Chapter 5.1 Five-membered ring systems: Thiophenes & Se, Te analogs

Chapter 5.1 Five-Membered Ring Systems: Thiophenes & Se, Te Analogs RONALD K. RUSSELL The R. W. Johnson Pharmaceutical Research Institute, Raritan, NJ, USA and

JEFFERY B. PRESS Emisphere Technologies Inc., Hawthome, NY, USA ,

5.1.1

i

i,ill i

i

INTRODUCTION The study of thiophenes has continued to receive significant attention during the period covered by this review (late 1993 and 1994). An increase in the number of thiophene derivatives under study in preclinical and clinical situations, further progress in superconductor research as well as continued need to understand the commercially important hydrodesulfurization (HDS) process underscore the importance of research on thiophene systems. The organization of this review follows that of the past, beginning with a discussion of electronic and physical properties of the thiophene ring and subsequent discussion of substitution and ring formation. The use of thiophene derivatives, both as intermediates as well as in various applications, is then discussed. The number of references to selenophene continues to be very modest and most of these references are incorporated into the pertinent sections in the discussion of thiophene chemistry. An interesting aspect of thiophene chemistry is the differences in reactivity between thiophene and its more aromatic isostere, benzene, and its less aromatic isosteres, furan and pyrrole. One interesting facet of this contrast is that metal cation-exchanged clay catalyzed Diels-Alder reactions work for furan and pyrrole to produce reaction with o~,~-unsaturated carbonyl compounds; the thiophene examples do not react <94JCS(Pl)761>. 5.1.2 E L E C T R O N I C S AND DESULFURIZATION Studies to further understand the electronic and spectral behavior of thiophene and its derivatives have continued. Vibrational spectroscopic studies of furan, pyrrole and thiophene have shown that earlier frequency assignments are correct and idealgas thermodynamic properties differ little from calorimetric data <94MI765>. Spin-spin couplings between 13C nuclei and 5-membered ring heteroaromatic ring systems may predict levels of aromaticity in these heterocycles. Of the 11 rings studied, only 1,2,3-thiadiazole, 1,3-thiazole and 1,2-thiazole are more aromatic than thiophene <94MI62>. The electronic structure of angular dithien,~pyridine isomers shows that they may be divided into two groups represented by I and 2. The mode of annelafion is reflected in bond lengths of both thiophene and pyridine rings <9MCS(P2)2045>. Further studies of b-side 82

Five-Membered Ring Systems: Thiophenes & Se, Te Analogs

83

contra c-side thiophene annelation to benzene or pyridine show electrophilic substitution, metallation and cycloaddition reactions occur at positions predicted by theoretical calculations <94JHC641>. Through-space interactions of phenylseleno- and phenylthio- moieties on 1,9-dibenzothiophene (3)cause significant distortion while dibenzofuran analogues are nearly planar <94JOC7117>. R1

1

2

R2

3

Studies of hydrodesulfurization (HDS) continue unabated. An excellent review of this process using transition metal complexes to remove sulfur (usually present as thiophene, benzo- and dibenzothiophene) from petroleum feed stocks discusses various mechanisms of heterogeneous HDS (for example, Scheme 1 depicts hydrogenolysis) <94MI287>. Another review models the HDS reaction of thiophene on a MoS2/AI203 catalyst at the molecular level <94JC288>. Fenske-Hall molecular orbital calculations for transition-metal complexes of thiophene show thiophene to be a poorer electron donor but better electron acceptor than cyclopentadienyl (Cp) complexes <94OM2628>. HDS of dibenzothiophene using Ni-Mo/AI203, Mo/AI203 and Ni/AI203 has been studied using a 35S label and shows that sulfur bonded to both Mo and Ni is more labile <94JC171>. Scheme 1

4-

s. I

E!I

Mo--- S - - - M o - - S -

s. , Mo

~

iT

s.

Mo--- S - - - M o - S -

Mo

sII

T

s

II M o - - S--- M o - S-- Mo

Chemistry studies of Ir, Co, Cr and Re complexes of thiophene have shown them as good model systems for HDS. Thermolysis of thiophene complex 4 produces thioallyl complex 5 by stereospecific endo migration. Further heating causes liberation of 2,5- and 2,3-dihydrothiophene and [(PPh3)2Ir(CO)3]PF6 <94OM721>. Reaction of TI4-benzene iridium complexes with benzo[b]thiophene produces the unprec~ented complex 6 which rearranges upon heating to a iridabenzothiabenzene complex <94JA4370>. Heating of [(C5Me5)IrH3]2 in thiophene gives a desulfurized cleavage product which liberates butadiene upon treatment with CO <94JA198>.

