2- Hydroxybenzo thiophene

Cyclization of the free acids in acetic anhydride may lead to the decarboxylated 3-acetoxy derivative (Section 3.15.2.2.3). Several 3-hydroxybenzo[ ]thiophenes were obtained in excellent yield by the interaction of phenylsulfonylbenzisothiazolone with substances containing a reactive methylene group in the presence of pyridine (equation... 

Benzo[ ]thiophene normally undergoes electrophilic substitution at the 3-position more rapidly than at the 2-position <1971AHC(13)284>, so both this and formation of the thioester group favor ketonization of 2-hydro-xybenzo[ ]thiophene which occurs 40 times faster than ketonization of 3-hydroxybenzo[ ]thiophene. The rapid rate of ketonization of the thio-ester enol 2-hydroxybenzo[ ]thiophene is also indicated by its 4.4-fold greater rate of ketonization compared to 2-hydroxyindene, which contrasts with what is found with 3-hydroxybenzo[. ]thiophene and 1-hydroxyindene <1986TL3275>. 

The effect of solvent on the equilibrium constants has been studied for the 3-hydroxybenzo[/ ]thiophenes <1986TL3275, 1989JA5346>. The enol is much more stable in hydrogen-bonding solvents than in aptotic solvents. Thus, while enol 213 is barely detected in 060, CCR, or CDCI3, it is predominant in CsDsN and DMSO-i/6. For acid-catalyzed ketonization, the 3-hydroxy monocyclic compounds tautomerize 10-10 times faster than their benzo analogues, presumably via a mesomeric effect due to the lone pair on the heteroatom. 

Hydroxybenzo[ ]thiophene could be generated in 100% yield as the enol form 216 by hydrolysis of its trimethylsilylether 215 (Scheme 13). After ISmin at 32°C, the trimethylsilyl ether 215 in 90% acetone-r4-10% D2O (5 X 10 M DCl) was converted into compound 216 (5(CH) = 6.45), and no keto form, 217 (5(CH2) = 3.92), could be detected. Under these conditions, the enol form has a half-life of ca. 1 day and changes slowly to an equilibrium mixture which contains approximately 40% of the keto form <1989JA5346>. 

The acetyl derivative of 3-hydroxybenzo[ ]thiophene-2-carbaldehyde 222 undergoes acylotropic acid-catalyzed rearrangement to the 2-acetoxymethylenebenzo[ ]thiophen-3(2//)-one 223, which is stable in hydrocarbon solvents up to 100°C (Scheme 15) <1985JOU862>. 

This can be achieved by an indirect method. The lithio derivative is first reacted with a borate ester. Sequential acid hydrolysis and oxidation yields the corresponding hydroxy derivative. This procedure is illustrated by the conversion of 2-lithiobenzo[6]thiophene to 2-hydroxybenzo[6]thiophene, which exists predominantly in the 2(3//)-one tautomeric form (200) <70JCS(C)1926). 

The reaction of methyl thiosalicylate with DMAD yields the Michael adduct (358), which undergoes cyclization on ammonolysis to give methyl 3-hydroxybenzo[fc]thiophene-2-carboxylate (360) through the postulated intermediate 359 (Scheme 55). On the other hand, the reaction of o-mercaptobenzamide with DMAD gives a 1 1 adduct (193) which is converted in the presence of base into the l,3-benzothiazin-4-one derivative (194) [Eq. (31)]. In the reaction of methyl... 

Equilibrium and rate constants for the keto-enol tautomerization of 3-hydroxy-indoles and -pyrroles are collected in Table 32 (86TL3275). The pyrroles ketonize substantially (103-104 times) faster than their sulfur or oxygen analogues, and faster still than the benzo-fused systems, indole, benzofuran, and benzothiophene. The rate of ketonization of the hydroxy-thiophenes and -benzothiophenes in acetonitrile-water (9 1) is as follows 2-hydroxybenzo[b]thiophene > 2,5-dihydroxythiophene > 2-hydroxythiophene > 3-hydroxybenzo[/ Jthiophene > 3-hydroxythiophene. 3-Hydroxythiophene does not ketonize readily in the above solvent system, but in 1 1 acetonitrile-water, it ketonizes 6.5 times slower than 2-hydroxythiophene (87PAC1577). 

Hydroxybenzo[6]thiophenes exist as oxo tautomers and are referred to as thiooxindoles. O- Alkylation of thiooxindole is favoured in polar aprotic solvents thus NaH/HMPT/Me2S04 gives a 90% yield of 2-methoxybenzo[6]thiophene. Treatment of thiooxindole with two equivalents of NaOH and dimethyl sulfate, or... 

