Benzo thiophene derivatives

Substituted benzo[ ]thiophene derivatives have been prepared in excellent yields by a tandem Pummer rearrange-ment/Diels-Alder reaction of the intermediate furan with maleic anhydride or A -phenylmaleimide (Equation 87) <1996JOC6166>. 

A Thorpe reaction scheme led to the synthesis of a benzo[( ]thiophene derivative (87) in 80% yield, when (86) was treated with sodamide in dry benzene (62JOC2821). While reactions are known to convert (87) into benzo[6]thiophene, this pathway has not yet been explored. 

See Nitric acid Benzo[ >]thiophene derivatives See other ARENEDIAZONIUM OXIDES... 

Much of the current interest in benzo[ ]thiophene chemistry owes its origins to the wide range of biological and other activities shown by many of its derivatives. In medicine, benzo[ ]thiophene derivatives have been patented as laxatives,7 contraceptives,8 and antiinfluenza agents.9 In... 

Active site directed thrombin inhibitors A broad screening approach for thrombin inhibitors led to the identification of the 2,3-disubstituted benzo thiophene derivative la (Fig. 5.9). A systematic structure-activity relationship study led to 31c which is 1271 times more potent. 

The detailed structure of the clathrate compound formed between 2,5,5-trimethylhex-3-yn-2-ol and 4-p hydroxyphenyl-2,2,4-trimethylthio> chroman has been determined by A -ray crystallography. tra/i5 -3,4-Dibromothiochroman and analogous dibromo-naphthothio-pyrans, prepared by addition of bromine to the appropriate A -thio-chromenes, may exist in sofa conformations. The dibromo-compounds undergo ring-contraction reactions with alkalis, yielding benzo[ ]thiophen derivatives. ... 

The much less sophisticated PPP approximation has been shown to well reproduce the electronic spectral features not only of the monocyclic furan, pyrrole, thiophene, selenophene and tellurophene but also many of the benzo fused derivatives as well (79MI30101, 68JPC3975, 68MI30100). 

Exposure of the benzo[b]thiophene derivative 44 to a palladium catalyst in the presence of tri(2-furyl)phosphine (TFP) as the ligand led to the product 45, which incorporated two heterocyclic units from the starting material. The mechanistic aspects of this transformation were also discussed, which appears to involve palladacycle intermediates <06JA722>. 

The benzo[fc]thiophene sulfoxides, such as (142), generated from the parent benzo-thiophene on the H202-TFA-mediated oxidation, undergoes Michael-type nucleophilic addition of oxygen and sulfur nucleophiles in acidic media to produce 3-substituted benzo[fc]thiophenes (143). This method provides an easy two-step functionalization of 2-acylbenzo[fc]thiophene derivatives. ... 

Treatment of the benzo[6]thiophene derivative (82) with perchloric acid yields 2,4-diphenyldibenzothiophene. Reaction of 2,3-dibromo-... 

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... 

Thiophenium bis(alkoxycarbonyl)methylides (44) are obtained in high yield by rhodium(II) carboxylate-catalyzed reaction of diazomalonate esters with thiophene derivatives (88JCS(P1)1023). Likewise, ylides from benzo[b]thiophene and dibenzothiophene (e.g. 45) have also been reported by tram-ylidation using phenyliodonium bis(phenylsulfonyl)methylide (88JHC1599). 

Although a limited range of Grignard reagents is available, the most widely used group is undoubtedly the lithio group introduced by direct lithiation (see Section 3.3.1.6.2). The ready formation of the lithio derivatives of pyrroles, furans and thiophenes and their benzo-fused derivatives has had a most important impact on the chemistry of these heterocyclic systems. Reaction of the... 

The first proton to be removed from N-methylpyrrole by n-butyllithium is from an a-position a second deprotonation occurs to give a mixture of 2,4- and 2,5-dilithiated derivatives. The formation of a 2,4-dilithio derivative is noteworthy since in the case of both furan and thiophene initial abstraction of a proton at C-2 is followed by proton abstraction from C-5 (77JCS(P1)887). Af-Methylindole, benzo[ >]furan and benzo[ >]thiophene are also deprotonated at C-2. Selenophene and benzo[ >]selenophene and tellurophene and benzo[6]tellurophene similarly yield 2-lithio derivatives (77AHC(2l)ll9). 