P 4

.,

,p

(D) H

5

S

84

Five-MemberedRing Systems: Thiophenes & Se, Te Analogs

Reaction of Cp*Co(C2H4)2 with thiophene produces a C-S insertion product (Eq. 1) which further reacts with H2S to produce a butadienedithiolate complex <94JOM311>. Since thiophene and its derivatives are the most difficult to desulfurize during HDS, presumably due to aromaticity, Cr complexes of both thiophene and selenophene were studied; rotational barriers for 7 and its selenophene isostere are larger than for Cr(CO)3(q6-arene) complexes as a consequence of chromium-heteroatom interactions <94OM1821>. Bimetallic Re complexes of benzothiophene (8) protonate on the Re coordinated with sulfur <94OM179>. Reactions of q l(S)-coordinated thiophenes with base produce thienyl complexes which form thienylcarbene complexes upon acidification (Eq. 2) <94JA5190>. S

+

CP*C~

(

/'~

~

Eq. 1

Co--

Cp* O~_

Cp*

~O

R--~C_r~'~ R

Re- CO

,,

CO ,, de" CO Op ~CO

C III O

7

+

I

[Re]

]

Base _

-H+

$

[Re]

o

_ ~_ .H§ .

o] +

[Re]

Eq. 2

Re = Op(NO)(PPh3)Re

5.1.3

RING SUBSTITUTION Substitution reactions may be effected on saturated analogues as well as on aromatic species. An interesting reaction of Tebbe's reagent with succinic thioanhydride derivatives 9 rapidly leads to monoolef'mation and, more slowly, to bisolefination. Acidic isomerization of the bis-adduct leads to 2,5-dimethyl thiophene derivatives (Eq. 3) <94JOC494>.

~,~R=~

~ Cp'n(CHa)2 ....... ~

O~'-~ S / ' ~ O

R1

R2

pTSA = ~ H3

Eq. 3 CH3

9

Electrophilic reactions on the electron-rich, aromatic thiophene nucleus continue to provide a powerful mute to substituted derivatives. Comparison of positional selectivity of the heteroarenium ions derived from furan, pyrrole or thiophene suggest that ease of [3-substitution correlates with the relative stabilities N + > S + > O + <94H2029>. Freidel-Crafts reaction of 2,5dichlorothiophene with aromatic compounds produces 10 which may be used as a precursor to 2,3-diaryl and 3,5-diaryl thiophene derivatives (Eq. 4) <94BCJ2187>.

Five-Membered Ring @stems: Thiophenes & Se, Te Analogs

85

Ar

AICla ~ / CI

CI

~CI" ~ S ~ 10

AICI3

Ar Ar

1. H~

Ar AICls

SO2CI2

9

Eq. 4

CI

1

N-Halosuccinimides effectively halogenate thiophene using H + ion exchange or ultrasonic irradiation <94MI377>. Control of electrophilic phenylselenenylation of thiophene may lead to mono, di-, tri- or poly(phenylseleno)thiophenes which may be utilized synthetically <94T10549>. Reaction of perfluoroalkanesulfonyl chloride with thiophene catalyzed by RuCI2(PPh3)3 leads to 2-perfluoroalkylated derivatives with loss of SO2 <94SL69>. More detailed study of this reaction shows that it occurs with substituted benzenes and thiophenes but not with pyrroles <94JCS(P1)1339>. Electrophilic reaction of chlorosulfonylisocyanate with thiophene or indole produces N-chlorosulfonylamides which are converted to analogous nitrile derivatives by treatment with triethylamine <94T6549>. Nitrile ylide elcctrophilic reaction on thiophene leads to novel tricyclic derivatives (Eq. 5) <94JCS (Pl) 1193>.

Eq. 5 "C--N--" CPh

H

h

Methyl 4,5,6,7-tetrafluorobenzo[b]thiophene-2-carboxylate is oxidized by trifluoroperacetic acid or m-CPBA to form a 2,3-epoxysulfone; reaction with chlorine or sulfuryl chloride produces a 2,3-dichloride derivative <94JFC51>. HOF-MeCN is a novel oxidant which oxidizes a variety of thiophene derivatives to S,S-dioxides <94CC1959>. Bromination of thieno[c]fused 1,5-naphthyridines occurs with tetrabutylammonium perbromide <94H331> or with dibromoisocyanuric acid/sulfuric acid <94JHC521>. The ease of producing 2-1ithio- and 3-1ithiothiophene derivatives by halogen-metal exchange or by deprotonation leads to synthetically useful intermediates for a variety of reactions. Thus, 11, a precursor for electropolymerization reactions, forms by quenching 3-1ithiothiophene with the appropriate perfluoroalkyldimethylsilyl chloride <94AM637>. 3-Bromo-, 3,5dibromo- and 3,4,5-tribromo-2-thienyllithium derivatives form by brominelithium exchange and react with DMF to produce 2-carbaldehydes <94JCS (P1)2735>. Reaction of 2-thienyllithium with 2,3-O-isopropylidene-5O-trityl-D-ribofuranonse forms C-ribonucleoside i2 after deprotection <94CL265>. The 2-1ithio derivative of benzo[b]thiophene is exchanged for the 2magnesium bromide analogue which reacts with N-glycosyl nitrones to prepare (+)-(R)- and (-)-(S)-zileuton <94JOC6103>. 3-Lithiothiophene is stable in hexane at room temperature and reacts with diiodoethane, n-Bu3SiCl, (n-BuS-)2, allyl bromide and MeSSMe to give 3-iodo-, 3-tri-n-butylsilyl-, 3-n-butylthio-, 3-

86

Five-MemberedRing Systems: Thiophenes & Se, Te Analogs

allyl and 3-methylthiothiophene, respectively <94TL3673>. Mercaptophosphonate 13 undergoes an S~C phosphonyl group migration after deprotonation with LDA <94TL3083>. 2,5-Dibromothiophene and dihalobenzene react with Rieke metals to form intexmediates which react further with a variety of electrophiles <94SC2379>. Directed lithiation of thiophene 2imidates occurs exclusively at the 5-position which contrasts to the 2-oxazoline directing influence at the 3-position <94T4149>. CHs I HO S,tCH2CH2(GF2)sGFs CHs q , ~ $ ~ S ~ P(O-I-Pr)=

