Benzo thiophenes, amino

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C(2) as nucleophile. These include useful ring syntheses for benzo[A]-fused compounds. The sequence 78 79 80 (Scheme 51) has been extensively applied to obtain benzo[A]furans <1948JCS2254>, benzo ]thiophenes <1931LA(488)259>, and less frequently, indoles <1927JCS1937>. Corresponding nitriles (e.g., 81) afford 3-amino derivatives (Scheme 52). 

Also the introduction of a methylene group between the six-membered ring and the nitrogen in 6-(N,N-di- -propyl)amino-4,5,6,7-tetrahydrobenzo[ ]thiophene (34) gives a compound with a moderate affinity for the dopamine D3 receptor and no affinity for the dopamine D2 receptor. This affinity resides in the (+)-enantiomer of the compound. Introduction of substituents on the 2-position of 6-(N,N-di- -propyl)aminomethyl-4,5,6,7-tetrahydro-benzo[/>]thiophene (36) gives compounds (70, 71) without affinity for the dopamine D2 and D3 receptors. 

Benzo[Z>]thiophen 5-Oxides. - Mild methods for the oxidation of 2,3-dihydrobenzo[Z>] thiophens to the sulphoxide have been developed. The photochemical reactions of various 2- and 3-substituted benzo[ ]-thiophen 1-oxides led to different photodimers. From 3-chlorobenzo[b]-thiophen-2-carboxylic acid 1,1-dioxide, 1,3-oxazinones of biological interest were obtained through cyclization reactions with cyanamides and carbodi-imides. Secondary amines add to 2-phenylbenzo [b] thiophen 1,1-dioxide to give 3-amino-substituted 2,3-dihydro-2-phenylbenzo[b]thiophen 1,1-dioxides. " ... 

Reaction at Sulphur.—The oxidation of benzo[6]thiophens to sulphoxides by t-butyl hypochlorite has been studied. In the presence of a ruthenium catalyst, dibenzothiophen was oxidized by oxygen to the sulphone. The reactions of benzo[ >]thiophen 1,1-dioxides with various reagents such as amines, amino-alcohols,3-aminopropylsilanes, and aromatic sulphonyl chlorides have been studied. Four detailed papers on the reaction of dibenzophenonium salts with aryl-lithiums have appeared in which the mechanism of ligand exchange was elucidated. " ... 

The use of free-radical reactions for this mode of ring formation has received rather more attention. The preparation of benzo[Z)]thiophenes by pyrolysis of styryl sulfoxides or styryl sulfides undoubtedly proceeds via formation of styrylthiyl radicals and their subsequent intramolecular substitution (Scheme 18a) (75CC704). An analogous example involving an amino radical is provided by the conversion of iV-chloro-iV-methylphenylethylamine to iV-methylindoline on treatment with iron(II) sulfate in concentrated sulfuric acid (Scheme 18b)(66TL2531). 

Benzo[6]thiophene, 2-acetyl-3-hydroxy-synthesis, 4, 892 Benzo[6]thiophene, 2-acyl-synthesis, 4, 918 Benzo[6]thiophene, 3-acyl-synthesis, 4, 918- 19 Benzo[6]thiophene, acylamino-synthesis, 4, 815 Benzo[6]thiophene, alkenyl-synthesis, 4, 917 Benzo[6]thiophene, 2-alkoxy-synthesis, 4, 929 Benzo[6]thiophene, 3-alkoxy-synthesis, 4, 929 Benzo[6]thiophene, 4-alkoxy-synthesis, 4, 930 Benzo[6]thiophene, 2-alkyl-synthesis, 4, 877-878 Benzo[6]thiophene, 2-alkylthio-synthesis, 4, 931 Benzo[6]thiophene, 2-amino-diazotization, 4, 810 reactivity, 4, 797 stability, 4, 810 synthesis, 4, 869, 924-925 tautomerism, 4, 38 Benzo[6]thiophene, 3-amino-cycloaddition reactions, 4, 68 synthesis, 4, 109, 881, 925 Benzo[6]thiophene, 4-amino-synthesis, 4, 925 Benzo[6]thiophene, 5-amino-synthesis, 4, 925 Benzo[6]thiophene, 7-amino-synthesis, 4, 925 Benzo[6]thiophene, 3-t-amyl-synthesis, 4, 915 Benzo[6]thiophene, 2-aryl-synthesis, 4, 881... 

Azido-2-formylbenzo[b]-thiophene 613 is thiated and cyclized by 601 and HCl to give benzothieno[3,2-c]isothiazole 614 in 50% yield whereas 613 is reduced on treatment with 601, in the absence of HCl, to give 3-amino-2-formyl-ben-zo[b]thiophene 615 this reacts with excess 601 and HCl to give 3-amino-2-thiofor-myl-benzo[b] thiophene 616 [156] (Scheme 5.50). 