Thermal and photochemical cycloaddition reactions undergone by thiophene and its derivatives are discussed in this section. The first number within parentheses refers to the number of 7r-electrons of the thiophene ring taking part in the cycloaddition, and the second number the contribution of the addend. Thermal and photochemical [2 + 2] cycloaddition reactions of thiophenes and benzo[ ]thiophenes form part of an extensive review on [2 + 2] cycloaddition reactions of heterocyclic compounds (77AHQ2l)253). 

The first successful Diels-Alder addition of thiophene appears to have been with tetrafluorobenzyne (66CC143). The adduct apparently loses sulfur, resulting in the isolation of the tetrafluoronaphthalene in 40% yield (Scheme 78). Other thiophene derivatives (69T25) and fluorinated benzynes <71JCS(C)604) have been similarly reacted. Subsequently it was found (80H 14)647) that unsubstituted benzyne, generated from diphenyliodonium-2-carboxylate, could be trapped with thiophene to form naphthalene in 33% yield. The earlier failure to add thiophene to benzyne generated by other methods must have been due to intervention of side reactions. Thiophyne also has been similarly trapped to yield benzo[A]thiophene (see Section 3.14.2.2). 

Incidentally, a 1,3-cycloaddition of benzyne to thiophene has been postulated (81CC124) to account for the small, but reproducible amount of benzo[ >]thiophene formed in this reaction (Scheme 79). Reactive alkynes have been successfully used as dienophiles to cycloadd with thiophenes benzene derivatives are obtained after extrusion of sulfur from the adduct (Scheme 80) (72TL605, 72TL1909, 73CB674). 

Michael addition of the carbanion flanked on one side by a 3-thienyl group, and on the other by a sulfoxide or a sulfone, to chalcone has been reported (81TL5097). Cyclization of the resultant anion with a suitable ortho-substituent is followed by elimination to give a benzo[6]thiophene derivative (Scheme 105). 

The direct formation of the S—C bond to form thiophenes is better illustrated by the conversion of 2-alkylthiophenols (1) to benzothiophenes (2) (48JA1561). Passing (1 n =2) over a chromium-aluminum oxide catalyst at 475 °C gave (2 R = R = H) in about 20-25% yield, while similar treatment of (1 n - 3) gave (2 R = H, R = Me) in only 10-12% yield. 2-Mercaptostyrene also cyclized to (2) over this same catalyst, and a number of substituted derivatives of (1), where n =2 and R = 5-NH2, 3-NH2, 5-CN or 5-C02Me, were also converted to benzo[6]thiophene derivatives in low yield (56JOC265). 

Alternative methods of preparing the starting acids can be used, but are generally less convenient. Benzo[6 ]thiophene derivatives were prepared from 2-methyl-3-(2 -thenoyl)propionic acid, which was obtained either by reacting 2-thienylmagnesium iodide with methylsuccinic anhydride, or by coupling 2-bromoacetylthiophene with the sodium salt of diethyl methylmalonate (45JA1645). 

Finally, the photocyclization of certain phenylthioethylenes to give benzo[6]thiophene derivatives [see, for example, Eq. (95)] has been reported.808... 

E. Campaigne, T. R. Bosin, and E. S. Neiss, Advan. Drug Res. (1969) (in press) a review entitled Biologically Active Benzo[6]thiophene Derivatives. ... 

The 4H NMR spectra of some methyl-,79-83 halo-,81 mercapto-,84 nitro-,84 and methoxybenzo[6]thiophenes,85 and of some sulfonic acids, sulfonyl chlorides, and sulfonate esters86 have been recorded. Two groups of workers87,88 have independently studied the 4H NMR spectra of a range of benzo[6]thiophene derivatives in an attempt to correlate the chemical shifts of the protons with the substituents. Such a correlation helps to assign structures to new benzo[6]thiophene derivatives, and it also throws light on the influence of substituents on the NMR parameters of heteroaromatic systems in general. 

---