent at the 3-position results in substitution at the 5-position since the effects of the oxygen atom and the substituent are in alliance. For disubstituted compounds the position of attack may be deduced from the known directive effects of the substituents and the heteroatom. In the case of 2,5-disubstituted compounds, electrophiles attack the position adjacent to the more electron releasing substituent. In such cases the preference for a-attack is so strong that ipso substitution with the expulsion of a group such as halogen or carboxy may occur. Such reactions are particularly common in nitrations as in those of 2,5-diiodofuran and 5-methylfuran-2-carboxylic acid. The prediction of the outcome of the electrophilic substitution of a benzo[6 ]furan is less certain since fewer data are available. It is true, however, that an electron releasing 2-substituent will usually direct the electrophile to the 3-position and conversely an electron releasing 3-substituent will direct the electrophile to the 2-position. Electron withdrawing substituents at the 2-position result in substitution in the benzene ring (homosubstitution): thus bromination and chloromethylation of esters of benzo[6]furan-2-carboxylic acid occur at the 5-position; nitration similarly gives 5-substitution as well as some at the 7-position. Strongly electron releasing groups in the benzene ring usually result in homosubstitution at a position ortho or para to the substituent whilst with electron withdrawing groups or alkyl groups in the benzene ring heterosubstitution at the 2-position often ensues. 3.11.2.2.2 Protonation Both furans and, less readily so, benzo[& ]furans are prone to undergo resinification on exposure to strong acids unless there is an electron withdrawing group at the 2-position. 2,5-Dialkylfurans are more stable. The rates for acid-catalyzed protodetritiation, protodedeuteration, deuterodeprotonation and deuterodetritiation for the 5-position of 2methylfuran have been determined. The isotope effects and activation parameters thus obtained are typical of an A-5 E 2 mechanism (73ACS153). It is now generally accepted that furan undergoes protonation at the 2-position rather than on oxygen and ab initio SCF calculations support this view. The protonation of 2,5-di-f-butylfuran occurs at a 2-position
Furans and their Benzo Derivatives: (ii) Reactivity
603
in concentrated sulfuric acid and the pKa has been estimated at -10.01, and by further approximations that of furan as —13± 1 (76T1767). Protonation can lead to ring opening but, for furan and 2-methylfuran, treatment with perchloric acid in aqueous DMSO leads only to polymerization and no hydrolytic cleavage. Anhydrous methanolic hydrogen chloride, however, affords monomeric ring opened products. 2,5-Dimethylfuran with perchloric acid in aqueous DMSO gives acetonylacetone at a rate approximating to that of its decomposition. Since this rate is 102 times slower than that for hydrogen exchange at an a-position it has been suggested that the cleavage is initiated by /3-protonation as in Scheme 7. These hydrolytic cleavages have been extensively exploited in synthesis and two examples are shown in Scheme 8.2-Methylfuran on treatment with phosphoric acid undergoes cationic oligomerization to produce tetramers, pentamers, hexamers and heptamers. The structure of the major tetramer (38%) and a plausible mode of formation are shown in Scheme 9 (74BCJ1467). Me _
Me O
OH
// MC
HO ( f 'Me
O O
Scheme 7
o , AcOH, H + ; ii, HOCH2CH2OH, H+ Scheme 8
i, 2-methylfuran, - H + ; ii, H + Scheme 9
3.11.2.2.3 Nitration Nitration of furans is best achieved with a mixture of fuming nitric acid and acetic anhydride, usually at -10 to -20 °C. A wide range of compounds has been nitrated by this technique and even a,/3-unsaturated aldehyde, ketone and carboxylic ester substituents will tolerate this reaction. More vigorous conditions may be applied to compounds with electron withdrawing groups; thus 2-bromo-5-nitrofuran on treatment in dichloromethane with concentrated nitric and sulfuric acids yields 2-bromo-3,5-dinitrofuran (14%) (79JHC477). 2-Nitrofuran may be nitrated with 70% nitric acid and then affords 2,5dinitrofuran (67%) and 2,4-dinitrofuran (5%) (78JOC4303). The acetyl nitrate method usually proceeds by an addition-elimination mechanism and in certain cases the addition products may be isolated and require treatment with a base such as pyridine to effect elimination of acetic acid. From the nitration of furan the intermediate addition product (31) may be isolated. Similar intermediates (32) and (33) are involved in the nitration of furan-2-carbaldehyde and its diacetate, and also in the nitration of methyl furan-2-carboxylate (76KGS601). Nitration of furan-2-methanol yields the nitro nitrate (34). Expulsion of substituents is common in nitration, as in that of 5-bromofuran-2-carboxylic acid which
604
Furans and their Benzo Derivatives: (//) Reactivity AcO -\NO2 / \\ X O 2 N ^ )>CH(OAc)2 2 O \ XT (31) R = H (33) (32) R = CH(OAc)2
// \\ O2N^ O (34)
yields 5-bromo-2-nitrofuran (47%), isolated by pouring on ice, ether extraction and steam distillation. Furan has been nitrated with nitronium tetrafluoroborate in poor yield (14%). Nitration of benzo[£ ]furan may be achieved with nitric acid in acetic acid and affords the 2-nitro compound, although nitrogen dioxide in benzene is reported to give the 3-nitro compound. 2-Phenylbenzo[£]furan with nitric acid in acetic acid yields the 3- and 6-nitro compounds. Treatment of 2-bromobenzo[£]furan with nitric acid and sodium nitrite yields 2-nitrobenzo[6]furan. The only electrophilic substitution reported with a benzo[c ]furan is nitration of l,3-diphenylbenzo[c]furan with sodium nitrate and sulfuric acid, and this occurs on a phenyl group. 3.11.2.2.4 Sulfonation Furan is resinified by sulfuric acid but it can be sulfonated with the complex of sulfur trioxide with pyridine or dioxane. Depending on conditions the 2-sulfonic or the 2,5disulfonic acid may be obtained. Furan-2-carboxylic acid can be sulfonated with oleum. Benzo[£]furan is polymerized by sulfuric acid. The 2-sulfonic acid has been obtained by oxidation of the sulfinic acid available in turn by treatment of the lithio derivative with sulfur dioxide. Benzo[£]furan with the sulfur trioxide-pyridine complex allegedly affords the 3-sulfonic acid. 3.11.2.2.5 Halogenation 2-Bromofuran is best obtained by treatment of furan with dioxane dibromide at —5 °C. It may also be obtained in 39% yield by NBS bromination in boiling benzene in the presence of toluene-p-sulfonic acid. 3-Methylfuran has also been brominated with NBS but in the presence of the radical initiator 2,2'-azobisisobutyronitrile the reaction can be controlled to give the 2-bromo (33%), the 2,5-dibromo (38%) or the 2,4,5-tribromo compound (64JOC1991). On the other hand, methyl 2-methylfuran-3-carboxylate and methyl 3-methylfuran-2-carboxylate yield the expected side-chain products under these conditions (70BSF1445). Furan with NBS and triethylamine and a catalytic amount of mercury(II) chloride in chloroform at ambient temperature yields 5,5'-dibromo-2,2'-bifuryl (40%) (79CB1493). It is tempting to speculate on the intermediacy of a furylmercury derivative. The bromination of furan with bromine at —50 °C in carbon disulflde has been studied by H NMR spectroscopy. Addition occurs and cis- and trans- 2,5-dibromo -2,5 -dihydrof uran and trans- 2,3-dibromo-2,3-dihydrofuran were detected. On warming, 2-bromofuran is obtained. Whether the addition products are genuine intermediates or the result of side equilibria is not known. Bromination of furan in methanol at - 1 0 °C in the presence of a base gives 2,5-dimethoxy-2,5-dihydrofuran (47%) via the 1,4-addition of bromine to the diene system. Bromination of furans with electron withdrawing groups at the 2-position proceeds by an electrophilic substitution mechanism and generally yields the 5-bromo compounds (Scheme 10). In the presence of aluminum chloride the swamping catalyst effect operates. With bromine and aluminum chloride, methyl furan-2-carboxylate affords starting material, the 5-bromo compound (35) and the 4,5-dibromo compounds (36). In the presence of solvents, Br/Cl exchange occurs and compounds (37) and (38) also result. Bromination of 3-acetylfuran in the presence of excess aluminum chloride gives products of 5-substitution (Scheme 11) (75BSF2334).
O'
O'
XT
*
(60%) Br2, S, quinol, C1CH2CH2C1; ii, Br2 C1CH2CH2C1, 20 °C Scheme 10
XT
CO2Me
(75%)
Furans and theirBenzo Derivatives: (ii) Reactivity
605
Br
o
CO, Me
Br
O
Br
o
CO, Me O (36) 4
(35) 3 Br CO, Me
(35)
+
(36) +
CI
O (37)
CO,Me
1
C K'/
>CO 2 Me O (38) 1
Ac 111
O
O 1
i, 1 mol Br2, 2.5 mol A1C13; ii, 12 mol C1CH2CH2C1; iii, 1.15 mol Br2, 2.5 mol A1C13, CH2C12, heat Scheme 11
Chlorination of furan at - 4 0 °C with 1.6 mol of chlorine affords 2-chloro- (64%), 2,5-dichloro- (29%) and 2,3,5-trichloro-furan (7%). By use of more chlorine the addition product 2,2,3,4,5,5-hexachloro-2,5-dihydrofuran and tetrachlorofuran are obtained. The chlorination of methyl furan-2-carboxylate obeys second order kinetics, when the 5-chloro compound is the only product. The behaviour of benzo[6 ]furan on bromination is complex although it probably involves a Wheland intermediate of the usual type for attack at C-2 which, depending on temperature, undergoes attack by bromide at C-3 to give the trans addition product, attack at the bromine atom to produce benzo[6 ]furan, or attack at the 2-H to give the 2-substitution product (76JCS(P2)266>. Thus at low temperature (-40 °C) addition to the furanoid double bond occurs and the trans-dibromo compound results; this is stable at room temperature. On gentle heating it is in equilibrium with benzo[6 ]furan but on heating in acetic acid it irreversibly gives the 2-bromo compound. Heating the addition product with bases, however, yields the 3-bromo compound. The behaviour of 2-methyl- and 3-methyl-benzo[£]furan is similar. In the case of the former, the addition product is obtained at low temperature; it is stable for 1 h at — 30 °C but rapidly gives the 3-bromo compound at 25 °C. In the latter case the addition product is less stable and gives the 2-bromo compound after 15 min at —40 °C. The bromination of 2,3-dimethylbenzo|7> ]furan, an example of 'non-conventional aromatic substitution', also gives addition at —40 °C but after 45 min the products are the side-chain bromo compounds (40) and (42) in the ratio 3.5:1, formed via the intermediates (39) and (41) (Scheme 12). Bromination of 2-phenylbenzo[6]furan results in the 3-bromo compound which on further bromination affords the 3,6-dibromo compound. CH2Br CH,Br Br
(42)
Scheme 12
Chlorination of benzo[6 ]furan in ether, acetic acid or carbon tetrachloride at 0 or 25 °C results in a 1:1 mixture of cis- and trans- 2,3-dichloro-2,3-dihydrobenzo[^]furans, although with iodobenzene dichloride as chlorinating agent more of the trans isomer results. Both isomers may be converted into 3-chlorobenzo[6]furan with ethanolic ethoxide although, as expected, the cis isomer reacts much faster. On heating in acetic acid at 100 °C the trans isomer affords 2-chlorobenzo[£]furan whilst the cis compound undergoes isomerization (77JHC359). On chlorination of 2-acetyl-3-acetylaminobenzo[6]furan, ipso substitution occurs and the acetyl group is lost from the 2-position (78JCS(P1)419). Trifluorofluorooxymethane reacts with benzo[£ ]furan to give electrophilic addition products (Scheme 13) <77JCS(Pl)2604>.
606
Furans and their Benzo Derivatives: (//) Reactivity OCE
OCF,
i, CF3OF, freon, -78 °C Scheme 13
3.11.2.2.6 Acylation Formylation of furans is best carried out by the Vilsmeier-Haack method at low temperature. Acylations are best performed with acid anhydrides and mild catalysts such as boron trifluoride etherate or phosphoric acid. Acetylation with acetyl p- toluenesulfonate is particularly effective (76H(4)lO2l), whilst trifluoroacetylation requires no catalyst. The competition method has been used in a study of the acetylation with tin (IV) chloride and acetic anhydride of 2-(4-X-phenyl)-5-methylfurans in 1,2-dichloroethane. The rates of reaction were correlated with the Brown cr+ parameter. A similar study was made with the rates of trifluoroacetylation of 2-arylfurans (73BSF1760). Compounds with an ester substituent at the 2-position usually afford the 5-acylated product with a mild catalyst like boron trifluoride etherate but with tin(IV) chloride both 4- and 5-substitution occur, presumably since the reacting species is complexed with the catalyst (Scheme 14) (66JOC4252,79JOC3420). Further transformations of the initial products are also common with the more vigorous catalysts (Scheme 15) (75JCS(P1)2O69, 72ACS2907). The 2:5 ratio in the acylation of 3methylfuran is dependent on the electrophile. Acetylation with acetic anhydride and phosphoric acid gives a 1.9:1 ratio; propionylation gives a 2.3:1 ratio; whilst VilsmeierHaack formylation gives a 14.4:1 ratio (71T3323). Me
Me MeO,C
'/ W o
MeO,C '/
o
COC 4 H 9
20%
o
COC5Hn
MeO2C
'I
\±
MeO,C
O
MeOX
o
O
1
1.6
(C4H9CO)2O, BF3 Et 2 O, PhH, 25-65 °C; ii, (C 5 HnCO) 2 O, SnCl4, PhH, 25 °C Scheme 14
H W CO, Me
MeO,C
O
72%
O
OH 11
o
CO, Me
MeO,C
41%
i, 2 mol Ac2O, 2 mol SnCl4, 0-25 °C; ii, PrCOCl, FeCl3 Scheme 15
Benzo[£ ]furan undergoes formylation by the Vilsmeier-Haack method and acylation using acid anhydrides and phosphoric acid or tin(IV) chloride as catalysts. 2-Alkylbenzo[£ ]furans undergo acylation at the 3-position with aliphatic acid chlorides and tin(IV) chloride, although many aromatic acid chlorides also afford 4- and 6-substituted products (77JHC861). 2,3-Dimethylbenzo[&]furan on acetylation gives some 2-acetyl-3ethylbenzo[6]furan by 'non-conventional substitution', as well as the expected 4- and 6-products (78CC597). Electron releasing groups on the benzene ring usually result in homoacylation; thus 4,6-dimethoxybenzo[6]furan undergoes acylation in the 7-position.
Furans and their Benzo Derivatives: (//) Reactivity
607
3.11.2.2.7 Alkylation Alkylation of furan may be achieved with alkenes and mild catalysts, e.g. phosphoric acid or boron trifluoride etherate, and 2-substituted products result. f-Butylation of furan with isobutene and phosphoric acid on kiesefguhr results in a mixture of the 2- and 3-substituted compounds the proportions of which are temperature dependent. 2,5-Di-fbutylfuran is available by alkylation of 2-chloromercuriofuran with ^-butyl bromide but is usually prepared by ring synthesis. f-Butylation of 2,5-di-^-butylfuran results in the 2,3,5trisubstituted compound but 5-f-butyl-2,3-dimethylfuran yields the dihydro compound (43) as a result of minimization of steric hindrance. Similarly, f-butylation of 3-f-butyl-2,5dimethylfuran affords (44; Scheme 16) (75TL3619). The isopropylation of furan-2-carbaldehyde with isopropyl chloride in carbon disulfide using an excess of aluminum chloride at room temperature affords a mixture of products which contains much 4-isopropylated compound as well as 3,5-disubstituted and trisubstituted products. The 5-isopropyl compound was stable under the reaction conditions; doubtless the isopropylation at the 4position is a result of the complexing of the substrate with aluminum chloride. Similar results have also been reported for the isopropylation of 2-acetylfuran (76CCC78) and methyl furan-2-carboxylate (70CJC1550). Furans can be allylated with allyl iodides and silver trifluoroacetate in liquid sulfur dioxide. The reaction may be an electrophilic substitution although a mechanism involving a cycloaddition to produce a bicyclic cation cannot be precluded (Scheme 17) (69JCS(C)1456). Furans, usually with electronegative groups at the a-position, can be chloromethylated with ease. 2,5-Diphenylfuran can be bischloromethylated in the /?-positions. The Mannich reaction also works well with furans. Me
But
Me
Bul
II (43) i, Bu'Cl, A1C13, CS2, 0 °C Scheme 16 £H 2 OH
CH,OH
CH,OH
7 \> o 5:1 i, CH 2 =CHCH 2 I, CF3CO2Ag, SO2(1) Scheme 17
Benzo[&]furan may be alkylated with t- butyl chloride and zinc chloride, the products being the 2- and 3-substituted compounds in the ratio 1:2. Benzo[£]furan is chloromethylated at the 2-position. 2-Methyl- and 2-phenyl-benzo[£]furan are chloromethylated in the 3-position. 3.11.2.2.8 Reactions with aldehydes and ketones Furans with a free a-position are susceptible to electrophilic attack by protonated aldehydes and ketones. The yields in these reactions are often poor because of the R
R (45)
R
\_J (46)
R
608
Furans and their Benzo Derivatives: {ii) Reactivity
resinification of the furan but methyl furan-2-carboxylate gives good yields of compounds of type (45) with both aliphatic and aromatic aldehydes in concentrated sulfuric acid (72ACS1018). Trimers are sometimes isolated but with ketones tetramerization often results and the tetraoxaquaterenes of type (46) are obtained, although in poor yield. In the case of acetone the yield of quaterene shows a 'template effect' and may be raised to 45% in the presence of lithium per chlorate. Furans are also susceptible to electrophilic attack by 2-acetyl-l,4-benzoquinone and 2-furylbenzoquinones are usually obtained by a subsequent redox reaction.
3.11.2.2.9 Mercuration Furan can be sequentially mercurated with mercury(II) chloride to give mono-, di- and tri-mercuriochlorides. The tetrakis(mercurioacetate) is available by heating furan with mercury(II) acetate in acetic acid. Alkylfurans readily give chloromercurio derivatives on treatment with mercury(II) chloride and sodium acetate in aqueous ethanol. The a-positions, if vacant, are always attacked in preference to )8-positions, which, however, are attacked if the furan is 2,5-disubstituted (55RTC763). Carboxy groups are readily displaced from a-positions in preference to (3-positions; thus sodium furan-2,4-dicarboxylate is readily converted into 4-carboxy-2-furylmercury(II) chloride. Ester substituents survive. Furans substituted with electron withdrawing groups are more difficult to mercurate but this may usually be achieved under forcing conditions. Thus treatment of sodium 5-nitrofuran-2carboxylate with aqueous mercury(II) chloride at 155 °C yields 5-nitro-2-furylmercury(II) chloride. Treatment of furan-2-carboxylic acid with aqueous mercury(II) acetate gives a mixed salt of the acid which on pyrolysis undergoes rearrangement predominantly to the 3-furylmercuric acetate, presumably via a cyclic transition state. 2-Chloromercuriofuran undergoes protodemercuration 26.7 times faster than the 3-isomer (65AJC1513).
3.11.2.2.10 Reactions with diazonium salts Furan, on reaction with 2,4-dinitrobenzenediazonium sulfate in aqueous acetic acid, undergoes ring opening and affords (47); similar results are obtained with 2- and 3-
OH O
1
I'
CHO O
NHNHAr
N=NAr_j
>T
O
NHAr (47) 72% NO,
N=NAr
//w
Me O
\—/
NNH/ OH ^
"O (48)
—^ c
\*^2 '
(49)
Me
~N' Ar (50)
i, AcOH, H2O, 15 min; ii, AcOH, H2O, 50 h; iii, HC1, H2O, EtOH Scheme 18
Furans and their Benzo Derivatives: (//) Reactivity
609
methylfuran. Whether the reaction involves an electrophilic substitution or a cycloaddition is not known. Under the same conditions, 2,5-dimethylfuran affords the azo compound (48). Similar results are given by 2,5-dimethylfuran and 4-nitrobenzenediazonium chloride, but in aqueous ethanol in the presence of sodium acetate, (49) is obtained which may be converted into the pyrazole (50) by action of hydrochloric acid (Scheme 18). Benzo[£]furan and 2-methylbenzo[£]furan are arylated at the 3-position by 2,4-dinitrobenzenediazonium sulfate in aqueous acetic acid (78JCS(Pl)40l). Reactions of the Gomberg type have also been described with furan. The highly nucleophilic 3,4-dimethoxyfuran, when treated with arene diazonium salts in aqueous pyridine, undergoes 1,4-addition to afford pyridinium salts (51). The pyridine is easily displaced by nucleophiles including alcohols and phenols, thereby affording 5-alkoxy or 5-phenoxy derivatives of 3,4-dimethoxyfuran-2(5//)-one (52; Scheme 19) (78HCA1033). MeO OMe O
MeO
)
(' \
/
OMe
MeO
OMe
iL
N—C
>=NNHAr - - • ROCX X>=NNHAr OX ~ (51) (52)
i, ArNzCF, C6H5N, H 3 O + ; ii, ROH Scheme 19
3.11.2.3 Reactions with Oxidants The furan nucleus, being electron rich, is particularly sensitive to oxidation and most reactions involve 1,4-addition of the oxidant to the diene system. Photooxidation is discussed later (Section 3.11.2.7.2). II
\\
>CHNHA
i,ii
/ — \
> MeO<
OMe
Y
96% CH2NHAc
MeO,C. f=\
Bu1 97%
MeO
u
OMe Me
O
^>CH 2CH2CH(OH)Me - ^ ^ MeOC X X
O^
X
76%
V>
i, Pt anode; ii, MeOH, NH4Br; iii, MeOH, H 2 SO 4 ; iv, C anode, MeOH, NH4Br Scheme 20
The anodic oxidation of furans is particularly important and in alcohols it gives rise to mixtures of cis- and frans-2,5-dialkoxy-2,5-dihydrofurans and is known as the ClausonKaas reaction. These compounds are valuable intermediates in synthesis and the reaction tolerates a wide range of substituents and can even be diverted to give intramolecular products (Scheme 20) (68CRV449). The method gives better results than the chemical method in which the furan is treated with bromine and methanol in the presence of a weak base (Scheme 21) (60MI31100). The mechanism (Scheme 22) of the anodic oxidation involves formation of a radical cation which is captured by a nucleophile, yielding a radical; further oxidation yields a cation, which is in turn captured. The nucleophile in the Clauson-Kaas reaction is methanol; in the case of 2,5-dimethylfuran in the presence of sodium methoxide a small amount of side-chain methoxylation occurs by the alternative pathway shown in Scheme 22 and some 2,5-bismethoxymethylfuran may be isolated (69JOC1018). With 2,5dimethylfuran in methanolic sodium cyanide the first nucleophilic attack is that of cyanide followed by methanol so that the major pathway is that of cyanomethoxylation and cisand trans- 2- cyano-5-methoxy-2,5-dimethyl-2,5-dihydrofuran result. Some of the dimethoxy products are also produced as well as traces of 2-methoxymethyl-5-methylfuran and 2,5-bismethoxymethylfuran (7UOC1523). In acetonitrile, in the presence of saturated aqueous sodium hydrogen carbonate with lithium fluoroborate as supporting electrolyte,
Furans and their Benzo Derivatives', (ii) Reactivity
610 H \
-HBr
-HBr
o
^ '
x
MeO O i, Br2, MeOH, 2 mol KOAc Scheme 21 e
/, + . «\
w
•
o
Nu
R%A
RC - . ^ > R -ZH-4-
O
O
Nu
°
4-MeOH
Br
Nu
Nu
H
•
MeO
"^F-
R
Nu
>O
/
^ ^ . ^
O
\
OMe
>O
Nu
R = Me -e
O
o
Nu
O'
O
VH 2 Nu
*" NuH2C7/
O
Scheme 22 MeO2CH2C
CH 2 CO 2 Me
MeO 2 CH 2 C McCN,NaHCO
o
CH 2 CO 2 Me
o
86%
Scheme 23
7 o
H
LTA AcOH
O
AcO
Pb(OAc)
Pb(OAc)
O
Scheme 24
3,4-disubstituted furans undergo anodic oxidation to cis- and toms-2,5-dihydroxy-2,5dihydrofurans which may be oxidized by Jones reagent to maleic anhydrides (Scheme 23) (75JOC122). Furan undergoes anodic oxidation in acetic acid containing sodium acetate to supply cis- and trans- 2,5- bisacetoxy-2,5-dihydrofuran. This reaction can also be achieved with LTA in acetic acid (Scheme 24) (68JCS(C)969>. With 2-alkyl- and 2,5-dialkyl-furans, products of side-chain acetoxylation result from both these methods. Thus with LTA 2-methylfuran gives 2-(bisacetoxymethyl)furan and in the electrolytic method this is accompanied by 2-acetoxymethylfuran. Treatment of 2-arylfurans with ruthenium tetroxide leads to radical cations which form purple solutions of a charge transfer complex with the reagent. Oxidation of 2-arylfurans in a two-phase system with ruthenium tetroxide and aqueous hypochlorite yields products whose formation can be interpreted in terms of the radical cation intermediate (76CC890). On treatment of furan at low temperature with hydrogen peroxide the peroxide (53) is obtained which may be partially hydrogenated to male aldehyde. 2,5-Dimethylfuran with acidic hydrogen peroxide yields the hydroperoxide (54) and the cyclic peroxides (55) and (56); mechanisms have been proposed. Ozonolysis of furan at — 60 °C in chloroform with reductive work up affords glyoxal and formic acid. Methylfurans behave similarly; thus 2,3,4-trimethylfuran affords methylglyoxal, dimethylglyoxal, formic acid and acetic acid. Me
OH
OOH
O I
o
I
OOH
HOO
OH (53)
Me
X Me
(54)
OOH (55)
OOH I O
Me
OOH (56)
(57)
Pyridinium chlorochromate in dichloromethane reacts with furans to give a range of products, but they are all formed by 1,4-electrophilic attack of chlorochromate on the furan ring; the fate of the resultant intermediate (57) by heterolytic cleavage of the Cr—O bond depends on the substituents at the a-positions of the substrate. 2,5-Dialkylfurans yield a, j8-unsaturated-y-dicarbonyl compounds, 5-methyl-2-furylcarbinols yield pyran derivatives, and 5-bromo-2-furylcarbinols yield 5-hydroxyfuran-2(5//)-ones (Scheme 25) (80T661).
Furans and their Benzo Derivatives: (ii) Reactivity
611 O
n w Me
CH(OH)Me
o
HO
X
o
O OH
OH
i, pyridinium chlorochromate, CH2C12 Scheme 25
The furanoid ring in benzo[£ ]furan is susceptible to attack by oxidants. Permanganate and chromic acid give derivatives of 2-hydroxybenzoic acid with compounds unsubstituted at the 3-position, but compounds with a 3-methyl or a 3-aryl substituent give derivatives of 2-hydroxyacetophenone or 2-hydroxybenzophenone. Ozonolysis of benzo[£ ]furan affords 2-hydroxybenzoic acid, 2-hydroxybenzaldehyde and some catechol produced via its diformate. Before the advent of NMR spectroscopy these methods were used in structural elucidation of benzof uranoid natural products, as in the case of O- methyleuparin (Scheme 26).
11
H
Ac OH
i, O 3 , CHC13; ii, KMnO4, H 2 O, Me2CO Scheme 26
1,3-Diphenylbenzo[c]furan is attacked by chromic acid, permanganate, ferricyanide, per acids and LTA, yielding 1,2-dibenzoylbenzene.
3.11.2.4 Reactions with Nucleophiles Nuclear carbanions are usually generated from furans by proton/lithium exchange or by halogen/lithium exchange, both with butyllithium (Section 3.11.3.9). The rate of exchange of deuterium for protium has been studied for fur an and some alkylfurans in DMSO with potassium f-butoxide as base. Exchange at a 2-position is 600 times faster than at a 3-position, but an alkyl group at the 3- or 5-position retards the rate by a factor of 10 (66KGS643). The thermodynamic acidity of benzo[£]furan has been determined in cyclohexylamine with cesium as gegenion. It was found by comparison of benzo[£ ]furan with benzo[6 ]thiophene that oxygen enhances the thermodynamic acidity more than sulfur, although the kinetic data for furan and thiophene surprisingly indicate the reverse (73JA6273). With an activating group present, as in furan-2-carboxylic acid, carbonate ion will catalyze H / D exchange and NaOD in boiling deuterium oxide will exchange all the nuclear positions. A mechanism involving nucleophilic addition rather than proton abstraction has been proposed (Scheme 27) (73JCS(Pl)20l). Furan-d 4 is then available by mercurationdeuterodemercuration. D(P-D D
D-°bD
OD
CO Scheme 27
D
ol >co2
612
Furans and their Benzo Derivatives: (ii) Reactivity
Most studies of nucleophilic substitution of furans have been made with a nucleofuge at the 2-position activated by a —M group at the 5-position. Reports of displacements from the 3-position are rare but 3-methoxyfuran is available from the iodo compound by reaction with methanolic sodium methoxide in presence of copper(II) oxide, and bromide can be displaced by azide from 3-bromofuran-2-carbaldehyde (75ACS(B)224). Early work indicated that 2-bromo- and 2-chloro-furan react with piperidine 10 times faster than the corresponding halobenzenes. No evidence for the intermediacy of furynes has ever been adduced. Mechanistic studies on the displacement of a nitro group from 2,5-dinitrofuran with piperidine and the anion of toluene-4-thiol have been carried out in acetonitrile and methanol respectively. The furan reacts some 106 times faster than the benzene analogue and is also 10 3 -10 times faster than l-methyl-2,5-dinitropyrrole in these 5NAr reactions (77JOC3550). Similar studies have been carried out for the displacement by secondary amines of 5-substituents in 2-furfurylidenemalononitriles and the nucleofugal ability is in the order: NO 2 > Br > PhSO2 > PhS (79CCC2417). The addition of methoxide ion to 2-nitrofuran in methanol or DMSO provides a deep red solution of the Meisenheimer adduct. The NMR spectrum and the rate and equilibrium constant for the formation of the adduct have been studied. Similar adducts are formed at a faster rate from 2,4-dinitrofuran and 2-nitrofuran-4carbonitrile (78JOC4303). The outcome of treating 2-nitrofuran with methoxide in methanol is ring fission and monomethyl fumarate and methyl fumaraldehydate are obtained presumably by way of a Nef reaction. Methyl 5-nitrofuran-2-carboxylate suffers a similar fission (58CA(52)16329>.
Soviet workers have suggested a mechanism other than SNAr for the displacement of chloride from 2-chloro-5-nitrofuran by potassium iodide in acetic acid or by sodium sulfide in water, and for the displacement of bromide by iodide in 2-bromofurans with CHO, COMe, CH2CHCOPh, CH2CHNO2 and NO 2 as 5-substituents. It is suggested that a reversible electron transfer to the furan occurs, resulting in a radical anion. This then expels a halide to form a furyl radical which leads to the products (76KGS1601). 5-Bromofuran-2carboxylates will react with methoxide and phenoxide to afford 5-methoxy- and 5-phenoxysubstituted compounds. Hydrolysis and decarboxylation of the former supplies 2methoxyfuran (56JOC516). The nitro group can also be displaced from 5-nitrofuran-2carbaldehydes by aryloxides (80CPB2846). Other nucleophiles which are effective in displacing the nitro group from this compound are azide, sulfide, sulfinate and xanthate. Enamines and amines, however, react at the aldehyde site (72LA(761)13O). On steam distillation with concentrated hydrochloric or hydrobromic acid, 5-nitrofuran-2-carbaldehyde furnishes the corresponding 5-halofuran-2-carbaldehyde (20%); doubtless protonation of the carbonyl group assists this transformation (73JHC385). Lithium fluoride will displace bromide from 5-bromofuran-2-carbaldehyde in DMF at 100 °C. A number of typical nucleophilic substitutions are shown in Scheme 28. Br
Q
CHO
N
II % CHO O
W)
45o/o
CHO 95%
PhS
43%
58%
74%
i, NaN3, DMSO, 60 °C; ii, Nal, AcOH, 20 min; Hi, NaN3, DMSO, 20 °C, 2 h; iv, PhSNa, MeOH, 20 °C; v, Na2S, H 2 O, 2 h Scheme 28
The reaction of furans with ammonia and its derivatives is of considerable synthetic utility (B-73MI31100). Substituted furan-2-carbaldehydes and 2-acylfurans on heating with ammonia and ammonium salts, often under pressure, yield 3-hydroxypyridines. The mechanism of this reaction is thought to involve nucleophilic attack of ammonia at the 2-position. Ring opening affords an amino aldehyde or ketone and thence, by reclosure, the 3-hydroxypyridine (Scheme 29). A wide range of substitutents is tolerated. Primary amines with furan-2-carbaldehydes yield N- substituted pyrroles, the closure of the intermediate
613
Furans and their Benzo Derivatives: (//) Reactivity
aminocarbonyl compound thus taking the alternative course. Attack of ammonia at the 2-position of 3-acylfurans affords 3-acylpyrroles; primary amines supply the TV-substituted analogues (74JHC905). When furan-2-carbaldehydes are treated with hydroxylamine a 2,3dihydroxypyridine is obtained and the carboxamide formed via the oxime (Scheme 30) is thought to be an intermediate. Similarly, when heated with ammonia in the presence of ammonium chloride at 240 °C in HMPT or acetonitrile, furan-2-carboxamide affords 2-amino-3-hydroxypyridines; furan-2-carboxylic acid and its esters give the same products by way of the amide (77JHC203). Hydrazine attacks 3-benzoyl-2,5-dimethylfuran to yield a pyrazole (77BSF1235). H
iOH
HICV^J
H2N O
R'
Scheme 29
^o
o
o Scheme 30
The result of treating 5-bromofuran-2-carbaldehyde with aniline is more complex and a salt resulting from anil formation and bromide displacement is formed (70CB2992). Furans can be converted into N- alkylpyrroles by heating with primary amines and alumina. Similar thermal conversions of furans and benzo[6]furans to their sulfur analogues in the presence of alumina or other metal oxide catalysts and hydrogen sulfide are also known. 1,3-Diphenylbenzo[c]furan is converted into the thiophene by heating with phosphorus pentasulfide. The mechanism of these reactions is obscure. In accord with MO calculations (67BCJ1580), benzo[6]furans are attacked by a variety of nucleophiles at the 2-position. Hydroxide under drastic conditions affords (59) and (60), which are presumably formed by Cannizzaro reaction of the aldehyde (58; Scheme 31). Methylsulfinyl anion in DMSO at 70 °C followed by aqueous work up affords 2-ethynylphenol (66JOC248). With a —M group at the 3-position, nucleophilic attack at the 2-position is facilitated. 3-Benzoyl-2-ethylbenzo[Z»]furan with hydroxide affords products which can be rationalized by /?- diketonic fission of the intermediate (61), further transformations of which produce (62) and (63) (Scheme 32). With a nitrile at the 3-position a similar degradation takes place but an ester is not sufficiently electron withdrawing and hydrolysis ensues. Ammonia will attack the ketone (64) at the 2-position, producing the unstable /3-enaminoketone (65; Scheme 33). Other nucleophiles attack in a similar manner; thus hydroxylamine under certain conditions will afford oxazoles (66BSF1587). KOH, EtOH 200 °C
O
OH (
CH=CH(OH)
Scheme 31 COEt " I iCHCOPh
PhCO2H + (62)
Scheme 32
614
Furans and their Benzo Derivatives: (ii) Reactivity ,OH NH 2
//T Et iiiifM
(65)
COEt
Scheme 33
3.11.2.5 Reactions with Reducing Agents The catalytic hydrogenation of furans has been studied in great detail, particularly from a technological point of view by workers in eastern Europe. A review is available (63RCR307). Conditions have been denned that effect reduction of furans with and without hydrogenolysis. Hydrogenation with Adams catalyst in acetic acid will cause rupture of either the 1,5or the 1,2-bond. 2-Methylfuran affords 2-pentanol and furan-2-methanol affords 1,2pentanediol by rupture of the 1,5-bond; on the other hand, furan-2-carboxylic acid affords 5-hydroxypentanoic acid by cleavage of the 1,2-bond. Reduction of the furans to tetrahydrofurans may be achieved with palladium catalysts in either the vapour or the liquid phase and stereoisomeric mixtures result. Nickel catalysts give higher yields of cis- disubstituted tetrahydrofurans than palladium (67T215) and rhodium behaves similarly (76CB2628). Conjugated alkenylf urans may be reduced to alkylf urans by careful operation but diimide reduction has also been used (Scheme 34) (66HCA858). CH2)2CO2H 35%
47%
i, NH2NH2) Cu2+, O2 Scheme 34
Catalytic reduction of benzo[6]furan to 2,3-dihydrobenzo[6]furan can be achieved by using a palladium on carbon catalyst at 100 °C and moderate pressure. At higher temperatures and pressures, Raney nickel causes reduction of the benzenoid ring as well, whereas under similar conditions copper chromite leads to hydrogenolysis products including 2-ethylcyclohexanol. Hydrogenolysis can be avoided by using rhodium on alumina when the ds-perhydro compound is obtained. 3-Acetoxybenzo[Z>]furans afford 2,3-dihydrobenzofurans under fairly mild conditions (Scheme 35) (50JCS3202, 50JCS3206). Hydrogenation of 2-acetylbenzo[6]furan gives the secondary alcohol with platinum at moderate pressure whilst Raney nickel under similar conditions furnishes 2-(l-hydroxyethyl)-2,3-dihydrobenzo[6]furan. Benzo[6]furan-2-carboxylic acid is reduced by Raney nickel alloy and aqueous sodium hydroxide to 3-(2-hydroxyphenyl)propanoic acid, which lactonizes to the dihydrocoumarin. AcO
AcO^ Jj
\ 96%
86%
i, Pd/BaSO4, AcOH, H2, 25 °C; ii, 10% Pd/C, AcOH, 65 °C, H2 Scheme 35
l-Phenylbenzo[c]furan-3-carbonitrile and the corresponding carboxylic acid are catalytically reduced in a cis manner to the expected 1,3-dihydro compounds. 1,3-Diarylbenzo[c]furans are also reduced to phthalans with sodium amalgam. Ring opening is common in the alkali metal and liquid ammonia reduction of furans unless an anion stabilizing group is present, so most work has been done with derivatives of furancarboxylic acids. Treatment of furan-2-carboxylic acid with lithium and ammonia at -78 °C followed by rapid addition of ammonium chloride affords 2,5-dihydrofuran-2carboxylic acid (80%). Reductive alkylation similarly gives 2-alkyl-2,5-dihydrofuran-2carboxylic acids. This method has been used in a synthesis of rosefuran, the intermediate dihydrofuran (66) being converted into the product (67) by oxidative decarboxylation with
Furans and their Benzo Derivatives: (ii) Reactivity
615
LTA (Scheme 36) (76TL2079). 5-Alkylfuran-2-carboxylic acids on reduction in liquid ammonia with lithium and methanol supply cis- and fraws-5-alkyl-2,5-dihydrofuran-2carboxylic acids (71-85%) (75BCJ491). Furan-3-carboxylic acid has been reduced using sodium and liquid ammonia. With 2-propanol as proton source, 2,3-dihydrofuran-3carboxylic acid is obtained, but with methanol or ethanol, addition to the double bond occurs during work up (75BCJ1865). In the absence of any added proton source and with 4 mol of lithium, ring opening and further reduction occurs giving the lactone (68; Scheme 37) (76AJC2553). Some asymmetric induction has been obtained in the sodium and liquid ammonia reduction of both furan-2- and -3-carboxylic acids when 1,2 ;5,6-di-Oisopropylidene-a-D-glucofuranose is used as proton source (74CC181). Me CO,H HO,C
i, Li, NH3, -78 °C; ii, LTA Scheme 36
Benzo[£]furan is cleaved on reduction with excess sodium in liquid ammonia, followed by quenching with ammonium chloride or methanol, to produce 2-ethylphenol (69%). 2-Methyl- and 2-phenyl-benzo[£]furan similarly yield 2-propylphenol (54%) and 2-(2phenylethyl)phenol (45%) (59JA2795). Similarly, 5-methoxybenzo(7>]furan, on reduction with 2 mol of lithium and a limited amount of t- butanol, gives the cleavage product, but by operating with 2 moleach of lithium and f-butanol, 5-methoxy-2-methylbenzo[6]furan supplies the 2,3-dihydro compound. With excess of the alcohol, however, 5-methoxy2,3,4,7-tetrahydrobenzo[£]furan is secured so that the reduction is stepwise (67JOC2794). CO, Me
CO, Me
CO,H
9 \ o
O
85%
in
CO
CO \\
o
•
<
Me O (68) 27%
i, Na, NH3, EtOH or MeOH, then NH4C1, then CH2N2; ii, Na, NH3, Me2CHOH, then NH4C1, then CH2N2; iii, Li, NH3, then NH4C1 Scheme 37
3.11.2.6 Reactions with Free Radicals and Other Electron Deficient Species Fur an is attacked by radicals at the 2-position and the intermediate can then lose a hydrogen atom to produce a 2-substituted furan or react with a further radical to produce a 2,5-disubstituted 2,5-dihydrofuran (Scheme 38). Arylation was the first reaction to be studied and the Gomberg method applied to 2-substituted furans gave only 5-substitution products. The method of choice involves the generation of aryl radicals from diazonium salts stabilized by zinc chloride (68JCS(C)2737). The Meerwein method (74CCC1892) and the generation of aryl radicals from diazoaminobenzenes with isopentyl nitrite at 30 °C (74T4123) have both been used to arylate furans. The relative rates of reaction of 4-chlorophenyl radicals, generated by the latter method, with 2-substituted furans have been determined by competition with furan. The relative rates are all faster than furan (furan-2-carbaldehyde, 3.14; 2-methylfuran, 1.87) except for furan-2-carbonitrile (0.92) (76CCC3398). Competition experiments with aryl radicals have been carried out for furan, thiophene and benzene (72JHC919). The aryl radicals were generated by the decomposition of N- nitrosoacetanilides, the aprotic diazotization of anilines, or under Gomberg conditions. Furan undergoes only
616
Furans and their Benzo Derivatives: {ii) Reactivity
arylation at the 2-position but thiophene gives some 3-arylation products. Furan was found to be 11.6 times more reactive than benzene and 4.5 times more reactive than thiophene. Partial rate factors with respect to benzene were determined for the 2-position for m- and p-substituted aryl radicals. A Hammett plot of these against the cr+ values gave a good correlation and a p value of 0.46.
