3- benzo thiophenes

PdClj (10 mol%), AgOAo (4.0 equiv.) lodobenzene (2.0 equiv.), AcOH (4.0 equiv.) 

---

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). 

Scheme 7.5 Heck reactions of dihydrofuran with phenyl- or cyclohexenyl-triflates with (benzo)thiophene-containing phosphinooxazoline ligands.

Hatanaka, S. Yamada, M., and Sadakane, O., HDS of Catalytic Cracked Gasoline. 1. Inhibiting Effects of Olefins on HDS of Alkyl(Benzo)Thiophenes Contained in Catalytic Cracked Gasoline. Ind. Eng. Chem. Res, 1997. 36 p. 1519. 

Intramolecular palladium catalyzed thio-enolate S-arylation has been used in a route to a set of fused benzo[ ]thiophenes, as illustrated by the conversion of the substrate 10 into the product 11 <06T11513>. 

Sulfur. Thiophene and benzo[ >] thiophene are both aromatic heterocycles, as discussed earlier in this review. Isothiazole is a planar molecule with an aromaticity comparable with those of thiazole and pyrazole, and higher than those of isoxazole and oxazole,122 140 as evaluated on the basis of Bird s aromaticity index A, based upon the statistical degree of uniformity of the bond orders of the ring periphery. Theoretical calculations and experimental data in connection with the aromaticity of isothiazole have been reviewed.141 Thiazole is also viewed as an aromatic molecule, similar to thiophene. It lacks an experimental aromaticity value, but the heat of formation together with bond lengths and angles have been calculated by various computational meth-... 

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. ... 

Q Why should thiophene 1.1-dioxide behaves as a diene in cycload-dition reactions, whereas benzo[/))thiophene . I-dioxide acts as a dienophilc ... 

Benzo[Z ]pyrrole, Benzo[Z ]furan and Benzo[ ]thiophene... 

Benzo[b]pyrrole, Benzo[b]furan and Benzo[(>]thiophene 111... 

A general route to both benzo[/)]furans and benzo[/>]thiophenes depends upon the cyclodehydration of either 2-hydroxy- or 2-sulfanylbenzyl ketones or aldehydes (Scheme 7.23a). 2-Acetylbenzo[6]furan can be obtained by reacting the sodium salt of 2-formylphenol with chloroace-tone (chloropropanone) (Scheme 7.23b). A similar reaction using sodium 2-formylbenzenethiolate yields 2-acetylbenzo[Z)]thiophene. 

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>. 

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... 

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>. 

H 1. R—MgBr/CuJ/THF/Elher Zugabe des Eduktes bei --10° dann 20 25s A- 6h 2. HCl/HjO R 5-Amino-4-butyl-l-benzo- thiophen 5-Amino-4-benzyl-l-benzo- thiophen 60 63 2... 

The chemistry of the o-quinonoidal heterocycles benzo[c] indole (isoindole, 1) and benzo[< ]thiophene (2) has been previously reviewed in this... 

Pathway III of Fig. 26 has been demonstrated for thiophene and benzo-thiophene with Ir complexes (4) and for all thiophenes, including dibenzo-thiophene, with Rh complexes (94, 95). These oxidative additions appear to be influenced by substituents present on the carbon atoms adjacent to the sulfur atom. Insertion between sulfur and the unsubstituted carbon is highly preferred. For 2-methylthiophene the exclusive product is the 1-5 bond insertion product, whereas for 3-methylthiophene, no preference for insertion was observed (1-2 and 1-5 bond insertion products were equal). In competitive studies, thiophene was found to be about twice as reactive as 2,5-dimethylthiophene. This behavior is similar to that observed for relative reaction rates of substituted thiophenes observed with conventional HDS catalysts. Thus steric limitations can occur, even with monomeric, homogeneous catalysts. 

The TT-electron excess of the five-membered rings is accompanied by a high rr-donor character. The best measure of rr-donation is the value of first ionization potential, IP, which for all aromatic heterocycles with one heteroatom of pyrrole type reflects the energy of highest occupied rr-orbital. IP, values decrease in the sequence pyrrole > indole > carbazole furan > benzo[/ ]furan > dibenzofuran thiophene > benzo[/ ]thiophene (Section 2.3.3.9, Tables 21 and 23). Thus, the more extensive the rr-system, the stronger is its electron donor ability. Furan and thiophene possess almost equal rr-donation, which is considerably lower than that of pyrrole. 

In fact, benzo[ ]furan undergoes mainly a-substitution, benzo[ ]thiophene undergoes mainly 13-substitution and indole undergoes almost exclusive (3-substitution. This again illustrates the very strong directing effect of the oxygen atom to the a-position. 

Indole is sulfonated under similar conditions to pyrrole the 3-sulfonic acid is formed. Benzo[ ]thiophene is also sulfonated in the 3-position (71AHC(13)235). 

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). 

Silica gel is an effective catalyst for the t-butylation of thiophene and benzo[/ ]thiophene using t-butyl bromide. 2,5-Di-r-butylthiophene and 3-f-butylbenzo[b]thiophene can be prepared easily by this procedure (84JOC4161). Alkylation of thiophene with f-butyl chloride, isopropyl chloride or ethyl chloride at - 70°C in the presence of A1C13 produced a-complexes under kinetic control. On thermal equilibration, migration of alkyl from position 3 to position 2, as well as disproportionation to dialkyl-and trialkyl thiophenes can occur (86T759). 

Benzo[ >]thiophene dianion (173) has been prepared by reduction of benzo[ >J thiophene with sodium metal at - 78°C in [2H8]THF. The H 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 (4n)Tr polycyclic dianion. The dianion undergoes oxidation to benzo[ ]thiophene with oxygen (85CC1033). 

To obtain compounds unsubstituted at positions 2 and 3, cyclization of the acetals (53) using polyphosphoric acid catalysis gives indoles (81JOC778), benzo[ >]furans, and benzo[ >]thiophenes (54) (71T1253). 

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). 

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). 

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. 

---