Thiophthalide (452) is the oxo form of l-hydroxybenzo[c]thiophene. It is a stable compound, being intermediate in oxidation level between o-xylene and phthalic acid. It can be formed from o-xylene by oxidation with a mixture of sulfur and water at high temperatures it can also be formed by reduction of phthalic anhydride with H2S + H2 (72AHC( 14)331). It reacts with vinyllithium to form a complex which on hydrolysis undergoes ring expansion to 4,5,6,7-tetrahydro-2//-benzo[c]thiepin-5-one (453), as shown in Scheme 154. 

These derivatives may be obtained by reduction of the appropriate nitro derivative catalytically or with a metal-acid system, or by Beckmann or Hofmann rearrangements of suitable acyl or carboxamido derivatives. 4-Aminobenzo[6]thiophene has also been prepared by means of a Bucherer reaction with 4-hydroxybenzo[6 Jthiophene. Several 5-aminobenzo[6]thiophenes have been prepared by cyclization reactions of p-acetamino-phenylthio derivatives. 6-Acetaminobenzo[6 Jthiophenes may be obtained from the corresponding 6-acetyl derivative by Schmidt or Beckmann rearrangements. 7-Aminobenzo[6 ]thiophene can also be prepared from 7-hydroxybenzo[6 ]thiophene by a Bucherer reaction (70AHC(ll)l77). 

Oxygen-linked Thiophenes and Benzo[6]thiophenes 3.1S.9.4.1 Hydroxy thiophenes and hydroxybenzo[b]thiophenes... 

The presence of benzo[6]thiophene and two methylbenzo[6]-thiophenes in coal tar has been known for some time.7 In 1959, 4- and 6-hydroxybenzo[6]thiophene were isolated from the phenolic portions of the washing oil from coal tar.42... 

When a cyclization reaction leads to mixtures of two isomeric benzo[6]thiophenes, their relative proportions are readily estimated by examination of the 1H NMR spectrum of the mixture.96 104-106 Mixtures obtained by acetylation98 and bromination 76,90 reactions and by Baeyer-Villiger oxidation of acetylbenzo[6]thiophenes107 have been similarly analyzed. The 19F NMR spectra of several polyfluoro-benzo[6]thiophenes have been examined,103,108-m and used to study the reaction of 4,5,6,7-tetrafluorobenzo[6]thiophene with nucleophiles.108 The tautomerism of 2-amino-,112-114 3-N-phenylamino-,116 and 3-hydroxybenzo[6]thiophene109,116-117 derivatives has been studied by 7H NMR spectroscopy. 

IR spectroscopy has been used to show that 2-aminobenzo[6]thio-phenes normally exist solely as the amino tautomer,112-114 and that 2 ii2,ii3 an(j 3-hydroxybenzo[6]thiophenes117,147 exist solely as the keto tautomers, except that compounds with an adjacent carbonyl-containing group exist mainly as the enols.109,116,147> 148 3-Hydroxy-2-nitrobenzo[6]thiophene-l,1-dioxide exists as a mixture of the keto and enol forms.149... 

The thermodynamic ionization constants of several hydroxybenzo-[6]thiophenes have been determined by spectroscopic measurements on the anions.196... 

Tetrahydrobenzo[6]thiophen-4-one may be converted into 4-hydroxybenzo[6] thiophene by heating it with sulfur,453 or by catalytic dehydrogenation.454,455 5-Methyl- and 5-ethyl-4-hydroxy-benzo[6]thiophene may be prepared similarly.437... 

Aminobenzo[6]thiophene is prepared from 7-hydroxybenzo[6]-thiophene by means of the Bucherer reaction it may be converted into 7-nitrobenzo[6]thiophene via the diazonium salt.84 5,7-Diamino-3-phenylbenzo[6]thiophene and its 2-carboxylic acid are prepared by reduction of the corresponding dinitro compound.334 Partial reduction of o,7-dinitro-3-phenylbenzo[6]thiophene-2-carboxylic acid with ethanolic ammonium sulfide affords 7-amino-5-nitro-3-phenylbenzo-[6]thiophene-2-carboxylic acid, the amino group of which may be replaced by hydrogen or iodine via the diazonium salt.334 7-Amino-4-methoxybenzo[6]thiophene is mentioned in the patent literature.560... 

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