When 2 -methoxy-2-biphenylamine is diazotized in fluoroboric acid, an 85% yield of solid 2 -methoxy-2-biphenylyldiazonium tetrafluoroborate is produced. On heating in dry benzene, this salt loses nitrogen and provides 0-methyldibenzofuranium tetrafluoroborate as an unstable solid. The latter salt, on account of the low basicity of dibenzofuran, reacts with a range of nucleophiles that undergo methylation with the release of dibenzofuran. Pyridine and pentachloropyridine are N-methylated, benzo[fc]thiophene is S-methylated, and tetrahydrofuran and phenetole are 0-methylated. ° Thus it is no surprise that diazotization of 2 -methoxy-2-biphenylamine, followed by boiling of the diazonium salt in acidic solution, provides dibenzofuran in 90% yield.The scope of this method of dibenzofuran synthesis (Scheme 18) has been little explored probably because of the difficulty of preparing the requisite biphenyls, which is usually accomplished by a crossed Ullmann reaction. A similar synthesis of xanthones from 2-amino-2 -methoxybenzophenones is known. ° ... 

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. 

Thioether cleavage of 68a with aluminum bromide in benzene112 or ethereal hydrogen chloride 285 affords 2-aminobenzo[6]thiophene in high yield. Similar cleavage of 68b and 68c gives 2-amino-3-methyl-benzo[6]thiophene and the imine (14), respectively.113... 

Nitrobenzo[6]thiophene may be prepared by reaction of the 3,4-dinitro compound with alcoholic ammonium sulfide422-538 other workers have claimed that this method yields only traces of the desired product.84 It may also be prepared by deamination of 5-amino-4-nitrobenzo[6]thiophene,162,422 or by decomposition of 4-benzo[6]-thiophene diazonium cobaltinitrite with aqueous sodium nitrite in the presence of cuprous oxide and cupric sulfate.84 7-Nitrobenzo[6]-thiophene may be obtained by the latter method (15% yield) from the corresponding amine.84... 

Cope and Burrows414 have prepared a number of aminoalkylbenzo-[6]thiophenes with the general formula (195) by Friedel-Crafts reaction between benzo[6]thiophene and various amino tertiary alcohols. On treatment with formamide in formic acid, (3-benzo[6]-thienyl)acetone affords 3-(2-aminopropyl)benzo[6]thiophene [Eq. (11)].557 Recent patents535,570 describe how isocyanates with the... 

Cyanomethylbenzo[6]thiophene condenses with 2-methylthio-1-naphthaldehyde to give 199,571 and it affords 200 on formylation with ethyl formate and sodium methoxide.524 Compound 200 reacts with hydrazine under suitable conditions to give either 201 or 3-amino-4-(3-benzo[6]thienyl)pyrazole (202).524 With ethylene-... 

Amino ketones are discussed in Section VI, L, 3,c, and amino alcohols and benzo[6]thiophenes containing the 2-haloethylamine moiety are considered in Section VI, J. 

Carbethoxycyanomethyl)benzo[6]thiophene - 4,5 - quinone (273 R = R = H)497 and its 3-bromo152 and 2-carboxy497 derivatives may be prepared also by reduction of the corresponding 5-hydroxy-4-nitroso(or 4-nitro)benzo[6]thiophene with Raney nickel and hydrazine in ethanol, to give an unstable 4-amino-5-hydroxybenzo[fr]thiophene, which is oxidized directly in situ by ferricyanide in the presence of base and ethyl cyanoacetate. Under these conditions, condensation of the resulting quinone occurs before its decomposition. 

Aminobenzo[6]thiophene-2-carhoxylic acids are conveniently obtained by reduction of the corresponding nitro compound.152,185,333, 334,33c, 338,497 Djazotization of these, followed by the usual replacement reactions of the diazonium group, provides many substituted benzo[6]thiophene-2-carboxylic acids, decarboxylation of which leads to some otherwise rather inaccessible benzo[6]thiophenes. 5-Hydroxy-benzo[6]thiophene-2-carboxylic acid is most conveniently prepared from the corresponding amino compound by means of the Bucherer reaction,338,497 in which the dicarboxylic acid (303) is formed as a by-product.152... 

The azlactone formed from benzo[6]thiophene-2-carboxaldehyde and hippuric acid reacts with hydriodic acid and red phosphorus to give a-amino-/9-(2-benzo[6]tbienyl)propionic acid, and with sodium hydroxide to give a-benzamido-j8-(2-benzo[6]thienyl)acrylic acid.477 A series of a-amino-j8-(5-substituted-3-benzo[6]thienyl)propionic acids (312 R = H) has been prepared by hydrolysis of the product of... 

Reaction of benzo[6]thiophene-2-carboxaldehyde with pyruvic acid yields the keto acid (321), the oxime of which gives a-amino-y-(2-benzo[6]thienyl)butyric acid (322) on catalytic hydrogenation, and j9-(2-benzo[6]thienyl)acrylonitrile on treatment with acetic anhydride the latter yields 8-(2-benzo[6]thienyl)acrylic acid on hydro-... 

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