~

11

HO OH

12

15 Metal catalyzed cross-coupling reactions are powerful tools in organic synthesis and work exceptionally well for thiophene and its derivatives. Molecular wires are prepared by itcrative divergent/convergentprocessesutilizing acctylenic derivatives such as 14 which form by CI2Pd(PPh3)2 coupling of 2iodo-3-ethyl thiophene and TMS acetylene <94PP202>. Palladium-catalyzed coupling of 2,5-dibromothiophene with ethyl acrylate produces 2,5-thiophene diacrylate <94H759>. Coupling of 2-iodothiophene derivatives with 1,2di(tributylstannylethene) catalyzed by palladium complexes produce 15, a precursor to elcctrochromic polymers <94SM223>. Similar coupling of stannyl allenes produces 2-allenylthiophene <94SC789>. 2-Stannyl thiophene derivatives also react; palladium-catalyzedcoupling with 4-iodoisoxazoles is a route to 3-thienyl-2,4-pentanediones <94SC709>. 2-Stannylthiophene also couples with pyrimidinyl triflates to produce 16 <94H501>. R

14

TMS

15

R1

R

16

S'-'u

Photochemical processes also produce coupling reactions. Bithienyl 17 forms by irradiating 3-(2-thienyl)allyl acetate with the corresponding 2substituted-5-iodothiophene; the alcohol fails to react <94JCS(PI)I245>. Photochemical coupling of indene with 5-iodo-2-nitrothiophene produces the unusual substitution of the nitro moiety to form 18 (75%) and 19 (25%) <94TL633>. Other photochemical reactions of 2-iodo-5-nitrothiophene in aromatic solvent produce the expected awl coupling at the 2-position <94G195>.

17

lS, X=I 19, X-, H Other means of forming biaryl derivatives include the use of zinc/silvergraphite reaction with aryl and heteroaryl (including thiophenyl) iodides

Five-Membered Ring Systems: Thiophenes & Se, Te Analogs

87

<94TL1047>. "Higher order" cuprates composed of one or two heteroaromatic ligands undergo oxidative coupling <94TL815>. 3-Thienyl zinc bromide couples with 4-alkylphenyl iodide to produce a compound that electmpolymerizes to form an isotropic conducting polymer <94TL8329>. Nucleophilic displacement reactions also produce substituted thiophene derivatives. Thus, potassium carbonate induced reaction of methyl 3hydroxyphenylacetate with 3-bromothiophene produces 20 <94JMC1402>. Similarly, 21 forms by alcohol displacement of the 2-chloro analogue <94M927>. When salicylates are used in this reaction, 21 is the precursor to thienoannellated [1,4]benzoxazepines <94JHC1053>. 2-Methoxy-3nitrothiophene derivatives react with amines to form 22 <94H1529>. Diether 23 forms by phenoxide displacement of the dichloro precursor and provides the basis of thiophene-based poly(arylene ether)s <94MI3782>. Conductive crown ether 24 forms by di-displacement of 3,4-dibromothiophene <94PP269>. Lastly, CsF provides the fluoride source to displace 3-chloro-2-cyanothiophene to produce the 3-fluoro derivative <94SC95>.

o

C02Me

OR

20 NO2

21

X ' ~ N(CH2). A r O ~ s ~0 23 22


5.1.4 T H I O P H E N E RING FORMATION Construction of the thiophcne ring may be accomplished utilizing sodium sulfide, phosphorus pentasulfide, sulfur dichloride or sulfur as the heteroatom source. Bromination of methyl neopentyl ketone produces a bromomethyl ketone which reacts with sodium sulfide; pinacol coupling then forms 2S <94TL2709>. 2,2'-Dilithio-l,l'-bicyclooctenyl reacts with sulfur dichloride to form 26 <94TL9197>. Lawesson's reagent reacts with diketones to form thiophene derivatives such as 27 <94JOC4308> or 28 <94JOC3695>. Reaction of phosphorus pentasulfide with 7-hydroxyketones affords dihydrothiophenes <94OPP349>. 3-Trifluoromethyl derivative 29 forms by reaction of P4S 10 with ~,3,-unsaturated ketones <94JFC13, 94H819>. Decomposition of a diazo compound in molten sulfur leads to a thione which reacts with additional diazo material to ultimately provide a dicyclo[b,d]thiophene derivative <94SL217>.

HOOH I

I

25

~8__~

CH2.t.Bu /

Ph

P

26

Ph-

27

9Ph

88

Five-MemberedRing Systems: Thiophenes & Se, Te Analogs

R1 28 Ph

F

C02Me

Fs

29

3O

Sulfur dioxide trapping of photochemically-generated quinodimethane leads to dihydrobenzo[c]thiophene derivatives (Eq. 6) <94TLA743>. Mercaptans may also provide the heteroatom source for the synthesis of thiophenes. The lithium salt of an isoquinolinethiol reacts with dimethyl acetylenedicarboxylate (DMAD) to form 30 <94JFC143>. 2-Mercaptoacetate forms a variety of thiophenes including 31 <94H1299> or thieno[2,3d]pyridazines <94S669>. Reaction with malonaldehyde derivatives gives 4-alkylor 4-aryl-2-thiophenecarboxylate products <94SC1721>. Utilizing benzenethiol, benzo[b]thiophene forms from a-bromoketones <94JCR(S)98>. Nitrothioacetamides react with a-bromoketones to form 2-amino-3-nitro-4substituted thiophenes <94H347>. 2-Ethoxycarbonylcyclopropyl(triphenyl)phosphonium fluoroborate reacts with thiolates to produce 4,5-dihydro-3thiophenecarboxylates (Eq. 7) which aromatize by the action of DDQ <94JCS(P1)2403>.

