Thieno thiophene, ring synthesis

The 2-(2-pheriylvinyl) derivative 18 and the thienyl compound 20 cyclize exclusively at the alkene carbon, and at the thiophene ring, to give 3,4-diphenyl-l//-2-benzazepine (19) and 4-phenyl-6-//-thieno[3,2-e]-2-benzazepine (21), respectively.48 A mechanistic rationale for these results has been offered. This method has been extended to the synthesis of 7Z7-pyrido[3,4-t/]-, 7//-pyrido[2,3-t/]- and 77/-pyrido[4,3-r/]benzazepincs and to other thieno- and furo-fused 2-benzazepines.244... 

Ya. L. Gol dfarb, I. P. Konyaeva, and V. P. Litvinov, Condensed heteroaromatic systems including the thiophene ring. 27. Synthesis of -bromosubstituted thieno-[2,3-6]thiophene and selenopheno[2,3-6]thiophene. Izv. Akad. Nauk SSSR, Ser. Khim. 1570 (1974). 

The protonation of 185 and 186 with trifluoroacetic acid (TFA) gave 4-(/i t/-butylthio)-3,6-diphenyl- 193 and 4-(ter1-butylthio)-3,6-di(2-thienyl)thieno[3,4-f]thiophene-l(3//)-thione 194 (Scheme 18). The treatment of 193 with sodium hydride and then isopropyl iodide led to 4-(/i< t/-butylthio)-3,6-diphenyl-l-(isopropylthio)thieno[3,4-f]thio-phene 195 by the regeneration of the thieno[3,4-f]thiophene ring system, thus making possible the synthesis of other alkylthio-substituted thieno[3,4-(r]thiophene derivatives. When the reaction of 185 with TFA was carried out... 

The chemistry of this series parallels that of the nitrogen and oxygen analogs. Hence the synthesis of thieno[2,3-tfl pyridazines can be accomplished from either a pyridazine or thiophene ring precursor. 

However, the synthesis of thieno[3,2-Z>]pyridines by cascade heterocyclization of simple and readily accessible reagents 62 and 135 holds more promise. In this process, the thiophene ring and then the pyridine ring are successively formed in the presence of a basic catalyst to give finally polyfunctionalized thieno[3,2-Z>]pyridine 136 (1996KGS413). 

The majority of methods for the synthesis of thieno[2,3-c]pyridines and related fused structures can be tentatively divided into two groups based on the construction of the pyridine or thiophene rings, respectively. 

Methods for the construction of the thieno[2,3-c]pyridine skeleton based on the formally simultaneous formation of both the pyridine and thiophene rings were documented. Under the Pummerer rearrangement conditions, ( -s ul liny lain idc 222 underwent a cascade transformation into 223, which was oxidized to fused lactam 224 in low yield (1999JOC2038). Data on the use of cascade transformations, including the Pummerer rearrangement - cycloaddition sequence, in the synthesis of complex heterocyclic systems were summarized in a review (1997S1353). 

This methodology has been extended to the synthesis of new thieno[3,2-c][l,2,6]thiadia-zine 2,2-dioxides bearing substituents on the thiophene ring, for example compounds (29a) and (29b). 

The oxidative ring-closure of (178) gave (179), and similarly (180) was obtained from 3,4-diamino-2,5-dithiocarbamino-thieno[2,3-6]thiophen. The synthesis of substituted (3//)-thieno[2,3-rf]imidazoles has been achieved by a Curtius rearrangement of (181). ... 

The thienothiophens, like thiophen, are smoothly metalated by ethereal butyl-lithium in the a-positions. By means of competitive metalation experiments, both thieno[2,3-Z>]thiophen and thieno[3,2-Z>]thiophen were found to be about six times more reactive. The unsymmetrical thieno-thiophen (296) gives the 4-lithio- and 2-lithio-derivatives in a 1 4 ratio. Also, (293) and (294) are smoothly metalated in the a-positions. Halogen-metal exchange between 2,3,5-tribromothieno[3,2-6]thiophen and butyl-lithium at — 70 °C followed by hydrolysis could be used for the synthesis of the 2,6-dibromo-compound. However, the same reaction with 2,3,5-tribromothieno[2,3-6]thiophen led to ring-opening. 

Dihydropyrrolo[2,l-6]thieno[3,2-/][l,3]thiazepin-4-one 34 as an intermediate for the synthesis of 4-(4-methylpiperazino)pyrrolo[2,l-i>]thieno[3,2-/ [l, 3]thiazepine 35 - a potential antipsychotic agent - was obtained from 2-[2-(thien-2-ylsulfanyl)-l//-l-pyrrolyl]acetic acid 33 by cyclisation onto the p-position of the thiophene ring using either exposure of the acid to phosphorus pentoxide (method A) or (method B) conversion to acid chloride followed by the addition of tin (IV) chloride (Scheme 35) [55],... 

