Of benzo thiophenes

Benzothiophenes have always been of interest for medicinal chemistry and can be found in a number of marketed drugs such as Sertaconazole (Gineder-mofix), Zileuton (Leutrol) and Raloxifene (Evista). The classical synthesis of benzo thiophenes starts from thiophenols, reacting with bromoacetaldehyde dimethyl acetal, followed by cycUzation using strong acid. An alternative and more convenient route was also described starting from benzaldehydes which... 

The oxidation of benzo[( ]thiophene by strains of pseudomonads produces the sulfoxide that undergoes an intramolecular Diels-Alder reaction followed by further transformation to benzo[fc]naphtho[l,2- (]thiophene (Figure 2.2b) (Kropp et al. 1994). 

Thiazine 280 can be prepared in low yield by the sulfimidation of benzo[/ ]thiophene 281 with chloramine-T 282 in the presence of a Cu-catalyst (Equation 39) <2003CC1736>. 

Halogens react with benzo[ ]furan by an addition-elimination mechanism to give 2- and 3-substituted products (76JCS(P2)266). Treatment of benzo[ ]thiophene with chlorine or bromine in acetic acid gives predominantly 3-substituted products (71JCS(B)79). 2,2,3,3,4,5,6,7-Octachloro-2,3-dihydrobenzothiophene is obtained when benzo[ ]thiophene is treated with chlorine in the presence of 1 equivalent of iodine (80JOC2151). 

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). 

In 1972 Wright79 prepared 3-chIorothieno[3,2- ]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[ ]-thiophene-2-carbonyl chloride derivatives.80-82 Methyl 3,5-dichloro-thieno[3,2- ]thiophene-2-carboxylate (95) and methyl 2-chloro-3-(5-chloro-2-thienyl)acrylate were also isolated. When the reaction was carried out in refluxing toluene or chlorobenzene, the acid chloride (94)... 

The cycloaddition of a variety of sulfur heterocycles to alkenes has also been reported. Dibromomaleic anhydride undergoes [ 2 + 2] cycloaddition to thiophen295 and to benzo[b]thiophen.296 The photoaddition of benzo-[(>]thiophen 1,1-dioxides to alkenes also affords cyclobutane derivatives.297 Of particular interest is the addition of 3-acetoxybenzo[6]thiophen (350) to cyclohexene to give the adduct (351), which on treatment with base, undergoes a retro-aldol ring opening to benzo[6]thiepinone (352).298 A mixture of stereoisomeric cyclobutane derivatives were obtained on irradiation of 2,6-diphenyl-4//-thiopyran-4-one 1,1-dioxide in cyclohexene.299 The [ 2 + 2] cycloaddition of sulfolen to maleic anhydride and to maleimide has been reported.300... 

The synthesis of benzo[ >]thiophenes from o-nitrobenzaldehydes or o-nitrobenzonitriles and methyl thioglycollate can be viewed as an extension of the foregoing approach (Scheme 64) (72JOC3224). 

Thiophenes are known to polymerize on treatment with acidic materials this is probably due to successive protonation and electrophilic substitution. It has been reported (79BCJ1126) that 2-chlorothiophene (80) on treatment with Amberlyst 15 (cation exchange resin) and 100% orthophosphoric acid gives (82) and (84) as major products and (83) as a minor one. The suggested mechanism involves initial protonation to form (81), which subsequently acts as an electrophile (Scheme 13). Related dimerizations have been reported on treatment of benzo[ >]thiophene with A1C13 (80JCS(P1)677, 81JCR(S)307>. 

A halogen attached to position 2 of benzo[ > ]thiophene can be selectively removed in the presence of a 3-halogen atom by H2/Pd or Zn/HOAc. Dehalogenation of a 3-halo derivative can be accomplished using Na/Hg or HI (70AHC(11)177). 

Scheme 8.2. Partial rate factors for detritiation of benzo[/>)thiophene in trifluoroacetic acid at 70°C. "Due to a numerical error, a larger value is given in the original paper.