OR

0

OR

I~

H

OH

hv

OR

OH

H -

OR

OR Ph

/ N t o ~ E

OR

NH2 C02Et

Eq. 6

2

[

0

C02EI + . ~ _....~ PPhs BF4 MS R +

/,~

02Et

Eq. 7

R

-

31

Production of a thiophene ring from acetylene and its derivatives has led to a variety of interesting compounds. An excellent review of thiophene synthesis by heterocyclization gives an overview of catalytic preparations <941VII23>. An extremely interesting [3+2] dipolar cycloaddition of cc,J3-alkynyltungsten carbene complexes with 1,3-thiazolium-4-olates, the synthetic equivalent of thiocarbonyl ylide, gives thienyl tungsten carbene complexes (Eq. 8) <94CL859>. Compound 32 forms by reaction of 4-hydroxydithiocoumarin with propargyl halides <94LIC(B)216>. Arylmethylthiols react with 1,4-disubstituted 1,3-butadiynes to produce 2-aryl-3-benzyl-5-phenylthiophenes <94JOC4350>. Free radical addition of alkanethiols to alkynes give J3-thiovinyl radicals which ring-close to form thiophene derivatives <94JOC2818>. As an alternative to intermolecular condensation, detritylation of 33 by HBr provides a facile synthesis of 3bromothiophene derivatives (Eq. 9) <94TL9387>. Treatment of bis(propargylic)sulfidr with KOH causes rearrangement to a bis(allenic)sulfide

Five-Membered Ring Systems: Thiophenes & Se, Te Analogs which ring closes <94TL1023>.

%W(CO)s MeO +

to a

3-vinylic thiophene by a diradical intermediate

.~~R2+O-

R1 Ph

89

S

0 R2,~N I~ R I ~ Ph

Ph

W(CO)5 OMe

= Ph" ~ S~ Ph Eq.8

N(CO)s Br

CHRR1 R/ O

\STr AcOH

Eq.9

33

32

Thermolysis of 2,5-dimethyl-3-hexyne-2,5-diol with elemental sulfur forms thieno[3,2-b]thiophene via the intermediacy of 2,5-dimethyl-1,5-hexadiene3-yne <94H143>. Similarly, reaction with selenium produces seleno[3,2b]selenophene. 1-Phenyl-l-benzothiophenium salts (35) form by acid-catalyzed ring closure of 1-[o-(phenylthio)phenyl]-2-(2-p-methoxyphenyl)ethyne (34) (Eq. 10) <94JCS(P1)1907>. Photocyclization of arylthiofluoro aromatic derivatives leads to the synthesis of benzo[b]thiophenes <94H1443>. Photolysis or thermolysis of 1,9-disubstituted dibenzochalcogenophenes produce dibenzo[bc, fg][1,4]dithia- and diselenapentalenes which were studied to determine their HOMO and LUMO <94H541>.

~SPh

(>

OMe

Ph I ~"

OMe Eq.10

Some examples of thiophene ring formation by ring contraction of larger rings have been reported. Treatment of 2,7-di-tert-butylthiepine with bromine gives either 36 or a thiopyran derivative depending on reaction conditions <94JCS(P1)2631>. Dithiin 37 is a kinetically stabilized disulfide and does not extrude sulfur to produce thiophene as is typical of dithiins but rather undergoes sulfur insertion to form a 1,2,3-trithiepine <94TL1973>.

3e

87

5.1.5 R I N G A N N E L A T I O N O N T H I O P H E N E Electrocyclic reactions provide a powerful tool for the creation of ring fused systems and the formation of thiophene rings is no exception. 3,4-Dimethylenetetrahydrothiophene (38) reacts with difluorocyclopropene to produce

90

Five-MemberedRing Systems: Thiophenes & Se, Te Analogs

cyclopropa[f][2]benzothiophene 39 <94HCA1826>. The preparation of 4//- and 5H-thieno[3,4-c]pyrroles begins with the tricyclic material 40. Treatment of this material with tosic acid produces a thienopyrrole in situ which is trapped with Nphenylmaleimide to afford the adduct 41 <94JCS(P1)3065>. An efficient synthesis of benzothiophene analogues of 1-arylnaphthalene lignans relies on the in situ preparation of 2-substituted thieno[2,3-c]- and thieno[3,2-c]furan followed by Diels-Alder reaction with DMAD <94JOC7353>. 5,5-Dimethyl-5Hthieno[3,2-b]pyrans are reported to exist in equilibrium with their open form 42 <93JOC4629>. Further investigations show that these trienones undergo an Eto Z-isomerization when exposed to acid or iodine; however, when X = H, the Ztrienone forms a single dimeric product 43 (Eq. 11) <94JOC5088>.

