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4.07 Electrophilic Cyclization
4.07 Electrophilic Cyclization X Jiang and H Liu, East China Normal University, Shanghai, People’s Republic of China r 2014 Elsevier Ltd. All rights reserved.
4.07.1 4.07.1.1 4.07.1.2 4.07.1.3 4.07.2 4.07.2.1 4.07.2.1.1 4.07.2.1.1.1 4.07.2.1.1.2 4.07.2.1.1.3 4.07.2.1.2 4.07.2.1.2.1 4.07.2.1.2.2 4.07.2.1.3 4.07.2.1.3.1 4.07.2.1.3.2 4.07.2.1.4 4.07.2.2 4.07.2.2.1 4.07.2.2.2 4.07.2.2.3 4.07.2.2.4 4.07.2.3 4.07.2.3.1 4.07.2.3.2 4.07.2.4 4.07.2.4.1 4.07.2.4.2 4.07.3 4.07.3.1 4.07.3.2 4.07.3.3 4.07.4 4.07.4.1 4.07.4.2 4.07.4.3 4.07.5 References
Introduction Coverage Mechanism Baldwin’s Rules for Ring Closure Halocyclization Iodocyclization Oxygen nucleophiles Cyclization involving alkenes Cyclization involving alkynes Cyclization of allenes N-nucleophiles Cyclization involving alkenes Cyclization involving alkynes C-nucleophiles Cyclization involving alkenes Cyclization involving alkynes S or Se-nucleophiles Bromocyclization Cyclization involving alkenes Cyclization involving alkynes Cyclization of allenes Cyclization of cyclopropane Chlorocyclization Cyclization involving alkenes Cyclization involving alkynes Fluorocyclization Cyclization involving alkenes Cyclization of allenes Sulfenylcyclization, Selenocyclization, and Tellurocyclization Cyclization Involving Alkenes Cyclization Involving Alkynes Cyclization Involving Allenes Hg-, Ag-, Au-, and Pt-Catalyzed Electrophilic Cyclization Mercury-Catalyzed Cyclization Silver-Catalyzed Cyclization Au- and Pt-Catalyzed Cyclization Conclusion
Glossary p-Acid p-Acid is a kind of Lewis acid that could accept electrons from Lewis base via antibonding p-orbitals. Electrophile Electrophile is the molecule or ion that is electron deficient and in some way could accept a pair of electrons to make a new covalent bond. Electron deficiency would include a formal positive charge or a partial positive charge. ‘E’ and ‘E þ ’ are common abbreviations for generic electrophiles. The common electrophiles include X2, X þ , RS þ , RSe þ , H þ , Lewis acid, and so on.
412
412 413 413 413 414 414 414 414 424 430 431 431 433 435 435 437 449 450 450 456 457 458 458 458 459 460 460 463 466 466 470 470 471 471 475 485 486 490
Halolactonization It is the reaction to form a lactone by the addition of halogen and oxygen in carboxylic acid or carboxylate across a carbon–carbon double bond. Nucleophile Nucleophile is the reactant that provides a pair of electrons to form a new covalent bond. A nucleophile that shares an electron pair with a proton is usually called a Brønsted–Lowry base, or just a base. The common nucleophiles include carboxylic acid, carboxylate, hydroxyl, amino, carbonyl oxygen, carbon, as well as thiol.
Comprehensive Organic Synthesis II, Volume 4
doi:10.1016/B978-0-08-097742-3.00409-2
Electrophilic Cyclization
4.07.1 4.07.1.1
413
Introduction Coverage
Electrophilic cyclizations are those reactions that involve the interaction of the electrophilic reagent to alkenes, alkynes, allenes, conjugated dienes, and other carbon–carbon multiple bonds, although followed by a subsequent intramolecular addition of an internal nucleophile (Scheme 1). These processes generate carbocycles from carbon-centered nucleophiles and heterocycles from heteroatom-centered nucleophiles, such as carboxylic acid, carboxylate, hydroxyl, amino, carbonyl oxygen, as well as thiol. Nu
Nu
Nu
E
R
R
or
(a)
R E
E
1
2a
Nu
Nu
Nu R
or
R E
R
4a
R
Nu or
E 4b
E
3
2b
E
R
Nu (b)
or E
4c
4d
Nu = C, O, N, S E+ = H+, X (I, Br, Cl, F), RSe+, RS+, M+ (Hg, Ag, Au, Pd, Rh, Lewis acid, e.g.) Scheme 1 Concept of the electrophilic cyclization.
Electrophilic cyclization was first reported by Bougault in 1904; it was about iodocyclization of unsaturated acids.1 Since then, this type of reaction has undergone incredible growth, especially over the past decades. There have been numerous examples of synthetic application of electrophilic cyclizations, and a large number of reviews on this subject have appeared.2 Therefore, only the most relevant achievements and synthetically useful electrophilic cyclization reactions after 1991 will be covered in this chapter. The sections of this chapter are summarized according to the type of electrophilic reagents, such as halocyclization, sulfenylcyclization, and selenocyclization; some metallic reagent-mediated reactions such as mercury-, gold-, silver-, and platinum-catalyzed electrophilic cyclization have also been discussed.
4.07.1.2
Mechanism
The general mechanism of electrophile-initiated cyclofunctionalization is shown in Scheme 2. First of all, the electrophile interacts with unsaturated carbon–carbon p-system 5 to generate activated intermediates cyclic ‘onium’ ion 6a and/or the p-complex 6b.2k Both intermediates 6a and 6b have two reactive centers a and b. Then nucleophilic anti attack of the nucleophile on the activated intermediate 6a or 6b generates two regioselective products: exo-product 7 or endo-product 8.
Nu R
+
E+
R
+E
5
Nu a
Nu a
6a
or R b
b E+ 6b
Nu
Nu or
R E exo-product 7
R E endo-product 8
Scheme 2 Mechanism of the electrophilic cyclization.
4.07.1.3
Baldwin’s Rules for Ring Closure
‘Baldwin’s rules’ historically have served as one of the most useful tools in the arsenal of synthetic organic chemists.3 Not only have they defined the nomenclature and the vocabulary for describing and classifying ring-closure steps, but it also combined the existing empirical knowledge with basic stereoelectronic considerations to predict the favorable modes of cyclization. Baldwin’s rules classify ring closures based on three factors: (1) the ring size being formed (indicated through a numerical prefix), (2) the position of the breaking bond that has to be broken in the cyclization, relative to the forming ring (exo, in which the breaking
414
Electrophilic Cyclization
bond is external to the newly formed ring, and endo, in which the breaking bond is within newly formed ring), and (3) the hybridized state of the carbon atom undergoing the ring-closing reaction (sp¼ digonal, sp2 ¼ trigonal, and sp3 ¼ tetrahedral). Baldwin summarized the relative nature of ring formation involving three- to seven- membered rings as either favorable or unfavorable.3a,4 These terms are not meant to describe the absolute probability that a reaction will or will not take place, but rather are used in a relative sense.
4.07.2
Halocyclization
Halocyclization is a powerful tool to construct rings by the addition of a nucleophile and halogen atom across unsaturated bonds. Oxygen-, nitrogen-, sulfur-, selenium-, halogen-, and carbon-centered nucleophiles are widely used in halocyclization reactions. Not only iodine, bromine, chlorine, and fluorine but also electrophilic halogen reagents such as IOAc, N-iodosuccinimide (NIS), NBS, NCS, ICl, IBr, I(collidine)2PF6, Br(collidine)2PF6, I(collidine)2ClO4, and Barluenga’s reagent (IPy2BF4) have been successfully used in halocyclization. Hypervalent iodine(III) compounds are also considered as efficient electrophiles. This section discusses the halocyclization reactions by various electrophilic halogen reagents.
4.07.2.1
Iodocyclization
Iodolactonization reactions are a well-known process to obtain rings (3–7). The lack of regioselectivity and slow reaction rates are the reasons why this methodology has been rarely used for medium and large macrolactones (Z8). Anyway, since the iodolactonization reaction was first reported by M. J. Bougalt in 1904, it has become one of the most effective protocols to synthesize lactones, which is widely applied in syntheses of many biologically important natural products.1,2 A large number of works dealing with iodolactonization reaction have been reported, and many comprehensive reviews have been presented.2h,2i,2f,2m,5 Although halogen molecules are nonpolar, they are easily polarized by the interaction with unsaturated C–C bonds. The electrophilic properties of iodine have been exploited over one century, and the use of molecular iodine as an inexpensive, nontoxic, and readily available electrophilic reagent has now received considerable attention in organic synthesis.2j,6 Not only was iodine molecule used as the electrophile, but a variety of new iodination reagents have also been developed, such as IOAc, NIS, ICl, IBr, and some hypervalent iodine(III) compounds.
4.07.2.1.1
Oxygen nucleophiles
4.07.2.1.1.1 Cyclization involving alkenes Oxygen nucleophiles have been extensively applied in cyclocyclization reactions. Some examples of nucleophiles with functional groups containing oxygen are shown in Figure 1. OH COOH OCO2R
OR COOR NRCO2R
RO
O
OH
N
O H
O
O NR2
R
N O
R
Figure 1 Oxygen nucleophiles.
Iodine-initiated cyclization of substrates with unsaturated bond is used extensively in the synthesis of oxygen heterocycles; in this chapter some representative examples and leading references will be described. Iodocyclizations of the homoallylic alcohols proceed with excellent stereoselectivity, generating tetrasubstituted tetrahydrofurans (THFs) in anhydrous MeCN (Scheme 3).7 This reaction follows antiaddition to give stereospecific products in high yields. Then 5-endo-trig iodocyclizations of homoallylic alcohols generate b-iodotetrahydrofurans in highly efficient and stereoselective manner in anhydrous MeCN with NaHCO3 as the base (Scheme 4).8 Such cyclizations are exceptional cases to Baldwin’s rules. They undergo well-ordered chair-like transition states (14 or 17) basing on the electrophile-driven to give 5-endo-trig cyclization product. Another example shows that tetrasubstituted THFs can be obtained from readily available homoallylic alcohols in excellent yields in the presence of I2 and AgTFA via a very unusual 5-endo cyclization (Scheme 5).9 The iodocyclization reactions of cyclohexa-1,4-diene derivatives containing chiral tether inducing high levels of diastereocontrol have been investigated, which is the desymmetrization of cyclohexa-1,4-diene (Scheme 6).10 To extend the methodology of I2-induced cyclization of 2-alkenyl-1,3-dicarbonyl compounds,11 Antonioletti and coworkers demonstrated an efficient approach to 2,3,4,5-tetrasubstituted furans (Scheme 7).12 Iodine-mediated cyclizations of a-keto esters and ketones bearing allylic and homoallylic chains were investigated, which resulted in the formation of diverse functionalized five- and six-membered ring enol ethers (Scheme 8).13 This methodology provides access to various functionalized cyclic ethers and tetrahydrobenzofuranones in moderate to very good yields.
Electrophilic Cyclization
I2 (3.0 equivalents) NaHCO3 (3.0 equivalents)
I Bu
MeCN, 0 °C, 0.75 h Yield = 87%
Bu HO
O
9
10 I2 (3.0 equivalents) NaHCO3 (3.0 equivalents)
Bu
I Bu
MeCN, 0 °C, 3 h Yield = 81%
HO
O
11
12
Scheme 3
H Et
Bu
I2 (3.0 equivalents) NaHCO3 (3.0 equivalents)
Et
O
MeCN, 0–5 °C, 3 h
OH
I
I H
Bu
Et
H
H
13
Bu
O
Yield = 90% 15
14 Bu I2 (3.0 equivalents) NaHCO3 (3.0 equivalents)
Et OH Bu 16
I
I Et
O
MeCN, 0–5 °C, 72 h
H
H
Et
H
H
Bu O Yield = 60%
17
18
Scheme 4
OH 20 O R
MeCN, −40 °C to r.t.
R
O 21
Yield = 72% (R = H) >95% (R = OBn) >95% (R = (thexyl)Me2SiO) I
I2 (1.2 equivalents) AgTFA (10 mol%)
R=H
19
I
I2 (1.2 equivalents) AgTFA (10 mol%)
R
OH
MeCN, −40 °C to r.t. Yield = 89%
22
O 23 I
I2 (1.2 equivalents) AgTFA (10 mol%) OH O
25
MeCN, −40 °C to r.t. Yield = 87%
O 26 I
I2 (1.2 equivalents) AgTFA (10 mol%) 24 OH 27 Scheme 5
MeCN, −40 °C to r.t. Yield = 35%
O 28
415
416
Electrophilic Cyclization
(1) n-BuLi (1.1 equivalents) TMEDA (1.1 equivalents) THF, −78 to 41 °C, 2.5 h (2) 30 (1.2 equivalents) THF, −41 °C to r.t., 1.1 h Yield = 27−66%
29
R1
R2 O
R1 R2
OH
R2 I2 (3.0 equivalents) Na2CO3 (3.0 equivalents) H MeCN, r.t., 10 min Yield = 60−66%
R1 O H
31
32
I
R1 = n-Bu, Ph, (CH2)4 R2 = H, H, (CH2)4
30 Scheme 6
O
O
O
R1
R2 R3 33
I2 (2.0 equivalents) Na2CO3 (2.0 equivalents) R4
DCM, r.t.
R1
O
R3
R2
DBU R4
O
I 34 Yields = 70-95%
R3
R2 H+
R1
R4 O 35
Scheme 7
A simple and efficient strategy to generate highly polyfunctionalized compounds in a diastereoselective via a substratecontrolled halocyclization reaction is shown in Scheme 9.14 IPy2BF4 was used for those iodofunctionalization reactions. A single diastereoisomer (single enantiomer) was favored when a phenyl or benzyloxy group was placed in a well-defined position of the terpene-derived compounds. Mphahlele and coworkers developed a new methodology that combined electrophilic and oxidative properties associated with iodine to synthesize novel iodofunctionalized tetrahydrobenzofuranones and dihydrobenzofuran derivatives in a one-pot reaction (Scheme 10).15 To further demonstrate the versatility of this methodology, 3-phosphonylmethyl-2-(2-propenyl)-2-cyclohexenone derivative and its 5-methyl derivative were subjected to the same reaction conditions; the corresponding 2-iodomethyl-2,3-dihydrobenzofuran derivatives were formed (Scheme 11).15 Under the identical conditions (I2, NaHCO3, MeCN), Lee and Oh tested a-allyl-substituted b-keto sulfones and isolated the corresponding 4,5-dihydro-5-iodomethylfurans, which could be easily converted to furan derivatives with excess 2,3,4,6,7,8,9,10octahydropyrimido[1,2-a]azepine (DBU) (Scheme 12).16 Kang and coworkers developed a catalytic enantioselective iodoetherification to generate THFs with up to 90% ee using a chiral salen complex (Scheme 13).17 Hennecke and coworkers recently reported a promising organocatalytic approach to haloetherfications by desymmetrization of in situ-generated meso-halonium ions (Scheme 14).18 By treatment of symmetrical diol with chiral phosphoric acid salt in the presence of electrophilic iodine source 73, enantioenriched ether product 74 was obtained under the practical reaction conditions. The bromoetherification of 75 using NBS also gave good yield with ee up to 67%. Chiral phosphoric acid salt 72 could also promote the iodoetherification of 70 in an efficient way (56% ee). Knight and coworkers used iodine monobromide in the cyclization of dihydroxy ester to generate THFs exclusively in a 5-endo manner in a good yield with a diastereomeric ratio of 14:1 (Scheme 15).19 The THF is the core structure of aplasmomycin precursor 79. Castillon also applied an iodoetherification strategy to form iodotetrahydrofuran in the natural products syntheses. The iodotetrahydrofuran as an equal mixture of diastereomers was obtained in a good yield as the key step in the synthesis of 10 -Cfluoromethyl- 20 ,30 -dideoxycytidine 82 (Scheme 16).20 Another key structure is Peri and coworkers’ synthesis of bicyclic sugar derivatives, which was further converted into avb3selective arginine-glycine-aspartate (RGD) peptides; the synthesis was generated by iodocyclization (Scheme 17).21 NIS induced a 5-exo cyclization with the adjacent benzyl ether oxygen in dry THF. Interestingly, a resolution of diastereomeric starting materials occurred; only the b-anomer cyclized formed a cis-fused ring, with the a-anomer recovered. The iodocyclization is also suitable for more complex systems. Nicolaou and coworkers have extensively applied the iodocyclization reaction in total synthesis, for example in the construction of the ring of azaspiracid-1,2,3 (Scheme 18).22 In the synthesis of fragment ABCD, 86 was exposed to NIS in the presence of NaHCO3 to yield THF derivative 87 in 70% yield
Electrophilic Cyclization
417
(a) Electrophilic Cyclization of β-Keto Esters Bearing a Monosubstitued Double Bond: O
O OEt
I2 (1.5 equivalents) Na2CO3 (1.5 equivalents)
R
I O
COOEt
DCM, r.t., 7−9 h
R
Yield = 81−84%
37
36 O
I2 (1.5 equivalents) Na2CO3 (1.5 equivalents)
O OEt
I O
DCM, r.t., 12 h
COOEt
Yield = 87%
38
39
(b) Electrophilic Cyclization of β-Keto Esters Bearing Non-terminal C=C bonds O
O OEt
O COOEt 41
O OEt
I2 (1.5 equivalents) Na2CO3 (1.5 equivalents)
COOEt O
DCM, r.t., 4 h Yield = 85%
42 O
I
DCM, r.t., 2 h Yield = 71%
40 O
I2 (1.5 equivalents) Na2CO3 (1.5 equivalents)
I 43
O OEt
COOEt
I2 (1.5 equivalents) Na2CO3 (1.5 equivalents) DCM, r.t., 6 h Yield = 86%
O I 45
44
(c) Electrophilic Cyclization of Alkenyl-β -diketones:
I2 (1.5 equivalents) OH Na CO (1.5 equivalents) 2 3
O
O I
DCM, r.t., 3 h 46
Yield = 85%
I2 (1.5 equivalents) OH Na2CO3 (1.5 equivalents)
O
O 47 O I
DCM, r.t., 0.5 h
O
Yield = 69% 48
49
Scheme 8
with the desired 2,5-trans stereochemistry. The same strategy has been used in constructing the ring G induced by NIS (Scheme 18). In the total synthesis of (þ)-lasonolide A, Kang et al. used iodine-induced substrate-controlled cyclization to afford a 27:1 mixture of cis-2,6-disubstituted tetrahydropyran and the corresponding trans isomer (Scheme 19).23 Some new chiral reagents have been developed to induce asymmetry together with electrophiles before racemizing, and the recent advances in this area have been highlighted.24 Grossman and Trupp described the first reagent-controlled stereoselective halolactonization using a chiral dihydroquinidine–iodine complex. However, only a 15% ee in the 5-exo iodolactonization was achieved (Scheme 20).25
418
Electrophilic Cyclization
O Ph
O
IPy2BF4 (1.1 equivalents) HBF4 (1.5 equivalents)
Yield = 70%
50
O Ph
O
51
IPy2BF4 (1.1 equivalents) HBF4 (1.5 equivalents)
Ph
DCM, −40 to 20 °C, 12 h
BnO
I
DCM, 20 °C, 0.5 h
Ph
O
O Ph
O
O
O
I
Yield = 40% 52
53
Scheme 9
O
O R3 R1 R2
OH
MeOH, reflux 3h
O
R3
I2 (2.0 equivalents)
R3
I
R1
R1, R2, R3 = H, Me
I
R1 O R2 Yield = 14−80%
OH
R2
55
56
54
+ MeOH − H2O OMe
OMe R3
+I2, −2HI R1 2 Yield = 60−75% R
O
R1
I
58
R3
(R2 = H)
I
O 57
Scheme 10
I
I O
I2 (2.0 equivalents) O P(OEt2)
R
MeOH, reflux 5h
MeO
O
OH O P(OEt2)
R
R = H, Me
R 61
60
59 I O
R Scheme 11
O P(OEt2)
O P(OEt2) 62
+
I2 I 2H − d
el Yi
9%
=
−6 65
Electrophilic Cyclization
419
SO2Ph DBU (1.2 equivalents)
O SO2Ph
I2 (3.0 equivalents) NaHCO3 (3.0 equivalents)
R
MeCN, r.t.
PhH, r.t.
R
DBU (5.0 equivalents)
I O
63
SO2Ph
PhH, r.t. 24 h
Yield = 62−85% 64
R = Me, Et, n-Pr i-Pr, Ph
DBU (3.0 equivalents) PhH, heat overnight
R O 65 Yield = 62−85% SO2Ph Me
R O 66 Yield = 75−95% SO2Ph
Me
R O 66 Yield = 75−95%
Scheme 12
I
1. 68A or 68B Toluene, −78 °C
O R 2. I2 (1.2 equivalents) 69 67 −78 °C, 20 h Condition a: 67A (30 mol%), NCS (0.75 equivalent) R = (CH2)3OTr, yield = 89%, ee = 90% OH
R
Condition b: 67B (7 mol%), NCS (0.7 equivalent) K2CO3 (0.5 equivalent)
N
R = (CH2)3OTr, yield = 90%, ee = 93% R = n-Alkyl, i-Pr, i-Bu, Bn, (CH2)3Ph (CH2)4N3, ee = 74−91% (Tr = tripheny)
N M
t-Bu
O
O
t-Bu
t-Bu t-Bu 68A: M=Co 68B: M=CrCl Scheme 13
Rousseau and coworkers investigated the enantioselective 5-endo iodolactonization and found that ephedrine-derived halobis (amine) salt was the most effective one to give a 45% ee (Scheme 21).26 But the chiral ammonium carboxylate gave only racemic product. Taguchi and coworkers reported an example of enantioselective iodolactonization reaction induced by a titanium complex generated from (Me, Ph)-taddol and Ti(Oi-Pr)4. The corresponding (3S,5S)-3-allyl-3-hydroxy-5-(iodomethyl) dihydrofuran2(3H)-one was obtained in a 65% ee (Scheme 22).27 Chiral cinchona alkaloid derivates induced low levels of asymmetry (o35% ee) during iodolactonizations of trans-5-aryl-4pentenoic acids under the catalytic conditions (Scheme 23).28 When stoichiometric amounts of alkaloids were used such as cinchonidine, exclusive six-member ring products were produced with a modest asymmetric induction.29 Jacobsen and coworkers used an anion-binding H-bonding catalysis strategy to accomplish enantioselective iodolactonization (Scheme 24).30 In the case of 5-substituted hexenoic acid derivatives (such as 110, and the transition states 116, 117, Scheme 24), a clear correlation between the electronic properties of the arene substituent and ee was observed, with electron-deficient derivatives undergoing more enantioselective cyclization. In the case of pentenoic acid 114, a slightly low I2 loading was needed for the optimal ee, and curiously, the absolute configuration was found to be opposite to the products of hexenoic acid cyclization. Martin et al. discovered enantioselective iodolactonizations of diversely substituted olefinic carboxylic acids, which was promoted by a BINOL-derived bifunctional catalyst 120 (Scheme 25).31 In Rizzacasa’s synthesis of the phospholipase A2 inhibitor, cinatrin B, a lactone moiety was closed in a 5-exo iodolactonization of the suitably protected, arabinose-derived alkenyl acid 121. This reaction proceeded in an efficient way in a high yield of the iodolactone 122 and a good diastereomeric ratio (94:6) (Scheme 26).32
420
Electrophilic Cyclization
OH
71 (20 mol%) 73 (1.2 equivalents)
HO
O
I OH
DCM, M.S. (4 Å) 0 °C, 2−12 h Yield = 81%, ee = 62%
70
71 A (20 mol%) NBS (1.2 equivalents) Ph Ph Ph DCM, M.S. (4 Å) Ph 0 °C, 2−12 h Yield = 81%, ee = 67%
OH Ph Ph
74
O
HO
75
Br OH Ph Ph
76
O
O O P O OM
N I
SiPh3 71 M = Na 72 M = Li
73
Scheme 14
O Ph OH
Ph
O IBr (2.0 equivalents), NaHCO3
O
CH3CN Yield = 78% dr = 14:1
OH
HO
O
O
O
I OH 79 Aplasmomycin precursor
OH
77
78
Scheme 15
OH
CH3CN, 0 °C Yield = 73%
80
NH2 N O HO
N O F
82 1′-C-fluoromethyl-ddc Scheme 16
O
I2, Na2CO3
TrO
TrO
I 81
Electrophilic Cyclization
BnO
H
O OBn
BnO
+ 83 O
Dry THF, r.t., 6 days Yield = 80%
BnO
83:83 = 1:1
H
dr = 6:4 84
83 O
NH H2N
I
O
NIS (3.0 equivalents) BnO
421
O
NH
N H O
NH
O OH
O NH
85 O BnO an v3-selective RGD peptide Scheme 17
Hart and coworkers, in their synthesis of a trans-fused perhydroindan analog of hispidospermidin, performed a 5-endo iodolactonization of dihydrobenzoic acid (Scheme 27).33 In Kim’s synthesis of pancratistatin, the stereochemistry of a hydroxy group was established by a 5-exo iodolactonization, elimination, and a subsequent hydrolysis/epimerization sequence (Scheme 28).34 Kishi and coworkers have used 6-exo iodolactonization of a chiral unsaturated acid to form the lactone with two new stereogenic centers (dr420:1) in their synthesis of fumonisin B2 (FB2). In contrasted with the sharpless asymmetric dihydroxylation of the 2-alkenes, it was considered as a better option (Scheme 29).35 In the synthesis of epoxyquinals A and B by Hayashi and coworkers, an iodolactonization of an in situ-generated bicyclic ether acid salt was performed. Then under basic conditions, iodolactone was opened with subsequent epoxide formation and methylation, which cleaved the ether, resulting in the formation of substituted cyclohexenol by treatment with lithium diisopropylamide (Scheme 30).36 Clarke et al. notified a significant solvent effect when iodonium acetate was used in the synthesis of the DEF ring of hexacyclinic acid. Taking CHCl3 as solvent, a chair–chair conformation was proposed to form the bicyclic lactone 140 as the only product. Alternatively, using HOAc as solvent, a boat–boat transition state led to the formation of the desired product 141 (Scheme 31).37 In the synthesis of both FB2 and ()-cinatrin B, iodolactonization was used to afford high diastereoselectivity (Scheme 32).32,35 Jung and coworkers synthesized 6-epiplakortolide E, a potent anticancer target, by using an iodolactonization of a cyclic peroxide in the presence of I2 and NaHCO3 with a long reaction time at room temperature (Scheme 33).38 Silver(I) triflate could accelerate iodocyclization of carbamates bearing electron-deficient olefins to give a-iodoesters in excellent anti-ring stereoselectivity. Epimerization happened during this process, and the rate of epimerization is solvent dependent (Scheme 34).39 Minakata and coworkers developed a cyclizative atmospheric CO2 fixation methodology by allyl amines, which is an efficient, metal/base-free process (Scheme 35).40 t-BuOI played an important role in the transformation to cyclic carbamates. The method was applicable to a wide range of unsaturated amines under mild conditions with good yield. The homoallylic tert-butyl carbonate was treated with iodine in MeCN at –20 1C to generate the iodocarbonate in a high diastereoselectivity (de¼ 95%) favored syn-isomer, which could be separated by column chromatography (Scheme 36).41 Besides the hydroxyls, esters and ketones, imides could also realize O-halocyclization. Generally, O-cyclization is preferred to N-cyclization in the halocyclization reactions of alkenylated amide, carbamate, and urea derivatives, which could be explained by Hard and Soft Acids and Bases theory shown in Figure 2.42 Of course, both the O-cyclization and N-cyclization are controllable depending on the experimental conditions.2e Some O-cyclization examples of imides are summarized in the following section. When b,g-unsaturated amides were subjected to t-BuOCl and I2 in dichloromethane (DCM), unsaturated iminolactones were obtained, which are hydrolyzed to the corresponding butenolides by the treatment with 3 N HCl (Scheme 37).43 I2-promoted cyclization of multisubstituted dienamides with halogenated cyclic iminoethersin excellent yields with perfect selectivity was reported by Xi et al. (Scheme 38).44 O-attack exo-cyclic imino ethers are the only product and no N-attack products or O-attack endo products are formed. Some more examples for diastereomeric preferences in the halolactonization of amides are shown in Scheme 39.2e,2f
422
Electrophilic Cyclization
NIS (5.0 equivalents) NaHCO3 (10.0 equivalents)
Me BnO
OH OH
THF, 0 °C, 2.5 h Yield = 70%
OH
86
HO Me D HO H OBn Me 87
H
Teoc Me
1.
N
I
H O
O
AF
Me
OTBDF
Me 89
A O
AcO H
O Me
O
H
F
(1. 0 TH M in TH F, 0 2. Yie °C F, 1. N ld , 20 2 e Na IS =8 q m HC (2. 0% in uiva 0 TH O3 len eq ( u F, ts) 1 i Yie 0 °C 0 eq valen ld , 1 uiva ts) =6 2 len 2% h ts)
O
B O
O
B O
H
H OH D O
C
Me
Me
H
O TBSO Teoc H O N I G H O I F O Me H Me
H
H OH D Me OHO Me H H O E H H Me NH O Me I H GO F O Me H Me A O
H
A D C O O Me H H 88
BzO
TBSO OH
O
B O
Me O
HH
Me
TB
H OH D O
C
Me
H
O
H
O
B O
A O
AcO
HO
OH
Me
90
C
91 Azaspiracid-1
R1
HO O
O
H
H OH D R2 OHO Me H H O E H H Me NH O Me I H GO F O Me H Me 92 A O
B O
C
Azaspiracd-2: R1 = R2 = Me Azaspiracd-3: R1 = R2 = H
Scheme 18
Intramolecular electrophilic cyclization of quinolones with iodine afforded racemic cis-diastereoisomers (Scheme 40).45 The results showed that the stereochemistry was influenced by the preexisting chirality of the alkenyl side chain. The transition state was proposed in Scheme 40. The 4-hydroxy group adopted an equatorial position and the C ¼ O bond coordinates to the activated alkene via oxygen leading to form cis-diastereoisomer predominantly. An iodolactonization of unsaturated chiral amide was applied in the synthesis of (þ)-citreoviral by Kobayashi and coworkers. The reaction could proceed smoothly to afford iodolactone in a 92% yield as a single isomer (Scheme 41).46 An example of the preparation of 2,5-disubstituted THFs from isoxazoline-based substrate is shown in Scheme 42.47 Dioxanes, trioxanes, or trioxepanes could be obtained from unsaturated hydroperoxyacetals and hydroperoxyketals via electrophilic cyclization in the presence of I2 and base (Scheme 43).48 Different conditions were screened; two isomers could be obtained from all of these reactions in different ratio.
Electrophilic Cyclization
O OH
I
I2, K2CO3 MeCN −30 to −20 °C
O O 93
423
O Ph
Yield = 95%
Ph
O
94
O O
O
A
OH OH
O O
O
B OH
(+)−lasonolide A
95
Scheme 19
97 (1.0 equivalent) I2 (1.0 equivalent) HOOC 96
DCM, −78 °C to r.t. Yield = 92% ee = 15%
I O
O
N
AcO
I+BF4−
MeO
98
2
N 97 Scheme 20
I2 (0.4 equivalent) N-methylephedrine (4.8 equivalents) AgSbF6 (100) (2.4 equivalents)
Me Ph
COOH 99
DCM, −78 °C Yield = 92% ee = 45%
O O Ph Me
I
+I
Me2 N Me
SbF6−
Ph
101 100
Scheme 21
Rodriguez and coworkers reported one example of an epoxide serving as the nucleophile in an iodoetherification reaction.49 Two diiodo ethers were isolated and characterized. If iodonium ion formation from the top face as 198a, 6-endo cyclization product 199 was obtained, otherwise it led to the formation of the THF 200 via a 5-exo cyclization from the bottom face via intermediate 198b (Scheme 44). An example of using sulfoxides as nucleophiles was reported by Abe and Harayama.50 Compound 201 underwent a 5-exo cyclization to provide the tricyclic intermediate 202, which was further hydrolyzed to afford the inverted sulfoxide 204, competing with the Pummerer rearrangement to form 1,3-oxathianes 203 (Scheme 45).
424
Electrophilic Cyclization
OH COOH 102
1. 103 (1.0 equivalent) Ti(Oi-Pr)4 (1.0 equivalent) I2 (1.5 equivalents) pyridine (1.0 equivalent) DCM, −78 to 0 °C 2. TsOH, benzene, reflux cis (ee = 65%) 67% (cis/trans 58:1)
O I
OH
Ph
O
Me
Ph O O Ph
104
Ph OH OH Ph
103
Scheme 22
106 (0.3 equivalent) I2 (1.5 equivalents) CH2Cl2, H2O NaHCO3, 0 °C Ratio = 56:44 Ph
O
I O
+
O
Ph 107 (ee = 17%)
I Ph
O O 108 (ee = 28%)
OH
105
109 (1.1 equivalents) I2 (1.5 equivalents)
I
DCM, 0 °C Ratio = 0:100
Ph
O
O
108 (ee = 35%)
Cl− HO
H
N
N
HO
106
H
N
109 N Cinchonidine
Scheme 23
4.07.2.1.1.2 Cyclization involving alkynes Compared to alkene cyclizations, the major difference of alkyne is that the electrophilic group in the initial product may be a vinyl substituent, such as vinyl iodide, which is the most useful precursors for cross couplings. Liang and coworkers reported an example of electrophilic cyclization with 1,4-butyne-diols derivates, which resulted in highly substituted dihalogenated dihydrofurans and dihydro-2H-pyrans in moderate to excellent yields (Scheme 46).51 Zhou and coworkers developed a facile and efficient method for the synthesis of 2,4-dihalo-3-thio-furans from 4-thiobut-2-yn1-ols (Scheme 47).52 A proposed mechanism including 1,2-migration of the thio group is shown in Scheme 48. The iodonium ion 213 was generated via iodine ion attacking the triple bond, followed by an intramolecular nucleophilic attack of sulfur atom offering thiiranium 214. In the presence of base, intermediate 214 could produce thiiranium zwitterion intermediate 215, which could form intermediate 216 through the intramolecular nucleophilic attack. The product 212 could be obtained via elimination and dihalogenation. Knight and coworkers have systematically investigated the cyclization of 3-alkynyl-1,2-diol derivates with iodine and NaHCO3 mixture in MeCN (Scheme 49).53 Aromatization via the elimination of 218 provides an efficient way to synthesize b-iodofurans. The iodocyclization of 2-enynols affords fully substituted 5-ylidene-2,5-dihydrofurans with high regio- and stereoselectivity under mild reaction conditions. This methodology provides a highly efficient route to access oxygen heterocycles bearing an exocyclic carbon–carbon double bond (Scheme 50).54 2-Substituted 3-iodobenzo[b]furans could be prepared by the iodocyclization of 2-alkynylanisole derivatives (Scheme 51).55 This type of product is a useful synthetic intermediate to introduce different groups to the 3-position via cross-coupling reactions. Both I2/CAN in MeCN and I2 in DCM could induce cyclization of 225 to afford 3-iodochromenones (3-iodo-4H-1benzopyran-4-ones) 226 in good yields (Scheme 52).55,56 A useful strategy to construct 2,3-disubstituted furopyridines induced by iodine at room temperature is developed by Arcadi and coworkers (Scheme 53).57
Electrophilic Cyclization
111 (15 mol%) 112 (2.0 equivalents)
O Ph
OH
O
111 (15 mol%) 112 (2.0 equivalents)
OH
O O
Ph
I2 (0.1 mol%) Toluene, −80 °C, 5 days Yield = 82%, ee = 90%
O
114
I 115
CF3
O O
F3C
N H
N N H
I
F O
NPent2
111
112 CF3
CF3
O
O F3C
I
113
Yield = 87% ee = 94%
Ph
O
Ph
I2 (15 mol%) Toluene, −80 °C, 5 days
110
425
N H
N H I NPent2
O
N
F3C
N H
O
O H
116
N H R NPent 2 I
O
O
N O
F
F
117
Scheme 24
120 (10 mol%) NIS (1.2 equivalents)
R2 n
DCM/tol (1:2) −20 °C, 14 h
COOH
118
R1
O
O
n
I 119
Yield = 88−99% >97:3 er Br
H *
H
R2
*
R1
Ph OH N N 120
Scheme 25
Two protocols for the synthesis of 4-iodo-3-furanones from 2-alkynyl-2-silyloxy carbonyl compounds have been developed (Scheme 54).58 A plausible mechanism is described in Scheme 54, which includes a heterocyclization with a 1,2-alkyl shift. As shown in path A, after the formation of iodonium intermediate 231 via the coordination of iodine to the triple bond, oxonium ion 232 could be formed by nucleophilic attack of the carbonyl oxygen. Subsequent 1,2-shift gives 4-iodo-3-furanone 230. In the presence of Au (Path B), it proceeds through the coordination of Au cation to the alkynyl 233 followed by 1,2-migration of the resulting oxonium ion 234 to yield 235. Then a rapid iododemetalation occurs in the presence of external NIS leaded to 3-furanone 230 containing the iodo substituent at C4.
426
Electrophilic Cyclization
BnO MeO
OBn R
O
BnO
I2 (0.6 equivalent) NaHCO3 (aqueous)
MeO
Et2O/H2O
OH
OBn
R
O
Yield = 97%, dr = 96:4
O R = n-C9H19
I
O O
122
121
HO HO CO2H MeO
R
O
O
O (−)-Cinatrin B
123
Scheme 26
Me
O
COOH
O
I
O
I2, NaHCO3
Yield = 80%
O
Me
THF-H2O
O O
124
125
Me NH(CH2)4NMe(CH2)3NMe2 O 126 O A trans-fused perhydroindan analog of hispidospermidin Scheme 27
O 1. KI3 (aqueous KI 12 equivalents, I2 5.0 equivalents) 1 N NaHCO3 (aqueous), CH2Cl2, r.t.