3
o R
Scheme 38
Attempted generation of phenyl radicals from N- nitrosoacetanilide in benzene containing 2,5-dimethylfuran gives 2-benzyl-5-methylfuran and no arylation at a ring position. NNitrosoacetanilide (69) is assumed to undergo isomerization to benzenediazoacetate (70), which is in equilibrium with the ion pair (71; Scheme 39). A TT-complex is formed between the electron-rich furan and the cation, and the acetate ion, a strong base in anhydrous medium, then abstracts a proton from the methyl group and the resulting 5-methylfurfuryl anion reacts with the adjacent benzenediazonium cation by nucleophilic displacement of nitrogen to give the observed product (72JCS(P1)13O4>. PhN(NO)Ac — • PhN=NOAc — • PhN2 OAc + (69)
(70)
M
J X
\M CT
—•
M
J
V O
H
Ph 2
(71) Scheme 39
Photolysis of iodohetarenes yields radicals which can arylate furan in the 2-position; this method has been used to prepare 3-(2-furyl)pyridine (72CC594) and a variety of 5-(2furyl)pyrimidines (77JCS(Pl)621). Furan reacts with both dibenzoyl peroxide (69CC1119) and phenylazotriphenylmethane (70JCS(B)l443>, which are common precursors of phenyl radicals, to give addition products (Scheme 40). With the former reagent 2,5-dimethylfuran is attacked at a methyl group, giving 5-methylfurfuryl benzoate, and 2-methylfuran exhibits both types of behaviour. *
phco2o2cph —> 2Phco2- -22=->
H, /
yL
PhCO,
\
XT
H
+
PhCO,
(T ^O2CPh
\f
y O
PhN=NCPh 3 — • Ph* + N 2 + CPh3 H Scheme 40
When methyl radicals are generated from diacetyl peroxide they give substitution products with monoalkylfurans, but 2,5-dimethylfuran is hardly attacked (Scheme 41) (73TL637). f-Butoxy radicals generated from t- butyl hydroperoxide and Fe 2+ in methanol react with furan to give addition products (64G67), but when generated photochemically from t- butyl peroxide they convert 2-methylfuran into the furfuryl radical, identified by ESR spectrosCOpy (71JOC3837). Me
o
Oo
Me
Oo
Me
o MeO o
3.5% 10% i, (MeCO2)2, 60 °C, 6 h; ii, (MeCO2)2, 80 °C, 4 h Scheme 41
Me
(o 15%
With aromatic thiyl radicals, generated from the thiol with Fenton's reagent, 2-monosubstituted and, anomalously, 2,3-disubstituted products are obtained from furan (Scheme 42).
Furans and their Benzo Derivatives: (//) Reactivity
617
The anomalous products are thought to be a result of cation formation, since in the absence of Fe 3+ the normal 2-substitution products are obtained (75JOC966). O
ArS.
O
u
ArS
ArS
rO . AArS v7
r^\
O
\\
W
ArSH ArS
O
ArS
o
o O
Scheme 42
Ipso attack has been detected at both a-positions in the reaction of methyl and adamantyl radicals with methyl 5-nitrofuran-2-carboxylate and 5-nitrofuran-2-carbaldehyde. A typical example is shown in Scheme 43. Ipso attack at the carbon bearing the nitro group leads to substitution via the a- complex (72) and the product is (73). Attack at the alternative site gives the a- complex (74) which can capture NO 2 to form (75) or rearrange to the nitrite radical (76) and expel NO leading to (77) (79CC800). MeC
\x),Me +NO (73)
o
Me O
CO2Me
NO2.
Mev f=\ MeO2C
(74)
/ ^
ONO<^
°
X
°
NO NO2
(75)
Me
CO2Me
(76) Scheme 43
The homolytic arylation of benzo[6 ]furan has been studied using aryl radicals generated by decomposition of 1,3-diaryltriazenes in the presence of isopentyl nitrite at 120 °C (79JHC97), or phenyl radicals produced by the decomposition of N- nitrosoacetanilide at 40 °C. The major position of attack is the 2-position (75.9%), but some occurs at the 4(17.5%) and 7-positions (6.6%). Benzo[£]furan is 8.3 times more reactive than benzene and 1.26 times more reactive than benzo[£]thiophene. Carbene attack on the furan ring usually leads to cyclopropanation followed by ring opening with loss of aromaticity. Thus carbene yields the expected product (78) with furan and similarly UV irradiation of a solution of methyl diazoacetate in furan yields the methoxycarbonylcarbene adduct (79) which on brief heating at 160 °C is converted into the cis,trans- muconaldehydate (80; Scheme 44) (63LA(668)19). A number of substituted furans, including 2-alkenylfurans, yield similar dienes with ethoxycarbonylcarbene; thus 2-isobutenylfuran is cyclopropanated at the least hindered double bond and ring opening ensues (Scheme 45) (77AG(E)646). The reaction with vinylcarbenes follows a similar course (73TL2875). The intramolecular ketocarbene addition depicted in Scheme 46 also leads to ring-opened products (74TL2255). Allenic carbenes add to furan in poor yield (77T73), and l,6-methano[10]annulen-ll-ylidene has been trapped with both furan and 1,3-diphenylbenzo[c ]furan (76JA6068). Q(78) 50%
^Q^ (79) 23%
CO2Me (80)
i, CH2N2, Cu2Br2; ii, N2CHCO2Me, hv; iii, 160 °C Scheme 44
618
Furans and their Benzo Derivatives: (//) Reactivity
Me 2 C=CHCOCH=CHCH=CHCO,Et Scheme 45 N,HC heat, CuSO4
fj
\/r^^f>o
CHO Scheme 46
Atomic carbon generated by the pyrolysis of 5-diazotetrazole in the presence of gaseous furan yields cw-2-penten-4-ynal by insertion into an a-CH bond, thus producing 2furylcarbene, and by addition to a 2,3-double bond, producing a cyclopropylidene intermediate. Both intermediates undergo ring opening to yield the product (Scheme 47) (79JA1303).
\ +C
Scheme 47
When the sodium salt of a furan-2-carbaldehyde or 2-acylfuran tosylhydrazone is pyrolyzed at 300 °C, a furyldiazoalkane is produced. This decomposes to a 2-furylcarbene which opens to a ds-2-alken-4-yn-l-one (Scheme 48). The 2-furylcarbenes may also be intercepted as insertion products with cyclooctane or as addition products with styrene. Analogous results were obtained with the carbene produced from ethyl 2-furyldiazoacetate, but products of a cationic mode of reaction are obtained in protic solvents (78JA7934). Generated by the tosylhydrazone or the aziridinylimine method (76JCS(P1)1257>, 3-furylcarbene is unexceptional in its reactions and does not undergo ring opening. It may be intercepted by insertion and addition reactions, and in the absence of a trap yields a stereoisomeric mixture of l,2-di(3-furyl)ethylene by dimerization.
Scheme 48
With benzo[& ]furan, dichlorocarbene in cyclohexane gives an unstable addition product which, on treatment with water, yields the chromenyl ether (81; Scheme 49) (63JOC577). Decomposition of ethyl diazoacetate in the presence of benzo[& ]furan yields the expected mixture of cyclopropanes. The major isomer has been cleaved under acidic conditions (Scheme 50) (77JOC3945).
O (81) 15%
Scheme 49
Nitrenes give both addition and insertion products with furans. Thermolysis of ethyl azidoformate in the presence of furan gives either (82) or (83) by a sequence involving addition and ring opening (Scheme 51). Generation of phthalimidonitrene in the presence of 2,5-dimethylfuran yields the 2-phthaloylhydrazone of cis-2-hex-3-ene-2,5-dione (29%), presumably by opening of the intermediate aziridine by CO or CN bond cleavage. 2Substituted furans are attacked at the 4,5-bond <72JCS(Pl)2728). Similar results are given by l,3-diphenylbenzo[c]furan and nitrenes. The nitrenes generated by reduction of 2-(2-nitrophenyl)furan with triethyl phosphite or by thermolysis of 2-(2-azidophenyl)furan in 1,2-dichlorobenzene undergo insertion into
Furans and their Benzo Derivatives: (ii) Reactivity
619
CO,Et
CO2Et +
CH2CO2Me CH,CO,Me 1
95%
i, N2CHCO2Et, CuSO4, heat; ii, MeOH, HC1; iii, H + , PhH Scheme 50
\
NCCKEt
N
no °c
/ N CO2Et
or
NT O CO 2 Et (82)
(83)
Scheme 51
the adjacent furan 0- hydrogen and 4//-furo[3,2-6]indole results (77JHC975). Furocarbazoles have been similarly obtained (77TL2457). The nitrenes formed from thermolysis of ethyl 3-(5-aryl-2-furyl)-2-azidoprop-2-enoates undergo similar insertion and yield ethyl 2-arylfuro[3,2-6]pyrrole-5-carboxylates (95%) (79CCC1799). Benzo[£]furan-2-ylvinyl azides afford analogous insertion products (77CL401). Conversely, furo[3,2-6]pyrroles are also formed by pyrolysis of 3-azido-2-vinylfurans (76ACS(B)39l). Photolysis or pyrolysis of the azide (84) affords the expected insertion product (85) and its dehydro derivative, but surprisingly it is accompanied by (86) and its dehydro derivative (Scheme 52) (79H(l2)lO2l).
1,2-dichlorobenzene
o (84)
CO,Me
(85)
MeO2C (86)
Scheme 52
Benzo[£]furan gives an unstable aziridine by addition of phthalimidonitrene to the 2,3-double bond (72JCS(P1)225>. 3.11.2.7 Cycloaddition Reactions 3.11,2.7.1 Thermal reactions Furan, in spite of its aromaticity, and unlike the other rr- excessive heterocycles thiophene and pyrrole, enters into [^4S + ,,.2S] cycloadditions, the classical Diels-Alder reaction, with some degree of facility. The thermal cycloreversion of the adducts is also easy. Arynes undergo cycloaddition with ease even to furans containing an electron withdrawing group at an a-position. Other alkynic dienophiles and ethylenes activated with two electron withdrawing groups also form adducts easily, but difficulty is encountered with ethylenic dienophiles activated by only one electron withdrawing group. As expected, electron releasing substituents on the furan nucleus, as in 3,4-dimethoxyfuran, which also do not cause steric hindrance in the transition state, increase reaction rates. As expected from Alder's endo rule, and justified by consideration of maximum accumulation of unsaturation in the transition state, secondary orbital interactions and dispersion forces, furan reacts with maleic anhydride in acetonitrile at 40 °C (78JOC518) to give initially
Furans and their Benzo Derivatives: {ii) Reactivity
620
(87)
a small amount of the endo adduct (87). After 20 min the proportions of exo (88) and endo (87) adducts are equal and after 48 h only the exo adduct can be detected. The pure exo adduct (88) decomposes thermally to the addends. The rate of formation of the endo adduct is 500 times faster than that of the exo adduct and both reactions are reversible. The exo adduct is 8.0 kJ moF 1 more stable than the endo adduct so that the reaction is quite typical. The exo adduct (88) has been used in a synthesis of butenolides (79BSF(2)325). Thus, on reduction with sodium borohydride and then with DIBAL at —78 °C, the lactol (89) results (Scheme 53). This reacts with Grignard reagents to give diols (90) which undergo oxidation with Collins reagent. The resultant lactones (91) on thermolysis undergo retro Diels-Alder reaction yielding butenolides (92) and furan. O IV
CH(OH)R
-•-•
OH (92)
(90)
(89)
i, NaBH4; ii, DIBAL; iii, RMgX; iv, Collins reagent; v, heat Scheme 53
With maleimide the endo adduct (93) results at 25 °C, but the exo adduct (94) at 90 °C; the endo adduct also yields the exo adduct on heating. Reaction of furan with maleic acid in water occurs slowly and the adducts readily revert thermally to the addends. As expected, the rate of formation of the endo adduct (95) is initially faster than that of the exo adduct (96), but after 10 days the ratio is 1:1; both isomers may be isolated (73T2491). Fumaric acid only adds in poor yield to furan under ordinary conditions, but this may be overcome by use of fumaryl chloride (79CC542).
NH NH (94)
CO2H CO2H (95)
(96)
(97)
(98)
Ethylenic dienophiles with only one electron withdrawing group react only slowly with furans at room temperature to afford low to moderate yields of both endo and exo adducts. At higher temperatures the reverse reaction, as well as polymerization of the dienophile, generally occurs. A typical example (75HCA1180) is the reaction of furan with acrylonitrile which after 5 weeks gives a 39% yield of a mixture of endo (97; 61%) and exo (98; 39%) adducts. By use of ultra high pressure (15 kbar) these difficulties may be overcome. Thus, furan or 2,5-dimethylfuran under these conditions reacts with acrylonitrile, methyl acrylate, acrolein or methyl vinyl ketone to produce adducts in at least 50% yield. The crotonic analogues of the dienophiles give lower yields because both steric and electronic factors produce rate retardation. Fumarate and maleate at 15 kbar react smoothly with furan,
(99)
(101) i, furan, 15 kbar; ii, Ni(R); EtOAc Scheme 54
(102)
Furans and their Benzo Derivatives', (ii) Reactivity
621
giving the corresponding cis,endo and trans adducts in high yield. This methodology has been applied to a synthesis of cantharidin (102) (80JA6893). Dimethylmaleic anhydride fails to add to furan at pressures up to 40 kbar because of steric crowding of the transition state and the reduced dienophilicity of the anhydride. The sulfur analogue (99), however, reacts smoothly during 6 h at 15 kbar at room temperature to yield a separable mixture of the exo anhydride (100; 85%) and the endo anhydride (101; 15%) (Scheme 54). Reduction of the mixture with Raney nickel then gives cantharidin (102) in 63% yield. Furan with a- nitrosostyrene (104), generated from a- chloroacetophenone oxime (103) by treatment with anhydrous sodium carbonate, yields the adduct (106; 45%). This reaction is thought to involve Diels-Alder addition of the styrene double bond to the furan to give the endo adduct (105) which then suffers a 3,3-sigmatropic rearrangement (76CC581). Similar adducts are formed by azoalkenes. Furan reacts with cyclopropene at room temperature to yield a 1:1 mixture of exo (107) and endo (108) adducts (70CC1353). With halocyclopropenes only the endo adducts have been isolated and these may undergo electrocyclic ring opening and stereospecific 1,2-halogen migration, e.g. Scheme 56 (68JA2376). Strained bridgehead alkenes and medium ring E- cycloalkenes may also be captured as their furan adducts; thus the ester (109) decomposes to 1,2-dehydroadamantene on heating in 2,5dimethylfuran at 70 °C and the adduct (110) can be isolated in 9% yield (Scheme 57) (73TL3047). Ph
T
CH2C1
Na,CO,. CH,C1
Ph
furan
NOH
ON (106)
(104)
(103)
Scheme 55
(107)
Cl
Cl furan, CCI2
Cl F
80 °C, 18 h
F Cl
Cl F Scheme 56 Me
CO3Bul CO3Bul
2,5-dimethylfuran 70 °C
(109)
(110) Scheme 57
Vinylene carbonate (111) undergoes cycloaddition to furan in 21% yield, giving a separable mixture containing the endo adduct (112) as well as a small amount of exo adduct (113), distinguishable on the grounds of their dipole moments (Scheme 58). The endo adduct has been used in a synthesis of inositols (73JOC117) and to prepare by a cycloreversion the dioxolene (114), a useful synthetic equivalent of acetylene in Diels-Alder reactions (73JA7161). With dichlorovinylene carbonate the adducts (115) and (116) are obtained in the ratio 1:2. On basic hydrolysis they yield the diketone (117) (76S256). Furans generally react with alkynic dienophiles under mild conditions affording oxanorbornadienes in high yield (Scheme 59). The products have found a variety of uses in synthesis. The unsubstituted double bond may be hydrogenated and the product, on thermolysis, undergoes cycloreversion, thus providing a convenient synthesis of 3,4-disubstituted furans
Furans and their Benzo Derivatives: (ii) Reactivity
622
O O' (111)
(113)
o
IV
o (114) i, furan, 120 °C; ii, 1 MKOH, 100 °C, 1 h; iii, N,N-thionocarbonylimidazole, toluene; iv, 160 °C. Scheme 58
(117)
(116)
known as the Alder-Rickert sequence. The same result can be achieved by treating the initial adduct with 3,6-di-(2'-pyridyl)-s-tetrazine (72CC211). UV irradiation of the oxanorbornadienes yield oxaquadricyclanes which, on thermolysis, afford the benzene oxide-oxepin system (Scheme 60) (71HCA2579,76CB2823). On treatment with aluminum chloride (74CJC143) or TFA the oxanorbornadienes rearrange to phenols (Scheme 61). Comparable results are obtained when the Diels-Alder reactions are carried out in the presence of aluminum chloride, which serves both to enhance the rate of cycloaddition, presumably by lowering the enthalpy of activation, and to induce rearrangement of the adduct. Yields are often poor due to polymerization of the diene under these conditions. The effect of aluminum chloride may be quite dramatic: 2,5-diphenylfuran fails to undergo cycloaddition with diethyl acetylenedicarboxylate under thermal conditions but in presence of aluminum chloride in dichloromethane at - 2 0 °C a 40% yield of the adduct may be secured. With ethyl propiolate the cycloaddition reactions are regiospecific (Scheme 62) (71CJC3152).
7 o
IIJ^ // C ° 2 M e 71% 81%
Br
Br
CO,Me
OJC°Mt CO, Me
V
in
81%
o
i, DMAD, CC14, 6.5 h; ii, DMAD, ether; iii, F3CC = CCF3, 0 °C, 100 h Scheme 59
O
O
MeO
CO,Me
MeO 2 C
CO 2 Me
CO, Me CO 2 Me 80% i, hv, - 2 0 °C, CH2C12, 30 h; ii, xylene Scheme 60
The course of the reaction of furan and DMAD is temperature dependent (73CJC4125). The initially formed monoadduct (118) acts as a dienophile and further addition of furan can occur at the di- or tetra-substituted double bonds. In such additions to norbornene-type dienophiles the diene is subject to steric approach control and approach to the exo face is preferred. At 25 °C the tetrasubstituted double bond acts as a dienophile and the endo,exo
Furans and their Benzo Derivatives: (ii) Reactivity
Me CO,Me
CF3CO2H 20 °C, 72 h
Me CO,Me
623
CO,Me Me CO,Me HO
OH
Me CO 2 Me
OH Me
CO 2 Me CO, Me
CO 2 Me
CO 2 Me CO,Me Me 80-85%
Me Scheme 61
Ph CO,Et
HC = CCO2Et
'I W Ph
±_j
A1CU
O
Ph CO,Et 2 —
48%
OH
Scheme 62
(or exo,endo) adduct (119) and the endo,endo adduct (121) result. The initial rate of formation of adduct (119) is greater than for adduct (121), and (119) is the major product at 25 °C. At higher temperatures the thermodynamically more stable (121) becomes the major product due to equilibration. Reaction of furan with the monoadduct (118) to yield the endo,endo adduct (123) and the endo,exo adduct (124) is slow and significant amounts of these adducts are formed only at higher temperatures and after shorter reaction times. Under these conditions, low yields of the four triadducts (125), (126), (127) and (128) are obtained. Adducts (127) and (128) similarly arise from (124). Aluminum chloride produces a rate enhancement of ca. 10 at 25 °C and the kinetic product (119) is formed. Di-f- butyl acetylenedicarboxylate gives similar adducts to DMAD on thermal reaction with furan (80CB531). With acetylenedicarboxylic acid in boiling ether containing two mol equivalents of furan, the diadducts (120) and (122) result in the ratio 2:1 after 10% reaction (1 h) but after 20% reaction (24 h) the ratio is 1:4, since adduct (120) has begun to crystallize out thereby driving the equilibrium in this direction. O
MeO2C
CO2Me CO2Me
CO2R CO2R (119) R = Me (120) R = H
(118)
CO2R CO2R (121) R = Me (122) R = H
MeO2C (123)
O
O
MeO2C
MeO2C
MeO2C
MeO2C
MeO2C (124)
MeO2C (126)
(125)
O
MeO2C
MeO2C
MeO2C
MeO2C (127)
Reaction of excess 2,5-dimethylfuran with DMAD gives a monoadduct but at 100 °C the diadduct (129) is formed (Scheme 63). The disubstituted double bond may be selectively reduced and pyrolysis then results in 2,5-dimethylfuran (131), the diester (130) and ethylene (70JOC3897). 2,2'-Bifuryl and DMAD give the adducts (132) and (133) <67JCS(C)2327>. The
Furans and theirBenzo Derivatives: (ii) Reactivity
624 O Me
Q Me MeO2C
Pd
MeO2C
CO2Me
heat
MeO2C cl^"—-X T--O Me (130)
Me (131) Scheme 63
MeO2C
MeO2C
CO2Me
MeO2C (132)
CO2Me
CO2Me (133)
cyclophane (29; Scheme 64) reacts with DM AD to produce the internal adduct (135), presumably via the monoadduct (134); on heating at 165 °C the adduct undergoes reversion to the addends (66JA515). Similar results are obtained with tetrachlorocyclopropene as dienophile.
AX XT
CO2Me
DMAP
105 °C
MeO 2 C
>
MeO2C
(29)
(135)
(134) Scheme 64
2,5-Dimethylfuran reacts with ethyl propiolate at 95-120 °C to give initially the monoadduct (136), which undergoes homo Diels-Alder reaction with itself yielding (137), and this, on retrogression, affords (138). Retrogression of the monoadduct (136) yields (139) and acetylene. The monoadduct (136) also undergoes further Diels-Alder reaction with 2,5dimethylfuran, yielding the diadducts (140) and (141). Cycloaddition of the monoadduct (136) with the dienophile in a [2 + 2] manner yields (142; Scheme 65). The ratio of the products is dependent on the reaction conditions (75CJC1496). In contrast, furan fails to react with ethyl propiolate at 25 °C and at 130 °C the only product isolated is the analogue of adduct (138; 9%) (74CJC1013). In the presence of aluminum chloride, however, normal diadducts may be isolated.
CO2Et +(136)
EtO2C
EtO2C (138)
(136)
CO2Et
O Me
Q
O Me
EtO2C
Me (139)
CO2Et Me |CO2Et H
Me CO2Et H (140)
Me
(141) Scheme 65
(142)
Furans and their Benzo Derivatives: (ii) Reactivity
625
It appears that 2-acetoxyfuran and the monomethoxyfurans undergo Diels-Alder reactions with more ease than furan itself, although no systematic work has been reported. 2-Acetoxyfuran (56JA2303) readily forms adducts with maleic anhydride, DMAD, maleimide and fumaronitrile. 3-Methoxyfuran (64JOC776) readily yields the endo adduct with maleic anhydride; 2-methoxy-5-methylfuran behaves similarly but the stereochemistry of the adduct has not been assigned (60JOC1028). 3,4-Dimethoxyfuran exhibits enhanced reactivity compared with furan (79HCA2211) and in contrast gives both exo and endo adducts with maleic anhydride at the same rate, but the exo product is thermodynamically more stable and can be isolated in 90% yield. Less reactive dienophiles also give mixtures of exo and endo adducts, except for methylmaleic anhydride which gives only the product (143) with an endo methyl group. Dimethylmaleic anhydride fails to react even at 150 atm. With methyl acrylate in the presence of a catalytic amount of sulfurous acid the lactone (144) is obtained via the endo adduct. With an equimolar amount of DMAD at 5 °C for 4 days, 71% of the monoadduct (145) and 26% of the diadduct (146) is obtained. With 2mol equivalents of the furan the yield of the diadduct is raised to 90%. 3,4-Dimethoxyfuran also undergoes cycloadditions with p-benzoquinones; these appear to be the first recorded reactions of furans, other than menthofuran, with p-benzoquinone. With p-benzoquinone the endo adduct (147) is formed, but on standing in deuteriochloroform this undergoes some dissociation to the addends as well as conversion into the exo isomer (149). With toluquinone the endo adduct (148) is formed, and although it is labile in solution, no exO adduct is formed. With xyloquinone only the exo isomer (150) is formed; this is stable in solution. 2,3-Dimethoxybenzoquinone at room temperature gives an exoyendo mixture; O
O
MeO MeO
MeO MeO OMe,
6
(145)
(144) O
CO2Me CO2Me OMe OMe
MeO MeO
MeO O (147) R = H (148) R = Me
(146)
MeO MeO
(149) R = (150) R = Me
again the endo isomer is labile in solution. Addition of chlorine to the p-benzoquinone adduct (147) occurs across the highly nucleophilic enediol ether double bond in a stereospecific cis manner and exclusively from the exo side. Methanolysis of the product yields the acetal (151; Scheme 66) which may be oxidized to the quinone (152) and this, on pyrolysis, affords the benzo[c]furan-4,7-quinone (153) and tetramethoxyethylene (154). MeO MeO MeO
MeO
OH Ag2O
OMe OH (151)
MeO.
.OMe
MeO
OMe
heat
MeO OMe
(154)
(152) Scheme 66
Attempts to isolate 2,3-dimethoxyfuran (156) have, as yet, been fruitless (79JCS(P1)1893), but it may be generated in situ and trapped with the propiolate (155); the initial adducts (157) are unstable under the acidic conditions and yield the biphenyls (158) and (159) (Scheme 67). 2,5-Bis(trimethylsilyloxy)furans, readily available from succinic anhydrides in one step, are also more reactive than furan in Diels-Alder reactions (80TL3423). They readily undergo reaction with both DMAD and ethyl acrylate. Thus at 50 °C in carbon tetrachloride the furan (160) with DMAD followed by detrimethylsilylation gave only the quinone (163). At 80 °C, however, the hydroquinone (164) is the major product. Both the intermediates (161) and (162) may be detected by *H NMR spectroscopy. The formation
Furans and their Benzo Derivatives', (ii) Reactivity
626
of (162) indicates that (161) must undergo deoxygenation; the mechanism is open to question and may not be a simple cycloreversion (Scheme 68). OMe
OMe O
xy ene
'
PhC=CCO 2 Et
OMe
P-TSOH
-
o
OMe O' (156)
(155)
Ph
OMe OMe
EtO,C Ph
EtO,C _EtO,C
OH (158)
(157)
OMe OMe
OH (159)
Scheme 67
DMAD
Me,SiO
OSiMe3 CO 2 Me
9 X>SiMe3
Me
CO 2 Me CO 2 Me OSiMe3 (161)
OSiMe O
(160)
Me
CO 2 Me OSiMe3 (162)
JNaF, wet MeCN
o
OH CO 2 Me
Me
CO 2 Me
CO 2 Me Me
CO,Me OH
O (163) Scheme 68
(164)
In the case of 2-vinylfuran there is the possibility of cycloaddition involving either the endocyclic diene system or the diene system including the exocyclic double bond. 2Vinylfuran reacts with maleic anhydride during 8 days in ether to yield an adduct (79%) by a cycloaddition involving the exocyclic double bond (43BSF163). In contrast, DMAD with 2-vinylfuran (165) at 25 °C undergoes both modes of addition, and the adducts (168) and (167), formed by aromatization of the adduct (166), are obtained in poor yield. At higher temperature the adduct (166) undergoes an ene reaction, resulting in the 2:1 adduct (169). The low yields in these reactions were ascribed to the ease of polymerization of 2-vinylfuran (Scheme 69). 5-(p-Nitrophenyl)-2-vinylfuran, being more stable, gave a 50% yield of the aromatized adduct of type (167) (73AJC1059). The vinylfurans (170) and (171) give good yields of adducts involving the exocyclic double bonds with fra«s-l,2-dibenzoylethylene (Scheme 70) (74BSF2105). Deactivation of the side-chain double bond with an electron withdrawing group prevents reaction. MeO,C
CO,Me
MeO,C CO, Me
DMAD 4 d, 25 °C
CO 2 Me (165)
(167) 5%
(166) PhH, 24 h
MeO 2 C
CO, Me + (167) 5% CO, Me
MeO 2 C (169) 3% Scheme 69
(168) 5%
Furans and their Benzo Derivatives: (ii) Reactivity
627
Ph
Ph'
O
(170)
60%
O
PhOC
(171)
O
60%
i, (E)-PhCOCH=CHCOPh, 150°C, 12 h; ii, (E)-PhCOC=CCOPh, xylene, 18 h Scheme 70
Furans with electron withdrawing groups at the 2-position exhibit reduced reactivity in Diels-Alder reactions as expected. Thus furan-2-carbaldehyde (172) at 80 °C gives the adduct (173) with DMAD which could not be obtained crystalline, nor isolated by distillation, because of its thermal lability. The yield was estimated by partial hydrogenation of the adduct and pyrolysis which yielded the substituted furfural (174) in 23% yield (Scheme 71) (67BSF1764). The yields of adducts from furan-2-carbonitrile and methyl furan-2carboxylate were similarly estimated at 12% and 25%. The reactivity of furan-2-carbaldehyde is restored in its acetals and its diacetate and the furan (174) may be prepared in 60% overall yield by recourse to this method. Electron withdrawing groups at the 3- or 3,4-positions appear to impair the diene character of furan very little. The diester (175) reacts smoothly with DMAD, affording the adduct (176) which on catalytic reduction affords the zW-endo isomer (177; Scheme 72); the all-exo isomer is available by carbonylation of the adduct (88) in methanol. Both of these last-mentioned compounds serve as a starting material for the synthesis of 2,3,5,6-tetramethylidene-7-oxabicyclo[2.2.1]heptane, a useful anthracyclinone synthon (80HCA1149). Similarly, the diester (178) yields the adduct (179) with dicyanoacetylene. The dinitrile (181) forms a bisadduct (184) with DMAD, but a monoadduct (180) with dicyanoacetylene. This adduct (180) on treatment with triphenylphosphine rapidly yields a betaine (183) which, on pyrolysis, affords the tetranitrile
O
CHO
MeO2C
CO2Me
fl ^
DMAD,
~ ^
(172)
(174)
O
'Q
DMAD 80°C,4d'
CO 2 Me ,
MeO 2 Q w
_
^
(
(176)
(175)
Pd. H 2
|
MeO2C \ CO2Me CO2Me (177)
Scheme 72 EtO 2 C
CO2Et
NC CN
o (178)
(182)
(183) 100%
i, NCC=CCN, 156 °C, 18 h; ii, DMAD, 110°C, 18 h; iii, PPh3, MeCN, 2 min; iv, 195 °C Scheme 73
Furans and their Benzo Derivatives: (ii) Reactivity
628
(182; Scheme 73) (62JOC3520). 2-Amino-3-cyanofurans readily form ring-opened adducts with dienophiles such as maleic anhydride, methyl acrylate and methyl vinyl ketone. Thus the nitrile (185) yields the adduct (186) which, on acidic treatment, undergoes dehydration affording the anthranilic acid derivative (187; Scheme 74) <80S56). The aminonitrile (188) is unique since it undergoes self Diels-Alder reaction. Attempts to prepare (188) yield the dimer (189; Scheme 75) <73JOC612). iCN
J
M
NH2
NH,
Me CN
H
Me Me
(185)
Me
OH
(186) 56%
(187) 90%
i, CH2=CHCO2Me, dioxane, 12 h; ii, HC1, AcOH, 25 °C Scheme 74 NH 2
Me CN
CN CH2
CH,OH
NC
NH,
Me
O
CN
/L o"
(188)
NH 2
(189)
Scheme 75
Dehydrobenzenes, generated by a variety of methods, readily undergo cycloaddition in high yield to furans bearing a wide range of substituents. These adducts are good precursors for the generation of benzo[c]furans and for the synthesis of naphthalenes. The reactions of 3-methyldehydrobenzene, prepared from the precursors (190)-(193) with a-substituted Me
Me
Me
"
NH,
(190)
(192)
(191)
a Me
2
(193)
furans, have been studied (76JOC3356). Although the total yields of adducts varied with each method of generation, the ratio of products was constant. Inspection of the results (Scheme 76) suggests that addition of an unsymmetrical benzyne to a furan is little affected by steric or polar effects. This method has been used with advantage in the preparation of naphthalenes which are subjected to large steric interactions at the peri positions (72JA4608). Thus the furan (194) was allowed to react with 3,5-di-?-butylbenzyne generated by the diazonium carboxylate method; this affords a 25% yield of a mixture of the adducts (195) and (196) in the ratio 58:42. Catalytic hydrogenation gives a mixture of the dihydro compounds (198) and (199), only one of which undergoes ring opening on brief exposure Me
CO2Me
61:39
50-81
57:43
54-82
Scheme 76
629
Furans and their Benzo Derivatives: (//) Reactivity
to dry ethanolic hydrogen chloride and yields the naphthalene (197; Scheme 77). In contrast to its reaction with DMAD and tetrachlorocyclopropene, the cyclophane (29) affords a mono- (200) and a bis-adduct (201; Scheme 78) with benzyne generated by the diazonium carboxylate method (73CC930). The monodiene (200) is a more efficient trap for benzyne than the cyclophane (29), presumably due to increased internal strain and electronic repulsions, but these factors are insufficient, in this case, to promote intramolecular cyclization. Bu1 Bu"
CH,Ph
CH 2 Ph
o
CH,Ph
(194)
(195)
(196)
Bu'
CH,Ph
11
CH,Ph
CH 2 Ph (197)
(199)
(198) i, H 2 , Pd/C; ii, HC1, EtOH, 2.5 h, 25 °C Scheme 77
(29)
(201) 13%
(200) 12% Scheme 78
There is a growing number of examples in which furans undergo Diels-Alder reaction in an intramolecular manner. If conditions are favourable, these reactions occur more easily, and often with higher stereoselectivity, than their intermolecular counterparts. Allusion
NMe (202)
(203)
(204)
Table 1 Intramolecular Cyclization of Compounds (205) and (206) Compound
O
(CH2), NMe
NMe
(206)
Conversion (%)
Time (d) 6 5 14 4
= H, R' = Me n = 3 ; R = R' = H = H, R' = Me
100 100 40 100 12 45 0
R = R' = H R = Me, R' = H R = H, R' = Me
100 0 0
n = l ; R = Me, R' = H n = l ; R = H, R' = Me
?•
6
Furans and theirBenzo Derivatives: (ii) Reactivity
630
has already been made to the intramolecular reactions of the cyclophane (29). Neither the esters (202) and (203) nor the amides (204; n = 1, 2, 3) undergo cyclization, presumably because the furan and dienophile cannot adopt a conformation for efficient TT-overlap in which the reacting moieties are cisoid about the ester linkage. However, a series of tertiary amides with both activated (205) and inactivated (206) dienophile moieties undergo cyclization in boiling benzene. Closure to five- and six-membered lactams occurs fairly readily but formation of seven-membered lactams is inhibited, a -Substitution in the dienophile is tolerated but substrates with a trans @ -substituent afford lower yields (Table 1). Only one of two regioisomers is possible and one stereoisomer is preferred, and in the case of five-membered lactams this results in the exo mode of cyclization with a trans ring junction, e.g. (207) yields (208) (78TL1689). The furylhexenone (209) undergoes efficient cyclization merely on passage over a column of florisil in dichloromethane (79SC771). NMe s
O
o
NMe
R (206)
NMe
(207)
(209)
The intramolecular Diels-Alder addition of a benzyne to a furan has been exploited in a synthesis of mansonone E (81TL4877). The benzyne (211), generated from the anthranilic acid (210), yields the adduct (212; 86%) which is easily converted into the naphthalene (213; Scheme 79). A similar addition was achieved by generating the benzyne by treating an o -dibromobenzene with butyllithium. HOX
(210)
(213) i, i-
+
, HC1, EtOH, 0 °C; ii, C1CH2CH2C1, propene oxide; iii, H2, Pd/C; iv, H , SiO2, CH2C12, 25 °C, 15 h Scheme 79
Methylcyclopropanone and 2,2-dimethylcyclopropanone react via their tautomeric oxyallyl cations to yield 1^+^] adducts with furan and alkylfurans (69JA2283), e.g. an 85% yield of a 1:1 mixture of the regioisomers (214) and (215) results from the reaction of 2-methylfuran with 2,2-dimethylcyclopropanone. With furan-2-carbaldehyde the only [4 + 2] adduct formed is (216); in addition, the dioxolane (217) resulting from 1,3-dipolar addition between the carbonyl group and the oxyallyl cation (218) is formed. Oxyallyl cations of type (218) can be generated by debromination of a,a '-dibromoketones with diiron enneacarbonyl or a zinc-copper couple and trapped with furan. Debromination of 2,12-dibromocyclododecanone with a zinc-copper couple in the presence of furan affords the three separable 1:1 adducts (219), (220) and (221) (74JA5466). On cooling a solution of (221) to 0 °C the *H NMR spectrum is clearly resolved into that of the diequatorially bridged chair (221a) and the diaxially bridged boat conformers (221b). When the aliphatic chain is lengthened by one methylene unit the chair-boat equilibrium is rapid at -80 °C on the aH NMR time scale, whilst shortening the chain by one methylene unit results in a stable boat form which does not flip below 160 °C. Under carefully controlled conditions the 2-methoxyallyl cation (223) can be generated from 2-methoxyallyl bromide (222) and in the presence of furan it reacts to form the adduct (224; Scheme 80) (73JA1338).
