Azepin-3-ones, 1,2,6,7-tetrahydro

Simple and elegant syntheses of five different heterocyclic systems, namely, hexahydro-1,4-epithiopyrimidin-3-ones, tetrahydro-1,4-epithio-azepin-3,7-diones, hexahydro-1,4-epithiopyridin-3-ones, tetrahydro-4,7-... 

A similar sequence of reactions on l,2-dihydroindeno[l,2-tautomeric mixture of the oxo 11a and hydroxy 12a forms.57 Prolonged treatment of the tetrahydro compound 10 with NBS in refluxing dibro-momethane results in bromination of the indene ring and formation of the 10-bromo derivative... 

Hydrogenation of 2-butoxy-3//-azepine (3) with palladium on charcoal and hydrogen affords 2-butoxy-4,5,6,7-tetrahydro-3f/-azepine (4),79 whereas reduction of the 2-benzyloxy derivative, under the same conditions, is accompanied by debenzylation and formation of hexahydroazepin-2-one (77% mp 67-69 C).79,241... 

Ring expansion of 4J5>6,7-tetrahydro-4-indolone oximes also underpinned the synthesis of the 3//-azeto[l,2-a]pyrrolo[3,2-c]azepin-8-ones 30 (eg. R = H, Me) in good yield <00H(53)557>. 

Some difficulty has been encountered with the TV-alkylation (e.g. with ethyl bromoacetate) of 2,3,4,5-tetrahydro-l//-l-benzazepin-5-one (31 R = H) (74JCS(P1)1828). The pharmacological activity (Section 5.16.5) of TV-substituted 5H-dibenz[6,/]azepine and its 10,11-dihydro derivatives has resulted in an intensive study of the TV-alkylation of these ring systems (74CRV101). Generally, alkylation is effected with an alkyl halide or tosylate in the presence of base. Phase transfer TV-alkylations of 5H- dibenz[6,/]azepine have been reported. The method, however, is less successful with the 10,11-dihydro derivatives (79MI51600). 

Examples of electrophilic substitution (other than protonation) at the heterocyclic ring of benz- and dibenz-azepines appear to be confined to a few Vilsmeier reactions. 8-Chloro-l//-l-benzazepin-2-one with a mixture of DMF and POCl3 yields the 2,8-dichloro aldehyde (106) (72CPB1325). Under similar conditions Ar-mesyl-4,5-dihydro-3//-3-benzazepine formylates at the 1-position (107 R1 = CHO, R2 = H) (71BSF3985). In contrast, (V-mesyl-1,2,4,5-tetrahydro-3/7-3 -benzazepin-1 -one yields a mixture of the 1-chloro dihydro compound (107 R1 = Cl, R2 = H) and the chloro aldehyde (107 R1 = Cl, R2 = CHO). 

Alkylation of 3-methyl-1,2,4,5-tetrahydro-3//-3-benzazepin-2-one in THF-DMF solution containing sodium hydride, with primary and secondary alkyl halides and with a-bromoesters, results predominantly in 1-monoalkyl derivatives, whereas with w,w-dibromoalkanes, 1,1-spiro derivatives are formed (80T1017). Apparently, 6,7-dihydro-5//-dibenz[6,rf]azepin-6-one does not condense with benzaldehyde or with nitrosobenzene at the active methylene group (55JA3393). 

Reports of pericyclic cyloadditions to other azepine systems are rare. Addition to the diene system of 6,7-dihydro-l//-azepines occurs readily with DMAD (72CPB1740) and with N-phenylmaleimide (73JA7320). The 5,5a-dihydro-3-benzazepin-2-one (157), a suspected but non-isolable intermediate in the formation of l,2,4,5-tetrahydro-3//-3-benzazepine-2,4-diones by photoaddition of diphenylketen to amino-2//-azirines, has been trapped in the photolysate by N-phenyl-1,3,4-triazoline-2,4-dione as the [4+2]tt adduct (158). Its structure was confirmed by X-ray analysis (80JOC2951). 

Hydrodebromination accompanies the partial reduction of the aminobromoazepine (111 X=Br) to its amidine hydrobromide (67JOC2367). Partial reduction of 2-dimethylamino-3H-azepine to the 4,5-dihydro derivative is possible with hydrogen and 5% Pd-C (73CC327). Wolff-Kishner reduction of 2,3,4,5-tetrahydro-2-phenyl-lfT-l-benzazepin-4-one proceeds normally to give the tetrahydroazepine (79JOC4213). 

The reduction of dibenz[6,e]azepine-5,ll-dione has been studied intensively (65CCC445). Clemmensen reduction, or reduction over palladium in acetic acid, yields the -ll//-5-one, whereas reduction over Adams catalyst furnishes the ll-hydroxy-5-one. Sodium in butanol effects reduction to a mixture of the -ll//-5-one and its 7,8,9,10-tetrahydro derivative. 

The bacterial translocase 1 inhibitor, A-500359C, 17 (and a methoxy analogue A-500359A), isolated from Streptomyces griseus SANK 60196, has been shown to incorporate a tetrahydro azepin-2-one unit <03JAN243>. 

---