O H O
COOH
2. DBU, PhH, reflux Yield = 78%
OMe
O H
MeO
H H 128
127 OH HO
OH
O H O OH
OH NH
O
129 (+)-Pancratistatin Scheme 28
O
O
Electrophilic Cyclization
427
I OH I2, CH3CN −30 °C O dr > 20:1
n-Bu
n-Bu O
Yield = 84%
130
O
CO2H CO2H
O
O
131
OH
OH
n-Bu NH2 O
CO2H O
CO2H
132
Fumonisin B2 Scheme 29
O + 8.0 equivalents 133
O
1. r.t. 2. 1.5 M NaOH (0.9 equivalent)
O
3. I2 (0.5 equivalent), CH2Cl2, 0 °C Cl Yield = 42% 1.0 equivalent 134
HO
HO
OH
(±)135
O
OH O
O O
O
O H
O
O
O
H3C
I
+
O H
O
136
(+)-Epoxyquinol A
O
O H3C
O
137
(+)-Epoxyquinol B
Scheme 30
Huang and coworkers report the electrophilic cyclization of 1-(1-alkynyl)-cyclopropyl ketones to afford highly substituted furans in good to excellent yields under mild conditions (Scheme 55).59 Efficient syntheses of substituted oxygen-containing heterocycles and carbocycles have been developed by Larock’s group, using acetylene-containing aldehydes and ketones as substrates (Scheme 56).60 During their further efforts, Larock and coworkers have realized, for the first time, the iodine-catalyzed selective synthesis of iodo-pyrano[4,3-b]-quinolines and ortho-alkynyl esters from ortho-alkynyl aldehydes (Scheme 57).61 This novel oxidative esterification process provides a powerful tool to construct a wide range of functionalized pyranoquinolinones as well as isocoumarin. The cyclofunctionalization of 2-(1-alkynyl)-2-alken-1-ones generated highly substituted halofurans in good to excellent yields under extremely mild conditions using the I2/K3PO4 system (Scheme 58).62 I2-Mediated electrophilic cyclization of a,a-disubstituted b-alkynyl esters could afford the functionalized g-lactone in an excellent yield (Scheme 59).63 Liang and coworkers developed an iodocyclization approach of propargylic epoxides to form polysubstituted 3-iodofuran (Scheme 60).64 After the formation of iodonium intermediate 253, subsequent anti attack by the oxygen on the iodonium ion and elimination of a hydrogen cation generated 3-iodofuran 252.
428
Electrophilic Cyclization
O CO2tBu
OTBS
H O tBuO
H
O
H
Yield = 49%
H
O OTBS
I
H Chair–chair 139a
O
2C
AcOI, CHCl3
H 140
OTBS CO2tBu H
138
CO2tBu
H
OTBS
AcOI, HOAc
O
AcO
Yield = 61%
OTBS O
H
I
H Boat-boat
141
139b O H
O HO
O
H
I
142 A model DEF-ring system of hexacyclinic acid Scheme 31
OBn
BnO
(CH2)8CH3 MeO
O
I2 (1.0 equivalent), NaHCO3 (aqueous) Et2O/H2O (2:1), 0 °C, 15 min Yield = 97%, ds = 88%
COOH
OBn
BnO
(CH2)8CH3
MeO
O
O O 144
143
O
HO MeO
OH
HO MeO
O
O
(CH2)8CH3
MeO
O
O 147
O
O 145
HO HO CO2H
H (CH2)8CH3
O
OBn
BnO (CH2)8CH3
O 146
(CH2)9CH3 O
O
O O
148
(−)-Cinatrin B Scheme 32
I
O
Electrophilic Cyclization
I2 (20 equivalents) NaHCO3 (9.0 equivalents)
O
9
O
O
H
I O
CHCl3/H2O r.t., 2 days Yield = 55%
OH
9
O
O O ts) H n e l 150 a uiv nts) q h 0 e ale (3. quiv °C, 1 H e n 0 0 8% u 3S (2. hH, 8 = 6 P ield n-B IBN A Y
149
429
H O
9
O 151
O O
H
6-Epiplakortolide E Scheme 33
BnO
R1 O
BnO
I2 (3.0 equivalents) AgOTf (3.0 equivalents) O NaHCO3 (3.0 equivalents)
EtO O
HN
HN
R
CO2Et
H
I EtO
TS-153a
O
CCl4, 25 °C
R1 R 152
I
HN
Yield = 96%
R1 HN H
R
CO2Et
O
O
O R1
153
I
H R OBn TS-153b Scheme 34
O CO2 (1 atm) t-BuOI (1.0 equivalent)
NH2
MeCN, −20 °C, 24 h
154
O NH
I 155
Yield = 54−94%
CO2
t-BuOI H
O
O
I
O NH
NH 156
O
t-BuOH
157
O I
O NH
158
Scheme 35
Substituted 2-alkyn-1-one O-methyl oximes could be cyclized in the presence of ICl to give the corresponding 3,4,5trisubstituted isoxazoles in high yields under mild reaction conditions (Scheme 61).65 This process can be readily scaled up on multigram scale.
430
Electrophilic Cyclization
O O
OBoc
O
I2
I
MeCN, −20 °C, 6 h
160
Yield = 72%
159
O OH
O
161 Scheme 36
Hard nucleophile X
N-cyclization
NR (
)n Y 163
Soft nucleophile
NHR (
O
X2
)n Y
X
O-cyclizaton
(
O
162
O )n Y
NR
164
X = electrophile
Hard nucleophile
Figure 2 Cyclization of amides.
R3
O
R1
t-BuOCl (3.0 equivalents) I2 (1.0 equivalent)
NHR5 R2
r.t., 2 h, In dark Yield = 95%
R4 165
R3
R4 HCl (3 N)
R1 R2
R3
O
NR5
R1
Reflux, 5 h Yield = 85%
166
R4
R2
O
O
167
Scheme 37
R1
R1 O
R1
R2 NH R1
I2 (1.1 equivalents) THF/H2O (1:1) or DCM r.t., 3 h Yield = 95%
168
R1 R1 R1
R1
O
N R2
I 169
Scheme 38
5-Endo-dig electrophilic cyclization of 5-alkynyl-20 -deoxyuridines with NIS or N-bromosuccinimide in acetone at room temperature gives 3-(20 -deoxy-b-D-ribofuranosyl)-5-halo-2,3-dihydrofuro[2,3-d]pyrimidin-2-ones that usually precipitate from the reaction mixture (Scheme 62).66
4.07.2.1.1.3 Cyclization of allenes The history of allenes dates back to 1874, when Jacobus H. van’t Hoff predicted the correct structure of this type of compounds. Till today, lots of natural products and pharmaceuticals containing the allene moiety are discovered, and some reactions with allenes have been successfully applied for the efficient synthesis of natural products.67 The rich abundance of electrophilic reactions of alkenes and alkynes indicates that allenes should also undergo electrophilic reactions easily.68
Electrophilic Cyclization
431
I
O NH2
N Ac
O
I2, THF/H2O
O
0 °C, 2 h Yield = 86%
N Ac 171
170
O I2, THF/H2O
O
O
0 °C, 2 h Yield = 67% ee = 74%
N H
Ph 172
I
Ph 173 OPMB
OPMB
I2, THF/H2O
N
0 °C O
O O
174
175
I
O
O Me2N
OMOM
OMOM
1. TMSCl, Et3N THF, r.t., 9 h
Me H
OTBS
TBSO OH 176
Me
TMSO 2. I2, NaHCO3 THF/H2O, −10 °C, 7 h TBSO
O
H I
177
F
I2
O
CF3
F3C F R = n-Bu, Me, H 178
OTBS H
O NEt2
R
O
R I
179
Scheme 39
Ma et al. have explored a large number of reactions of allenes with many different electrophiles.69 In the presence of I2, 3-allenoic acids could be cyclized to afford b-halobutenolides (Scheme 63).70 With 4,5-allenoic acids, the iodolactonization reaction in cyclohexane with I2 or NIS afforded the five-membered lactones exclusively in fairly good yields and a very high Z/E selectivity (Scheme 64).71 Besides the allenoic acids, allenoates are successfully applied in iodolactonization. A direct iodolactonization of 2,3-allenoates with I2 was successfully developed in MeCN and H2O, affording b-iodobutenolides in good to excellent yields (Scheme 65).72 Ma and coworkers developed a facile and efficient method for the synthesis of 4,5-dihydrofuran derivates via electrophilic cyclization of 2-(20 ,30 -allenyl)acetylacetates in the presence of I2 at room temperature (Scheme 66).73 To extend the application of iodolactonization of allene, Ma et al. applied this methodology in the synthesis of (þ)-transwhisky lactone 270a in 11 steps from propargyl alcohol recently (Scheme 67).74a By using a new electrophilic iodination reagent, the same group reported a highly stereoselective iodolactonization of 4-allenoic acids, which has been successfully utilized in the synthesis of naturally occurring compounds (þ)-cis-whisky lactone 270b.74b
4.07.2.1.2
N-nucleophiles
4.07.2.1.2.1 Cyclization involving alkenes A simple and efficient method for the cyclization of various alkenylamides using chloramine-T and I2 was developed by Minakata’s group (Scheme 68).75 Gouverneur et al. reported the first examples of iodocyclization with functionalized allylic fluorides bearing nitrogen nucleophiles. It is an efficient method to prepare 3-fluoropyrrolidines via 5-exo-trig cyclization in high yields and with good diastereocontrol (Scheme 69).76 Huang et al. have developed a highly stereoselective iodocyclization reactions of methylenecyclopropanes with iodine in the presence of K2CO3, leading to the formation of 1-iodo-2-aryl-3-azabicyclo[3.1.0]hexanes in good yields under mild conditions (Scheme 70).77 Methylenecyclopropanes are highly strained but readily accessible molecules, and the relief of ring strain provides a potent thermodynamic driving force, which makes it a useful synthetic intermediate.
432
Electrophilic Cyclization
HO I
H O NH R 183
OH
HO
I2 (2.1 equivalents) NaHCO3 (2.3 equivalents)
THF, r.t., 2.5−4 h N O R H R = H, 6-Me, 7-Me, 7-OMe, 8-Me, 8-Et
N
R
H
O
HO CH2I + H R
N 182
181 Yield = 81−88% 181:182 Ratio ranging from 77:23 to 100:0
180
HO H O
I
NH R 184 Scheme 40
Ph OBn N OH
O 165
I2 (2.0 equivalents) NaHCO3 (4.0 equivalents)
O
MeCN/H2O (4:1), r.t. Yield = 92%
O
HO H I
Me
Me OBn
O
Me
O
166
Me OH Me
O
OH
Me CHO
Me
167
(+)-Citreoviral Scheme 41
R
N
O
I2 (2.0 equivalents)
DCM, reflux, 48 h Yield = 40−59% 188 cis:trans ratio range from 1:0.15 to 1:1.6 R = TMS, MeCH(OSiMe3), i-PrCH(OSiMe3) Scheme 42
NC
I O 189
H
O
H CH2I
Electrophilic Cyclization
O
O
E+ Bn
O O H OMe
Bn
190
E
Pyridine/I2
I
t-BuOK/I2 t-BuOK/I2/18-C-6
OH O H3C(H2C)6
Bn
Temperature (°C)
OMe
192:193
0
DCM
50
1:1
I
r.t.
THF
48
1:1.7
I
r.t..
Benzene
34
1:2.5
H3C(H2C)6
O O O ( )n
E E +
H3C(H2C)6
O O O ( )n H
H
H
195
196
Temperature (°C)
Solvent
Yield (%)
195:196
n-BuLi/I2
I
−78
THF
20
10:1
KH/I2
I
0−r.t.
THF
24
7:1
I
r.t.
Benzene
22
6:1
t-BuOK/I2
I
0
DCM
19
4:1
Cs2CO3/I2
I
r.t.
THF
12
10:1
t-BuOK/I2/18-C-6
H
OMe 193
Yield (%)
E+
E
O O
Bn
Solvent
194 Reagent
+
192
H O ( )n H
E
O O
191 Reagent
E
H
E+
OH
433
Scheme 43
4.07.2.1.2.2 Cyclization involving alkynes The electrophilic cyclization of propargylic aziridines is developed to construct 3-iodopyrroles with a variety of substituents (Scheme 71).78 Kundu and coworkers have developed an efficient synthetic strategy toward the synthesis of the naturally occurring indoloazepinone scaffold via a three-component reaction involving indole-2-carboxamide, 1,3-disubstituted propargyl alcohols, and I2 via a regioselective 7-endo-dig iodo-cyclization pathway (Scheme 72).79 The Larock group developed a method for the synthesis of a wide variety of N-alkyl-3-iodoindoles under very mild reaction conditions by the Pd/Cu-catalyzed cross coupling of N,N-dialkyl-o-iodoanilines and terminal alkynes, followed by electrophilic cyclization with I2. Alkyl-, aryl-, and vinylic-substituted alkynes all underwent iodocyclization in excellent yields (Scheme 73).80 By using substrate 286 bearing a hydroxyl on the benzyl position, Flynn et al. described a highly selective endo/exo iodocyclization procedure for a divergent synthesis of indoles, quinolines, and quinolinones (Scheme 74).81 Changing the protecting group of nitrogen from dimethyl to Ts, Liang et al. reported an efficient and highly regioselective protocol for preparing 3-iodoquinolines (Scheme 75).82 The resulting 3-iodoquinolines can be further functionalized by using cross-coupling reactions. When the terminal alkynes were used as substrates, Chan et al. developed an NIS-mediated cycloisomerization reaction of 1(20 -anilinyl)prop-2-yn-1-ol to gem-3-(diiodomethyl)indolin-2-one and 2-(iodomethylene)indolin-3-one. The reaction was shown to be chemoselective that secondary and tertiary alcoholic substrates exclusively produced the 3- and 2-oxindole products, respectively (Scheme 76).83 Tellitu and coworkers report an example of the hypervalent iodine reagent PIFA-promoted intramolecular electrophilic cyclization of alkynyl amides and alkynyl carboxylic acids, leading to the formation of pyrrolidinone and lactone skeletons, respectively, in a very efficient way (Scheme 77).84 Electrophilic cyclizations of a,b-alkynic hydrazones by molecular iodine afford synthesis of 4-iodopyrazoles in good to high yields (Scheme 78).85 Wu and coworkers have described a highly efficient electrophilic cyclization of N0 -(2-alkynylbenzylidene)-hydrazide with I2, Br2, or ICl in DCM at room temperature. It provides an efficient method to construct functionalized isoquinolinium-2-yl amides (Scheme 79).86 Recently, they reported a multicomponent reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, electrophile (bromine or iodine), and ketone or aldehyde under mild conditions, which generates the halo-containing H-pyrazolo[5,1-a]isoquinolines in good yields (Scheme 80).87
434
Electrophilic Cyclization
Me
O CH2
Me
O CH3 197 Ph3P (1.0 equivalent) I2 (1.0 equivalent) NaHCO3 (aqueous)
Me
Me O
O
CH3
Me 198a
Me
I Me
CH2
O
I
CH2
O
I
Me
I
Me I
CH2Cl2/CHCl3 20 min, 0 °C
198b
I
O
Me
H CH2
Me I
I CH2
O
O
O
Me 200
Me 199 Yield = 6%
Yield = 6%
Scheme 44
I
I
I
1. I2, CH2Cl2, 0 °C O
S
201
Ph 2. DABCO, r.t.
+ O
S 202
Ph
O
S Ph 203
Yield = 24%
OH
O
S
Ph
204 Yield = 69%
Scheme 45
Verma et al. demonstrated an I2-induced electrophilic cyclization, which is a facile synthesis of substituted pyrrolo[1,2a]quinolines (Scheme 81).88 Li et al. have developed an electrophilic tandem cyclization protocol for the synthesis of haloisoquinoline-fused benzimidazoles via CuI-promoted tandem cyclization of 2-ethynylbenzaldehydes with o-benzenediamines and iodine (Scheme 82).89 This protocol allows the formation of imidazo[1,2-a]pyridine ring in a one-pot reaction through the electrophilic annulation. In 2007, Yamamoto and coworkers presented a general and flexible approach to synthesize highly substituted isoquinoline building blocks, which can be further functionalized (Scheme 83).90 Depending on the nature of the substrates employed, acidic, basic, or neutral reaction conditions can be used, which makes this method compatible with sensitive, highly functionalized molecules. Their further research was reported in 2008, which presented a general and flexible approach to access highly substituted isoquinoline building blocks (Scheme 84).91 They finished the total synthesis of norchelerythrine by using the developed methodology to construct ring B (Scheme 85). Yamamoto et al. and Wu et al. separately reported an efficient procedure for the synthesis of 3,4-disubstituted iodoisoquinoline N-oxides from 2-alkynylbenzaldoximes (Scheme 86).92
Electrophilic Cyclization
HO R′ R
OH R′′′ R′′ 205
R
IX (2.0 equivalents) Wet DCM, r.t. Yield = 55−99%
OH
I 206
Wet DCM, r.t.
R′
X I
207
208
X = I, Br, Cl HO R′ R′′
Ts N R′′ R′
IX (2.0 equivalents) NHTs
Wet DCM, r.t.
X I
Yield = 45−89%
209
R
O
IX (2.0 equivalents) Yield = 33−82%
R
O R′′ R′′′
X
X = I, Br, Cl
HO R′
R′
435
210
X = I, Br, Cl Scheme 46
R1S
OH R2 211
NXS (3.5 equivalents) K2CO3 (3.5 equivalents) MeCN, 50 °C Yield = 42−71%
R1S X
X
O
NXS = NBS, NIS, NCS
R2
212
Scheme 47
H R1S
OH
NIS
R1S
I
OH
I
H S
R2
R2 213
211
R1
R2 HO
214 Base
R1S I
I O 212
HI elimination R2
R1S
R1 S
I
I H R2
Dihalogenation O 216
R2
O 215 H
Scheme 48
4.07.2.1.3
C-nucleophiles
4.07.2.1.3.1 Cyclization involving alkenes Taguchi and coworkers reported some iodocarbocyclization examples induced by chiral titanium taddolate 322.93,94 When CuO and the chiral titanium taddolate 322 were used for the iodocarbocyclization of dibenzyl 2-(4-pentenyl)malonate, it gave the corresponding product 323 in a 96% yield with a 85% ee (Scheme 87).93 If 2,6-dimethoxypyridine (DMP) was used instead of CuO in DCM/THF (4:1), a catalytic amount of the chiral titanium taddolate could still promote the transformation to afford bicyclic lactones 326 with 96–99% ee (Scheme 87).94 A stoichiometric amount of the binol-based phosphoramidite was used to induce enantioselectivity in the asymmetric iodocarbocyclization of alkadienyl or alkatrienyl arenes to afford the product 328 with up to 91% ee (Scheme 88).95
436
Electrophilic Cyclization
I2 (3.3 equivalents) NaHCO3 (3.3 equivalents)
OH R1 OH
R2
I
I HO
MeCN, 0−20 °C, 1 h
R2
R2 R1
217
O
R1
O 219
218
R1 = R2 = Ph (Yield = 60%) R1 = Ph; R2 = Bu (Yield = 71%) R1 = Bu; R2 = Ph (Yield = 77%) R1 = Me; R2 = Ph (Yield = 88%) R1 = Me; R2 = Bu (Yield = 65%) R1 = CO2Me; R2 = Ph (Yield = 47%) Scheme 49
R1
I2 ( 3.0 equivalents) K3PO4 (3.0 equivalents)
R1 R4
HO
R3
THF, 25 °C, 1−12 h
R2
R1
R1
R3
R4
Yield = 66−86%
O
R2
I
220
221
Scheme 50
OBn I I2 (1.2 equivalents) TsO
DCM, r.t.
OMe
OBn O
TsO
223
222 BnO
OH
O
OTs HO
224
Scheme 51
O
O I2 (1.2 equivalents) CAN (1.2 equivalents) OMe
R
225 R = Ph 4-Me-C6H4 Hexyl 4-MeO-C6H4 Scheme 52
MeCN, r.t.
I O 226 Yield = 97% 95% 91% 98%
R
Electrophilic Cyclization
R3 R1 N
I2 (3.0 equivalents) NaHCO3 (3.0 equivalents)
OE
R2
MeOH, r.t. Yield = 50−76%
227
437
I
R1
R3
N O
R2 228
E = CH3CO, PhCH2 Scheme 53
R1
R3
R3
O
O
I R2 OTMS 231
Path A
I
R1 R2 OTMS 232
NIS (1.5 equivalents) DCM, 23 °C R3 R3
O
O
R1
R1
R2 OTMS 229
I
R2 O 230
AuCl3 (5 mol%) Path B NIS (1.5 equivalents) DCM, 23 °C R3 O R1
R3
Au3+ OTMS 2 R 233
O
R3 O
Au2+
R1
R1 R2 OTMS 234
R1 = R2 = −C4H8−, Ph, Et R3 = Ph, 2-thienyl, 1-eyclohexenyl, n-Pent
Au2+
R2 O 235
Yield = 27−99%
Scheme 54
In the total synthesis of garsubellin A, Danishefsky and coworkers used iodocarbocyclization as the key step under the standard conditions in a 85% yield (Scheme 89).96 Then the same group applied the I2-induced electrophilic cyclization in the total synthesis of nemorosone and clusianone. A significant complication arose in the iodonium-induced carbocyclization reaction, shown in Scheme 90. Compounds 336 and 337 could be reconverted into 334 by treating them with zinc in aqueous THF in high yield.97 In addition to the desired carbocyclization product 335 (obtained only in a 32% yield), substantial quantities (i.e., 50%) of a virtually 1:1 mixture of oxygen competitive products 336 and 337 were also obtained. Fortunately, both the oxygen competitive products could be reconverted into the starting material in a very high yield by the action of zinc in aqueous THF.
4.07.2.1.3.2 Cyclization involving alkynes 3-Iodo-1H-indene derivatives are synthesized by iodonium-promoted 5-endo-dig carbocyclization of 2-substituted ethynylmalonates (Scheme 91).98 If the substrate 340 was modified to 342, both of 5-exo-dig and 6-endo-dig cyclization would be possible. Liang and coworkers reported a methodology for the synthesis of indene or naphthalene derivatives with high regio- and stereoselectivity under mild reaction conditions (Scheme 92).99 The resonance and electronic effects force the carbon of the malonate group closer to C-1 or C-2 of the acetylenic malonates, leading to the formation of five- or six-membered ring. Electron-rich aryls are also a type of good C-nucleophiles. When aryl propargylic alcohols are used as substrates, diiodinated carbocycles and oxygen heterocycles can be readily synthesized (Scheme 93).100 In the presence of protons, substrate 347 could lose a hydroxyl group to afford the propargylic carbocations intermediate, which is in resonance with allene cation 348. Then
438
Electrophilic Cyclization
R3 I (1.1 equivalents) 2 NuH (10.0 equivalents) NaHCO3 (3.0 equivalents)
O R1
R3 O
DCM, 2 h Yield = 67−92%
R2 236
E
R1 R2 Nu
237
R3
R3 O
O
E+
R1
E
R1
R2 238
R2
NuH
239
R1/R2 = −(CH2)3−, Ar/H, n-C3H7/H R3 = Ph, C4H9 NuH = MeOH, t-BuOH, i-PrOH, I2 Scheme 55
Y
I2 (2.5 equivalents) K2CO3 (1.0 equivalent) NuH (1.2 equivalents)
O
Nu
Y O
DCM, r.t. 240
R
R 241
I
Y = H, Me R = alkyl, vinylic, aryl, etc. Nu = MeOH, EtOH, PhNMe2, PhOH, etc. R4
I2 (2.5 equivalents) K2CO3 (1.0 equivalent) R4HC=CHR5 DCM
H O
242
R1
R5 O R1 243
I2 (2.5 equivalents) K2CO3 (1.0 equivalent) R2
R2
R3 DCM
Yield = 73−80%
R3 I 244
Scheme 56
OMe CHO
I2 (2.5 equivalents) K2CO3 (2.5 equivalents)
N Ph 245 Scheme 57
MeOH, 70 °C, 2.5 h Yield = 92%
O N 246
Ph I
Electrophilic Cyclization
R1 R1
O
+ NuH
O
I2 (1.1 equivalents) K3PO4 (1.1 equivalents)
I
DCM, r.t., 0.5 h Yield = 44−79%
Nu
247
248
Scheme 58
n-C6H13
CO2Et
I
I2 (1.5 equivalents)
O
DCM, r.t. Yield = 96%
O
n-C6H13
249
250
Scheme 59
R2
O R1
I
I2 (2.0 equivalents) NaHCO3 (2.0 equivalents) THF, r.t.
(CH2)n 251
R2 O
R1
(CH2)n 252
−H+ R2
I
I
R2 O R1
R1
(CH2)n
(CH2)H n 254
253 Scheme 60
N
OMe
R1 R2
DCM, r.t., 0.5−2 h Yield = 68−100%
255 R1 = H, Me, Ar, n-C6H13, t-Bu, etc. R2 = Me, Ar, t-Bu, etc. Scheme 61
N O
ICl (1.2 equivalents) R1
I 256
R2
O
439
440
Electrophilic Cyclization
O
R
R
O
HN N
O HO
X
N NIS (2.0 equivalents), 2 h or NBS (1.9 equivalents), 5 h
O
N
O HO
Acetone, r.t. Yield = 74−86%
O
OH
OH 258
257 R = p-CH3C6H4, p-(CH3)3CC6H4, c-C3H5 Scheme 62
1. I2 (1.0 equivalent) THF, 0 °C, 1 h 2. K2CO3 (1.0 equivalent) 10 h
R CO2H 259 R = n-C4H9, n-C7H15
I R
Yield = 36−91%
O
O 260
Scheme 63
R1
R1 R2
O 262
O dr > 99:1, 99% ee Z/E up to 98:2 I R1
NIS (2.0 equivalents) Cs2CO3 (1.0 equivalent) R=H Cyclohexane, −60 °C Yield = 86−91%
CO2H
261
R2
Cyclohexane, r.t., 1 h Yield = 75−88%
R3
R1 = H, alkyl R2 = H, alkyl R3 = H, alkyl
I R3
I2 (1.5 equivalents) K2CO3 (0 or 1.0 equivalent)
R2 O 263 O >98% ee Z/E up to 98:2
Scheme 64
R1
R3
R2
COOEt 264
R1 = alkyl, phenyl R2 = H, alkyl R3 = H, alkyl, benzyl Scheme 65
I2 (2.0 equivalents) MeCN:H2O = 15:1 r.t., 0.7−20 h Yield = 60−94%
I
R3
R1 R2 O 265
O
Electrophilic Cyclization
COOR2 R4
O
I2 (6.0 equivalents) CaH2 (0.6 equivalent)
COOR2
THF, r.t., 0.5 h Yield = 52−83%
R3 R1
R4
266
R3
R1
I
O R4
R4
267
R1 = Me, Et, i-Pr, Bn, Ph R2 = Et, Me R3 = H, Et, Bn R4 = H, Me, (CH2)5 Scheme 66
I2 (1.5 equivalents) cyclohexane, r.t., 2 h
Et
I
Et
Yield = 86% Z/E = 98:2
CO2H
O
268a
269a O
n-Bu O 270a O (+)-trans-whisky lactone Et
Et
I
271 (2.0 equivalents) Cs2CO3 (1.0 equivalent) 268b
CO2H DCM, −60 °C, 10 h Yield = 70%, ee = 99%
O O 269b
n-Bu
O O N I
270b
O (+)-cis-whisky lactone
271
O
Scheme 67
Ts
H N n 272
Chloramine-T (1.0 or 2.0 equivalents) I2 (1.0 or 2.0 equivalents) MeCN, r.t., 5−24 h Yield = 8−81%
n = 1−4 Chloramine-T = Scheme 68
Cl
N Ts
Na
Ts N n 273
I
441
442
Electrophilic Cyclization
R2 PHN
I2 (1.0 equivalent) DCM/NaHCO3 16 h, r.t.
R2
Yield = 62−97% dr = 4:1−17:1
R1
R1 F P = Ts, Boc 274
F I
F
R2
I
+
N P 275
N P 276
R1
Scheme 69
NHBn
Aryl
I2 (1.5 equivalents) K2CO3 (1.7 equivalents)
I R
CH3CN, r.t., 2 h Yield = 75−92%
H
H N H Bn 278
277 Scheme 70
Bn
R2
N
I2 (2.0 equivalents) NaHCO3 (5.0 equivalents)
Bn N
R1
R2
Dioxane, 100 °C, 10 min Yield = 76−95%
R1
I
279 R1 = alkyl, phenyl, 2-naphthyl R2 = alkyl, phenyl, benzyl
280
Scheme 71
R1 NH
OH +
R2
N O H 1.0 equivalent 281 R1 =
R3
R2 I2 (6.8 equivalents) CH3CN, r.t., 30 min N H 283
1.0 equivalent 282
aryl R3 = aryl, alkyl
Scheme 72
R2 N R1 284 2=
Me
R3
I2 (2.0 equivalents) CH2Cl2, r.t., 2 h Yield = 73−100%
R Me, n-C6H13, Ph R3 = Ph, n-C6H13, t-Bu Scheme 73
R2 N R1
R3
285
R3 N R1
Yield = 52−71%
R2 =
alkyl, benzyl
I
I
O
Electrophilic Cyclization
R2
HO R2 I R3 I
N
R
I2 (1.0 equivalent) MeCN
O
I2 (1.0 equivalent) R3
NMe2
Yield = 71−89%
EtOH
N
286
287
R
Yield = 68−92% 288
Scheme 74
R2
HO R2 I2 (2.0 equivalents)
R1 NHTs
R3
MeOH, 60 °C
I R1
289
R3
N
Yield = 40−99%
290
Scheme 75
O
I
HO R2 NIS (3.0 equivalents) I MeNO2 r.t., 3−6 h R2 = H Yield = 66−92% Z/E = 1.6:1−5:1
N Ts 292
NIS (3.0 equivalents) MeNO2
R1 NTs 291
Reflux, 2−3 h R2 ≠ H Yield = 32−98%
R2 R1 N Ts 293
Scheme 76
O PIFA (1.5 equivalents) Ar Ar
RHN 294
O
CF3CH2OH, 0 °C Yield = 55−65%
RN 295
O
Ar = Ph, p-MeOC6H4, 1-naphthyl, 2-thienyl R = Ph, Bn, Me Scheme 77
R3 HN
N R2
R1
I
DCM or CH3CN, r.t., N2, 30 min Yield = 40−95%
R1
296
R1 = alkyl, aryl, heteroaryl, ferrocenyl R2 = H, methyl, phenyl R3 = alkyl, aryl Scheme 78
R2
I2 (3.0 equivalents) NaHCO3 (3.0 equivalents)
N N R3 297
I O
443
444
Electrophilic Cyclization
N
R1
H N
R3
I2 (2.0 equivalents) or ICl (1.0 equivalent)
N
R3
R2
DCM, r.t. Yield = 70−99%
R2
298
N
R1 I 299
R1 = H, F, alkyloxyl R2 = phenyl, aryl, alkyl R3 = Ts, SO2Ph, COPh Scheme 79
O
O H
R1
TsNHNH2
+ R2
300
301
R1 = H, Cl,F R2 = phenyl, alkyl
+
R3
K3PO4 (3.0 equivalents) R4
R4
R3
I2 (1.1 equivalents)
N N
R1
EtOH, 70 °C Yield = 45−86%
R2 303
302
I
R3 = alkyl, H R4 = alkyl, H
Scheme 80
OMe
O
O I2 (3.0 equivalents)
N
O N
DCM, 25 °C Yield = 70−84%
R
R 304
I 305
Scheme 81
R2 NH2 + R1 306
CHO
NH2
R3 307
N I2 (2.0 equivalents), CuI (10 mol%) DMSO, 120 °C, 24 h Yield = 35−72%
R3
R1
N R2
I 308 R1 = H, methyl, methyoxyl, Cl, F, formyl R2 = phenyl, alkyl, aryl R3 = H, methyl, Cl, CF3
Scheme 82
intermediate 348 reacts with an iodide anion to give allenyl iodide 349, which can be further activated by an iodide cation. Then it is attacked by phenyl to produce the diiodinated product 350. The Larock group developed a series of methodologies for the synthesis of quinoline, naphthalene, and 2H-benzopyran derivates using electrophilic cyclization via the electron-rich aryl as nucleophile (Scheme 94).101
Electrophilic Cyclization
I
R1
I2 (5.0 equivalents) K3PO4 (5.0 equivalents)
N3
N
CH2Cl2, r.t., 24 h Yield = 82−95%
R2
309
R1
R2 310
R1 = Ph, p-OMePh, 1-cyclohexenyl R2 = H Py2IBF4 (2.0 equivalents) HBF4 in Et2O (2.0 equivalents) CH2Cl2, −78 °C, Ar Yield = 55−69%
R1
I R1 N
N3 R2 311 R1 = Me, n-butyl, t-butyl, CH2TMS R2 = H
R2
NIS (5.0 equivalents) NaHCO3 (1.0 equivalent)
312
CH2Cl2, 50 °C, Ar Yield = 42−62%
Scheme 83
R5
Ph
N3
R3 R2
R5
I2 (5.0 equivalents) NaHCO3 (1.0 equivalent)
R4
CH2Cl2 (0.1 M), r.t., 24 h, Ar
R3
R4
R1
Ph N R2
313 R1 = Me, R2 = H, R3 = H, R4 = H, R5 = H R1 = n-hexyl, R2 = H, R3 = H, R4 = H, R5 = H R1 = cyclopropyl, R2 = H, R3 = H, R4 = NO2, R5 = H
I
R1 314
Yield = 69% Yield = 73% Yield = 72%
Scheme 84
O
TBDMSO OHC
O
O
OTBDMS I2 (5.0 equivalents), K3PO4 (5.0 equivalents)
I
CH2Cl2, r.t., 24 h Yield = 94%
B
O
Br 315
MeO
O
MeO
OMe N3
OMe
316 O O MeO OMe
318
Norchelerythrine Scheme 85
O
317
445
446
Electrophilic Cyclization
R2
R1 N
I
R1
I2 (5.0 equivalents)
R2
EtOH, r.t., 15 min Yield = 71−90%
OH
N
319
O
320
R1 = H R2 = OMe, CF3, Ph Scheme 86
322 (1.0 equivalent) I2 (1.2 equivalents) CuO (1.2 equivalents)
COOBn
X
H 323
Yield = 96% ee = 85%
321
322 (0.2−0.3 equivalent) I2 (4.0 equivalents) DMP (2.0 equivalents)
ROOC
DCM/THF 4:1
X
COOR
X = CH2, CMe2, O R = Me, Bn 324
COOBn I
DCM, −78 to 0 °C
COOBn
COOR
BnOOC
O
COOR Heat I
325
Me Me
Ph O
O O Ph Ph 2 322
Ti
Scheme 87
OMe
OMe 1. NIS (1.1 equivalents) Chiral promoter 329 Toluene, −40 °C, 24 h 2. ClSO3H, i-PrNO2 −78 °C, 24 h
I
Yield = 58% ee = 91%
327
SiPh3
P N O H
Ph O I P N O O H
SiPh3
SiPh3
O
Chiral promoter: 329 Scheme 88
H 328
SiPh3 Ph
330
O X H 96−99% ee 326
H
Ph O
COOR
N O
Electrophilic Cyclization
H3C
CH3
I
I2 (3.0 equivalents) KI (3.0 equivalents) KHCO3 (3.0 equivalents)
O HO
CH3 O
CH3
HO
THF/H2O, r.t. Yield = 85%
H3C H3C H O
447
I
H3C H3C H O
O
331
O 332
H3C
CH3
CH3 O
CH3 O
HO H3C H3C H O
O H3C
CH3 333
CH3 Garsubellin A
H3C Scheme 89
Me
I
Me
I2 (3.0 equivalents) KI (3.0 equivalents) KHCO3 (3.0 equivalents)
O
Me
THF/H2O, r.t.
Me MeO
I HO 335
334
O
O
Me Me MeO
Me
Me
Me
O
O
Me
Me Me O
Me
Me Me
Me
HO
Me
O 337 24%
Ph
Me
Me MeO
Me
Me
Me O
I
+ Me
336 29%
32%
I O
I
+
Me
O
I
O
Me
Me Me
Me Me
Me Me
O
Me
338 Nemorosone
HO
O
Me
Me 339 Clusianone
Scheme 90
Yamamoto and coworkers have developed an efficient and general iodine-mediated electrophilic cyclization for the synthesis of 2,3-diiodo-dihydronaphthalenes from aryl propargyl alcohols (Scheme 95).102 Li’s group described an example that 4-(p-methylaryl)-1-alkynes could undergo the intramolecular ipso-iodocyclization process with ICl or I2 to afford the corresponding 8-methylene-1-azaspiro[4,5]trienes in moderate to good yields (Scheme 96).103 Four different types of fused arenes, fluoranthene, indeno-[2,1-a]phenalene, (8H)cyclopenta[a]acenaphthylene, and pyridine[a]acenaphthylene, were efficiently constructed through iodine-mediated electrophilic cyclizations of 1,8-dialkynyl naphthalenes in a single step (Scheme 97).104
448
Electrophilic Cyclization
COOEt COOEt
THF, reflux, 2 h Yield = 62−78%
R
340
COOEt COOEt R
I2 (1.5 equivalents) NaH (1.5 equivalents)
341
I
R = Ph, 2-naphthyl, 3-MeOC6H4, CH2OBn Scheme 91
E1
E1 E2
E (2.0 equivalents) t-BuOK (2.0 equivalents)
E2
I 343
R
R I 344
E1, E2 = COOMe, COOEt, COMe R = alkyl, aryl E = I2, NIS, ICI
E1 E2 I+
E1
−H+
E2
+
THF, r.t.