Furans and their Benzo Derivatives: (ii) Reactivity
631
OHC
| o \=o
o (214)
I o \=o
(215)
(218)
(216) (217)
CH2)9
:CH 2 ) 9 (219)
(221a)
OMe
°n
OMe
Br (222)
(223)
(224)
o
i, PhH, furan, C5Hi2, Na2CO3, AgOCOCF3; ii, 7% HNO3 Scheme 80
Furan, in keeping with its aromaticity, and in contrast to 2,5- and 2,3-dihydrofurans, behaves as only a weak dipolarophile. Generation of benzonitrile oxide in the presence of a large excess of furan yields (91%) the adducts (225) and (226) in the ratio 97:3 (76JOC3349). Similarly, the nitrile oxide (227) affords the regioisomer of type (225) with furan (77JCS(P2)706>. Benzo[6]furan also yields regioisomeric adducts with nitrile oxides (78JOC3006). Similar adducts are formed by 3-pyrrolidinobenzo[6]furan (228) <74RTC32l). Both furan and benzo[6]furan give adducts of type (229) with TCNE oxide. These reactions are thought to be non-concerted 1,3-dipolar cycloadditions since the reactions show many similarities to electrophilic aromatic substitutions, e.g. furan reacts 10.4 times faster than thiophene (75ACS(B)44l). Cl Me Me
o (226)
(225)
(228)
Cl Me (227)
(229)
Examples of furans acting as dienophiles are not common. Reaction of furan-2-carbaldehyde with butadiene gives mono- and bis-adducts. The diterpene (230) on heating undergoes a 1,5-sigmatropic shift and lactonization yielding (231), which because of favourable stereochemistry affords (232) by an intramolecular Diels-Alder reaction (Scheme 81) (74T3099). When 3,4-dichlorothiophene dioxide (233) is dissolved in excess 2,5-dimethylfuran an exothermic reaction ensues, yielding the adduct (234; 68%). If the reaction mixture is heated the adduct undergoes loss of sulfur dioxide and rearrangement, and the benzenoid compound (235) is isolated (77%). When the reaction is applied to other furans using halothiophene dioxides the initial adduct cannot be isolated but the rearrangement products are obtained in good yield. Furan with tetrachlorothiophene dioxide affords only 8% of
632
Furans and theirBenzo Derivatives: (ii) Reactivity
the usual rearrangement product. The major product (237; 27%) arises from furan functioning as a diene and the intermediate (236) then adds a further molecule of thiophene dioxide and undergoes loss of sulfur dioxide (Scheme 82) (80JOC867).
MeO2C CH 2 OH (230)
(231) i, diglyme, heat, 6 h; ii, diglyme, heat, 32 h Scheme 81
Cl
Cl (237)
i, 2,5-dimethylfuran; ii, 2-methoxyfuran, CH2C12, 30 °C; iii, 2-acetoxyfuran, 125 °C Scheme 82
Furans also undergo cycloadditions with o-benzoquinones. Thus furan, 2-methylfuran, 2,5-diphenylfuran and benzo[6]furan yield dihydrofurobenzodioxins of type (238) with tetrachloro-l,2-benzoquinone (Scheme 83). The reaction of furan with 1,2-benzoquinone affords only a 1% yield of adduct because most of the quinone undergoes polymerization. The reaction with 2-methylfuran produces a 25% yield of adduct, however. The reactions are thought to involve the electrophilic attack of the quinone on the furan to produce a carbonium ion. In the case of 2-methylfuran the more stable carbonium ion (239) is produced. Evidence for a two-step mechanism is the diversion of the intermediate (239) to the addition product (240) which may be isolated when the reaction is conducted in the presence of ethanol (69JCS(C)1694).
(238) 62% H
°^L^\ Me OEt
O
(239) Scheme 83
(240)
Furans and their Benzo Derivatives: (ii) Reactivity
(241)
(242)
633
(244)
(243)
In the fused compounds (241) and (242) the furan ring fails to react as a diene and Diels-Alder reaction with dienophiles occurs on the terminal carbocyclic rings. However, (243) and (244) afford monoadducts with dimethyl fumarate by addition to the furan rings (70JA972). The rates of reaction (Table 2) of a number of dehydroannuleno[c]furans with maleic anhydride, which yield fully conjugated dehydroannulenes of the exo type (247), have been correlated with the aromaticity or 'antiaromaticity' of the products (76JA6052). It was assumed that the transition state for the reactions resembled products to some extent, and the relative rates therefore are a measure of the resonance energy of the products. The reaction of the open-chain compound (250), which yields the adduct (251), was taken as a model. Hence the dehydro[4n + 2]annulenes from (246) and (249) are stabilized compared to (251), and the dehydro[4n]annulenes from (245) and (248) are destabilized (Scheme 84). Table 2 Relative Rates of Reaction of Dehydroannuleno[c]furans with Maleic Anhydride Relative rate
Compound
0.02 6.1 0.2 3.9 1.0
Dehydro[12]annuleno[c]furan (245) Dehydro[14]annuleno[c]furan (246) Dehydro[16]annulenoj>]furan (248) Dehydro[18]annuleno[c]furan(249) Open model (250)
Me
' •" (245) n = 1 (246) n = 2
Me
Me (247)
(250)
Me (248) m = 1, n = 2 (249) m = n = 2
(251) Scheme 84
Benzo[c]furan, isobenzofuran, although of limited stability, is easily generated by thermal cycloreversion of precursors such as (252) and (253) which are available in turn from the adduct (254). Indeed, flash vacuum pyrolysis of the dihydro adduct (255) offers the most attractive synthesis of benzo[c]furan. Solutions of benzo[c]furan in ether at 0°C react instantaneously with maleic anhydride, iV-phenylmaleimide and methyl vinyl ketone to yield endo : exo (3:1) mixtures of adducts such as (256) from maleic anhydride. With styrene and cyclohexene reaction is slower and yields are lower due to polymerization; isobutene fails to react. A large number of trapping experiments has been reported. Thus boiling the tetracyclone adduct (257) with (254) in diglyme affords the adducts (258) and (259) in the ratio 1:1.4. Benzo[c]furan generated by this method has also been trapped as Diels-Alder adducts with the thietes (260) and (261) and with N- substituted azepines. When generated
Furans and their Benzo Derivatives: (ii) Reactivity
634
from (253), benzo[c]furan has been trapped with the naphthalene oxide (254), cyclopentene, cycloheptene, cycloheptatriene and norbornadiene. Benzo[c]furan has also been trapped with tropone and substituted tropones. A [4 + 6] adduct (262) has been obtained when benzo[c]furan is generated in the presence of 6,6-dimethylfulvene. Adducts of benzo[c]furan have also found use in anthracyclinone synthesis. When generated from the a-pyrone adduct (253) in the presence of the quinone (263) the expected endo and exo adducts were obtained in a yield of 96% in the ratio 3:1. These were converted into (±)-4-demethyldaunomycinone in several steps.
(253)
(254)
(255)
(256)
L
SO2 (260) R = H (261)R = M
(262)
(263)
Treatment of the acetal (264), available from 6-bromoveratraldehyde, with dienophiles including DMAD, methyl vinyl ketone, acrylonitrile and quinones in boiling chlorohydrocarbon solvents in the presence of acetic acid gives good yields of adducts in which the endo isomers predominate (80TL3663). The phthalan (265) is thought to be the immediate precursor of the benzo[c]furan (266) since it can be isolated under sufficiently mild conditions. The analogue (267) is readily available by oxidation of the diol (268) in acidic methanol. On treatment with LDA the phthalan (267) yields solutions of benzo[c]furan (80JOC4061). This general method has been used in the synthesis of 1-arylnaphthalide lignans (80CC354). MeO CH,OH OMe (264)
(266)
(265)
(267)
(268)
Benzo[c]furans with alkyl or alkoxy substituents at the 1-position are also unstable compounds but have been generated by methods similar to those for the parent. They undergo cycloadditions with a diverse range of compounds including quinones, quinone acetals (81CC942) and ethylenic and alkynic dienophiles. Treatment of the phthalan (269) with LDA by inverse addition generates l-methoxybenzo[c]furan (271), which has been trapped with norbornene (8UOC2734). Heating the phthalan (269) with maleate, fumarate or DMAD in the presence of acid gives aromatized adducts of (271); maleic anhydride undergoes addition without added acid, presumably due to the adventitious presence of maleic acid. On heating the ethoxy analogue (270) with activated acetylenes at 140-160 °C, aromatized adducts of l-ethoxybenzo[c]furan (272) are obtained <80CJC2573>. The hydroxyphthalan (273) yields adducts of l-benzylbenzo[c]furan on reaction with maleic anhydride or p-benzoquinone in the presence of acid (80JOC1817).
RO (269)R = Me (270)R = Et
HO (271)R = (272)R =
(273)
CH2Ph
Furans and their Benzo Derivatives: (ii) Reactivity
635
1,3-Diarylbenzo[c]furans are stable compounds and the diphenyl compound has long been used as a trap for unstable unsaturated compounds including cycloalkenes, cycloalkynes and dehydrobenzenes. Its high reactivity in cycloadditions, invariably at the furanoid diene site, is accounted for by the regeneration of the benzenoid sextet. Its reactions with simple alkenes and alkynes have been studied kinetically. The adducts are readily converted into naphthalenes by dehydration with acidic reagents or with phosphorus pentasulfide. Adducts from alkynes cannot lose water; those from cycloalkynes undergo rearrangement under acidic conditions (Scheme 85). 1,3-Diphenylisobenzofuran undergoes [4 + 6] and [4 + 2] cycloadditions with cycloheptatriene (Section 3.11.2.7.2); [4 + 2] adducts similar to those with furan are formed with o-benzoquinones.
(CH2)n
Scheme 85
Benzo[fe]furans do not take part in Diels-Alder reactions because of their enhanced aromaticity, but 2-vinylbenzo[6]furans give adducts involving the exocyclic double bond. The isopropenylbenzo[6]furan (274) forms the adducts (275; 89%) and (276; 80%) with TCNE and maleic anhydride respectively. With DMAD a 25% yield of the aromatized adduct (277) is obtained and methyl propiolate regioselectively yields a similar adduct (278) (70AJC2119). 2-Isopropenyl-3-methylbenzo[6]furan also affords adducts <69TL290l). Reaction of 2-isopropenyl-6-methoxybenzo[6]furan (279) with methyl propiolate affords the dibenzof uran (280) which has been used in a synthesis of the naturally occurring ruscodibenzofuran (Scheme 86) <80CC1103>. The (.E)-2-methoxyvinyl compound (281) yields the expected mixture (28%) of isomers (282) and (283) with methyl fumarate, but with DMAD the major product (36%) is the rearranged adduct (284). Other compounds isolated are the methanol elimination product (285; 20%) and the dibenzof uran (287) which arises by further addition of DMAD to (284) followed by cycloreversion of the adduct (286) with loss of methyl /? -methoxyacrylate (Scheme 87). Benzo-substituted analogues of (281) give similar products with DMAD, one of which has been used in a synthesis of di-O-methylstrepsilin (72AJC545). 2-Isopropenyl-3-methoxybenzo[6]furan (289) yields the expected adduct with TCNE, but with maleic anhydride elimination of methanol occurs and the adduct (288; 82%) is obtained. With DMAD the dibenzofuran (290; 33%) is obtained (Scheme 88) (71AJC1883).
S O (277)
Me
Meo
CO2Me
\JCX) CT
Y (279)
Me
(280)
i, TCNE, CHC13, 25 °C; ii, maleic anhydride, PhH; iii, DMAD, PhH; iv, HC=CCO2Me, PhMe Scheme 86
636
Furans and their Benzo Derivatives: (ii) Reactivity CO2Me
CO,Me OMe (282)
CO2Me ^.CO2Me OMe
(283)
+
O
^^^O'
(285)
(287)
i, (£)-MeO2CCH=CHCO2Me, xylene; ii, DMAD, PhMe Scheme 87
OMe O"
O
(288)
(289)
Me
(290)
i, maleic anhydride, PhH; ii, DMAD, xylene Scheme 88
3-Pyrrolidinobenzo[6]furan (228) can function as a dienophile and by inverse electron demand it forms the [4 + 2] adduct (291; 70%) with 1,4-diphenyl-s-tetrazine. With DMAD a [2 + 2] adduct (292) is formed which is easily converted into the benzoxepin (293) on heating (74RTC321>.
CO2Me CO,Me
3.11.2.7.2 Photochemical reactions Furan does not undergo photodimerization, but benzo[6]furan gives low yields of the syn and anti dimers (294) and (295) on acetophenone sensitized irradiation in benzene <75HOU(4/5a)552>. 2-Phenyl- and 2-cyano-benzo[6]furan and methyl benzo[6]furan-2carboxylate give photodimers of unknown structure. Codimerization of benzo[i]furan with the pyridyl compound (296), available from the irradiation of benzo[Z>]furan in the presence of 3-iodopyridine, gives the head-to-tail dimers (297) and (298) in the ratio 3:2. The reaction is thought to involve an excited singlet of benzo[Z>]furan (76JOC541). 1,3-Diphenylbenzo[c]furan affords the photodimer (299) of unknown stereochemistry. Furans which are part of a hexatriene system undergo oxidative photocyclization via a concerted 6TT-process (Scheme 89). Usually the dihydro intermediates cannot be isolated but compound (300) is
Furans and their Benzo Derivatives: (ii) Reactivity
637
(299)
(298)
an exception (79T2639). When the reaction is conducted in the presence of iodine the aromatized product is isolated.
22%
Ph
(300) i, A > 300 nm, 450 W, air, cyclohexane; ii, A > 300 nm, ether, N2 Scheme 89
Furans are able to undergo photocycloaddition of the [W2S + ,r2s] and the [W4S+W4S] type to suitable substrates. With benzene (8OJCS(P1)2174) five 1:1 products are obtained. The relative proportions of these products are highly variable and depend on the relative concentration of the reactants, the irradiation time, the light intensity and the temperature of the solution. For the shortest irradiation time with a low-pressure mercury lamp at 15 °C, the relative proportions are 1:1:10:40:2. The major product is the 2,5: l',4'-adduct (301) and the next most prolific is the 2,3: l',2'-adduct (302). Adduct (301) is unreactive to dienophiles but gives adduct (302) by Cope reaction at 60-70 °C. This reaction can also be achieved by irradiation of a cyclohexane solution of (301). Adduct (302) reacts readily with dienophiles in ethereal solution to form Diels-Alder adducts. The minor adducts possess structures (303), (304) and (305). The reaction is thought to involve the first excited triplet of benzene or an excited state complex. A [,,4,4-,,4,] photoadduct (306) is formed H H
(306)
(307)
(308)
Furans and their Benzo Derivatives: (ii) Reactivity
638
from furan and 1-cyanonaphthalene, but 2-cyanonaphthalene yields the [2 + 2 + 2 + 2] adduct (307). With 9-cyanoanthracene, irradiation of furan and alkylfurans gives high yields of [W4S + W4S] adducts. Thus 2-methylfuran and 3-methylfuran regiospecifically give (308) and (309). An exciplex between the singlet excited anthracene and the ground state of the furan is supposedly involved (74JCS(P1)236O>. Furan and 2-methylfuran form [4 + 2] cycloadducts with 1,1-diphenylethylene and indene in the presence of electron acceptors such as cyanonaphthalenes. Irradiation of indene and furan in acetonitrile with a 300 W high-pressure mercury lamp gives the [4 + 2] adduct (310; 35%) as well as (311; 20%) and (312; 10%). Product formation is thought to occur by electron transfer from the alkene to the excited singlet of the nitrile which suffers nucleophilic attack by the furan (78CC594). When furan is irradiated in methanol containing phenanthrene and 1,4-dicyanobenzene the dihydrofuran (313) is produced. This reaction is thought to involve electron transfer from the phenanthrene excited singlet to the dicyanobenzene, yielding a radical anion and a phenanthrene radical cation which in turn abstracts an electron from furan to yield a furan radical cation. This species reacts with methanol yielding a methoxyfuran radical and thence forms the product by cyanide displacement from the dicyanobenzene radical anion (77JA5806).
(310)
(312)
(311)
O"
OMe
(313)
Thermally unstable azetidines may be obtained by irradiation of furan in the presence of oxazolinones or 3-ethoxyisoindolone by [OT2S + W2S] cycloaddition (Scheme 90) (75JA7298). Benzophenone photosensitized [W2s + ff2s] cycloaddition of furan to dimethylmaleic anhydride yields an adduct (34%). This reaction has been extended to 2,5-dimethylfuran and other maleic anhydrides and maleimides (76CA(84)120785). O
b-4>h
V 54%
H i, 450 W Hg lamp, glyme; ii, A > 300 ran, CH2C12 Scheme 90
Photosensitized [W2S+W2S] cycloaddition of DMAD to benzo[6]furan yields the mixture of adducts (314), (315), (316) and (318) <77JOC2374>. Adduct (314) is the primary photoproduct and it rearranges via a diradical to the other products. Irradiation of any of the pure isomers yields the same mixture of products. Thermolysis of the adducts (314) and (318) affords the benzoxepins (317) and (319) which may be reclosed photochemically (Scheme 91). 2-Methylbenzo[6]furan yields similar products but only two adducts are formed from benzo[6]furan and methyl propiolate. The photoaddition of benzo[c]furan to a variety of alkenes has been described. With cycloheptatriene the [4+4] adducts (320) and (321) and the [4 + 6] adducts (322) and (323) are obtained in addition to the photodimer (301) and the photooxidation product 1,2dibenzoylbenzene. The [4 + 4] adducts may be formed in a concerted manner via an exciplex intermediate in a TT-TT* singlet state. The [4 + 6] adducts, formally symmetry forbidden,
Furans and their Benzo Derivatives: (ii) Reactivity
639 CO 2 Me
CO, Me
O" (318)
H
(319)
i, DMAD, A >300nm, 70 h, MeCOPh; ii, 185 °C; iii, hv; iv, 210 °C Scheme 91
probably arise in a stepwise manner from an excited TT-TT* triplet of 1,3-diphenylbenzo[c]furan. In contrast, the thermal reaction (benzene, 80°C) yields the exo-[4 + 6] adduct (322) and the endo-[4 + 2] adduct (324). Selective photoexcitation of 1,3-diphenylbenzo[c]furan in benzene in the presence of a number of acyclic dienes leads to a product distribution different from that of the thermal reactions; invariably the photodimer (301) is also isolated. 1,3-Cyclohexadiene affords only the [4 + 2] adducts (325) and (326); similar results are given by methyl 5-phenyl-2,4-pentadienecarboxylate, 1,4-diphenylbutadiene and a) -nitrostyrene, whilst methyl sorbate yields both [4 + 2] adducts (327) and (328) and [4+4] adducts (329) and (330). Dioxoles such as (331) are formed photochemically from benzo[c]furans and polycyclic o -quinones such as 9,10-phenanthrenequinone. O Ph
O Ph
O Ph
PhH
(325) CO2Me
CO, Me
Me CO2Me (329)
Furans undergo photochemical [2 + 2] cycloaddition with a large range of carbonyl compounds, including aliphatic aldehydes and ketones (66BCJ1806), a,/3 -unsaturated aldehydes, diketones (73JOC2860) and aromatic and heteroaromatic aldehydes and ketones to yield oxetanes (Scheme 92). Furan and benzo[6]furan (74BCJ2660) and their alkyl derivatives have been subjected to this reaction. The mechanism probably involves the electrophilic attack of the oxygen radical of the excited triplet of the carbonyl group on the furan, and oxetane formation is a result of coupling of the diradical thus produced. The regiochemistry with respect to the disposition of the two heterocyclic atoms is therefore always as shown. With 2-methylfuran, aldehydes attack either double bond of the furan, but benzophenone adds to 2- and 3-methylfuran to produce only the regioisomers (332) and (333) (67JOC2918). With unsymmetrical carbonyl addends there is the possibility of geometrical isomerism of
Furans and their Benzo Derivatives: (ii) Reactivity
640
the products. This configurational question has been studied for several pyridyloxetanodihydrofurans by measuring the NMR pseudo-contact shifts produced by cobalt(II) acetylacetonate. One isomer is usually produced and the bulkier group adopts the anti position (68T1299). With benzophenone, furan yields the 1:1 adduct (334) and after prolonged irradiation the two 2:1 adducts (335) and (336) (67TL4119). Furylquinones of type (337) on irradiation yield benzo[c]furoquinones of type (338; Scheme 93) (66HCA1806).
o
+ EtCHO
H
O+O
CHO
I
1 + MeCOCOMe O i, hv, 5-10 °C, N 2 ; ii, hv, 48 h, PhH Scheme 92
o Ac1
Me O (337)
(338) 60%
i, hv, 100W,N2 Scheme 93
Furans are highly susceptible to photooxygenation and the reactions are usually carried out at low temperature. The singlet oxygen, which adds to the diene system in a 1,4-fashion yielding bicyclic peroxides, is generated by sensitization with agents such as Rose Bengal, methylene blue or tetraphenylporphin (75HOU(4/5b)1488). Furan yields the peroxide (339) which explodes above - 2 0 °C but may be obtained crystalline at -100 °C. In methanol the hydroperoxide (340) is obtained by nucleophilic attack at an a-position, but above - 2 0 °C it loses water and forms the lactone (341). With furan-2-carbaldehyde, irradiation in ethanol yields the lactone (342), the intermediate hydroperoxide undergoing rearrangement with loss of formic acid. Tetraphenlyporphin-sensitized photooxidation of 2,5-dimethylfuran (Scheme 94) yields the peroxide (343) which is relatively stable in solution and can be O
O
(339)
(340)
(341)R = Me (342)R = Et
Furans and theirBenzo Derivatives: (ii) Reactivity
641
codistilled with carbon tetrachloride at -20 °C under reduced pressure. On treatment with methanol it yields the hydroperoxide (344), also available by photooxygenation of 2,5dimethylfuran in methanol, and on treatment with triphenylphosphine it is deoxygenated to 1,2-diacetylethylene (79JOC1727). The ester (345; Scheme 95) on photooxygenation yields the peroxide (346), m.p. 78 °C, which is stable at -15 °C under anhydrous conditions. Reaction with methanol gives the hydroperoxide (347). On standing for 15 days at room temperature the peroxide (346) furnishes the epoxide (348; 62%) and the stereoisomers (349) and (350) (5%) (Scheme 95). The reaction is thought to involve inter- or intramolecular epoxidation. These products, as well as unidentified peroxy compounds, are produced when (346) is exposed to aqueous acetone at 0 °C. Deoxygenation of (346) with diethyl sulfide affords (349) as the initial product (80JCS(Pl)l955>. 3-Methylfuran on photooxygenation, followed by chromatography and kugelrohr distillation of the product at 20 °C and low pressure, yields the products (351; 54%), (352; 10%), (353; 23%) and citraconic anhydride (354; 13%) (Scheme 96) (79LA1571). Tetraphenylfuran on photooxygenation in methanol is reported to give (355) and (356), but in acetone the products isolated are (357) and (358). The photooxygenation of the cyclophane (29) is particularly interesting. In methanol the intermediate hydroperoxide (359) undergoes intramolecular Diels-Alder reaction- and affords (360; Scheme 97), but in dichloromethane the tetraepoxide (362), formed via (361), is isolated. Photooxygenation of the sesquiterpene furanofukinal has been used in the synthesis of eremophilane type lactones <78H(1O)177).
Me O
HOO
>Oc M e °
OMe
(344) i, hv, O2, 5 °C, tetraphenylporphin, CC14 or CFC13; ii, MeOH, -78 °C, 2 h Scheme 94
>Q<
MeO Ph (346) CO2Me PhOC
'COMe
PhOC
(348)
O NQOH (347)
PhOC
CO,Me >=< H COMe (350)
COMe (349)
i, hv, O2, methylene blue, CC14; ii, MeOH; iii, 15 d, 25 °C Scheme 95
Me
r o
A ILKo
Me
Me I
Me I
Me
^O /
o
O
(351)
(352)
Me
O (353)
i, hv, O2, methylene blue, CH2C12> 0 °C Scheme 96 Ph Ph
OO (355)
Ph MeO
Ph Ph
>O<
Ph
O OMe (356)
Ph
O
Ph
o=c c=o \Ph Ph/ (357)
O (354)
642
Furans and their Benzo Derivatives: (ii) Reactivity O
OOH 'Me MeO
w
OOH
(359)
(360) 42%
O
o \ (361)
/ o
(362)75% i, hv, O2, photosensitizer; ii, MeOH; iii, CH2C12 Scheme 97
Benzo[6]furan and 2-methylbenzo[6]furan fail to undergo photooxygenation but 2,3dimethylbenzo[6]furan yields 2-acetoxyacetophenone (364). At -78 °C the peroxide (363) is produced which at higher temperature rearranges to the acetophenone (364; Scheme 98). 2-Vinylbenzo[6]furans, e.g. trans-2-styrylbenzo[6]furan (365; Scheme 99), yield photooxides which may be isolated. Compound (366) on treatment with a catalytic amount of triethylamine yields the lactone (367) (77BCJ3026). Me
o'' M e (363)
(364)
i, hv, O2, photosensitizer, -78 "C; ii, 20 °C Scheme 98
o (365)
(366) 70% (367) 58% i, hv, O2, tetraphenylporphin, CC14; ii, NEt3, Et 2 O, 20 min Scheme 99
Benzo[c]furans undergo very rapid photooxidation. 1,3-Diphenylbenzo[c]furan yields the oxide (368) on sensitized photooxygenation in ether at -50 °C. Reduction of the oxide with potassium iodide in acetic acid affords 1,2-dibenzoylbenzene and reaction with methanol supplies the hydroperoxide (369).
(368)
3.11.3 FULLY CONJUGATED RINGS: REACTIVITY OF SUBSTITUENTS 3.11.3.1 Fused Benzene Rings The chemistry of dibenzofuran is that expected of a 2,2'-linked diphenyl ether. The partial rate factors for protodetritiation (370), protodetrimethylsilylation (371) (6UCS5077)
Furans and their Benzo Derivatives: (ii) Reactivity
643
and nitration (372) with nitric acid in acetic anhydride (58JCS3079) have been determine'd and compared for those of diphenyl ether. The data for protodetritiation and protodetrimethylsilylation are consistent with the majority of electrophilic aromatic substitutions of dibenzofuran. The reactivity of the positions ortho and para to the oxygen atom is reduced in going from diphenyl ether to dibenzofuran and this is attributable to the participation of the lone pair in the aromaticity of the five-membered ring. The reactivity of the 4-position is reduced more than the 2-position and this is attributable to the strain in the five-membered ring produced in the transition state for substitution (68JCS(B)1559>. Bromination (6UCS4921), chlorination (55JOC657), iodination (65MI31100), sulfonation (49JA1593), acylation (50RTC861), benzoylation (54JA6407) and chloromethylation (56JOC457) all take place at the 2-position. Further substitution by these methods results in the production of the 2,8-disubstituted compounds. Formylation in the 2-position can be achieved by the Gattermann method but not by the Vilsmeier-Haack method (57JIC347). Nitration is anomalous and results in the 3-nitro compound; dinitration results in the 3,8-dinitro compound. The partial rate factors reported for nitration should be viewed with suspicion because of the difficulty generally encountered in introduction of a 1-substituent by electrophilic substitution or by ring synthesis. 0.65
(371)
An electron releasing substituent in one ring generally leads to electrophilic substitution in that ring. 2-Methoxydibenzofuran undergoes acylation and Vilsmeier formylation at the 3-position (56JCS4276), but 2-hydroxydibenzofuran is reported to undergo bromination and Mannich reaction at the 1-position. Benzoylation of 2-methyldibenzofuran results in substitution at the 8-position, but 2-acetylaminodibenzofuran undergoes bromination and nitration at the 3-position. 3-Hydroxydibenzofuran undergoes bromination at the 2-position, 3-acetylaminodibenzofuran undergoes bromination and nitration at the 2-position and 3-methyldibenzofuran undergoes benzoylation at the 2-position. 4-Methoxy- and 4hydroxy-dibenzofuran yield 1-substituted derivatives on acylation, formylation and halogenation. Nitration of 4-acetylamino- and 4-hydroxy-dibenzofuran with nitric acid in acetic anhydride at 0 °C gives the 3-nitro compounds. With nitric acid in acetic acid at 60 °C the 1-nitro compound results from 4-acetylaminodibenzofuran; 4-methoxydibenzofuran behaves similarly. Lithiation of dibenzofuran with butyllithium and mercuration both occur at the 4-position. Thallation occurs at the 2-position, however (57IZV1391). The mercury and thallium derivatives serve as a source of the iodo compounds by reaction with iodine. Bromodibenzofurans undergo bromine/lithium exchange with butyllithium and the derived lithio compounds may be converted into phenols by reaction with molecular oxygen in the presence of a Grignard reagent, into amines by reaction with O-methylhydroxylamine, into sulfinic acids by reaction with sulfur dioxide, into carboxylic acids by reaction with carbon dioxide and into methyl derivatives by reaction with methyl sulfate (Scheme 100). This last reaction
\JCxs Me
Scheme 100
CT 63%
Me
644
Furans and their Benzo Derivatives: (//) Reactivity
has been applied to the 2,8-dilithio compound prepared by bromine/lithium exchange and to the 4,6-dilithio compound prepared by proton/lithium exchange (65JA213). The lithiation of a number of alkyl- and methoxy-substituted dibenzofurans has also been studied. Nucleophilic substitution of dibenzofurans has been little studied. Bromo and iodo compounds are converted into the amino compounds on autoclaving with aqueous ammonia in the presence of copper(I) bromide (73OPP125). Iodo compounds can be converted into phenols with aqueous potassium hydroxide at 250 °C (65MI31100), but dibenzofuran is cleaved to 2,2'-dihydroxybiphenyl on fusion with sodium hydroxide. Animation of halo compounds can be achieved with sodamide but 4-halo compounds undergo cine substitution on treatment with sodamide or lithium dialkylamides and the 2-substituted compounds result (56JOC457). 1,2,3,4-Tetrafluoro- and octafluoro-dibenzofuran react with nucleophiles at the 3-position (Scheme 101) <67T404l,68JCS(C)1560>. LAH
Me
Scheme 101
Homolytic substitution of dibenzofuran with methoxycarbonylmethyl radicals gives poor yields of dibenzofuranacetic acids; the ratio of products at the 1-, 4- and 3-positions is 3.67:2:1 (6UA1358). Hydrogenation of dibenzofuran over a platinum catalyst yields 1,2,3,4-tetrahydrodibenzofuran, whilst hydrogenation over a sodium/rubidium catalyst at high temperature and pressure brings about ring cleavage and phenylcyclohexane (80%) and biphenyl (10%) result (7UOC694). Boiling dibenzofuran with W7 Raney nickel in methanol results in a moderate yield of frarcs-2-phenylcyclohexanol (63AJC20). Birch reduction affords the 1,4dihydro compound (82%). The radical anion of dibenzofuran is produced by the action of alkali metals in 1,2-dimethoxyethane or by electroreduction at a stationary mercury electrode. When treated with lithium in boiling ether, dibenzofuran is cleaved and carbonation results in the coumarin (374; Scheme 102). In boiling dioxane, carbonation results in none of the coumarin but hydrolysis results in 2-hydroxybiphenyl; the intermediate (373) can presumably abstract a proton from dioxane (57JOC851). Cleavage of dibenzofurans with lithium in boiling dioxane has been advocated as a general method of synthesis of 2hydroxybiphenyls (80S634).
(373)
(374) 40%
Scheme 102
3.11.3.2 Alkyl and Substituted Alkyl Substituents Alkylfurans are usually obtained by ring synthesis, decarboxylation of alkylfurancarboxylic acids, Wolff-Kishner reduction of aldehydes or ketones, or by reduction of halomethyl groups with zinc and acetic acid or LAH (79JOC3420); alkylation is of limited value. The chemistry of these compounds is conventional but oxidation to furancarboxylic acids cannot usually be carried out due to the lability of the ring. NBS bromination (Section 3.11.2.2.5) is a useful route to side-chain substituted compounds but reduction of esters to hydroxymethyl groups and subsequent transformation is often preferable. The haloalkyl compounds are extremely sensitive to resinification but if adequate precautions are taken they are
Furans and their Benzo Derivatives: (ii) Reactivity
645
tractable. Their reaction with nucleophiles is worthy of comment. With aqueous cyanide, 2-chloromethylfuran provides the intimate ion pair (375) and cyanide attacks to give the product of side-chain substitution (376), but the major pathway provides the product (378) of nuclear substitution by aromatization of the intermediate (377; Scheme 103). Spectroscopic evidence for the intermediate (377), which may also be isolated, has been obtained and the effect on the product ratio of different substituents has been investigated (76JOC2835). By working in DMSO the conventional product (376) is obtained. 3-Chloromethylfuran yields a similar mixture of nitriles on treatment with cyanide so that for the preparation of 3-furylacetonitrile, methyl 3-bromomethylfuran-2-carboxylate is allowed to react with cyanide in aqueous benzene in the presence of tetrabutylammonium bromide, and the nitrile produced is subjected to partial hydrolysis and decarboxylation (78BSF(2)27l). 2,5Bis(chloromethyl)furan gives a mixture of the normal product and 2-chloromethyl-5methylene-2,5-dihydrofuran-2-carbonitrile on treatment with cyanide. Nuclear substitution is only a minor pathway when methyl 2-bromomethylfuran-3-carboxylate is treated with cyanide in aqueous benzene but in ethanol the methylene group reacts with the formation of (379) and (380). Similar products are obtained from methyl 2-chloromethylfuran-5carboxylate (76JHC89). 2-Bromomethyl-5-nitrofuran on treatment with sodium hydride in DMF gives bis(5-nitro-2-furyl)ethylene by a carbanion mechanism, but azide and malononitrile in DMF give 5-aminofuran-2-methylidenemalononitrile by a mechanism suggested to involve a furfurylnitrene (80CCC752). When 2-chloromethyl-3,4-diphenylfuran is treated with aqueous cyanide, 5-methyl-3,4-diphenylfuran-2-(5/f)-one is obtained (79JHC1293). Halomethyl compounds in the furan series react well with triphenylphosphine to afford phosphonium salts which have been extensively used in Wittig reactions to form annulenes (69AJC1951) and annulenones (75MI31100). Furan-2-methanamine (furfurylamine) reacts with 2,4,6-trimethyl- or 2,4,6-triphenyl-pyrylium perchlorate in ether to supply the appropriate iV-(2-furylmethyl)pyridinium perchlorate. The pyridine is readily displaced by a variety of nucleophiles (79JCS(P1)426). CH,CN
O
(376) O"
CH 2 Ci
CH2 " (375)
cr .civr
'A o )cN
O (378)
(377) Scheme 103
//
CO2Me \\ MeO2C
MeO2C (380)
(379)
2-Furanmethyl benzoate (381) on flash vacuum pyrolysis affords the cyclobutenone (382; 40%). Deuterium labelling established the mechanism shown in Scheme 104. The 5-methyl analogue (383), however, gives the dihydrofuran (30) (74JOC1448). Ph
/
o
CH,
(30)
Scheme 104
(382)
646
Furans and their Benzo Derivatives: (ii) Reactivity
(5-Methyl-2-furylmethyl)trimethylammonium hydroxide undergoes 1,6-Hofmann elimination on heating with the production of 2,5-dimethylenedihydrofuran (30), which undergoes dimerization to afford the cyclophane (29). By 'cross breeding' of this intermediate with similar dimethylene compounds, ready access is given to mixed cyclophane systems, an area which has been extensively investigated. Furan-2-methanols are cleaved to derivatives of levulinic ester by methanolic hydrogen chloride; a mechanism involving the carbonium ion (375) has been proposed. Under similar conditions, a,/3-unsaturated carbonyl compounds of type (384) undergo a similar rearrangement, a reaction known as the Marckwald rearrangement, and afford keto esters of type (385), as shown in Scheme 105 in an example drawn from a synthesis of equilenin (70AJC547). EtO2C^
o
IT
II
\
\\ HCl/EtOH
o MeO^
(384)
(385) Scheme 105
3.11.3.3 Carboxylic Acids Carbonation of lithiofurans is a useful method for obtaining these compounds. Furan-2carboxylic acid (plsTa3.15) is a stronger acid than the 3-carboxylic acid (pKa 4.0) because of the inductive effect of the ring oxygen, and both are stronger than benzoic acid. Furancarboxylic acids can be decarboxylated by the copper-quinoline method or merely by heating. The 2-carboxylic acids are more easily decarboxylated than the 3-isomers, so furan-3-carboxylic acid can be obtained by stepwise decarboxylation of the tetracarboxylic acid via the 2,3,4-tricarboxylic acid and the 3,4-dicarboxylic acid. A more convenient source of the 3-carboxylic acid is by partial hydrolysis and decarboxylation of the readily available diethyl furan-3,4-dicarboxylate (71S545). Methyl benzo[6]furan-3-carboxylate is more easily hydrolyzed than its 2-isomer. 3.11.3.4 Acyl Substituents Furan-2-carbaldehyde is the most important furan of commerce and processes are available for its decarbonylation to furan. The polyaldehydes of the furan series are all known and are available by reduction of nitriles (70BSF1445), reduction and oxidation of esters (80S950) or from halofurans by lithiation and formylation with DMF (70BSF1838). The Vilsmeier-Haack method may be applied to alkylfurans. Furan-2-carbaldehyde undergoes the Cannizzaro reaction, and oxidation of furanaldehydes to the carboxylic acids may be brought about with silver oxide. The aldehydes also undergo the Wittig reaction. Furan-2carbaldehyde, on reaction with primary arylamines in acidic solution, affords the salt (386) which can be converted into a pyridinium salt (388) with acid or a cyclopentenone (387) with base. Cyclopentenones (387) can also be formed directly by the reaction of furan-2carbaldehyde with arylamines (Scheme 106) (70AJC2315).