CI

CI

38

39

R1

~

R1

'lN TsOH

Et02 O

NH+ R I = R 2 =

---S

h

C02E t

0

40

41

jJ. =

o

42

H

o.

o

11 o

43

Intramolecular electrocyclic reactions are also an excellent method to afford novel structures. Thermolysis of thiophene or benzothiophene alkynyl nitrones 44 gives either thienopyrrole 45 and/or thieno-a-pyridone 46 ~ products. The product ratio is strongly influenced by the terminal R substituent which suggests an oxo carbene as a pivotal intermediate (Eq. 12) <94CB247>. The hereto DielsAlder of thiophene or benzothiophene thioketones with a-bromoacrylic esters produces thieno- or benzothienothiopyrans 47 <94S727>. Flash vacuum pyrolysis of 5.methylthienyl benzoate affords 2,5-dimethylene-2,5dihydrothiophene. This material forms the dimeric and trimeric products 48 and 49 in degassed solutions. However, in solutions without exclusion of oxygen, the major product is the cyclic bisperoxide 50 <94TLA175>. Intramolecular cycloadditions onto the thiophene ring can be accomplished using a cobaltmediated process. Thus, the treatment of 51 with CpCo in bis(trimethylsilyl)acetylene produces either 52 or 53, depending on substiment R (Eq. 13). The conversion of 52 to 53 is postulated to occur by an enol ether "walk" mechanism <94JA11153>.

Five-Membered Ring Systems: Thiophenes & Se, Te Analogs

91

o

Eq 12

44 R2

R~

R2

R

B1

n s ~ N O

R,..=~ "S ~

.

R'

and/or

Me

45 R2

46

R2

R

H H H H H ,-Bu CH=CH-CH=CH H CH=CH-CH=CH t-Bu

E 0 I 0

0 I 0

R3

R1=R2 =H R1-R~'= CH=CH-CH=CH 47

48

SiMe3 ~ S i M e 3

49

SO ~ ~ ~ ~

SiMe3

51 53 Friedel-Crafts chemistry provides a convenient route to thienoquinolizidinones 54 or [1]benzothieno[b]quinolizidinone. These materials are converted by the Schmidt reaction or the Beckmann rearrangement of the corresponding oximes to the piperidino[1,2-a] [1,3]- or [1,4]diazepines fused to a thiophene ring <94JHC495>. 10H-Pyrrolo[ 1,2-a]thieno[3,4-e][ 1,4]diazepin5(4H)-one is prepared from carbonylazide 55 when exposed to AICI3 at 140 "C <94JHC341>. 8-H-Thieno[2,3-b]pyrrolizine derivatives 56 are prepared from the corresponding 2-thiophene-N-pyrrolidinocarboxamide <94JHC501>. Ketone 57 is prepared in 80% overall yield from 3-thienyl propionic acid. This material is used to prepared a dimer (McMurry conditions) that affords a conducting polymer with a rigidified structure <94CC2249>. An improved yield of thieno[2,3c]pyridine is realized when aceta158 was treated with concentrated hydrochloric acid in dioxane at reflux <94DDDl>.

Five-Membered Ring Systems: Thiophenes & Se, Te Analogs

92

0

H

S4

0

0

NH BeckmannProduct

SchmidtProduct R

Tos

CON3

Ar

55

56

0

57

OMo

58

Palladium-catalyzed coupling is also a well suited method for ring annelation of thiophene. Palladium-catalyzed coupling of 2-iodothiophene with homochiral N-benzyl-2-azabicyclo[2.2.1]hept-5-en-3-oneunder a carbon monoxide atmosphere in the presence of TIOAc produces a mixture (1:1) of 59 and 60 <94TL3197>. The thiophene boronic acid derivatives 61 and 62 as well as the tin derivative 63 afford the thieno[c]-fused 13- and 1,8-naphthyridines when coupled with the necessary 3-amino-2-iodo- or 2-amino-3-bromopyridines <94JHC11>. Twelve thieno[b]fused naphthyridines are prepared by Pd(0)catalyzed coupling of thiophenes 64-66 with various trimethyltin pyridinecarboxaldehydes <94JHCl161>. The Pd(OAc)2 coupling of Nphenylsulfonyl compound 67 to spiroindoline 68 is accomplished in a modest 24-26% yield (Eq. 14). The addition of TIOAc (1 equivalent) to the Pd(II)coupling conditions produces 68 in 41% <94T359>. Other interesting fused thiophene derivatives are prepared by radical mediated cyclizations. Tributyltin hydride treatment of bromide 69 produces the mixture 70 in 59% yield (trans:cis = >5:1) <94TL5301>. Treatment of malonate 71 with various olefins and managanese (III) acetate produces 72. Examples of intramolecular cyclization are also reported <94SC1493>. O

..H

f/ S\ H

B(OH)~OH(;.

"no. J'Z40 59

~'~ 63

SnBu3

c"~

60

CHO

61

62

NHCO2t-Bu Br~NHCO2t-Bu ~

Br

Br 64

B(OH)2

NHCOit-Bu 65

66

Five-Membered Ring Systems: Thiophenes & Se, Te Analogs

iS02Ph~ - ~

PhO~% A

........

93

_S

Eq. 14

"~r

~'~'~ N t S02Ph

I

S02Ph 67

68

0Me

0Me

s

s

_

J~.. / CO2Me ' '

A

,~1~ "[ ~ \S~ CO,~

~'C02Me

C02ie R

69

71

70 ~

72

The photochemical ring closure of a l-chloronaphtho[2,l-b]thiophene derivative produces the complex heterocycle 73 (Eq. 15) <94JHC553>.