R
342
E1
b
a
E2
a
b I+
R
345
R
346
Scheme 92
n
n
I2 (2.0 equivalents) R1 OH R2
CH3NO2, r.t. Yield = 68−74%
R1 R 350
347
I
2
I
H+ n
I2
R3
n
I
R3 I
R1
R2
348
R1
R2
349
R1 = H R2 = Ph, p-MeOC6H4, p-MeC6H4, m-MeC6H4 Scheme 93
Kirsch et al. investigated the reactivity of 1,5-enynes and 1,6-enynes in the presence of electrophilic iodine sources (Scheme 98).105 1,5-Enynes favored the formation of six-membered carbocycles with great structural diversity, whereas 1,6-enynes favored the more rapid 5-exo cyclization yielding the corresponding five-membered carbocycles in moderate to good yields. Wang and coworkers developed a methodology to assemble the azaanthraquinone and diazaanthraquinone skeletons from Npropargylaminoquinones by utilizing an iodine-induced 6-endo-dig electrophilic cyclization (Scheme 99).106 With Cu(OTf)2, 3-alkylation of indole resulted in the formation of 3-propargylic indole, which could be further converted into 2-iodo-1,4-dihydrocyclopenta[b]indoles in the presence of NIS and boron trifluoride etherate (Scheme 100).107
Electrophilic Cyclization
H N
R1
Ar
E (3.0 equivalents) NaHCO3 (2.0 equivalents)
R1
N Ar
Yield = 43−88% 351
R2
R3
R4
E R2 352
E = I2, ICl
R1 = H, Me R2 = aryl, n-Bu
R3 OH
Ar
R4
E (3.0 equivalents) NaHCO3 (2.0 equivalents)
Ar E
Yield = 18−94% 353
449
R5
R5 354
E = I2, ICl
R3 = H, Me; R4 = H, Me, alkyl R5 = aryl, arkyl, vinylic, silyl, OEt O
OH
E (3.0 equivalents) NaHCO3 (2.0 equivalents)
I
Yield = 45−98% 355
R6 356
R6
R6 = aryl, arkyl, vinylic O
E = I2, Cl
I2 (3.0 equivalents) or ICl (1.5 equivalents)
Ar
O Ar I
Yield = 52−96% R7 358
R7 357 7 R = H, Ar Scheme 94
R3
R3 I2 (3.0 equivalents) R1
OH R2
CH3NO2, r.t. Yield = 61−98%
359
I R1 I R2 360
R1 = Me, OMe, Cl, Ar R2 = aryl, naphthyl, thienyl, (1-tosyl)pyrroyl R3 = Me, Ph Scheme 95
4.07.2.1.4
S or Se-nucleophiles
An efficient synthesis of 3-halo-chalcogenophene[3,2-c]chromene has been accomplished via electrophilic cyclization reaction of 3-alkynyl-4-chalcogen-2H-chromene (Scheme 101).108 Zeni’s group presented the electrophilic cyclization reactions of 3-alkynylthiophenes, which proceeds cleanly under mild reaction conditions, and gives fused 4-iodoselenophene-[2,3-b]thiophenes in excellent yields (Scheme 102).109 Zeni et al. developed an efficient method for the synthesis of tetrahydroselenophene derivatives by electrophilic cyclization of 1-butylseleno-4-alkynes. The cyclized 5-exo-dig products were obtained in high yields under mild conditions (Scheme 103).110 A formal total synthesis of the benzothiophene selective estrogen receptor modulator (SERM) desketoraloxifene analogs has been accomplished from alkynes bearing electron-rich aromatic rings by electrophilic cyclization using I2 (Scheme 104).111 Compound 392 could be converted to oxygen-bearing 3-iodobenzo[b]thiophenes in excellent yields via a two-step approach involving Suzuki–Miyaura coupling and Mitsunobu reactions.
450
Electrophilic Cyclization
Ph MeO
Ph I2/NaHCO3/MeCN/r.t.
N O 361 R1 R1 = Me, H, Ac, Bn
or ICI/CH2Cl2/−78 °C
R3 ICI (1.5 equivalents) H2O/CH2Cl2/−25 °C N R2
O
363 R2 = Me, H, Ac, Bn R3 = Ph
or I2 (2.0 equivalents)/MeCN/r.t. Yield = 48−89%
I O N R1 362
O
R3 I N R2 364
O
Scheme 96
4.07.2.2 4.07.2.2.1
Bromocyclization Cyclization involving alkenes
Oxetanes can be obtained in good yields from cinnamyl alcohols using bis(collidine) bromine(I) hexafluorophosphate as electrophile (Scheme 105).112 It is an efficient way to get Oxetin (oxetan-2-carboxylic acid), which is a natural product possessing antibiotic activities. It is developed by the same group that developed silicon-directed 4-exo-rig electrophilic cyclizations of homoallylic alcohols to prepare oxetanes (Scheme 106).113 Shi and coworkers reported that various g-hydroxyalkenes and g-amino-alkenes could efficiently undergo bromocyclization using NBS as the Br þ source with chiral phosphoric acid 401 as the catalyst, giving 2-substituted THFs and tetrahydropyrroles with generally good yields and up to 91% ee (Scheme 107).114 Fujioka and coworkers reported an example of asymmetric bromolactonization of 5-substituted 5-hexenoic acids catalyzed by a C3-symmetric chiral trisimidazoline (Scheme 108).115 The use of 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) instead of NBS as the bromine source could increase the selectivity, although the conversion was moderate when 0.6 equivalent was used. With 1.0 equivalent of DBDMH, the reaction proceeds in a high yield with good selectivity. Yeung and coworkers developed an S-alkyl thiocarbamate catalyst for the same reaction with high yields and good ees (Scheme 109).116 Very recently, Yeung et al. developed the first organocatalytic halolactonization of unsaturated carboxylic acids using zwitterionic catalyst 411 and stoichiometric N-bromosuccinimide halogen source, resulting in the formation of mediumsized lactones (Scheme 110).117 The Tang group recently discovered a DABCO-catalyzed syn-selective 1,4-bromolactonization of enynes. This reaction gave axially chiral allenes as the main products.118 In 2010, the same group described the mechanism that catalyst 413 (which has a bridgehead nitrogen similar to DABCO) promotes highly enantioselective bromolactonization of 2-enynes 412 and 415 to give bromoallenes 414 and 416 (Scheme 111).119 A facile, efficient, and enantioselective approach toward 4-bromo-3-aryl-3,4-dihydroisocoumarins through an aminothiocarbamate-catalyzed bromocyclization process has been developed by Yeung’s group (Scheme 112).120 This method is used for the synthesis of biologically important 3-substituted 3,4-dihydroisocoumarins and its related compounds. Very recently, Martin and coworkers reported a novel bifunctional catalyst from BINOL to accelerate highly efficient and enantioselective bromolactonizations of unsaturated acids (Scheme 113).121 These reactions represent the first catalytic bromolactonizations of alkylsubstituted olefinic acids to give lactones via 5-exo mode cyclizations, and the new carbon–bromine bonds are formed at the stereogenic center with high enantioselectivity. Also a tentative stereochemical model for enantioselective bromolactonizations is proposed (Scheme 114). Fujioka and coworkers applied the asymmetric bromolactonization of 5-substituted 5-hexenoic acids catalyzed by a C3-symmetric chiral trisimidazoline in the total synthesis of tanikolide (Scheme 115).115b Snyder and coworkers developed simple reagents such as 432, for direct halonium-induced polyene cyclizations.122 Electronrich and -deficient terpenes derived from geraniol, farnesol, and nerol could be used for the synthesis of a diverse array of complexes with chlorine-, bromine-, and iodine-containing polycyclic frameworks. Total synthesis of many natural products are achieved with this protocol, such as peyssonol A, peyssonoic acid A (Scheme 116), and formal racemic total syntheses of aplysin20, loliolide, and K-76. Treatment of g-disubstituted b,g-unsaturated hydroxamates with bis(collidine)bromine(I) hexafluorophosphate led mainly to the formation of cyclic bromo imidates – the thermodynamic products (Scheme 117).123
Electrophilic Cyclization
R1
451
R2 R2 I2 (3.0 equivalents) NaHCO3 (2.0 equivalents) CH3CN, 50 °C, 12 h
R1
I
366
365
R1 = R2 = H, F, CH3, OMe, Yield = 86−92% R1 = H, R2 = F, Br, CH3, OCH3, Yield = 72−91% R3
HO
R1
R2 R1
R3
R2
I
I2 (3.0 equivalents) DCE, r.t., 8 h Yield = 42−72%
367
368 R1 = R2 = CH3, R3 = H, Me, F, Br, H
OH
I OH
I2 (1.1 equivalents) DCM, r.t., 8 h Yield = 78%
369
HO
370 R3
R2 R1
R1 I2 (3.0 equivalents)
N
R3
R2
CH3CN, r.t., 8 h Yield = 48−69% 372
371 R1
=
R2
= CH3
R3
= H, CH3, F, Br
Scheme 97
In the total synthesis of (þ)-chaetocin, bromocyclization induced by NBS is used in the assemblage of the five-membered ring, which affords the desired product 448 in 88% yield (Scheme 118).124 This reaction was highly stereoselective, and no appreciable amount of the other stereoisomer was detected. Lera and coworkers have developed a versatile synthetic route leading to WIN 64821 (452) and WIN 64745 (453) (Scheme 119).125,126 Bromohexahydropyrroloindole 451 could be easily achieved from commercial D-tryptophan via stereoselective bromocyclization of the tryptophan derivative 450 in the presence of N-bromosuccinimide, according to the methodology recently developed by the same group.126 In the asymmetric total synthesis of loline alkaloids, the Trauner group used bromine-induced electrophilic cyclization to construct the key ring (Scheme 120).127 It goes through an unprecedented transannular aminobromination, which converts an eight-membered cyclic carbamate into a bromopyrrolizidine.
452
Electrophilic Cyclization
R1
R3
R5 R4
NIS (3.0 equivalents)
R2
DCM, 50 °C, Yield = 13−96%
I
R2
373
R4 R5 R1 374
R3
R1 = Ar, H, Me, Br, alkene R2 = H, Me R3 = TIPSO(CH2)3, Me, Ph, alkyl R4 = Me, Ph, alkyl R5 = H, Me H
H
NIS (3.0 equivalents)
I
DCM, 23 °C or 50 °C Yield = 40−55%
X 375 X = (MeO2C)2C, (PhO2S)2C, O, NTs
X 376
H H I
NIS (3.0 equivalents) DCM, 23 °C Yield = 67%
EtOOC COOEt
EtOOC COOEt 378
377 Scheme 98
I2 (3.0 equivalents) NaHCO3 (2.0 equivalents)
O
O I
MeNO2, 100 °C, 4 h Yield = 77% O 379
N H
N O 380
Scheme 99
R2 N
R3
R4
R2 N OH
+
Cu(OTf)2 (10 mol%) DCM, r.t.
R1
R1 R3
R4
Scheme 100
382
Yield = 16−54%
383
R5
R5
R1 R3
R5 381
R2 N
NIS (3.0 equivalents) BF3.Et2O DCM, r.t.
384
R4
I
Electrophilic Cyclization
I O
O I2 (2.0 equivalents)
R
385
YR1
Y
CH2Cl2, r.t. Yield = 50−86%
R2
R2
R 386
Y = S, Se; R = aryl, alkyl; R1 = Me, butyl; R2 = alkyl, aryl, alcohol Scheme 101
Ph
I E (1.1 equivalents)
S 387
Ph
DCM, r.t. Yield = 38−89%
YnBu
S
Y 388
Y = Se, Te; E = I2, ICl Scheme 102
I2 (1.1 equivalents) SeBu R1
R2
I
DCM, 4 h, r.t.
R2
R1
Se
60−93%
389
390
R1 = aryl, heteroaryl, alkyl, SeBu, Si(CH3)3, propargyl alcohol R2 = H, OH, OBz Scheme 103
R2
SMe R3 R2
R3
R1
R4 R7 391
R5
I2 (1.2 equivalents) DCM, r.t. Yield = 88−95%
R5 I 392
R1, R2, R3, R4, R5, R6, R7 = MeO or H R3
R4
S R5
R1
R7
393
O
R6
N
Desketoraloxifene analogs Scheme 104
S
R1
R6
R2
R4
R7
R6
453
454
Electrophilic Cyclization
394
R
OH R
Br+(coll)2PF6− (1.3 equivalents) CH2Cl2, r.t., 6.5 h R=H Yield = 36% R = Me Yield = 67%
R 395
RuCl (cat.) NaIO4
R
O
Br
CH3CN-EA-H2O R = Me Yield = 90%
O HO2C
Me Me
Br 396
Scheme 105
OH
Br
398 (2.5 equivalents) TMS
CH2Cl2, reflux, 6 h Yield = 89%
397
H
O
TMS H
399 398 = Br+(collidine)2SbF6−
Scheme 106
R Chiral acid 401 (10 mol%) XH NBS (1.2 equivalents) X
DCM, 0 °C Yield = 45−97% ee = 2−91%
R 400
O O P OH O
Br 402
R
R 401
X = O, NsN, or TrisylN R = aryl, alkyl
R = 2,4,6-(i-Pr)3C6H2
Scheme 107
R
X
Br
DBDMH (1.2 equivalents) 404 (10 mol%)
O
O
Toluene Yield = 74−99%
OH
R X 405
403 R = aryl, 2-naphthyl, cyclohexyl X = CH2, CMe2, O, NTs Ph
Ph
N
NH
H N
Ph
N
Ph
HN
N Ph
O
404
Ph
Scheme 108
In the synthesis of pallidol, ampelopsin F, paucifloral F, and diptoindonesin A, Snyder and coworkers used bromine-induced electrophilic cyclization as a key step (Scheme 121).128 Take pallidol as an example; a possible pathway of the bromocyclization induced by Br2 is proposed in Scheme 121.
Electrophilic Cyclization
NBP (1.2 equivalents) 407 (10 mol%)
O R1
OH
Toluene, −78 °C Yield = 95−99% ee up to 92%
406 R1 =
aryl, 2-naphthyl, alkyl
H
Br O
O R1 408
R2
N S
H N
Ar
O R2 = Ph, naphthyl 407 Scheme 109
411 (10 mol%)
OH
O
NBS (2.0 equivalents) DCM, 0 °C Yield = 54%
O 409
F3C
O
Br
410
S N
N
N 411
F3C Scheme 110
X O
R1
R2
R1
X
413 (20 mol%)
OH 412
NBS (1.2 equivalents) DCE, r.t. O
Yeild = 62−87%
Br
O 414
R2
R1 = H, n-Pr, i-Pr, t-Bu, TES, CH2OPh, CH2OPMB R2 = H, Me X = O, CH2, NTs R
R O
NBS (1.2 equivalents) DCE, r.t. 413 (20 mol%) Yeild = 44−88%
HO2C 415 R = H, Me, OMe, Cl, CF3, NO2
O
OMe
NH N
O 413
Scheme 111
O
NTs
O 416
H Br
455
456
Electrophilic Cyclization
Br
Br R2 OH R1 O 417
R2 H O
R2
418 (10 mol%) O
NBS, CH2Cl2 Yield = 87−98% ee = 24−95%
R1 419
R1 = H, CH3, F, Cl R2 = aryl
R1
O
O 420
419:420 Ratio range from 2.5:1 to 50:1 MeO
S
OMe
N H
O N
N
H OMe
418 Scheme 112
O R1 = H, R2 = Et, i-Bu, i-Pr, Cy, t-Bu
O R2
R1
R2
R1
TBCO (1.2 equivalents) Catalyst 422 OH O
DCM/Tol = (1:2) −50 °C, 14 h
R1 = Ph, 1-Np, 2-thienyl R2 = H
421
Br 423 O
O R2
O
R1
OH
R4 O 425
TBCO (1.2 equivalents) Catalyst 422 DCM/Tol = (1:2) −50 °C, 14 h
Yield = 92−97% er ratio range 94:6 to 98:2
(2)
Br 424
O
R3
Yield = 89−99% (1) er ratio range 85:15 to 98.5:1.5
O Yield = 89−99% er ratio range 71:29 to 91:9
R2 Br R1 426
(3)
R3 = H, Me R4 = Ph, m-CNPh, p-CN-Ph, Me Ph OH N Me 422
Me N Me
Scheme 113
4.07.2.2.2
Cyclization involving alkynes
Wu and coworkers developed an efficient route for the synthesis of isoquinoline-based azomethine ylides from 2-alkynylbenzaldoximes, DMAD, and bromine via tandem electrophilic cyclization-[3 þ 2] cycloaddition-rearrangement reactions (Scheme 122).129 When the DMAD is replaced by carbodiimide derivates, this process affords functionalized 1-amino-4-bromoisoquinolines in high yields (Scheme 123).130 Then two efficient methods for the synthesis of functionalized H-pyrazolo[5,1a]isoquinolines are developed subsequently, shown in Schemes 124.87,131
Electrophilic Cyclization
O
O O H
O
O
H Br H
Alk
H
NMe2
Disfavored
Br
O O
H Ar
N Me
Br
Br H
H
H
Alk Me
NMe2 Favored O
O
H
Alk H BrH
N
O
O
Ar
O
H
(a) Preferred mode for cyclizations (1)
O O H
O O H
O H
Alk
N Me
O
Br
N Me
(b) Preferred mode for cyclizations (2)
Br
OH
N Me
Br
H
NMe2
Favored
O O H
Ar
H
NMe2
Disfavored
OH
O H Ar
H
Br
457
O O
O
O H
H O
Ar
Ar
NMe2
O
O Ar
Br
Me
Br
Disfavored
Ar H
N
Br H NMe2
Favored (c) Preferred mode for cyclizations (3)
Scheme 114
C10H21
DBDMH (1.0 equivalent) Trisimidazoline (10 mol%)
O
Ph
OH 427
Toluene Yield = 99%
C10H21 Br (s) O (s) Ph
C10H21 O n-Bu3SnH, AIBN Yield = 91% ee = 91%
Ph
O (s)
O
429
428 C10H21 HO
O (s)
O
430 (−)-Tanikolide Scheme 115
In the synthesis of a-saxitoxinol, an analog of saxitoxin, Nishikawa and coworkers used the key bromocyclization reaction and subsequent intramolecular N-alkylation to construct a dibromomethylene intermediate 476 on treatment of 475 with pyridinium tribromide (PyHBr3) at room temperature (Scheme 125).132 Then another six steps were carried out to give a-saxitoxinol.
4.07.2.2.3
Cyclization of allenes
Vanadium bromoperoxidase is an enzyme present in marine algae, which catalyzed electrophilic halogenation reactions using hydrogen peroxide to oxidize and thereby activate bromide ion. Butler and coworkers well summarized the examples of vanadium bromoperoxidase in the biosynthesis of halogenated marine natural products.133 Ma and coworkers reported the studies on electrophilic reaction of tertiary 2,3-allenols with NBS in H2O or aqueous MeCN (Scheme 126).134 It provides an efficiently selective method for the synthesis of 3-bromo-2,5-dihydrofurans.
458
Electrophilic Cyclization
HO Me
Me 432 (1.0 equivalent) MeNO2, −25 to 25 °C Yield = 26%
Br
Me
Me
Me 431
OH
Me
O Me Br
H Me Me 433
Br S+
O
O
O
RO
Cl Cl Cl Sb− Cl Cl Br
H Me Me 434 Peyssonol A
432
OMOM OMOM MOMO
HO
CO2H
432 (1.1 equivalents) Me
Me
MeNO2, −25 °C Yield = 31% Br
Me
Br H Me Me
Me
H Me Me 437
436
435 Me
OH
Me
Me O
Peyssonoic acid A
Me CN Me CN 432 (1.1 equivalents) Me
Me
MeNO2, 25 °C Yield = 72%
Me
OH
Me
Me 438
Br
H Me Me 439
Br
H Me Me
Me Me OH
440
Aplysin-20
Scheme 116
4.07.2.2.4
Cyclization of cyclopropane
Highly efficient C–O bond formation has been developed via carboxylic acid catalyzed reaction of 1-acetylcyclopropanecarboxamides with NBS, which provides strategically novel and atom-economic access to biologically important 5amino-3(2H)-furanones (Scheme 127).135
4.07.2.3
Chlorocyclization
Iodocyclization and bromocyclization have been extensively investigated, and numerous electrophilic reagents have been developed. However, the research on chlorocyclization is not as many as that on the former two. The reason is partially due to the highly reactive nature of chloronium ions, which might exist in equilibrium with the corresponding carbocation rather than exclusively as cyclic chloronium ions. Thus, it makes chlorocyclization a formidable challenge for stereoselectivity control.136 So far, a lot of Cl þ reagents have been used for chlorocyclization, such as NCS, DCDMH, TCCA, chloramine-T, and DCDPH.
4.07.2.3.1
Cyclization involving alkenes
Borhan and coworkers reported catalytic enantioselective chlorolactonization of exocyclic 4-substituted pentenoic acids mediated by (DHQ)2PHAL or (DHQD)2PHAL and DCDPH (1,3-dichloro-5,5-diphenylhydantoin).137 When the acid substrates were selected to react in CHCl3-hexane in the presence of benzoic acid, the corresponding chlorolactones were obtained in high
Electrophilic Cyclization
459
Et3N, DCM, r.t. Yield = 80% O
N O 442 (1.1 equivalents)
O
N OAc Me
N O
+
O
+
443
444
Yield =12%
Yield = 29%
HN OAc O
O O
Br
DCM, r.t., 1 h
Me
445 Yield = 59% N OH
441 442 (1.1 equivalents)
443
Toluene, −20 °C, 2 h Yield = 100%
LiAlH4 (1.0 equivalent)
O
Ether, r.t. Yield = 95%
442 = Br+ source: bis(collidine)bromine(I) hexafluorophosphate [Br+(coll)2PF6−]
446
Scheme 117
H O N HN
Boc 447
O
Br NBS (1.2 equivalents) MeCN, −30 °C Yield = 88%
NMe
NMe H
N N H Boc
O TBSO
O
OTBS
448
HO MeN
Boc H N
O S2
N O
O N 449
N H Boc
S2 O
NMe OH
(+)-Chaetocin Scheme 118
enantioselectivities (Scheme 128). Then they developed another highly stereoselective chlorocyclization of unsaturated amides to chiral heterocycles mediated by catalytic amounts (1–2 mol%) of commercially available (DHQD)2PHAL (Scheme 129).138 The reaction is simply handled without strictly anhydrous or inert reaction conditions. The reaction scope is fairly general with regard to the substitution pattern of the olefin.
4.07.2.3.2
Cyclization involving alkynes
The 5-endo-dig chlorocyclization of 1,4-disubstituted alk-3-yn-1-ones (propargylic ketones) with trichloro-striazinetrione (trichloroisocyanuric acid, TCCA; 0.4 equivalent) in toluene at room temperature in the absence of base was developed, which provided 2,5-disubstituted 3-chlorofurans in high yields (79–96%) (Scheme 130).139
460
Electrophilic Cyclization
O
OMe
H Br
NBS (1.0 equivalent) NHBoc PPTS (1.0 equivalent)
O
Ph
H
OMe NBoc
DCM, 25 °C Yield = 85%
N Boc 450
O
N H Boc 451
H N
N HN
O O N N H H
452
H H N
O
NH
N O
Ph
HN
O O
WIN 64821
NH N N H
453
H
O
Ph
WIN 64745 Scheme 119
Br
N Cbz
N3
Br2 (1.0 equivalent)
OH
MeOH, 0 °C, 12 h Yield = 97%
454
H
N3
N+ H Br−
OH
455 CHO N O N 456 N-formyl loline
Scheme 120
4.07.2.4
Fluorocyclization
Although fluorinated molecules widely exist in pharmaceuticals and agrochemicals,140 the development of fluorocyclization reactions is not too many. The low reactivity of commonly used N-F electrophilic fluorinating reagents is particularly restrictive in the fluorocyclization. This section summarizes the progress in fluorocyclization.
4.07.2.4.1
Cyclization involving alkenes
The Taguchi group developed a fluorolactonization of 4-alkenoic acid derivatives containing an aryl substituent at the 4- or 5position with N-fluoropentachloropyridinium triflate, which proceeds smoothly in a regioselective manner with little or even no diastereoselectivity (Scheme 131).141 The Serguchev group realized the selective fluorolactonization of cis-5-norbornene-2,3-endo-dicarboxylic acid or its monomethyl and dimethyl esters with F-TEDA-BF4 or XeF2 (Scheme 132).142 The reactions of 5-norbornene-endo-2-carboxylic acid or
Electrophilic Cyclization
OMe
461
OMe
OMe
OMe
OMe
OMe
Br
OMe
Br2 (2.0 equivalents) CH2Cl2, −78 °C, 2 h, then r.t., 1 h OMe Yield = 81% OMe
MeO
MeO OMe 458
457
OMe
OMe
MeO Br
OMe
Br
OMe
Br
OMe
Br
OMe
MeO
OMe
OMe
Br Br
OMe
OMe
460
459 Friedal-Crafts alkylation
OMe
MeO
OMe
Br Br
H Br
MeO
OMe
MeO
BBr3 (12 equivalents), CH2Cl2, 0°C, 4 h, then 25 °C, 20 h Yield = 83%
OH
HO
Pd/C (20 mol%), H2, MeOH, 25 °C, 24 h Yield = 76%
OH H
H
HO
OH
HO 462
461
Pallidol Scheme 121
R1
N
OH
R2
CO2Me
CO2Me
463 464 R1 = H, F R2 = n-Bu, Ph, PMP
Br2 (1.0 equivalent) NaOAc (1.2 equivalents) CH2Cl2, r.t. Yield = 42−98%
N
R1
CO2Me CO2Me R2
O
Br 465
Scheme 122
its methyl ester with F-TEDA-BF4 or XeF2 proceed unselectively with the formation of products of lactonization, addition, and rearrangements. In 2003, Gouverneur and coworkers demonstrated that the electrophilic fluorodesilylation of allyl silanes combined with the use of enantiopure N-fluorocinchona alkaloids provided a highly efficient method for preparation of allylic fluorides with high ee values.143 The (DHQ)2PYR/Selectfluor combination fluorinated cyclic allylsilanes in MeCN to give five- and six-membered chiral allyl fluorides. The first asymmetric example was reported by Gouverneur and coworkers during a study of electrophilic
462
Electrophilic Cyclization
R3 N
R1
OH R3 N C N R3
R2
Br2 (1.0 equivalent)
N
R1
DCM, 1,4-dioxane, 60 °C
R2
Yield = 41−99%
466
NH
467
468
Br
R1 = H, F, Cl, Me, OMe R2 = Ph, 4-ClC6H4, 4-MeC6H4, 4-MeOC6H4, cyclopropyl Scheme 123
R3 N
R1
OH
R2 Br 470
R1 = H, F, OMe R2 = Ph, n-Bu R3 = Ph, n-Bu, PMP, CH2OH; cyclopropyl
CHO R3 471
TsNHNH2 (1.1 equivalents) Br2 (1.1 equivalents) K3PO4 (3.0 equivalents)
O
R1 R2
N
R1
R3 AgOTf (10 mol%) DBU, CH2Cl2 Yield = 50−91%
2. R2
469
N
1. Br2 (1.0 equivalent), DCM
R4 472
R4
R3
N N
R1
EtOH, 70 °C Yield = 45−86%
R2 Br
R1 = H, F, Cl R2 = Ph,n-Bu,cyclopropyl R3 = H, Me, Et, −(CH2)4− R4 = H, Et
473
Scheme 124
OH
CbzHN
HO CbzHN
N
HN
N3
NH
NBoc
PyHBr3 (5.0 equivalents) K2CO3 (10 equivalents)
N3 O HN
DCM, H2O, r.t., 1 h Yield = 24% for 6 steps
CbzN 476
474
OTBS
475
OMs OH H N
HN H2N
N
NH2 NH OH H
477 Decarbamoyl -saxitoxinol Scheme 125
Br N
Br
Electrophilic Cyclization
R3
Br
H R1 NBS (1.5 equivalents)
R4 HO R2 478
H
R3
R1
R4
CH3CN/H2O = 15/1 or H2O (R1 or R2 ≠ H)
463
R2
O 479
Yield = 61−84% Scheme 126
O
O
O
NBS NHR1
R2 480
NHR1
O
R3CO2H Yield = 73−94%
Nu 481
R1 = alkyl R2 = H, Me R3 = H, alkyl, aryl Nu = OR, O2CR, X
Scheme 127
O
483 (10 mol%) 484 (1.1 equivalents) OH
R1 482
O
Benzoic acid (1.0 equivalent), CHCl3/hexane (1:1), −40 °C,
O
R1
Yield = 75−86%, ee = 74−90%
Cl
485
R1 = Ph, p-(Me/Cl/F/CF3)C6H4, cyclohexyl OR2
OMe O
N
O N Cl 484 = DCDPH
Ph
R2 =
N
Cl N
OR2
N
N
Ph
Et
(DHQD)2PHAL (483)
Et Et N H H
Cl N Ph
O Cl
N
Ph O
486
or
N H Cl
O N
O Ph 487
N Cl Ph
Scheme 128
fluorocyclizations (Scheme 133).144 The (DHQ)2PHAL/Selectfluor combination could induce asymmetry in the cyclization of prochiral allyl silane 510 to produce 511 (70% yield, one diastereomer, 45% ee).
4.07.2.4.2
Cyclization of allenes
The fluorohydroxylation of 3-aryl-substituted-1,2-allenes with Selectfluor in aqueous MeCN at room temperature is reported by Ma’s group.145 This electrophilic reaction is highly regioselective with the more substituted and electron-rich C¼ C bond. However, the substrate scope is so far still very limited since the presence of the aryl group in allenes is important for the success of
464
Electrophilic Cyclization
H N
Ph
Ar
483 (2 mol%) 484 (1.1 equivalents)
Ar
TFE, −30 °C, 2 h Yield = 79−96%, ee = 59−98%
O
O
488
N Cl Ph 489
Scheme 129
O
491 (40 mol%)
R1 R2
R2
O R1
Toluene, 22 °C Yield = 79−96%,
Cl
490
492
R1 = Ph, p-ClC6H4, p-BrC6H4 R2 = p-MeC6H4, c-C6H6, p-(t-Bu)C6H4 O Cl
N
Cl
N
N O Cl 491 = TCCA
O
Scheme 130
R1
494 or 495 (1.2 equivalents) CO2H
MeCN, r.t., 1 h
R1
493
496
497
A
45%
45%
B
74%
−
Ph
494 (1.2 equivalents) NaHCO3 (1.5 equivalents)
Ph
MeCN, r.t., 1 h
Et
CO2H R3
498
2.1 : 1
51%
1 : 2.4
494 (1.2 equivalents) NaHCO3 (1.5 equivalents) CO2H R5 500
Scheme 131
F 499
E-498 R2 = H, R3 = Et
Z-500 E-500
R4
Cl
+ Ph
O
Cl
Cl
Cl N − F OTf 494
Cl
N F 475
F
F
MeCN, r.t., 1 h
Cl
O
72%
R4
O
O
Z-498 R2 = Et, R3 = H
R4
O
F
R1 = Ph
R2
R1 Me
O +
O
O
501
= Me,
R5
= Ph
59%
1 : 2.5
= Ph,
R5
= Me
20%
1 : 2.2
Ph
O 502
O
Cl −OTf
Electrophilic Cyclization
F
F
F-TEDA-BF4 (1.2 equivalents)
CO2R
CO2R + F CO2R MeOCHN
CO2R +
CH3CN, r.t., 40 h
CO2R
O O 504
503 R=H R = Me
73% 71% XeF2 (1.0 equivalent), BF3.OEt2 (75 mol%)
CO2Me
CH2Cl2, −78 °C, 24 h
CO2Me 503
506
Trace 4%
4% F
CO2Me O
+
F
CO2Me
CO2Me
+
O
CO2Me
O 504
O 507
508
45%
6%
7%
F CO2Me
F
CO2Me
509 6%
Scheme 132
Ph
Selectflour (1.2 equivalents), (DHQD)2PHAL (1.2 equivalents),
SiiPr2p-Tol
NaHCO3, MeCN, −20 °C, 4 days Yield = 70%, ee = 45%
510
CO2R CO2R
505
F
+
HO
465
O F SiiPr2p-Tol
Ph
(+)-511 trans/cis >20:1
Z/E > 20:1 Scheme 133
this transformation. With Selectfluor as the electrophile, 2,3-allenoic acids may also be cyclized to afford b-fluorobutenolides (Scheme 134).146 2,3-Allenoates, which are more readily available, are developed to prepare 4-fluoro-2(5H)-furanones (Scheme 135).147 If 3.0 equivalents Selectfluor and 0.5 equivalent H2O were used, 3-fluoro-4-oxo-2(E)-alkenoates could be obtained.147
R1
Selectfluor (1.1−1.5 equivalents) MeCN, H2O (10 equivalents)
R3
R2
COOH
R2
or H2O 80−100 °C Yield = 39−96%
512 R1 = alkyl, phenyl R2 = H, alkyl, phenyl R3 = H, alkyl
R3
F R1
O
O 513
Scheme 134
R1 R2
R3
Selectfluor (1.7 equivalents) MeCN/H2O (2:1)
COOEt
514 R1 = alkyl, phenyl R2 = H, alkyl, phenyl R3 = H, alkyl Scheme 135
80 °C Yield = 30−95%
R3
F R1 R2
O 515
O
466
Electrophilic Cyclization
In this part, iodocyclization, bromocyclization, chlorocyclization, and fluorocyclization are summarized. Many wonderful methodologies have been used as key steps in the synthesis of natural products. Besides halocyclization, selenocyclization, sulfenylcyclization, and tellurocyclization are also traditional electrophilic cyclization, which will be discussed in the next section.