To study the effect of ring strain (Mills-Nixon effect) on the properties of five-membered heteroaromatics, Wynberg and Zwanenburg developed a new synthesis of l/f,3H-thieno[3,4-c]thiophene (112) [Eq. (37)]. They obtained 3,4-dimethylthiophene-2,5-dicarboxylate (113) by... 

Castle and co-workers <1996JHC119, 1996JHC185, 1997JHC1597, 1998JHC1441> used 3-chlorothieno [2,3-3]thiophene-2-carbonyl chloride 280 in the synthesis of the appropriate amides, which by oxidative photo-cyclization gave novel polycyclic heterocyclic ring systems thieno[3, 2 4,5]thieno[2,3-f][l,10]phenanthroline 281, thieno[3, 2 4,5]thieno[2,3-f]naphtho[2,iy ]quinoline 282 and thieno[3, 2 4,5]thieno[2,3-f]naphtho[l,2-g]qui-noline 283, thieno[3, 2 4,5]thieno[2,3-f]naphtho[l,2y ]quinoline 284, thieno[3, 2 4,5]thieno[2,3-f]naphtho[l,2 7]-[l,2,4]triazolo[3,4- ]quinoline 286, thieno[3, 2 4,5]thieno[2,3-f]naphtho[l,2-/]tetrazolo[l,5- ]quinoline 288, benzo[ ]thieno[3, 2 4,5]thieno[2,3-f]quinoline 285, benzo /]thieno[3, 2 4,5]thieno[2,3-f]quinoline 287, benzol/] thieno[3, 2 4,5]thieno[2,3-f]tetrazolo[l,5- ]quinoline 289, and benzo[/jthieno[3, 2 4,5]thieno[2.3-f][l,2,4]triazolo[4,3- ]-quinoline 290. 

The first synthesis of the parent compound of the benzo[4,5]thieno[2,3-f]pyrrole ring system 387 <2003T1477> and its derivatives was accomplished using the same synthetic sequence (Scheme 42). Starting with 2-methyl-benzo[ ]thiophene-3-carbaldehyde 388, an intermediate 389 was obtained. Treatment of bromo compound 389 with sodium azide in ethanol led to the stable triazoline 390. 1,3-Dipolar cycloreversion of 390 was induced by a catalytic amount of />-TsOH to give the parent 2//-benzo[4,5]thieno[2,3-c]pyrrole 387. Alternatively, direct treatment of bromo compound 389 with excess ammonia furnished 387 in one step. Compound 387 was treated with di-/-butyl dicarbonate and 4-dimethylaminopyridine (DMAP) to give iV-BOC derivative 391. Reaction of 389 with... 

Saito et al. [33] described a new method for the synthesis of heterocycle-fused[c]thiophenes via reaction of aryl heteroaryl thioketones with carbene precursors. Heteroaromatic thioketones A react with carbenoids generated from bis(arylsulfon yl)diazomethanes or phenyliodonium bis(phenylsulfonyl)methylides to give hete-rocycle-fused[c]thiophenes B (Scheme 20). The reaction involves the ring closure of the intermediary thiocarbonyl ylides, followed by restorative aromatization via the elimination of a sulfenic acid. The present method provides simple and facile access to a variety of furo- 118, benzofuro- 119, thieno- 120, benzothieno- 121, pyrrolo-122, and indolo-123 fused [c]thiophenes (Scheme 20). 

In addition to procedures for pyridine ring closure based on the use of 3-amino-thiophene derivatives, there are alternative methods for the construction of thieno [3,2-Z>]pyridines. One approach made use of cyclic (3-keto sulfones, which proved to be convenient synthons for the modified Hantzsch synthesis of fused pyridines (1986KGS1563, 1990JHC1453, 2000MI1, 2002USP6191140). For example, the reactions of benzothiophene 1,1-dioxide 168 with enamines 169 or methylene-active compounds 170 in the presence of NH4OAc produced fused dihydropyridines 171 (1990JHC1453). 

A similar type of reaction, with bond formation between a chlorine substituted thiophene moiety and a phenyl ring connected to the thiophene via an amide bond, was used in the synthesis of 12-carbomethoxy-2-chloronaphtho[2",r, 2,3,-/ ]thieno[4,5, 2,3]-... 

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