0 73 0 Other annelation reactions as well as bond reorganizations form interesting thiophene derivatives. Anion 74 was found not to cyclize to the desired dihydrothiepino[2,3-b]pyridine, but the thieno[2,3-h][1,6]naphthyridine forms instead as a result of anion rearrangement (Eq. 16). This material may be oxidized by DDQ to afford the thiophene analogue <94CC1767>.

C

,CN

a

~

H2N"

CN

CN~

S"

NH2

Eq. 16 ,>S N "~N

O2 7S

76

94

Five-Membered Ring Systems: Thiophenes & Se, Te Analogs

Carbon-carbon bond forming reactions are not the only method of forming fused thiophene derivatives. For example, 3-amino-2-carbomethoxythiophene is transformed to its 3-sulfonyl chloride derivative that is then converted to the thienoisothiazol-l,l-dioxide 7S <94PHA317>. Sequential treatment of 3,4diaminothiophene with phenyl isothiocyanate and tfimethylsilyl chloride in pyridine produces thienothiadiazole 76 <94H693>. Tetrathiafulvalene ~-electron donors 77 and 78 are both produced from the tosyl hydrazone of tetrahydrothiophen-3-one <94JOC3307>. A simple four step synthesis of [l]benzothieno[3,2-b]furan 79 starts with methyl thiosalicylate <93CCC2983>.

0~

77

78

79

5.1.6 T H I O P H E N E S AS I N T E R M E D I A T E S Extrusion of sulfur dioxide from oxidized thiophene derivatives is an exceptional method to prepare cis-~enes as components for Diels-Alder reactions. An example of this approach utilizes the Diels-Alder reactivity of the furan ring in substituted 4H,6H-thieno[3,4-c]furan.5,5-dioxides to react with a variety of dienophiles such as DMAD, dimethyl male.ate and dimethyl fumarate which then lose SO2 to form another reactive diene (Eq. 17) <94H961>. A review of the preparation and use of 4H,6H.thieno[3,4-c]furan-5,5-dioxides as well as other heteroaromatic-fused 3-sulfolenes is reported <94H1417>. The preparation of dihydrothienooxazole 80 requires the careful control of the reaction time and temperature as well as the reactants molar ratio <94JOC2241>. Specific control of the alkylation conditions for 81 (X = COCH3) allows for the preparation of either 1,4-disubstituted or 1,6-disubstituted 4H,6H-thieno[3,4-c]furan-5,5dioxides. These molecules could be used as intermediates for the preparation of novel pentacyclic compounds <94JCS(P1)1371>. R

-~ 02 81

+ S 02 80

~

,*UlX

Eq, 17

C02Me

The proper choice of substituents at the 2-position of the 2,5dihydrothiophene-1,1-dioxide ring system provides, after cheletropic expulsion of SO2, uniquely substituted bicyclic compounds. The preparation of bicyclic Tand 8-1actones 82 is accomplished in a modest yield from ester 83 <94MI448>. A similar strategy is used to prepare hexahydroindene and octahydronaphthalene ring systems 84 <94JOC2010>. The key synthetic step in an apoyohimbine synthesis was SO2 extrusion from a sulfolene starting material. The proper choice of reaction temperature and time was critical in optimizing the yield of an isoquinoline intermediate <94TL1071>. An example of a 3-substituted sulfolene-

Five-Membered Ring Systems: Thiophenes & Se, Te Analogs

95

1,1-dioxide is the pyridinium bromide 85. When this material is warmed to 140 "C, the diene 86 is formed in a quantitative yield and is stable at room temperature for over 1 month <94JOC4367>. S02Ph

0

0

02 O

~..

A+

(CH2)n

O

n=0,1 82

m=1,2 x ,, H, TMS, PhS 84

83

H

O

H_ --

~

Ph- N

L

O

n

N- Ph O

Oz

S

R = S4Me3

85

86

87

Ph

88

The thiophene-l,l-dioxide moiety is also used as a diene in Diels-Alder reactions. These molecules react with dienophiles such as N-phenylmaleimide to produce disubstituted phthalimides or in some cases the bismaleimide adduct 87 <94T[A425>. When a bisthiophene crown ether is treated with MCPBA and Nphenylmaleimide, a bicyclic sulfoxide is isolated. When this material is treated with potassium permanganate, the SO moiety is oxidatively removed to form phthalimide crown ether 88 <94JCS(P1)2323>. The 2,5-disubstituted thiophene1,1-dioxide 89 reacts with piperidine at 100 "C to form the piperidine adduct 90 <94S40>. The addition of DMAD to thiophene 91 affords the quinoline compound 92 after bisaddition of the DMAD followed by bond reorganization and loss of MeS- <94JHC771>. Treatment of thieno[3,4-c][1]benzopyran 93 with dimethyl maleate or dimethyl fumarate produces the dimethylphthalate 94 after loss of H2S. However, when 93 is treated with DMAD a thiepine product is isolated instead <94JCS (P1)2191>. The acid-catalyzed rearrangement of dihydrothiophene carbinol 95 was found to be much slower than the corresponding dihydrofuran case and product distribution was dependent on the ring size of 9$ <94H187>. /

Me

SiMes Me3Si.,. ~ Me

4

02

89

Me ~

N" J

l

I

~

J.