4.07.3
Sulfenylcyclization, Selenocyclization, and Tellurocyclization
4.07.3.1
Cyclization Involving Alkenes
Over the past more than 20 years, a large number of researches on intramolecular selenocyclization, sulfenylcyclization and tellurocyclization have been reported. In 2004, Huang and coworkers reported a selenium-induced intramolecular electrophilic cyclization for the synthesis of polysubstituted dihydrofurans and THFs, followed by selenoxide syn-elimination or novel nucleophilic substitution cleavage of selenium resin with good yields and purities (Scheme 136).148 Then in 2009, the same group developed a new method for the preparation of 3-oxabicyclo[3.1.0]hexan-2-ols by the cyclization of (E)-2-(arylmethylene)cyclopropylaldehyde mediated by different organoselenium reagents (Scheme 137).149
O
O
R2
O R2 OR1
SeBr
R1O
R3
R3
THF, r.t. quantitative
O R2
NaI, CH3I Se
O
516
R1O
+
DMF, 75 °C, 18 h Yield = 72−86%
R3
517
SeCH3
O I
518
519
SeBr = selenium bromide resin Scheme 136
Ph O
PhSeBr (1.2 equivalents) K2CO3 (1.2 equivalents)
H H
MeCN/H2O r.t., 20 min, Yield = 89%
H 520
HO
SePh H O
Ph
521
PhSe
−H
Ph
Ph H2O
PhSe
PhSe
O
CHO 523
522
H
OH
Scheme 137
A solid-phase synthetic method is developed for the preparation of flavonoids with good yields and purities (Scheme 138).150 The THF moiety of amphidinolides 528 and 529 is achieved in excellent yields by a cyclization of an anti dihydroxy (allylic and homoallylic), unprecedented trisubstituted-alkene substrate (527), followed by deselenylation. The highly selective selenocyclization reaction is the key step in this transformation (Scheme 139).151
OH
SeBr
O
CH2Cl2, r.t., 12 h O 524
Se O 525
SeBr = selenium bromide resin Scheme 138
30% H2O2 THF, 0 °C, 24 h Yield = 83%
O
O 526
Electrophilic Cyclization
PhSeCl (1.5 equivalents) additive (1.0 equivalent)
OH NC
NC
NC
O
467
O
+
THF
HO
OH 527
HO SePh
SePh 529
528
Additive = ZnBr2, r.t., 15 min K2CO3, r.t., 30 min ZnBr2, −78 °C, 30 min K2CO3, −78 °C, 6 h EtiPr2N, −78 °C, 8 h
Yield = 60% Yield = 75% Yield = 85% Yield = 92% Yield = 92%
Yield = 18% Yield = 10% Yield = 8% Yield = 3% Yield = 3%
Scheme 139
Some chiral electrophilic selenium reagents have been developed for reagent-controlled asymmetric synthesis, such as chiral aryl and terpene-derived selenides. The selenoetherification of compound 530 gave product 532 in 88% yield with a diastereomeric ratio of 93:7, and compound 533 converted into product 534 in 75% yield with a diastereomeric ratio of 89:11. In both cases, ArSeOTf 531 should be prepared at 78 1C and then the mixture should be allowed to reach room temperature and stirred for another 6 h (Scheme 140).152 SeAr* Ph
OH 530
531 (1.2 equivalents) Ph
O
CH2Cl2, MeOH, −78 °C to r.t., 6 h, Yield = 88%
532 SeAr*
OH 533
Et
531 (1.2 equivalents) CH2Cl2, −78 °C to r.t., 6 h, Yield = 75%
SMe
O 534
Et
Ar*SeOTf
SeOTf
531
Scheme 140
Chiral sulfur-containing selenides have been used successfully in promoting the asymmetric electrophilic functionalizations affording furan derivatives. The diastereoselectivities of these reactions are proved to be good (Scheme 141).153
SeAr*
OH
Ph
531 (1.2 equivalents) CH2Cl2, MeOH, −78 °C to r.t., 5 h, Yield = 89%
535
Ph O dr = 97:3 536
531 (1.2 equivalents) O
OH 537
Ph
CH2Cl2, −50 °C to r.t., 4 h, Yield = 95%
Ph O
O
SeAr*
dr = 89:11 538
Scheme 141
The polymer-bound selenium bromide 541 has been applied for the two-step transformation of PGF2a methyl ester 539 to the PGI2 analogs 540 (94% yield, approximately 2:1 ratio of C-6 epimer). This method is used successfully in preparing a series of polymer-bound selenium reagents/linkers (Scheme 142).154
468
Electrophilic Cyclization
CO2Me
OH
H
1. 541 (1.5 equivalents) THF, 278 °C, 30 min 2. H2O2 (30%) (2.0 equivalents) −78 to 23 °C, 20 h
CO2Me
HO
Yield = 94%
HO
O
HO
HO
540
539 =
541 =
SeBr
Polystyrene Scheme 142
Diastereoselective synthesis of enantiopure morpholines by electrophilic selenium-induced 6-exo cyclizations on chiral 3-allyl2-hydroxymethylperhydro-1,3-benzoxazine derivatives is developed by Pedrosa and coworkers (Scheme 143).155
R3 R2
R1
R1 N O 542
R5 OH PhSeCl (1.1 equivalents) MeOH-CH2Cl2 R4 0 to −78 °C
O N O 543
R4
R1
R2
R2
SePh R5
SePh
R3
R2 R3
O N
O N
+
R5
R4
O 544
O
R3 R5
R4
545
R3 R2
R1 O TsN 546
R5
R4
Scheme 143
In 2000, Nicolaou and coworkers reported a method for the solid-phase construction of 2,2-dimethylbenzopyrans employing a selenium-based linking strategy wherein the loading step constitutes a key ring-forming reaction. Once the benzopyrans form, they can be elaborated to a variety of natural products and analogs thereof. Finally, it is easy to cleavage the resin and functionalize in high purity and efficiency (Scheme 144).156 The hepta-acetate of the natural product macropylloside D is synthesized. Using the same strategy, some examples of potential pharmaceutical candidates incorporating the 2,2-dimethylbenzopyran moiety are synthesized.157 In the total synthesis of phytuberin, an unprecedented 4-exo selenocyclization of a homoallylic alcohol affording oxetane derivatives is developed (Scheme 145).158 In the total synthesis of leucascandrolide A, Carreira and coworkers constructed a 2,6-trans-substituted tetrahydropyran by selenium-mediated intramolecular cyclization in a high yield (Scheme 146).159 It is the first example of a stereoselective synthesis of a 2,6-trans-disubstituted tetrahydropyran mediated by a bulky Se-electrophile. In the field of Se-induced cyclization, the use of catalytic selenium electrophiles is reported.160 Butenoic acids 558 are exposed to 5 mol% diphenyl diselenide and stoichiometric [bis(trifluoroacetoxy)iodo]benzene in acetonitrile affording butenolides 559 in high yields (Scheme 147).160 When a catalytic amount of Lewis base is used, significant rate enhancement is observed in the typical selenolactonizatin reactions (Scheme 148).160b The asymmetric synthesis of cyclic ethers by selenocyclizations has attracted broad interest in recent years, especially in the total synthesis of natural products.161 In the total synthesis of salinosporamide A, Danishefsky and coworkers used a selenocyclization with an in situ formed nucleophilic hydroxyl group as a key step (Scheme 149).162 Kim and coworkers accomplished an asymmetric total synthesis of trilobacin via organoselenium-mediated oxonium ion formation/SiO2-promoted fragmentation (Scheme 150).163
Electrophilic Cyclization
469
R4 R4
OH
R3
R1
SeBr (0.33 equivalent) CH2Cl2, 0−25 °C
R3
Se
R2
O
Me Me
R1 548
R2 547
OAc AcO AcO
O
O
O OAc AcO AcO
O
O OAc MeO
O
Me Me
549 Hepta-acetate of macropylloside D Scheme 144
O
554 (1.5 equivalents) TsOH (50 mol%)
O O
COOR2
OH
O O
DCM, r.t., 6.5 h
OH
OH
SePh
OR1 550
552
551
O O O 553 Phytuberin
N Se
OAc 554
O
Scheme 145
Very recently, Kim and coworkers completed the first total syntheses of both enantiomers of the marine natural product elatenyne as well as its double-bond isomer (E)-elatenyne (Scheme 151).164 Selenocyclization was used for the construction of two furan rings. The dibrominated 2,20 -bifuranyl 582 was obtained in 70% yield through exposure the substrate 577 to PhSeBr, activated silica gel and potassium carbonate. The reaction of (E)-N-benzyl-1-(2-benzylidenecyclopropyl)methanamine with PhSeBr stereoselectively gives ring-closure product 1-phenylselenenyl-2-aryl-3-azabicyclo[3.1.0]-hexane in good yields at room temperature (Scheme 152).77 An application of electrophilic selenium reagent N-PSP to promote a cyclization with an internal nitrogen nucleophile is reported by Yao and coworkers in the total synthesis of chloptosin. The diastereoselective selenocyclization and oxidative deselenation successfully serve as the key steps in the effective bidirectional synthesis of the core amino acid in this work (Scheme 153).165 Ley and coworkers developed an interesting application of the selenocyclization of amines to construct the important 3ahydroxypyrrole[2,3-b]indole core. This method has been applied successfully in the total synthesis of okaramine C (Scheme 154).166 An improved procedure for the selenium-mediated cyclization of alkenyl-substituted b-dicarbonyls to form a variety of bicyclo[3.3.1]nonan-9-ones has been developed for the synthesis of bicyclic natural products from the Guttiferae classification by the Nicolaou group (Scheme 155).167 The reaction proceeds successfully both in solution and on solid support, and the behaviors is closely correlated almost in the all cases. Wirth and coworkers reported a new cyclization of b-keto ester-substituted stilbene derivative 605 using PhSeCl in the presence of Lewis acid FeCl3 (Scheme 156).168
470
Electrophilic Cyclization
Me OTBS O
O
OH
TIPPSe
OMe O
O
Me OTBS OH
OH
O
OH
(TIPPSe)2 (2.1 equivalents) Br2 (2.0 equivalents) Base (5.0 equivalents)
Me Me
O
O 556a dr = 12:88 56a to 556a
+
DCM, −78 °C, 1 h Yield = 74%
OMe
O Me Me
OH
Me OTBS
O
O
555
OH OH
TIPPSe
OMe O
O
O OMe
Me
HN
Me Me
O
O 556b
Me O
O N O
O O
O
Me
Se TIPPSe =
OMe
O 557
Leucascandrolide A
Base = 2,6-di-tert-butyl-4-methyl pyridine
Scheme 146
Shaw et al. developed a new methodology for the synthesis of substituted tetrahydroquinolines with Sc(OTf)3 as an effective and practical precatalyst. Two rings, three bonds, and three stereogenic centers with excellent stereo- and regiocontrol were constructed in a single step (Scheme 157).169
4.07.3.2
Cyclization Involving Alkynes
Electrophilic cyclization of 1-(1-alkynyl)-cyclopropyl ketones affords highly substituted furans in good to excellent yields under mild conditions (Scheme 158).59 The methodologies of selenocyclization and sulfenylcyclization of alkyne have also been widely investigated by Larock and coworkers, and some of the typical examples are shown in Schemes 159.101,170
4.07.3.3
Cyclization Involving Allenes
Ma and coworkers developed a facile and effective synthesis of b-organoselenium-substituted butenolides from 2,3-allenoates and PhSeCl in water (Scheme 160).171 A convenient and highly efficient method for the preparation of b-organotellurobutenolides via ArTeCl-induced electrophilic tellurolactonization of a-allenoic acids is developed by Huang et al. (Scheme 161).172 The cyclization of allenylcarbinol 573 with PhSeCl in DCM afforded a single selenophenyl dihydrofuran 574 in 66% yield along with 17% of the presumed (E)-allylic alcohol 575 (one isomer). Both AgNO3 and NBS could promote the cyclization in good yields with high stereoselectivity (Scheme 162).173
Electrophilic Cyclization
R
CO2H
558 R = alkyl,aryl
(PhSe)2 (5 mol%) PhI(OCOCF3)2 (1.05 equivalents)
471
O
O R
CH3CN, r.t. Yield = 49−96%
559
(PhSe)2, PhI(OCOCF3)2 O
O R
OCOCF3 559
R
Ph
I
SePh 562
PhI
O
O PhSe CF3COO− H I Ph OCOCF3 561
PhSe+CF3COO− 563
R
PhI(OCOCF3)2
O O
PhSe
560
R
558
CO2H
Scheme 147
R
CO2H 564
+
PhSe N O
O O
Lewis base (10 mol%) CH2Cl2, 23 °C, 3 h
565
O
R PhSe 566
R = Ph Lewis Base: (Me2N)3P=O (Me2N)3P=S (Me2N)3P=Se None
Yield = 55% 89% 95% 8%
Scheme 148
4.07.4
Hg-, Ag-, Au-, and Pt-Catalyzed Electrophilic Cyclization
Besides the traditional electrophiles mentioned in Figure 3(a)), transition metal, as a p-acid catalyst, could also activate C–C multiple bond via coordination, which is fundamental to organometallic chemistry (Figure 3(b)). The M þ could play the same role as E þ to induce the cyclization. The Wacker process for the conversion of ethylene into acetaldehyde is a classic example of an efficient electronphilic-type cyclization that begins with the coordination of ethylene to PdII, which activates the ethylene moiety toward nucleophilic attack by water.174 Till now, Pd, Pt, Hg, Au, and Ag have been employed to induce the cyclizations. Besides palladium, which has developed into a diversity and complicated system, mercury-, gold-, silver-, and platinum-catalyzed electrophilic cyclization used in the synthetic applications will be discussed in the following section.
4.07.4.1
Mercury-Catalyzed Cyclization
Cyclization promoted by mercury salts is of certain synthetic interest, owing to the easy replacement of the mercury-containing residue by an oxygen or nitrogen nucleophiles. There have been numerous synthetic applications of the reaction, and some reviews have been published.175 A 60 (R)-hydroxymethyl derivative of the locked nucleic acid (LNA)-thymidine monomer has been synthesized by a stereoselective mercury cyclization, and there has been subsequent use of TEMPO as a radical scavenger. It is finally reduced by zinc and HOAc to give compound 638 in an yield of 83% (Scheme 163).176
472
Electrophilic Cyclization
PMB CO2Bn
PMB CO2t-Bu O N O
O
N
CO2t-Bu PhSeBr (4.0 equivalents) AgBF4 (4.0 equivalents)
O
PMB CO2Bn N CO2t-Bu
O BnOH (4.0 equivalents) CH2Cl2, −20 to 0 °C
CHO HO 567
O
SePh
OBn 569
568
Yield = 74%, an anomeric mixture, 12:1
H O NH
Cl
OH C O
O Me 570 Salinosporaminde
Scheme 149
PMBO H BnO R1
OH H
PhSe
PhSeCl (5.0 equivalents) OBn K2CO3 (6.0 equivalents) R2
CH2Cl2, SiO2, r.t., 24 h, Yield = 83%
571
BnO
H
transannular attack
H O H R1
R1 = n-C10H21; R2 = (CH2)5OBn
H
PhSe PhSeCl
OH H
OBn BnO
R2
Cl
H O H R1
OH H
OBn R2
573
572
H
SePh H
H
O H BnO R1
O H H R2 574
n-C10H21 H OBn
OBn
O
H H
O
H
OBn OBn
575
O O
MC Threo
HO H O H H O H
Erythro
Threo
trans Trilobacin
cis
HO 576 Scheme 150
Stereocontrolled routes to 2,3-dihydro-4H-pyran-4-ones by the Hg(II)-catalyzed rearrangement of 1-alkynyl-2,3-epoxy alcohols in acidic media has been developed by Marson and coworkers (Scheme 164).177 Deslongchamps and coworkers demonstrated that the Hg(II) catalysts are highly efficient and economical (HgCl2) by utilizing a simple experimental procedure for the synthesis of various saturated and unsaturated spiroketals and furans (Scheme 165).178
Electrophilic Cyclization
PhSe
Br
BnO
O
H
3
H OH
Me BnO
DCM, r.t., 20 h
577
O
3
O
Br
H
H
Me 579
578 H O
BnO
O
H
O 3
H OH
O
BnO
BnO
3
SePh H SePh
PhSeBr
H SePh
Br
Me PhSeBr, SiO2, K2CO3
473
3
Br
O
Br
H
Me
Me Br
581
580
Yield = 70% Br
O H Br
Br
O H
BnO
Me
H O
Me
H O
Br
583
582
(E )-elatenyne Scheme 151
Ar
BnHN
PhSe Ar
PhSeBr (1.2 equivalents) CH2Cl2, r.t., 1 h Yield = 72−85%
H
584
H N Bn 585
Ar = Ph, p-MeOC6H4, p-BrhC6H4, o-MeOC6H4, o-BrC6H4 Scheme 152
Boc N
t-BuO
BocHN Cl t-BuO2C CO2t-Bu
Na2SO4, CH2Cl2, r.t. Yield = 89%
NHBoc 586
H N
HN
N
O O
O O
N NH
Scheme 153
BocN
O O
O PhSe NBoc
BocN SePh O
N Boc
H3CO
N H
Cl
N-PSP (10 equivalents) PPTS (2.0 equivalents)
NBoc Cl
Ot-Bu 587
HN N
OH H N
HN
Cl HO
N
O N
OH NH
Cl 588 Chloptosin
N H OH
O N H
O O
O
O N
H N
N Se
O O NH N-PSP OCH3
474
Electrophilic Cyclization
CO2Me
SePh H
N-PSP, PPTS, Na2SO4
NHZ
DCM, Yield = 93%
N Boc 589
HO
N
N Boc H 590
CO2Me
NZ
H O N
HO
NH
H O
N H Boc
NH
H NH
CO2Me
591
592 Okaramine C Scheme 154
PhSe X or X.Se
OAc O R3
R1 R2
R1
O SePh
SnCl4, −23 °C Yield = 65−98%
593
R2 R3
O 594
OH O
O
O i -Pr
O
595
Garsubellin A Scheme 155
Kim and coworkers developed a facile method for the synthesis of 3-(alkylamino)-5-arylthiophenes having acyl-, aroyl-, or ethoxycarbonyl substituents at C-2 using thioaroylketene S,N-acetals, mercury(II) acetate, and active methylene compounds (Scheme 166).179 Bhattacharjya and coworkers describe Hg(II)-mediated reaction of O-propargyl glycolaldehyde dithioacetals and an expedient general route to 6H-pyran-3-ones (Scheme 167).180 An efficient method for the construction of dihydroquinoline derivatives possessing a quaternary carbon center is developed by an application of Hg(OTf)2-catalyzed vinylogous semi-pinacol-type rearrangement. The reaction was found to be specifically catalyzed by mercury salt via a bicyclic aminal (Scheme 168).181 Hg(OTf)2-catalyzed arylene cyclization was achieved with highly efficient catalytic turnover (up to 200 times) by Nishizawa’s group. The reaction takes place via protonation of allylic hydroxyl group by in situ formed TfOH of an organomercuric intermediate to generate a cationic species (Scheme 169).182 In 2007, Nishizawa and coworkers report that a 10:1 mixed reagent of Hg(OAc)2 and Sc(OTf)3 showed remarkable catalytic activity for the Friedel-Crafts-type cycloisomerization of 2-(4-pentynyl)furan (Scheme 170).183 The actual reacting species is presumed to be Hg(OAc)(OTf), which is efficiently generated in situ by mixing the two reagents. Cycloisomerizations of allenynes to allenenes have been investigated in the presence of [Hg(OTf)2] in MeCN. It is quite effective for constructing terminal 1,6-allenynes (Scheme 171).184
Electrophilic Cyclization
475
OH O
O
CO2Et
PhSeCl (2.0 equivalents) FeCl3 (1.1 equivalents)
OEt
DCM, −78 °C
R
R 606
R = 4-Me-C6H4 605 Cl3 Fe O O
OH CO2Et OEt
Se
Ar
Ar
SePh 608
Ph 607 OH
Ph Se
OH
OH CO2Et
CO2Et
Ar
Ar
CO2Et
Ar
SePh
609
611
610
Scheme 156
R
R Sc(OTf)3 (12 mol%) PhXCl (1.2 equivalents)
N
Ns
CH3NO2, 23 °C, 16 h Yield = 60−88% X = S or Se
NNs
PhX
H
612
613
Scheme 157
R1
O R3
R2
NuH PhSeBr (1.2 equivalents) r.t., 1 h, Yield = 41−82% NuH = MeOH or Br
524
R2
R1
O R3
Nu 525
SePh
Scheme 158
Yamamoto and coworkers described the preparation of solid-supported silaphenylmercuric triflate. Several examples of silaphenylmercuric triflate-catalyzed reactions such as indole synthesis, furanoyne cyclization, arylyne cyclization, and tandem carbocyclizations have been developed (Scheme 172).185 An efficient synthesis of hippuristanol and some of the close analogs has been achieved from readily available hecogenin acetate through an unprecedented Hg(OTf)2-catalyzed cascade spiroketalization as the most convenient strategy (Scheme 173).186 In the total synthesis of (7)-thallusin, homofarnesyl acetate performs cyclization using Hg(OTf)2.PhNMe2-induced olefin cyclization in an excellent yield (Scheme 174).187
4.07.4.2
Silver-Catalyzed Cyclization
Mercuric salts were used for more than 70 years, leading to many applications to intermolecular and intramolecular additions of various nucleophiles to unsaturated C–C bonds. Because of the high toxicity of mercuric salts, several other catalysts are
476
Electrophilic Cyclization
O
O OR1
E+
(1.2 equivalents)
O
DCM, r.t., 0.5−1 h R2 614
(1)
R2
Yield = 60−95% E+ = p-O2NC6H4SCl, PhSeCl
E+ 615
OMe
E+ (2.0 equivalents)
R1
O
DCM, r.t., 3 h Yield = 60−95%
R2 616
R2
R1
E+ =
E+ (1.2 equivalents) NuH (1.2 equivalents) K2CO3 (1.0 equivalent)
O
Nu Y O
DCM, r.t. Yield = 65−74%
R
618
E 617
p-O2NC6H4SCl, PhSeBr
Y
(2)
(3) R
619
E
Y = H, Me NuH = R1OH, PhNMe2, etc. E+ = p-O2NC6H4SCl, PhSeBr R = Ph, alkyl, alkene N
OMe
N O
PhSeBr (3.0 equivalents) Ph
DCM, r.t., Yield = 88−91%
R R = Ph, alkene
R
(4)
Ph SePh
620
621
SMe
E+ (1.5 equivalents)
R1
S
(5)
R2
R1
DCM, r.t., 10 min R2 622
E
Yield = 60−100%
E+ = p-O2NC6H4SCl, PhSeCl
623
SeMe
Se
PhSeBr (1.1 equivalents) R
622
R
DCM, r.t., 0.5 h Yield = 84−95%
(6)
SePh 624
R = Ph, alkyl, alkene SMe
O
H3COOC S
PhSeCl (1.5 equivalents)
O
DCM, r.t., 1 h
(7)
SePh 626 Yield = 56%
H3COOC 625 N
SePh 627 Yield = 44%
tBu N PhSeCl (1.5 equivalents)
MeO 628
Scheme 159
SMe
+
DCM, r.t., 1 h Yield = 70%
OMe (8)
SePh 629
Electrophilic Cyclization
H N
477
N PhSeBr (2.0 equivalents) NaHCO3 (2.0 equivalents)
SePh (9)
MeCN, r.t. Yield = 74% OMe
OMe 630
631
Ph
p-O2NC6H4SCl (1.2 equivalents)
Sp-O2NC6H4
DCM, r.t., 0.5 h Yield = 92%
Ph
632
(10)
633
OH PhSeCl (2.0 equivalents) NaHCO3 (2.0 equivalents) MeCN, r.t., 2 h Yield = 36%
Ph 634
(11)
SePh Ph 635
Scheme 159 (continued)
R1
R3
R2
COOEt 569
PhSeCl (2.0 equivalents) CH3CN/H2O = 10/1, r.t. Yield = 22−100%
R3
PhSe R1 R2
O
O 570
R1 =
Ar, alkyl R2 = H, Me R3 = alkyl
Scheme 160
R1
R3
R2
CO2H
ArTeCl (1.1 equivalents) MeCN, r.t., 5−30 min Yield = 79−94%
571 R1 = aryl, R2 = H, R3 = alkyl
R3
ArTe R1 R2
O 572
O
Scheme 161
developed. The silver salts are proved to be the most efficient catalysts. Cyclization reactions exhibit high interest in organic synthesis, especially when starting from alkynes or allenes since the cyclization products retain an olefin, which can be further manipulated, opening a wide variety and diversity of applications. Moreover, the nature of the cyclization products can be varied by changing silver counterion and/or reaction conditions, and many intramolecular heterocyclizations proceed with high diastereoselectivities. There have been many reviews summarizing this kind of reaction.188 Silver-induced cyclization reactions have been used in the total synthesis widely used in recent years. In the total synthesis of (þ)-pamamycin-607, silver-assisted iodoetherification is proved to be a key step for its high enantioselectivity. The tetrahydrofurans rings with complete cis-stereoselectivity are formed from silylated hydroxalkene and iodine in the presence of silver carbonate (Scheme 175).189
478
Electrophilic Cyclization
OH MeO2C (S) H C7H15 (R)
C7H15
H
Conditions a, b, or c
H MeO2C
CH3
CH3 H
O
573
MeO2C
X
SePh
H
+
C7H15 Cl 575
574 66% 84% 66%
a. PhSeCl, CH2Cl2, r.t, 5 min; X = SePh b. AgNO3, Ca2CO3, MeOH-H2O, r.t., 48 h; X = H c. NBS, CH2Cl2, r.t., 48 h; X = Br
OH
H CH3
17%
Scheme 162
Nu
Nu
E+
M+
E+ = Halogen, S, Se, Te (a)
M+ = Transition Metal (b)
Figure 3 Electronphilic activation.
O
O NH
BnO
N
O
NH Hg(TFA)2 (1.5 equivalents) THF, r.t., 12 h Yield = 98%
O BnO
BnO
N
O
O
OH
BrHg
636
BnO O 637
1. TEMPO, NaBH4, 77% 2. Zn, HOAc, 83% O NH BnO
N
O
O HO
BnO
O
638 Scheme 163
R3
H
639 Scheme 164
R2
OH R1
O
R3
R2
R4
HgO in dil. H2SO4
OH O R1 H 640
Yield = 50−80% R4
H R3 R2
O R1 641
R4
Electrophilic Cyclization
O
Hg(OTf)2 (10 mol%)
O
m 643 Yield = 90−94%
CHCN3, r.t. R1 = OH, R2 = H R2
(II)Hg R1
R
CHCN3, r.t. n = 1, R2 = OH, R3 = H
R3
m
O
Hg(OTf)2 (10 mol%)
OH n
R3 n
1
m 644 Yield = 90−96%
642
Hg(OTf)2 (10 mol%)
O
CHCN3, r.t. R1 = OH, R2 = OH
O
R3 n
m 645 Yield = 95−98%
Scheme 165
O R3
NHR1
O R4
647
COR3 S 649
Ar NHR1S
Hg(OAc)2 (1.0−1.5 equivalents)
R2S
Ar
O
O
Yield = 38−92%
DCM, r.t., 1 h COOEt
646
NHR1
648
COOEt S 650
Ar
Yield = 82−94% Scheme 166
HgCl2 or Hg(OTFA)2 (10 mol%) base (2.0 equivalents)
S O
S
Ph Me 651
Solvent-H2O (4:1), 25 °C, 4 h Yield = 0−53%
Ph Me
R S
O
O
S
R
S S
R
S
O
Scheme 167
HgX
655
HgX S
O
HgX
O 654
O 658
653 HgX
R
O
652
S R
O
R S
O
S
S
656
657
479
480
Electrophilic Cyclization
n-Bu Hg(OTf)2 (1.0 mol%) O NH OMe Ts
CH2Cl2, r.t., 6 min
TfO Hg
n-Bu
O OTf
n-Bu
O N Ts
Yield = 98%
659
N Ts 661
660
Scheme 168
OMe OMe
Hg(OTf)2 (0.5 mol%) PhMe, reflux, 5 min Yield = 96%
OMe
OMe
OH 663
662
OMe
OMe
OMe
OMe Tf OH
(TfO)2Hg
OMe
H
OMe
TfOHg
OH 664
OMe
TfOHg OH
TfO−
OH
665
OMe
TfOHg
666
OH2 667
Scheme 169
Hg(OAc)2 (5.0 mol%) Sc(OTf)3 (0.5 mol%)
O
O
CH3CN, r.t., 20 min Yield = 80% 668
O
R
O
O
O
HgOAc 670
669
HgOAc
HgOAc 671
672
HgOAc 673
Scheme 170
The Ag þ -mediated cyclization of allenic alcohols has been applied to the synthesis of various natural products and analogs. Verrucosidin, citreoviridin, and their metabolite citreal have been prepared via an Ag þ -promoted stereoselective cyclization of a dihydroxyallene (Scheme 176).190 Standaert and coworkers reported a concise and modular synthesis from the Garner aldehyde and proceeding in seven steps to furanomycin. The key steps include a stereoselective acetylide addition and the Ag þ -mediated cyclization of an a-allenic alcohol to construct the trans-2,5-dihydrofuran (Scheme 177).191
Electrophilic Cyclization
R3
R3
H(D)
R3 R1
Hg(OTf)2 (10 mol%) (D)H
MeCN, r.t., 1 h
R2
X
R3
Yield = 22−79%
R2 X
R1
674
675
X = NTs, NMts, C(SO2Ph)2 R1 = −H, −Me, −Et, −Ph R2 = −H, −Me R3 = −H, Me, −(CH2)3−, −(CH2)5−
Hg(OTf)2
R3
H(D)
R3 TfOHg R3
TfOHg R1
TfOHg R1
R2
X
R3 R2
X
676
R3
R3
R3
R3
R3
OTf− R1
X 678
677
1 R2 R
R2
X
R1
679
Scheme 171
MeO
Si
OMe
MeO
OMe
HgOTf (10 mol%) CH3NO2, r.t., 40 min
H
Yield = 99%
682
681 Si = Silicycle, 230−400 mesh, loading 1.62 mmol g−1 Scheme 172
OH BnO H
HO H 683
OH
OTHP
H 684
BnO
H
Hg(OTf)2 (20 mol%) H2O (3.0 equivalents) CH3CN, 5 min, r.t. Yield = 90% OH O
OH O
BnO
HO H H
BnO
O H HO
685
Scheme 173
H
H
H
R3
O H
686 H Hippuristanol
X 680
R2
481
482
Electrophilic Cyclization
OAc
OAc 1. Hg(OTf)2.PhNMe2 (1.2 equivalents) CH3NO2, −20 °C, 3 h 2. LAH (3.0 equivalents)/THF 0 °C, 1 h 3. Ac2O (1.7 equivalents), DMAP (8.3 mmol%)/Py
687
H 688 Yield = 94%
COONa N COONa COONa O H 689
H
(±)-Thallusin Scheme 174
I O O
O
TESO TESO
I2, Ag2CO3
TESO
O
TESO O
Et2O, r.t. BnO
Yield = 81%
BnO
690
O
691
O
O O
O O
O
Me2N 692 (+)-Pamamycin-607 Scheme 175
The cytotoxic amphidinolide 702 has been obtained by a Claesson’s cyclization of 6-methylnona-4,5-dien-1,3-diol, derived from a chiral epoxyalcohol produced by the Sharpless asymmetric epoxidation (Scheme 178).192 The allene alcohol was treated with AgNO3/CaCO3 in aqueous acetone to afford the corresponding dihydrofuran with strict chirality transfer. As the first approach toward the cembranoid eunicin, a silver-mediated cyclization of a suitable functionalized allene was performed with the aim of controlling the stereochemistry in the construction of the tetrahydropyran ring (Scheme 179).193 The trans-bicyclic dihydro-2H-pyran within the tricyclic framework of eunicins was obtained from silver nitrate-promoted cyclization. The tetradecane ring system of the anticancer and antiparasitic bielschowskysin was ingeniously built up through a stereoselective [2 þ 2] photocycloaddition of an alkenyl alkylidenebutenolide. Silver-catalyzed cyclization of the corresponding ynenoic acid is used for the construction of g-alkylidene butenolide (Scheme 180).194
Electrophilic Cyclization
OTBS Me Me
Me
AgNO3 (0.8 equivalent) CaCO3 (0.8 equivalent)
TBSO
O Me
H2O/Acetone = 2:3 r.t., 20 h Yield = 81%
OH
Me
694
Me
693
Me
HO Me
Me
HO
O
OMe
O
Me
O
695 Citreoviridin
Scheme 176
O
Boc N
OH
H3C
AgNO3 (1.0 equivalent) CaCO3 (2.0 equivalents)
Boc N
Acetone:H2O = 10:3 overnight, dark Yield > 95%
O
O
697
696
N H3C
OH H
O 699 Furanomycin Scheme 177
AgNO3 (1.1 equivalents) CaCO3 (2.0 equivalents)
OH
TBDPSO
Actone:H2O = 4:1 15 h, dark Yield = 90%
700
Me
O O
O
Me O
Me
702
Amphidinolide Scheme 178
O TBDPSO 701
Me
Me
O
O H 698
NH2
O
H3C
Boc
483
484
Electrophilic Cyclization
O
HO HO
O O
703
AgNO3 (1.1 equivalents)
HO
Acetone r.t., 7 h Yield = 70%
O O
H
O O
704
O
O
O
O
705 Scheme 179
Mes O
Mes
O Me
AgNO3 (4.6 mol%) CO2H
CO2Me
MeO2C
O
O Me
MeOH, r.t., 1 h Yield = 35% 707
Me
O
706 O
Me HO
H
Me
O O
H O 708
O
Bielschowskysin Scheme 180
b-Allenic acids are used for the synthesis of d-lactones in the presence of AgNO3 and DIPEA. The reaction is proved to be an efficient asymmetric synthesis of the naturally occurring antibiotic ()-malyngolide (Scheme 181).195 The cyclization of a-allenones was also successfully applied in the total synthesis of natural products. The furanocembranes, kallolide A, is obtained through Ag-catalyzed cyclization via key steps, using a catalytic amount of AgNO3 in acetone, which led to a key furan building block in good yields.196 The same strategy is applied in the synthesis of kallolide B (Scheme 182).196 In the total synthesis of (þ)-longifolicin skeleton, sequential reactions of Pd-catalyzed hydrocarbonylation of a chiral homopropargylic mesylate and Ag þ -catalyzed cyclization of the intermediate allenic acid are carried out, and the desired product is successfully obtained (Scheme 183).197 Nagarajan and coworkers developed an efficient methodology for the synthesis of highly functionalized ellipticinium and ellipticine derivatives via an AgOTf-catalyzed cyclization of 2-alkynyl-3-carbazolylaldimines (Scheme 184).198 The total synthesis of clavepictines was skillfully designed and realized with Ag þ -catalyzed cyclization of a piperidinoallene as the key step affording the desired cis-quinolizidine derivative in 48% yield (7% of vinyl isomer is obtained) (Scheme 185).199 When the substrate is modified, the cyclization yield is significantly improved as well as the diastereoselectivity, and no other isomer could be detected. During the synthesis of the antibiotic anisomycin, Ag-catalyzed cyclization of an alkoxyaminoallene was the key step (Scheme 186).200
Electrophilic Cyclization
nC H 9 19
H Me
AgNO3 (10 mol%) i-Pr2NEt (5 mol%) Yield = 80%
OBn CO2H
485
Me nC
O
O
9H19
OBn
710
709 Me nC
9H19
O
O OH 711 (−)-Malyngolide
Scheme 181
H
Me
Me AgNO3 (10 mol%)
ODPS
O
H
Acetone, reflux, 1 h Yield = 88%
OBz
O O
OBz 713
712
Me Me
OSEM O
OSEM O
AgNO3 (1.5 equivalents) Acetone, r.t., 1 day Yield = 60%
O O
H RO2C
714
R = H, CH2CH2TMS, Me 715 Me OH O O 716 O
Kallolide B
Scheme 182
4.07.4.3
Au- and Pt-Catalyzed Cyclization
Pt and Au [gold(III) and cationic gold(I)] show an exceptional ability to accelerate a variety of organic transformations of unsaturated precursors. These processes result from the peculiar Lewis acid properties of these metals: the alkynophilic character of these soft metals and the p-acid activation of unsaturated groups promote the intra- or intermolecular attack of a nucleophile. Due to the soft and carbophilic character, gold and platinium catalysts are particularly well suited for the selective activation of allenes in the presence of other reactive functionalities. In the past decades, great progress has been achieved in developing efficient and selective Au- and Pt-catalyzed transformations, and prodigious number of reviews are available on various aspects.201 This section is focusing on Au-catalyzed particular classes of synthetic reactions applied in total synthesis. The first total synthesis of the b-carboline alkaloids ()-isocyclocapitelline and ()-isochrysotricine by Pictet–Spengler reaction of a chiral THF with tryptamine is reported by Volz and Krause (Scheme 187).202 Key intermediate 2,5-dihydrofuran was obtained from the corresponding a,b-dihydroxyallene with complete axis-to-center chirality transfer by the use of only 0.05 mol% of gold(III) chloride in THF. Erdsack and Krause used Garner’s aldehyde as a precursor for a-hydroxyallenes, treated with 1 mol% of gold(III) chloride in THF, which undergo cycloisomerization to the dihydrofurans derivates. Subsequent modification affords analogs of the antibiotic amino acid furanomycin (Scheme 188).203
486
Electrophilic Cyclization
Me MOMO C14H29 O
MOMO H
Me
6
H
1. (CF3CO)2O, Py 2. Pd(PPh3)4, CO, H2O
MOMO C14H29
3. AgNO3, Et2O
OMOM
OH
O H MOMO H OMOM 718
Yield = 62%
717 (CF3CO)2O, Py
7
R
R O
OTFA
O PdII
H
721
720
719
R H2O
CO PdII
OH H 722
H
MOMO R=
O
AgNO3 Me Pd(PPh3)4
R
O
C14H29 MOMO H
O
Me HO
6
H
O
Me
OMOM
12
HO H
O
7
H OH
O
723
(+)-Longifolicin Scheme 183
Me
CHO Ph N Et 724
N
1. p-Toluidine (1.0 equivalent) MgSO4 (69.4 equivalents) DCM, reflux, 1 h 2. AgOTf (1.0 equivalent) DCM, r.t., 1 h Yield = 95%
OTf Ph
N Et 725 Ellipticine derivatives
Scheme 184
Krause and coworkers accomplished the first diastereo- and enantioselective total synthesis of (R,R,R)-bejarol and its (3R,5S,9R)-isomer. The gold-catalyzed cycloisomerization is used as a key step, which converts the enantiomerically pure bhydroxyallenes 739/740 to the corresponding dihydropyrans 741a/741b (Scheme 189).204 A cationic gold catalyst is used for activating the allene for nucleophilic attack of the pyrrole ring to deliver tetrahydroindolizine in a high yield with excellent chirality transfer, which is the precursor of alkaloid ()-rhazinilam (Scheme 190).205 In the Construction of the Communesin Ring, Funk and coworkers treated the alkyne 748 with AuCl(PPh3) to provide the enamine 749 via a 7-exo-dig ring closure with the nearby piperidine nitrogen (Scheme 191).206 Oh and coworkers reported a Pt-catalyzed domino process involving a Huisgen-type [3 þ 2] cyclization and subsequent insertion of the proposed platinum carbene intermediate into a benzylic bond to form highly complicated products that are difficult to access by other means. Byproducts 753 and 754 are obtained with PtCl2, PtCl4 in toluene, or PtCl2(PPh3)2 in DCE or dioxane. A possible pathway through a platinum carbene intermediate is proposed for the three products in Scheme 192.207
4.07.5
Conclusion
The electrophilic cyclization reaction is one of the most classic organic reactions. There are a huge number of works reported in the literature, and it is difficult to cover all of them. As so many methodologies were developed to construct all kinds of rings, the
Electrophilic Cyclization
H
C6H13 TESO H NH
TIPSO
AgNO3 (30 mol%)
H
Me
N
TIPSO
Me
Acetone:H2O = 1:1 r.t., 18 h Yield = 48%
H
OTES
726
C6H13
727 H N
RO
Me
C6H13
728 R = Ac R=H
clavepictine A clavepictine B
Scheme 185
ODAF ODAF
1. AgNO3 (0.2 equivalent) K2CO3, MeCN
TsHN
2. HPLC separation Yield = 46% 729
N Ts
OMe
OMe
730
R/S:2/1 mixture DAF = diacetonefructose
HO
HCl
OMe
OAc
N H
731
Antibiotic anisomycin Scheme 186
Me
AuCl3 (0.05 mol%)
OH
THF, r.t. Yield = 97%
OH BnO
2 732
BnO
2
O
HO de = 96%, ee > 98% 733
N Me Me N O 735 (−)-Isochrysotricine
Scheme 187
HO
H
N Me
MeI NaOH
N 734
O HO
(−)-Isocyclocapitelline
H
487
488
Electrophilic Cyclization
n-Bu
Boc N
R O
Boc N
AuCl3 (1 mol%) THF, 0 °C
H
O
H OH 736
n-Bu O
R
737 Yield = 86% 34%
R = Me t-Bu
H 2N
n-Bu O
R
H O 738 Analogues of (+)-furanomycin HO
Scheme 188
O OH
O +
O
OH
O
740
739
3:2 Ph3PAuCl (5 mol%) AgBF4 (5 mol%)
O
O O
+
O 741a
741b
O O O 741c Toluene, r.t., 10 min Toluene, −15 °C, 1.5 h THF, r.t., 2 h
O
+
O O 741d
741a 741b 741c/d 42% 35% 16% 42% 29% 2% 50% 35% <1%
OH 741a
O 742 (R, R, R)-Bejarol OH
741b O 743 (3R, 5S, 9R)-Bejarol Scheme 189
O
O
Electrophilic Cyclization
N
N AgNO3 (5 mol%) Ph3PAuOTf (5 mol%)
H Me
CH2Cl2, r.t., 16 h
Et
MeO
N Et
H [Au] Et O
Me
O 744
489
MeO2C
MeO 745
Me
746 Yield = 92% dr = 97:3
N Et
N O H 747 (−)-Rhazinilam Scheme 190
O H H N
O H
AuCl(PPh3) AgOTf, DCM 40 °C, 12 h
O H N
O H
Yield = 89% N
N HH
N
748
N HH 749
O O H
HN N
N
N HH
750 Communesin B Scheme 191
electrophilic cyclization becomes a valuable tool in organic chemistry. In recent years, the research on halocyclization is focusing on asymmetric methodologies and applications in natural product synthesis. Fluorocyclization has coursed more attention due to the excellent bioactivity of fluoro-containing molecules. Selenocyclization, tellurolactonization, and sulfenylcyclization have proved to be very efficient in introducing S, Se, and Te elements into the target molecules. Besides the traditional electrophiles mentioned in Sections 4.07.2 and 4.07.3, transition metal-mediated electrophilic-type cyclizations have been developed. The transition metal playing as a p-acid catalyst could also activate C–C multiple bond via coordination inducing the electrophilictype cyclization. The applications of mercury-catalyzed electrophilic cyclization and silver-, gold-, and platinum-catalyzed electrophilic cyclization in natural product synthesis have been summarized. Palladium-induced electrophilic cyclization is also a very powerful tool in the synthesis, and there are lots of reviews presented in recent years,208 which should be the topic of another big chapter. Lewis acid and Brønsted acid could also induce the electrophilic cyclization, and numerous applications in the synthesis of natural products have been reported in recent years.209 These reviews could draw an outline for electrophilic cyclization in a different way.