ArHNP (387) Scheme 106
Furans and their Benzo Derivatives: (ii) Reactivity
647
Furyl ketones are conventional in their reactions. 2-Acetylfuran forms enamines which on heating yield 2-dialkylaminophenols (62CB183). The tosylate of the oxime of 2-acetylfuran is solvolyzed in methanol to a stereoisomeric mixture of 2-acetyl-2,5-dimethoxy-2,5dihydrofurans (75KGS1026). The tosylate of the oxime of 2-acetylbenzo[£]furan also undergoes unusual rearrangements on solvolysis. Di-2-furylethanedione (furil) undergoes the benzilic acid change and at low temperatures furilic acid can be isolated as a salt or as the methyl ester (prepared with diazomethane). Furilic acid itself is unstable, especially to acids, and acetic acid will induce decomposition to 2,2'-difuryl ketone (72ACS1280). 3.11.3.5 JV-linked Substituents Few simple amines are known in either the furan or the benzo[& ]furan series. Simple nitrofurans on attempted reduction by mild chemical methods suffer what is probably a deaminative degradation. Similarly, attempted reduction of 2-nitrobenzo[6]furan affords not the amine but the product of its hydrolysis, benzofuran-2(3//)-one. Other classical synthetic approaches to 2-furanamine have failed, including the Curtius method and Beckmann rearrangement of 2-benzoylfuran oxime. However, hydrazinolysis of iV-(2-furyl)phthalimide, obtained from phthalimide and 2,5-dimethoxy-2,5-dihydrofuran, gives 2-furanamine which was not isolated but detected by GLC-MS and * NMR spectroscopy. The latter reveals the absence of imino tautomers (75AP713). The chemistry of 2-dialkylamino-5-phenylfurans is typical of enamines; protonation occurs on carbon to produce iminium salts. They are stable to base but afford 5-phenylfuran-2(3/f )one on hydrolysis with dilute acid. 2-Morpholino-5-phenylfuran couples with diazonium salts and affords Diels-Alder adducts with maleic anhydride and iV-phenylmaleimide <73JCS(P1)2523>.
Furan-2-amines substituted with electron withdrawing groups are stable compounds and exist as the amino tautomers. Ethyl 5-acetylaminofuran-2-carboxylate may be nitrated and brominated. The product of nitration, the 4-nitro compound, undergoes hydrolysis to the amine and reduction to the 5-acetylamino-4-amino compound. The nitroamine may be diazotized and then gives a coupling product with 2-naphthol. 5-Nitrofuran-2-carbaldehyde may be catalytically hydrogenated to the 5-amino compound (74H(2)391). Alkyl- and arylsubstituted 2-aminofuran-3-carbonitriles, as expected of enamines, yield iminium salts on protonation, and on acidic hydrolysis they afford furan-2(3//)-ones. With benzaldehydes they afford anils and they participate in Diels-Alder reactions with maleic anhydride, affording derivatives of phthalic anhydride by concomitant dehydration (68TL4605). 3-Acetyl2-amino-5-methylfuran-4-carbonitrile has been synthesized and its structure determined by X-ray crystallography, but the exploration of its chemistry was confined to the observation that it gave 2,5-dimethylpyrrole-3,4-dicarbonitrile on treatment with hot aqueous ammonia (78JOC3821). 3,5-Dinitrofuran-2-amine is known but does not undergo any reactions characteristic of an aromatic amine (79JHC477), A stable furan-2-diazonium fluoroborate has been prepared which gives some reactions characteristic of an aromatic species (63LA(667)96). Two C-alkylf uran-3-amines are known; they both resinify very rapidly in air. They are sensitive to hot acid and alkali and ammonia is liberated. It is reported that they react with nitrous acid and that coupling products are obtained with 2-naphthol. It has been suggested that they exist as imino tautomers, but there is no spectroscopic information on this point (B-76MI31101). 5-Methyl-2,4-diphenylfuran-3-amine has been prepared by the Curtius method but its chemistry remains unexplored (73TL3353). 3-Morpholino-2,5-diphenylfuran (389) forms a a--complex (390) with bromine. When treated with boiling ethanol, (390) yields the furanone (391; Scheme 107) (70JHC569). 3-Azidofuran-2-carbaldehyde and 3-azidofuran-2-carbonitrile are reduced by hydrogen sulfide in methanol in the presence
a (389)
(390) Scheme 107
(391)
648
Furans and their Benzo Derivatives: (ii) Reactivity
of piperidine to the respective furan-3-amines which exist as such (75ACS(B)224). Application of the Friedlander synthesis to 3-aminofuran-2-carbaldehyde yields furo[3,2-6]pyridines. 2-Aminobenzo[6]furan-2-carboxylates and 2-acylbenzo[7>]furan-3 -amines exist as the amino tautomers. 3-Pyrrolidinobenzo[6]furan is available from benzo[&]furan-3(2jF/)-one (74RTC321).
3.11.3.6 O-Linked Substituents Simple furanols (hydroxyfurans) never exist as such but as their keto tautomers (B76MI31100). Furan-2(3//)-one (but-3-enolide) (392) is formally the tautomer of 2-furanol, but its isomer furan-2(5//)-one (but-2-enolide) (393), in which the double bond is in
(392)
(393)
conjugation with the carbonyl group, is more stable and the conversion can be achieved by acid or base. The chemistry of butenolides, which are important as many natural products, is properly that of lactones rather than of furans and has been extensively reviewed (76CRV625,78FOR(35)133>. Butenolides show little evidence of enolic behaviour, as indicated by their gas phase ionization potentials and their photochemistry. 5-Methylfuran-2(3//)-one fails to undergo O-alkylation and under phase transfer conditions methylation occurs at the 3-position and 5-methylfuran-2(5//)-one is also formed. However, 3,4,5-triphenylfuran-2(3//)-one is converted into 2-methoxy-3,4,5-triphenylfuran, as well as undergoing C- methylation, by treatment with iodomethane and potassium in benzene. Bases such as LDA give enolate anions with butenolides. 5-Methylfuran-2(3//)-one with LDA followed by acetyl chloride affords 2-acetoxy-5-methylfuran (40%) which, with boron trifluoride etherate, undergoes a rearrangement of the Fries type yielding 5-acetyl-5-methylfuran2(5H)-one (78JOC2072). C-Alkylation of butenolides can be achieved by generation of their enolate anions with LDA in the presence of HMPT in THF, followed by treatment with reagents such as geranyl or prenyl bromide. Thus 3- and 4-methylfuran-2(5//)-one are alkylated at the 3- and 5-positions. Since furan-2(5//)-ones are readily reduced to furans with DIBAL, this constitutes a useful furan synthesis (77TL4443). 5-Substituted furan-2(3//)ones condense with aromatic aldehydes, affording (£j)-3-arylmethylidenefuran-2(3//)-ones which on flash vacuum pyrolysis undergo decarbonylation (Scheme 108) (80AG555).
700 °C
10 4mmHg
RCOCH=C = CHAr
Scheme 108
2-Methoxyfuran and 2-acetoxyfuran are readily prepared by heating the appropriate 2,5-disubstituted 2,5-dihydrofuran with a trace of naphthalene-2-sulfonic acid in an inert solvent at high temperature. 2-Alkoxyfurans are also available from 5-bromofuran-2carboxylates by nucleophilic substitution, hydrolysis and decarboxylation (56JOC516). Their cycloaddition reactions have been mentioned previously (Section 3.11.2.7.1). 2-tButoxyfuran is also readily available and trimethylsilyloxy compounds are available from butenolides by reaction with chlorotrimethylsilane, triethylamine and zinc chloride in acetonitrile. Acid hydrolysis of 2-alkoxyfurans occurs chiefly by 5-protonation to give a furan-2(5if )-one which subsequently affords an acrylate (74JOC2920). With halogens or LTA, 2-acetoxyfurans yield 5-halo- or 5-acetoxy-furan-2(5//)-ones. The cycloaddition reactions of 2,5-bis(trimethylsilyloxy)furans have been discussed (Section 3.11.2.7.1). The reactions of these compounds with aldehydes and ketones and with quinone acetals have also been investigated (80TL3431). Attempts to prepare 2,4-dimethoxyfuran have been fruitless but 2,3- and 2,5dimethoxyfuran are well known (79JCS(P1)1893). 4-Hydroxyfuran-2(5//)-ones (tetronic acids) are an important group of natural products and they are dealt with in the aforementioned reviews. 3-Furanol is formally the enolic form of furan-3(2//)-one (394). Compounds with
Furans and their Benzo Derivatives: (ii) Reactivity
649
a carbonyl substituent at the 2-position behave as genuine 3-furanols but without this substituent, or even with a carbonyl substituent at the 4-position, the compounds exist in the keto form and behave as vinylogous lactones. 2-Acetyl-3-furanol (isomaltol) is readily available and is an acidic enol (pKa 5.7) which gives a deep red colour with Fe .
O (394)
Diazomethane furnishes the methyl ether which has been degraded to 3-methoxyfuran which, however, is more easily available from 3-iodofuran. 3-Methoxyfuran is cleaved by acid to furan-3(2//)-one. Other 3-furanols with ester, acetyl or benzoyl substituents at the 2-position are also available. They exist in the enolic form but their chemistry has not been investigated (76JCS(P1)1688). Furan-3(2i/)-ones with acetyl or ester substituents at the 4-position are readily available. They exist in the keto form but show some evidence for enolic behaviour and their chemistry is similar to that of enolizable ketones. They enter into cycloaddition with maleic anhydride, are alkylated at the 2-position, condense with aldehydes and ketones and are oxidized by LTA to the 2-acetoxy compounds (74BSF2061). The simple furan-3(2i/)-ones exist in the keto form but may be O-acylated with acetic anhydride and sodium acetate; however, they undergo C-alkylation. They are usually stable to acid, merely being protonated. 4-Alkoxyfuran-3(2i/)-ones are readily hydrolyzed to tetronic acids. Furan-3(2/f )-ones are degraded by aqueous base which attacks in a conjugate fashion so that 2,5-dimethylfuran-3(2i/)-one, readily available from biacetyl, furnishes acetate and acetoin, but compounds with an ester group at the 4-position furnish tetronic acids (Scheme 109). //
\
,—P
-OJI^Mer^
—
Me /
OH
\
^ ^ Me /
#
MeCOCH,COCHMe — • MeCOT + MeCOCHOHMe O *\
CO2Et
Me Scheme 109
2,5-Dimethylfuran-3(2/f)-one undergoes coupling with arenediazonium salts at pH 0 and furnishes 2-arylazo-2,5-dimethylfuran-3(2i/)-ones which are readily converted into l-aryl-5-methyl-3-pyrazolones (79S283). 3,4-Dimethoxyfuran is readily available from the enolic dimethyl 3,4-dihydroxyfuran-2,5dicarboxylate. This intermediate, like a phenol, can be readily O -methylated or O-benzylated. Hydrolysis and decarboxylation then furnishes the 3,4-dialkoxy compounds (78HCA430). The dimethoxy compound readily enters into Diels-Alder reactions, the Mannich reaction, and may be lithiated. On mild acid hydrolysis it supplies, in poor yield, 4-methoxyfuran-3(2//)-one and not tetrahydrofuran-3,4-dione, which is not produced by attempted hydrogenolysis of 3,4-dibenzyloxyfuran either. The dione, however, is known, and surprisingly exists in the diketo form (60JA3219).
O (395)
The chemistry of benzo[£]furan-2(3//)-one (395) which exists in the keto form, is that expected of the lactone of 2-hydroxyphenylacetic acid. Grignard reagents bring about the expected ring opening. Condensations may be effected at the 3-position, especially with aromatic aldehydes. Methylation with iodomethane and potassium carbonate in DMF furnishes the 3-methyl and the 3,3-dimethyl compound. Methylation, with diazomethane,
650
Furans and their Benzo Derivatives: (ii) Reactivity
of 3-acetylbenzo[6]furan-2(3//)-one provides some 3-acetyl-2-methoxybenzo[Z>]furan so that the benzofuranol tautomer is involved. 3-Acetyl-2-methoxybenzo[£]furan undergoes acid catalyzed rearrangement to methyl 2-methylbenzo[6]furan-3-carboxylate (73AJC1079). Benzofuran-3(2H)-ones (396) exist in the keto form but undergo ready enolization. Acetylation with acetic anhydride and sodium acetate affords 3-acetoxybenzo[6]furans, but reaction under acidic conditions usually supplies these products admixed with 3-acetoxy-2acetylbenzo[6]furans. Alkylation usually furnishes a mixture of O- and C-alkylated products. 3-Acetoxy-6-methoxy-4-methylbenzo[fe]furan, on Vilsmeier reaction, supplies the 3-chlorobenzo[6]furan-2-carbaldehyde, the product expected from an enolizable ketone (72AJC545). Benzofuran-3(2//)-ones react normally with carbonyl reagents. Grignard reagents react in the expected way and dehydration of the intermediate affords a 3substituted benzo[Z>]furan. The methylene group is reactive so that self condensation, condensation with aldehydes and ketones and reaction with Michael acceptors all occur readily. P
(396)
3.11.3.7 S- Linked Substituents Furanthiol derivatives are available by treating lithiofurans with sulfur; acidification then affords the thiols, acetic anhydride affords thiol acetates, and alkyl halides give thioethers. The thiols exist predominantly as such rather than as their thione tautomers. Hydrolysis of 2-thioethers with acid is accompanied by ring opening. 3.11.3.8 Halogen Substituents The halo-furans and -benzo[£]furans are particularly important as precursors of the lithio derivatives (Section 3.11.3.9). Direct halogenation of furan (Section 3.11.2.2.5) is unsatisfactory, and halofurans are prepared by decarboxylation of halofurancarboxylic acids, from chloromercurio compounds, by decarboxylative halogenation of furancarboxylic acids or by partial dehalogenation of polyhalofurans. Decarboxylation of halofurancarboxylic acids is usually carried out with copper and quinoline at 150-230 °C and the product often distills from the reaction mixture (71BSF242). Heating chloromercuriofurans with iodine and potassium iodide in water yields iodofurans. Thus 3,4-bis(chloromercurio)-2,5-dimethylfuran yields the diiodo compound (41%), and tetrakis(chloromercurio)furan yields tetraiodofuran (67%). Boiling sodium furan-2,5-dicarboxylate with potassium iodide and iodine in water yields the diiodofuran, and 2,5dibromofuran (78%) is similarly available from sodium 5-bromofuran-2-carboxylate, potassium bromide and bromine (74ZOR1341). Tetraiodofuran may be converted to the 3,4-diiodo compound (48%) or the 2,3,4-triiodo compound (85%), depending on the proportions of reagents, by brief entrainment with bromoethane and magnesium and subsequent hydrolysis. 2,3-Dibromofuran and 3,4diiodofuran are converted into the 3-halo compounds by reaction with one mol of ethyllithium and subsequent hydrolysis (70BSF1838). The best entry to the 3-substituted furan series is provided by the bromination of the furan/maleic anhydride adduct. The intermediate dibromo compound (78%) on heating with quinoline at 210 °C undergoes elimination of hydrogen bromide and retro diene reaction, affording 3-bromofuran (45%) (69KGS17). The halofurans are generally highly unstable to light and air. 2-Bromo- or 2-iodo-furans with electron withdrawing groups at the 5-position afford good yields of 2,2'-bifuryls on reaction with copper bronze in boiling DMF (66JCS(C)976). 3.11.3.9 Metal Substituents Mercury compounds are seldom used in modern furan chemistry. Deuterodemercuration finds use in the preparation of deuterofurans (Scheme 110) <,74JCS(Pl)ll4l). 3-Chloromer-
Furans and their Benzo Derivatives: (ii) Reactivity
651
curiofuran is available by pyrolysis of the mixed salt (397) and is readily converted into the iodo compound (398; Scheme 111), which is a valuable source of 3-substituted furans via the lithio derivative (72CJC3749). Treatment of the mercuriochlorides with aqueous sodium thiosulfate yields difuryl mercury compounds which are sometimes used in the preparation of lithio derivatives by mercury/lithium exchange (Scheme 112) (68JOC1227). The bis(benzo[6]furyl)mercury (400) is available from the lithio compound (399); on pyrolysis in the presence of tetracyclone the dibenzofuran (401) is isolated, suggesting the intermediacy of benzo[6]furyne (Scheme 113). H CI
fi~\
MeO2C<\ ^Br
«
HoCl O
CO,H
-W/
-o
CO 2 H g OAc
"' 51%
(397) 81%
(398)75%
i, Hg(OAc)2, H2O; ii, xylene, 23 h; iii, NaCl, AcOH; iv, I2, KI Scheme 111
Scheme 112
Ph (399)
(400)
(401) 70%
Scheme 113
Grignard reagents are difficult to prepare in both the furan and benzo[6]furan series and their use has been superseded by the more tractable lithio compounds. Bromofurans are best converted into the Grignard reagents by treatment with a copper-magnesium alloy in THF (80JOC3125).
Butylpotassium and butylcesium deprotonate furan at the 2-position (75BSF1302), but butyllithium is the reagent of choice. When furan is treated with butyllithium the reactions in Scheme 114 occur (77JCS(P1)887). The conditions, however, may be controlled to yield predominantly the mono- or the di-lithio derivative. By carbonation and esterification of the reaction mixture obtained by treatment of furan with butyllithium and TMEDA (1:1:1) in ether at 25 c Cior 30 min, a 98% yield of methyl f uran-2-carboxylate is obtained. Similarly, a butyllithium: TMEDA: furan ratio of 2.5:2.5:1 in boiling hexane for 30 min results in 91% of dimethyl furan-2,5-dicarboxylate and 9% of the monoester. Competition experiments indicate that furan reacts with butyllithium faster than thiophene under non-ionizing conditions but that the order is reversed in ether or in the presence of TMEDA.
// \\+BuLi —// W i ; +BuH
X
Vii+BuLi
A +BuH
O
O
Scheme 114
3,4-Dimethoxyfuran can be mono- and di-lithiated and the intermediates undergo conventional reactions (78HCA430). Furan-2-carboxylic acid on treatment with LDA in THF at -78 °C for 0.5 h yields the dilithio compound (402), which is stable up to -10 °C; above this temperature, proton abstraction from THF occurs. It reacts smoothly with both chlorotrimethylsilane and iodomethane at -78 °C (Scheme 115), but other alkylations
652
Furans and their Benzo Derivatives: (ii) Reactivity
require a temperature of - 3 0 °C and yields are lower. Reactions with aldehydes and ketones are rapid and clean at —78 °C and give alcohols in 80-85% yield. These may be converted into alkenes by dehydration. 3-Methylfuran-2-carboxylic acid is lithiated at the 5-position with LDA, and furan-3-carboxylic acid is similarly lithiated at the 2-position <8UCS(Pl)ll25). j)CO2H
Li(^ J )
2
3(^
(402) Scheme 115
Halofurans with vacant a-positions undergo proton/lithium exchange rather than halogen/lithium exchange with LDA due to its weak nucleophilic character and strong basicity (72TL3507). Advantage has been taken of this in a neat synthesis of rosefuran (Scheme 116) (77HCA2085). 2-Lithiofurans are also available by halogen/lithium exchange and with 2,3-dihalo compounds this can be controlled to occur only at a 2-position (70BSF1838). 3-Lithiofuran is readily available by halogen/lithium exchange from 3iodofuran, or more conveniently from 3-bromofuran (74S443). /
\Br
66%
71%
i, LDA, -80 °C, THF; ii, Me2C=CHCH2Br; iii, BuLi, -80 °C; iv, Mel Scheme 116
Lithiofurans on carbonation readily give carboxylic acids; they react with DMF to give aldehydes, with hexachloroethane to give chloro compounds and with alkyl halides to give alkyl compounds (76JOC2075). They undergo coupling with copper(II) chloride to give 2,2'-bifuryls (75AG745). 2,5-Diaryl-3-lithiofurans on heating in hexane undergo ring cleavage (76JCS(Pl)989). A few examples are shown in Scheme 117.
32%
59%
i, BuLi; ii, Me2NCO2Et; iii, H + Scheme 117
Furfuryl compounds with an anion stabilizing substituent such as a phenyl, a trimethylsilyl, or a 1,3-dithiane group yield the 2-furfuryl carbanion when treated with butyllithium. A facile ring cleavage then ensues (79JA2208,78JOC4235). 2-Lithiobenzo[6]furan is available by bromine/lithium exchange from 2bromobenzo[Z>]furan but is more conveniently prepared from benzo[6]furan with butyllithium in ether at - 1 0 °C. It affords alkylation, formylation and carboxylation products in high yield (77BSF142). When 3-bromobenzo[£]furan is treated with butyllithium at 15 to - 6 0 °C, much ring cleavage to 2-ethynylphenol occurs, but by operating at -115 °C the
Furans and their Benzo Derivatives: (ii) Reactivity
653
3-lithio derivative is stable and may be carboxylated to benzo[6]furan-3-carboxylic acid in 62% yield. 2,3-Dibromobenzo|7>]furan undergoes bromine/lithium exchange at the 2position when treated with an equivalent of butyllithium at -75 °C. Subsequent hydrolysis, formylation and carbonation yield the corresponding 3-bromo derivatives. By use of a large excess of butyllithium, the dilithio compound can be prepared which on carbonation yields benzo[6]furan-2,3-dicarboxylic acid (60%). 2-Furylcopper is available from 2-lithiofuran by treatment with copper(I) bromide in ether at 0 °C (72ACS3383). It may be obtained as an air unstable greenish-yellow solid soluble only in solvents like pyridine and quinoline. By reaction with iodoarenes in pyridine, moderate yields of Ullmann coupling products are obtained. 3-Furylcopper has also been obtained. Both isomers undergo Stephens-Castro coupling with iodoacetylenes (75JCS(P1)641). Lithium di(3-furyl)cuprate has been generated from 3-lithiofuran by treatment with copper(I) iodide in ether at -78 °C; it behaves as a hard nucleophile and adds in 1,2-fashion to carbonyl compounds. Alternatively, treatment of 3-bromofuran with two equivalents of f-butyllithium in THF and adding copper(I) iodide and dimethyl sulfide at -50 °C gives a reagent which behaves as a soft nucleophile and adds in a conjugate fashion to cyclohexen-2-one. It further gives 3-alkylfurans by substitution with alkyl halides (79TL4577).
3.11.4 SATURATED AND PARTIALLY SATURATED RINGS A review is available (65HOU(6/3)517>.
3.11.4.1 2,3-Dihydrofurans The chemistry of 2,3-dihydrofuran is that of an enol ether since it is the internal enol ether of 4-hydroxybutanal, which it affords on acid hydrolysis. Dry hydrogen chloride will add to afford 2-chlorotetrahydrofuran and chlorine affords frans-2,3-dichlorotetrahydrofuran. It is polymerized by boron trifluoride. Alcohols add readily in the presence of a trace of toluene-p-sulfonic acid to afford 2-alkoxytetrahydrofurans (65JOC2441). These, however, are more conveniently prepared by the reaction of the alcohol, in the presence of triethylamine, with 2-chlorotetrahydrofuran available by chlorination of tetrahydrofuran with sulfuryl chloride. This method is useful for the protection of hydroxy groups since the 2-alkoxytetrahydrofurans are generally stable to nucleophiles and bases, but they are more easily removed under acidic conditions than the tetrahydropyranyl ethers, and indeed can be cleaved in their presence (79RTC371). 2-Alkoxytetrahydrofurans are cleaved by LAH in the presence of aluminum chloride or boron trifluoride. If complexation occurs at the ring oxygen the products are 4-alkoxybutanols, but this is not invariably the case. The 2thioalkyltetrahydrofurans, however, always undergo cleavage of the 1,2-bond. Ethoxycarbonylcarbene affords the expected ethyl 2-oxabicyclo[3.1.0]hexane-6-carboxylate, which may be hydrogenolyzed to 3-tetrahydrofurylacetic acid. Dichlorocarbene, generated from chloroform with aqueous sodium hydroxide under phase-transfer conditions, affords a similar product (403) (79LA1456), which on thermolysis affords the dihydropyran (404; Scheme 118); on heating with quinoline this yields the aldehyde (405) (64T2091). Similar ring openings of alkyl-2-oxabicyclo[3.1.0]hexanes, available by carbene addition to 2,3-dihydrofurans, occur on heating (73TL1635).
2,3-Dihydrofuran undergoes a thermal rearrangement to cyclopropanecarbaldehyde, and 5-methyl-2,3-dihydrofuran similarly affords acetylcyclopropane. 2,5-Dimethyl-2-vinyl-2,3dihydrofuran undergoes thermal rearrangement to 4-methyl-4-cycloheptenone (66JA4294). 4-Hydroxy-3-tetrahydrofuranols are available by lengthy transformation of sugars and are readily converted into esters which undergo enolate Claisen rearrangement (Scheme
Furans and their Benzo Derivatives: (ii) Reactivity
654
119), affording functionalized 2,5-dihydrofurans useful in synthesis of ionophoric antibiotics (80JOC4259). H
OSiMe3
OCOEt /
Me
\
P
OCH,OMe O
OCH2OMe
, LDA, THF, Me3SiCl; ii, H2O, OH"; iii, CH2N2 Scheme 119
3.11.4.2 2,3-Dihydrobenzo[6]furans The chemistry of 2,3-dihydrobenzo|7>]furan (coumaran) is unexceptional, and it behaves as a typical aralkyl ether. Thus it is cleaved by hydriodic acid to 2-(2-iodoethyl)phenol. Sodium in pyridine effects cleavage to 2-vinylphenol and Birch reduction can be controlled to preserve the fur an ring. Dehydrogenation to benzo[6]furan can be effected with palladium on carbon or by radical bromination by NBS followed by dehydrobromination with a tertiary amine. Electrophilic substitution occurs at the 5- and 7-positions, and nitration, formylation, acylation and chloromethylation have all been studied. It is a common stratagem in the synthesis of benzofuranoid natural products to ensure that electrophilic substitution occurs in the benzenoid ring by prior reduction of the double bond; dehydrogenation is then achieved at a late stage in the synthesis. A typical example taken from the synthesis of cyperaquinone is shown in Scheme 120 (78AJC1533). OH
OH MeO
94%
100% i, H2, Pd/C, EtOH; ii, Br2, CHC13, 0°C; iii, Cl2GHOMe, TiCl4, CH2C12, 0°C Scheme 120
3.11.4.3 2,5-Dihydrofurans On treatment with potassium f-butoxide in t- butyl alcohol, 2,5-dihydrofuran is isomerized to the 2,3-isomer, and it is cleaved by butyllithium or potassamide in liquid ammonia to the s-trans enolate of 2-butenal <72JOC560). 2,5-Dihydrofuran is more stable to acids than the 2,3-isomer; with halo acids it is cleaved to l,4-dihalo-2-butenes and acid chlorides effect a similar cleavage to esters of 4-chloro-2-buten-l-ol. Dehydrogenation of 2,5dihydrofurans can be effected but noble metal catalysts can also effect cleavage so that 2-ethyl-2,5-dihydrofuran is converted into 2-ethylfuran and hexen-3-one. Reduction to tetrahydrofurans can be achieved with rhodium catalysts and is important in the synthesis of ionophore antibiotics (80T72). Oxidation to maleic acid can be effected with air at 370 °C and a catalyst consisting of oxides of molybdenum, vanadium and titanium. The double bond will take part in Diels-Alder reactions with 1,3-cyclopentadienes, butadiene and anthracene, and may be epoxidized with 80% hydrogen peroxide and TFAA. Carbenes will also add. Dihalocarbenes give mixtures of 6,6-dihalo-3-oxabicyclo[3.1.0]hexane and the product of insertion into the a-CH bond (79LA1456). Vinylcyclopropanation has also been achieved (75JOC756). The most important derivatives of 2,5-dihydrofuran are the 2,5-dialkoxy and 2,5diacetoxy compounds which are easily prepared from furans (Section 3.11.2.3). Their vast utility is as synthetic equivalents of malealdehyde and its derivatives (60MI31100). Suitable intermediates for Robinson-Schopf synthesis have been obtained in this way. Pyridazines are readily obtained (Scheme 121), and 3-pyridinols are available from 2-furylmethanamines (Scheme 122). This approach has been used in a synthesis of pyridoxine. The 2,5-diacetoxy
Furans and their Benzo Derivatives: (ii) Reactivity
655
compounds can be cleaved under mild acidic conditions (77JA194) or the 2,5-dimethoxy compounds can be cleaved with boron trichloride at low temperature (80S950), thus unmasking the dialdehyde as a hemiacetal suitable for use in Wittig reactions (Scheme 123). The double bond can be hydrogenated in the 2,5-dimethoxy compounds, usually in the presence of Raney nickel, and the resultant tetrahydrofurans may be converted into AT-substituted pyrroles by reaction with primary aliphatic or aromatic amines. The double bond in these compounds reacts with hypohalous acids and can also be hydroxylated. MeO
MeO / = \ O M e
_H^ | J
\nll
Mu
| __
f
|]OH
Scheme 122 EtO,C
CO2Et
EtO2C
Scheme 123
3.11.4.4 Tetrahydrofurans Tetrahydrofuran is a commonly used solvent, having the advantage that it is a relatively inert water-miscible ether. It is often used as a solvent in organometallic chemistry and it is particularly useful in the preparation of Grignard reagents from chlorobenzenes and vinyl chlorides. However, it undergoes reaction with butyllithium by proton/lithium exchange at the a-position; a cycloreversion then provides ethylene and the enolate anion of ethanal. The half life is lOmin at 35 °C. 3,4-Dialkyl and 3,3,4,4-tetraalkyltetrahydrofurans are similarly, but more slowly, cleaved and 3-methyltetrahydrofuran cleaves to afford ethylene, propene, and the enolates of ethanal and propanal. 2-Alkyltetrahydrofurans are cleaved only slowly, the major pathway being proton/lithium exchange at the methyl group (72JOC560). Autoxidation of tetrahydrofuran, or aerial oxidation in presence of cobalt(II) or nickel(II) acetate, affords the 2-hydroperoxide which is converted into 4-hydroxybutanal by reaction with triphenylphosphine (55LA(591)138) or into tetrahydrofuran-2-one with LTA. On standing, the hydroperoxide affords a highly explosive peroxide. Addition of tetrahydrofuran to alkenes and alkynes occurs by a radical chain reaction which can be initiated by dibenzoyl peroxide or photochemically, and affords 2-substituted products. DMAD affords a 1:1 mixture of the (E)- and (Z)-alkenes (73JOC1369). Photochemical decomposition of diazomethane in THF yields the insertion products 2- and 3-methyltetrahydrofuran. The ring may be cleaved hydrogenolytically. Halo acids afford 4-halobutanols or 1,4dihalobutanes, depending on the reaction conditions. Acid chlorides in the presence of zinc chloride afford esters of 4-chlorobutanol, and LAH and aluminum chloride give butanol. Reaction with carbon monoxide and nickel tetracarbonyl affords adipic acid. Chlorination of THF is achieved with chlorine at low temperature and affords the 2-chloro and 2,5-dichloro compounds. The latter with primary amines gives AT-substituted pyrroles. Monochlorination is best achieved with sulfuryl chloride (Section 3.11.4.1), and the 2,3dichloro compound is available by addition of chlorine to 2,3-dihydrofuran. This compound
656
Furans and their Benzo Derivatives: (ii) Reactivity
will react with Grignard reagents to afford 2-alkyl-3-chlorotetrahydrofurans, which are cleaved by sodium in ether to unsaturated alcohols (Scheme 124) (50JCS2685). RMgBr Cl
/ * (
\P )R
Na /~CH=CHR Et2O * (
Scheme 124
Bamford-Stevens reaction of the tosylhydrazones of the readily available tetrahydrofuran3-ones provides a useful synthesis of 2,3-dihydrofurans which may be dehydrogenated to furans with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (66CJC1083). Tetrahydrofuran-2ones (y-butyrolactones) may be alkylated in the 3-position with LDA and an alkyl halide. The products on reaction with phenyl selenylchloride and LDA, and subsequent oxidation, yield 3-alkylfuran-2(5//)-ones reducible with DIBAL to furans (75JOC542). Passage of tetrahydrofuran-2-methanol over hot alumina affords 3,4-dihydro-2//-pyran; the mechanism has been studied (67JOC200,67BSF2472). Both 3,4-dimethylenetetrahydrofuran (63JOC802) and tetramethylenetetrahydrofuran (80TL611) are known.
Copyright © 1984 Elsevier Ltd.
Comprehensive Heterocyclic Chemistry
and F. M. DEAN University of Liverpool 3.11.1 INTRODUCTION 3.11.2 FULLY CONJUGATED RINGS: REACTIVITY AT RING ATOMS 3.11.2.1 Thermal and Photochemical Reactions involving No Other Species 3.11.2.2 Reactions with Electrophiles 3.11.2.2.1 Reactivity and directive effects 3.11.2.2.2 Protonation 3.11.2.2.3 Nitration 3.11.2:2.4 Sulfonation 3.11.2.2.5 Halogenation 3.11.2.2.6 Acylation 3.11.2.2.7 Alkylation 3.11.2.2.8 Reactions with aldehydes and ketones 3/il.2.2.9 Mercuration /3.11.2.2.10 Reactions with diazonium salts 3.11.2.3 Reactions with Oxidants 3.11.2.4 Reactions with Nucleophiles 3.11.2.5 Reactions with Reducing Agents 3.11.2.6 Reactions with Free Radicals and Other Electron Deficient Species 3.11.2.7 Cycloaddition Reactions 3.11.2.7.1 Thermal reactions 3.11.2.7.2 Photochemical reactions 3.11.3 FULLY CONJUGATED RINGS: REACTIVITY OF SUBSTITUENTS 3.11.3.1 Fused Benzene Rings 3.11.3.2 Alkyl and Substituted Alkyl Substituents 3.11.3.3 Carboxylic Acids 3.11.3.4 Acyl Substituents 3.11.3.5 N-Linked Substituents 3.11.3.6 O-Linked Substituents 3.11.3.7 S-Linked Substituents 3.11.3.8 Halogen Substituents 3.11.3.9 Metal Substituents 3.11.4 SATURATED AND PARTIALLY SATURATED RINGS 3.11.4.1 2,3-Dih ydrofurans 3.11.4.2 2,3-Dihydrobenzo[b]furans 3.11.4.3 2,5-Dihydrofurans 3.11.4.4 Tetrahydrofurans
599 600 600 601 601 602 603 604 604 606 607 607 608 608 609 611 614 615 619 619 636 642
642 644 646 646 647 648 650 650 650 653 653 654 654 655
3.11.1 INTRODUCTION The chemistry of furan (1) has been fully reviewed from time to time. The text by Dunlop and Peters (B-53MI31100) covers the literature exhaustively up to 1953. Bosshard and Eugster <66AHC(7)377) and Dean <82AHC(3O)167, 82AHC(3l)237> have updated the treatment to the end
599
Furans and their Benzo Derivatives: (ii) Reactivity
600
of 1979. A text is available on benzo[& ]furan (2) (74HC(29)l) and the chemistry of benzofc]furan (3) has been reviewed by Friedrichsen (80AHC(26)l35). The chemistry of dibenzofuran (4) has received scant attention and the last full review was published in 1951 (B-51MI31100). The treatment in the present chapter is of necessity somewhat selective and to some degree idiosyncratic, but an attempt has been made to reflect the more modern developments in the subject. Where no reference is given in the text the appropriate monograph mentioned above should be consulted.