NC

NH2

eS

CO2Me MeO2C"

SH

T

NH2

- N"

CO, 90

91

92

- CO2Me

96

Five-MemberedRing Systems: Thiophenes & Se, Te Analogs c%Me ,~

NH2

-0"

" NH 95

93

5.1.7 I N T E R E S T I N G T H I O P H E N E D E R I V A T I V E S There are thiophcne derivatives with very interesting structures not easily categorized. For example, the air Sensitive naphtho[l,8.bc:4,5-b'c'idithiophene (96) was prepared by a bisintramolecular Wittig-Homer reaction. The electronic spectrum of 96 is contrasted to its isoelectronic hydrocarbon, pyrene, and isomer 97 <94CC1859>. The design and synthesis of a-oligothiophenes 98 allows for the investigation of intramolecular interactions. This cofacially oriented arrangement of thiophene rings along the pefi positions of naphthalene ring could provide insight into new molecular switches <94TL3957>. $

/F'3

S

s

98

McMurry coupling of selected dialdehydes allows for the synthesis of novel porphyfin-like and extended conjugated ring systems. Thioozaphyrin (99) is an example of a stable conjugated 22 ~-electron porphyrin-like molecule <94JOC2877>. The macrolido 100 is another example of a conjugated 22 ~ ring system. This is the first example of a neutral 22 ~ annulene that is comprised solely of thiopheno and methine units <94TL3493, 94JOC8071>. Extended electron delocalization is also present in the &cation 101; largely through the two i-PrS-C-C-C-SPr-i moieties <94JHC325>. Treatment of tri(2thicnyl)methane with 3.3 equivalents of LDA followed by Ar2C--O affords the corresponding triol. When this triol is dissolved in TFA and studied by 1H NMR, the dication is observed which shows considerable resonance contribution of the tetrapolar structure 102 <94CL1901>.

Five-Membered Ring Systems: Thiophenes & Se, Te Analogs

97

Pr

Pr

--:t['i'Pr~

SPr-i

2+

i

/-

r-i

r

(BF4-)2

100

99

101

Thiophene derivatives also form interesting metal complexes that are unrelated to the HDS process. The macrocycle trithienocyclotriyne CIVIC) was prepared by the Stephens-Castro coupling reaction of 3-ethynyl-2-iodothiophene (Eq. 18) and was compared by X-ray to tribenzocyclotriyne (TBC). TIC has a larger cavity than TBC which significantly alters the way TIC binds to transition metals such as cobalt <94OM451>. Ar S

H

__ is

$ +

Ar

102

Ar

s -2,py ,uxOIl

.....O

Ar

The preparation of thiophene-cyclopentadienone cooligomers 104 is accomplished by treating the bisalkyne 103 with 2,6-xylyl isocyanide (XyNC) in the presence of Ni(c~)2 (Eq. 19) <94CC229>. R R

R

R

R = CO2Et 103 The presence of a thiophone moiety in several biologically interesting molecules is noteworthy. The syntheses of the desmethyl (105) <94H783> and 5-hydroxy (106) <94T8699> analogues of the novel GABA reuptake inhibitor, tiagabine, are reported. The key intermediate in each report is the cyclopropyl alcohol 107. 3-Substituted thieno[2,3-b][1,4lthiazine-6-sulfonamides 108 are a novel class of topically active carbonic anhydrase inhibitors (CAIs). None of these compounds were as active as the thienothiopyran-2-sulfonamide clinical

98

Five-MemberedRing Systems: Thiophenes & Se, Te Analogs

candidates MK-927 or MK-507 in the normotensive albino rabbit model <94JMC240>. R2 R1 $