490
Electrophilic Cyclization
H O
H OBn
H
+
H
Toluene, 120 °C, 4 h 751
PhCOO
O
PtCl2(PPh3)2 (5 mol%)
O
H
Ph 752
H O
+
H
H
754
753
Yield = 77% H
O O
Pt+
Pt PtII
OBn 751
OBn
O
O
Ph 756
PhCOO
757
H
H
a
Pt
O
Ph
755
H
H
O
H
O
O
O
b
PtIIB: H
H 753 1. NaOH 2. PCC
Pt H-B:+ Ph
Pt
a
O
760 b
Ph H 758 PtII +
H Pt O
B
H
O Ph
759
PhCHO + B:
O H
H
H
O
O H H
761
754
H
O Ph 751
Scheme 192
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491
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4.07.1 4.07.1.1 4.07.1.2 4.07.1.3 4.07.2 4.07.2.1 4.07.2.1.1 4.07.2.1.1.1 4.07.2.1.1.2 4.07.2.1.1.3 4.07.2.1.2 4.07.2.1.2.1 4.07.2.1.2.2 4.07.2.1.3 4.07.2.1.3.1 4.07.2.1.3.2 4.07.2.1.4 4.07.2.2 4.07.2.2.1 4.07.2.2.2 4.07.2.2.3 4.07.2.2.4 4.07.2.3 4.07.2.3.1 4.07.2.3.2 4.07.2.4 4.07.2.4.1 4.07.2.4.2 4.07.3 4.07.3.1 4.07.3.2 4.07.3.3 4.07.4 4.07.4.1 4.07.4.2 4.07.4.3 4.07.5 References
Introduction Coverage Mechanism Baldwin’s Rules for Ring Closure Halocyclization Iodocyclization Oxygen nucleophiles Cyclization involving alkenes Cyclization involving alkynes Cyclization of allenes N-nucleophiles Cyclization involving alkenes Cyclization involving alkynes C-nucleophiles Cyclization involving alkenes Cyclization involving alkynes S or Se-nucleophiles Bromocyclization Cyclization involving alkenes Cyclization involving alkynes Cyclization of allenes Cyclization of cyclopropane Chlorocyclization Cyclization involving alkenes Cyclization involving alkynes Fluorocyclization Cyclization involving alkenes Cyclization of allenes Sulfenylcyclization, Selenocyclization, and Tellurocyclization Cyclization Involving Alkenes Cyclization Involving Alkynes Cyclization Involving Allenes Hg-, Ag-, Au-, and Pt-Catalyzed Electrophilic Cyclization Mercury-Catalyzed Cyclization Silver-Catalyzed Cyclization Au- and Pt-Catalyzed Cyclization Conclusion
Glossary p-Acid p-Acid is a kind of Lewis acid that could accept electrons from Lewis base via antibonding p-orbitals. Electrophile Electrophile is the molecule or ion that is electron deficient and in some way could accept a pair of electrons to make a new covalent bond. Electron deficiency would include a formal positive charge or a partial positive charge. ‘E’ and ‘E þ ’ are common abbreviations for generic electrophiles. The common electrophiles include X2, X þ , RS þ , RSe þ , H þ , Lewis acid, and so on.
412
412 413 413 413 414 414 414 414 424 430 431 431 433 435 435 437 449 450 450 456 457 458 458 458 459 460 460 463 466 466 470 470 471 471 475 485 486 490
Halolactonization It is the reaction to form a lactone by the addition of halogen and oxygen in carboxylic acid or carboxylate across a carbon–carbon double bond. Nucleophile Nucleophile is the reactant that provides a pair of electrons to form a new covalent bond. A nucleophile that shares an electron pair with a proton is usually called a Brønsted–Lowry base, or just a base. The common nucleophiles include carboxylic acid, carboxylate, hydroxyl, amino, carbonyl oxygen, carbon, as well as thiol.
Comprehensive Organic Synthesis II, Volume 4
doi:10.1016/B978-0-08-097742-3.00409-2
Electrophilic Cyclization
4.07.1 4.07.1.1
413
Introduction Coverage
Electrophilic cyclizations are those reactions that involve the interaction of the electrophilic reagent to alkenes, alkynes, allenes, conjugated dienes, and other carbon–carbon multiple bonds, although followed by a subsequent intramolecular addition of an internal nucleophile (Scheme 1). These processes generate carbocycles from carbon-centered nucleophiles and heterocycles from heteroatom-centered nucleophiles, such as carboxylic acid, carboxylate, hydroxyl, amino, carbonyl oxygen, as well as thiol. Nu
Nu
Nu
E
R
R
or
(a)
R E
E
1
2a
Nu
Nu
Nu R
or
R E
R
4a
R
Nu or
E 4b
E
3
2b
E
R
Nu (b)
or E
4c
4d
Nu = C, O, N, S E+ = H+, X (I, Br, Cl, F), RSe+, RS+, M+ (Hg, Ag, Au, Pd, Rh, Lewis acid, e.g.) Scheme 1 Concept of the electrophilic cyclization.
Electrophilic cyclization was first reported by Bougault in 1904; it was about iodocyclization of unsaturated acids.1 Since then, this type of reaction has undergone incredible growth, especially over the past decades. There have been numerous examples of synthetic application of electrophilic cyclizations, and a large number of reviews on this subject have appeared.2 Therefore, only the most relevant achievements and synthetically useful electrophilic cyclization reactions after 1991 will be covered in this chapter. The sections of this chapter are summarized according to the type of electrophilic reagents, such as halocyclization, sulfenylcyclization, and selenocyclization; some metallic reagent-mediated reactions such as mercury-, gold-, silver-, and platinum-catalyzed electrophilic cyclization have also been discussed.
4.07.1.2
Mechanism
The general mechanism of electrophile-initiated cyclofunctionalization is shown in Scheme 2. First of all, the electrophile interacts with unsaturated carbon–carbon p-system 5 to generate activated intermediates cyclic ‘onium’ ion 6a and/or the p-complex 6b.2k Both intermediates 6a and 6b have two reactive centers a and b. Then nucleophilic anti attack of the nucleophile on the activated intermediate 6a or 6b generates two regioselective products: exo-product 7 or endo-product 8.
Nu R
+
E+
R
+E
5
Nu a
Nu a
6a
or R b
b E+ 6b
Nu
Nu or
R E exo-product 7
R E endo-product 8
Scheme 2 Mechanism of the electrophilic cyclization.
4.07.1.3
Baldwin’s Rules for Ring Closure
‘Baldwin’s rules’ historically have served as one of the most useful tools in the arsenal of synthetic organic chemists.3 Not only have they defined the nomenclature and the vocabulary for describing and classifying ring-closure steps, but it also combined the existing empirical knowledge with basic stereoelectronic considerations to predict the favorable modes of cyclization. Baldwin’s rules classify ring closures based on three factors: (1) the ring size being formed (indicated through a numerical prefix), (2) the position of the breaking bond that has to be broken in the cyclization, relative to the forming ring (exo, in which the breaking
414
Electrophilic Cyclization
bond is external to the newly formed ring, and endo, in which the breaking bond is within newly formed ring), and (3) the hybridized state of the carbon atom undergoing the ring-closing reaction (sp¼ digonal, sp2 ¼ trigonal, and sp3 ¼ tetrahedral). Baldwin summarized the relative nature of ring formation involving three- to seven- membered rings as either favorable or unfavorable.3a,4 These terms are not meant to describe the absolute probability that a reaction will or will not take place, but rather are used in a relative sense.
4.07.2
Halocyclization
Halocyclization is a powerful tool to construct rings by the addition of a nucleophile and halogen atom across unsaturated bonds. Oxygen-, nitrogen-, sulfur-, selenium-, halogen-, and carbon-centered nucleophiles are widely used in halocyclization reactions. Not only iodine, bromine, chlorine, and fluorine but also electrophilic halogen reagents such as IOAc, N-iodosuccinimide (NIS), NBS, NCS, ICl, IBr, I(collidine)2PF6, Br(collidine)2PF6, I(collidine)2ClO4, and Barluenga’s reagent (IPy2BF4) have been successfully used in halocyclization. Hypervalent iodine(III) compounds are also considered as efficient electrophiles. This section discusses the halocyclization reactions by various electrophilic halogen reagents.
4.07.2.1
Iodocyclization
Iodolactonization reactions are a well-known process to obtain rings (3–7). The lack of regioselectivity and slow reaction rates are the reasons why this methodology has been rarely used for medium and large macrolactones (Z8). Anyway, since the iodolactonization reaction was first reported by M. J. Bougalt in 1904, it has become one of the most effective protocols to synthesize lactones, which is widely applied in syntheses of many biologically important natural products.1,2 A large number of works dealing with iodolactonization reaction have been reported, and many comprehensive reviews have been presented.2h,2i,2f,2m,5 Although halogen molecules are nonpolar, they are easily polarized by the interaction with unsaturated C–C bonds. The electrophilic properties of iodine have been exploited over one century, and the use of molecular iodine as an inexpensive, nontoxic, and readily available electrophilic reagent has now received considerable attention in organic synthesis.2j,6 Not only was iodine molecule used as the electrophile, but a variety of new iodination reagents have also been developed, such as IOAc, NIS, ICl, IBr, and some hypervalent iodine(III) compounds.
4.07.2.1.1
Oxygen nucleophiles
4.07.2.1.1.1 Cyclization involving alkenes Oxygen nucleophiles have been extensively applied in cyclocyclization reactions. Some examples of nucleophiles with functional groups containing oxygen are shown in Figure 1. OH COOH OCO2R
OR COOR NRCO2R
RO
O
OH
N
O H
O
O NR2
R
N O
R
Figure 1 Oxygen nucleophiles.
Iodine-initiated cyclization of substrates with unsaturated bond is used extensively in the synthesis of oxygen heterocycles; in this chapter some representative examples and leading references will be described. Iodocyclizations of the homoallylic alcohols proceed with excellent stereoselectivity, generating tetrasubstituted tetrahydrofurans (THFs) in anhydrous MeCN (Scheme 3).7 This reaction follows antiaddition to give stereospecific products in high yields. Then 5-endo-trig iodocyclizations of homoallylic alcohols generate b-iodotetrahydrofurans in highly efficient and stereoselective manner in anhydrous MeCN with NaHCO3 as the base (Scheme 4).8 Such cyclizations are exceptional cases to Baldwin’s rules. They undergo well-ordered chair-like transition states (14 or 17) basing on the electrophile-driven to give 5-endo-trig cyclization product. Another example shows that tetrasubstituted THFs can be obtained from readily available homoallylic alcohols in excellent yields in the presence of I2 and AgTFA via a very unusual 5-endo cyclization (Scheme 5).9 The iodocyclization reactions of cyclohexa-1,4-diene derivatives containing chiral tether inducing high levels of diastereocontrol have been investigated, which is the desymmetrization of cyclohexa-1,4-diene (Scheme 6).10 To extend the methodology of I2-induced cyclization of 2-alkenyl-1,3-dicarbonyl compounds,11 Antonioletti and coworkers demonstrated an efficient approach to 2,3,4,5-tetrasubstituted furans (Scheme 7).12 Iodine-mediated cyclizations of a-keto esters and ketones bearing allylic and homoallylic chains were investigated, which resulted in the formation of diverse functionalized five- and six-membered ring enol ethers (Scheme 8).13 This methodology provides access to various functionalized cyclic ethers and tetrahydrobenzofuranones in moderate to very good yields.
Electrophilic Cyclization
I2 (3.0 equivalents) NaHCO3 (3.0 equivalents)
I Bu
MeCN, 0 °C, 0.75 h Yield = 87%
Bu HO
O
9
10 I2 (3.0 equivalents) NaHCO3 (3.0 equivalents)
Bu
I Bu
MeCN, 0 °C, 3 h Yield = 81%
HO
O
11
12
Scheme 3
H Et
Bu
I2 (3.0 equivalents) NaHCO3 (3.0 equivalents)
Et
O
MeCN, 0–5 °C, 3 h
OH
I
I H
Bu
Et
H
H
13
Bu
O
Yield = 90% 15
14 Bu I2 (3.0 equivalents) NaHCO3 (3.0 equivalents)
Et OH Bu 16
I
I Et
O
MeCN, 0–5 °C, 72 h
H
H
Et
H
H
Bu O Yield = 60%
17
18
Scheme 4
OH 20 O R
MeCN, −40 °C to r.t.
R
O 21
Yield = 72% (R = H) >95% (R = OBn) >95% (R = (thexyl)Me2SiO) I
I2 (1.2 equivalents) AgTFA (10 mol%)
R=H
19
I
I2 (1.2 equivalents) AgTFA (10 mol%)
R
OH
MeCN, −40 °C to r.t. Yield = 89%
22
O 23 I
I2 (1.2 equivalents) AgTFA (10 mol%) OH O
25
MeCN, −40 °C to r.t. Yield = 87%
O 26 I
I2 (1.2 equivalents) AgTFA (10 mol%) 24 OH 27 Scheme 5
MeCN, −40 °C to r.t. Yield = 35%
O 28
415
416
Electrophilic Cyclization
(1) n-BuLi (1.1 equivalents) TMEDA (1.1 equivalents) THF, −78 to 41 °C, 2.5 h (2) 30 (1.2 equivalents) THF, −41 °C to r.t., 1.1 h Yield = 27−66%
29
R1
R2 O
R1 R2
OH
R2 I2 (3.0 equivalents) Na2CO3 (3.0 equivalents) H MeCN, r.t., 10 min Yield = 60−66%
R1 O H
31
32
I
R1 = n-Bu, Ph, (CH2)4 R2 = H, H, (CH2)4
30 Scheme 6
O
O
O
R1
R2 R3 33
I2 (2.0 equivalents) Na2CO3 (2.0 equivalents) R4
DCM, r.t.
R1
O
R3
R2
DBU R4
O
I 34 Yields = 70-95%
R3
R2 H+
R1
R4 O 35
Scheme 7
A simple and efficient strategy to generate highly polyfunctionalized compounds in a diastereoselective via a substratecontrolled halocyclization reaction is shown in Scheme 9.14 IPy2BF4 was used for those iodofunctionalization reactions. A single diastereoisomer (single enantiomer) was favored when a phenyl or benzyloxy group was placed in a well-defined position of the terpene-derived compounds. Mphahlele and coworkers developed a new methodology that combined electrophilic and oxidative properties associated with iodine to synthesize novel iodofunctionalized tetrahydrobenzofuranones and dihydrobenzofuran derivatives in a one-pot reaction (Scheme 10).15 To further demonstrate the versatility of this methodology, 3-phosphonylmethyl-2-(2-propenyl)-2-cyclohexenone derivative and its 5-methyl derivative were subjected to the same reaction conditions; the corresponding 2-iodomethyl-2,3-dihydrobenzofuran derivatives were formed (Scheme 11).15 Under the identical conditions (I2, NaHCO3, MeCN), Lee and Oh tested a-allyl-substituted b-keto sulfones and isolated the corresponding 4,5-dihydro-5-iodomethylfurans, which could be easily converted to furan derivatives with excess 2,3,4,6,7,8,9,10octahydropyrimido[1,2-a]azepine (DBU) (Scheme 12).16 Kang and coworkers developed a catalytic enantioselective iodoetherification to generate THFs with up to 90% ee using a chiral salen complex (Scheme 13).17 Hennecke and coworkers recently reported a promising organocatalytic approach to haloetherfications by desymmetrization of in situ-generated meso-halonium ions (Scheme 14).18 By treatment of symmetrical diol with chiral phosphoric acid salt in the presence of electrophilic iodine source 73, enantioenriched ether product 74 was obtained under the practical reaction conditions. The bromoetherification of 75 using NBS also gave good yield with ee up to 67%. Chiral phosphoric acid salt 72 could also promote the iodoetherification of 70 in an efficient way (56% ee). Knight and coworkers used iodine monobromide in the cyclization of dihydroxy ester to generate THFs exclusively in a 5-endo manner in a good yield with a diastereomeric ratio of 14:1 (Scheme 15).19 The THF is the core structure of aplasmomycin precursor 79. Castillon also applied an iodoetherification strategy to form iodotetrahydrofuran in the natural products syntheses. The iodotetrahydrofuran as an equal mixture of diastereomers was obtained in a good yield as the key step in the synthesis of 10 -Cfluoromethyl- 20 ,30 -dideoxycytidine 82 (Scheme 16).20 Another key structure is Peri and coworkers’ synthesis of bicyclic sugar derivatives, which was further converted into avb3selective arginine-glycine-aspartate (RGD) peptides; the synthesis was generated by iodocyclization (Scheme 17).21 NIS induced a 5-exo cyclization with the adjacent benzyl ether oxygen in dry THF. Interestingly, a resolution of diastereomeric starting materials occurred; only the b-anomer cyclized formed a cis-fused ring, with the a-anomer recovered. The iodocyclization is also suitable for more complex systems. Nicolaou and coworkers have extensively applied the iodocyclization reaction in total synthesis, for example in the construction of the ring of azaspiracid-1,2,3 (Scheme 18).22 In the synthesis of fragment ABCD, 86 was exposed to NIS in the presence of NaHCO3 to yield THF derivative 87 in 70% yield
Electrophilic Cyclization
417
(a) Electrophilic Cyclization of β-Keto Esters Bearing a Monosubstitued Double Bond: O
O OEt
I2 (1.5 equivalents) Na2CO3 (1.5 equivalents)
R
I O
COOEt
DCM, r.t., 7−9 h
R
Yield = 81−84%
37
36 O
I2 (1.5 equivalents) Na2CO3 (1.5 equivalents)
O OEt
I O
DCM, r.t., 12 h
COOEt
Yield = 87%
38
39
(b) Electrophilic Cyclization of β-Keto Esters Bearing Non-terminal C=C bonds O
O OEt
O COOEt 41
O OEt
I2 (1.5 equivalents) Na2CO3 (1.5 equivalents)
COOEt O
DCM, r.t., 4 h Yield = 85%
42 O
I
DCM, r.t., 2 h Yield = 71%
40 O
I2 (1.5 equivalents) Na2CO3 (1.5 equivalents)
I 43
O OEt
COOEt
I2 (1.5 equivalents) Na2CO3 (1.5 equivalents) DCM, r.t., 6 h Yield = 86%
O I 45
44
(c) Electrophilic Cyclization of Alkenyl-β -diketones:
I2 (1.5 equivalents) OH Na CO (1.5 equivalents) 2 3
O
O I
DCM, r.t., 3 h 46
Yield = 85%
I2 (1.5 equivalents) OH Na2CO3 (1.5 equivalents)
O
O 47 O I
DCM, r.t., 0.5 h
O
Yield = 69% 48
49
Scheme 8
with the desired 2,5-trans stereochemistry. The same strategy has been used in constructing the ring G induced by NIS (Scheme 18). In the total synthesis of (þ)-lasonolide A, Kang et al. used iodine-induced substrate-controlled cyclization to afford a 27:1 mixture of cis-2,6-disubstituted tetrahydropyran and the corresponding trans isomer (Scheme 19).23 Some new chiral reagents have been developed to induce asymmetry together with electrophiles before racemizing, and the recent advances in this area have been highlighted.24 Grossman and Trupp described the first reagent-controlled stereoselective halolactonization using a chiral dihydroquinidine–iodine complex. However, only a 15% ee in the 5-exo iodolactonization was achieved (Scheme 20).25
418
Electrophilic Cyclization
O Ph
O
IPy2BF4 (1.1 equivalents) HBF4 (1.5 equivalents)
Yield = 70%
50
O Ph
O
51
IPy2BF4 (1.1 equivalents) HBF4 (1.5 equivalents)
Ph
DCM, −40 to 20 °C, 12 h
BnO
I
DCM, 20 °C, 0.5 h
Ph
O
O Ph
O
O
O
I
Yield = 40% 52
53
Scheme 9
O
O R3 R1 R2
OH
MeOH, reflux 3h
O
R3
I2 (2.0 equivalents)
R3
I
R1
R1, R2, R3 = H, Me
I
R1 O R2 Yield = 14−80%
OH
R2
55
56
54
+ MeOH − H2O OMe
OMe R3
+I2, −2HI R1 2 Yield = 60−75% R
O
R1
I
58
R3
(R2 = H)
I
O 57
Scheme 10
I
I O
I2 (2.0 equivalents) O P(OEt2)
R
MeOH, reflux 5h
MeO
O
OH O P(OEt2)
R
R = H, Me
R 61
60
59 I O
R Scheme 11
O P(OEt2)
O P(OEt2) 62
+
I2 I 2H − d
el Yi
9%
=
−6 65
Electrophilic Cyclization
419
SO2Ph DBU (1.2 equivalents)
O SO2Ph
I2 (3.0 equivalents) NaHCO3 (3.0 equivalents)
R
MeCN, r.t.
PhH, r.t.
R
DBU (5.0 equivalents)
I O
63
SO2Ph
PhH, r.t. 24 h
Yield = 62−85% 64
R = Me, Et, n-Pr i-Pr, Ph
DBU (3.0 equivalents) PhH, heat overnight
R O 65 Yield = 62−85% SO2Ph Me
R O 66 Yield = 75−95% SO2Ph
Me
R O 66 Yield = 75−95%
Scheme 12
I
1. 68A or 68B Toluene, −78 °C
O R 2. I2 (1.2 equivalents) 69 67 −78 °C, 20 h Condition a: 67A (30 mol%), NCS (0.75 equivalent) R = (CH2)3OTr, yield = 89%, ee = 90% OH
R
Condition b: 67B (7 mol%), NCS (0.7 equivalent) K2CO3 (0.5 equivalent)
N
R = (CH2)3OTr, yield = 90%, ee = 93% R = n-Alkyl, i-Pr, i-Bu, Bn, (CH2)3Ph (CH2)4N3, ee = 74−91% (Tr = tripheny)
N M
t-Bu
O
O
t-Bu
t-Bu t-Bu 68A: M=Co 68B: M=CrCl Scheme 13
Rousseau and coworkers investigated the enantioselective 5-endo iodolactonization and found that ephedrine-derived halobis (amine) salt was the most effective one to give a 45% ee (Scheme 21).26 But the chiral ammonium carboxylate gave only racemic product. Taguchi and coworkers reported an example of enantioselective iodolactonization reaction induced by a titanium complex generated from (Me, Ph)-taddol and Ti(Oi-Pr)4. The corresponding (3S,5S)-3-allyl-3-hydroxy-5-(iodomethyl) dihydrofuran2(3H)-one was obtained in a 65% ee (Scheme 22).27 Chiral cinchona alkaloid derivates induced low levels of asymmetry (o35% ee) during iodolactonizations of trans-5-aryl-4pentenoic acids under the catalytic conditions (Scheme 23).28 When stoichiometric amounts of alkaloids were used such as cinchonidine, exclusive six-member ring products were produced with a modest asymmetric induction.29 Jacobsen and coworkers used an anion-binding H-bonding catalysis strategy to accomplish enantioselective iodolactonization (Scheme 24).30 In the case of 5-substituted hexenoic acid derivatives (such as 110, and the transition states 116, 117, Scheme 24), a clear correlation between the electronic properties of the arene substituent and ee was observed, with electron-deficient derivatives undergoing more enantioselective cyclization. In the case of pentenoic acid 114, a slightly low I2 loading was needed for the optimal ee, and curiously, the absolute configuration was found to be opposite to the products of hexenoic acid cyclization. Martin et al. discovered enantioselective iodolactonizations of diversely substituted olefinic carboxylic acids, which was promoted by a BINOL-derived bifunctional catalyst 120 (Scheme 25).31 In Rizzacasa’s synthesis of the phospholipase A2 inhibitor, cinatrin B, a lactone moiety was closed in a 5-exo iodolactonization of the suitably protected, arabinose-derived alkenyl acid 121. This reaction proceeded in an efficient way in a high yield of the iodolactone 122 and a good diastereomeric ratio (94:6) (Scheme 26).32
420
Electrophilic Cyclization
OH
71 (20 mol%) 73 (1.2 equivalents)
HO
O
I OH
DCM, M.S. (4 Å) 0 °C, 2−12 h Yield = 81%, ee = 62%
70
71 A (20 mol%) NBS (1.2 equivalents) Ph Ph Ph DCM, M.S. (4 Å) Ph 0 °C, 2−12 h Yield = 81%, ee = 67%
OH Ph Ph
74
O
HO
75
Br OH Ph Ph
76
O
O O P O OM
N I
SiPh3 71 M = Na 72 M = Li
73
Scheme 14
O Ph OH
Ph
O IBr (2.0 equivalents), NaHCO3
O
CH3CN Yield = 78% dr = 14:1
OH
HO
O
O
O
I OH 79 Aplasmomycin precursor
OH
77
78
Scheme 15
OH
CH3CN, 0 °C Yield = 73%
80
NH2 N O HO
N O F
82 1′-C-fluoromethyl-ddc Scheme 16
O
I2, Na2CO3
TrO
TrO
I 81
Electrophilic Cyclization
BnO
H
O OBn
BnO
+ 83 O
Dry THF, r.t., 6 days Yield = 80%
BnO
83:83 = 1:1
H
dr = 6:4 84
83 O
NH H2N
I
O
NIS (3.0 equivalents) BnO
421
O
NH
N H O
NH
O OH
O NH
85 O BnO an v3-selective RGD peptide Scheme 17
Hart and coworkers, in their synthesis of a trans-fused perhydroindan analog of hispidospermidin, performed a 5-endo iodolactonization of dihydrobenzoic acid (Scheme 27).33 In Kim’s synthesis of pancratistatin, the stereochemistry of a hydroxy group was established by a 5-exo iodolactonization, elimination, and a subsequent hydrolysis/epimerization sequence (Scheme 28).34 Kishi and coworkers have used 6-exo iodolactonization of a chiral unsaturated acid to form the lactone with two new stereogenic centers (dr420:1) in their synthesis of fumonisin B2 (FB2). In contrasted with the sharpless asymmetric dihydroxylation of the 2-alkenes, it was considered as a better option (Scheme 29).35 In the synthesis of epoxyquinals A and B by Hayashi and coworkers, an iodolactonization of an in situ-generated bicyclic ether acid salt was performed. Then under basic conditions, iodolactone was opened with subsequent epoxide formation and methylation, which cleaved the ether, resulting in the formation of substituted cyclohexenol by treatment with lithium diisopropylamide (Scheme 30).36 Clarke et al. notified a significant solvent effect when iodonium acetate was used in the synthesis of the DEF ring of hexacyclinic acid. Taking CHCl3 as solvent, a chair–chair conformation was proposed to form the bicyclic lactone 140 as the only product. Alternatively, using HOAc as solvent, a boat–boat transition state led to the formation of the desired product 141 (Scheme 31).37 In the synthesis of both FB2 and ()-cinatrin B, iodolactonization was used to afford high diastereoselectivity (Scheme 32).32,35 Jung and coworkers synthesized 6-epiplakortolide E, a potent anticancer target, by using an iodolactonization of a cyclic peroxide in the presence of I2 and NaHCO3 with a long reaction time at room temperature (Scheme 33).38 Silver(I) triflate could accelerate iodocyclization of carbamates bearing electron-deficient olefins to give a-iodoesters in excellent anti-ring stereoselectivity. Epimerization happened during this process, and the rate of epimerization is solvent dependent (Scheme 34).39 Minakata and coworkers developed a cyclizative atmospheric CO2 fixation methodology by allyl amines, which is an efficient, metal/base-free process (Scheme 35).40 t-BuOI played an important role in the transformation to cyclic carbamates. The method was applicable to a wide range of unsaturated amines under mild conditions with good yield. The homoallylic tert-butyl carbonate was treated with iodine in MeCN at –20 1C to generate the iodocarbonate in a high diastereoselectivity (de¼ 95%) favored syn-isomer, which could be separated by column chromatography (Scheme 36).41 Besides the hydroxyls, esters and ketones, imides could also realize O-halocyclization. Generally, O-cyclization is preferred to N-cyclization in the halocyclization reactions of alkenylated amide, carbamate, and urea derivatives, which could be explained by Hard and Soft Acids and Bases theory shown in Figure 2.42 Of course, both the O-cyclization and N-cyclization are controllable depending on the experimental conditions.2e Some O-cyclization examples of imides are summarized in the following section. When b,g-unsaturated amides were subjected to t-BuOCl and I2 in dichloromethane (DCM), unsaturated iminolactones were obtained, which are hydrolyzed to the corresponding butenolides by the treatment with 3 N HCl (Scheme 37).43 I2-promoted cyclization of multisubstituted dienamides with halogenated cyclic iminoethersin excellent yields with perfect selectivity was reported by Xi et al. (Scheme 38).44 O-attack exo-cyclic imino ethers are the only product and no N-attack products or O-attack endo products are formed. Some more examples for diastereomeric preferences in the halolactonization of amides are shown in Scheme 39.2e,2f
422
Electrophilic Cyclization
NIS (5.0 equivalents) NaHCO3 (10.0 equivalents)
Me BnO
OH OH
THF, 0 °C, 2.5 h Yield = 70%
OH
86
HO Me D HO H OBn Me 87
H
Teoc Me
1.
N
I
H O
O
AF
Me
OTBDF
Me 89
A O
AcO H
O Me
O
H
F
(1. 0 TH M in TH F, 0 2. Yie °C F, 1. N ld , 20 2 e Na IS =8 q m HC (2. 0% in uiva 0 TH O3 len eq ( u F, ts) 1 i Yie 0 °C 0 eq valen ld , 1 uiva ts) =6 2 len 2% h ts)
O
B O
O
B O
H
H OH D O
C
Me
Me
H
O TBSO Teoc H O N I G H O I F O Me H Me
H
H OH D Me OHO Me H H O E H H Me NH O Me I H GO F O Me H Me A O
H
A D C O O Me H H 88
BzO
TBSO OH
O
B O
Me O
HH
Me
TB
H OH D O
C
Me
H
O
H
O
B O
A O
AcO
HO
OH
Me
90
C
91 Azaspiracid-1
R1
HO O
O
H
H OH D R2 OHO Me H H O E H H Me NH O Me I H GO F O Me H Me 92 A O
B O
C
Azaspiracd-2: R1 = R2 = Me Azaspiracd-3: R1 = R2 = H
Scheme 18
Intramolecular electrophilic cyclization of quinolones with iodine afforded racemic cis-diastereoisomers (Scheme 40).45 The results showed that the stereochemistry was influenced by the preexisting chirality of the alkenyl side chain. The transition state was proposed in Scheme 40. The 4-hydroxy group adopted an equatorial position and the C ¼ O bond coordinates to the activated alkene via oxygen leading to form cis-diastereoisomer predominantly. An iodolactonization of unsaturated chiral amide was applied in the synthesis of (þ)-citreoviral by Kobayashi and coworkers. The reaction could proceed smoothly to afford iodolactone in a 92% yield as a single isomer (Scheme 41).46 An example of the preparation of 2,5-disubstituted THFs from isoxazoline-based substrate is shown in Scheme 42.47 Dioxanes, trioxanes, or trioxepanes could be obtained from unsaturated hydroperoxyacetals and hydroperoxyketals via electrophilic cyclization in the presence of I2 and base (Scheme 43).48 Different conditions were screened; two isomers could be obtained from all of these reactions in different ratio.
Electrophilic Cyclization
O OH
I
I2, K2CO3 MeCN −30 to −20 °C
O O 93
423
O Ph
Yield = 95%
Ph
O
94
O O
O
A
OH OH
O O
O
B OH
(+)−lasonolide A
95
Scheme 19
97 (1.0 equivalent) I2 (1.0 equivalent) HOOC 96
DCM, −78 °C to r.t. Yield = 92% ee = 15%
I O
O
N
AcO
I+BF4−
MeO
98
2
N 97 Scheme 20
I2 (0.4 equivalent) N-methylephedrine (4.8 equivalents) AgSbF6 (100) (2.4 equivalents)
Me Ph
COOH 99
DCM, −78 °C Yield = 92% ee = 45%
O O Ph Me
I
+I
Me2 N Me
SbF6−
Ph
101 100
Scheme 21
Rodriguez and coworkers reported one example of an epoxide serving as the nucleophile in an iodoetherification reaction.49 Two diiodo ethers were isolated and characterized. If iodonium ion formation from the top face as 198a, 6-endo cyclization product 199 was obtained, otherwise it led to the formation of the THF 200 via a 5-exo cyclization from the bottom face via intermediate 198b (Scheme 44). An example of using sulfoxides as nucleophiles was reported by Abe and Harayama.50 Compound 201 underwent a 5-exo cyclization to provide the tricyclic intermediate 202, which was further hydrolyzed to afford the inverted sulfoxide 204, competing with the Pummerer rearrangement to form 1,3-oxathianes 203 (Scheme 45).
424
Electrophilic Cyclization
OH COOH 102
1. 103 (1.0 equivalent) Ti(Oi-Pr)4 (1.0 equivalent) I2 (1.5 equivalents) pyridine (1.0 equivalent) DCM, −78 to 0 °C 2. TsOH, benzene, reflux cis (ee = 65%) 67% (cis/trans 58:1)
O I
OH
Ph
O
Me
Ph O O Ph
104
Ph OH OH Ph
103
Scheme 22
106 (0.3 equivalent) I2 (1.5 equivalents) CH2Cl2, H2O NaHCO3, 0 °C Ratio = 56:44 Ph
O
I O
+
O
Ph 107 (ee = 17%)
I Ph
O O 108 (ee = 28%)
OH
105
109 (1.1 equivalents) I2 (1.5 equivalents)
I
DCM, 0 °C Ratio = 0:100
Ph
O
O
108 (ee = 35%)
Cl− HO
H
N
N
HO
106
H
N
109 N Cinchonidine
Scheme 23
4.07.2.1.1.2 Cyclization involving alkynes Compared to alkene cyclizations, the major difference of alkyne is that the electrophilic group in the initial product may be a vinyl substituent, such as vinyl iodide, which is the most useful precursors for cross couplings. Liang and coworkers reported an example of electrophilic cyclization with 1,4-butyne-diols derivates, which resulted in highly substituted dihalogenated dihydrofurans and dihydro-2H-pyrans in moderate to excellent yields (Scheme 46).51 Zhou and coworkers developed a facile and efficient method for the synthesis of 2,4-dihalo-3-thio-furans from 4-thiobut-2-yn1-ols (Scheme 47).52 A proposed mechanism including 1,2-migration of the thio group is shown in Scheme 48. The iodonium ion 213 was generated via iodine ion attacking the triple bond, followed by an intramolecular nucleophilic attack of sulfur atom offering thiiranium 214. In the presence of base, intermediate 214 could produce thiiranium zwitterion intermediate 215, which could form intermediate 216 through the intramolecular nucleophilic attack. The product 212 could be obtained via elimination and dihalogenation. Knight and coworkers have systematically investigated the cyclization of 3-alkynyl-1,2-diol derivates with iodine and NaHCO3 mixture in MeCN (Scheme 49).53 Aromatization via the elimination of 218 provides an efficient way to synthesize b-iodofurans. The iodocyclization of 2-enynols affords fully substituted 5-ylidene-2,5-dihydrofurans with high regio- and stereoselectivity under mild reaction conditions. This methodology provides a highly efficient route to access oxygen heterocycles bearing an exocyclic carbon–carbon double bond (Scheme 50).54 2-Substituted 3-iodobenzo[b]furans could be prepared by the iodocyclization of 2-alkynylanisole derivatives (Scheme 51).55 This type of product is a useful synthetic intermediate to introduce different groups to the 3-position via cross-coupling reactions. Both I2/CAN in MeCN and I2 in DCM could induce cyclization of 225 to afford 3-iodochromenones (3-iodo-4H-1benzopyran-4-ones) 226 in good yields (Scheme 52).55,56 A useful strategy to construct 2,3-disubstituted furopyridines induced by iodine at room temperature is developed by Arcadi and coworkers (Scheme 53).57
Electrophilic Cyclization
111 (15 mol%) 112 (2.0 equivalents)
O Ph
OH
O
111 (15 mol%) 112 (2.0 equivalents)
OH
O O
Ph
I2 (0.1 mol%) Toluene, −80 °C, 5 days Yield = 82%, ee = 90%
O
114
I 115
CF3
O O
F3C
N H
N N H
I
F O
NPent2
111
112 CF3
CF3
O
O F3C
I
113
Yield = 87% ee = 94%
Ph
O
Ph
I2 (15 mol%) Toluene, −80 °C, 5 days
110
425
N H
N H I NPent2
O
N
F3C
N H
O
O H
116
N H R NPent 2 I
O
O
N O
F
F
117
Scheme 24
120 (10 mol%) NIS (1.2 equivalents)
R2 n
DCM/tol (1:2) −20 °C, 14 h
COOH
118
R1
O
O
n
I 119
Yield = 88−99% >97:3 er Br
H *
H
R2
*
R1
Ph OH N N 120
Scheme 25
Two protocols for the synthesis of 4-iodo-3-furanones from 2-alkynyl-2-silyloxy carbonyl compounds have been developed (Scheme 54).58 A plausible mechanism is described in Scheme 54, which includes a heterocyclization with a 1,2-alkyl shift. As shown in path A, after the formation of iodonium intermediate 231 via the coordination of iodine to the triple bond, oxonium ion 232 could be formed by nucleophilic attack of the carbonyl oxygen. Subsequent 1,2-shift gives 4-iodo-3-furanone 230. In the presence of Au (Path B), it proceeds through the coordination of Au cation to the alkynyl 233 followed by 1,2-migration of the resulting oxonium ion 234 to yield 235. Then a rapid iododemetalation occurs in the presence of external NIS leaded to 3-furanone 230 containing the iodo substituent at C4.
426
Electrophilic Cyclization
BnO MeO
OBn R
O
BnO
I2 (0.6 equivalent) NaHCO3 (aqueous)
MeO
Et2O/H2O
OH
OBn
R
O
Yield = 97%, dr = 96:4
O R = n-C9H19
I
O O
122
121
HO HO CO2H MeO
R
O
O
O (−)-Cinatrin B
123
Scheme 26
Me
O
COOH
O
I
O
I2, NaHCO3
Yield = 80%
O
Me
THF-H2O
O O
124
125
Me NH(CH2)4NMe(CH2)3NMe2 O 126 O A trans-fused perhydroindan analog of hispidospermidin Scheme 27
O 1. KI3 (aqueous KI 12 equivalents, I2 5.0 equivalents) 1 N NaHCO3 (aqueous), CH2Cl2, r.t.