O 1
(2)
(1)
(4)
(3)
3.11.2 FULLY CONJUGATED RINGS: REACTIVITY AT RING ATOMS 3.11.2.1 Thermal and Photochemical Reactions involving No Other Species The thermal reactions of furans merit only brief mention. Ligularone (5) is isomerized to isoligularone (6) without a catalyst at 260 °C and diradical intermediates have been postulated (73TL3999). The double bond of furan can be forced to participate in electrocyclic
O
(6)
(5)
reactions. Thus the 2-methylbuta-l,3-dienyl ethers (7) of both furan-2-methanol (Scheme 1) and furan-3-methanol undergo thermal rearrangement, as does the vinyl ether of furan-2-methanol. The intermediate (8) undergoes both 1,3-hydrogen shift producing (9) and Cope rearrangement producing (10) (70HCA605). Gas phase pyrolysis of l-(2'furyl)buta-l,3-diene produces 4,5-dihydrobenzo[&]furan; there is no scrambling of deuterium when the 4,4-dideutero derivative is pyrolyzed and a mechanism involving trans-cis isomerization, thermally allowed disrotatory cyclization and 1,5-sigmatropic hydrogen shift has been proposed (77TL151). CHO
CHO
heat
CHO (7)
(9)
(8)
(10)
Scheme 1
The photorearrangement of furans has been extensively studied (B-80MI31100) and involves fission of the weaker C—O bond in the lowest excited state. The intermediate diradical recloses to a cyclopropane carbonyl derivative or to the original furan. The cyclopropane can sometimes be isolated but its fate on absorption of a further photon varies. Irradiation of 2,5-di-f-butylfuran (Scheme 2) in pentane yields (11; 3%), (13; 4%) and (16; 6%). The initial product is (12) which can open by photolysis of the 2,3-bond leading to (13) via the diradical (14), or by breaking of the 1,3-bond to yield (16) via hydrogen migration in the intermediate diradical (15). In the case of 2,3,5-tri-f-butylfuran (Scheme 3) the products are (21; 90%) and (20; 5%). The alternative modes of cleavage afford the intermediates (17) and (18) which close to the cyclopropenes (20) and (19). Cyclopropene (19) is photolabile and intramolecular hydrogen abstraction gives the diradical (22) which cyclizes to the ketone (21). In certain cases the intermediate cyclopropenes may be trapped; amines ultimately afford N- alkylpyrroles. Methanol traps the cyclopropene (24) from furan-2carbonitrile as a stereoisomeric mixture of cyclopropenes (25; Scheme 4). In the case of
Furans and their Benzo Derivatives', (ii) Reactivity
V
%.
o
O
iBu1
Bu1 O (12)
(11)
Bu 1
Bu l
601
O 1
Bu
o
o
(13)
(14)
Bu1
(15)
(16)
Scheme 2 Bu1
Bu1
Bu1
Bu l / : . ;>Bu
Bu1
o
O
O Bu1 (19)
(18)
Bu1
Bu1
/ARM1
Bu1
Bu1
o
(20) (22)
(21) Scheme 3
o
hv MeOH
V
CN"
OHC
L CHO (24) Scheme 4
(23)
V
OMe
CN (25)
2-nitrofuran the initial product is thought to be the nitrite (26) which on thermolysis or photolysis yields nitric oxide and furyloxyl radical (27). Recombination then affords the hydroxyiminolactone (28; 79%) (Scheme 5) <72JCS(P1)2527>. NOH hv
NO,
Me2CO
+ NO
ONO (27)
Scheme 5
The cyclophane (29) on irradiation with a low-pressure mercury lamp at 20 °C or —190 °C undergoes opening to aflEord relatively stable solutions of (30; Scheme 6) which was detected by its UV spectrum (76AG(E)442>.
O O
"-Q-
(29)
(30) Scheme 6
3.11.2.2 Reactions with Electrophiles 3.11.2.2,1 Reactivity and directive effects Furan exhibits great reactivity towards electrophiles (71PMH(4)55, 71AHC(13)235> and the conditions under which these reactions are carried out require to be carefully controlled.
602
Furans and their Benzo Derivatives: (//) Reactivity
Furans substituted with electron releasing groups usually undergo polymerization with mineral acids due to facile protonation at the 2-position. Aluminum chloride also causes resiniflcation of furan but benzo[& ]furan and compounds with electron withdrawing groups are, however, more stable. The reversion to type so characteristic of the electrophilic substitution of benzene is by no means prevalent in the chemistry of furan and benzo[& ]furan and many apparent electrophilic substitutions in reality proceed by addition. The reactivity order of five-membered heterocycles has already been treated (Section 3.02.2.3) and it can merely be noted that furan lies between pyrrole and thiophene. Furan is estimated to be 4.8-3.3 x 102 times more reactive than benzo[&]furan in a number of acylation reactions. Substitution at the 2- or 5-positions in furan is paramount unless these positions are blocked and this position is estimated to be 6 x 1011 times more reactive than a benzene position. The a : /3 ratios for acylation of furan under various conditions are in the range 8 x 102 to 6.8 x 103 but the 3- or 4-position is still much more reactive than a benzene position. The isomer distribution in the acetylation of benzo[£ ]furan has been studied under a range of conditions and here the preference for 2-substitution is less marked since the 2:3 ratio varies between 1.7 to 8.4 and there is a significant temperature dependence, lower values being obtained at higher temperature. The reactivity of furan and benzo[6 ]furan has also been considered from the standpoint of linear free energy relationships and transmission effects. Empirical correlations can readily be made on the directing effects of substituents from the large body of data available. Furans with a + / or a —I/+M substituent at the 2-position invariably give 5-substituted products. For a —I/—M substituent at the 2-position the substituent mesomeric effect will deactivate the 5-position but this is usually outweighed by the powerful orientational effect of the ring oxygen and 5-substitution usually ensues in the absence of Lewis acids. Lewis acids enhance the —M effect of a 2-carbonyl substituent (the 'swamping catalyst effect') and electrophilic substitution then occurs at the 4-position although 4,5-disubstituted compounds are also isolated (68AG(E)519). For a + / substituent at the 3-position the 2-position is more activated by electronic effects than the 5-position but the 5-position is unhindered and mixtures of 2- and 5-substituted isomers are usually obtained, the composition of which depends on the size of both the 3-substituent and the electrophile. A —I/—M substituent at the 3-position results in substitution at the 5-position since the effects of the oxygen atom and the substituent are in alliance. For disubstituted compounds the position of attack may be deduced from the known directive effects of the substituents and the heteroatom. In the case of 2,5-disubstituted compounds, electrophiles attack the position adjacent to the more electron releasing substituent. In such cases the preference for a-attack is so strong that ipso substitution with the expulsion of a group such as halogen or carboxy may occur. Such reactions are particularly common in nitrations as in those of 2,5-diiodofuran and 5-methylfuran-2-carboxylic acid. The prediction of the outcome of the electrophilic substitution of a benzo[6 ]furan is less certain since fewer data are available. It is true, however, that an electron releasing 2-substituent will usually direct the electrophile to the 3-position and conversely an electron releasing 3-substituent will direct the electrophile to the 2-position. Electron withdrawing substituents at the 2-position result in substitution in the benzene ring (homosubstitution): thus bromination and chloromethylation of esters of benzo[6]furan-2-carboxylic acid occur at the 5-position; nitration similarly gives 5-substitution as well as some at the 7-position. Strongly electron releasing groups in the benzene ring usually result in homosubstitution at a position ortho or para to the substituent whilst with electron withdrawing groups or alkyl groups in the benzene ring heterosubstitution at the 2-position often ensues. 3.11.2.2.2 Protonation Both furans and, less readily so, benzo[& ]furans are prone to undergo resinification on exposure to strong acids unless there is an electron withdrawing group at the 2-position. 2,5-Dialkylfurans are more stable. The rates for acid-catalyzed protodetritiation, protodedeuteration, deuterodeprotonation and deuterodetritiation for the 5-position of 2methylfuran have been determined. The isotope effects and activation parameters thus obtained are typical of an A-5 E 2 mechanism (73ACS153). It is now generally accepted that furan undergoes protonation at the 2-position rather than on oxygen and ab initio SCF calculations support this view. The protonation of 2,5-di-f-butylfuran occurs at a 2-position
Furans and their Benzo Derivatives: (ii) Reactivity
603
in concentrated sulfuric acid and the pKa has been estimated at -10.01, and by further approximations that of furan as —13± 1 (76T1767). Protonation can lead to ring opening but, for furan and 2-methylfuran, treatment with perchloric acid in aqueous DMSO leads only to polymerization and no hydrolytic cleavage. Anhydrous methanolic hydrogen chloride, however, affords monomeric ring opened products. 2,5-Dimethylfuran with perchloric acid in aqueous DMSO gives acetonylacetone at a rate approximating to that of its decomposition. Since this rate is 102 times slower than that for hydrogen exchange at an a-position it has been suggested that the cleavage is initiated by /3-protonation as in Scheme 7. These hydrolytic cleavages have been extensively exploited in synthesis and two examples are shown in Scheme 8.2-Methylfuran on treatment with phosphoric acid undergoes cationic oligomerization to produce tetramers, pentamers, hexamers and heptamers. The structure of the major tetramer (38%) and a plausible mode of formation are shown in Scheme 9 (74BCJ1467). Me _
Me O
OH
// MC
HO ( f 'Me
O O
Scheme 7
o , AcOH, H + ; ii, HOCH2CH2OH, H+ Scheme 8
i, 2-methylfuran, - H + ; ii, H + Scheme 9
3.11.2.2.3 Nitration Nitration of furans is best achieved with a mixture of fuming nitric acid and acetic anhydride, usually at -10 to -20 °C. A wide range of compounds has been nitrated by this technique and even a,/3-unsaturated aldehyde, ketone and carboxylic ester substituents will tolerate this reaction. More vigorous conditions may be applied to compounds with electron withdrawing groups; thus 2-bromo-5-nitrofuran on treatment in dichloromethane with concentrated nitric and sulfuric acids yields 2-bromo-3,5-dinitrofuran (14%) (79JHC477). 2-Nitrofuran may be nitrated with 70% nitric acid and then affords 2,5dinitrofuran (67%) and 2,4-dinitrofuran (5%) (78JOC4303). The acetyl nitrate method usually proceeds by an addition-elimination mechanism and in certain cases the addition products may be isolated and require treatment with a base such as pyridine to effect elimination of acetic acid. From the nitration of furan the intermediate addition product (31) may be isolated. Similar intermediates (32) and (33) are involved in the nitration of furan-2-carbaldehyde and its diacetate, and also in the nitration of methyl furan-2-carboxylate (76KGS601). Nitration of furan-2-methanol yields the nitro nitrate (34). Expulsion of substituents is common in nitration, as in that of 5-bromofuran-2-carboxylic acid which
604
Furans and their Benzo Derivatives: (//) Reactivity AcO -\NO2 / \\ X O 2 N ^ )>CH(OAc)2 2 O \ XT (31) R = H (33) (32) R = CH(OAc)2
// \\ O2N^ O (34)
yields 5-bromo-2-nitrofuran (47%), isolated by pouring on ice, ether extraction and steam distillation. Furan has been nitrated with nitronium tetrafluoroborate in poor yield (14%). Nitration of benzo[£ ]furan may be achieved with nitric acid in acetic acid and affords the 2-nitro compound, although nitrogen dioxide in benzene is reported to give the 3-nitro compound. 2-Phenylbenzo[£]furan with nitric acid in acetic acid yields the 3- and 6-nitro compounds. Treatment of 2-bromobenzo[£]furan with nitric acid and sodium nitrite yields 2-nitrobenzo[6]furan. The only electrophilic substitution reported with a benzo[c ]furan is nitration of l,3-diphenylbenzo[c]furan with sodium nitrate and sulfuric acid, and this occurs on a phenyl group. 3.11.2.2.4 Sulfonation Furan is resinified by sulfuric acid but it can be sulfonated with the complex of sulfur trioxide with pyridine or dioxane. Depending on conditions the 2-sulfonic or the 2,5disulfonic acid may be obtained. Furan-2-carboxylic acid can be sulfonated with oleum. Benzo[£]furan is polymerized by sulfuric acid. The 2-sulfonic acid has been obtained by oxidation of the sulfinic acid available in turn by treatment of the lithio derivative with sulfur dioxide. Benzo[£]furan with the sulfur trioxide-pyridine complex allegedly affords the 3-sulfonic acid. 3.11.2.2.5 Halogenation 2-Bromofuran is best obtained by treatment of furan with dioxane dibromide at —5 °C. It may also be obtained in 39% yield by NBS bromination in boiling benzene in the presence of toluene-p-sulfonic acid. 3-Methylfuran has also been brominated with NBS but in the presence of the radical initiator 2,2'-azobisisobutyronitrile the reaction can be controlled to give the 2-bromo (33%), the 2,5-dibromo (38%) or the 2,4,5-tribromo compound (64JOC1991). On the other hand, methyl 2-methylfuran-3-carboxylate and methyl 3-methylfuran-2-carboxylate yield the expected side-chain products under these conditions (70BSF1445). Furan with NBS and triethylamine and a catalytic amount of mercury(II) chloride in chloroform at ambient temperature yields 5,5'-dibromo-2,2'-bifuryl (40%) (79CB1493). It is tempting to speculate on the intermediacy of a furylmercury derivative. The bromination of furan with bromine at —50 °C in carbon disulflde has been studied by H NMR spectroscopy. Addition occurs and cis- and trans- 2,5-dibromo -2,5 -dihydrof uran and trans- 2,3-dibromo-2,3-dihydrofuran were detected. On warming, 2-bromofuran is obtained. Whether the addition products are genuine intermediates or the result of side equilibria is not known. Bromination of furan in methanol at - 1 0 °C in the presence of a base gives 2,5-dimethoxy-2,5-dihydrofuran (47%) via the 1,4-addition of bromine to the diene system. Bromination of furans with electron withdrawing groups at the 2-position proceeds by an electrophilic substitution mechanism and generally yields the 5-bromo compounds (Scheme 10). In the presence of aluminum chloride the swamping catalyst effect operates. With bromine and aluminum chloride, methyl furan-2-carboxylate affords starting material, the 5-bromo compound (35) and the 4,5-dibromo compounds (36). In the presence of solvents, Br/Cl exchange occurs and compounds (37) and (38) also result. Bromination of 3-acetylfuran in the presence of excess aluminum chloride gives products of 5-substitution (Scheme 11) (75BSF2334).
O'
O'
XT
*
(60%) Br2, S, quinol, C1CH2CH2C1; ii, Br2 C1CH2CH2C1, 20 °C Scheme 10
XT
CO2Me
(75%)
Furans and theirBenzo Derivatives: (ii) Reactivity
605
Br
o
CO, Me
Br
O
Br
o
CO, Me O (36) 4
(35) 3 Br CO, Me
(35)
+
(36) +
CI
O (37)
CO,Me
1
C K'/
>CO 2 Me O (38) 1
Ac 111
O
O 1
i, 1 mol Br2, 2.5 mol A1C13; ii, 12 mol C1CH2CH2C1; iii, 1.15 mol Br2, 2.5 mol A1C13, CH2C12, heat Scheme 11
Chlorination of furan at - 4 0 °C with 1.6 mol of chlorine affords 2-chloro- (64%), 2,5-dichloro- (29%) and 2,3,5-trichloro-furan (7%). By use of more chlorine the addition product 2,2,3,4,5,5-hexachloro-2,5-dihydrofuran and tetrachlorofuran are obtained. The chlorination of methyl furan-2-carboxylate obeys second order kinetics, when the 5-chloro compound is the only product. The behaviour of benzo[6 ]furan on bromination is complex although it probably involves a Wheland intermediate of the usual type for attack at C-2 which, depending on temperature, undergoes attack by bromide at C-3 to give the trans addition product, attack at the bromine atom to produce benzo[6 ]furan, or attack at the 2-H to give the 2-substitution product (76JCS(P2)266>. Thus at low temperature (-40 °C) addition to the furanoid double bond occurs and the trans-dibromo compound results; this is stable at room temperature. On gentle heating it is in equilibrium with benzo[6 ]furan but on heating in acetic acid it irreversibly gives the 2-bromo compound. Heating the addition product with bases, however, yields the 3-bromo compound. The behaviour of 2-methyl- and 3-methyl-benzo[£]furan is similar. In the case of the former, the addition product is obtained at low temperature; it is stable for 1 h at — 30 °C but rapidly gives the 3-bromo compound at 25 °C. In the latter case the addition product is less stable and gives the 2-bromo compound after 15 min at —40 °C. The bromination of 2,3-dimethylbenzo|7> ]furan, an example of 'non-conventional aromatic substitution', also gives addition at —40 °C but after 45 min the products are the side-chain bromo compounds (40) and (42) in the ratio 3.5:1, formed via the intermediates (39) and (41) (Scheme 12). Bromination of 2-phenylbenzo[6]furan results in the 3-bromo compound which on further bromination affords the 3,6-dibromo compound. CH2Br CH,Br Br
(42)
Scheme 12
Chlorination of benzo[6 ]furan in ether, acetic acid or carbon tetrachloride at 0 or 25 °C results in a 1:1 mixture of cis- and trans- 2,3-dichloro-2,3-dihydrobenzo[^]furans, although with iodobenzene dichloride as chlorinating agent more of the trans isomer results. Both isomers may be converted into 3-chlorobenzo[6]furan with ethanolic ethoxide although, as expected, the cis isomer reacts much faster. On heating in acetic acid at 100 °C the trans isomer affords 2-chlorobenzo[£]furan whilst the cis compound undergoes isomerization (77JHC359). On chlorination of 2-acetyl-3-acetylaminobenzo[6]furan, ipso substitution occurs and the acetyl group is lost from the 2-position (78JCS(P1)419). Trifluorofluorooxymethane reacts with benzo[£ ]furan to give electrophilic addition products (Scheme 13) <77JCS(Pl)2604>.
606
Furans and their Benzo Derivatives: (//) Reactivity OCE
OCF,
i, CF3OF, freon, -78 °C Scheme 13
3.11.2.2.6 Acylation Formylation of furans is best carried out by the Vilsmeier-Haack method at low temperature. Acylations are best performed with acid anhydrides and mild catalysts such as boron trifluoride etherate or phosphoric acid. Acetylation with acetyl p- toluenesulfonate is particularly effective (76H(4)lO2l), whilst trifluoroacetylation requires no catalyst. The competition method has been used in a study of the acetylation with tin (IV) chloride and acetic anhydride of 2-(4-X-phenyl)-5-methylfurans in 1,2-dichloroethane. The rates of reaction were correlated with the Brown cr+ parameter. A similar study was made with the rates of trifluoroacetylation of 2-arylfurans (73BSF1760). Compounds with an ester substituent at the 2-position usually afford the 5-acylated product with a mild catalyst like boron trifluoride etherate but with tin(IV) chloride both 4- and 5-substitution occur, presumably since the reacting species is complexed with the catalyst (Scheme 14) (66JOC4252,79JOC3420). Further transformations of the initial products are also common with the more vigorous catalysts (Scheme 15) (75JCS(P1)2O69, 72ACS2907). The 2:5 ratio in the acylation of 3methylfuran is dependent on the electrophile. Acetylation with acetic anhydride and phosphoric acid gives a 1.9:1 ratio; propionylation gives a 2.3:1 ratio; whilst VilsmeierHaack formylation gives a 14.4:1 ratio (71T3323). Me
Me MeO,C
'/ W o
MeO,C '/
o
COC 4 H 9
20%
o
COC5Hn
MeO2C
'I
\±
MeO,C
O
MeOX
o
O
1
1.6
(C4H9CO)2O, BF3 Et 2 O, PhH, 25-65 °C; ii, (C 5 HnCO) 2 O, SnCl4, PhH, 25 °C Scheme 14
H W CO, Me
MeO,C
O
72%
O
OH 11
o
CO, Me
MeO,C
41%
i, 2 mol Ac2O, 2 mol SnCl4, 0-25 °C; ii, PrCOCl, FeCl3 Scheme 15
Benzo[£ ]furan undergoes formylation by the Vilsmeier-Haack method and acylation using acid anhydrides and phosphoric acid or tin(IV) chloride as catalysts. 2-Alkylbenzo[£ ]furans undergo acylation at the 3-position with aliphatic acid chlorides and tin(IV) chloride, although many aromatic acid chlorides also afford 4- and 6-substituted products (77JHC861). 2,3-Dimethylbenzo[&]furan on acetylation gives some 2-acetyl-3ethylbenzo[6]furan by 'non-conventional substitution', as well as the expected 4- and 6-products (78CC597). Electron releasing groups on the benzene ring usually result in homoacylation; thus 4,6-dimethoxybenzo[6]furan undergoes acylation in the 7-position.
Furans and their Benzo Derivatives: (//) Reactivity
607
3.11.2.2.7 Alkylation Alkylation of furan may be achieved with alkenes and mild catalysts, e.g. phosphoric acid or boron trifluoride etherate, and 2-substituted products result. f-Butylation of furan with isobutene and phosphoric acid on kiesefguhr results in a mixture of the 2- and 3-substituted compounds the proportions of which are temperature dependent. 2,5-Di-fbutylfuran is available by alkylation of 2-chloromercuriofuran with ^-butyl bromide but is usually prepared by ring synthesis. f-Butylation of 2,5-di-^-butylfuran results in the 2,3,5trisubstituted compound but 5-f-butyl-2,3-dimethylfuran yields the dihydro compound (43) as a result of minimization of steric hindrance. Similarly, f-butylation of 3-f-butyl-2,5dimethylfuran affords (44; Scheme 16) (75TL3619). The isopropylation of furan-2-carbaldehyde with isopropyl chloride in carbon disulfide using an excess of aluminum chloride at room temperature affords a mixture of products which contains much 4-isopropylated compound as well as 3,5-disubstituted and trisubstituted products. The 5-isopropyl compound was stable under the reaction conditions; doubtless the isopropylation at the 4position is a result of the complexing of the substrate with aluminum chloride. Similar results have also been reported for the isopropylation of 2-acetylfuran (76CCC78) and methyl furan-2-carboxylate (70CJC1550). Furans can be allylated with allyl iodides and silver trifluoroacetate in liquid sulfur dioxide. The reaction may be an electrophilic substitution although a mechanism involving a cycloaddition to produce a bicyclic cation cannot be precluded (Scheme 17) (69JCS(C)1456). Furans, usually with electronegative groups at the a-position, can be chloromethylated with ease. 2,5-Diphenylfuran can be bischloromethylated in the /?-positions. The Mannich reaction also works well with furans. Me
But
Me
Bul
II (43) i, Bu'Cl, A1C13, CS2, 0 °C Scheme 16 £H 2 OH
CH,OH
CH,OH
7 \> o 5:1 i, CH 2 =CHCH 2 I, CF3CO2Ag, SO2(1) Scheme 17
Benzo[&]furan may be alkylated with t- butyl chloride and zinc chloride, the products being the 2- and 3-substituted compounds in the ratio 1:2. Benzo[£]furan is chloromethylated at the 2-position. 2-Methyl- and 2-phenyl-benzo[£]furan are chloromethylated in the 3-position. 3.11.2.2.8 Reactions with aldehydes and ketones Furans with a free a-position are susceptible to electrophilic attack by protonated aldehydes and ketones. The yields in these reactions are often poor because of the R
R (45)
R
\_J (46)
R
608
Furans and their Benzo Derivatives: {ii) Reactivity
resinification of the furan but methyl furan-2-carboxylate gives good yields of compounds of type (45) with both aliphatic and aromatic aldehydes in concentrated sulfuric acid (72ACS1018). Trimers are sometimes isolated but with ketones tetramerization often results and the tetraoxaquaterenes of type (46) are obtained, although in poor yield. In the case of acetone the yield of quaterene shows a 'template effect' and may be raised to 45% in the presence of lithium per chlorate. Furans are also susceptible to electrophilic attack by 2-acetyl-l,4-benzoquinone and 2-furylbenzoquinones are usually obtained by a subsequent redox reaction.
3.11.2.2.9 Mercuration Furan can be sequentially mercurated with mercury(II) chloride to give mono-, di- and tri-mercuriochlorides. The tetrakis(mercurioacetate) is available by heating furan with mercury(II) acetate in acetic acid. Alkylfurans readily give chloromercurio derivatives on treatment with mercury(II) chloride and sodium acetate in aqueous ethanol. The a-positions, if vacant, are always attacked in preference to )8-positions, which, however, are attacked if the furan is 2,5-disubstituted (55RTC763). Carboxy groups are readily displaced from a-positions in preference to (3-positions; thus sodium furan-2,4-dicarboxylate is readily converted into 4-carboxy-2-furylmercury(II) chloride. Ester substituents survive. Furans substituted with electron withdrawing groups are more difficult to mercurate but this may usually be achieved under forcing conditions. Thus treatment of sodium 5-nitrofuran-2carboxylate with aqueous mercury(II) chloride at 155 °C yields 5-nitro-2-furylmercury(II) chloride. Treatment of furan-2-carboxylic acid with aqueous mercury(II) acetate gives a mixed salt of the acid which on pyrolysis undergoes rearrangement predominantly to the 3-furylmercuric acetate, presumably via a cyclic transition state. 2-Chloromercuriofuran undergoes protodemercuration 26.7 times faster than the 3-isomer (65AJC1513).
3.11.2.2.10 Reactions with diazonium salts Furan, on reaction with 2,4-dinitrobenzenediazonium sulfate in aqueous acetic acid, undergoes ring opening and affords (47); similar results are obtained with 2- and 3-
OH O
1
I'
CHO O
NHNHAr
N=NAr_j
>T
O
NHAr (47) 72% NO,
N=NAr
//w
Me O
\—/
NNH/ OH ^
"O (48)
—^ c
\*^2 '
(49)
Me
~N' Ar (50)
i, AcOH, H2O, 15 min; ii, AcOH, H2O, 50 h; iii, HC1, H2O, EtOH Scheme 18
Furans and their Benzo Derivatives: (//) Reactivity
609
methylfuran. Whether the reaction involves an electrophilic substitution or a cycloaddition is not known. Under the same conditions, 2,5-dimethylfuran affords the azo compound (48). Similar results are given by 2,5-dimethylfuran and 4-nitrobenzenediazonium chloride, but in aqueous ethanol in the presence of sodium acetate, (49) is obtained which may be converted into the pyrazole (50) by action of hydrochloric acid (Scheme 18). Benzo[£]furan and 2-methylbenzo[£]furan are arylated at the 3-position by 2,4-dinitrobenzenediazonium sulfate in aqueous acetic acid (78JCS(Pl)40l). Reactions of the Gomberg type have also been described with furan. The highly nucleophilic 3,4-dimethoxyfuran, when treated with arene diazonium salts in aqueous pyridine, undergoes 1,4-addition to afford pyridinium salts (51). The pyridine is easily displaced by nucleophiles including alcohols and phenols, thereby affording 5-alkoxy or 5-phenoxy derivatives of 3,4-dimethoxyfuran-2(5//)-one (52; Scheme 19) (78HCA1033). MeO OMe O
MeO
)
(' \
/
OMe
MeO
OMe
iL
N—C
>=NNHAr - - • ROCX X>=NNHAr OX ~ (51) (52)
i, ArNzCF, C6H5N, H 3 O + ; ii, ROH Scheme 19
3.11.2.3 Reactions with Oxidants The furan nucleus, being electron rich, is particularly sensitive to oxidation and most reactions involve 1,4-addition of the oxidant to the diene system. Photooxidation is discussed later (Section 3.11.2.7.2). II
\\
>CHNHA
i,ii
/ — \
> MeO<
OMe
Y
96% CH2NHAc
MeO,C. f=\
Bu1 97%
MeO
u
OMe Me
O
^>CH 2CH2CH(OH)Me - ^ ^ MeOC X X
O^
X
76%
V>
i, Pt anode; ii, MeOH, NH4Br; iii, MeOH, H 2 SO 4 ; iv, C anode, MeOH, NH4Br Scheme 20
The anodic oxidation of furans is particularly important and in alcohols it gives rise to mixtures of cis- and frans-2,5-dialkoxy-2,5-dihydrofurans and is known as the ClausonKaas reaction. These compounds are valuable intermediates in synthesis and the reaction tolerates a wide range of substituents and can even be diverted to give intramolecular products (Scheme 20) (68CRV449). The method gives better results than the chemical method in which the furan is treated with bromine and methanol in the presence of a weak base (Scheme 21) (60MI31100). The mechanism (Scheme 22) of the anodic oxidation involves formation of a radical cation which is captured by a nucleophile, yielding a radical; further oxidation yields a cation, which is in turn captured. The nucleophile in the Clauson-Kaas reaction is methanol; in the case of 2,5-dimethylfuran in the presence of sodium methoxide a small amount of side-chain methoxylation occurs by the alternative pathway shown in Scheme 22 and some 2,5-bismethoxymethylfuran may be isolated (69JOC1018). With 2,5dimethylfuran in methanolic sodium cyanide the first nucleophilic attack is that of cyanide followed by methanol so that the major pathway is that of cyanomethoxylation and cisand trans- 2- cyano-5-methoxy-2,5-dimethyl-2,5-dihydrofuran result. Some of the dimethoxy products are also produced as well as traces of 2-methoxymethyl-5-methylfuran and 2,5-bismethoxymethylfuran (7UOC1523). In acetonitrile, in the presence of saturated aqueous sodium hydrogen carbonate with lithium fluoroborate as supporting electrolyte,
Furans and their Benzo Derivatives', (ii) Reactivity
610 H \
-HBr
-HBr
o
^ '
x
MeO O i, Br2, MeOH, 2 mol KOAc Scheme 21 e
/, + . «\
w
•
o
Nu
R%A
RC - . ^ > R -ZH-4-
O
O
Nu
°
4-MeOH
Br
Nu
Nu
H
•
MeO
"^F-
R
Nu
>O
/
^ ^ . ^
O
\
OMe
>O
Nu
R = Me -e
O
o
Nu
O'
O
VH 2 Nu
*" NuH2C7/
O
Scheme 22 MeO2CH2C
CH 2 CO 2 Me
MeO 2 CH 2 C McCN,NaHCO
o
CH 2 CO 2 Me
o
86%
Scheme 23
7 o
H
LTA AcOH
O
AcO
Pb(OAc)
Pb(OAc)
O
Scheme 24
3,4-disubstituted furans undergo anodic oxidation to cis- and toms-2,5-dihydroxy-2,5dihydrofurans which may be oxidized by Jones reagent to maleic anhydrides (Scheme 23) (75JOC122). Furan undergoes anodic oxidation in acetic acid containing sodium acetate to supply cis- and trans- 2,5- bisacetoxy-2,5-dihydrofuran. This reaction can also be achieved with LTA in acetic acid (Scheme 24) (68JCS(C)969>. With 2-alkyl- and 2,5-dialkyl-furans, products of side-chain acetoxylation result from both these methods. Thus with LTA 2-methylfuran gives 2-(bisacetoxymethyl)furan and in the electrolytic method this is accompanied by 2-acetoxymethylfuran. Treatment of 2-arylfurans with ruthenium tetroxide leads to radical cations which form purple solutions of a charge transfer complex with the reagent. Oxidation of 2-arylfurans in a two-phase system with ruthenium tetroxide and aqueous hypochlorite yields products whose formation can be interpreted in terms of the radical cation intermediate (76CC890). On treatment of furan at low temperature with hydrogen peroxide the peroxide (53) is obtained which may be partially hydrogenated to male aldehyde. 2,5-Dimethylfuran with acidic hydrogen peroxide yields the hydroperoxide (54) and the cyclic peroxides (55) and (56); mechanisms have been proposed. Ozonolysis of furan at — 60 °C in chloroform with reductive work up affords glyoxal and formic acid. Methylfurans behave similarly; thus 2,3,4-trimethylfuran affords methylglyoxal, dimethylglyoxal, formic acid and acetic acid. Me
OH
OOH
O I
o
I
OOH
HOO
OH (53)
Me
X Me
(54)
OOH (55)
OOH I O
Me
OOH (56)
(57)
Pyridinium chlorochromate in dichloromethane reacts with furans to give a range of products, but they are all formed by 1,4-electrophilic attack of chlorochromate on the furan ring; the fate of the resultant intermediate (57) by heterolytic cleavage of the Cr—O bond depends on the substituents at the a-positions of the substrate. 2,5-Dialkylfurans yield a, j8-unsaturated-y-dicarbonyl compounds, 5-methyl-2-furylcarbinols yield pyran derivatives, and 5-bromo-2-furylcarbinols yield 5-hydroxyfuran-2(5//)-ones (Scheme 25) (80T661).
Furans and their Benzo Derivatives: (ii) Reactivity
611 O
n w Me
CH(OH)Me
o
HO
X
o
O OH
OH
i, pyridinium chlorochromate, CH2C12 Scheme 25
The furanoid ring in benzo[£ ]furan is susceptible to attack by oxidants. Permanganate and chromic acid give derivatives of 2-hydroxybenzoic acid with compounds unsubstituted at the 3-position, but compounds with a 3-methyl or a 3-aryl substituent give derivatives of 2-hydroxyacetophenone or 2-hydroxybenzophenone. Ozonolysis of benzo[£ ]furan affords 2-hydroxybenzoic acid, 2-hydroxybenzaldehyde and some catechol produced via its diformate. Before the advent of NMR spectroscopy these methods were used in structural elucidation of benzof uranoid natural products, as in the case of O- methyleuparin (Scheme 26).
11
H
Ac OH
i, O 3 , CHC13; ii, KMnO4, H 2 O, Me2CO Scheme 26
1,3-Diphenylbenzo[c]furan is attacked by chromic acid, permanganate, ferricyanide, per acids and LTA, yielding 1,2-dibenzoylbenzene.
3.11.2.4 Reactions with Nucleophiles Nuclear carbanions are usually generated from furans by proton/lithium exchange or by halogen/lithium exchange, both with butyllithium (Section 3.11.3.9). The rate of exchange of deuterium for protium has been studied for fur an and some alkylfurans in DMSO with potassium f-butoxide as base. Exchange at a 2-position is 600 times faster than at a 3-position, but an alkyl group at the 3- or 5-position retards the rate by a factor of 10 (66KGS643). The thermodynamic acidity of benzo[£]furan has been determined in cyclohexylamine with cesium as gegenion. It was found by comparison of benzo[£ ]furan with benzo[6 ]thiophene that oxygen enhances the thermodynamic acidity more than sulfur, although the kinetic data for furan and thiophene surprisingly indicate the reverse (73JA6273). With an activating group present, as in furan-2-carboxylic acid, carbonate ion will catalyze H / D exchange and NaOD in boiling deuterium oxide will exchange all the nuclear positions. A mechanism involving nucleophilic addition rather than proton abstraction has been proposed (Scheme 27) (73JCS(Pl)20l). Furan-d 4 is then available by mercurationdeuterodemercuration. D(P-D D
D-°bD
OD
CO Scheme 27
D
ol >co2
612
Furans and their Benzo Derivatives: (ii) Reactivity
Most studies of nucleophilic substitution of furans have been made with a nucleofuge at the 2-position activated by a —M group at the 5-position. Reports of displacements from the 3-position are rare but 3-methoxyfuran is available from the iodo compound by reaction with methanolic sodium methoxide in presence of copper(II) oxide, and bromide can be displaced by azide from 3-bromofuran-2-carbaldehyde (75ACS(B)224). Early work indicated that 2-bromo- and 2-chloro-furan react with piperidine 10 times faster than the corresponding halobenzenes. No evidence for the intermediacy of furynes has ever been adduced. Mechanistic studies on the displacement of a nitro group from 2,5-dinitrofuran with piperidine and the anion of toluene-4-thiol have been carried out in acetonitrile and methanol respectively. The furan reacts some 106 times faster than the benzene analogue and is also 10 3 -10 times faster than l-methyl-2,5-dinitropyrrole in these 5NAr reactions (77JOC3550). Similar studies have been carried out for the displacement by secondary amines of 5-substituents in 2-furfurylidenemalononitriles and the nucleofugal ability is in the order: NO 2 > Br > PhSO2 > PhS (79CCC2417). The addition of methoxide ion to 2-nitrofuran in methanol or DMSO provides a deep red solution of the Meisenheimer adduct. The NMR spectrum and the rate and equilibrium constant for the formation of the adduct have been studied. Similar adducts are formed at a faster rate from 2,4-dinitrofuran and 2-nitrofuran-4carbonitrile (78JOC4303). The outcome of treating 2-nitrofuran with methoxide in methanol is ring fission and monomethyl fumarate and methyl fumaraldehydate are obtained presumably by way of a Nef reaction. Methyl 5-nitrofuran-2-carboxylate suffers a similar fission (58CA(52)16329>.