Benzo[ ]thiophene dianion 210 can be prepared by reduction of benzo[ ]thiophene with sodium metal at 78C in [2Hg]THF. The 1H and 13C NMR spectra of the purple solution obtained prove that it is the dianion and not a radical anion. This is the first example of a sulfur-containing (4 )-polycyclic dianion. The dianion is converted back to benzo[ ] thiophene with oxygen. 

The benzo[ ]-fused systems participate in a number of [2 + 2] cycloaddition reactions. The photocycloaddition products of benzo ] thiophenes and DMAD are dependent on the irradiation wavelength at 330 nm 240 is formed, while at 360 nm the rearranged product 241 is produced. 

The IPs of benzo[. ]thiophene <1969IJM471> and DBT have also been determined and the assignments compared with various theoretical calculations <1983JST(105)375>. 

The NICS of each ring, as a criterion of aromaticity, has been used to explain the stability order of benzo[/)]thio-phene and its isomer. The results indicate that the benzene ring is aromatic in all the systems. The five-membered ring of benzo[. ]thiophene is also aromatic, whereas in benzo[r]thiophene it is nonaromatic. This could be an explanation of the stability of the former molecule. The MOS and the condensed Fukui functions derived from the electronic-structure calculations explain the expected electrophilic substitution of these compounds. The theoretical structure, ionization energies, order of aromaticity, stability, and reactivity are in good agreement with the experimental results <2003T6415>. 

For benzo [, ]thiophene, S and C-3 are the most reactive sites. Note the large condensed Fukui function on the S-atom of benzo[ ]thiophene. The results concur with the experimental information concerning the reactivity and stability of these systems. The principle of maximum hardness establishes that the system would be more stable if the global hardness, related to the FIOMO-LUMO gap, was a maximum. The FIOMO-LUMO gap correlates well with the expected stability of these molecules. This is an indication of the possibility to use hardness as a criterion of stability. 

The same authors also found that the phenylation of benzo[. ]thiophenes and thiophene 2-carbaldehyde proceeded in >80% yields in the presence of Cul (Equations 26 and 27). 

As with thiophene, 2,3-dibromobenzo[/ ]thiophene also exhibits a high regioselectivity in coupling reactions <2005T2245>. For example, Sonogashira coupling with /-butylacetylene leads exclusively to the 3-bromo derivative 90. 2,3-Unsymmetrically substituted derivatives of benzo[/ ]thiophene can be obtained by two successive crosscoupling reactions (Scheme 18). 

Diels-Alder cycloadditions of thiophene-1,1-dioxides with cyclopentadiene can take place either in the (2-1-4) or (4-1-2) mode depending on whether the thiophene dioxide has two or one electron-withdrawing substituents <2006T4139>. 1,3-Dipolar cycloaddition of benzo[/)]thiophene 1,1-dioxide with azomethine ylides has been reported <2006TL5139>. 

Fig. 43. Comparison of differing angles of benzo-, thiophene-, furano- and pyrrolo-building units...

Benzo[fr]thiophene 1,1-dioxide and its derivatives are reduced to the corresponding 2,3-dihydro derivatives by catalytic hydrogenation in good yields (Scheme 94). In this reduction, the sulfonyl moiety remains unchanged [13,189, 238, 239]. However, reduction of benzo[ ]thiophene 1,1-dioxide with LiAlH4 affords deoxygenated 2,3-dihydrobenzo[ ]thiophene in 79% yield [233]. Benzo[fr]thiophene 1,1-dioxide was also reduced to the 2,3-dihydro derivative by an electrochemical method (Scheme 95) [240]. 

Pharmacologically Active Compounds. - 2-Aryl-3-alkoxybenzo[Z)]thiophens have been shown to possess hypolipidemic activity. Alkyl and poly-halophenyl esters of benzo[ ] thiophen-3-carbamic acid show antibacterial and antifungal activities. Benzo[Z ]thiophen-3-sulphonamides show herbicidal activity. Derivatives of 2-cyano-3-hydroxybenzo[Z>] thiophen show sympatholytic activity. ... 

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