O H O
COOH
2. DBU, PhH, reflux Yield = 78%
OMe
O H
MeO
H H 128
127 OH HO
OH
O H O OH
OH NH
O
129 (+)-Pancratistatin Scheme 28
O
O
Electrophilic Cyclization
427
I OH I2, CH3CN −30 °C O dr > 20:1
n-Bu
n-Bu O
Yield = 84%
130
O
CO2H CO2H
O
O
131
OH
OH
n-Bu NH2 O
CO2H O
CO2H
132
Fumonisin B2 Scheme 29
O + 8.0 equivalents 133
O
1. r.t. 2. 1.5 M NaOH (0.9 equivalent)
O
3. I2 (0.5 equivalent), CH2Cl2, 0 °C Cl Yield = 42% 1.0 equivalent 134
HO
HO
OH
(±)135
O
OH O
O O
O
O H
O
O
O
H3C
I
+
O H
O
136
(+)-Epoxyquinol A
O
O H3C
O
137
(+)-Epoxyquinol B
Scheme 30
Huang and coworkers report the electrophilic cyclization of 1-(1-alkynyl)-cyclopropyl ketones to afford highly substituted furans in good to excellent yields under mild conditions (Scheme 55).59 Efficient syntheses of substituted oxygen-containing heterocycles and carbocycles have been developed by Larock’s group, using acetylene-containing aldehydes and ketones as substrates (Scheme 56).60 During their further efforts, Larock and coworkers have realized, for the first time, the iodine-catalyzed selective synthesis of iodo-pyrano[4,3-b]-quinolines and ortho-alkynyl esters from ortho-alkynyl aldehydes (Scheme 57).61 This novel oxidative esterification process provides a powerful tool to construct a wide range of functionalized pyranoquinolinones as well as isocoumarin. The cyclofunctionalization of 2-(1-alkynyl)-2-alken-1-ones generated highly substituted halofurans in good to excellent yields under extremely mild conditions using the I2/K3PO4 system (Scheme 58).62 I2-Mediated electrophilic cyclization of a,a-disubstituted b-alkynyl esters could afford the functionalized g-lactone in an excellent yield (Scheme 59).63 Liang and coworkers developed an iodocyclization approach of propargylic epoxides to form polysubstituted 3-iodofuran (Scheme 60).64 After the formation of iodonium intermediate 253, subsequent anti attack by the oxygen on the iodonium ion and elimination of a hydrogen cation generated 3-iodofuran 252.
428
Electrophilic Cyclization
O CO2tBu
OTBS
H O tBuO
H
O
H
Yield = 49%
H
O OTBS
I
H Chair–chair 139a
O
2C
AcOI, CHCl3
H 140
OTBS CO2tBu H
138
CO2tBu
H
OTBS
AcOI, HOAc
O
AcO
Yield = 61%
OTBS O
H
I
H Boat-boat
141
139b O H
O HO
O
H
I
142 A model DEF-ring system of hexacyclinic acid Scheme 31
OBn
BnO
(CH2)8CH3 MeO
O
I2 (1.0 equivalent), NaHCO3 (aqueous) Et2O/H2O (2:1), 0 °C, 15 min Yield = 97%, ds = 88%
COOH
OBn
BnO
(CH2)8CH3
MeO
O
O O 144
143
O
HO MeO
OH
HO MeO
O
O
(CH2)8CH3
MeO
O
O 147
O
O 145
HO HO CO2H
H (CH2)8CH3
O
OBn
BnO (CH2)8CH3
O 146
(CH2)9CH3 O
O
O O
148
(−)-Cinatrin B Scheme 32
I
O
Electrophilic Cyclization
I2 (20 equivalents) NaHCO3 (9.0 equivalents)
O
9
O
O
H
I O
CHCl3/H2O r.t., 2 days Yield = 55%
OH
9
O
O O ts) H n e l 150 a uiv nts) q h 0 e ale (3. quiv °C, 1 H e n 0 0 8% u 3S (2. hH, 8 = 6 P ield n-B IBN A Y
149
429
H O
9
O 151
O O
H
6-Epiplakortolide E Scheme 33
BnO
R1 O
BnO
I2 (3.0 equivalents) AgOTf (3.0 equivalents) O NaHCO3 (3.0 equivalents)
EtO O
HN
HN
R
CO2Et
H
I EtO
TS-153a
O
CCl4, 25 °C
R1 R 152
I
HN
Yield = 96%
R1 HN H
R
CO2Et
O
O
O R1
153
I
H R OBn TS-153b Scheme 34
O CO2 (1 atm) t-BuOI (1.0 equivalent)
NH2
MeCN, −20 °C, 24 h
154
O NH
I 155
Yield = 54−94%
CO2
t-BuOI H
O
O
I
O NH
NH 156
O
t-BuOH
157
O I
O NH
158
Scheme 35
Substituted 2-alkyn-1-one O-methyl oximes could be cyclized in the presence of ICl to give the corresponding 3,4,5trisubstituted isoxazoles in high yields under mild reaction conditions (Scheme 61).65 This process can be readily scaled up on multigram scale.
430
Electrophilic Cyclization
O O
OBoc
O
I2
I
MeCN, −20 °C, 6 h
160
Yield = 72%
159
O OH
O
161 Scheme 36
Hard nucleophile X
N-cyclization
NR (
)n Y 163
Soft nucleophile
NHR (
O
X2
)n Y
X
O-cyclizaton
(
O
162
O )n Y
NR
164
X = electrophile
Hard nucleophile
Figure 2 Cyclization of amides.
R3
O
R1
t-BuOCl (3.0 equivalents) I2 (1.0 equivalent)
NHR5 R2
r.t., 2 h, In dark Yield = 95%
R4 165
R3
R4 HCl (3 N)
R1 R2
R3
O
NR5
R1
Reflux, 5 h Yield = 85%
166
R4
R2
O
O
167
Scheme 37
R1
R1 O
R1
R2 NH R1
I2 (1.1 equivalents) THF/H2O (1:1) or DCM r.t., 3 h Yield = 95%
168
R1 R1 R1
R1
O
N R2
I 169
Scheme 38
5-Endo-dig electrophilic cyclization of 5-alkynyl-20 -deoxyuridines with NIS or N-bromosuccinimide in acetone at room temperature gives 3-(20 -deoxy-b-D-ribofuranosyl)-5-halo-2,3-dihydrofuro[2,3-d]pyrimidin-2-ones that usually precipitate from the reaction mixture (Scheme 62).66
4.07.2.1.1.3 Cyclization of allenes The history of allenes dates back to 1874, when Jacobus H. van’t Hoff predicted the correct structure of this type of compounds. Till today, lots of natural products and pharmaceuticals containing the allene moiety are discovered, and some reactions with allenes have been successfully applied for the efficient synthesis of natural products.67 The rich abundance of electrophilic reactions of alkenes and alkynes indicates that allenes should also undergo electrophilic reactions easily.68
Electrophilic Cyclization
431
I
O NH2
N Ac
O
I2, THF/H2O
O
0 °C, 2 h Yield = 86%
N Ac 171
170
O I2, THF/H2O
O
O
0 °C, 2 h Yield = 67% ee = 74%
N H
Ph 172
I
Ph 173 OPMB
OPMB
I2, THF/H2O
N
0 °C O
O O
174
175
I
O
O Me2N
OMOM
OMOM
1. TMSCl, Et3N THF, r.t., 9 h
Me H
OTBS
TBSO OH 176
Me
TMSO 2. I2, NaHCO3 THF/H2O, −10 °C, 7 h TBSO
O
H I
177
F
I2
O
CF3
F3C F R = n-Bu, Me, H 178
OTBS H
O NEt2
R
O
R I
179
Scheme 39
Ma et al. have explored a large number of reactions of allenes with many different electrophiles.69 In the presence of I2, 3-allenoic acids could be cyclized to afford b-halobutenolides (Scheme 63).70 With 4,5-allenoic acids, the iodolactonization reaction in cyclohexane with I2 or NIS afforded the five-membered lactones exclusively in fairly good yields and a very high Z/E selectivity (Scheme 64).71 Besides the allenoic acids, allenoates are successfully applied in iodolactonization. A direct iodolactonization of 2,3-allenoates with I2 was successfully developed in MeCN and H2O, affording b-iodobutenolides in good to excellent yields (Scheme 65).72 Ma and coworkers developed a facile and efficient method for the synthesis of 4,5-dihydrofuran derivates via electrophilic cyclization of 2-(20 ,30 -allenyl)acetylacetates in the presence of I2 at room temperature (Scheme 66).73 To extend the application of iodolactonization of allene, Ma et al. applied this methodology in the synthesis of (þ)-transwhisky lactone 270a in 11 steps from propargyl alcohol recently (Scheme 67).74a By using a new electrophilic iodination reagent, the same group reported a highly stereoselective iodolactonization of 4-allenoic acids, which has been successfully utilized in the synthesis of naturally occurring compounds (þ)-cis-whisky lactone 270b.74b
4.07.2.1.2
N-nucleophiles
4.07.2.1.2.1 Cyclization involving alkenes A simple and efficient method for the cyclization of various alkenylamides using chloramine-T and I2 was developed by Minakata’s group (Scheme 68).75 Gouverneur et al. reported the first examples of iodocyclization with functionalized allylic fluorides bearing nitrogen nucleophiles. It is an efficient method to prepare 3-fluoropyrrolidines via 5-exo-trig cyclization in high yields and with good diastereocontrol (Scheme 69).76 Huang et al. have developed a highly stereoselective iodocyclization reactions of methylenecyclopropanes with iodine in the presence of K2CO3, leading to the formation of 1-iodo-2-aryl-3-azabicyclo[3.1.0]hexanes in good yields under mild conditions (Scheme 70).77 Methylenecyclopropanes are highly strained but readily accessible molecules, and the relief of ring strain provides a potent thermodynamic driving force, which makes it a useful synthetic intermediate.
432
Electrophilic Cyclization
HO I
H O NH R 183
OH
HO
I2 (2.1 equivalents) NaHCO3 (2.3 equivalents)
THF, r.t., 2.5−4 h N O R H R = H, 6-Me, 7-Me, 7-OMe, 8-Me, 8-Et
N
R
H
O
HO CH2I + H R
N 182
181 Yield = 81−88% 181:182 Ratio ranging from 77:23 to 100:0
180
HO H O
I
NH R 184 Scheme 40
Ph OBn N OH
O 165
I2 (2.0 equivalents) NaHCO3 (4.0 equivalents)
O
MeCN/H2O (4:1), r.t. Yield = 92%
O
HO H I
Me
Me OBn
O
Me
O
166
Me OH Me
O
OH
Me CHO
Me
167
(+)-Citreoviral Scheme 41
R
N
O
I2 (2.0 equivalents)
DCM, reflux, 48 h Yield = 40−59% 188 cis:trans ratio range from 1:0.15 to 1:1.6 R = TMS, MeCH(OSiMe3), i-PrCH(OSiMe3) Scheme 42
NC
I O 189
H
O
H CH2I
Electrophilic Cyclization
O
O
E+ Bn
O O H OMe
Bn
190
E
Pyridine/I2
I
t-BuOK/I2 t-BuOK/I2/18-C-6
OH O H3C(H2C)6
Bn
Temperature (°C)
OMe
192:193
0
DCM
50
1:1
I
r.t.
THF
48
1:1.7
I
r.t..
Benzene
34
1:2.5
H3C(H2C)6
O O O ( )n
E E +
H3C(H2C)6
O O O ( )n H
H
H
195
196
Temperature (°C)
Solvent
Yield (%)
195:196
n-BuLi/I2
I
−78
THF
20
10:1
KH/I2
I
0−r.t.
THF
24
7:1
I
r.t.
Benzene
22
6:1
t-BuOK/I2
I
0
DCM
19
4:1
Cs2CO3/I2
I
r.t.
THF
12
10:1
t-BuOK/I2/18-C-6
H
OMe 193
Yield (%)
E+
E
O O
Bn
Solvent
194 Reagent
+
192
H O ( )n H
E
O O
191 Reagent
E
H
E+
OH
433
Scheme 43
4.07.2.1.2.2 Cyclization involving alkynes The electrophilic cyclization of propargylic aziridines is developed to construct 3-iodopyrroles with a variety of substituents (Scheme 71).78 Kundu and coworkers have developed an efficient synthetic strategy toward the synthesis of the naturally occurring indoloazepinone scaffold via a three-component reaction involving indole-2-carboxamide, 1,3-disubstituted propargyl alcohols, and I2 via a regioselective 7-endo-dig iodo-cyclization pathway (Scheme 72).79 The Larock group developed a method for the synthesis of a wide variety of N-alkyl-3-iodoindoles under very mild reaction conditions by the Pd/Cu-catalyzed cross coupling of N,N-dialkyl-o-iodoanilines and terminal alkynes, followed by electrophilic cyclization with I2. Alkyl-, aryl-, and vinylic-substituted alkynes all underwent iodocyclization in excellent yields (Scheme 73).80 By using substrate 286 bearing a hydroxyl on the benzyl position, Flynn et al. described a highly selective endo/exo iodocyclization procedure for a divergent synthesis of indoles, quinolines, and quinolinones (Scheme 74).81 Changing the protecting group of nitrogen from dimethyl to Ts, Liang et al. reported an efficient and highly regioselective protocol for preparing 3-iodoquinolines (Scheme 75).82 The resulting 3-iodoquinolines can be further functionalized by using cross-coupling reactions. When the terminal alkynes were used as substrates, Chan et al. developed an NIS-mediated cycloisomerization reaction of 1(20 -anilinyl)prop-2-yn-1-ol to gem-3-(diiodomethyl)indolin-2-one and 2-(iodomethylene)indolin-3-one. The reaction was shown to be chemoselective that secondary and tertiary alcoholic substrates exclusively produced the 3- and 2-oxindole products, respectively (Scheme 76).83 Tellitu and coworkers report an example of the hypervalent iodine reagent PIFA-promoted intramolecular electrophilic cyclization of alkynyl amides and alkynyl carboxylic acids, leading to the formation of pyrrolidinone and lactone skeletons, respectively, in a very efficient way (Scheme 77).84 Electrophilic cyclizations of a,b-alkynic hydrazones by molecular iodine afford synthesis of 4-iodopyrazoles in good to high yields (Scheme 78).85 Wu and coworkers have described a highly efficient electrophilic cyclization of N0 -(2-alkynylbenzylidene)-hydrazide with I2, Br2, or ICl in DCM at room temperature. It provides an efficient method to construct functionalized isoquinolinium-2-yl amides (Scheme 79).86 Recently, they reported a multicomponent reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, electrophile (bromine or iodine), and ketone or aldehyde under mild conditions, which generates the halo-containing H-pyrazolo[5,1-a]isoquinolines in good yields (Scheme 80).87
434
Electrophilic Cyclization
Me
O CH2
Me
O CH3 197 Ph3P (1.0 equivalent) I2 (1.0 equivalent) NaHCO3 (aqueous)
Me
Me O
O
CH3
Me 198a
Me
I Me
CH2
O
I
CH2
O
I
Me
I
Me I
CH2Cl2/CHCl3 20 min, 0 °C
198b
I
O
Me
H CH2
Me I
I CH2
O
O
O
Me 200
Me 199 Yield = 6%
Yield = 6%
Scheme 44
I
I
I
1. I2, CH2Cl2, 0 °C O
S
201
Ph 2. DABCO, r.t.
+ O
S 202
Ph
O
S Ph 203
Yield = 24%
OH
O
S
Ph
204 Yield = 69%
Scheme 45
Verma et al. demonstrated an I2-induced electrophilic cyclization, which is a facile synthesis of substituted pyrrolo[1,2a]quinolines (Scheme 81).88 Li et al. have developed an electrophilic tandem cyclization protocol for the synthesis of haloisoquinoline-fused benzimidazoles via CuI-promoted tandem cyclization of 2-ethynylbenzaldehydes with o-benzenediamines and iodine (Scheme 82).89 This protocol allows the formation of imidazo[1,2-a]pyridine ring in a one-pot reaction through the electrophilic annulation. In 2007, Yamamoto and coworkers presented a general and flexible approach to synthesize highly substituted isoquinoline building blocks, which can be further functionalized (Scheme 83).90 Depending on the nature of the substrates employed, acidic, basic, or neutral reaction conditions can be used, which makes this method compatible with sensitive, highly functionalized molecules. Their further research was reported in 2008, which presented a general and flexible approach to access highly substituted isoquinoline building blocks (Scheme 84).91 They finished the total synthesis of norchelerythrine by using the developed methodology to construct ring B (Scheme 85). Yamamoto et al. and Wu et al. separately reported an efficient procedure for the synthesis of 3,4-disubstituted iodoisoquinoline N-oxides from 2-alkynylbenzaldoximes (Scheme 86).92
Electrophilic Cyclization
HO R′ R
OH R′′′ R′′ 205
R
IX (2.0 equivalents) Wet DCM, r.t. Yield = 55−99%
OH
I 206
Wet DCM, r.t.
R′
X I
207
208
X = I, Br, Cl HO R′ R′′
Ts N R′′ R′
IX (2.0 equivalents) NHTs
Wet DCM, r.t.
X I
Yield = 45−89%
209
R
O
IX (2.0 equivalents) Yield = 33−82%
R
O R′′ R′′′
X
X = I, Br, Cl
HO R′
R′
435
210
X = I, Br, Cl Scheme 46
R1S
OH R2 211
NXS (3.5 equivalents) K2CO3 (3.5 equivalents) MeCN, 50 °C Yield = 42−71%
R1S X
X
O
NXS = NBS, NIS, NCS
R2
212
Scheme 47
H R1S
OH
NIS
R1S
I
OH
I
H S
R2
R2 213
211
R1
R2 HO
214 Base
R1S I
I O 212
HI elimination R2
R1S
R1 S
I
I H R2
Dihalogenation O 216
R2
O 215 H
Scheme 48
4.07.2.1.3
C-nucleophiles
4.07.2.1.3.1 Cyclization involving alkenes Taguchi and coworkers reported some iodocarbocyclization examples induced by chiral titanium taddolate 322.93,94 When CuO and the chiral titanium taddolate 322 were used for the iodocarbocyclization of dibenzyl 2-(4-pentenyl)malonate, it gave the corresponding product 323 in a 96% yield with a 85% ee (Scheme 87).93 If 2,6-dimethoxypyridine (DMP) was used instead of CuO in DCM/THF (4:1), a catalytic amount of the chiral titanium taddolate could still promote the transformation to afford bicyclic lactones 326 with 96–99% ee (Scheme 87).94 A stoichiometric amount of the binol-based phosphoramidite was used to induce enantioselectivity in the asymmetric iodocarbocyclization of alkadienyl or alkatrienyl arenes to afford the product 328 with up to 91% ee (Scheme 88).95
436
Electrophilic Cyclization
I2 (3.3 equivalents) NaHCO3 (3.3 equivalents)
OH R1 OH
R2
I
I HO
MeCN, 0−20 °C, 1 h
R2
R2 R1
217
O
R1
O 219
218
R1 = R2 = Ph (Yield = 60%) R1 = Ph; R2 = Bu (Yield = 71%) R1 = Bu; R2 = Ph (Yield = 77%) R1 = Me; R2 = Ph (Yield = 88%) R1 = Me; R2 = Bu (Yield = 65%) R1 = CO2Me; R2 = Ph (Yield = 47%) Scheme 49
R1
I2 ( 3.0 equivalents) K3PO4 (3.0 equivalents)
R1 R4
HO
R3
THF, 25 °C, 1−12 h
R2
R1
R1
R3
R4
Yield = 66−86%
O
R2
I
220
221
Scheme 50
OBn I I2 (1.2 equivalents) TsO
DCM, r.t.
OMe
OBn O
TsO
223
222 BnO
OH
O
OTs HO
224
Scheme 51
O
O I2 (1.2 equivalents) CAN (1.2 equivalents) OMe
R
225 R = Ph 4-Me-C6H4 Hexyl 4-MeO-C6H4 Scheme 52
MeCN, r.t.
I O 226 Yield = 97% 95% 91% 98%
R
Electrophilic Cyclization
R3 R1 N
I2 (3.0 equivalents) NaHCO3 (3.0 equivalents)
OE
R2
MeOH, r.t. Yield = 50−76%
227
437
I
R1
R3
N O
R2 228
E = CH3CO, PhCH2 Scheme 53
R1
R3
R3
O
O
I R2 OTMS 231
Path A
I
R1 R2 OTMS 232
NIS (1.5 equivalents) DCM, 23 °C R3 R3
O
O
R1
R1
R2 OTMS 229
I
R2 O 230
AuCl3 (5 mol%) Path B NIS (1.5 equivalents) DCM, 23 °C R3 O R1
R3
Au3+ OTMS 2 R 233
O
R3 O
Au2+
R1
R1 R2 OTMS 234
R1 = R2 = −C4H8−, Ph, Et R3 = Ph, 2-thienyl, 1-eyclohexenyl, n-Pent
Au2+
R2 O 235
Yield = 27−99%
Scheme 54
In the total synthesis of garsubellin A, Danishefsky and coworkers used iodocarbocyclization as the key step under the standard conditions in a 85% yield (Scheme 89).96 Then the same group applied the I2-induced electrophilic cyclization in the total synthesis of nemorosone and clusianone. A significant complication arose in the iodonium-induced carbocyclization reaction, shown in Scheme 90. Compounds 336 and 337 could be reconverted into 334 by treating them with zinc in aqueous THF in high yield.97 In addition to the desired carbocyclization product 335 (obtained only in a 32% yield), substantial quantities (i.e., 50%) of a virtually 1:1 mixture of oxygen competitive products 336 and 337 were also obtained. Fortunately, both the oxygen competitive products could be reconverted into the starting material in a very high yield by the action of zinc in aqueous THF.
4.07.2.1.3.2 Cyclization involving alkynes 3-Iodo-1H-indene derivatives are synthesized by iodonium-promoted 5-endo-dig carbocyclization of 2-substituted ethynylmalonates (Scheme 91).98 If the substrate 340 was modified to 342, both of 5-exo-dig and 6-endo-dig cyclization would be possible. Liang and coworkers reported a methodology for the synthesis of indene or naphthalene derivatives with high regio- and stereoselectivity under mild reaction conditions (Scheme 92).99 The resonance and electronic effects force the carbon of the malonate group closer to C-1 or C-2 of the acetylenic malonates, leading to the formation of five- or six-membered ring. Electron-rich aryls are also a type of good C-nucleophiles. When aryl propargylic alcohols are used as substrates, diiodinated carbocycles and oxygen heterocycles can be readily synthesized (Scheme 93).100 In the presence of protons, substrate 347 could lose a hydroxyl group to afford the propargylic carbocations intermediate, which is in resonance with allene cation 348. Then
438
Electrophilic Cyclization
R3 I (1.1 equivalents) 2 NuH (10.0 equivalents) NaHCO3 (3.0 equivalents)
O R1
R3 O
DCM, 2 h Yield = 67−92%
R2 236
E
R1 R2 Nu
237
R3
R3 O
O
E+
R1
E
R1
R2 238
R2
NuH
239
R1/R2 = −(CH2)3−, Ar/H, n-C3H7/H R3 = Ph, C4H9 NuH = MeOH, t-BuOH, i-PrOH, I2 Scheme 55
Y
I2 (2.5 equivalents) K2CO3 (1.0 equivalent) NuH (1.2 equivalents)
O
Nu
Y O
DCM, r.t. 240
R
R 241
I
Y = H, Me R = alkyl, vinylic, aryl, etc. Nu = MeOH, EtOH, PhNMe2, PhOH, etc. R4
I2 (2.5 equivalents) K2CO3 (1.0 equivalent) R4HC=CHR5 DCM
H O
242
R1
R5 O R1 243
I2 (2.5 equivalents) K2CO3 (1.0 equivalent) R2
R2
R3 DCM
Yield = 73−80%
R3 I 244
Scheme 56
OMe CHO
I2 (2.5 equivalents) K2CO3 (2.5 equivalents)
N Ph 245 Scheme 57
MeOH, 70 °C, 2.5 h Yield = 92%
O N 246
Ph I
Electrophilic Cyclization
R1 R1
O
+ NuH
O
I2 (1.1 equivalents) K3PO4 (1.1 equivalents)
I
DCM, r.t., 0.5 h Yield = 44−79%
Nu
247
248
Scheme 58
n-C6H13
CO2Et
I
I2 (1.5 equivalents)
O
DCM, r.t. Yield = 96%
O
n-C6H13
249
250
Scheme 59
R2
O R1
I
I2 (2.0 equivalents) NaHCO3 (2.0 equivalents) THF, r.t.
(CH2)n 251
R2 O
R1
(CH2)n 252
−H+ R2
I
I
R2 O R1
R1
(CH2)n
(CH2)H n 254
253 Scheme 60
N
OMe
R1 R2
DCM, r.t., 0.5−2 h Yield = 68−100%
255 R1 = H, Me, Ar, n-C6H13, t-Bu, etc. R2 = Me, Ar, t-Bu, etc. Scheme 61
N O
ICl (1.2 equivalents) R1
I 256
R2
O
439
440
Electrophilic Cyclization
O
R
R
O
HN N
O HO
X
N NIS (2.0 equivalents), 2 h or NBS (1.9 equivalents), 5 h
O
N
O HO
Acetone, r.t. Yield = 74−86%
O
OH
OH 258
257 R = p-CH3C6H4, p-(CH3)3CC6H4, c-C3H5 Scheme 62
1. I2 (1.0 equivalent) THF, 0 °C, 1 h 2. K2CO3 (1.0 equivalent) 10 h
R CO2H 259 R = n-C4H9, n-C7H15
I R
Yield = 36−91%
O
O 260
Scheme 63
R1
R1 R2
O 262
O dr > 99:1, 99% ee Z/E up to 98:2 I R1
NIS (2.0 equivalents) Cs2CO3 (1.0 equivalent) R=H Cyclohexane, −60 °C Yield = 86−91%
CO2H
261
R2
Cyclohexane, r.t., 1 h Yield = 75−88%
R3
R1 = H, alkyl R2 = H, alkyl R3 = H, alkyl
I R3
I2 (1.5 equivalents) K2CO3 (0 or 1.0 equivalent)
R2 O 263 O >98% ee Z/E up to 98:2
Scheme 64
R1
R3
R2
COOEt 264
R1 = alkyl, phenyl R2 = H, alkyl R3 = H, alkyl, benzyl Scheme 65
I2 (2.0 equivalents) MeCN:H2O = 15:1 r.t., 0.7−20 h Yield = 60−94%
I
R3
R1 R2 O 265
O
Electrophilic Cyclization
COOR2 R4
O
I2 (6.0 equivalents) CaH2 (0.6 equivalent)
COOR2
THF, r.t., 0.5 h Yield = 52−83%
R3 R1
R4
266
R3
R1
I
O R4
R4
267
R1 = Me, Et, i-Pr, Bn, Ph R2 = Et, Me R3 = H, Et, Bn R4 = H, Me, (CH2)5 Scheme 66
I2 (1.5 equivalents) cyclohexane, r.t., 2 h
Et
I
Et
Yield = 86% Z/E = 98:2
CO2H
O
268a
269a O
n-Bu O 270a O (+)-trans-whisky lactone Et
Et
I
271 (2.0 equivalents) Cs2CO3 (1.0 equivalent) 268b
CO2H DCM, −60 °C, 10 h Yield = 70%, ee = 99%
O O 269b
n-Bu
O O N I
270b
O (+)-cis-whisky lactone
271
O
Scheme 67
Ts
H N n 272
Chloramine-T (1.0 or 2.0 equivalents) I2 (1.0 or 2.0 equivalents) MeCN, r.t., 5−24 h Yield = 8−81%
n = 1−4 Chloramine-T = Scheme 68
Cl
N Ts
Na
Ts N n 273
I
441
442
Electrophilic Cyclization
R2 PHN
I2 (1.0 equivalent) DCM/NaHCO3 16 h, r.t.
R2
Yield = 62−97% dr = 4:1−17:1
R1
R1 F P = Ts, Boc 274
F I
F
R2
I
+
N P 275
N P 276
R1
Scheme 69
NHBn
Aryl
I2 (1.5 equivalents) K2CO3 (1.7 equivalents)
I R
CH3CN, r.t., 2 h Yield = 75−92%
H
H N H Bn 278
277 Scheme 70
Bn
R2
N
I2 (2.0 equivalents) NaHCO3 (5.0 equivalents)
Bn N
R1
R2
Dioxane, 100 °C, 10 min Yield = 76−95%
R1
I
279 R1 = alkyl, phenyl, 2-naphthyl R2 = alkyl, phenyl, benzyl
280
Scheme 71
R1 NH
OH +
R2
N O H 1.0 equivalent 281 R1 =
R3
R2 I2 (6.8 equivalents) CH3CN, r.t., 30 min N H 283
1.0 equivalent 282
aryl R3 = aryl, alkyl
Scheme 72
R2 N R1 284 2=
Me
R3
I2 (2.0 equivalents) CH2Cl2, r.t., 2 h Yield = 73−100%
R Me, n-C6H13, Ph R3 = Ph, n-C6H13, t-Bu Scheme 73
R2 N R1
R3
285
R3 N R1
Yield = 52−71%
R2 =
alkyl, benzyl
I
I
O
Electrophilic Cyclization
R2
HO R2 I R3 I
N
R
I2 (1.0 equivalent) MeCN
O
I2 (1.0 equivalent) R3
NMe2
Yield = 71−89%
EtOH
N
286
287
R
Yield = 68−92% 288
Scheme 74
R2
HO R2 I2 (2.0 equivalents)
R1 NHTs
R3
MeOH, 60 °C
I R1
289
R3
N
Yield = 40−99%
290
Scheme 75
O
I
HO R2 NIS (3.0 equivalents) I MeNO2 r.t., 3−6 h R2 = H Yield = 66−92% Z/E = 1.6:1−5:1
N Ts 292
NIS (3.0 equivalents) MeNO2
R1 NTs 291
Reflux, 2−3 h R2 ≠ H Yield = 32−98%
R2 R1 N Ts 293
Scheme 76
O PIFA (1.5 equivalents) Ar Ar
RHN 294
O
CF3CH2OH, 0 °C Yield = 55−65%
RN 295
O
Ar = Ph, p-MeOC6H4, 1-naphthyl, 2-thienyl R = Ph, Bn, Me Scheme 77
R3 HN
N R2
R1
I
DCM or CH3CN, r.t., N2, 30 min Yield = 40−95%
R1
296
R1 = alkyl, aryl, heteroaryl, ferrocenyl R2 = H, methyl, phenyl R3 = alkyl, aryl Scheme 78
R2
I2 (3.0 equivalents) NaHCO3 (3.0 equivalents)
N N R3 297
I O
443
444
Electrophilic Cyclization
N
R1
H N
R3
I2 (2.0 equivalents) or ICl (1.0 equivalent)
N
R3
R2
DCM, r.t. Yield = 70−99%
R2
298
N
R1 I 299
R1 = H, F, alkyloxyl R2 = phenyl, aryl, alkyl R3 = Ts, SO2Ph, COPh Scheme 79
O
O H
R1
TsNHNH2
+ R2
300
301
R1 = H, Cl,F R2 = phenyl, alkyl
+
R3
K3PO4 (3.0 equivalents) R4
R4
R3
I2 (1.1 equivalents)
N N
R1
EtOH, 70 °C Yield = 45−86%
R2 303
302
I
R3 = alkyl, H R4 = alkyl, H
Scheme 80
OMe
O
O I2 (3.0 equivalents)
N
O N
DCM, 25 °C Yield = 70−84%
R
R 304
I 305
Scheme 81
R2 NH2 + R1 306
CHO
NH2
R3 307
N I2 (2.0 equivalents), CuI (10 mol%) DMSO, 120 °C, 24 h Yield = 35−72%
R3
R1
N R2
I 308 R1 = H, methyl, methyoxyl, Cl, F, formyl R2 = phenyl, alkyl, aryl R3 = H, methyl, Cl, CF3
Scheme 82
intermediate 348 reacts with an iodide anion to give allenyl iodide 349, which can be further activated by an iodide cation. Then it is attacked by phenyl to produce the diiodinated product 350. The Larock group developed a series of methodologies for the synthesis of quinoline, naphthalene, and 2H-benzopyran derivates using electrophilic cyclization via the electron-rich aryl as nucleophile (Scheme 94).101
Electrophilic Cyclization
I
R1
I2 (5.0 equivalents) K3PO4 (5.0 equivalents)
N3
N
CH2Cl2, r.t., 24 h Yield = 82−95%
R2
309
R1
R2 310
R1 = Ph, p-OMePh, 1-cyclohexenyl R2 = H Py2IBF4 (2.0 equivalents) HBF4 in Et2O (2.0 equivalents) CH2Cl2, −78 °C, Ar Yield = 55−69%
R1
I R1 N
N3 R2 311 R1 = Me, n-butyl, t-butyl, CH2TMS R2 = H
R2
NIS (5.0 equivalents) NaHCO3 (1.0 equivalent)
312
CH2Cl2, 50 °C, Ar Yield = 42−62%
Scheme 83
R5
Ph
N3
R3 R2
R5
I2 (5.0 equivalents) NaHCO3 (1.0 equivalent)
R4
CH2Cl2 (0.1 M), r.t., 24 h, Ar
R3
R4
R1
Ph N R2
313 R1 = Me, R2 = H, R3 = H, R4 = H, R5 = H R1 = n-hexyl, R2 = H, R3 = H, R4 = H, R5 = H R1 = cyclopropyl, R2 = H, R3 = H, R4 = NO2, R5 = H
I
R1 314
Yield = 69% Yield = 73% Yield = 72%
Scheme 84
O
TBDMSO OHC
O
O
OTBDMS I2 (5.0 equivalents), K3PO4 (5.0 equivalents)
I
CH2Cl2, r.t., 24 h Yield = 94%
B
O
Br 315
MeO
O
MeO
OMe N3
OMe
316 O O MeO OMe
318
Norchelerythrine Scheme 85
O
317
445
446
Electrophilic Cyclization
R2
R1 N
I
R1
I2 (5.0 equivalents)
R2
EtOH, r.t., 15 min Yield = 71−90%
OH
N
319
O
320
R1 = H R2 = OMe, CF3, Ph Scheme 86
322 (1.0 equivalent) I2 (1.2 equivalents) CuO (1.2 equivalents)
COOBn
X
H 323
Yield = 96% ee = 85%
321
322 (0.2−0.3 equivalent) I2 (4.0 equivalents) DMP (2.0 equivalents)
ROOC
DCM/THF 4:1
X
COOR
X = CH2, CMe2, O R = Me, Bn 324
COOBn I
DCM, −78 to 0 °C
COOBn
COOR
BnOOC
O
COOR Heat I
325
Me Me
Ph O
O O Ph Ph 2 322
Ti
Scheme 87
OMe
OMe 1. NIS (1.1 equivalents) Chiral promoter 329 Toluene, −40 °C, 24 h 2. ClSO3H, i-PrNO2 −78 °C, 24 h
I
Yield = 58% ee = 91%
327
SiPh3
P N O H
Ph O I P N O O H
SiPh3
SiPh3
O
Chiral promoter: 329 Scheme 88
H 328
SiPh3 Ph
330
O X H 96−99% ee 326
H
Ph O
COOR
N O
Electrophilic Cyclization
H3C
CH3
I
I2 (3.0 equivalents) KI (3.0 equivalents) KHCO3 (3.0 equivalents)
O HO
CH3 O
CH3
HO
THF/H2O, r.t. Yield = 85%
H3C H3C H O
447
I
H3C H3C H O
O
331
O 332
H3C
CH3
CH3 O
CH3 O
HO H3C H3C H O
O H3C
CH3 333
CH3 Garsubellin A
H3C Scheme 89
Me
I
Me
I2 (3.0 equivalents) KI (3.0 equivalents) KHCO3 (3.0 equivalents)
O
Me
THF/H2O, r.t.
Me MeO
I HO 335
334
O
O
Me Me MeO
Me
Me
Me
O
O
Me
Me Me O
Me
Me Me
Me
HO
Me
O 337 24%
Ph
Me
Me MeO
Me
Me
Me O
I
+ Me
336 29%
32%
I O
I
+
Me
O
I
O
Me
Me Me
Me Me
Me Me
O
Me
338 Nemorosone
HO
O
Me
Me 339 Clusianone
Scheme 90
Yamamoto and coworkers have developed an efficient and general iodine-mediated electrophilic cyclization for the synthesis of 2,3-diiodo-dihydronaphthalenes from aryl propargyl alcohols (Scheme 95).102 Li’s group described an example that 4-(p-methylaryl)-1-alkynes could undergo the intramolecular ipso-iodocyclization process with ICl or I2 to afford the corresponding 8-methylene-1-azaspiro[4,5]trienes in moderate to good yields (Scheme 96).103 Four different types of fused arenes, fluoranthene, indeno-[2,1-a]phenalene, (8H)cyclopenta[a]acenaphthylene, and pyridine[a]acenaphthylene, were efficiently constructed through iodine-mediated electrophilic cyclizations of 1,8-dialkynyl naphthalenes in a single step (Scheme 97).104
448
Electrophilic Cyclization
COOEt COOEt
THF, reflux, 2 h Yield = 62−78%
R
340
COOEt COOEt R
I2 (1.5 equivalents) NaH (1.5 equivalents)
341
I
R = Ph, 2-naphthyl, 3-MeOC6H4, CH2OBn Scheme 91
E1
E1 E2
E (2.0 equivalents) t-BuOK (2.0 equivalents)
E2
I 343
R
R I 344
E1, E2 = COOMe, COOEt, COMe R = alkyl, aryl E = I2, NIS, ICI
E1 E2 I+
E1
−H+
E2
+
THF, r.t.