Soviet workers have suggested a mechanism other than SNAr for the displacement of chloride from 2-chloro-5-nitrofuran by potassium iodide in acetic acid or by sodium sulfide in water, and for the displacement of bromide by iodide in 2-bromofurans with CHO, COMe, CH2CHCOPh, CH2CHNO2 and NO 2 as 5-substituents. It is suggested that a reversible electron transfer to the furan occurs, resulting in a radical anion. This then expels a halide to form a furyl radical which leads to the products (76KGS1601). 5-Bromofuran-2carboxylates will react with methoxide and phenoxide to afford 5-methoxy- and 5-phenoxysubstituted compounds. Hydrolysis and decarboxylation of the former supplies 2methoxyfuran (56JOC516). The nitro group can also be displaced from 5-nitrofuran-2carbaldehydes by aryloxides (80CPB2846). Other nucleophiles which are effective in displacing the nitro group from this compound are azide, sulfide, sulfinate and xanthate. Enamines and amines, however, react at the aldehyde site (72LA(761)13O). On steam distillation with concentrated hydrochloric or hydrobromic acid, 5-nitrofuran-2-carbaldehyde furnishes the corresponding 5-halofuran-2-carbaldehyde (20%); doubtless protonation of the carbonyl group assists this transformation (73JHC385). Lithium fluoride will displace bromide from 5-bromofuran-2-carbaldehyde in DMF at 100 °C. A number of typical nucleophilic substitutions are shown in Scheme 28. Br
Q
CHO
N
II % CHO O
W)
45o/o
CHO 95%
PhS
43%
58%
74%
i, NaN3, DMSO, 60 °C; ii, Nal, AcOH, 20 min; Hi, NaN3, DMSO, 20 °C, 2 h; iv, PhSNa, MeOH, 20 °C; v, Na2S, H 2 O, 2 h Scheme 28
The reaction of furans with ammonia and its derivatives is of considerable synthetic utility (B-73MI31100). Substituted furan-2-carbaldehydes and 2-acylfurans on heating with ammonia and ammonium salts, often under pressure, yield 3-hydroxypyridines. The mechanism of this reaction is thought to involve nucleophilic attack of ammonia at the 2-position. Ring opening affords an amino aldehyde or ketone and thence, by reclosure, the 3-hydroxypyridine (Scheme 29). A wide range of substitutents is tolerated. Primary amines with furan-2-carbaldehydes yield N- substituted pyrroles, the closure of the intermediate
613
Furans and their Benzo Derivatives: (//) Reactivity
aminocarbonyl compound thus taking the alternative course. Attack of ammonia at the 2-position of 3-acylfurans affords 3-acylpyrroles; primary amines supply the TV-substituted analogues (74JHC905). When furan-2-carbaldehydes are treated with hydroxylamine a 2,3dihydroxypyridine is obtained and the carboxamide formed via the oxime (Scheme 30) is thought to be an intermediate. Similarly, when heated with ammonia in the presence of ammonium chloride at 240 °C in HMPT or acetonitrile, furan-2-carboxamide affords 2-amino-3-hydroxypyridines; furan-2-carboxylic acid and its esters give the same products by way of the amide (77JHC203). Hydrazine attacks 3-benzoyl-2,5-dimethylfuran to yield a pyrazole (77BSF1235). H
iOH
HICV^J
H2N O
R'
Scheme 29
^o
o
o Scheme 30
The result of treating 5-bromofuran-2-carbaldehyde with aniline is more complex and a salt resulting from anil formation and bromide displacement is formed (70CB2992). Furans can be converted into N- alkylpyrroles by heating with primary amines and alumina. Similar thermal conversions of furans and benzo[6]furans to their sulfur analogues in the presence of alumina or other metal oxide catalysts and hydrogen sulfide are also known. 1,3-Diphenylbenzo[c]furan is converted into the thiophene by heating with phosphorus pentasulfide. The mechanism of these reactions is obscure. In accord with MO calculations (67BCJ1580), benzo[6]furans are attacked by a variety of nucleophiles at the 2-position. Hydroxide under drastic conditions affords (59) and (60), which are presumably formed by Cannizzaro reaction of the aldehyde (58; Scheme 31). Methylsulfinyl anion in DMSO at 70 °C followed by aqueous work up affords 2-ethynylphenol (66JOC248). With a —M group at the 3-position, nucleophilic attack at the 2-position is facilitated. 3-Benzoyl-2-ethylbenzo[Z»]furan with hydroxide affords products which can be rationalized by /?- diketonic fission of the intermediate (61), further transformations of which produce (62) and (63) (Scheme 32). With a nitrile at the 3-position a similar degradation takes place but an ester is not sufficiently electron withdrawing and hydrolysis ensues. Ammonia will attack the ketone (64) at the 2-position, producing the unstable /3-enaminoketone (65; Scheme 33). Other nucleophiles attack in a similar manner; thus hydroxylamine under certain conditions will afford oxazoles (66BSF1587). KOH, EtOH 200 °C
O
OH (
CH=CH(OH)
Scheme 31 COEt " I iCHCOPh
PhCO2H + (62)
Scheme 32
614
Furans and their Benzo Derivatives: (ii) Reactivity ,OH NH 2
//T Et iiiifM
(65)
COEt
Scheme 33
3.11.2.5 Reactions with Reducing Agents The catalytic hydrogenation of furans has been studied in great detail, particularly from a technological point of view by workers in eastern Europe. A review is available (63RCR307). Conditions have been denned that effect reduction of furans with and without hydrogenolysis. Hydrogenation with Adams catalyst in acetic acid will cause rupture of either the 1,5or the 1,2-bond. 2-Methylfuran affords 2-pentanol and furan-2-methanol affords 1,2pentanediol by rupture of the 1,5-bond; on the other hand, furan-2-carboxylic acid affords 5-hydroxypentanoic acid by cleavage of the 1,2-bond. Reduction of the furans to tetrahydrofurans may be achieved with palladium catalysts in either the vapour or the liquid phase and stereoisomeric mixtures result. Nickel catalysts give higher yields of cis- disubstituted tetrahydrofurans than palladium (67T215) and rhodium behaves similarly (76CB2628). Conjugated alkenylf urans may be reduced to alkylf urans by careful operation but diimide reduction has also been used (Scheme 34) (66HCA858). CH2)2CO2H 35%
47%
i, NH2NH2) Cu2+, O2 Scheme 34
Catalytic reduction of benzo[6]furan to 2,3-dihydrobenzo[6]furan can be achieved by using a palladium on carbon catalyst at 100 °C and moderate pressure. At higher temperatures and pressures, Raney nickel causes reduction of the benzenoid ring as well, whereas under similar conditions copper chromite leads to hydrogenolysis products including 2-ethylcyclohexanol. Hydrogenolysis can be avoided by using rhodium on alumina when the ds-perhydro compound is obtained. 3-Acetoxybenzo[Z>]furans afford 2,3-dihydrobenzofurans under fairly mild conditions (Scheme 35) (50JCS3202, 50JCS3206). Hydrogenation of 2-acetylbenzo[6]furan gives the secondary alcohol with platinum at moderate pressure whilst Raney nickel under similar conditions furnishes 2-(l-hydroxyethyl)-2,3-dihydrobenzo[6]furan. Benzo[6]furan-2-carboxylic acid is reduced by Raney nickel alloy and aqueous sodium hydroxide to 3-(2-hydroxyphenyl)propanoic acid, which lactonizes to the dihydrocoumarin. AcO
AcO^ Jj
\ 96%
86%
i, Pd/BaSO4, AcOH, H2, 25 °C; ii, 10% Pd/C, AcOH, 65 °C, H2 Scheme 35
l-Phenylbenzo[c]furan-3-carbonitrile and the corresponding carboxylic acid are catalytically reduced in a cis manner to the expected 1,3-dihydro compounds. 1,3-Diarylbenzo[c]furans are also reduced to phthalans with sodium amalgam. Ring opening is common in the alkali metal and liquid ammonia reduction of furans unless an anion stabilizing group is present, so most work has been done with derivatives of furancarboxylic acids. Treatment of furan-2-carboxylic acid with lithium and ammonia at -78 °C followed by rapid addition of ammonium chloride affords 2,5-dihydrofuran-2carboxylic acid (80%). Reductive alkylation similarly gives 2-alkyl-2,5-dihydrofuran-2carboxylic acids. This method has been used in a synthesis of rosefuran, the intermediate dihydrofuran (66) being converted into the product (67) by oxidative decarboxylation with
Furans and their Benzo Derivatives: (ii) Reactivity
615
LTA (Scheme 36) (76TL2079). 5-Alkylfuran-2-carboxylic acids on reduction in liquid ammonia with lithium and methanol supply cis- and fraws-5-alkyl-2,5-dihydrofuran-2carboxylic acids (71-85%) (75BCJ491). Furan-3-carboxylic acid has been reduced using sodium and liquid ammonia. With 2-propanol as proton source, 2,3-dihydrofuran-3carboxylic acid is obtained, but with methanol or ethanol, addition to the double bond occurs during work up (75BCJ1865). In the absence of any added proton source and with 4 mol of lithium, ring opening and further reduction occurs giving the lactone (68; Scheme 37) (76AJC2553). Some asymmetric induction has been obtained in the sodium and liquid ammonia reduction of both furan-2- and -3-carboxylic acids when 1,2 ;5,6-di-Oisopropylidene-a-D-glucofuranose is used as proton source (74CC181). Me CO,H HO,C
i, Li, NH3, -78 °C; ii, LTA Scheme 36
Benzo[£]furan is cleaved on reduction with excess sodium in liquid ammonia, followed by quenching with ammonium chloride or methanol, to produce 2-ethylphenol (69%). 2-Methyl- and 2-phenyl-benzo[£]furan similarly yield 2-propylphenol (54%) and 2-(2phenylethyl)phenol (45%) (59JA2795). Similarly, 5-methoxybenzo(7>]furan, on reduction with 2 mol of lithium and a limited amount of t- butanol, gives the cleavage product, but by operating with 2 moleach of lithium and f-butanol, 5-methoxy-2-methylbenzo[6]furan supplies the 2,3-dihydro compound. With excess of the alcohol, however, 5-methoxy2,3,4,7-tetrahydrobenzo[£]furan is secured so that the reduction is stepwise (67JOC2794). CO, Me
CO, Me
CO,H
9 \ o
O
85%
in
CO
CO \\
o
•
<
Me O (68) 27%
i, Na, NH3, EtOH or MeOH, then NH4C1, then CH2N2; ii, Na, NH3, Me2CHOH, then NH4C1, then CH2N2; iii, Li, NH3, then NH4C1 Scheme 37
3.11.2.6 Reactions with Free Radicals and Other Electron Deficient Species Fur an is attacked by radicals at the 2-position and the intermediate can then lose a hydrogen atom to produce a 2-substituted furan or react with a further radical to produce a 2,5-disubstituted 2,5-dihydrofuran (Scheme 38). Arylation was the first reaction to be studied and the Gomberg method applied to 2-substituted furans gave only 5-substitution products. The method of choice involves the generation of aryl radicals from diazonium salts stabilized by zinc chloride (68JCS(C)2737). The Meerwein method (74CCC1892) and the generation of aryl radicals from diazoaminobenzenes with isopentyl nitrite at 30 °C (74T4123) have both been used to arylate furans. The relative rates of reaction of 4-chlorophenyl radicals, generated by the latter method, with 2-substituted furans have been determined by competition with furan. The relative rates are all faster than furan (furan-2-carbaldehyde, 3.14; 2-methylfuran, 1.87) except for furan-2-carbonitrile (0.92) (76CCC3398). Competition experiments with aryl radicals have been carried out for furan, thiophene and benzene (72JHC919). The aryl radicals were generated by the decomposition of N- nitrosoacetanilides, the aprotic diazotization of anilines, or under Gomberg conditions. Furan undergoes only
616
Furans and their Benzo Derivatives: {ii) Reactivity
arylation at the 2-position but thiophene gives some 3-arylation products. Furan was found to be 11.6 times more reactive than benzene and 4.5 times more reactive than thiophene. Partial rate factors with respect to benzene were determined for the 2-position for m- and p-substituted aryl radicals. A Hammett plot of these against the cr+ values gave a good correlation and a p value of 0.46.
3
o R
Scheme 38
Attempted generation of phenyl radicals from N- nitrosoacetanilide in benzene containing 2,5-dimethylfuran gives 2-benzyl-5-methylfuran and no arylation at a ring position. NNitrosoacetanilide (69) is assumed to undergo isomerization to benzenediazoacetate (70), which is in equilibrium with the ion pair (71; Scheme 39). A TT-complex is formed between the electron-rich furan and the cation, and the acetate ion, a strong base in anhydrous medium, then abstracts a proton from the methyl group and the resulting 5-methylfurfuryl anion reacts with the adjacent benzenediazonium cation by nucleophilic displacement of nitrogen to give the observed product (72JCS(P1)13O4>. PhN(NO)Ac — • PhN=NOAc — • PhN2 OAc + (69)
(70)
M
J X
\M CT
—•
M
J
V O
H
Ph 2
(71) Scheme 39
Photolysis of iodohetarenes yields radicals which can arylate furan in the 2-position; this method has been used to prepare 3-(2-furyl)pyridine (72CC594) and a variety of 5-(2furyl)pyrimidines (77JCS(Pl)621). Furan reacts with both dibenzoyl peroxide (69CC1119) and phenylazotriphenylmethane (70JCS(B)l443>, which are common precursors of phenyl radicals, to give addition products (Scheme 40). With the former reagent 2,5-dimethylfuran is attacked at a methyl group, giving 5-methylfurfuryl benzoate, and 2-methylfuran exhibits both types of behaviour. *
phco2o2cph —> 2Phco2- -22=->
H, /
yL
PhCO,
\
XT
H
+
PhCO,
(T ^O2CPh
\f
y O
PhN=NCPh 3 — • Ph* + N 2 + CPh3 H Scheme 40
When methyl radicals are generated from diacetyl peroxide they give substitution products with monoalkylfurans, but 2,5-dimethylfuran is hardly attacked (Scheme 41) (73TL637). f-Butoxy radicals generated from t- butyl hydroperoxide and Fe 2+ in methanol react with furan to give addition products (64G67), but when generated photochemically from t- butyl peroxide they convert 2-methylfuran into the furfuryl radical, identified by ESR spectrosCOpy (71JOC3837). Me
o
Oo
Me
Oo
Me
o MeO o
3.5% 10% i, (MeCO2)2, 60 °C, 6 h; ii, (MeCO2)2, 80 °C, 4 h Scheme 41
Me
(o 15%
With aromatic thiyl radicals, generated from the thiol with Fenton's reagent, 2-monosubstituted and, anomalously, 2,3-disubstituted products are obtained from furan (Scheme 42).
Furans and their Benzo Derivatives: (//) Reactivity
617
The anomalous products are thought to be a result of cation formation, since in the absence of Fe 3+ the normal 2-substitution products are obtained (75JOC966). O
ArS.
O
u
ArS
ArS
rO . AArS v7
r^\
O
\\
W
ArSH ArS
O
ArS
o
o O
Scheme 42
Ipso attack has been detected at both a-positions in the reaction of methyl and adamantyl radicals with methyl 5-nitrofuran-2-carboxylate and 5-nitrofuran-2-carbaldehyde. A typical example is shown in Scheme 43. Ipso attack at the carbon bearing the nitro group leads to substitution via the a- complex (72) and the product is (73). Attack at the alternative site gives the a- complex (74) which can capture NO 2 to form (75) or rearrange to the nitrite radical (76) and expel NO leading to (77) (79CC800). MeC
\x),Me +NO (73)
o
Me O
CO2Me
NO2.
Mev f=\ MeO2C
(74)
/ ^
ONO<^
°
X
°
NO NO2
(75)
Me
CO2Me
(76) Scheme 43
The homolytic arylation of benzo[6 ]furan has been studied using aryl radicals generated by decomposition of 1,3-diaryltriazenes in the presence of isopentyl nitrite at 120 °C (79JHC97), or phenyl radicals produced by the decomposition of N- nitrosoacetanilide at 40 °C. The major position of attack is the 2-position (75.9%), but some occurs at the 4(17.5%) and 7-positions (6.6%). Benzo[£]furan is 8.3 times more reactive than benzene and 1.26 times more reactive than benzo[£]thiophene. Carbene attack on the furan ring usually leads to cyclopropanation followed by ring opening with loss of aromaticity. Thus carbene yields the expected product (78) with furan and similarly UV irradiation of a solution of methyl diazoacetate in furan yields the methoxycarbonylcarbene adduct (79) which on brief heating at 160 °C is converted into the cis,trans- muconaldehydate (80; Scheme 44) (63LA(668)19). A number of substituted furans, including 2-alkenylfurans, yield similar dienes with ethoxycarbonylcarbene; thus 2-isobutenylfuran is cyclopropanated at the least hindered double bond and ring opening ensues (Scheme 45) (77AG(E)646). The reaction with vinylcarbenes follows a similar course (73TL2875). The intramolecular ketocarbene addition depicted in Scheme 46 also leads to ring-opened products (74TL2255). Allenic carbenes add to furan in poor yield (77T73), and l,6-methano[10]annulen-ll-ylidene has been trapped with both furan and 1,3-diphenylbenzo[c ]furan (76JA6068). Q(78) 50%
^Q^ (79) 23%
CO2Me (80)
i, CH2N2, Cu2Br2; ii, N2CHCO2Me, hv; iii, 160 °C Scheme 44
618
Furans and their Benzo Derivatives: (//) Reactivity
Me 2 C=CHCOCH=CHCH=CHCO,Et Scheme 45 N,HC heat, CuSO4
fj
\/r^^f>o
CHO Scheme 46
Atomic carbon generated by the pyrolysis of 5-diazotetrazole in the presence of gaseous furan yields cw-2-penten-4-ynal by insertion into an a-CH bond, thus producing 2furylcarbene, and by addition to a 2,3-double bond, producing a cyclopropylidene intermediate. Both intermediates undergo ring opening to yield the product (Scheme 47) (79JA1303).
\ +C
Scheme 47
When the sodium salt of a furan-2-carbaldehyde or 2-acylfuran tosylhydrazone is pyrolyzed at 300 °C, a furyldiazoalkane is produced. This decomposes to a 2-furylcarbene which opens to a ds-2-alken-4-yn-l-one (Scheme 48). The 2-furylcarbenes may also be intercepted as insertion products with cyclooctane or as addition products with styrene. Analogous results were obtained with the carbene produced from ethyl 2-furyldiazoacetate, but products of a cationic mode of reaction are obtained in protic solvents (78JA7934). Generated by the tosylhydrazone or the aziridinylimine method (76JCS(P1)1257>, 3-furylcarbene is unexceptional in its reactions and does not undergo ring opening. It may be intercepted by insertion and addition reactions, and in the absence of a trap yields a stereoisomeric mixture of l,2-di(3-furyl)ethylene by dimerization.
Scheme 48
With benzo[& ]furan, dichlorocarbene in cyclohexane gives an unstable addition product which, on treatment with water, yields the chromenyl ether (81; Scheme 49) (63JOC577). Decomposition of ethyl diazoacetate in the presence of benzo[& ]furan yields the expected mixture of cyclopropanes. The major isomer has been cleaved under acidic conditions (Scheme 50) (77JOC3945).
O (81) 15%
Scheme 49
Nitrenes give both addition and insertion products with furans. Thermolysis of ethyl azidoformate in the presence of furan gives either (82) or (83) by a sequence involving addition and ring opening (Scheme 51). Generation of phthalimidonitrene in the presence of 2,5-dimethylfuran yields the 2-phthaloylhydrazone of cis-2-hex-3-ene-2,5-dione (29%), presumably by opening of the intermediate aziridine by CO or CN bond cleavage. 2Substituted furans are attacked at the 4,5-bond <72JCS(Pl)2728). Similar results are given by l,3-diphenylbenzo[c]furan and nitrenes. The nitrenes generated by reduction of 2-(2-nitrophenyl)furan with triethyl phosphite or by thermolysis of 2-(2-azidophenyl)furan in 1,2-dichlorobenzene undergo insertion into
Furans and their Benzo Derivatives: (ii) Reactivity
619
CO,Et
CO2Et +
CH2CO2Me CH,CO,Me 1
95%
i, N2CHCO2Et, CuSO4, heat; ii, MeOH, HC1; iii, H + , PhH Scheme 50
\
NCCKEt
N
no °c
/ N CO2Et
or
NT O CO 2 Et (82)
(83)
Scheme 51
the adjacent furan 0- hydrogen and 4//-furo[3,2-6]indole results (77JHC975). Furocarbazoles have been similarly obtained (77TL2457). The nitrenes formed from thermolysis of ethyl 3-(5-aryl-2-furyl)-2-azidoprop-2-enoates undergo similar insertion and yield ethyl 2-arylfuro[3,2-6]pyrrole-5-carboxylates (95%) (79CCC1799). Benzo[£]furan-2-ylvinyl azides afford analogous insertion products (77CL401). Conversely, furo[3,2-6]pyrroles are also formed by pyrolysis of 3-azido-2-vinylfurans (76ACS(B)39l). Photolysis or pyrolysis of the azide (84) affords the expected insertion product (85) and its dehydro derivative, but surprisingly it is accompanied by (86) and its dehydro derivative (Scheme 52) (79H(l2)lO2l).
1,2-dichlorobenzene
o (84)
CO,Me
(85)
MeO2C (86)
Scheme 52
Benzo[£]furan gives an unstable aziridine by addition of phthalimidonitrene to the 2,3-double bond (72JCS(P1)225>. 3.11.2.7 Cycloaddition Reactions 3.11,2.7.1 Thermal reactions Furan, in spite of its aromaticity, and unlike the other rr- excessive heterocycles thiophene and pyrrole, enters into [^4S + ,,.2S] cycloadditions, the classical Diels-Alder reaction, with some degree of facility. The thermal cycloreversion of the adducts is also easy. Arynes undergo cycloaddition with ease even to furans containing an electron withdrawing group at an a-position. Other alkynic dienophiles and ethylenes activated with two electron withdrawing groups also form adducts easily, but difficulty is encountered with ethylenic dienophiles activated by only one electron withdrawing group. As expected, electron releasing substituents on the furan nucleus, as in 3,4-dimethoxyfuran, which also do not cause steric hindrance in the transition state, increase reaction rates. As expected from Alder's endo rule, and justified by consideration of maximum accumulation of unsaturation in the transition state, secondary orbital interactions and dispersion forces, furan reacts with maleic anhydride in acetonitrile at 40 °C (78JOC518) to give initially
Furans and their Benzo Derivatives: {ii) Reactivity
620
(87)
a small amount of the endo adduct (87). After 20 min the proportions of exo (88) and endo (87) adducts are equal and after 48 h only the exo adduct can be detected. The pure exo adduct (88) decomposes thermally to the addends. The rate of formation of the endo adduct is 500 times faster than that of the exo adduct and both reactions are reversible. The exo adduct is 8.0 kJ moF 1 more stable than the endo adduct so that the reaction is quite typical. The exo adduct (88) has been used in a synthesis of butenolides (79BSF(2)325). Thus, on reduction with sodium borohydride and then with DIBAL at —78 °C, the lactol (89) results (Scheme 53). This reacts with Grignard reagents to give diols (90) which undergo oxidation with Collins reagent. The resultant lactones (91) on thermolysis undergo retro Diels-Alder reaction yielding butenolides (92) and furan. O IV
CH(OH)R
-•-•
OH (92)
(90)
(89)
i, NaBH4; ii, DIBAL; iii, RMgX; iv, Collins reagent; v, heat Scheme 53
With maleimide the endo adduct (93) results at 25 °C, but the exo adduct (94) at 90 °C; the endo adduct also yields the exo adduct on heating. Reaction of furan with maleic acid in water occurs slowly and the adducts readily revert thermally to the addends. As expected, the rate of formation of the endo adduct (95) is initially faster than that of the exo adduct (96), but after 10 days the ratio is 1:1; both isomers may be isolated (73T2491). Fumaric acid only adds in poor yield to furan under ordinary conditions, but this may be overcome by use of fumaryl chloride (79CC542).
NH NH (94)
CO2H CO2H (95)
(96)
(97)
(98)
Ethylenic dienophiles with only one electron withdrawing group react only slowly with furans at room temperature to afford low to moderate yields of both endo and exo adducts. At higher temperatures the reverse reaction, as well as polymerization of the dienophile, generally occurs. A typical example (75HCA1180) is the reaction of furan with acrylonitrile which after 5 weeks gives a 39% yield of a mixture of endo (97; 61%) and exo (98; 39%) adducts. By use of ultra high pressure (15 kbar) these difficulties may be overcome. Thus, furan or 2,5-dimethylfuran under these conditions reacts with acrylonitrile, methyl acrylate, acrolein or methyl vinyl ketone to produce adducts in at least 50% yield. The crotonic analogues of the dienophiles give lower yields because both steric and electronic factors produce rate retardation. Fumarate and maleate at 15 kbar react smoothly with furan,
(99)
(101) i, furan, 15 kbar; ii, Ni(R); EtOAc Scheme 54
(102)
Furans and their Benzo Derivatives', (ii) Reactivity
621
giving the corresponding cis,endo and trans adducts in high yield. This methodology has been applied to a synthesis of cantharidin (102) (80JA6893). Dimethylmaleic anhydride fails to add to furan at pressures up to 40 kbar because of steric crowding of the transition state and the reduced dienophilicity of the anhydride. The sulfur analogue (99), however, reacts smoothly during 6 h at 15 kbar at room temperature to yield a separable mixture of the exo anhydride (100; 85%) and the endo anhydride (101; 15%) (Scheme 54). Reduction of the mixture with Raney nickel then gives cantharidin (102) in 63% yield. Furan with a- nitrosostyrene (104), generated from a- chloroacetophenone oxime (103) by treatment with anhydrous sodium carbonate, yields the adduct (106; 45%). This reaction is thought to involve Diels-Alder addition of the styrene double bond to the furan to give the endo adduct (105) which then suffers a 3,3-sigmatropic rearrangement (76CC581). Similar adducts are formed by azoalkenes. Furan reacts with cyclopropene at room temperature to yield a 1:1 mixture of exo (107) and endo (108) adducts (70CC1353). With halocyclopropenes only the endo adducts have been isolated and these may undergo electrocyclic ring opening and stereospecific 1,2-halogen migration, e.g. Scheme 56 (68JA2376). Strained bridgehead alkenes and medium ring E- cycloalkenes may also be captured as their furan adducts; thus the ester (109) decomposes to 1,2-dehydroadamantene on heating in 2,5dimethylfuran at 70 °C and the adduct (110) can be isolated in 9% yield (Scheme 57) (73TL3047). Ph
T
CH2C1
Na,CO,. CH,C1
Ph
furan
NOH
ON (106)
(104)
(103)
Scheme 55
(107)
Cl
Cl furan, CCI2
Cl F
80 °C, 18 h
F Cl
Cl F Scheme 56 Me
CO3Bul CO3Bul
2,5-dimethylfuran 70 °C
(109)
(110) Scheme 57
Vinylene carbonate (111) undergoes cycloaddition to furan in 21% yield, giving a separable mixture containing the endo adduct (112) as well as a small amount of exo adduct (113), distinguishable on the grounds of their dipole moments (Scheme 58). The endo adduct has been used in a synthesis of inositols (73JOC117) and to prepare by a cycloreversion the dioxolene (114), a useful synthetic equivalent of acetylene in Diels-Alder reactions (73JA7161). With dichlorovinylene carbonate the adducts (115) and (116) are obtained in the ratio 1:2. On basic hydrolysis they yield the diketone (117) (76S256). Furans generally react with alkynic dienophiles under mild conditions affording oxanorbornadienes in high yield (Scheme 59). The products have found a variety of uses in synthesis. The unsubstituted double bond may be hydrogenated and the product, on thermolysis, undergoes cycloreversion, thus providing a convenient synthesis of 3,4-disubstituted furans
Furans and their Benzo Derivatives: (ii) Reactivity
622
O O' (111)
(113)
o
IV
o (114) i, furan, 120 °C; ii, 1 MKOH, 100 °C, 1 h; iii, N,N-thionocarbonylimidazole, toluene; iv, 160 °C. Scheme 58
(117)
(116)
known as the Alder-Rickert sequence. The same result can be achieved by treating the initial adduct with 3,6-di-(2'-pyridyl)-s-tetrazine (72CC211). UV irradiation of the oxanorbornadienes yield oxaquadricyclanes which, on thermolysis, afford the benzene oxide-oxepin system (Scheme 60) (71HCA2579,76CB2823). On treatment with aluminum chloride (74CJC143) or TFA the oxanorbornadienes rearrange to phenols (Scheme 61). Comparable results are obtained when the Diels-Alder reactions are carried out in the presence of aluminum chloride, which serves both to enhance the rate of cycloaddition, presumably by lowering the enthalpy of activation, and to induce rearrangement of the adduct. Yields are often poor due to polymerization of the diene under these conditions. The effect of aluminum chloride may be quite dramatic: 2,5-diphenylfuran fails to undergo cycloaddition with diethyl acetylenedicarboxylate under thermal conditions but in presence of aluminum chloride in dichloromethane at - 2 0 °C a 40% yield of the adduct may be secured. With ethyl propiolate the cycloaddition reactions are regiospecific (Scheme 62) (71CJC3152).
7 o
IIJ^ // C ° 2 M e 71% 81%
Br
Br
CO,Me
OJC°Mt CO, Me
V
in
81%
o
i, DMAD, CC14, 6.5 h; ii, DMAD, ether; iii, F3CC = CCF3, 0 °C, 100 h Scheme 59
O
O
MeO
CO,Me
MeO 2 C
CO 2 Me
CO, Me CO 2 Me 80% i, hv, - 2 0 °C, CH2C12, 30 h; ii, xylene Scheme 60
The course of the reaction of furan and DMAD is temperature dependent (73CJC4125). The initially formed monoadduct (118) acts as a dienophile and further addition of furan can occur at the di- or tetra-substituted double bonds. In such additions to norbornene-type dienophiles the diene is subject to steric approach control and approach to the exo face is preferred. At 25 °C the tetrasubstituted double bond acts as a dienophile and the endo,exo
Furans and their Benzo Derivatives: (ii) Reactivity
Me CO,Me
CF3CO2H 20 °C, 72 h
Me CO,Me
623
CO,Me Me CO,Me HO
OH
Me CO 2 Me
OH Me
CO 2 Me CO, Me
CO 2 Me
CO 2 Me CO,Me Me 80-85%
Me Scheme 61
Ph CO,Et
HC = CCO2Et
'I W Ph
±_j
A1CU
O
Ph CO,Et 2 —
48%
OH
Scheme 62
(or exo,endo) adduct (119) and the endo,endo adduct (121) result. The initial rate of formation of adduct (119) is greater than for adduct (121), and (119) is the major product at 25 °C. At higher temperatures the thermodynamically more stable (121) becomes the major product due to equilibration. Reaction of furan with the monoadduct (118) to yield the endo,endo adduct (123) and the endo,exo adduct (124) is slow and significant amounts of these adducts are formed only at higher temperatures and after shorter reaction times. Under these conditions, low yields of the four triadducts (125), (126), (127) and (128) are obtained. Adducts (127) and (128) similarly arise from (124). Aluminum chloride produces a rate enhancement of ca. 10 at 25 °C and the kinetic product (119) is formed. Di-f- butyl acetylenedicarboxylate gives similar adducts to DMAD on thermal reaction with furan (80CB531). With acetylenedicarboxylic acid in boiling ether containing two mol equivalents of furan, the diadducts (120) and (122) result in the ratio 2:1 after 10% reaction (1 h) but after 20% reaction (24 h) the ratio is 1:4, since adduct (120) has begun to crystallize out thereby driving the equilibrium in this direction. O
MeO2C
CO2Me CO2Me
CO2R CO2R (119) R = Me (120) R = H
(118)
CO2R CO2R (121) R = Me (122) R = H
MeO2C (123)
O
O
MeO2C
MeO2C
MeO2C
MeO2C
MeO2C (124)
MeO2C (126)
(125)
O
MeO2C
MeO2C
MeO2C
MeO2C (127)
Reaction of excess 2,5-dimethylfuran with DMAD gives a monoadduct but at 100 °C the diadduct (129) is formed (Scheme 63). The disubstituted double bond may be selectively reduced and pyrolysis then results in 2,5-dimethylfuran (131), the diester (130) and ethylene (70JOC3897). 2,2'-Bifuryl and DMAD give the adducts (132) and (133) <67JCS(C)2327>. The
Furans and theirBenzo Derivatives: (ii) Reactivity
624 O Me
Q Me MeO2C
Pd
MeO2C
CO2Me
heat
MeO2C cl^"—-X T--O Me (130)
Me (131) Scheme 63
MeO2C
MeO2C
CO2Me
MeO2C (132)
CO2Me
CO2Me (133)
cyclophane (29; Scheme 64) reacts with DM AD to produce the internal adduct (135), presumably via the monoadduct (134); on heating at 165 °C the adduct undergoes reversion to the addends (66JA515). Similar results are obtained with tetrachlorocyclopropene as dienophile.
AX XT
CO2Me
DMAP
105 °C
MeO 2 C
>
MeO2C
(29)
(135)
(134) Scheme 64
2,5-Dimethylfuran reacts with ethyl propiolate at 95-120 °C to give initially the monoadduct (136), which undergoes homo Diels-Alder reaction with itself yielding (137), and this, on retrogression, affords (138). Retrogression of the monoadduct (136) yields (139) and acetylene. The monoadduct (136) also undergoes further Diels-Alder reaction with 2,5dimethylfuran, yielding the diadducts (140) and (141). Cycloaddition of the monoadduct (136) with the dienophile in a [2 + 2] manner yields (142; Scheme 65). The ratio of the products is dependent on the reaction conditions (75CJC1496). In contrast, furan fails to react with ethyl propiolate at 25 °C and at 130 °C the only product isolated is the analogue of adduct (138; 9%) (74CJC1013). In the presence of aluminum chloride, however, normal diadducts may be isolated.
CO2Et +(136)
EtO2C
EtO2C (138)
(136)
CO2Et
O Me
Q
O Me
EtO2C
Me (139)
CO2Et Me |CO2Et H
Me CO2Et H (140)
Me
(141) Scheme 65
(142)
Furans and their Benzo Derivatives: (ii) Reactivity
625
It appears that 2-acetoxyfuran and the monomethoxyfurans undergo Diels-Alder reactions with more ease than furan itself, although no systematic work has been reported. 2-Acetoxyfuran (56JA2303) readily forms adducts with maleic anhydride, DMAD, maleimide and fumaronitrile. 3-Methoxyfuran (64JOC776) readily yields the endo adduct with maleic anhydride; 2-methoxy-5-methylfuran behaves similarly but the stereochemistry of the adduct has not been assigned (60JOC1028). 3,4-Dimethoxyfuran exhibits enhanced reactivity compared with furan (79HCA2211) and in contrast gives both exo and endo adducts with maleic anhydride at the same rate, but the exo product is thermodynamically more stable and can be isolated in 90% yield. Less reactive dienophiles also give mixtures of exo and endo adducts, except for methylmaleic anhydride which gives only the product (143) with an endo methyl group. Dimethylmaleic anhydride fails to react even at 150 atm. With methyl acrylate in the presence of a catalytic amount of sulfurous acid the lactone (144) is obtained via the endo adduct. With an equimolar amount of DMAD at 5 °C for 4 days, 71% of the monoadduct (145) and 26% of the diadduct (146) is obtained. With 2mol equivalents of the furan the yield of the diadduct is raised to 90%. 3,4-Dimethoxyfuran also undergoes cycloadditions with p-benzoquinones; these appear to be the first recorded reactions of furans, other than menthofuran, with p-benzoquinone. With p-benzoquinone the endo adduct (147) is formed, but on standing in deuteriochloroform this undergoes some dissociation to the addends as well as conversion into the exo isomer (149). With toluquinone the endo adduct (148) is formed, and although it is labile in solution, no exO adduct is formed. With xyloquinone only the exo isomer (150) is formed; this is stable in solution. 2,3-Dimethoxybenzoquinone at room temperature gives an exoyendo mixture; O
O
MeO MeO
MeO MeO OMe,
6
(145)
(144) O
CO2Me CO2Me OMe OMe
MeO MeO
MeO O (147) R = H (148) R = Me
(146)
MeO MeO
(149) R = (150) R = Me
again the endo isomer is labile in solution. Addition of chlorine to the p-benzoquinone adduct (147) occurs across the highly nucleophilic enediol ether double bond in a stereospecific cis manner and exclusively from the exo side. Methanolysis of the product yields the acetal (151; Scheme 66) which may be oxidized to the quinone (152) and this, on pyrolysis, affords the benzo[c]furan-4,7-quinone (153) and tetramethoxyethylene (154). MeO MeO MeO
MeO
OH Ag2O
OMe OH (151)
MeO.
