Tetrahydrobenzo thiophen-4-ones

The oximes of 4,5,6,7-tetrahydrobenzo[6]thiophen-4-one and -7-one undergo the Beckmann rearrangement to give 146 354 451 and 147 (R = H),362 respectively. Compound 147 (R=C1) may be prepared similarly and by treating 2-chloro-4,5,6,7-tetrahydrobenzo[ ]thio-phen-7-one with ammonia in the presence of PPA.356 The oxime of 4,5,6,7 -tetrahydrobenzo [6]thiophene- 4-one affords 4-aminobenzo [6]-thiophene in a modified Leuckart reaction.241,355 The same oxime may be converted into 4-amino-4,5,6,7-tetrahydrobenzo[ ]thiophene by reduction with aluminum amalgam in methanol.452 The parent ketone also affords 4-amino-4,5,6,7-tetrahydrobenzo[6]thiophene on reaction with formamide at 165°, followed by acidic hydrolysis of the resulting 4-formylamino compound.355... 

In a series of tetrahydrobenzo[ ]thiophene analogues, we have identified novel selective dopamine D3 receptor agents, one of which displays a 100-fold selectivity over dopamine D2 receptors. These results provide information for the development of pharmacophoric models of the dopamine D2 and D3 receptor subtypes that can be used for the future development of selective agonists at these receptor subtypes. 

Substituted derivatives of l-(tetrahydrobenzo[b]thiophen-2-yl-3-carboxylate)-5-phenyl-6-thio-l,2,4-triazin-4-one have been synthesized by heterocyclization reactions of different hydrazones obtained from 2-amino-tetrahydrobenzo[b]thiophene-3-carboxylate with phenyl isothiocyanate <00PS275>. Reaction of 5-methyl isothiosemicarbazide with a-amino acid vicinal tricarbonyl reactive substrates 1 and 2 yields 1,2,4-triazine substituted a-amino acids, as an equimolar mixture of regioisomers 3a/3b and 4a /4b, respectively <00JCS(P1)299>. 

When 3-mercaptocyclohexanone condenses with dichloroacet-aldehyde or chloroacetaldehyde in the presence of a catalytic quantity of acid (e.g., p-toluenesulfonic acid), simultaneous cyclization occurs to give 4,5,6,7-tetrahydrobenzo[6]thiophen-4-one (see Section VI, B, 4) and 2,4,5,6,7,7a-hexahydrobenzo[6]thiophen-4-one (see Section... 

Tetrahydrobenzo[6]thiophen-4-one (103) may be prepared from y-(2-thienyl)butyric acid by cyclization with phosphoric acid854 or by Friedel-Crafts cyclization of the corresponding acid chloride.194, 355.358 j s 5-methyl,357 2-ethyl,194 2-isopropyl,358 2- and 3-tert-butyl,359 2,3-dimethyl,360 2-ethyl-3-methyl,360 and 2-bromo 354 derivatives and diethyl 4,5,6,7-tetrahydrobenzo[6]thiophene-4,5-di-carboxylate861 may be prepared similarly. 4,5,6,7-Tetrahydrobenzo-[6]thiophen-7-one (104)357 362,863 and its 5- and 6-methyl 357 and 2-chloro 362 derivatives are obtained from the appropriately substituted y-(3-thienyl)butyric acid, A recent patent 364 describes the vapor phase cyclization of y-(2-thienyl)butyric acid to 103. Ketones (103 and 104) are useful intermediates for the synthesis of 4- and 7-substituted benzo[6]thiophenes, respectively their reactions are discussed in Section VI, B, 4. 

Tetrahydrobenzo[6]thiophene may be prepared by Clem-mensen355 or Huang-Minlon194,356,436 reduction of 4,5,6,7-tetra-hydrobenzo[6]thiophen-4-one (103) or by Wolff-Kishner reduction of... 

The synthesis of 4,5,6,7-tetrahydrobenzo[6]thiophen-4-one and -7-one has been described in Section IV, G 4-methyl-4,5,6,7-tetra-hydrobenzo[6]thiophen-5-one is obtained on oxidation of 136 (R = Me) with per benzoic acid.438... 

