Methyl thieno thiophene-2-carboxylates

More vigorous conditions were required for the formylation of thienothiophene 3 with an electron acceptor group in the molecule. Thus, refluxing methyl thieno[3,4-6]thiophene-2-carboxylate, iV-methyl-formanilide and phosphorus oxychloride for 1 hour gave a mixture (1 1)... 

As in the synthesis of thieno[2,3-,7]-l,2,3-thiadiazoles, thieno[3,2-.7 -l,2,3-thiadiazoles are made using diazotization of aminothio-substituted thiophenes and by Hurd-Mori reaction of hydrazones. Diazotization of compound 134 with NaN02 in AcOH/HCl at 0°C produced methyl thieno[3,2- / -l,2,3-thiadiazole-5-carboxylate 135 but in only low yield. Hydrazone tautomer 136 treated with excess SOCI2 in CH2CI2 at room temperature gave dimethyl thieno[3,2- / -l,2,3-thiadiazole-5,6-dicarboxylate 137 and dimethyl 5,6-dihydrothieno[3,2- / -l,2,3-thiadiazole-5,6-dicarboxylate 138 in a ratio of 3 2 (Equations 20 and 21) <1998H(48)259>. 

Cyclization of isomeric thiophenes 65 and 66 containing the aldehyde function and the SCH2C02Me group in positions 2 and 3 by reaction with l,5-diazabicyclo[4.3.0]-non-5-ene (DBN) affords methyl thieno[2,3- )]- (67) and -[3,2-i ]thiophene-2-carboxylates (68), respectively (91JMC1805). 

In contrast to 6-azidobenzo[/)]thiophene, which yields only benzo[i]thiophen-6-amine (9 %) and JVh,Ar(1-diethylbenzo[/)]thiopheiie-6,7-diamine (25 % bp 175-177 C/0.7 Torr), 6-azido-2,3-dibromobcnzojhjthiophene (1 a, R = R2 = Br) on irradiation in diethylamine in the presence of pyrene, a triplet nitrene quenching agent, yields a mixture of 2,3-dibromo-./V6,./V6-diethyl-benzo[5]thiophene-6,7-diamine (2a, R1 = R2 = Br 13%) and the 8W-thieno[2,3-r]azepine 3a.14<1 Likewise, methyl 6-azidobenzo[6]thiophene-2-carboxylate (lb, R1 = C02Me R2 = H) yields the thienoazepine ester 3b.147... 

In 1972 Wright prepared 3-chlorothieno[3,2-6]thiophene-2-carbonyl chloride (94) in 11-13% yield by heating 3-(2-thienyl)acrylic acid, thionyl chloride, and pyridine, a method of synthesis of benzo[6]-thiophene-2-carbonyl chloride derivatives. " Methyl 3,5-dichloro-thieno[3,2-6]thiophene-2-carboxylate (95) and methyl 2-chloro-3-(5-chloro-2-thienyl)acrylate were also isolated. When fte reaction was carried out in refluxing toluene or chlorobenzene, the acid chloride (94)... 

Dihydrothieno[3,4-Z ]thiophene (131) was prepared by two methods. In the first (Scheme 8), chloromethylation of methyl thiophene-2-carboxylate (132) forms methyl 2,3-bischloromethyl-thiophene-5-carboxylate (133) (85%) cyclization of 133 with sodium sulfide in methanol yields (66%) methyl 4,6-dihydrothieno[3,4-i]-thiophene-2-carboxylate (134). Peroxide oxidation of 134 gives 2-methoxycarbonyl-4,6-dihydrothieno[3,4-h]thiophene 5,5-dioxide (135) and hydrolysis of 134 followed by metaperiodate oxidation furnishes the sulfoxide (91). Thienothiophene (131) was produced by hydrolysis and decarboxylation of 134. As indicated above, the sulfoxide (91) was used for the synthesis of thieno[3,4-6]thiophene (3). 

Fiessdmann and Pfeiffer" passed HCl at 0° through acetoacetic ester and thioglycolic ester in dcohol to obtain triethyl y3, -bis(carbo-methoxymethylthio)butyrate (169) Dieckmann condensation reportedly furnish ethyl 3,4-dihydroxy-6a-methyl-3a,6a-dihydro-thieno(2,3-b]-thiophene-2-carbOxylate (170) [Eq. (48)]. 

Similarly, acetylation of thieno[3,2-6]thiophene (2) afforded 2-acetyl-thieno[3,2-6]thiophene, which was converted into methyl n-hexyl ketone by desulfurization with Raney nickel. Oxidation of 2-acetylthieno-[3,2-i]thiophene followed by nitration gave 5-nitrothieno[3,2-6]-thiophene-2-carboxylic acid. Decarboxylation of the latter furnished 2-nitrothieno[3,2-ft]thiophene identical with the compound obtained by direct nitration of thienothiophene 2 [Eq. (60)]. 