R2 ~

~

R1

~q,~~

~~~e's~'~HC

I

N

S~ ~ "

CO,H ~

Me 105R1,R2- H

OH R " ~

"~

~~S S02NH2

R2 o~ S

Me

106 R~ = Me; R2 = OH

107

108

5.1.8 S E L E N O P H E N E S A N D T E L L U R O P H E N E S As mentioned in the introduction, very few examples to selenophene or tellurophene were reported this year. Metallacycle transfer from zirconium metallacycles such as to the corresponding selenophenes can be accomplished in "one-pot" synthesis (Eq. 20) <94JA1880>. Treatment of the dilithio intermediate 109 with either red selenium or tellurium powder affords the corresponding 1benzometalloles. The trimethylsilyl group is later removed with TBAF <94CPB 1437>.

Me

I.i 109

Me

Eq. 20

THF Me

Me

5.1.9 C O N D U C T I V I T Y A N D P O L Y M E R S The unique chemical and electronic properties of thiophene make it the subject of continued intense study for the design of low-gap polymers as organic conductors, molecular switches (electrochemical or photochemical), nonlinear optical devices as well as other electrochemical devices. Linearly-condensed polythiophenes, push-pull thiophenes connected by ethylene and acetylene bridges, 3-substituted oligothiophenes and thiophene-pyrrole mixed polymers are the subjects of most interest. Reviews that cover some of these topics are reported <94MI353, 94MI1893, 94H2069>. The brevity of this section is not an indication of low interest in the area but rather of space limitations. Polymerization and electrochemistry of thiophene and its derivatives represents the greatest single area of thiophene research as judged by the number of citations. Light-triggered electrical and optical switching devices such as push-pull thiophenes <94MCLC323>, carboxyalkyl or alkyl mercaptan containing benzothiophenes <94JA9894>, and polythiophenes <94CC2123> use the hexafluorocyclopentene backbone to place the bisthien-3-yl moiety in proximity such that a "switch" from open- to closed- form results upon irradiation. This "switching" causes extended conjugation and dramatic color changes. An extension of this theme is the preparation of dual mode switch compound 110 (Eq. 21) <94CC1011>.

Five-Membered Ring Systems: Thiophenes & Se, Te Analogs

F 2 ~

~

,~..~l F2~~.~~)..,.~ F2

UV(321nm) Ar~r~S/~

/ ' ~ S / --Ar

99

~

-(2e',2H+)

VIS(>600rim) JJ ~ ~ ~(2e',2H") F2 A r / ~ S " ~ -"S~'~"Ar

Ar -~ 1

1

0

~

O" "~

Eq.21

-:"

0

The push-pull (donor-acceptor) design is a typical approach for examining extended conjugation of organic metals. This concept is apparent in the thienothiophene I U <94CM2210>. Examples exist where the dicyano moiety is replaced with N,N-diethylthiobarbituric acid. This acceptor group enhances the second-order hyperpolarization by extended charge-separation <94MI485, 94CM1603>. The rigidity offered by the thienothiophene ring system as well as the cyclopenta[2,l.b;3,4-b']~thiophen-4-one moiety is often used to prepare polymeric derivatives <94JOC442> or novel monomers, such as 112 <94CC1765>. The 1,3-bis(2-thienylmethylene)thieno[3,4-c]thiophene ring system is prepared by Knoevenagel-type condensation of the starting 2-oxide with 2-thiophenecarbaldehyde. Reduction with 2-chloro-l,3,2-benzodioxaphosphole affords 113 which serves as a precursor for polymerization <93S634, 93SMI 193, 93CB 1487>. R O R

111

CN

R = SMe 112

S

CN

,......,.

NG

0"

NC

CN R

113

114

R = t-Buor Me 115

R

100

Five-Membered Ring Systems: Thiophenes & Se, Te Analogs

A series of benzobithiophene derivatives are electron accepters in chargetransfer complexes. Of the three isomers reported, 114 is the most stable and soluble <93SM1910, 94JOC3077>. [3]Radialene derivative 115 was also prepared as an electron accepter. Extensive delocalization of these molecules produces powerful accepters with E11/2 to be more positive by 0.2-0.25 V than the reference compound 2,5-bis(dicyanomethylene)-2,5-dihydrothiophene <94CC519>. A related t r i s [ 5 - ( 3 , 5 - d i - t - b u t y l - 4 - h y d r o x y p h e n y l ) - 2 thienyl]cycloproponylium ion is also reported <93CL911>.

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Five-Membered Ring Systems: Thiophenes & Se, Te Analogs

94CM1603 94CM2210 94CPB1437 94DDD1 94G195 94H143 94H187 94H331 94H347 94H501 94H541 94H693 94H759 94H783 94H819 94H961 94H1299 94H1417 94H1443 94H1529 94H2029 94H2069 94HCA1826 94IJC(B)216 94JA198 94JA1880 94JA4370 94JA5190 94JA9894 94JAl1153 94JC171

101

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102

Five-Membered Ring Systems: Thiophenes & Se, Te Analogs

94JC288 94JCR(S)98 94JCS(Pl)761 94JCS(Pl)l193 94JCS(P1)1245 94JCS(P1)1339 94JCS(Pl)1371 94JCS(Pl)1907 94JCS(Pl)2191 94JCS(P1)2323 94JCS(Pl)2403 94JCS(Pl)2631 94JCS(P1)2735 94JCS(P1)3065 94JCS(P2)2045 94JFC13 94JFC51 94JFC143 94JHC11 94JHC325 94JHC341 94JHC495 94JHC501 94JHC521 94JHC553 94JHC641 94JHC771 94JHC1053 94JHCl161 94JMC240

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Five-Membered Ring @stems: Thiophenes & Se, Te Analogs

94JMC1402

94JOC442 94JOC494 94JOC2010 94JOC2241 94JOC2818 94JOC2877 94JOC3077 94JOC3307

94JOC3695 94JOC4308 94JOC4350 94JOC4367 94JOC5088 94JOC6103 94JOC7117 94JOC7353 94JOC8071 94JOM311 94M927 94MCLC323 94MI23 94MI62 94MI287 94MI353 94MI377 94MI448 94MI485 94MI765

103

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104

Five-Membered Ring Systems: Thiophenes & Se, Te Analogs

94MI1893 94MI3782 94OM179 94OM451 94OM721 94OM1821 94OM2628 94OPP349 94PHA317 94PP202

94PP269 94S40 94S669

94S727 94SC95 94SC709 94SC789 94SC1493 94SC1721 94SC2379 94SL69 94SL217 94SM223 94T359 94T4149 94T6549 94T8699

94TI0549 94TL633 94TL815

94TL1023 94TL1047

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Five-Membered Ring @stems: Thiophenes & Se, Te Analogs

105

1047.

94TL1071 94TL1973 94TL2709 94TL3083 94TL3197 94TL3493 94TL3673 94TL3957 94TL4175 94TL4425 94TL4743 94TL5301 94TL8329 94TL9197 94TL9387

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