Bromination (Br2) of 4,5,6,7-tetrahydrobenzo[6]thiophen-4-one affords either a 2-bromo or a 5-bromo derivative, depending on whether the reaction is carried out at 0° in ether,445,446 or at—5 to 0°in 50% aqueous acetic acid.354 The 5-bromo derivative condenses with morpholine or potassium phthalimide to give 140a or 140b, respectively.445, 446 Hydrazinolysis of 140b fails to give any of the 5-amino derivative.445,446 On nitration, the 2-bromo derivative affords the 3-nitro compound or 141 (R = N02), depending on the reaction conditions.354 With sodium azide in PPA the 2-bromo and 2-bromo-3-... 

Tetrahydrobenzo[6]thiophen-4-one undergoes the Stobbe condensation with diethyl succinate to give the half-ester (143), hydrolysis of which yields the corresponding diacid.447 Decarboxylation of the diacid affords the spirolactone (144). 

In a Reformatsky reaction with ethyl bromoacetate, 4,5,6,7-tetrahydrobenzo[6]thiophen-4-one affords a mixture of two esters [Eq. (10)].355 448 4,5,6,7-Tetrahydrobenzo[6]thiophen-7-one behaves analogously.363... 

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... 

Arylbenzo[6]thiophenes can be prepared by ring closure (Section IV) 2-phenylbenzo 7 ]thiophene may be prepared by treating 2-benzo-[6]thienyllithium with fluorobenzene 185,307 and 4- and 7-phenylbenzo-[6]thiophene can be synthesized from 4,5,6,7-tetrahydrobenzo[ ]thio-phen-4-one and -7-one, respectively (Section VI, B, 4). Arylbenzo[6]-thiophenes have been synthesized by cyclodehydration of keto-derivatives (Section VI,L, 3). 6-Phenylbenzo[6]thiophene has not yet been reported. 

Hydroxybenzo[6]thiophene has been isolated from coal tar.42 It may be prepared by dehydrogenation of 4,5,6,7-tetrahydrobenzo-[6]thiophen-4-one (Section VI,B, 4), and from 4-aminobenzo[6]thio-phene by standard procedures.422... 

Successive reduction of l,3-dimethyl-4,5,6,7-tetrahydrobenzo[c]-thiophen-4-one (Section III,C) with sodium borohydride and dehydration of the resulting alcohol with polyphosphoric acid gives the unstable 1,3-dimethyl derivative [(18) R = H] in excellent yield,35 and successive treatment of the same ketone with methylmagnesium iodide and acid gives the 1,3,7-trimethyl derivative [(18) R=Me] (Table IV) and a second compound which is reported to be a dimer. 36 When l,3-dimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one is treated with a mixture of phosphorus oxychloride and dimethyl-formamide (Vilsmeier-Haack formylation), it gives compound 19, which yields 20 on being treated successively with thioglycolic acid... 

Several derivatives of 4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (Table III) have been prepared by the sequence of reactions exemplified by Eq. (2) or by a closely related sequence of reactions. When... 

Tetrahydrobenzo[c]thiophen-4-one and its derivatives may be reduced to the corresponding 4,5,6,7-tetrahydrobenzo[c]thiophene (Table II) by the Clemmensen41 or Wolff-Kishner-Huang Minion10, 35,42 procedure catalytic reduction of the parent ketone gives the saturated alcohol (29).43 Several reactions of l,3-dimethyl-4,5,6,7-... 

Several thieno[3,2-6]thiophenes (67) are produced by pyrolysis of various 1,2-dithioles, including bi(l,2-dithiol-3-ylidenes) (20), alkali metal salts of l,2-dithiole-3-sulfonyI hydrazides (68) (75TL3473), and tetrahydrobenzo-l,2-dithiol-3-ones (69) (63BSF161). 

Aminofuran-, -pyrrole-, and -thiophene-3-carboxylates and -3-nitriles such as 58 are obtained in a simple, one-step reaction from a-oxo-alcohols, -amines, and -thiols (57) with methylene-active nitriles.53 Thus ethyl 2-amino-4,5,6,7-tetrahydrobenzo[h]thiophene-3-carboxylate (59) results from cyclohexanone, sulfur, and ethyl cyanoacetate26,53 (Scheme 11). The accessible... 

Scheme 8.2. Synthesis of tetrahydrobenzo[/j]thiophene-annulated 1,3-oxazin-6-ones.

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