.OMe
MeO
OMe
heat
MeO OMe
(154)
(152) Scheme 66
Attempts to isolate 2,3-dimethoxyfuran (156) have, as yet, been fruitless (79JCS(P1)1893), but it may be generated in situ and trapped with the propiolate (155); the initial adducts (157) are unstable under the acidic conditions and yield the biphenyls (158) and (159) (Scheme 67). 2,5-Bis(trimethylsilyloxy)furans, readily available from succinic anhydrides in one step, are also more reactive than furan in Diels-Alder reactions (80TL3423). They readily undergo reaction with both DMAD and ethyl acrylate. Thus at 50 °C in carbon tetrachloride the furan (160) with DMAD followed by detrimethylsilylation gave only the quinone (163). At 80 °C, however, the hydroquinone (164) is the major product. Both the intermediates (161) and (162) may be detected by *H NMR spectroscopy. The formation
Furans and their Benzo Derivatives', (ii) Reactivity
626
of (162) indicates that (161) must undergo deoxygenation; the mechanism is open to question and may not be a simple cycloreversion (Scheme 68). OMe
OMe O
xy ene
'
PhC=CCO 2 Et
OMe
P-TSOH
-
o
OMe O' (156)
(155)
Ph
OMe OMe
EtO,C Ph
EtO,C _EtO,C
OH (158)
(157)
OMe OMe
OH (159)
Scheme 67
DMAD
Me,SiO
OSiMe3 CO 2 Me
9 X>SiMe3
Me
CO 2 Me CO 2 Me OSiMe3 (161)
OSiMe O
(160)
Me
CO 2 Me OSiMe3 (162)
JNaF, wet MeCN
o
OH CO 2 Me
Me
CO 2 Me
CO 2 Me Me
CO,Me OH
O (163) Scheme 68
(164)
In the case of 2-vinylfuran there is the possibility of cycloaddition involving either the endocyclic diene system or the diene system including the exocyclic double bond. 2Vinylfuran reacts with maleic anhydride during 8 days in ether to yield an adduct (79%) by a cycloaddition involving the exocyclic double bond (43BSF163). In contrast, DMAD with 2-vinylfuran (165) at 25 °C undergoes both modes of addition, and the adducts (168) and (167), formed by aromatization of the adduct (166), are obtained in poor yield. At higher temperature the adduct (166) undergoes an ene reaction, resulting in the 2:1 adduct (169). The low yields in these reactions were ascribed to the ease of polymerization of 2-vinylfuran (Scheme 69). 5-(p-Nitrophenyl)-2-vinylfuran, being more stable, gave a 50% yield of the aromatized adduct of type (167) (73AJC1059). The vinylfurans (170) and (171) give good yields of adducts involving the exocyclic double bonds with fra«s-l,2-dibenzoylethylene (Scheme 70) (74BSF2105). Deactivation of the side-chain double bond with an electron withdrawing group prevents reaction. MeO,C
CO,Me
MeO,C CO, Me
DMAD 4 d, 25 °C
CO 2 Me (165)
(167) 5%
(166) PhH, 24 h
MeO 2 C
CO, Me + (167) 5% CO, Me
MeO 2 C (169) 3% Scheme 69
(168) 5%
Furans and their Benzo Derivatives: (ii) Reactivity
627
Ph
Ph'
O
(170)
60%
O
PhOC
(171)
O
60%
i, (E)-PhCOCH=CHCOPh, 150°C, 12 h; ii, (E)-PhCOC=CCOPh, xylene, 18 h Scheme 70
Furans with electron withdrawing groups at the 2-position exhibit reduced reactivity in Diels-Alder reactions as expected. Thus furan-2-carbaldehyde (172) at 80 °C gives the adduct (173) with DMAD which could not be obtained crystalline, nor isolated by distillation, because of its thermal lability. The yield was estimated by partial hydrogenation of the adduct and pyrolysis which yielded the substituted furfural (174) in 23% yield (Scheme 71) (67BSF1764). The yields of adducts from furan-2-carbonitrile and methyl furan-2carboxylate were similarly estimated at 12% and 25%. The reactivity of furan-2-carbaldehyde is restored in its acetals and its diacetate and the furan (174) may be prepared in 60% overall yield by recourse to this method. Electron withdrawing groups at the 3- or 3,4-positions appear to impair the diene character of furan very little. The diester (175) reacts smoothly with DMAD, affording the adduct (176) which on catalytic reduction affords the zW-endo isomer (177; Scheme 72); the all-exo isomer is available by carbonylation of the adduct (88) in methanol. Both of these last-mentioned compounds serve as a starting material for the synthesis of 2,3,5,6-tetramethylidene-7-oxabicyclo[2.2.1]heptane, a useful anthracyclinone synthon (80HCA1149). Similarly, the diester (178) yields the adduct (179) with dicyanoacetylene. The dinitrile (181) forms a bisadduct (184) with DMAD, but a monoadduct (180) with dicyanoacetylene. This adduct (180) on treatment with triphenylphosphine rapidly yields a betaine (183) which, on pyrolysis, affords the tetranitrile
O
CHO
MeO2C
CO2Me
fl ^
DMAD,
~ ^
(172)
(174)
O
'Q
DMAD 80°C,4d'
CO 2 Me ,
MeO 2 Q w
_
^
(
(176)
(175)
Pd. H 2
|
MeO2C \ CO2Me CO2Me (177)
Scheme 72 EtO 2 C
CO2Et
NC CN
o (178)
(182)
(183) 100%
i, NCC=CCN, 156 °C, 18 h; ii, DMAD, 110°C, 18 h; iii, PPh3, MeCN, 2 min; iv, 195 °C Scheme 73
Furans and their Benzo Derivatives: (ii) Reactivity
628
(182; Scheme 73) (62JOC3520). 2-Amino-3-cyanofurans readily form ring-opened adducts with dienophiles such as maleic anhydride, methyl acrylate and methyl vinyl ketone. Thus the nitrile (185) yields the adduct (186) which, on acidic treatment, undergoes dehydration affording the anthranilic acid derivative (187; Scheme 74) <80S56). The aminonitrile (188) is unique since it undergoes self Diels-Alder reaction. Attempts to prepare (188) yield the dimer (189; Scheme 75) <73JOC612). iCN
J
M
NH2
NH,
Me CN
H
Me Me
(185)
Me
OH
(186) 56%
(187) 90%
i, CH2=CHCO2Me, dioxane, 12 h; ii, HC1, AcOH, 25 °C Scheme 74 NH 2
Me CN
CN CH2
CH,OH
NC
NH,
Me
O
CN
/L o"
(188)
NH 2
(189)
Scheme 75
Dehydrobenzenes, generated by a variety of methods, readily undergo cycloaddition in high yield to furans bearing a wide range of substituents. These adducts are good precursors for the generation of benzo[c]furans and for the synthesis of naphthalenes. The reactions of 3-methyldehydrobenzene, prepared from the precursors (190)-(193) with a-substituted Me
Me
Me
"
NH,
(190)
(192)
(191)
a Me
2
(193)
furans, have been studied (76JOC3356). Although the total yields of adducts varied with each method of generation, the ratio of products was constant. Inspection of the results (Scheme 76) suggests that addition of an unsymmetrical benzyne to a furan is little affected by steric or polar effects. This method has been used with advantage in the preparation of naphthalenes which are subjected to large steric interactions at the peri positions (72JA4608). Thus the furan (194) was allowed to react with 3,5-di-?-butylbenzyne generated by the diazonium carboxylate method; this affords a 25% yield of a mixture of the adducts (195) and (196) in the ratio 58:42. Catalytic hydrogenation gives a mixture of the dihydro compounds (198) and (199), only one of which undergoes ring opening on brief exposure Me
CO2Me
61:39
50-81
57:43
54-82
Scheme 76
629
Furans and their Benzo Derivatives: (//) Reactivity
to dry ethanolic hydrogen chloride and yields the naphthalene (197; Scheme 77). In contrast to its reaction with DMAD and tetrachlorocyclopropene, the cyclophane (29) affords a mono- (200) and a bis-adduct (201; Scheme 78) with benzyne generated by the diazonium carboxylate method (73CC930). The monodiene (200) is a more efficient trap for benzyne than the cyclophane (29), presumably due to increased internal strain and electronic repulsions, but these factors are insufficient, in this case, to promote intramolecular cyclization. Bu1 Bu"
CH,Ph
CH 2 Ph
o
CH,Ph
(194)
(195)
(196)
Bu'
CH,Ph
11
CH,Ph
CH 2 Ph (197)
(199)
(198) i, H 2 , Pd/C; ii, HC1, EtOH, 2.5 h, 25 °C Scheme 77
(29)
(201) 13%
(200) 12% Scheme 78
There is a growing number of examples in which furans undergo Diels-Alder reaction in an intramolecular manner. If conditions are favourable, these reactions occur more easily, and often with higher stereoselectivity, than their intermolecular counterparts. Allusion
NMe (202)
(203)
(204)
Table 1 Intramolecular Cyclization of Compounds (205) and (206) Compound
O
(CH2), NMe
NMe
(206)
Conversion (%)
Time (d) 6 5 14 4
= H, R' = Me n = 3 ; R = R' = H = H, R' = Me
100 100 40 100 12 45 0
R = R' = H R = Me, R' = H R = H, R' = Me
100 0 0
n = l ; R = Me, R' = H n = l ; R = H, R' = Me
?•
6
Furans and theirBenzo Derivatives: (ii) Reactivity
630
has already been made to the intramolecular reactions of the cyclophane (29). Neither the esters (202) and (203) nor the amides (204; n = 1, 2, 3) undergo cyclization, presumably because the furan and dienophile cannot adopt a conformation for efficient TT-overlap in which the reacting moieties are cisoid about the ester linkage. However, a series of tertiary amides with both activated (205) and inactivated (206) dienophile moieties undergo cyclization in boiling benzene. Closure to five- and six-membered lactams occurs fairly readily but formation of seven-membered lactams is inhibited, a -Substitution in the dienophile is tolerated but substrates with a trans @ -substituent afford lower yields (Table 1). Only one of two regioisomers is possible and one stereoisomer is preferred, and in the case of five-membered lactams this results in the exo mode of cyclization with a trans ring junction, e.g. (207) yields (208) (78TL1689). The furylhexenone (209) undergoes efficient cyclization merely on passage over a column of florisil in dichloromethane (79SC771). NMe s
O
o
NMe
R (206)
NMe
(207)
(209)
The intramolecular Diels-Alder addition of a benzyne to a furan has been exploited in a synthesis of mansonone E (81TL4877). The benzyne (211), generated from the anthranilic acid (210), yields the adduct (212; 86%) which is easily converted into the naphthalene (213; Scheme 79). A similar addition was achieved by generating the benzyne by treating an o -dibromobenzene with butyllithium. HOX
(210)
(213) i, i-
+
, HC1, EtOH, 0 °C; ii, C1CH2CH2C1, propene oxide; iii, H2, Pd/C; iv, H , SiO2, CH2C12, 25 °C, 15 h Scheme 79
Methylcyclopropanone and 2,2-dimethylcyclopropanone react via their tautomeric oxyallyl cations to yield 1^+^] adducts with furan and alkylfurans (69JA2283), e.g. an 85% yield of a 1:1 mixture of the regioisomers (214) and (215) results from the reaction of 2-methylfuran with 2,2-dimethylcyclopropanone. With furan-2-carbaldehyde the only [4 + 2] adduct formed is (216); in addition, the dioxolane (217) resulting from 1,3-dipolar addition between the carbonyl group and the oxyallyl cation (218) is formed. Oxyallyl cations of type (218) can be generated by debromination of a,a '-dibromoketones with diiron enneacarbonyl or a zinc-copper couple and trapped with furan. Debromination of 2,12-dibromocyclododecanone with a zinc-copper couple in the presence of furan affords the three separable 1:1 adducts (219), (220) and (221) (74JA5466). On cooling a solution of (221) to 0 °C the *H NMR spectrum is clearly resolved into that of the diequatorially bridged chair (221a) and the diaxially bridged boat conformers (221b). When the aliphatic chain is lengthened by one methylene unit the chair-boat equilibrium is rapid at -80 °C on the aH NMR time scale, whilst shortening the chain by one methylene unit results in a stable boat form which does not flip below 160 °C. Under carefully controlled conditions the 2-methoxyallyl cation (223) can be generated from 2-methoxyallyl bromide (222) and in the presence of furan it reacts to form the adduct (224; Scheme 80) (73JA1338).
Furans and their Benzo Derivatives: (ii) Reactivity
631
OHC
| o \=o
o (214)
I o \=o
(215)
(218)
(216) (217)
CH2)9
:CH 2 ) 9 (219)
(221a)
OMe
°n
OMe
Br (222)
(223)
(224)
o
i, PhH, furan, C5Hi2, Na2CO3, AgOCOCF3; ii, 7% HNO3 Scheme 80
Furan, in keeping with its aromaticity, and in contrast to 2,5- and 2,3-dihydrofurans, behaves as only a weak dipolarophile. Generation of benzonitrile oxide in the presence of a large excess of furan yields (91%) the adducts (225) and (226) in the ratio 97:3 (76JOC3349). Similarly, the nitrile oxide (227) affords the regioisomer of type (225) with furan (77JCS(P2)706>. Benzo[6]furan also yields regioisomeric adducts with nitrile oxides (78JOC3006). Similar adducts are formed by 3-pyrrolidinobenzo[6]furan (228) <74RTC32l). Both furan and benzo[6]furan give adducts of type (229) with TCNE oxide. These reactions are thought to be non-concerted 1,3-dipolar cycloadditions since the reactions show many similarities to electrophilic aromatic substitutions, e.g. furan reacts 10.4 times faster than thiophene (75ACS(B)44l). Cl Me Me
o (226)
(225)
(228)
Cl Me (227)
(229)
Examples of furans acting as dienophiles are not common. Reaction of furan-2-carbaldehyde with butadiene gives mono- and bis-adducts. The diterpene (230) on heating undergoes a 1,5-sigmatropic shift and lactonization yielding (231), which because of favourable stereochemistry affords (232) by an intramolecular Diels-Alder reaction (Scheme 81) (74T3099). When 3,4-dichlorothiophene dioxide (233) is dissolved in excess 2,5-dimethylfuran an exothermic reaction ensues, yielding the adduct (234; 68%). If the reaction mixture is heated the adduct undergoes loss of sulfur dioxide and rearrangement, and the benzenoid compound (235) is isolated (77%). When the reaction is applied to other furans using halothiophene dioxides the initial adduct cannot be isolated but the rearrangement products are obtained in good yield. Furan with tetrachlorothiophene dioxide affords only 8% of
632
Furans and theirBenzo Derivatives: (ii) Reactivity
the usual rearrangement product. The major product (237; 27%) arises from furan functioning as a diene and the intermediate (236) then adds a further molecule of thiophene dioxide and undergoes loss of sulfur dioxide (Scheme 82) (80JOC867).
MeO2C CH 2 OH (230)
(231) i, diglyme, heat, 6 h; ii, diglyme, heat, 32 h Scheme 81
Cl
Cl (237)
i, 2,5-dimethylfuran; ii, 2-methoxyfuran, CH2C12, 30 °C; iii, 2-acetoxyfuran, 125 °C Scheme 82
Furans also undergo cycloadditions with o-benzoquinones. Thus furan, 2-methylfuran, 2,5-diphenylfuran and benzo[6]furan yield dihydrofurobenzodioxins of type (238) with tetrachloro-l,2-benzoquinone (Scheme 83). The reaction of furan with 1,2-benzoquinone affords only a 1% yield of adduct because most of the quinone undergoes polymerization. The reaction with 2-methylfuran produces a 25% yield of adduct, however. The reactions are thought to involve the electrophilic attack of the quinone on the furan to produce a carbonium ion. In the case of 2-methylfuran the more stable carbonium ion (239) is produced. Evidence for a two-step mechanism is the diversion of the intermediate (239) to the addition product (240) which may be isolated when the reaction is conducted in the presence of ethanol (69JCS(C)1694).
(238) 62% H
°^L^\ Me OEt
O
(239) Scheme 83
(240)
Furans and their Benzo Derivatives: (ii) Reactivity
(241)
(242)
633
(244)
(243)
In the fused compounds (241) and (242) the furan ring fails to react as a diene and Diels-Alder reaction with dienophiles occurs on the terminal carbocyclic rings. However, (243) and (244) afford monoadducts with dimethyl fumarate by addition to the furan rings (70JA972). The rates of reaction (Table 2) of a number of dehydroannuleno[c]furans with maleic anhydride, which yield fully conjugated dehydroannulenes of the exo type (247), have been correlated with the aromaticity or 'antiaromaticity' of the products (76JA6052). It was assumed that the transition state for the reactions resembled products to some extent, and the relative rates therefore are a measure of the resonance energy of the products. The reaction of the open-chain compound (250), which yields the adduct (251), was taken as a model. Hence the dehydro[4n + 2]annulenes from (246) and (249) are stabilized compared to (251), and the dehydro[4n]annulenes from (245) and (248) are destabilized (Scheme 84). Table 2 Relative Rates of Reaction of Dehydroannuleno[c]furans with Maleic Anhydride Relative rate
Compound
0.02 6.1 0.2 3.9 1.0
Dehydro[12]annuleno[c]furan (245) Dehydro[14]annuleno[c]furan (246) Dehydro[16]annulenoj>]furan (248) Dehydro[18]annuleno[c]furan(249) Open model (250)
Me
' •" (245) n = 1 (246) n = 2
Me
Me (247)
(250)
Me (248) m = 1, n = 2 (249) m = n = 2
(251) Scheme 84
Benzo[c]furan, isobenzofuran, although of limited stability, is easily generated by thermal cycloreversion of precursors such as (252) and (253) which are available in turn from the adduct (254). Indeed, flash vacuum pyrolysis of the dihydro adduct (255) offers the most attractive synthesis of benzo[c]furan. Solutions of benzo[c]furan in ether at 0°C react instantaneously with maleic anhydride, iV-phenylmaleimide and methyl vinyl ketone to yield endo : exo (3:1) mixtures of adducts such as (256) from maleic anhydride. With styrene and cyclohexene reaction is slower and yields are lower due to polymerization; isobutene fails to react. A large number of trapping experiments has been reported. Thus boiling the tetracyclone adduct (257) with (254) in diglyme affords the adducts (258) and (259) in the ratio 1:1.4. Benzo[c]furan generated by this method has also been trapped as Diels-Alder adducts with the thietes (260) and (261) and with N- substituted azepines. When generated
Furans and their Benzo Derivatives: (ii) Reactivity
634
from (253), benzo[c]furan has been trapped with the naphthalene oxide (254), cyclopentene, cycloheptene, cycloheptatriene and norbornadiene. Benzo[c]furan has also been trapped with tropone and substituted tropones. A [4 + 6] adduct (262) has been obtained when benzo[c]furan is generated in the presence of 6,6-dimethylfulvene. Adducts of benzo[c]furan have also found use in anthracyclinone synthesis. When generated from the a-pyrone adduct (253) in the presence of the quinone (263) the expected endo and exo adducts were obtained in a yield of 96% in the ratio 3:1. These were converted into (±)-4-demethyldaunomycinone in several steps.
(253)
(254)
(255)
(256)
L
SO2 (260) R = H (261)R = M
(262)
(263)
Treatment of the acetal (264), available from 6-bromoveratraldehyde, with dienophiles including DMAD, methyl vinyl ketone, acrylonitrile and quinones in boiling chlorohydrocarbon solvents in the presence of acetic acid gives good yields of adducts in which the endo isomers predominate (80TL3663). The phthalan (265) is thought to be the immediate precursor of the benzo[c]furan (266) since it can be isolated under sufficiently mild conditions. The analogue (267) is readily available by oxidation of the diol (268) in acidic methanol. On treatment with LDA the phthalan (267) yields solutions of benzo[c]furan (80JOC4061). This general method has been used in the synthesis of 1-arylnaphthalide lignans (80CC354). MeO CH,OH OMe (264)
(266)
(265)
(267)
(268)
Benzo[c]furans with alkyl or alkoxy substituents at the 1-position are also unstable compounds but have been generated by methods similar to those for the parent. They undergo cycloadditions with a diverse range of compounds including quinones, quinone acetals (81CC942) and ethylenic and alkynic dienophiles. Treatment of the phthalan (269) with LDA by inverse addition generates l-methoxybenzo[c]furan (271), which has been trapped with norbornene (8UOC2734). Heating the phthalan (269) with maleate, fumarate or DMAD in the presence of acid gives aromatized adducts of (271); maleic anhydride undergoes addition without added acid, presumably due to the adventitious presence of maleic acid. On heating the ethoxy analogue (270) with activated acetylenes at 140-160 °C, aromatized adducts of l-ethoxybenzo[c]furan (272) are obtained <80CJC2573>. The hydroxyphthalan (273) yields adducts of l-benzylbenzo[c]furan on reaction with maleic anhydride or p-benzoquinone in the presence of acid (80JOC1817).
RO (269)R = Me (270)R = Et
HO (271)R = (272)R =
(273)
CH2Ph
Furans and their Benzo Derivatives: (ii) Reactivity
635
1,3-Diarylbenzo[c]furans are stable compounds and the diphenyl compound has long been used as a trap for unstable unsaturated compounds including cycloalkenes, cycloalkynes and dehydrobenzenes. Its high reactivity in cycloadditions, invariably at the furanoid diene site, is accounted for by the regeneration of the benzenoid sextet. Its reactions with simple alkenes and alkynes have been studied kinetically. The adducts are readily converted into naphthalenes by dehydration with acidic reagents or with phosphorus pentasulfide. Adducts from alkynes cannot lose water; those from cycloalkynes undergo rearrangement under acidic conditions (Scheme 85). 1,3-Diphenylisobenzofuran undergoes [4 + 6] and [4 + 2] cycloadditions with cycloheptatriene (Section 3.11.2.7.2); [4 + 2] adducts similar to those with furan are formed with o-benzoquinones.
(CH2)n
Scheme 85
Benzo[fe]furans do not take part in Diels-Alder reactions because of their enhanced aromaticity, but 2-vinylbenzo[6]furans give adducts involving the exocyclic double bond. The isopropenylbenzo[6]furan (274) forms the adducts (275; 89%) and (276; 80%) with TCNE and maleic anhydride respectively. With DMAD a 25% yield of the aromatized adduct (277) is obtained and methyl propiolate regioselectively yields a similar adduct (278) (70AJC2119). 2-Isopropenyl-3-methylbenzo[6]furan also affords adducts <69TL290l). Reaction of 2-isopropenyl-6-methoxybenzo[6]furan (279) with methyl propiolate affords the dibenzof uran (280) which has been used in a synthesis of the naturally occurring ruscodibenzofuran (Scheme 86) <80CC1103>. The (.E)-2-methoxyvinyl compound (281) yields the expected mixture (28%) of isomers (282) and (283) with methyl fumarate, but with DMAD the major product (36%) is the rearranged adduct (284). Other compounds isolated are the methanol elimination product (285; 20%) and the dibenzof uran (287) which arises by further addition of DMAD to (284) followed by cycloreversion of the adduct (286) with loss of methyl /? -methoxyacrylate (Scheme 87). Benzo-substituted analogues of (281) give similar products with DMAD, one of which has been used in a synthesis of di-O-methylstrepsilin (72AJC545). 2-Isopropenyl-3-methoxybenzo[6]furan (289) yields the expected adduct with TCNE, but with maleic anhydride elimination of methanol occurs and the adduct (288; 82%) is obtained. With DMAD the dibenzofuran (290; 33%) is obtained (Scheme 88) (71AJC1883).
S O (277)
Me
Meo
CO2Me
\JCX) CT
Y (279)
Me
(280)
i, TCNE, CHC13, 25 °C; ii, maleic anhydride, PhH; iii, DMAD, PhH; iv, HC=CCO2Me, PhMe Scheme 86
636
Furans and their Benzo Derivatives: (ii) Reactivity CO2Me
CO,Me OMe (282)
CO2Me ^.CO2Me OMe
(283)
+
O
^^^O'
(285)
(287)
i, (£)-MeO2CCH=CHCO2Me, xylene; ii, DMAD, PhMe Scheme 87
OMe O"
O
(288)
(289)
Me
(290)
i, maleic anhydride, PhH; ii, DMAD, xylene Scheme 88
3-Pyrrolidinobenzo[6]furan (228) can function as a dienophile and by inverse electron demand it forms the [4 + 2] adduct (291; 70%) with 1,4-diphenyl-s-tetrazine. With DMAD a [2 + 2] adduct (292) is formed which is easily converted into the benzoxepin (293) on heating (74RTC321>.
CO2Me CO,Me
3.11.2.7.2 Photochemical reactions Furan does not undergo photodimerization, but benzo[6]furan gives low yields of the syn and anti dimers (294) and (295) on acetophenone sensitized irradiation in benzene <75HOU(4/5a)552>. 2-Phenyl- and 2-cyano-benzo[6]furan and methyl benzo[6]furan-2carboxylate give photodimers of unknown structure. Codimerization of benzo[i]furan with the pyridyl compound (296), available from the irradiation of benzo[Z>]furan in the presence of 3-iodopyridine, gives the head-to-tail dimers (297) and (298) in the ratio 3:2. The reaction is thought to involve an excited singlet of benzo[Z>]furan (76JOC541). 1,3-Diphenylbenzo[c]furan affords the photodimer (299) of unknown stereochemistry. Furans which are part of a hexatriene system undergo oxidative photocyclization via a concerted 6TT-process (Scheme 89). Usually the dihydro intermediates cannot be isolated but compound (300) is
Furans and their Benzo Derivatives: (ii) Reactivity
637
(299)
(298)
an exception (79T2639). When the reaction is conducted in the presence of iodine the aromatized product is isolated.
22%
Ph
(300) i, A > 300 nm, 450 W, air, cyclohexane; ii, A > 300 nm, ether, N2 Scheme 89
Furans are able to undergo photocycloaddition of the [W2S + ,r2s] and the [W4S+W4S] type to suitable substrates. With benzene (8OJCS(P1)2174) five 1:1 products are obtained. The relative proportions of these products are highly variable and depend on the relative concentration of the reactants, the irradiation time, the light intensity and the temperature of the solution. For the shortest irradiation time with a low-pressure mercury lamp at 15 °C, the relative proportions are 1:1:10:40:2. The major product is the 2,5: l',4'-adduct (301) and the next most prolific is the 2,3: l',2'-adduct (302). Adduct (301) is unreactive to dienophiles but gives adduct (302) by Cope reaction at 60-70 °C. This reaction can also be achieved by irradiation of a cyclohexane solution of (301). Adduct (302) reacts readily with dienophiles in ethereal solution to form Diels-Alder adducts. The minor adducts possess structures (303), (304) and (305). The reaction is thought to involve the first excited triplet of benzene or an excited state complex. A [,,4,4-,,4,] photoadduct (306) is formed H H
(306)
(307)
(308)
Furans and their Benzo Derivatives: (ii) Reactivity
638
from furan and 1-cyanonaphthalene, but 2-cyanonaphthalene yields the [2 + 2 + 2 + 2] adduct (307). With 9-cyanoanthracene, irradiation of furan and alkylfurans gives high yields of [W4S + W4S] adducts. Thus 2-methylfuran and 3-methylfuran regiospecifically give (308) and (309). An exciplex between the singlet excited anthracene and the ground state of the furan is supposedly involved (74JCS(P1)236O>. Furan and 2-methylfuran form [4 + 2] cycloadducts with 1,1-diphenylethylene and indene in the presence of electron acceptors such as cyanonaphthalenes. Irradiation of indene and furan in acetonitrile with a 300 W high-pressure mercury lamp gives the [4 + 2] adduct (310; 35%) as well as (311; 20%) and (312; 10%). Product formation is thought to occur by electron transfer from the alkene to the excited singlet of the nitrile which suffers nucleophilic attack by the furan (78CC594). When furan is irradiated in methanol containing phenanthrene and 1,4-dicyanobenzene the dihydrofuran (313) is produced. This reaction is thought to involve electron transfer from the phenanthrene excited singlet to the dicyanobenzene, yielding a radical anion and a phenanthrene radical cation which in turn abstracts an electron from furan to yield a furan radical cation. This species reacts with methanol yielding a methoxyfuran radical and thence forms the product by cyanide displacement from the dicyanobenzene radical anion (77JA5806).
(310)
(312)
(311)
O"
OMe
(313)
Thermally unstable azetidines may be obtained by irradiation of furan in the presence of oxazolinones or 3-ethoxyisoindolone by [OT2S + W2S] cycloaddition (Scheme 90) (75JA7298). Benzophenone photosensitized [W2s + ff2s] cycloaddition of furan to dimethylmaleic anhydride yields an adduct (34%). This reaction has been extended to 2,5-dimethylfuran and other maleic anhydrides and maleimides (76CA(84)120785). O
b-4>h
V 54%
H i, 450 W Hg lamp, glyme; ii, A > 300 ran, CH2C12 Scheme 90
Photosensitized [W2S+W2S] cycloaddition of DMAD to benzo[6]furan yields the mixture of adducts (314), (315), (316) and (318) <77JOC2374>. Adduct (314) is the primary photoproduct and it rearranges via a diradical to the other products. Irradiation of any of the pure isomers yields the same mixture of products. Thermolysis of the adducts (314) and (318) affords the benzoxepins (317) and (319) which may be reclosed photochemically (Scheme 91). 2-Methylbenzo[6]furan yields similar products but only two adducts are formed from benzo[6]furan and methyl propiolate. The photoaddition of benzo[c]furan to a variety of alkenes has been described. With cycloheptatriene the [4+4] adducts (320) and (321) and the [4 + 6] adducts (322) and (323) are obtained in addition to the photodimer (301) and the photooxidation product 1,2dibenzoylbenzene. The [4 + 4] adducts may be formed in a concerted manner via an exciplex intermediate in a TT-TT* singlet state. The [4 + 6] adducts, formally symmetry forbidden,
Furans and their Benzo Derivatives: (ii) Reactivity
639 CO 2 Me
CO, Me
O" (318)
H
(319)
i, DMAD, A >300nm, 70 h, MeCOPh; ii, 185 °C; iii, hv; iv, 210 °C Scheme 91
probably arise in a stepwise manner from an excited TT-TT* triplet of 1,3-diphenylbenzo[c]furan. In contrast, the thermal reaction (benzene, 80°C) yields the exo-[4 + 6] adduct (322) and the endo-[4 + 2] adduct (324). Selective photoexcitation of 1,3-diphenylbenzo[c]furan in benzene in the presence of a number of acyclic dienes leads to a product distribution different from that of the thermal reactions; invariably the photodimer (301) is also isolated. 1,3-Cyclohexadiene affords only the [4 + 2] adducts (325) and (326); similar results are given by methyl 5-phenyl-2,4-pentadienecarboxylate, 1,4-diphenylbutadiene and a) -nitrostyrene, whilst methyl sorbate yields both [4 + 2] adducts (327) and (328) and [4+4] adducts (329) and (330). Dioxoles such as (331) are formed photochemically from benzo[c]furans and polycyclic o -quinones such as 9,10-phenanthrenequinone. O Ph
O Ph
O Ph
PhH
(325) CO2Me
CO, Me
Me CO2Me (329)
Furans undergo photochemical [2 + 2] cycloaddition with a large range of carbonyl compounds, including aliphatic aldehydes and ketones (66BCJ1806), a,/3 -unsaturated aldehydes, diketones (73JOC2860) and aromatic and heteroaromatic aldehydes and ketones to yield oxetanes (Scheme 92). Furan and benzo[6]furan (74BCJ2660) and their alkyl derivatives have been subjected to this reaction. The mechanism probably involves the electrophilic attack of the oxygen radical of the excited triplet of the carbonyl group on the furan, and oxetane formation is a result of coupling of the diradical thus produced. The regiochemistry with respect to the disposition of the two heterocyclic atoms is therefore always as shown. With 2-methylfuran, aldehydes attack either double bond of the furan, but benzophenone adds to 2- and 3-methylfuran to produce only the regioisomers (332) and (333) (67JOC2918). With unsymmetrical carbonyl addends there is the possibility of geometrical isomerism of
Furans and their Benzo Derivatives: (ii) Reactivity
640
the products. This configurational question has been studied for several pyridyloxetanodihydrofurans by measuring the NMR pseudo-contact shifts produced by cobalt(II) acetylacetonate. One isomer is usually produced and the bulkier group adopts the anti position (68T1299). With benzophenone, furan yields the 1:1 adduct (334) and after prolonged irradiation the two 2:1 adducts (335) and (336) (67TL4119). Furylquinones of type (337) on irradiation yield benzo[c]furoquinones of type (338; Scheme 93) (66HCA1806).
o
+ EtCHO
H
O+O
CHO
I
1 + MeCOCOMe O i, hv, 5-10 °C, N 2 ; ii, hv, 48 h, PhH Scheme 92
o Ac1
Me O (337)
(338) 60%
i, hv, 100W,N2 Scheme 93
Furans are highly susceptible to photooxygenation and the reactions are usually carried out at low temperature. The singlet oxygen, which adds to the diene system in a 1,4-fashion yielding bicyclic peroxides, is generated by sensitization with agents such as Rose Bengal, methylene blue or tetraphenylporphin (75HOU(4/5b)1488). Furan yields the peroxide (339) which explodes above - 2 0 °C but may be obtained crystalline at -100 °C. In methanol the hydroperoxide (340) is obtained by nucleophilic attack at an a-position, but above - 2 0 °C it loses water and forms the lactone (341). With furan-2-carbaldehyde, irradiation in ethanol yields the lactone (342), the intermediate hydroperoxide undergoing rearrangement with loss of formic acid. Tetraphenlyporphin-sensitized photooxidation of 2,5-dimethylfuran (Scheme 94) yields the peroxide (343) which is relatively stable in solution and can be O
O
(339)
(340)
(341)R = Me (342)R = Et
Furans and theirBenzo Derivatives: (ii) Reactivity
641
codistilled with carbon tetrachloride at -20 °C under reduced pressure. On treatment with methanol it yields the hydroperoxide (344), also available by photooxygenation of 2,5dimethylfuran in methanol, and on treatment with triphenylphosphine it is deoxygenated to 1,2-diacetylethylene (79JOC1727). The ester (345; Scheme 95) on photooxygenation yields the peroxide (346), m.p. 78 °C, which is stable at -15 °C under anhydrous conditions. Reaction with methanol gives the hydroperoxide (347). On standing for 15 days at room temperature the peroxide (346) furnishes the epoxide (348; 62%) and the stereoisomers (349) and (350) (5%) (Scheme 95). The reaction is thought to involve inter- or intramolecular epoxidation. These products, as well as unidentified peroxy compounds, are produced when (346) is exposed to aqueous acetone at 0 °C. Deoxygenation of (346) with diethyl sulfide affords (349) as the initial product (80JCS(Pl)l955>. 3-Methylfuran on photooxygenation, followed by chromatography and kugelrohr distillation of the product at 20 °C and low pressure, yields the products (351; 54%), (352; 10%), (353; 23%) and citraconic anhydride (354; 13%) (Scheme 96) (79LA1571). Tetraphenylfuran on photooxygenation in methanol is reported to give (355) and (356), but in acetone the products isolated are (357) and (358). The photooxygenation of the cyclophane (29) is particularly interesting. In methanol the intermediate hydroperoxide (359) undergoes intramolecular Diels-Alder reaction- and affords (360; Scheme 97), but in dichloromethane the tetraepoxide (362), formed via (361), is isolated. Photooxygenation of the sesquiterpene furanofukinal has been used in the synthesis of eremophilane type lactones <78H(1O)177).
Me O
HOO
>Oc M e °
OMe
(344) i, hv, O2, 5 °C, tetraphenylporphin, CC14 or CFC13; ii, MeOH, -78 °C, 2 h Scheme 94
>Q<
MeO Ph (346) CO2Me PhOC
'COMe
PhOC
(348)
O NQOH (347)
PhOC
CO,Me >=< H COMe (350)
COMe (349)
i, hv, O2, methylene blue, CC14; ii, MeOH; iii, 15 d, 25 °C Scheme 95
Me
r o
A ILKo
Me
Me I
Me I
Me
^O /
o
O
(351)
(352)
Me
O (353)
i, hv, O2, methylene blue, CH2C12> 0 °C Scheme 96 Ph Ph
OO (355)
Ph MeO
Ph Ph
>O<
Ph
O OMe (356)
Ph
O
Ph
o=c c=o \Ph Ph/ (357)
O (354)
642
Furans and their Benzo Derivatives: (ii) Reactivity O
OOH 'Me MeO
w
OOH
(359)
(360) 42%
O
o \ (361)
/ o
(362)75% i, hv, O2, photosensitizer; ii, MeOH; iii, CH2C12 Scheme 97
Benzo[6]furan and 2-methylbenzo[6]furan fail to undergo photooxygenation but 2,3dimethylbenzo[6]furan yields 2-acetoxyacetophenone (364). At -78 °C the peroxide (363) is produced which at higher temperature rearranges to the acetophenone (364; Scheme 98). 2-Vinylbenzo[6]furans, e.g. trans-2-styrylbenzo[6]furan (365; Scheme 99), yield photooxides which may be isolated. Compound (366) on treatment with a catalytic amount of triethylamine yields the lactone (367) (77BCJ3026). Me
o'' M e (363)
(364)
i, hv, O2, photosensitizer, -78 "C; ii, 20 °C Scheme 98
o (365)
(366) 70% (367) 58% i, hv, O2, tetraphenylporphin, CC14; ii, NEt3, Et 2 O, 20 min Scheme 99
Benzo[c]furans undergo very rapid photooxidation. 1,3-Diphenylbenzo[c]furan yields the oxide (368) on sensitized photooxygenation in ether at -50 °C. Reduction of the oxide with potassium iodide in acetic acid affords 1,2-dibenzoylbenzene and reaction with methanol supplies the hydroperoxide (369).
(368)
3.11.3 FULLY CONJUGATED RINGS: REACTIVITY OF SUBSTITUENTS 3.11.3.1 Fused Benzene Rings The chemistry of dibenzofuran is that expected of a 2,2'-linked diphenyl ether. The partial rate factors for protodetritiation (370), protodetrimethylsilylation (371) (6UCS5077)
Furans and their Benzo Derivatives: (ii) Reactivity
643
and nitration (372) with nitric acid in acetic anhydride (58JCS3079) have been determine'd and compared for those of diphenyl ether. The data for protodetritiation and protodetrimethylsilylation are consistent with the majority of electrophilic aromatic substitutions of dibenzofuran. The reactivity of the positions ortho and para to the oxygen atom is reduced in going from diphenyl ether to dibenzofuran and this is attributable to the participation of the lone pair in the aromaticity of the five-membered ring. The reactivity of the 4-position is reduced more than the 2-position and this is attributable to the strain in the five-membered ring produced in the transition state for substitution (68JCS(B)1559>. Bromination (6UCS4921), chlorination (55JOC657), iodination (65MI31100), sulfonation (49JA1593), acylation (50RTC861), benzoylation (54JA6407) and chloromethylation (56JOC457) all take place at the 2-position. Further substitution by these methods results in the production of the 2,8-disubstituted compounds. Formylation in the 2-position can be achieved by the Gattermann method but not by the Vilsmeier-Haack method (57JIC347). Nitration is anomalous and results in the 3-nitro compound; dinitration results in the 3,8-dinitro compound. The partial rate factors reported for nitration should be viewed with suspicion because of the difficulty generally encountered in introduction of a 1-substituent by electrophilic substitution or by ring synthesis. 0.65
(371)
An electron releasing substituent in one ring generally leads to electrophilic substitution in that ring. 2-Methoxydibenzofuran undergoes acylation and Vilsmeier formylation at the 3-position (56JCS4276), but 2-hydroxydibenzofuran is reported to undergo bromination and Mannich reaction at the 1-position. Benzoylation of 2-methyldibenzofuran results in substitution at the 8-position, but 2-acetylaminodibenzofuran undergoes bromination and nitration at the 3-position. 3-Hydroxydibenzofuran undergoes bromination at the 2-position, 3-acetylaminodibenzofuran undergoes bromination and nitration at the 2-position and 3-methyldibenzofuran undergoes benzoylation at the 2-position. 4-Methoxy- and 4hydroxy-dibenzofuran yield 1-substituted derivatives on acylation, formylation and halogenation. Nitration of 4-acetylamino- and 4-hydroxy-dibenzofuran with nitric acid in acetic anhydride at 0 °C gives the 3-nitro compounds. With nitric acid in acetic acid at 60 °C the 1-nitro compound results from 4-acetylaminodibenzofuran; 4-methoxydibenzofuran behaves similarly. Lithiation of dibenzofuran with butyllithium and mercuration both occur at the 4-position. Thallation occurs at the 2-position, however (57IZV1391). The mercury and thallium derivatives serve as a source of the iodo compounds by reaction with iodine. Bromodibenzofurans undergo bromine/lithium exchange with butyllithium and the derived lithio compounds may be converted into phenols by reaction with molecular oxygen in the presence of a Grignard reagent, into amines by reaction with O-methylhydroxylamine, into sulfinic acids by reaction with sulfur dioxide, into carboxylic acids by reaction with carbon dioxide and into methyl derivatives by reaction with methyl sulfate (Scheme 100). This last reaction
\JCxs Me
Scheme 100
CT 63%
Me
644
Furans and their Benzo Derivatives: (//) Reactivity
has been applied to the 2,8-dilithio compound prepared by bromine/lithium exchange and to the 4,6-dilithio compound prepared by proton/lithium exchange (65JA213). The lithiation of a number of alkyl- and methoxy-substituted dibenzofurans has also been studied. Nucleophilic substitution of dibenzofurans has been little studied. Bromo and iodo compounds are converted into the amino compounds on autoclaving with aqueous ammonia in the presence of copper(I) bromide (73OPP125). Iodo compounds can be converted into phenols with aqueous potassium hydroxide at 250 °C (65MI31100), but dibenzofuran is cleaved to 2,2'-dihydroxybiphenyl on fusion with sodium hydroxide. Animation of halo compounds can be achieved with sodamide but 4-halo compounds undergo cine substitution on treatment with sodamide or lithium dialkylamides and the 2-substituted compounds result (56JOC457). 1,2,3,4-Tetrafluoro- and octafluoro-dibenzofuran react with nucleophiles at the 3-position (Scheme 101) <67T404l,68JCS(C)1560>. LAH
Me
Scheme 101
Homolytic substitution of dibenzofuran with methoxycarbonylmethyl radicals gives poor yields of dibenzofuranacetic acids; the ratio of products at the 1-, 4- and 3-positions is 3.67:2:1 (6UA1358). Hydrogenation of dibenzofuran over a platinum catalyst yields 1,2,3,4-tetrahydrodibenzofuran, whilst hydrogenation over a sodium/rubidium catalyst at high temperature and pressure brings about ring cleavage and phenylcyclohexane (80%) and biphenyl (10%) result (7UOC694). Boiling dibenzofuran with W7 Raney nickel in methanol results in a moderate yield of frarcs-2-phenylcyclohexanol (63AJC20). Birch reduction affords the 1,4dihydro compound (82%). The radical anion of dibenzofuran is produced by the action of alkali metals in 1,2-dimethoxyethane or by electroreduction at a stationary mercury electrode. When treated with lithium in boiling ether, dibenzofuran is cleaved and carbonation results in the coumarin (374; Scheme 102). In boiling dioxane, carbonation results in none of the coumarin but hydrolysis results in 2-hydroxybiphenyl; the intermediate (373) can presumably abstract a proton from dioxane (57JOC851). Cleavage of dibenzofurans with lithium in boiling dioxane has been advocated as a general method of synthesis of 2hydroxybiphenyls (80S634).