Annelation of a furan ring onto a thiophene is also possible by flash vacuum pyrolysis at 650 °C of the acrylate 368 and malonate 369, which gave 2-(methylthio)thieno[3,2-/ ]furan 370 and methyl-5-(methylthio)thieno[3,2- ]furan-2-carboxylate 371, respectively, in yields of 21% and 22% <1997J(P1)2483>. 

Nielsen (81CS(18)135) prepared thieno[2,3-4]pyrimidin-4(3//)-ones in 43-90% yield by heating 2-acylaminothiophene-3-carboxylates (330) with phosphorus pentoxide, N,N -dimethylcyclohexylamine and an amine hydrochloride at 180 °C. By raising the temperature to 240 °C, thieno[2,3-4]pyrimidin-4-amines (331) were obtained in 27-34% yield (Scheme 92). Phenyl N,N -dimethylphosphorodiamidate [(MeNH)2P(0)OPh], a well-known reagent for the synthesis of 3-methyl-4-oxo-3,4-dihydroquinazolines (77S180), reacts with thiophene derivatives of type (330) to give 3-methylthieno[2,3-4]pyrimidin-4(3/f)-ones (78ACS(B)303). 

Condensation of 5 with methyl tetrahydro-4-oxothiophene-3-carboxyl-ate (64) led to the formation of the ring-closed enamino thiolactone 65. Chemical transformation of 65 with sodium hydride/methyl iodide gave 67, whereas 4H, 10//-thieno[3,4-c][l,5]benzothiazepin-10-one (66) was obtained upon aromatization of the thiophene ring by the action of sulfuryl chloride (Scheme 18) (80JOC497). 

Treatment of the sulfone 35 with three equivalents of butyllithium gave an intermediate selectively dimetalated at C-2 and the adjacent methyl group. Subsequent reactions of this species with aromatic or heteroaromatic esters, such as methyl thiophene-2-carboxylate, and final acid induced elimination of water, gave a series of thieno[ 3,2 -6] thiophene 1,1-dioxide systems, for example 36 <07S1827>. On the other hand, 3-methylthiophene undergoes selective deprotonation at C-5 upon treatment with lithium 2,2,6,6-tetramethylpiperidide (LiTMP), giving access to a 2,4-disubstituted thiophene derivatives <07JOC 1031>. 

The preparation of two of the three possible isomeric thieno-1,2-thiazin-4-ones (Schemes 5 and 6)128 involved reactions reported12 for the corresponding benzothiazines (see Scheme 1 ). Thus, methyl 3-chlorosul-fonylthiophene-2-carboxylate (152) with sarcosine ethyl ester gave thiophene sulfonamide (153) which, with methanolic sodium methoxide, yielded 3-methoxycarbonyl-4-hydroxy-2-methyl-2H-thieno[2,3-c]-l,2-thiazine 1,1-dioxide (154). Heating 154 with 2-aminothiazole gave 155, a thieno-1,2-thiazine analog of sudoxicam (20) (Scheme 5). 

Methyl 4,5,6,7-tetrafiuorobenzo[h](hiophene-2-carboxylate is oxidized by trifluoroperacetic acid or m-CPBA to form a 2,3-epoxysulfbne reaction with chlorine or sulfuryl chloride produces a 2,3-dichIoride derivative <94JFCS1>. HOF MeCN is a novel oxidant which oxidizes a variety of thiophene derivatives to 3,5-dioxides <94CC1959>. Bromination of thieno[c]fused l,S-n hthyridines occurs with tetrabutylammonium perbromide <94H331> or with dibromoisocyanuric acid/sulfuric acid <94JHCS21>. 

Friedel-Crafts condensation of benzo[Z ]thieno[3,2-Z ]thiophene-2-carboxylic acid chloride with m- and / -xylene affords ketones, which undergo Elbs pyrolysis (420 °C, 15 min) to form pentacyclic derivative 230 (2000JA1082). Analogous products were prepared from benzo[Z ]thieno[3,2-Z ]thiophene and (di)methyl homologues of benzoyl chloride. 

Synthesis.—The reactions of thiophen-2- and 3-acrylic acid with thionyl chloride in the presence of pyridine yield a mixture of chlorinated derivatives of thieno[3,2-b]thiophen-2-carboxylic acid and thieno[2,3-b]-thiophen-2-acrylic acid. From thiophen-2,5-diacrylic acid, (241) was obtained. Aromatization of (66) gives thieno[2,3-b]thiophens. Reaction of (242) with methyl thioglycolate yielded (243)." Ethylthiophen was... 

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