R
342
E1
b
a
E2
a
b I+
R
345
R
346
Scheme 92
n
n
I2 (2.0 equivalents) R1 OH R2
CH3NO2, r.t. Yield = 68−74%
R1 R 350
347
I
2
I
H+ n
I2
R3
n
I
R3 I
R1
R2
348
R1
R2
349
R1 = H R2 = Ph, p-MeOC6H4, p-MeC6H4, m-MeC6H4 Scheme 93
Kirsch et al. investigated the reactivity of 1,5-enynes and 1,6-enynes in the presence of electrophilic iodine sources (Scheme 98).105 1,5-Enynes favored the formation of six-membered carbocycles with great structural diversity, whereas 1,6-enynes favored the more rapid 5-exo cyclization yielding the corresponding five-membered carbocycles in moderate to good yields. Wang and coworkers developed a methodology to assemble the azaanthraquinone and diazaanthraquinone skeletons from Npropargylaminoquinones by utilizing an iodine-induced 6-endo-dig electrophilic cyclization (Scheme 99).106 With Cu(OTf)2, 3-alkylation of indole resulted in the formation of 3-propargylic indole, which could be further converted into 2-iodo-1,4-dihydrocyclopenta[b]indoles in the presence of NIS and boron trifluoride etherate (Scheme 100).107
Electrophilic Cyclization
H N
R1
Ar
E (3.0 equivalents) NaHCO3 (2.0 equivalents)
R1
N Ar
Yield = 43−88% 351
R2
R3
R4
E R2 352
E = I2, ICl
R1 = H, Me R2 = aryl, n-Bu
R3 OH
Ar
R4
E (3.0 equivalents) NaHCO3 (2.0 equivalents)
Ar E
Yield = 18−94% 353
449
R5
R5 354
E = I2, ICl
R3 = H, Me; R4 = H, Me, alkyl R5 = aryl, arkyl, vinylic, silyl, OEt O
OH
E (3.0 equivalents) NaHCO3 (2.0 equivalents)
I
Yield = 45−98% 355
R6 356
R6
R6 = aryl, arkyl, vinylic O
E = I2, Cl
I2 (3.0 equivalents) or ICl (1.5 equivalents)
Ar
O Ar I
Yield = 52−96% R7 358
R7 357 7 R = H, Ar Scheme 94
R3
R3 I2 (3.0 equivalents) R1
OH R2
CH3NO2, r.t. Yield = 61−98%
359
I R1 I R2 360
R1 = Me, OMe, Cl, Ar R2 = aryl, naphthyl, thienyl, (1-tosyl)pyrroyl R3 = Me, Ph Scheme 95
4.07.2.1.4
S or Se-nucleophiles
An efficient synthesis of 3-halo-chalcogenophene[3,2-c]chromene has been accomplished via electrophilic cyclization reaction of 3-alkynyl-4-chalcogen-2H-chromene (Scheme 101).108 Zeni’s group presented the electrophilic cyclization reactions of 3-alkynylthiophenes, which proceeds cleanly under mild reaction conditions, and gives fused 4-iodoselenophene-[2,3-b]thiophenes in excellent yields (Scheme 102).109 Zeni et al. developed an efficient method for the synthesis of tetrahydroselenophene derivatives by electrophilic cyclization of 1-butylseleno-4-alkynes. The cyclized 5-exo-dig products were obtained in high yields under mild conditions (Scheme 103).110 A formal total synthesis of the benzothiophene selective estrogen receptor modulator (SERM) desketoraloxifene analogs has been accomplished from alkynes bearing electron-rich aromatic rings by electrophilic cyclization using I2 (Scheme 104).111 Compound 392 could be converted to oxygen-bearing 3-iodobenzo[b]thiophenes in excellent yields via a two-step approach involving Suzuki–Miyaura coupling and Mitsunobu reactions.
450
Electrophilic Cyclization
Ph MeO
Ph I2/NaHCO3/MeCN/r.t.
N O 361 R1 R1 = Me, H, Ac, Bn
or ICI/CH2Cl2/−78 °C
R3 ICI (1.5 equivalents) H2O/CH2Cl2/−25 °C N R2
O
363 R2 = Me, H, Ac, Bn R3 = Ph
or I2 (2.0 equivalents)/MeCN/r.t. Yield = 48−89%
I O N R1 362
O
R3 I N R2 364
O
Scheme 96
4.07.2.2 4.07.2.2.1
Bromocyclization Cyclization involving alkenes
Oxetanes can be obtained in good yields from cinnamyl alcohols using bis(collidine) bromine(I) hexafluorophosphate as electrophile (Scheme 105).112 It is an efficient way to get Oxetin (oxetan-2-carboxylic acid), which is a natural product possessing antibiotic activities. It is developed by the same group that developed silicon-directed 4-exo-rig electrophilic cyclizations of homoallylic alcohols to prepare oxetanes (Scheme 106).113 Shi and coworkers reported that various g-hydroxyalkenes and g-amino-alkenes could efficiently undergo bromocyclization using NBS as the Br þ source with chiral phosphoric acid 401 as the catalyst, giving 2-substituted THFs and tetrahydropyrroles with generally good yields and up to 91% ee (Scheme 107).114 Fujioka and coworkers reported an example of asymmetric bromolactonization of 5-substituted 5-hexenoic acids catalyzed by a C3-symmetric chiral trisimidazoline (Scheme 108).115 The use of 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) instead of NBS as the bromine source could increase the selectivity, although the conversion was moderate when 0.6 equivalent was used. With 1.0 equivalent of DBDMH, the reaction proceeds in a high yield with good selectivity. Yeung and coworkers developed an S-alkyl thiocarbamate catalyst for the same reaction with high yields and good ees (Scheme 109).116 Very recently, Yeung et al. developed the first organocatalytic halolactonization of unsaturated carboxylic acids using zwitterionic catalyst 411 and stoichiometric N-bromosuccinimide halogen source, resulting in the formation of mediumsized lactones (Scheme 110).117 The Tang group recently discovered a DABCO-catalyzed syn-selective 1,4-bromolactonization of enynes. This reaction gave axially chiral allenes as the main products.118 In 2010, the same group described the mechanism that catalyst 413 (which has a bridgehead nitrogen similar to DABCO) promotes highly enantioselective bromolactonization of 2-enynes 412 and 415 to give bromoallenes 414 and 416 (Scheme 111).119 A facile, efficient, and enantioselective approach toward 4-bromo-3-aryl-3,4-dihydroisocoumarins through an aminothiocarbamate-catalyzed bromocyclization process has been developed by Yeung’s group (Scheme 112).120 This method is used for the synthesis of biologically important 3-substituted 3,4-dihydroisocoumarins and its related compounds. Very recently, Martin and coworkers reported a novel bifunctional catalyst from BINOL to accelerate highly efficient and enantioselective bromolactonizations of unsaturated acids (Scheme 113).121 These reactions represent the first catalytic bromolactonizations of alkylsubstituted olefinic acids to give lactones via 5-exo mode cyclizations, and the new carbon–bromine bonds are formed at the stereogenic center with high enantioselectivity. Also a tentative stereochemical model for enantioselective bromolactonizations is proposed (Scheme 114). Fujioka and coworkers applied the asymmetric bromolactonization of 5-substituted 5-hexenoic acids catalyzed by a C3-symmetric chiral trisimidazoline in the total synthesis of tanikolide (Scheme 115).115b Snyder and coworkers developed simple reagents such as 432, for direct halonium-induced polyene cyclizations.122 Electronrich and -deficient terpenes derived from geraniol, farnesol, and nerol could be used for the synthesis of a diverse array of complexes with chlorine-, bromine-, and iodine-containing polycyclic frameworks. Total synthesis of many natural products are achieved with this protocol, such as peyssonol A, peyssonoic acid A (Scheme 116), and formal racemic total syntheses of aplysin20, loliolide, and K-76. Treatment of g-disubstituted b,g-unsaturated hydroxamates with bis(collidine)bromine(I) hexafluorophosphate led mainly to the formation of cyclic bromo imidates – the thermodynamic products (Scheme 117).123
Electrophilic Cyclization
R1
451
R2 R2 I2 (3.0 equivalents) NaHCO3 (2.0 equivalents) CH3CN, 50 °C, 12 h
R1
I
366
365
R1 = R2 = H, F, CH3, OMe, Yield = 86−92% R1 = H, R2 = F, Br, CH3, OCH3, Yield = 72−91% R3
HO
R1
R2 R1
R3
R2
I
I2 (3.0 equivalents) DCE, r.t., 8 h Yield = 42−72%
367
368 R1 = R2 = CH3, R3 = H, Me, F, Br, H
OH
I OH
I2 (1.1 equivalents) DCM, r.t., 8 h Yield = 78%
369
HO
370 R3
R2 R1
R1 I2 (3.0 equivalents)
N
R3
R2
CH3CN, r.t., 8 h Yield = 48−69% 372
371 R1
=
R2
= CH3
R3
= H, CH3, F, Br
Scheme 97
In the total synthesis of (þ)-chaetocin, bromocyclization induced by NBS is used in the assemblage of the five-membered ring, which affords the desired product 448 in 88% yield (Scheme 118).124 This reaction was highly stereoselective, and no appreciable amount of the other stereoisomer was detected. Lera and coworkers have developed a versatile synthetic route leading to WIN 64821 (452) and WIN 64745 (453) (Scheme 119).125,126 Bromohexahydropyrroloindole 451 could be easily achieved from commercial D-tryptophan via stereoselective bromocyclization of the tryptophan derivative 450 in the presence of N-bromosuccinimide, according to the methodology recently developed by the same group.126 In the asymmetric total synthesis of loline alkaloids, the Trauner group used bromine-induced electrophilic cyclization to construct the key ring (Scheme 120).127 It goes through an unprecedented transannular aminobromination, which converts an eight-membered cyclic carbamate into a bromopyrrolizidine.
452
Electrophilic Cyclization
R1
R3
R5 R4
NIS (3.0 equivalents)
R2
DCM, 50 °C, Yield = 13−96%
I
R2
373
R4 R5 R1 374
R3
R1 = Ar, H, Me, Br, alkene R2 = H, Me R3 = TIPSO(CH2)3, Me, Ph, alkyl R4 = Me, Ph, alkyl R5 = H, Me H
H
NIS (3.0 equivalents)
I
DCM, 23 °C or 50 °C Yield = 40−55%
X 375 X = (MeO2C)2C, (PhO2S)2C, O, NTs
X 376
H H I
NIS (3.0 equivalents) DCM, 23 °C Yield = 67%
EtOOC COOEt
EtOOC COOEt 378
377 Scheme 98
I2 (3.0 equivalents) NaHCO3 (2.0 equivalents)
O
O I
MeNO2, 100 °C, 4 h Yield = 77% O 379
N H
N O 380
Scheme 99
R2 N
R3
R4
R2 N OH
+
Cu(OTf)2 (10 mol%) DCM, r.t.
R1
R1 R3
R4
Scheme 100
382
Yield = 16−54%
383
R5
R5
R1 R3
R5 381
R2 N
NIS (3.0 equivalents) BF3.Et2O DCM, r.t.
384
R4
I
Electrophilic Cyclization
I O
O I2 (2.0 equivalents)
R
385
YR1
Y
CH2Cl2, r.t. Yield = 50−86%
R2
R2
R 386
Y = S, Se; R = aryl, alkyl; R1 = Me, butyl; R2 = alkyl, aryl, alcohol Scheme 101
Ph
I E (1.1 equivalents)
S 387
Ph
DCM, r.t. Yield = 38−89%
YnBu
S
Y 388
Y = Se, Te; E = I2, ICl Scheme 102
I2 (1.1 equivalents) SeBu R1
R2
I
DCM, 4 h, r.t.
R2
R1
Se
60−93%
389
390
R1 = aryl, heteroaryl, alkyl, SeBu, Si(CH3)3, propargyl alcohol R2 = H, OH, OBz Scheme 103
R2
SMe R3 R2
R3
R1
R4 R7 391
R5
I2 (1.2 equivalents) DCM, r.t. Yield = 88−95%
R5 I 392
R1, R2, R3, R4, R5, R6, R7 = MeO or H R3
R4
S R5
R1
R7
393
O
R6
N
Desketoraloxifene analogs Scheme 104
S
R1
R6
R2
R4
R7
R6
453
454
Electrophilic Cyclization
394
R
OH R
Br+(coll)2PF6− (1.3 equivalents) CH2Cl2, r.t., 6.5 h R=H Yield = 36% R = Me Yield = 67%
R 395
RuCl (cat.) NaIO4
R
O
Br
CH3CN-EA-H2O R = Me Yield = 90%
O HO2C
Me Me
Br 396
Scheme 105
OH
Br
398 (2.5 equivalents) TMS
CH2Cl2, reflux, 6 h Yield = 89%
397
H
O
TMS H
399 398 = Br+(collidine)2SbF6−
Scheme 106
R Chiral acid 401 (10 mol%) XH NBS (1.2 equivalents) X
DCM, 0 °C Yield = 45−97% ee = 2−91%
R 400
O O P OH O
Br 402
R
R 401
X = O, NsN, or TrisylN R = aryl, alkyl
R = 2,4,6-(i-Pr)3C6H2
Scheme 107
R
X
Br
DBDMH (1.2 equivalents) 404 (10 mol%)
O
O
Toluene Yield = 74−99%
OH
R X 405
403 R = aryl, 2-naphthyl, cyclohexyl X = CH2, CMe2, O, NTs Ph
Ph
N
NH
H N
Ph
N
Ph
HN
N Ph
O
404
Ph
Scheme 108
In the synthesis of pallidol, ampelopsin F, paucifloral F, and diptoindonesin A, Snyder and coworkers used bromine-induced electrophilic cyclization as a key step (Scheme 121).128 Take pallidol as an example; a possible pathway of the bromocyclization induced by Br2 is proposed in Scheme 121.
Electrophilic Cyclization
NBP (1.2 equivalents) 407 (10 mol%)
O R1
OH
Toluene, −78 °C Yield = 95−99% ee up to 92%
406 R1 =
aryl, 2-naphthyl, alkyl
H
Br O
O R1 408
R2
N S
H N
Ar
O R2 = Ph, naphthyl 407 Scheme 109
411 (10 mol%)
OH
O
NBS (2.0 equivalents) DCM, 0 °C Yield = 54%
O 409
F3C
O
Br
410
S N
N
N 411
F3C Scheme 110
X O
R1
R2
R1
X
413 (20 mol%)
OH 412
NBS (1.2 equivalents) DCE, r.t. O
Yeild = 62−87%
Br
O 414
R2
R1 = H, n-Pr, i-Pr, t-Bu, TES, CH2OPh, CH2OPMB R2 = H, Me X = O, CH2, NTs R
R O
NBS (1.2 equivalents) DCE, r.t. 413 (20 mol%) Yeild = 44−88%
HO2C 415 R = H, Me, OMe, Cl, CF3, NO2
O
OMe
NH N
O 413
Scheme 111
O
NTs
O 416
H Br
455
456
Electrophilic Cyclization
Br
Br R2 OH R1 O 417
R2 H O
R2
418 (10 mol%) O
NBS, CH2Cl2 Yield = 87−98% ee = 24−95%
R1 419
R1 = H, CH3, F, Cl R2 = aryl
R1
O
O 420
419:420 Ratio range from 2.5:1 to 50:1 MeO
S
OMe
N H
O N
N
H OMe
418 Scheme 112
O R1 = H, R2 = Et, i-Bu, i-Pr, Cy, t-Bu
O R2
R1
R2
R1
TBCO (1.2 equivalents) Catalyst 422 OH O
DCM/Tol = (1:2) −50 °C, 14 h
R1 = Ph, 1-Np, 2-thienyl R2 = H
421
Br 423 O
O R2
O
R1
OH
R4 O 425
TBCO (1.2 equivalents) Catalyst 422 DCM/Tol = (1:2) −50 °C, 14 h
Yield = 92−97% er ratio range 94:6 to 98:2
(2)
Br 424
O
R3
Yield = 89−99% (1) er ratio range 85:15 to 98.5:1.5
O Yield = 89−99% er ratio range 71:29 to 91:9
R2 Br R1 426
(3)
R3 = H, Me R4 = Ph, m-CNPh, p-CN-Ph, Me Ph OH N Me 422
Me N Me
Scheme 113
4.07.2.2.2
Cyclization involving alkynes
Wu and coworkers developed an efficient route for the synthesis of isoquinoline-based azomethine ylides from 2-alkynylbenzaldoximes, DMAD, and bromine via tandem electrophilic cyclization-[3 þ 2] cycloaddition-rearrangement reactions (Scheme 122).129 When the DMAD is replaced by carbodiimide derivates, this process affords functionalized 1-amino-4-bromoisoquinolines in high yields (Scheme 123).130 Then two efficient methods for the synthesis of functionalized H-pyrazolo[5,1a]isoquinolines are developed subsequently, shown in Schemes 124.87,131
Electrophilic Cyclization
O
O O H
O
O
H Br H
Alk
H
NMe2
Disfavored
Br
O O
H Ar
N Me
Br
Br H
H
H
Alk Me
NMe2 Favored O
O
H
Alk H BrH
N
O
O
Ar
O
H
(a) Preferred mode for cyclizations (1)
O O H
O O H
O H
Alk
N Me
O
Br
N Me
(b) Preferred mode for cyclizations (2)
Br
OH
N Me
Br
H
NMe2
Favored
O O H
Ar
H
NMe2
Disfavored
OH
O H Ar
H
Br
457
O O
O
O H
H O
Ar
Ar
NMe2
O
O Ar
Br
Me
Br
Disfavored
Ar H
N
Br H NMe2
Favored (c) Preferred mode for cyclizations (3)
Scheme 114
C10H21
DBDMH (1.0 equivalent) Trisimidazoline (10 mol%)
O
Ph
OH 427
Toluene Yield = 99%
C10H21 Br (s) O (s) Ph
C10H21 O n-Bu3SnH, AIBN Yield = 91% ee = 91%
Ph
O (s)
O
429
428 C10H21 HO
O (s)
O
430 (−)-Tanikolide Scheme 115
In the synthesis of a-saxitoxinol, an analog of saxitoxin, Nishikawa and coworkers used the key bromocyclization reaction and subsequent intramolecular N-alkylation to construct a dibromomethylene intermediate 476 on treatment of 475 with pyridinium tribromide (PyHBr3) at room temperature (Scheme 125).132 Then another six steps were carried out to give a-saxitoxinol.
4.07.2.2.3
Cyclization of allenes
Vanadium bromoperoxidase is an enzyme present in marine algae, which catalyzed electrophilic halogenation reactions using hydrogen peroxide to oxidize and thereby activate bromide ion. Butler and coworkers well summarized the examples of vanadium bromoperoxidase in the biosynthesis of halogenated marine natural products.133 Ma and coworkers reported the studies on electrophilic reaction of tertiary 2,3-allenols with NBS in H2O or aqueous MeCN (Scheme 126).134 It provides an efficiently selective method for the synthesis of 3-bromo-2,5-dihydrofurans.
458
Electrophilic Cyclization
HO Me
Me 432 (1.0 equivalent) MeNO2, −25 to 25 °C Yield = 26%
Br
Me
Me
Me 431
OH
Me
O Me Br
H Me Me 433
Br S+
O
O
O
RO
Cl Cl Cl Sb− Cl Cl Br
H Me Me 434 Peyssonol A
432
OMOM OMOM MOMO
HO
CO2H
432 (1.1 equivalents) Me
Me
MeNO2, −25 °C Yield = 31% Br
Me
Br H Me Me
Me
H Me Me 437
436
435 Me
OH
Me
Me O
Peyssonoic acid A
Me CN Me CN 432 (1.1 equivalents) Me
Me
MeNO2, 25 °C Yield = 72%
Me
OH
Me
Me 438
Br
H Me Me 439
Br
H Me Me
Me Me OH
440
Aplysin-20
Scheme 116
4.07.2.2.4
Cyclization of cyclopropane
Highly efficient C–O bond formation has been developed via carboxylic acid catalyzed reaction of 1-acetylcyclopropanecarboxamides with NBS, which provides strategically novel and atom-economic access to biologically important 5amino-3(2H)-furanones (Scheme 127).135
4.07.2.3
Chlorocyclization
Iodocyclization and bromocyclization have been extensively investigated, and numerous electrophilic reagents have been developed. However, the research on chlorocyclization is not as many as that on the former two. The reason is partially due to the highly reactive nature of chloronium ions, which might exist in equilibrium with the corresponding carbocation rather than exclusively as cyclic chloronium ions. Thus, it makes chlorocyclization a formidable challenge for stereoselectivity control.136 So far, a lot of Cl þ reagents have been used for chlorocyclization, such as NCS, DCDMH, TCCA, chloramine-T, and DCDPH.
4.07.2.3.1
Cyclization involving alkenes
Borhan and coworkers reported catalytic enantioselective chlorolactonization of exocyclic 4-substituted pentenoic acids mediated by (DHQ)2PHAL or (DHQD)2PHAL and DCDPH (1,3-dichloro-5,5-diphenylhydantoin).137 When the acid substrates were selected to react in CHCl3-hexane in the presence of benzoic acid, the corresponding chlorolactones were obtained in high
Electrophilic Cyclization
459
Et3N, DCM, r.t. Yield = 80% O
N O 442 (1.1 equivalents)
O
N OAc Me
N O
+
O
+
443
444
Yield =12%
Yield = 29%
HN OAc O
O O
Br
DCM, r.t., 1 h
Me
445 Yield = 59% N OH
441 442 (1.1 equivalents)
443
Toluene, −20 °C, 2 h Yield = 100%
LiAlH4 (1.0 equivalent)
O
Ether, r.t. Yield = 95%
442 = Br+ source: bis(collidine)bromine(I) hexafluorophosphate [Br+(coll)2PF6−]
446
Scheme 117
H O N HN
Boc 447
O
Br NBS (1.2 equivalents) MeCN, −30 °C Yield = 88%
NMe
NMe H
N N H Boc
O TBSO
O
OTBS
448
HO MeN
Boc H N
O S2
N O
O N 449
N H Boc
S2 O
NMe OH
(+)-Chaetocin Scheme 118
enantioselectivities (Scheme 128). Then they developed another highly stereoselective chlorocyclization of unsaturated amides to chiral heterocycles mediated by catalytic amounts (1–2 mol%) of commercially available (DHQD)2PHAL (Scheme 129).138 The reaction is simply handled without strictly anhydrous or inert reaction conditions. The reaction scope is fairly general with regard to the substitution pattern of the olefin.
4.07.2.3.2
Cyclization involving alkynes
The 5-endo-dig chlorocyclization of 1,4-disubstituted alk-3-yn-1-ones (propargylic ketones) with trichloro-striazinetrione (trichloroisocyanuric acid, TCCA; 0.4 equivalent) in toluene at room temperature in the absence of base was developed, which provided 2,5-disubstituted 3-chlorofurans in high yields (79–96%) (Scheme 130).139
460
Electrophilic Cyclization
O
OMe
H Br
NBS (1.0 equivalent) NHBoc PPTS (1.0 equivalent)
O
Ph
H
OMe NBoc
DCM, 25 °C Yield = 85%
N Boc 450
O
N H Boc 451
H N
N HN
O O N N H H
452
H H N
O
NH
N O
Ph
HN
O O
WIN 64821
NH N N H
453
H
O
Ph
WIN 64745 Scheme 119
Br
N Cbz
N3
Br2 (1.0 equivalent)
OH
MeOH, 0 °C, 12 h Yield = 97%
454
H
N3
N+ H Br−
OH
455 CHO N O N 456 N-formyl loline
Scheme 120
4.07.2.4
Fluorocyclization
Although fluorinated molecules widely exist in pharmaceuticals and agrochemicals,140 the development of fluorocyclization reactions is not too many. The low reactivity of commonly used N-F electrophilic fluorinating reagents is particularly restrictive in the fluorocyclization. This section summarizes the progress in fluorocyclization.
4.07.2.4.1
Cyclization involving alkenes
The Taguchi group developed a fluorolactonization of 4-alkenoic acid derivatives containing an aryl substituent at the 4- or 5position with N-fluoropentachloropyridinium triflate, which proceeds smoothly in a regioselective manner with little or even no diastereoselectivity (Scheme 131).141 The Serguchev group realized the selective fluorolactonization of cis-5-norbornene-2,3-endo-dicarboxylic acid or its monomethyl and dimethyl esters with F-TEDA-BF4 or XeF2 (Scheme 132).142 The reactions of 5-norbornene-endo-2-carboxylic acid or
Electrophilic Cyclization
OMe
461
OMe
OMe
OMe
OMe
OMe
Br
OMe
Br2 (2.0 equivalents) CH2Cl2, −78 °C, 2 h, then r.t., 1 h OMe Yield = 81% OMe
MeO
MeO OMe 458
457
OMe
OMe
MeO Br
OMe
Br
OMe
Br
OMe
Br
OMe
MeO
OMe
OMe
Br Br
OMe
OMe
460
459 Friedal-Crafts alkylation
OMe
MeO
OMe
Br Br
H Br
MeO
OMe
MeO
BBr3 (12 equivalents), CH2Cl2, 0°C, 4 h, then 25 °C, 20 h Yield = 83%
OH
HO
Pd/C (20 mol%), H2, MeOH, 25 °C, 24 h Yield = 76%
OH H
H
HO
OH
HO 462
461
Pallidol Scheme 121
R1
N
OH
R2
CO2Me
CO2Me
463 464 R1 = H, F R2 = n-Bu, Ph, PMP
Br2 (1.0 equivalent) NaOAc (1.2 equivalents) CH2Cl2, r.t. Yield = 42−98%
N
R1
CO2Me CO2Me R2
O
Br 465
Scheme 122
its methyl ester with F-TEDA-BF4 or XeF2 proceed unselectively with the formation of products of lactonization, addition, and rearrangements. In 2003, Gouverneur and coworkers demonstrated that the electrophilic fluorodesilylation of allyl silanes combined with the use of enantiopure N-fluorocinchona alkaloids provided a highly efficient method for preparation of allylic fluorides with high ee values.143 The (DHQ)2PYR/Selectfluor combination fluorinated cyclic allylsilanes in MeCN to give five- and six-membered chiral allyl fluorides. The first asymmetric example was reported by Gouverneur and coworkers during a study of electrophilic
462
Electrophilic Cyclization
R3 N
R1
OH R3 N C N R3
R2
Br2 (1.0 equivalent)
N
R1
DCM, 1,4-dioxane, 60 °C
R2
Yield = 41−99%
466
NH
467
468
Br
R1 = H, F, Cl, Me, OMe R2 = Ph, 4-ClC6H4, 4-MeC6H4, 4-MeOC6H4, cyclopropyl Scheme 123
R3 N
R1
OH
R2 Br 470
R1 = H, F, OMe R2 = Ph, n-Bu R3 = Ph, n-Bu, PMP, CH2OH; cyclopropyl
CHO R3 471
TsNHNH2 (1.1 equivalents) Br2 (1.1 equivalents) K3PO4 (3.0 equivalents)
O
R1 R2
N
R1
R3 AgOTf (10 mol%) DBU, CH2Cl2 Yield = 50−91%
2. R2
469
N
1. Br2 (1.0 equivalent), DCM
R4 472
R4
R3
N N
R1
EtOH, 70 °C Yield = 45−86%
R2 Br
R1 = H, F, Cl R2 = Ph,n-Bu,cyclopropyl R3 = H, Me, Et, −(CH2)4− R4 = H, Et
473
Scheme 124
OH
CbzHN
HO CbzHN
N
HN
N3
NH
NBoc
PyHBr3 (5.0 equivalents) K2CO3 (10 equivalents)
N3 O HN
DCM, H2O, r.t., 1 h Yield = 24% for 6 steps
CbzN 476
474
OTBS
475
OMs OH H N
HN H2N
N
NH2 NH OH H
477 Decarbamoyl -saxitoxinol Scheme 125
Br N
Br
Electrophilic Cyclization
R3
Br
H R1 NBS (1.5 equivalents)
R4 HO R2 478
H
R3
R1
R4
CH3CN/H2O = 15/1 or H2O (R1 or R2 ≠ H)
463
R2
O 479
Yield = 61−84% Scheme 126
O
O
O
NBS NHR1
R2 480
NHR1
O
R3CO2H Yield = 73−94%
Nu 481
R1 = alkyl R2 = H, Me R3 = H, alkyl, aryl Nu = OR, O2CR, X
Scheme 127
O
483 (10 mol%) 484 (1.1 equivalents) OH
R1 482
O
Benzoic acid (1.0 equivalent), CHCl3/hexane (1:1), −40 °C,
O
R1
Yield = 75−86%, ee = 74−90%
Cl
485
R1 = Ph, p-(Me/Cl/F/CF3)C6H4, cyclohexyl OR2
OMe O
N
O N Cl 484 = DCDPH
Ph
R2 =
N
Cl N
OR2
N
N
Ph
Et
(DHQD)2PHAL (483)
Et Et N H H
Cl N Ph
O Cl
N
Ph O
486
or
N H Cl
O N
O Ph 487
N Cl Ph
Scheme 128
fluorocyclizations (Scheme 133).144 The (DHQ)2PHAL/Selectfluor combination could induce asymmetry in the cyclization of prochiral allyl silane 510 to produce 511 (70% yield, one diastereomer, 45% ee).
4.07.2.4.2
Cyclization of allenes
The fluorohydroxylation of 3-aryl-substituted-1,2-allenes with Selectfluor in aqueous MeCN at room temperature is reported by Ma’s group.145 This electrophilic reaction is highly regioselective with the more substituted and electron-rich C¼ C bond. However, the substrate scope is so far still very limited since the presence of the aryl group in allenes is important for the success of
464
Electrophilic Cyclization
H N
Ph
Ar
483 (2 mol%) 484 (1.1 equivalents)
Ar
TFE, −30 °C, 2 h Yield = 79−96%, ee = 59−98%
O
O
488
N Cl Ph 489
Scheme 129
O
491 (40 mol%)
R1 R2
R2
O R1
Toluene, 22 °C Yield = 79−96%,
Cl
490
492
R1 = Ph, p-ClC6H4, p-BrC6H4 R2 = p-MeC6H4, c-C6H6, p-(t-Bu)C6H4 O Cl
N
Cl
N
N O Cl 491 = TCCA
O
Scheme 130
R1
494 or 495 (1.2 equivalents) CO2H
MeCN, r.t., 1 h
R1
493
496
497
A
45%
45%
B
74%
−
Ph
494 (1.2 equivalents) NaHCO3 (1.5 equivalents)
Ph
MeCN, r.t., 1 h
Et
CO2H R3
498
2.1 : 1
51%
1 : 2.4
494 (1.2 equivalents) NaHCO3 (1.5 equivalents) CO2H R5 500
Scheme 131
F 499
E-498 R2 = H, R3 = Et
Z-500 E-500
R4
Cl
+ Ph
O
Cl
Cl
Cl N − F OTf 494
Cl
N F 475
F
F
MeCN, r.t., 1 h
Cl
O
72%
R4
O
O
Z-498 R2 = Et, R3 = H
R4
O
F
R1 = Ph
R2
R1 Me
O +
O
O
501
= Me,
R5
= Ph
59%
1 : 2.5
= Ph,
R5
= Me
20%
1 : 2.2
Ph
O 502
O
Cl −OTf
Electrophilic Cyclization
F
F
F-TEDA-BF4 (1.2 equivalents)
CO2R
CO2R + F CO2R MeOCHN
CO2R +
CH3CN, r.t., 40 h
CO2R
O O 504
503 R=H R = Me
73% 71% XeF2 (1.0 equivalent), BF3.OEt2 (75 mol%)
CO2Me
CH2Cl2, −78 °C, 24 h
CO2Me 503
506
Trace 4%
4% F
CO2Me O
+
F
CO2Me
CO2Me
+
O
CO2Me
O 504
O 507
508
45%
6%
7%
F CO2Me
F
CO2Me
509 6%
Scheme 132
Ph
Selectflour (1.2 equivalents), (DHQD)2PHAL (1.2 equivalents),
SiiPr2p-Tol
NaHCO3, MeCN, −20 °C, 4 days Yield = 70%, ee = 45%
510
CO2R CO2R
505
F
+
HO
465
O F SiiPr2p-Tol
Ph
(+)-511 trans/cis >20:1
Z/E > 20:1 Scheme 133
this transformation. With Selectfluor as the electrophile, 2,3-allenoic acids may also be cyclized to afford b-fluorobutenolides (Scheme 134).146 2,3-Allenoates, which are more readily available, are developed to prepare 4-fluoro-2(5H)-furanones (Scheme 135).147 If 3.0 equivalents Selectfluor and 0.5 equivalent H2O were used, 3-fluoro-4-oxo-2(E)-alkenoates could be obtained.147
R1
Selectfluor (1.1−1.5 equivalents) MeCN, H2O (10 equivalents)
R3
R2
COOH
R2
or H2O 80−100 °C Yield = 39−96%
512 R1 = alkyl, phenyl R2 = H, alkyl, phenyl R3 = H, alkyl
R3
F R1
O
O 513
Scheme 134
R1 R2
R3
Selectfluor (1.7 equivalents) MeCN/H2O (2:1)
COOEt
514 R1 = alkyl, phenyl R2 = H, alkyl, phenyl R3 = H, alkyl Scheme 135
80 °C Yield = 30−95%
R3
F R1 R2
O 515
O
466
Electrophilic Cyclization
In this part, iodocyclization, bromocyclization, chlorocyclization, and fluorocyclization are summarized. Many wonderful methodologies have been used as key steps in the synthesis of natural products. Besides halocyclization, selenocyclization, sulfenylcyclization, and tellurocyclization are also traditional electrophilic cyclization, which will be discussed in the next section.