(373)
(374) 40%
Scheme 102
3.11.3.2 Alkyl and Substituted Alkyl Substituents Alkylfurans are usually obtained by ring synthesis, decarboxylation of alkylfurancarboxylic acids, Wolff-Kishner reduction of aldehydes or ketones, or by reduction of halomethyl groups with zinc and acetic acid or LAH (79JOC3420); alkylation is of limited value. The chemistry of these compounds is conventional but oxidation to furancarboxylic acids cannot usually be carried out due to the lability of the ring. NBS bromination (Section 3.11.2.2.5) is a useful route to side-chain substituted compounds but reduction of esters to hydroxymethyl groups and subsequent transformation is often preferable. The haloalkyl compounds are extremely sensitive to resinification but if adequate precautions are taken they are
Furans and their Benzo Derivatives: (ii) Reactivity
645
tractable. Their reaction with nucleophiles is worthy of comment. With aqueous cyanide, 2-chloromethylfuran provides the intimate ion pair (375) and cyanide attacks to give the product of side-chain substitution (376), but the major pathway provides the product (378) of nuclear substitution by aromatization of the intermediate (377; Scheme 103). Spectroscopic evidence for the intermediate (377), which may also be isolated, has been obtained and the effect on the product ratio of different substituents has been investigated (76JOC2835). By working in DMSO the conventional product (376) is obtained. 3-Chloromethylfuran yields a similar mixture of nitriles on treatment with cyanide so that for the preparation of 3-furylacetonitrile, methyl 3-bromomethylfuran-2-carboxylate is allowed to react with cyanide in aqueous benzene in the presence of tetrabutylammonium bromide, and the nitrile produced is subjected to partial hydrolysis and decarboxylation (78BSF(2)27l). 2,5Bis(chloromethyl)furan gives a mixture of the normal product and 2-chloromethyl-5methylene-2,5-dihydrofuran-2-carbonitrile on treatment with cyanide. Nuclear substitution is only a minor pathway when methyl 2-bromomethylfuran-3-carboxylate is treated with cyanide in aqueous benzene but in ethanol the methylene group reacts with the formation of (379) and (380). Similar products are obtained from methyl 2-chloromethylfuran-5carboxylate (76JHC89). 2-Bromomethyl-5-nitrofuran on treatment with sodium hydride in DMF gives bis(5-nitro-2-furyl)ethylene by a carbanion mechanism, but azide and malononitrile in DMF give 5-aminofuran-2-methylidenemalononitrile by a mechanism suggested to involve a furfurylnitrene (80CCC752). When 2-chloromethyl-3,4-diphenylfuran is treated with aqueous cyanide, 5-methyl-3,4-diphenylfuran-2-(5/f)-one is obtained (79JHC1293). Halomethyl compounds in the furan series react well with triphenylphosphine to afford phosphonium salts which have been extensively used in Wittig reactions to form annulenes (69AJC1951) and annulenones (75MI31100). Furan-2-methanamine (furfurylamine) reacts with 2,4,6-trimethyl- or 2,4,6-triphenyl-pyrylium perchlorate in ether to supply the appropriate iV-(2-furylmethyl)pyridinium perchlorate. The pyridine is readily displaced by a variety of nucleophiles (79JCS(P1)426). CH,CN
O
(376) O"
CH 2 Ci
CH2 " (375)
cr .civr
'A o )cN
O (378)
(377) Scheme 103
//
CO2Me \\ MeO2C
MeO2C (380)
(379)
2-Furanmethyl benzoate (381) on flash vacuum pyrolysis affords the cyclobutenone (382; 40%). Deuterium labelling established the mechanism shown in Scheme 104. The 5-methyl analogue (383), however, gives the dihydrofuran (30) (74JOC1448). Ph
/
o
CH,
(30)
Scheme 104
(382)
646
Furans and their Benzo Derivatives: (ii) Reactivity
(5-Methyl-2-furylmethyl)trimethylammonium hydroxide undergoes 1,6-Hofmann elimination on heating with the production of 2,5-dimethylenedihydrofuran (30), which undergoes dimerization to afford the cyclophane (29). By 'cross breeding' of this intermediate with similar dimethylene compounds, ready access is given to mixed cyclophane systems, an area which has been extensively investigated. Furan-2-methanols are cleaved to derivatives of levulinic ester by methanolic hydrogen chloride; a mechanism involving the carbonium ion (375) has been proposed. Under similar conditions, a,/3-unsaturated carbonyl compounds of type (384) undergo a similar rearrangement, a reaction known as the Marckwald rearrangement, and afford keto esters of type (385), as shown in Scheme 105 in an example drawn from a synthesis of equilenin (70AJC547). EtO2C^
o
IT
II
\
\\ HCl/EtOH
o MeO^
(384)
(385) Scheme 105
3.11.3.3 Carboxylic Acids Carbonation of lithiofurans is a useful method for obtaining these compounds. Furan-2carboxylic acid (plsTa3.15) is a stronger acid than the 3-carboxylic acid (pKa 4.0) because of the inductive effect of the ring oxygen, and both are stronger than benzoic acid. Furancarboxylic acids can be decarboxylated by the copper-quinoline method or merely by heating. The 2-carboxylic acids are more easily decarboxylated than the 3-isomers, so furan-3-carboxylic acid can be obtained by stepwise decarboxylation of the tetracarboxylic acid via the 2,3,4-tricarboxylic acid and the 3,4-dicarboxylic acid. A more convenient source of the 3-carboxylic acid is by partial hydrolysis and decarboxylation of the readily available diethyl furan-3,4-dicarboxylate (71S545). Methyl benzo[6]furan-3-carboxylate is more easily hydrolyzed than its 2-isomer. 3.11.3.4 Acyl Substituents Furan-2-carbaldehyde is the most important furan of commerce and processes are available for its decarbonylation to furan. The polyaldehydes of the furan series are all known and are available by reduction of nitriles (70BSF1445), reduction and oxidation of esters (80S950) or from halofurans by lithiation and formylation with DMF (70BSF1838). The Vilsmeier-Haack method may be applied to alkylfurans. Furan-2-carbaldehyde undergoes the Cannizzaro reaction, and oxidation of furanaldehydes to the carboxylic acids may be brought about with silver oxide. The aldehydes also undergo the Wittig reaction. Furan-2carbaldehyde, on reaction with primary arylamines in acidic solution, affords the salt (386) which can be converted into a pyridinium salt (388) with acid or a cyclopentenone (387) with base. Cyclopentenones (387) can also be formed directly by the reaction of furan-2carbaldehyde with arylamines (Scheme 106) (70AJC2315).
ArHNP (387) Scheme 106
Furans and their Benzo Derivatives: (ii) Reactivity
647
Furyl ketones are conventional in their reactions. 2-Acetylfuran forms enamines which on heating yield 2-dialkylaminophenols (62CB183). The tosylate of the oxime of 2-acetylfuran is solvolyzed in methanol to a stereoisomeric mixture of 2-acetyl-2,5-dimethoxy-2,5dihydrofurans (75KGS1026). The tosylate of the oxime of 2-acetylbenzo[£]furan also undergoes unusual rearrangements on solvolysis. Di-2-furylethanedione (furil) undergoes the benzilic acid change and at low temperatures furilic acid can be isolated as a salt or as the methyl ester (prepared with diazomethane). Furilic acid itself is unstable, especially to acids, and acetic acid will induce decomposition to 2,2'-difuryl ketone (72ACS1280). 3.11.3.5 JV-linked Substituents Few simple amines are known in either the furan or the benzo[& ]furan series. Simple nitrofurans on attempted reduction by mild chemical methods suffer what is probably a deaminative degradation. Similarly, attempted reduction of 2-nitrobenzo[6]furan affords not the amine but the product of its hydrolysis, benzofuran-2(3//)-one. Other classical synthetic approaches to 2-furanamine have failed, including the Curtius method and Beckmann rearrangement of 2-benzoylfuran oxime. However, hydrazinolysis of iV-(2-furyl)phthalimide, obtained from phthalimide and 2,5-dimethoxy-2,5-dihydrofuran, gives 2-furanamine which was not isolated but detected by GLC-MS and * NMR spectroscopy. The latter reveals the absence of imino tautomers (75AP713). The chemistry of 2-dialkylamino-5-phenylfurans is typical of enamines; protonation occurs on carbon to produce iminium salts. They are stable to base but afford 5-phenylfuran-2(3/f )one on hydrolysis with dilute acid. 2-Morpholino-5-phenylfuran couples with diazonium salts and affords Diels-Alder adducts with maleic anhydride and iV-phenylmaleimide <73JCS(P1)2523>.
Furan-2-amines substituted with electron withdrawing groups are stable compounds and exist as the amino tautomers. Ethyl 5-acetylaminofuran-2-carboxylate may be nitrated and brominated. The product of nitration, the 4-nitro compound, undergoes hydrolysis to the amine and reduction to the 5-acetylamino-4-amino compound. The nitroamine may be diazotized and then gives a coupling product with 2-naphthol. 5-Nitrofuran-2-carbaldehyde may be catalytically hydrogenated to the 5-amino compound (74H(2)391). Alkyl- and arylsubstituted 2-aminofuran-3-carbonitriles, as expected of enamines, yield iminium salts on protonation, and on acidic hydrolysis they afford furan-2(3//)-ones. With benzaldehydes they afford anils and they participate in Diels-Alder reactions with maleic anhydride, affording derivatives of phthalic anhydride by concomitant dehydration (68TL4605). 3-Acetyl2-amino-5-methylfuran-4-carbonitrile has been synthesized and its structure determined by X-ray crystallography, but the exploration of its chemistry was confined to the observation that it gave 2,5-dimethylpyrrole-3,4-dicarbonitrile on treatment with hot aqueous ammonia (78JOC3821). 3,5-Dinitrofuran-2-amine is known but does not undergo any reactions characteristic of an aromatic amine (79JHC477), A stable furan-2-diazonium fluoroborate has been prepared which gives some reactions characteristic of an aromatic species (63LA(667)96). Two C-alkylf uran-3-amines are known; they both resinify very rapidly in air. They are sensitive to hot acid and alkali and ammonia is liberated. It is reported that they react with nitrous acid and that coupling products are obtained with 2-naphthol. It has been suggested that they exist as imino tautomers, but there is no spectroscopic information on this point (B-76MI31101). 5-Methyl-2,4-diphenylfuran-3-amine has been prepared by the Curtius method but its chemistry remains unexplored (73TL3353). 3-Morpholino-2,5-diphenylfuran (389) forms a a--complex (390) with bromine. When treated with boiling ethanol, (390) yields the furanone (391; Scheme 107) (70JHC569). 3-Azidofuran-2-carbaldehyde and 3-azidofuran-2-carbonitrile are reduced by hydrogen sulfide in methanol in the presence
a (389)
(390) Scheme 107
(391)
648
Furans and their Benzo Derivatives: (ii) Reactivity
of piperidine to the respective furan-3-amines which exist as such (75ACS(B)224). Application of the Friedlander synthesis to 3-aminofuran-2-carbaldehyde yields furo[3,2-6]pyridines. 2-Aminobenzo[6]furan-2-carboxylates and 2-acylbenzo[7>]furan-3 -amines exist as the amino tautomers. 3-Pyrrolidinobenzo[6]furan is available from benzo[&]furan-3(2jF/)-one (74RTC321).
3.11.3.6 O-Linked Substituents Simple furanols (hydroxyfurans) never exist as such but as their keto tautomers (B76MI31100). Furan-2(3//)-one (but-3-enolide) (392) is formally the tautomer of 2-furanol, but its isomer furan-2(5//)-one (but-2-enolide) (393), in which the double bond is in
(392)
(393)
conjugation with the carbonyl group, is more stable and the conversion can be achieved by acid or base. The chemistry of butenolides, which are important as many natural products, is properly that of lactones rather than of furans and has been extensively reviewed (76CRV625,78FOR(35)133>. Butenolides show little evidence of enolic behaviour, as indicated by their gas phase ionization potentials and their photochemistry. 5-Methylfuran-2(3//)-one fails to undergo O-alkylation and under phase transfer conditions methylation occurs at the 3-position and 5-methylfuran-2(5//)-one is also formed. However, 3,4,5-triphenylfuran-2(3//)-one is converted into 2-methoxy-3,4,5-triphenylfuran, as well as undergoing C- methylation, by treatment with iodomethane and potassium in benzene. Bases such as LDA give enolate anions with butenolides. 5-Methylfuran-2(3//)-one with LDA followed by acetyl chloride affords 2-acetoxy-5-methylfuran (40%) which, with boron trifluoride etherate, undergoes a rearrangement of the Fries type yielding 5-acetyl-5-methylfuran2(5H)-one (78JOC2072). C-Alkylation of butenolides can be achieved by generation of their enolate anions with LDA in the presence of HMPT in THF, followed by treatment with reagents such as geranyl or prenyl bromide. Thus 3- and 4-methylfuran-2(5//)-one are alkylated at the 3- and 5-positions. Since furan-2(5//)-ones are readily reduced to furans with DIBAL, this constitutes a useful furan synthesis (77TL4443). 5-Substituted furan-2(3//)ones condense with aromatic aldehydes, affording (£j)-3-arylmethylidenefuran-2(3//)-ones which on flash vacuum pyrolysis undergo decarbonylation (Scheme 108) (80AG555).
700 °C
10 4mmHg
RCOCH=C = CHAr
Scheme 108
2-Methoxyfuran and 2-acetoxyfuran are readily prepared by heating the appropriate 2,5-disubstituted 2,5-dihydrofuran with a trace of naphthalene-2-sulfonic acid in an inert solvent at high temperature. 2-Alkoxyfurans are also available from 5-bromofuran-2carboxylates by nucleophilic substitution, hydrolysis and decarboxylation (56JOC516). Their cycloaddition reactions have been mentioned previously (Section 3.11.2.7.1). 2-tButoxyfuran is also readily available and trimethylsilyloxy compounds are available from butenolides by reaction with chlorotrimethylsilane, triethylamine and zinc chloride in acetonitrile. Acid hydrolysis of 2-alkoxyfurans occurs chiefly by 5-protonation to give a furan-2(5if )-one which subsequently affords an acrylate (74JOC2920). With halogens or LTA, 2-acetoxyfurans yield 5-halo- or 5-acetoxy-furan-2(5//)-ones. The cycloaddition reactions of 2,5-bis(trimethylsilyloxy)furans have been discussed (Section 3.11.2.7.1). The reactions of these compounds with aldehydes and ketones and with quinone acetals have also been investigated (80TL3431). Attempts to prepare 2,4-dimethoxyfuran have been fruitless but 2,3- and 2,5dimethoxyfuran are well known (79JCS(P1)1893). 4-Hydroxyfuran-2(5//)-ones (tetronic acids) are an important group of natural products and they are dealt with in the aforementioned reviews. 3-Furanol is formally the enolic form of furan-3(2//)-one (394). Compounds with
Furans and their Benzo Derivatives: (ii) Reactivity
649
a carbonyl substituent at the 2-position behave as genuine 3-furanols but without this substituent, or even with a carbonyl substituent at the 4-position, the compounds exist in the keto form and behave as vinylogous lactones. 2-Acetyl-3-furanol (isomaltol) is readily available and is an acidic enol (pKa 5.7) which gives a deep red colour with Fe .
O (394)
Diazomethane furnishes the methyl ether which has been degraded to 3-methoxyfuran which, however, is more easily available from 3-iodofuran. 3-Methoxyfuran is cleaved by acid to furan-3(2//)-one. Other 3-furanols with ester, acetyl or benzoyl substituents at the 2-position are also available. They exist in the enolic form but their chemistry has not been investigated (76JCS(P1)1688). Furan-3(2i/)-ones with acetyl or ester substituents at the 4-position are readily available. They exist in the keto form but show some evidence for enolic behaviour and their chemistry is similar to that of enolizable ketones. They enter into cycloaddition with maleic anhydride, are alkylated at the 2-position, condense with aldehydes and ketones and are oxidized by LTA to the 2-acetoxy compounds (74BSF2061). The simple furan-3(2i/)-ones exist in the keto form but may be O-acylated with acetic anhydride and sodium acetate; however, they undergo C-alkylation. They are usually stable to acid, merely being protonated. 4-Alkoxyfuran-3(2i/)-ones are readily hydrolyzed to tetronic acids. Furan-3(2/f )-ones are degraded by aqueous base which attacks in a conjugate fashion so that 2,5-dimethylfuran-3(2i/)-one, readily available from biacetyl, furnishes acetate and acetoin, but compounds with an ester group at the 4-position furnish tetronic acids (Scheme 109). //
\
,—P
-OJI^Mer^
—
Me /
OH
\
^ ^ Me /
#
MeCOCH,COCHMe — • MeCOT + MeCOCHOHMe O *\
CO2Et
Me Scheme 109
2,5-Dimethylfuran-3(2/f)-one undergoes coupling with arenediazonium salts at pH 0 and furnishes 2-arylazo-2,5-dimethylfuran-3(2i/)-ones which are readily converted into l-aryl-5-methyl-3-pyrazolones (79S283). 3,4-Dimethoxyfuran is readily available from the enolic dimethyl 3,4-dihydroxyfuran-2,5dicarboxylate. This intermediate, like a phenol, can be readily O -methylated or O-benzylated. Hydrolysis and decarboxylation then furnishes the 3,4-dialkoxy compounds (78HCA430). The dimethoxy compound readily enters into Diels-Alder reactions, the Mannich reaction, and may be lithiated. On mild acid hydrolysis it supplies, in poor yield, 4-methoxyfuran-3(2//)-one and not tetrahydrofuran-3,4-dione, which is not produced by attempted hydrogenolysis of 3,4-dibenzyloxyfuran either. The dione, however, is known, and surprisingly exists in the diketo form (60JA3219).
O (395)
The chemistry of benzo[£]furan-2(3//)-one (395) which exists in the keto form, is that expected of the lactone of 2-hydroxyphenylacetic acid. Grignard reagents bring about the expected ring opening. Condensations may be effected at the 3-position, especially with aromatic aldehydes. Methylation with iodomethane and potassium carbonate in DMF furnishes the 3-methyl and the 3,3-dimethyl compound. Methylation, with diazomethane,
650
Furans and their Benzo Derivatives: (ii) Reactivity
of 3-acetylbenzo[6]furan-2(3//)-one provides some 3-acetyl-2-methoxybenzo[Z>]furan so that the benzofuranol tautomer is involved. 3-Acetyl-2-methoxybenzo[£]furan undergoes acid catalyzed rearrangement to methyl 2-methylbenzo[6]furan-3-carboxylate (73AJC1079). Benzofuran-3(2H)-ones (396) exist in the keto form but undergo ready enolization. Acetylation with acetic anhydride and sodium acetate affords 3-acetoxybenzo[6]furans, but reaction under acidic conditions usually supplies these products admixed with 3-acetoxy-2acetylbenzo[6]furans. Alkylation usually furnishes a mixture of O- and C-alkylated products. 3-Acetoxy-6-methoxy-4-methylbenzo[fe]furan, on Vilsmeier reaction, supplies the 3-chlorobenzo[6]furan-2-carbaldehyde, the product expected from an enolizable ketone (72AJC545). Benzofuran-3(2//)-ones react normally with carbonyl reagents. Grignard reagents react in the expected way and dehydration of the intermediate affords a 3substituted benzo[Z>]furan. The methylene group is reactive so that self condensation, condensation with aldehydes and ketones and reaction with Michael acceptors all occur readily. P
(396)
3.11.3.7 S- Linked Substituents Furanthiol derivatives are available by treating lithiofurans with sulfur; acidification then affords the thiols, acetic anhydride affords thiol acetates, and alkyl halides give thioethers. The thiols exist predominantly as such rather than as their thione tautomers. Hydrolysis of 2-thioethers with acid is accompanied by ring opening. 3.11.3.8 Halogen Substituents The halo-furans and -benzo[£]furans are particularly important as precursors of the lithio derivatives (Section 3.11.3.9). Direct halogenation of furan (Section 3.11.2.2.5) is unsatisfactory, and halofurans are prepared by decarboxylation of halofurancarboxylic acids, from chloromercurio compounds, by decarboxylative halogenation of furancarboxylic acids or by partial dehalogenation of polyhalofurans. Decarboxylation of halofurancarboxylic acids is usually carried out with copper and quinoline at 150-230 °C and the product often distills from the reaction mixture (71BSF242). Heating chloromercuriofurans with iodine and potassium iodide in water yields iodofurans. Thus 3,4-bis(chloromercurio)-2,5-dimethylfuran yields the diiodo compound (41%), and tetrakis(chloromercurio)furan yields tetraiodofuran (67%). Boiling sodium furan-2,5-dicarboxylate with potassium iodide and iodine in water yields the diiodofuran, and 2,5dibromofuran (78%) is similarly available from sodium 5-bromofuran-2-carboxylate, potassium bromide and bromine (74ZOR1341). Tetraiodofuran may be converted to the 3,4-diiodo compound (48%) or the 2,3,4-triiodo compound (85%), depending on the proportions of reagents, by brief entrainment with bromoethane and magnesium and subsequent hydrolysis. 2,3-Dibromofuran and 3,4diiodofuran are converted into the 3-halo compounds by reaction with one mol of ethyllithium and subsequent hydrolysis (70BSF1838). The best entry to the 3-substituted furan series is provided by the bromination of the furan/maleic anhydride adduct. The intermediate dibromo compound (78%) on heating with quinoline at 210 °C undergoes elimination of hydrogen bromide and retro diene reaction, affording 3-bromofuran (45%) (69KGS17). The halofurans are generally highly unstable to light and air. 2-Bromo- or 2-iodo-furans with electron withdrawing groups at the 5-position afford good yields of 2,2'-bifuryls on reaction with copper bronze in boiling DMF (66JCS(C)976). 3.11.3.9 Metal Substituents Mercury compounds are seldom used in modern furan chemistry. Deuterodemercuration finds use in the preparation of deuterofurans (Scheme 110) <,74JCS(Pl)ll4l). 3-Chloromer-
Furans and their Benzo Derivatives: (ii) Reactivity
651
curiofuran is available by pyrolysis of the mixed salt (397) and is readily converted into the iodo compound (398; Scheme 111), which is a valuable source of 3-substituted furans via the lithio derivative (72CJC3749). Treatment of the mercuriochlorides with aqueous sodium thiosulfate yields difuryl mercury compounds which are sometimes used in the preparation of lithio derivatives by mercury/lithium exchange (Scheme 112) (68JOC1227). The bis(benzo[6]furyl)mercury (400) is available from the lithio compound (399); on pyrolysis in the presence of tetracyclone the dibenzofuran (401) is isolated, suggesting the intermediacy of benzo[6]furyne (Scheme 113). H CI
fi~\
MeO2C<\ ^Br
«
HoCl O
CO,H
-W/
-o
CO 2 H g OAc
"' 51%
(397) 81%
(398)75%
i, Hg(OAc)2, H2O; ii, xylene, 23 h; iii, NaCl, AcOH; iv, I2, KI Scheme 111
Scheme 112
Ph (399)
(400)
(401) 70%
Scheme 113
Grignard reagents are difficult to prepare in both the furan and benzo[6]furan series and their use has been superseded by the more tractable lithio compounds. Bromofurans are best converted into the Grignard reagents by treatment with a copper-magnesium alloy in THF (80JOC3125).
Butylpotassium and butylcesium deprotonate furan at the 2-position (75BSF1302), but butyllithium is the reagent of choice. When furan is treated with butyllithium the reactions in Scheme 114 occur (77JCS(P1)887). The conditions, however, may be controlled to yield predominantly the mono- or the di-lithio derivative. By carbonation and esterification of the reaction mixture obtained by treatment of furan with butyllithium and TMEDA (1:1:1) in ether at 25 c Cior 30 min, a 98% yield of methyl f uran-2-carboxylate is obtained. Similarly, a butyllithium: TMEDA: furan ratio of 2.5:2.5:1 in boiling hexane for 30 min results in 91% of dimethyl furan-2,5-dicarboxylate and 9% of the monoester. Competition experiments indicate that furan reacts with butyllithium faster than thiophene under non-ionizing conditions but that the order is reversed in ether or in the presence of TMEDA.
// \\+BuLi —// W i ; +BuH
X
Vii+BuLi
A +BuH
O
O
Scheme 114
3,4-Dimethoxyfuran can be mono- and di-lithiated and the intermediates undergo conventional reactions (78HCA430). Furan-2-carboxylic acid on treatment with LDA in THF at -78 °C for 0.5 h yields the dilithio compound (402), which is stable up to -10 °C; above this temperature, proton abstraction from THF occurs. It reacts smoothly with both chlorotrimethylsilane and iodomethane at -78 °C (Scheme 115), but other alkylations
652
Furans and their Benzo Derivatives: (ii) Reactivity
require a temperature of - 3 0 °C and yields are lower. Reactions with aldehydes and ketones are rapid and clean at —78 °C and give alcohols in 80-85% yield. These may be converted into alkenes by dehydration. 3-Methylfuran-2-carboxylic acid is lithiated at the 5-position with LDA, and furan-3-carboxylic acid is similarly lithiated at the 2-position <8UCS(Pl)ll25). j)CO2H
Li(^ J )
2
3(^
(402) Scheme 115
Halofurans with vacant a-positions undergo proton/lithium exchange rather than halogen/lithium exchange with LDA due to its weak nucleophilic character and strong basicity (72TL3507). Advantage has been taken of this in a neat synthesis of rosefuran (Scheme 116) (77HCA2085). 2-Lithiofurans are also available by halogen/lithium exchange and with 2,3-dihalo compounds this can be controlled to occur only at a 2-position (70BSF1838). 3-Lithiofuran is readily available by halogen/lithium exchange from 3iodofuran, or more conveniently from 3-bromofuran (74S443). /
\Br
66%
71%
i, LDA, -80 °C, THF; ii, Me2C=CHCH2Br; iii, BuLi, -80 °C; iv, Mel Scheme 116
Lithiofurans on carbonation readily give carboxylic acids; they react with DMF to give aldehydes, with hexachloroethane to give chloro compounds and with alkyl halides to give alkyl compounds (76JOC2075). They undergo coupling with copper(II) chloride to give 2,2'-bifuryls (75AG745). 2,5-Diaryl-3-lithiofurans on heating in hexane undergo ring cleavage (76JCS(Pl)989). A few examples are shown in Scheme 117.
32%
59%
i, BuLi; ii, Me2NCO2Et; iii, H + Scheme 117
Furfuryl compounds with an anion stabilizing substituent such as a phenyl, a trimethylsilyl, or a 1,3-dithiane group yield the 2-furfuryl carbanion when treated with butyllithium. A facile ring cleavage then ensues (79JA2208,78JOC4235). 2-Lithiobenzo[6]furan is available by bromine/lithium exchange from 2bromobenzo[Z>]furan but is more conveniently prepared from benzo[6]furan with butyllithium in ether at - 1 0 °C. It affords alkylation, formylation and carboxylation products in high yield (77BSF142). When 3-bromobenzo[£]furan is treated with butyllithium at 15 to - 6 0 °C, much ring cleavage to 2-ethynylphenol occurs, but by operating at -115 °C the
Furans and their Benzo Derivatives: (ii) Reactivity
653
3-lithio derivative is stable and may be carboxylated to benzo[6]furan-3-carboxylic acid in 62% yield. 2,3-Dibromobenzo|7>]furan undergoes bromine/lithium exchange at the 2position when treated with an equivalent of butyllithium at -75 °C. Subsequent hydrolysis, formylation and carbonation yield the corresponding 3-bromo derivatives. By use of a large excess of butyllithium, the dilithio compound can be prepared which on carbonation yields benzo[6]furan-2,3-dicarboxylic acid (60%). 2-Furylcopper is available from 2-lithiofuran by treatment with copper(I) bromide in ether at 0 °C (72ACS3383). It may be obtained as an air unstable greenish-yellow solid soluble only in solvents like pyridine and quinoline. By reaction with iodoarenes in pyridine, moderate yields of Ullmann coupling products are obtained. 3-Furylcopper has also been obtained. Both isomers undergo Stephens-Castro coupling with iodoacetylenes (75JCS(P1)641). Lithium di(3-furyl)cuprate has been generated from 3-lithiofuran by treatment with copper(I) iodide in ether at -78 °C; it behaves as a hard nucleophile and adds in 1,2-fashion to carbonyl compounds. Alternatively, treatment of 3-bromofuran with two equivalents of f-butyllithium in THF and adding copper(I) iodide and dimethyl sulfide at -50 °C gives a reagent which behaves as a soft nucleophile and adds in a conjugate fashion to cyclohexen-2-one. It further gives 3-alkylfurans by substitution with alkyl halides (79TL4577).
3.11.4 SATURATED AND PARTIALLY SATURATED RINGS A review is available (65HOU(6/3)517>.
3.11.4.1 2,3-Dihydrofurans The chemistry of 2,3-dihydrofuran is that of an enol ether since it is the internal enol ether of 4-hydroxybutanal, which it affords on acid hydrolysis. Dry hydrogen chloride will add to afford 2-chlorotetrahydrofuran and chlorine affords frans-2,3-dichlorotetrahydrofuran. It is polymerized by boron trifluoride. Alcohols add readily in the presence of a trace of toluene-p-sulfonic acid to afford 2-alkoxytetrahydrofurans (65JOC2441). These, however, are more conveniently prepared by the reaction of the alcohol, in the presence of triethylamine, with 2-chlorotetrahydrofuran available by chlorination of tetrahydrofuran with sulfuryl chloride. This method is useful for the protection of hydroxy groups since the 2-alkoxytetrahydrofurans are generally stable to nucleophiles and bases, but they are more easily removed under acidic conditions than the tetrahydropyranyl ethers, and indeed can be cleaved in their presence (79RTC371). 2-Alkoxytetrahydrofurans are cleaved by LAH in the presence of aluminum chloride or boron trifluoride. If complexation occurs at the ring oxygen the products are 4-alkoxybutanols, but this is not invariably the case. The 2thioalkyltetrahydrofurans, however, always undergo cleavage of the 1,2-bond. Ethoxycarbonylcarbene affords the expected ethyl 2-oxabicyclo[3.1.0]hexane-6-carboxylate, which may be hydrogenolyzed to 3-tetrahydrofurylacetic acid. Dichlorocarbene, generated from chloroform with aqueous sodium hydroxide under phase-transfer conditions, affords a similar product (403) (79LA1456), which on thermolysis affords the dihydropyran (404; Scheme 118); on heating with quinoline this yields the aldehyde (405) (64T2091). Similar ring openings of alkyl-2-oxabicyclo[3.1.0]hexanes, available by carbene addition to 2,3-dihydrofurans, occur on heating (73TL1635).
2,3-Dihydrofuran undergoes a thermal rearrangement to cyclopropanecarbaldehyde, and 5-methyl-2,3-dihydrofuran similarly affords acetylcyclopropane. 2,5-Dimethyl-2-vinyl-2,3dihydrofuran undergoes thermal rearrangement to 4-methyl-4-cycloheptenone (66JA4294). 4-Hydroxy-3-tetrahydrofuranols are available by lengthy transformation of sugars and are readily converted into esters which undergo enolate Claisen rearrangement (Scheme
Furans and their Benzo Derivatives: (ii) Reactivity
654
119), affording functionalized 2,5-dihydrofurans useful in synthesis of ionophoric antibiotics (80JOC4259). H
OSiMe3
OCOEt /
Me
\
P
OCH,OMe O
OCH2OMe
, LDA, THF, Me3SiCl; ii, H2O, OH"; iii, CH2N2 Scheme 119
3.11.4.2 2,3-Dihydrobenzo[6]furans The chemistry of 2,3-dihydrobenzo|7>]furan (coumaran) is unexceptional, and it behaves as a typical aralkyl ether. Thus it is cleaved by hydriodic acid to 2-(2-iodoethyl)phenol. Sodium in pyridine effects cleavage to 2-vinylphenol and Birch reduction can be controlled to preserve the fur an ring. Dehydrogenation to benzo[6]furan can be effected with palladium on carbon or by radical bromination by NBS followed by dehydrobromination with a tertiary amine. Electrophilic substitution occurs at the 5- and 7-positions, and nitration, formylation, acylation and chloromethylation have all been studied. It is a common stratagem in the synthesis of benzofuranoid natural products to ensure that electrophilic substitution occurs in the benzenoid ring by prior reduction of the double bond; dehydrogenation is then achieved at a late stage in the synthesis. A typical example taken from the synthesis of cyperaquinone is shown in Scheme 120 (78AJC1533). OH
OH MeO
94%
100% i, H2, Pd/C, EtOH; ii, Br2, CHC13, 0°C; iii, Cl2GHOMe, TiCl4, CH2C12, 0°C Scheme 120
3.11.4.3 2,5-Dihydrofurans On treatment with potassium f-butoxide in t- butyl alcohol, 2,5-dihydrofuran is isomerized to the 2,3-isomer, and it is cleaved by butyllithium or potassamide in liquid ammonia to the s-trans enolate of 2-butenal <72JOC560). 2,5-Dihydrofuran is more stable to acids than the 2,3-isomer; with halo acids it is cleaved to l,4-dihalo-2-butenes and acid chlorides effect a similar cleavage to esters of 4-chloro-2-buten-l-ol. Dehydrogenation of 2,5dihydrofurans can be effected but noble metal catalysts can also effect cleavage so that 2-ethyl-2,5-dihydrofuran is converted into 2-ethylfuran and hexen-3-one. Reduction to tetrahydrofurans can be achieved with rhodium catalysts and is important in the synthesis of ionophore antibiotics (80T72). Oxidation to maleic acid can be effected with air at 370 °C and a catalyst consisting of oxides of molybdenum, vanadium and titanium. The double bond will take part in Diels-Alder reactions with 1,3-cyclopentadienes, butadiene and anthracene, and may be epoxidized with 80% hydrogen peroxide and TFAA. Carbenes will also add. Dihalocarbenes give mixtures of 6,6-dihalo-3-oxabicyclo[3.1.0]hexane and the product of insertion into the a-CH bond (79LA1456). Vinylcyclopropanation has also been achieved (75JOC756). The most important derivatives of 2,5-dihydrofuran are the 2,5-dialkoxy and 2,5diacetoxy compounds which are easily prepared from furans (Section 3.11.2.3). Their vast utility is as synthetic equivalents of malealdehyde and its derivatives (60MI31100). Suitable intermediates for Robinson-Schopf synthesis have been obtained in this way. Pyridazines are readily obtained (Scheme 121), and 3-pyridinols are available from 2-furylmethanamines (Scheme 122). This approach has been used in a synthesis of pyridoxine. The 2,5-diacetoxy
Furans and their Benzo Derivatives: (ii) Reactivity
655
compounds can be cleaved under mild acidic conditions (77JA194) or the 2,5-dimethoxy compounds can be cleaved with boron trichloride at low temperature (80S950), thus unmasking the dialdehyde as a hemiacetal suitable for use in Wittig reactions (Scheme 123). The double bond can be hydrogenated in the 2,5-dimethoxy compounds, usually in the presence of Raney nickel, and the resultant tetrahydrofurans may be converted into AT-substituted pyrroles by reaction with primary aliphatic or aromatic amines. The double bond in these compounds reacts with hypohalous acids and can also be hydroxylated. MeO
MeO / = \ O M e
_H^ | J
\nll
Mu
| __
f
|]OH
Scheme 122 EtO,C
CO2Et
EtO2C
Scheme 123
3.11.4.4 Tetrahydrofurans Tetrahydrofuran is a commonly used solvent, having the advantage that it is a relatively inert water-miscible ether. It is often used as a solvent in organometallic chemistry and it is particularly useful in the preparation of Grignard reagents from chlorobenzenes and vinyl chlorides. However, it undergoes reaction with butyllithium by proton/lithium exchange at the a-position; a cycloreversion then provides ethylene and the enolate anion of ethanal. The half life is lOmin at 35 °C. 3,4-Dialkyl and 3,3,4,4-tetraalkyltetrahydrofurans are similarly, but more slowly, cleaved and 3-methyltetrahydrofuran cleaves to afford ethylene, propene, and the enolates of ethanal and propanal. 2-Alkyltetrahydrofurans are cleaved only slowly, the major pathway being proton/lithium exchange at the methyl group (72JOC560). Autoxidation of tetrahydrofuran, or aerial oxidation in presence of cobalt(II) or nickel(II) acetate, affords the 2-hydroperoxide which is converted into 4-hydroxybutanal by reaction with triphenylphosphine (55LA(591)138) or into tetrahydrofuran-2-one with LTA. On standing, the hydroperoxide affords a highly explosive peroxide. Addition of tetrahydrofuran to alkenes and alkynes occurs by a radical chain reaction which can be initiated by dibenzoyl peroxide or photochemically, and affords 2-substituted products. DMAD affords a 1:1 mixture of the (E)- and (Z)-alkenes (73JOC1369). Photochemical decomposition of diazomethane in THF yields the insertion products 2- and 3-methyltetrahydrofuran. The ring may be cleaved hydrogenolytically. Halo acids afford 4-halobutanols or 1,4dihalobutanes, depending on the reaction conditions. Acid chlorides in the presence of zinc chloride afford esters of 4-chlorobutanol, and LAH and aluminum chloride give butanol. Reaction with carbon monoxide and nickel tetracarbonyl affords adipic acid. Chlorination of THF is achieved with chlorine at low temperature and affords the 2-chloro and 2,5-dichloro compounds. The latter with primary amines gives AT-substituted pyrroles. Monochlorination is best achieved with sulfuryl chloride (Section 3.11.4.1), and the 2,3dichloro compound is available by addition of chlorine to 2,3-dihydrofuran. This compound
656
Furans and their Benzo Derivatives: (ii) Reactivity
will react with Grignard reagents to afford 2-alkyl-3-chlorotetrahydrofurans, which are cleaved by sodium in ether to unsaturated alcohols (Scheme 124) (50JCS2685). RMgBr Cl
/ * (
\P )R
Na /~CH=CHR Et2O * (
Scheme 124
Bamford-Stevens reaction of the tosylhydrazones of the readily available tetrahydrofuran3-ones provides a useful synthesis of 2,3-dihydrofurans which may be dehydrogenated to furans with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (66CJC1083). Tetrahydrofuran-2ones (y-butyrolactones) may be alkylated in the 3-position with LDA and an alkyl halide. The products on reaction with phenyl selenylchloride and LDA, and subsequent oxidation, yield 3-alkylfuran-2(5//)-ones reducible with DIBAL to furans (75JOC542). Passage of tetrahydrofuran-2-methanol over hot alumina affords 3,4-dihydro-2//-pyran; the mechanism has been studied (67JOC200,67BSF2472). Both 3,4-dimethylenetetrahydrofuran (63JOC802) and tetramethylenetetrahydrofuran (80TL611) are known.
Copyright © 1984 Elsevier Ltd.
Comprehensive Heterocyclic Chemistry