4.07.3
Sulfenylcyclization, Selenocyclization, and Tellurocyclization
4.07.3.1
Cyclization Involving Alkenes
Over the past more than 20 years, a large number of researches on intramolecular selenocyclization, sulfenylcyclization and tellurocyclization have been reported. In 2004, Huang and coworkers reported a selenium-induced intramolecular electrophilic cyclization for the synthesis of polysubstituted dihydrofurans and THFs, followed by selenoxide syn-elimination or novel nucleophilic substitution cleavage of selenium resin with good yields and purities (Scheme 136).148 Then in 2009, the same group developed a new method for the preparation of 3-oxabicyclo[3.1.0]hexan-2-ols by the cyclization of (E)-2-(arylmethylene)cyclopropylaldehyde mediated by different organoselenium reagents (Scheme 137).149
O
O
R2
O R2 OR1
SeBr
R1O
R3
R3
THF, r.t. quantitative
O R2
NaI, CH3I Se
O
516
R1O
+
DMF, 75 °C, 18 h Yield = 72−86%
R3
517
SeCH3
O I
518
519
SeBr = selenium bromide resin Scheme 136
Ph O
PhSeBr (1.2 equivalents) K2CO3 (1.2 equivalents)
H H
MeCN/H2O r.t., 20 min, Yield = 89%
H 520
HO
SePh H O
Ph
521
PhSe
−H
Ph
Ph H2O
PhSe
PhSe
O
CHO 523
522
H
OH
Scheme 137
A solid-phase synthetic method is developed for the preparation of flavonoids with good yields and purities (Scheme 138).150 The THF moiety of amphidinolides 528 and 529 is achieved in excellent yields by a cyclization of an anti dihydroxy (allylic and homoallylic), unprecedented trisubstituted-alkene substrate (527), followed by deselenylation. The highly selective selenocyclization reaction is the key step in this transformation (Scheme 139).151
OH
SeBr
O
CH2Cl2, r.t., 12 h O 524
Se O 525
SeBr = selenium bromide resin Scheme 138
30% H2O2 THF, 0 °C, 24 h Yield = 83%
O
O 526
Electrophilic Cyclization
PhSeCl (1.5 equivalents) additive (1.0 equivalent)
OH NC
NC
NC
O
467
O
+
THF
HO
OH 527
HO SePh
SePh 529
528
Additive = ZnBr2, r.t., 15 min K2CO3, r.t., 30 min ZnBr2, −78 °C, 30 min K2CO3, −78 °C, 6 h EtiPr2N, −78 °C, 8 h
Yield = 60% Yield = 75% Yield = 85% Yield = 92% Yield = 92%
Yield = 18% Yield = 10% Yield = 8% Yield = 3% Yield = 3%
Scheme 139
Some chiral electrophilic selenium reagents have been developed for reagent-controlled asymmetric synthesis, such as chiral aryl and terpene-derived selenides. The selenoetherification of compound 530 gave product 532 in 88% yield with a diastereomeric ratio of 93:7, and compound 533 converted into product 534 in 75% yield with a diastereomeric ratio of 89:11. In both cases, ArSeOTf 531 should be prepared at 78 1C and then the mixture should be allowed to reach room temperature and stirred for another 6 h (Scheme 140).152 SeAr* Ph
OH 530
531 (1.2 equivalents) Ph
O
CH2Cl2, MeOH, −78 °C to r.t., 6 h, Yield = 88%
532 SeAr*
OH 533
Et
531 (1.2 equivalents) CH2Cl2, −78 °C to r.t., 6 h, Yield = 75%
SMe
O 534
Et
Ar*SeOTf
SeOTf
531
Scheme 140
Chiral sulfur-containing selenides have been used successfully in promoting the asymmetric electrophilic functionalizations affording furan derivatives. The diastereoselectivities of these reactions are proved to be good (Scheme 141).153
SeAr*
OH
Ph
531 (1.2 equivalents) CH2Cl2, MeOH, −78 °C to r.t., 5 h, Yield = 89%
535
Ph O dr = 97:3 536
531 (1.2 equivalents) O
OH 537
Ph
CH2Cl2, −50 °C to r.t., 4 h, Yield = 95%
Ph O
O
SeAr*
dr = 89:11 538
Scheme 141
The polymer-bound selenium bromide 541 has been applied for the two-step transformation of PGF2a methyl ester 539 to the PGI2 analogs 540 (94% yield, approximately 2:1 ratio of C-6 epimer). This method is used successfully in preparing a series of polymer-bound selenium reagents/linkers (Scheme 142).154
468
Electrophilic Cyclization
CO2Me
OH
H
1. 541 (1.5 equivalents) THF, 278 °C, 30 min 2. H2O2 (30%) (2.0 equivalents) −78 to 23 °C, 20 h
CO2Me
HO
Yield = 94%
HO
O
HO
HO
540
539 =
541 =
SeBr
Polystyrene Scheme 142
Diastereoselective synthesis of enantiopure morpholines by electrophilic selenium-induced 6-exo cyclizations on chiral 3-allyl2-hydroxymethylperhydro-1,3-benzoxazine derivatives is developed by Pedrosa and coworkers (Scheme 143).155
R3 R2
R1
R1 N O 542
R5 OH PhSeCl (1.1 equivalents) MeOH-CH2Cl2 R4 0 to −78 °C
O N O 543
R4
R1
R2
R2
SePh R5
SePh
R3
R2 R3
O N
O N
+
R5
R4
O 544
O
R3 R5
R4
545
R3 R2
R1 O TsN 546
R5
R4
Scheme 143
In 2000, Nicolaou and coworkers reported a method for the solid-phase construction of 2,2-dimethylbenzopyrans employing a selenium-based linking strategy wherein the loading step constitutes a key ring-forming reaction. Once the benzopyrans form, they can be elaborated to a variety of natural products and analogs thereof. Finally, it is easy to cleavage the resin and functionalize in high purity and efficiency (Scheme 144).156 The hepta-acetate of the natural product macropylloside D is synthesized. Using the same strategy, some examples of potential pharmaceutical candidates incorporating the 2,2-dimethylbenzopyran moiety are synthesized.157 In the total synthesis of phytuberin, an unprecedented 4-exo selenocyclization of a homoallylic alcohol affording oxetane derivatives is developed (Scheme 145).158 In the total synthesis of leucascandrolide A, Carreira and coworkers constructed a 2,6-trans-substituted tetrahydropyran by selenium-mediated intramolecular cyclization in a high yield (Scheme 146).159 It is the first example of a stereoselective synthesis of a 2,6-trans-disubstituted tetrahydropyran mediated by a bulky Se-electrophile. In the field of Se-induced cyclization, the use of catalytic selenium electrophiles is reported.160 Butenoic acids 558 are exposed to 5 mol% diphenyl diselenide and stoichiometric [bis(trifluoroacetoxy)iodo]benzene in acetonitrile affording butenolides 559 in high yields (Scheme 147).160 When a catalytic amount of Lewis base is used, significant rate enhancement is observed in the typical selenolactonizatin reactions (Scheme 148).160b The asymmetric synthesis of cyclic ethers by selenocyclizations has attracted broad interest in recent years, especially in the total synthesis of natural products.161 In the total synthesis of salinosporamide A, Danishefsky and coworkers used a selenocyclization with an in situ formed nucleophilic hydroxyl group as a key step (Scheme 149).162 Kim and coworkers accomplished an asymmetric total synthesis of trilobacin via organoselenium-mediated oxonium ion formation/SiO2-promoted fragmentation (Scheme 150).163
Electrophilic Cyclization
469
R4 R4
OH
R3
R1
SeBr (0.33 equivalent) CH2Cl2, 0−25 °C
R3
Se
R2
O
Me Me
R1 548
R2 547
OAc AcO AcO
O
O
O OAc AcO AcO
O
O OAc MeO
O
Me Me
549 Hepta-acetate of macropylloside D Scheme 144
O
554 (1.5 equivalents) TsOH (50 mol%)
O O
COOR2
OH
O O
DCM, r.t., 6.5 h
OH
OH
SePh
OR1 550
552
551
O O O 553 Phytuberin
N Se
OAc 554
O
Scheme 145
Very recently, Kim and coworkers completed the first total syntheses of both enantiomers of the marine natural product elatenyne as well as its double-bond isomer (E)-elatenyne (Scheme 151).164 Selenocyclization was used for the construction of two furan rings. The dibrominated 2,20 -bifuranyl 582 was obtained in 70% yield through exposure the substrate 577 to PhSeBr, activated silica gel and potassium carbonate. The reaction of (E)-N-benzyl-1-(2-benzylidenecyclopropyl)methanamine with PhSeBr stereoselectively gives ring-closure product 1-phenylselenenyl-2-aryl-3-azabicyclo[3.1.0]-hexane in good yields at room temperature (Scheme 152).77 An application of electrophilic selenium reagent N-PSP to promote a cyclization with an internal nitrogen nucleophile is reported by Yao and coworkers in the total synthesis of chloptosin. The diastereoselective selenocyclization and oxidative deselenation successfully serve as the key steps in the effective bidirectional synthesis of the core amino acid in this work (Scheme 153).165 Ley and coworkers developed an interesting application of the selenocyclization of amines to construct the important 3ahydroxypyrrole[2,3-b]indole core. This method has been applied successfully in the total synthesis of okaramine C (Scheme 154).166 An improved procedure for the selenium-mediated cyclization of alkenyl-substituted b-dicarbonyls to form a variety of bicyclo[3.3.1]nonan-9-ones has been developed for the synthesis of bicyclic natural products from the Guttiferae classification by the Nicolaou group (Scheme 155).167 The reaction proceeds successfully both in solution and on solid support, and the behaviors is closely correlated almost in the all cases. Wirth and coworkers reported a new cyclization of b-keto ester-substituted stilbene derivative 605 using PhSeCl in the presence of Lewis acid FeCl3 (Scheme 156).168
470
Electrophilic Cyclization
Me OTBS O
O
OH
TIPPSe
OMe O
O
Me OTBS OH
OH
O
OH
(TIPPSe)2 (2.1 equivalents) Br2 (2.0 equivalents) Base (5.0 equivalents)
Me Me
O
O 556a dr = 12:88 56a to 556a
+
DCM, −78 °C, 1 h Yield = 74%
OMe
O Me Me
OH
Me OTBS
O
O
555
OH OH
TIPPSe
OMe O
O
O OMe
Me
HN
Me Me
O
O 556b
Me O
O N O
O O
O
Me
Se TIPPSe =
OMe
O 557
Leucascandrolide A
Base = 2,6-di-tert-butyl-4-methyl pyridine
Scheme 146
Shaw et al. developed a new methodology for the synthesis of substituted tetrahydroquinolines with Sc(OTf)3 as an effective and practical precatalyst. Two rings, three bonds, and three stereogenic centers with excellent stereo- and regiocontrol were constructed in a single step (Scheme 157).169
4.07.3.2
Cyclization Involving Alkynes
Electrophilic cyclization of 1-(1-alkynyl)-cyclopropyl ketones affords highly substituted furans in good to excellent yields under mild conditions (Scheme 158).59 The methodologies of selenocyclization and sulfenylcyclization of alkyne have also been widely investigated by Larock and coworkers, and some of the typical examples are shown in Schemes 159.101,170
4.07.3.3
Cyclization Involving Allenes
Ma and coworkers developed a facile and effective synthesis of b-organoselenium-substituted butenolides from 2,3-allenoates and PhSeCl in water (Scheme 160).171 A convenient and highly efficient method for the preparation of b-organotellurobutenolides via ArTeCl-induced electrophilic tellurolactonization of a-allenoic acids is developed by Huang et al. (Scheme 161).172 The cyclization of allenylcarbinol 573 with PhSeCl in DCM afforded a single selenophenyl dihydrofuran 574 in 66% yield along with 17% of the presumed (E)-allylic alcohol 575 (one isomer). Both AgNO3 and NBS could promote the cyclization in good yields with high stereoselectivity (Scheme 162).173
Electrophilic Cyclization
R
CO2H
558 R = alkyl,aryl
(PhSe)2 (5 mol%) PhI(OCOCF3)2 (1.05 equivalents)
471
O
O R
CH3CN, r.t. Yield = 49−96%
559
(PhSe)2, PhI(OCOCF3)2 O
O R
OCOCF3 559
R
Ph
I
SePh 562
PhI
O
O PhSe CF3COO− H I Ph OCOCF3 561
PhSe+CF3COO− 563
R
PhI(OCOCF3)2
O O
PhSe
560
R
558
CO2H
Scheme 147
R
CO2H 564
+
PhSe N O
O O
Lewis base (10 mol%) CH2Cl2, 23 °C, 3 h
565
O
R PhSe 566
R = Ph Lewis Base: (Me2N)3P=O (Me2N)3P=S (Me2N)3P=Se None
Yield = 55% 89% 95% 8%
Scheme 148
4.07.4
Hg-, Ag-, Au-, and Pt-Catalyzed Electrophilic Cyclization
Besides the traditional electrophiles mentioned in Figure 3(a)), transition metal, as a p-acid catalyst, could also activate C–C multiple bond via coordination, which is fundamental to organometallic chemistry (Figure 3(b)). The M þ could play the same role as E þ to induce the cyclization. The Wacker process for the conversion of ethylene into acetaldehyde is a classic example of an efficient electronphilic-type cyclization that begins with the coordination of ethylene to PdII, which activates the ethylene moiety toward nucleophilic attack by water.174 Till now, Pd, Pt, Hg, Au, and Ag have been employed to induce the cyclizations. Besides palladium, which has developed into a diversity and complicated system, mercury-, gold-, silver-, and platinum-catalyzed electrophilic cyclization used in the synthetic applications will be discussed in the following section.
4.07.4.1
Mercury-Catalyzed Cyclization
Cyclization promoted by mercury salts is of certain synthetic interest, owing to the easy replacement of the mercury-containing residue by an oxygen or nitrogen nucleophiles. There have been numerous synthetic applications of the reaction, and some reviews have been published.175 A 60 (R)-hydroxymethyl derivative of the locked nucleic acid (LNA)-thymidine monomer has been synthesized by a stereoselective mercury cyclization, and there has been subsequent use of TEMPO as a radical scavenger. It is finally reduced by zinc and HOAc to give compound 638 in an yield of 83% (Scheme 163).176
472
Electrophilic Cyclization
PMB CO2Bn
PMB CO2t-Bu O N O
O
N
CO2t-Bu PhSeBr (4.0 equivalents) AgBF4 (4.0 equivalents)
O
PMB CO2Bn N CO2t-Bu
O BnOH (4.0 equivalents) CH2Cl2, −20 to 0 °C
CHO HO 567
O
SePh
OBn 569
568
Yield = 74%, an anomeric mixture, 12:1
H O NH
Cl
OH C O
O Me 570 Salinosporaminde
Scheme 149
PMBO H BnO R1
OH H
PhSe
PhSeCl (5.0 equivalents) OBn K2CO3 (6.0 equivalents) R2
CH2Cl2, SiO2, r.t., 24 h, Yield = 83%
571
BnO
H
transannular attack
H O H R1
R1 = n-C10H21; R2 = (CH2)5OBn
H
PhSe PhSeCl
OH H
OBn BnO
R2
Cl
H O H R1
OH H
OBn R2
573
572
H
SePh H
H
O H BnO R1
O H H R2 574
n-C10H21 H OBn
OBn
O
H H
O
H
OBn OBn
575
O O
MC Threo
HO H O H H O H
Erythro
Threo
trans Trilobacin
cis
HO 576 Scheme 150
Stereocontrolled routes to 2,3-dihydro-4H-pyran-4-ones by the Hg(II)-catalyzed rearrangement of 1-alkynyl-2,3-epoxy alcohols in acidic media has been developed by Marson and coworkers (Scheme 164).177 Deslongchamps and coworkers demonstrated that the Hg(II) catalysts are highly efficient and economical (HgCl2) by utilizing a simple experimental procedure for the synthesis of various saturated and unsaturated spiroketals and furans (Scheme 165).178
Electrophilic Cyclization
PhSe
Br
BnO
O
H
3
H OH
Me BnO
DCM, r.t., 20 h
577
O
3
O
Br
H
H
Me 579
578 H O
BnO
O
H
O 3
H OH
O
BnO
BnO
3
SePh H SePh
PhSeBr
H SePh
Br
Me PhSeBr, SiO2, K2CO3
473
3
Br
O
Br
H
Me
Me Br
581
580
Yield = 70% Br
O H Br
Br
O H
BnO
Me
H O
Me
H O
Br
583
582
(E )-elatenyne Scheme 151
Ar
BnHN
PhSe Ar
PhSeBr (1.2 equivalents) CH2Cl2, r.t., 1 h Yield = 72−85%
H
584
H N Bn 585
Ar = Ph, p-MeOC6H4, p-BrhC6H4, o-MeOC6H4, o-BrC6H4 Scheme 152
Boc N
t-BuO
BocHN Cl t-BuO2C CO2t-Bu
Na2SO4, CH2Cl2, r.t. Yield = 89%
NHBoc 586
H N
HN
N
O O
O O
N NH
Scheme 153
BocN
O O
O PhSe NBoc
BocN SePh O
N Boc
H3CO
N H
Cl
N-PSP (10 equivalents) PPTS (2.0 equivalents)
NBoc Cl
Ot-Bu 587
HN N
OH H N
HN
Cl HO
N
O N
OH NH
Cl 588 Chloptosin
N H OH
O N H
O O
O
O N
H N
N Se
O O NH N-PSP OCH3
474
Electrophilic Cyclization
CO2Me
SePh H
N-PSP, PPTS, Na2SO4
NHZ
DCM, Yield = 93%
N Boc 589
HO
N
N Boc H 590
CO2Me
NZ
H O N
HO
NH
H O
N H Boc
NH
H NH
CO2Me
591
592 Okaramine C Scheme 154
PhSe X or X.Se
OAc O R3
R1 R2
R1
O SePh
SnCl4, −23 °C Yield = 65−98%
593
R2 R3
O 594
OH O
O
O i -Pr
O
595
Garsubellin A Scheme 155
Kim and coworkers developed a facile method for the synthesis of 3-(alkylamino)-5-arylthiophenes having acyl-, aroyl-, or ethoxycarbonyl substituents at C-2 using thioaroylketene S,N-acetals, mercury(II) acetate, and active methylene compounds (Scheme 166).179 Bhattacharjya and coworkers describe Hg(II)-mediated reaction of O-propargyl glycolaldehyde dithioacetals and an expedient general route to 6H-pyran-3-ones (Scheme 167).180 An efficient method for the construction of dihydroquinoline derivatives possessing a quaternary carbon center is developed by an application of Hg(OTf)2-catalyzed vinylogous semi-pinacol-type rearrangement. The reaction was found to be specifically catalyzed by mercury salt via a bicyclic aminal (Scheme 168).181 Hg(OTf)2-catalyzed arylene cyclization was achieved with highly efficient catalytic turnover (up to 200 times) by Nishizawa’s group. The reaction takes place via protonation of allylic hydroxyl group by in situ formed TfOH of an organomercuric intermediate to generate a cationic species (Scheme 169).182 In 2007, Nishizawa and coworkers report that a 10:1 mixed reagent of Hg(OAc)2 and Sc(OTf)3 showed remarkable catalytic activity for the Friedel-Crafts-type cycloisomerization of 2-(4-pentynyl)furan (Scheme 170).183 The actual reacting species is presumed to be Hg(OAc)(OTf), which is efficiently generated in situ by mixing the two reagents. Cycloisomerizations of allenynes to allenenes have been investigated in the presence of [Hg(OTf)2] in MeCN. It is quite effective for constructing terminal 1,6-allenynes (Scheme 171).184
Electrophilic Cyclization
475
OH O
O
CO2Et
PhSeCl (2.0 equivalents) FeCl3 (1.1 equivalents)
OEt
DCM, −78 °C
R
R 606
R = 4-Me-C6H4 605 Cl3 Fe O O
OH CO2Et OEt
Se
Ar
Ar
SePh 608
Ph 607 OH
Ph Se
OH
OH CO2Et
CO2Et
Ar
Ar
CO2Et
Ar
SePh
609
611
610
Scheme 156
R
R Sc(OTf)3 (12 mol%) PhXCl (1.2 equivalents)
N
Ns
CH3NO2, 23 °C, 16 h Yield = 60−88% X = S or Se
NNs
PhX
H
612
613
Scheme 157
R1
O R3
R2
NuH PhSeBr (1.2 equivalents) r.t., 1 h, Yield = 41−82% NuH = MeOH or Br
524
R2
R1
O R3
Nu 525
SePh
Scheme 158
Yamamoto and coworkers described the preparation of solid-supported silaphenylmercuric triflate. Several examples of silaphenylmercuric triflate-catalyzed reactions such as indole synthesis, furanoyne cyclization, arylyne cyclization, and tandem carbocyclizations have been developed (Scheme 172).185 An efficient synthesis of hippuristanol and some of the close analogs has been achieved from readily available hecogenin acetate through an unprecedented Hg(OTf)2-catalyzed cascade spiroketalization as the most convenient strategy (Scheme 173).186 In the total synthesis of (7)-thallusin, homofarnesyl acetate performs cyclization using Hg(OTf)2.PhNMe2-induced olefin cyclization in an excellent yield (Scheme 174).187
4.07.4.2
Silver-Catalyzed Cyclization
Mercuric salts were used for more than 70 years, leading to many applications to intermolecular and intramolecular additions of various nucleophiles to unsaturated C–C bonds. Because of the high toxicity of mercuric salts, several other catalysts are
476
Electrophilic Cyclization
O
O OR1
E+
(1.2 equivalents)
O
DCM, r.t., 0.5−1 h R2 614
(1)
R2
Yield = 60−95% E+ = p-O2NC6H4SCl, PhSeCl
E+ 615
OMe
E+ (2.0 equivalents)
R1
O
DCM, r.t., 3 h Yield = 60−95%
R2 616
R2
R1
E+ =
E+ (1.2 equivalents) NuH (1.2 equivalents) K2CO3 (1.0 equivalent)
O
Nu Y O
DCM, r.t. Yield = 65−74%
R
618
E 617
p-O2NC6H4SCl, PhSeBr
Y
(2)
(3) R
619
E
Y = H, Me NuH = R1OH, PhNMe2, etc. E+ = p-O2NC6H4SCl, PhSeBr R = Ph, alkyl, alkene N
OMe
N O
PhSeBr (3.0 equivalents) Ph
DCM, r.t., Yield = 88−91%
R R = Ph, alkene
R
(4)
Ph SePh
620
621
SMe
E+ (1.5 equivalents)
R1
S
(5)
R2
R1
DCM, r.t., 10 min R2 622
E
Yield = 60−100%
E+ = p-O2NC6H4SCl, PhSeCl
623
SeMe
Se
PhSeBr (1.1 equivalents) R
622
R
DCM, r.t., 0.5 h Yield = 84−95%
(6)
SePh 624
R = Ph, alkyl, alkene SMe
O
H3COOC S
PhSeCl (1.5 equivalents)
O
DCM, r.t., 1 h
(7)
SePh 626 Yield = 56%
H3COOC 625 N
SePh 627 Yield = 44%
tBu N PhSeCl (1.5 equivalents)
MeO 628
Scheme 159
SMe
+
DCM, r.t., 1 h Yield = 70%
OMe (8)
SePh 629
Electrophilic Cyclization
H N
477
N PhSeBr (2.0 equivalents) NaHCO3 (2.0 equivalents)
SePh (9)
MeCN, r.t. Yield = 74% OMe
OMe 630
631
Ph
p-O2NC6H4SCl (1.2 equivalents)
Sp-O2NC6H4
DCM, r.t., 0.5 h Yield = 92%
Ph
632
(10)
633
OH PhSeCl (2.0 equivalents) NaHCO3 (2.0 equivalents) MeCN, r.t., 2 h Yield = 36%
Ph 634
(11)
SePh Ph 635
Scheme 159 (continued)
R1
R3
R2
COOEt 569
PhSeCl (2.0 equivalents) CH3CN/H2O = 10/1, r.t. Yield = 22−100%
R3
PhSe R1 R2
O
O 570
R1 =
Ar, alkyl R2 = H, Me R3 = alkyl
Scheme 160
R1
R3
R2
CO2H
ArTeCl (1.1 equivalents) MeCN, r.t., 5−30 min Yield = 79−94%
571 R1 = aryl, R2 = H, R3 = alkyl
R3
ArTe R1 R2
O 572
O
Scheme 161
developed. The silver salts are proved to be the most efficient catalysts. Cyclization reactions exhibit high interest in organic synthesis, especially when starting from alkynes or allenes since the cyclization products retain an olefin, which can be further manipulated, opening a wide variety and diversity of applications. Moreover, the nature of the cyclization products can be varied by changing silver counterion and/or reaction conditions, and many intramolecular heterocyclizations proceed with high diastereoselectivities. There have been many reviews summarizing this kind of reaction.188 Silver-induced cyclization reactions have been used in the total synthesis widely used in recent years. In the total synthesis of (þ)-pamamycin-607, silver-assisted iodoetherification is proved to be a key step for its high enantioselectivity. The tetrahydrofurans rings with complete cis-stereoselectivity are formed from silylated hydroxalkene and iodine in the presence of silver carbonate (Scheme 175).189
478
Electrophilic Cyclization
OH MeO2C (S) H C7H15 (R)
C7H15
H
Conditions a, b, or c
H MeO2C
CH3
CH3 H
O
573
MeO2C
X
SePh
H
+
C7H15 Cl 575
574 66% 84% 66%
a. PhSeCl, CH2Cl2, r.t, 5 min; X = SePh b. AgNO3, Ca2CO3, MeOH-H2O, r.t., 48 h; X = H c. NBS, CH2Cl2, r.t., 48 h; X = Br
OH
H CH3
17%
Scheme 162
Nu
Nu
E+
M+
E+ = Halogen, S, Se, Te (a)
M+ = Transition Metal (b)
Figure 3 Electronphilic activation.
O
O NH
BnO
N
O
NH Hg(TFA)2 (1.5 equivalents) THF, r.t., 12 h Yield = 98%
O BnO
BnO
N
O
O
OH
BrHg
636
BnO O 637
1. TEMPO, NaBH4, 77% 2. Zn, HOAc, 83% O NH BnO
N
O
O HO
BnO
O
638 Scheme 163
R3
H
639 Scheme 164
R2
OH R1
O
R3
R2
R4
HgO in dil. H2SO4
OH O R1 H 640
Yield = 50−80% R4
H R3 R2
O R1 641
R4
Electrophilic Cyclization
O
Hg(OTf)2 (10 mol%)
O
m 643 Yield = 90−94%
CHCN3, r.t. R1 = OH, R2 = H R2
(II)Hg R1
R
CHCN3, r.t. n = 1, R2 = OH, R3 = H
R3
m
O
Hg(OTf)2 (10 mol%)
OH n
R3 n
1
m 644 Yield = 90−96%
642
Hg(OTf)2 (10 mol%)
O
CHCN3, r.t. R1 = OH, R2 = OH
O
R3 n
m 645 Yield = 95−98%
Scheme 165
O R3
NHR1
O R4
647
COR3 S 649
Ar NHR1S
Hg(OAc)2 (1.0−1.5 equivalents)
R2S
Ar
O
O
Yield = 38−92%
DCM, r.t., 1 h COOEt
646
NHR1
648
COOEt S 650
Ar
Yield = 82−94% Scheme 166
HgCl2 or Hg(OTFA)2 (10 mol%) base (2.0 equivalents)
S O
S
Ph Me 651
Solvent-H2O (4:1), 25 °C, 4 h Yield = 0−53%
Ph Me
R S
O
O
S
R
S S
R
S
O
Scheme 167
HgX
655
HgX S
O
HgX
O 654
O 658
653 HgX
R
O
652
S R
O
R S
O
S
S
656
657
479
480
Electrophilic Cyclization
n-Bu Hg(OTf)2 (1.0 mol%) O NH OMe Ts
CH2Cl2, r.t., 6 min
TfO Hg
n-Bu
O OTf
n-Bu
O N Ts
Yield = 98%
659
N Ts 661
660
Scheme 168
OMe OMe
Hg(OTf)2 (0.5 mol%) PhMe, reflux, 5 min Yield = 96%
OMe
OMe
OH 663
662
OMe
OMe
OMe
OMe Tf OH
(TfO)2Hg
OMe
H
OMe
TfOHg
OH 664
OMe
TfOHg OH
TfO−
OH
665
OMe
TfOHg
666
OH2 667
Scheme 169
Hg(OAc)2 (5.0 mol%) Sc(OTf)3 (0.5 mol%)
O
O
CH3CN, r.t., 20 min Yield = 80% 668
O
R
O
O
O
HgOAc 670
669
HgOAc
HgOAc 671
672
HgOAc 673
Scheme 170
The Ag þ -mediated cyclization of allenic alcohols has been applied to the synthesis of various natural products and analogs. Verrucosidin, citreoviridin, and their metabolite citreal have been prepared via an Ag þ -promoted stereoselective cyclization of a dihydroxyallene (Scheme 176).190 Standaert and coworkers reported a concise and modular synthesis from the Garner aldehyde and proceeding in seven steps to furanomycin. The key steps include a stereoselective acetylide addition and the Ag þ -mediated cyclization of an a-allenic alcohol to construct the trans-2,5-dihydrofuran (Scheme 177).191
Electrophilic Cyclization
R3
R3
H(D)
R3 R1
Hg(OTf)2 (10 mol%) (D)H
MeCN, r.t., 1 h
R2
X
R3
Yield = 22−79%
R2 X
R1
674
675
X = NTs, NMts, C(SO2Ph)2 R1 = −H, −Me, −Et, −Ph R2 = −H, −Me R3 = −H, Me, −(CH2)3−, −(CH2)5−
Hg(OTf)2
R3
H(D)
R3 TfOHg R3
TfOHg R1
TfOHg R1
R2
X
R3 R2
X
676
R3
R3
R3
R3
R3
OTf− R1
X 678
677
1 R2 R
R2
X
R1
679
Scheme 171
MeO
Si
OMe
MeO
OMe
HgOTf (10 mol%) CH3NO2, r.t., 40 min
H
Yield = 99%
682
681 Si = Silicycle, 230−400 mesh, loading 1.62 mmol g−1 Scheme 172
OH BnO H
HO H 683
OH
OTHP
H 684
BnO
H
Hg(OTf)2 (20 mol%) H2O (3.0 equivalents) CH3CN, 5 min, r.t. Yield = 90% OH O
OH O
BnO
HO H H
BnO
O H HO
685
Scheme 173
H
H
H
R3
O H
686 H Hippuristanol
X 680
R2
481
482
Electrophilic Cyclization
OAc
OAc 1. Hg(OTf)2.PhNMe2 (1.2 equivalents) CH3NO2, −20 °C, 3 h 2. LAH (3.0 equivalents)/THF 0 °C, 1 h 3. Ac2O (1.7 equivalents), DMAP (8.3 mmol%)/Py
687
H 688 Yield = 94%
COONa N COONa COONa O H 689
H
(±)-Thallusin Scheme 174
I O O
O
TESO TESO
I2, Ag2CO3
TESO
O
TESO O
Et2O, r.t. BnO
Yield = 81%
BnO
690
O
691
O
O O
O O
O
Me2N 692 (+)-Pamamycin-607 Scheme 175
The cytotoxic amphidinolide 702 has been obtained by a Claesson’s cyclization of 6-methylnona-4,5-dien-1,3-diol, derived from a chiral epoxyalcohol produced by the Sharpless asymmetric epoxidation (Scheme 178).192 The allene alcohol was treated with AgNO3/CaCO3 in aqueous acetone to afford the corresponding dihydrofuran with strict chirality transfer. As the first approach toward the cembranoid eunicin, a silver-mediated cyclization of a suitable functionalized allene was performed with the aim of controlling the stereochemistry in the construction of the tetrahydropyran ring (Scheme 179).193 The trans-bicyclic dihydro-2H-pyran within the tricyclic framework of eunicins was obtained from silver nitrate-promoted cyclization. The tetradecane ring system of the anticancer and antiparasitic bielschowskysin was ingeniously built up through a stereoselective [2 þ 2] photocycloaddition of an alkenyl alkylidenebutenolide. Silver-catalyzed cyclization of the corresponding ynenoic acid is used for the construction of g-alkylidene butenolide (Scheme 180).194
Electrophilic Cyclization
OTBS Me Me
Me
AgNO3 (0.8 equivalent) CaCO3 (0.8 equivalent)
TBSO
O Me
H2O/Acetone = 2:3 r.t., 20 h Yield = 81%
OH
Me
694
Me
693
Me
HO Me
Me
HO
O
OMe
O
Me
O
695 Citreoviridin
Scheme 176
O
Boc N
OH
H3C
AgNO3 (1.0 equivalent) CaCO3 (2.0 equivalents)
Boc N
Acetone:H2O = 10:3 overnight, dark Yield > 95%
O
O
697
696
N H3C
OH H
O 699 Furanomycin Scheme 177
AgNO3 (1.1 equivalents) CaCO3 (2.0 equivalents)
OH
TBDPSO
Actone:H2O = 4:1 15 h, dark Yield = 90%
700
Me
O O
O
Me O
Me
702
Amphidinolide Scheme 178
O TBDPSO 701
Me
Me
O
O H 698
NH2
O
H3C
Boc
483
484
Electrophilic Cyclization
O
HO HO
O O
703
AgNO3 (1.1 equivalents)
HO
Acetone r.t., 7 h Yield = 70%
O O
H
O O
704
O
O
O
O
705 Scheme 179
Mes O
Mes
O Me
AgNO3 (4.6 mol%) CO2H
CO2Me
MeO2C
O
O Me
MeOH, r.t., 1 h Yield = 35% 707
Me
O
706 O
Me HO
H
Me
O O
H O 708
O
Bielschowskysin Scheme 180
b-Allenic acids are used for the synthesis of d-lactones in the presence of AgNO3 and DIPEA. The reaction is proved to be an efficient asymmetric synthesis of the naturally occurring antibiotic ()-malyngolide (Scheme 181).195 The cyclization of a-allenones was also successfully applied in the total synthesis of natural products. The furanocembranes, kallolide A, is obtained through Ag-catalyzed cyclization via key steps, using a catalytic amount of AgNO3 in acetone, which led to a key furan building block in good yields.196 The same strategy is applied in the synthesis of kallolide B (Scheme 182).196 In the total synthesis of (þ)-longifolicin skeleton, sequential reactions of Pd-catalyzed hydrocarbonylation of a chiral homopropargylic mesylate and Ag þ -catalyzed cyclization of the intermediate allenic acid are carried out, and the desired product is successfully obtained (Scheme 183).197 Nagarajan and coworkers developed an efficient methodology for the synthesis of highly functionalized ellipticinium and ellipticine derivatives via an AgOTf-catalyzed cyclization of 2-alkynyl-3-carbazolylaldimines (Scheme 184).198 The total synthesis of clavepictines was skillfully designed and realized with Ag þ -catalyzed cyclization of a piperidinoallene as the key step affording the desired cis-quinolizidine derivative in 48% yield (7% of vinyl isomer is obtained) (Scheme 185).199 When the substrate is modified, the cyclization yield is significantly improved as well as the diastereoselectivity, and no other isomer could be detected. During the synthesis of the antibiotic anisomycin, Ag-catalyzed cyclization of an alkoxyaminoallene was the key step (Scheme 186).200
Electrophilic Cyclization
nC H 9 19
H Me
AgNO3 (10 mol%) i-Pr2NEt (5 mol%) Yield = 80%
OBn CO2H
485
Me nC
O
O
9H19
OBn
710
709 Me nC
9H19
O
O OH 711 (−)-Malyngolide
Scheme 181
H
Me
Me AgNO3 (10 mol%)
ODPS
O
H
Acetone, reflux, 1 h Yield = 88%
OBz
O O
OBz 713
712
Me Me
OSEM O
OSEM O
AgNO3 (1.5 equivalents) Acetone, r.t., 1 day Yield = 60%
O O
H RO2C
714
R = H, CH2CH2TMS, Me 715 Me OH O O 716 O
Kallolide B
Scheme 182
4.07.4.3
Au- and Pt-Catalyzed Cyclization
Pt and Au [gold(III) and cationic gold(I)] show an exceptional ability to accelerate a variety of organic transformations of unsaturated precursors. These processes result from the peculiar Lewis acid properties of these metals: the alkynophilic character of these soft metals and the p-acid activation of unsaturated groups promote the intra- or intermolecular attack of a nucleophile. Due to the soft and carbophilic character, gold and platinium catalysts are particularly well suited for the selective activation of allenes in the presence of other reactive functionalities. In the past decades, great progress has been achieved in developing efficient and selective Au- and Pt-catalyzed transformations, and prodigious number of reviews are available on various aspects.201 This section is focusing on Au-catalyzed particular classes of synthetic reactions applied in total synthesis. The first total synthesis of the b-carboline alkaloids ()-isocyclocapitelline and ()-isochrysotricine by Pictet–Spengler reaction of a chiral THF with tryptamine is reported by Volz and Krause (Scheme 187).202 Key intermediate 2,5-dihydrofuran was obtained from the corresponding a,b-dihydroxyallene with complete axis-to-center chirality transfer by the use of only 0.05 mol% of gold(III) chloride in THF. Erdsack and Krause used Garner’s aldehyde as a precursor for a-hydroxyallenes, treated with 1 mol% of gold(III) chloride in THF, which undergo cycloisomerization to the dihydrofurans derivates. Subsequent modification affords analogs of the antibiotic amino acid furanomycin (Scheme 188).203
486
Electrophilic Cyclization
Me MOMO C14H29 O
MOMO H
Me
6
H
1. (CF3CO)2O, Py 2. Pd(PPh3)4, CO, H2O
MOMO C14H29
3. AgNO3, Et2O
OMOM
OH
O H MOMO H OMOM 718
Yield = 62%
717 (CF3CO)2O, Py
7
R
R O
OTFA
O PdII
H
721
720
719
R H2O
CO PdII
OH H 722
H
MOMO R=
O
AgNO3 Me Pd(PPh3)4
R
O
C14H29 MOMO H
O
Me HO
6
H
O
Me
OMOM
12
HO H
O
7
H OH
O
723
(+)-Longifolicin Scheme 183
Me
CHO Ph N Et 724
N
1. p-Toluidine (1.0 equivalent) MgSO4 (69.4 equivalents) DCM, reflux, 1 h 2. AgOTf (1.0 equivalent) DCM, r.t., 1 h Yield = 95%
OTf Ph
N Et 725 Ellipticine derivatives
Scheme 184
Krause and coworkers accomplished the first diastereo- and enantioselective total synthesis of (R,R,R)-bejarol and its (3R,5S,9R)-isomer. The gold-catalyzed cycloisomerization is used as a key step, which converts the enantiomerically pure bhydroxyallenes 739/740 to the corresponding dihydropyrans 741a/741b (Scheme 189).204 A cationic gold catalyst is used for activating the allene for nucleophilic attack of the pyrrole ring to deliver tetrahydroindolizine in a high yield with excellent chirality transfer, which is the precursor of alkaloid ()-rhazinilam (Scheme 190).205 In the Construction of the Communesin Ring, Funk and coworkers treated the alkyne 748 with AuCl(PPh3) to provide the enamine 749 via a 7-exo-dig ring closure with the nearby piperidine nitrogen (Scheme 191).206 Oh and coworkers reported a Pt-catalyzed domino process involving a Huisgen-type [3 þ 2] cyclization and subsequent insertion of the proposed platinum carbene intermediate into a benzylic bond to form highly complicated products that are difficult to access by other means. Byproducts 753 and 754 are obtained with PtCl2, PtCl4 in toluene, or PtCl2(PPh3)2 in DCE or dioxane. A possible pathway through a platinum carbene intermediate is proposed for the three products in Scheme 192.207
4.07.5
Conclusion
The electrophilic cyclization reaction is one of the most classic organic reactions. There are a huge number of works reported in the literature, and it is difficult to cover all of them. As so many methodologies were developed to construct all kinds of rings, the
Electrophilic Cyclization
H
C6H13 TESO H NH
TIPSO
AgNO3 (30 mol%)
H
Me
N
TIPSO
Me
Acetone:H2O = 1:1 r.t., 18 h Yield = 48%
H
OTES
726
C6H13
727 H N
RO
Me
C6H13
728 R = Ac R=H
clavepictine A clavepictine B
Scheme 185
ODAF ODAF
1. AgNO3 (0.2 equivalent) K2CO3, MeCN
TsHN
2. HPLC separation Yield = 46% 729
N Ts
OMe
OMe
730
R/S:2/1 mixture DAF = diacetonefructose
HO
HCl
OMe
OAc
N H
731
Antibiotic anisomycin Scheme 186
Me
AuCl3 (0.05 mol%)
OH
THF, r.t. Yield = 97%
OH BnO
2 732
BnO
2
O
HO de = 96%, ee > 98% 733
N Me Me N O 735 (−)-Isochrysotricine
Scheme 187
HO
H
N Me
MeI NaOH
N 734
O HO
(−)-Isocyclocapitelline
H
487
488
Electrophilic Cyclization
n-Bu
Boc N
R O
Boc N
AuCl3 (1 mol%) THF, 0 °C
H
O
H OH 736
n-Bu O
R
737 Yield = 86% 34%
R = Me t-Bu
H 2N
n-Bu O
R
H O 738 Analogues of (+)-furanomycin HO
Scheme 188
O OH
O +
O
OH
O
740
739
3:2 Ph3PAuCl (5 mol%) AgBF4 (5 mol%)
O
O O
+
O 741a
741b
O O O 741c Toluene, r.t., 10 min Toluene, −15 °C, 1.5 h THF, r.t., 2 h
O
+
O O 741d
741a 741b 741c/d 42% 35% 16% 42% 29% 2% 50% 35% <1%
OH 741a
O 742 (R, R, R)-Bejarol OH
741b O 743 (3R, 5S, 9R)-Bejarol Scheme 189
O
O
Electrophilic Cyclization
N
N AgNO3 (5 mol%) Ph3PAuOTf (5 mol%)
H Me
CH2Cl2, r.t., 16 h
Et
MeO
N Et
H [Au] Et O
Me
O 744
489
MeO2C
MeO 745
Me
746 Yield = 92% dr = 97:3
N Et
N O H 747 (−)-Rhazinilam Scheme 190
O H H N
O H
AuCl(PPh3) AgOTf, DCM 40 °C, 12 h
O H N
O H
Yield = 89% N
N HH
N
748
N HH 749
O O H
HN N
N
N HH
750 Communesin B Scheme 191
electrophilic cyclization becomes a valuable tool in organic chemistry. In recent years, the research on halocyclization is focusing on asymmetric methodologies and applications in natural product synthesis. Fluorocyclization has coursed more attention due to the excellent bioactivity of fluoro-containing molecules. Selenocyclization, tellurolactonization, and sulfenylcyclization have proved to be very efficient in introducing S, Se, and Te elements into the target molecules. Besides the traditional electrophiles mentioned in Sections 4.07.2 and 4.07.3, transition metal-mediated electrophilic-type cyclizations have been developed. The transition metal playing as a p-acid catalyst could also activate C–C multiple bond via coordination inducing the electrophilictype cyclization. The applications of mercury-catalyzed electrophilic cyclization and silver-, gold-, and platinum-catalyzed electrophilic cyclization in natural product synthesis have been summarized. Palladium-induced electrophilic cyclization is also a very powerful tool in the synthesis, and there are lots of reviews presented in recent years,208 which should be the topic of another big chapter. Lewis acid and Brønsted acid could also induce the electrophilic cyclization, and numerous applications in the synthesis of natural products have been reported in recent years.209 These reviews could draw an outline for electrophilic cyclization in a different way.
490
Electrophilic Cyclization
H O
H OBn
H
+
H
Toluene, 120 °C, 4 h 751
PhCOO
O
PtCl2(PPh3)2 (5 mol%)
O
H
Ph 752
H O
+
H
H
754
753
Yield = 77% H
O O
Pt+
Pt PtII
OBn 751
OBn
O
O
Ph 756
PhCOO
757
H
H
a
Pt
O
Ph
755
H
H
O
H
O
O
O
b
PtIIB: H
H 753 1. NaOH 2. PCC
Pt H-B:+ Ph
Pt
a
O
760 b
Ph H 758 PtII +
H Pt O
B
H
O Ph
759
PhCHO + B:
O H
H
H
O
O H H
761
754
H
O Ph 751
Scheme 192
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492
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