Studies on the syntheses of analgesics. Part XXXI. Synthesis of 1,2,3,4,5,6-Hexahydro-3-methyl-6-phenyl-2,6-melhano-2,3-benzo[g] diazocine [studies on the syntheses of heterocyclic compounds. Part CDLXXIX]

1,2,3,4,5,6 Hexahydro-8-methoxy-3-methyl-6-phenyl-2,6-methano-2,3-benzo[g]diazocine (IIa) was synthesized from 1-(3-methoxyphenyl)phenylaeetonitrile (III), readily available by the benzyne reaction of o-chloroanisole with phenylacetonitrile, through several steps. Treatment of IIa with 47% hydrobromic acid afforded 1,2,3,4,5,6-hexahydro-8-hydroxy-3-methyl-6-phenyl-2,6-methano-2,3-benzo[g]diazocine (IIb).     

Snytheses of analgesics. Part XXXVII. An alternative synthesis of 1,2,3,4, 5, 6-hexahydro-8-hydroxy-2,6-methano-6, h-dimethyl-3-phenethyl-3-benzazoeine [studies on the syntheses of heterocyclic compounds. Part DXXI]

Acid treatment of the alkylated products of (Va, Vb, and VIII) of piperidinols IVa and IVb, and tetrahydropyridine VII with β-bromoethylbenzene, afforded 1,2,3,4,5,6-hexahydro-8-hydroxy-2,6-methano-6,1 1-dimethyl-3-phenethyl-3-benzazocine (la) in good yield. Piperidinols Va and Vb were also obtained from the reaction of N-(3-methyl-3-pentenyl)-β-phenethylamine (IIb) with methyl 3-(4-methoxyphenyl)-2,3-epoxypropionate.     

Syntheses of benzomorphan and related compounds. Part III. An alternate synthesis of 3-substituted-1,2,3,4,5,6-hexahydro-8-hydroxy-2,6-methano-6,11-dimethyl-3-benzazocine

Reduction of the appropriate Schiff bases gave 5-benzylamino-3-methyl-2-pentene (XVII) and l-benzylamino-3-methylpentane (XVIII), the condensation of which with methyl 3-(4-methoxyphenyl)-2,3-epoxypropionate afforded a mixture of the isomeric 1-benzyl-2-(4-methoxy-benzyl)-3,4-dimethyl-4-hydroxypiperidines (XIXa and XIXb). The piperidinols were heated with hydrobromic acid, respectively, to afford 3-benzyl-1,2,3,4,5,6-hexahydro-8-hydroxy-2,6-methano-6,11-dimethyl-3-benzazocine (II). Since the conversion of II to pentazocine (Ic) had already been accomplished, an alternate synthesis of Ic was achieved.     

Syntheses of benzomorphan and related compounds. Part 1. Synthesis of N-substituted-l,2,3,4,5,6-hexahydro-8-hydroxy-2,6-methano-6,11-dimethyl-3-benzazocine [studies on the syntheses of heterocyclic compounds. Part CCLXXXII ]

A modified synthesis of pentazocine, l,2,3,4,5,6-hexahydro-8-hydroxy-2,6-methano-6, H-dimethyl-3-(3-methyl-2-butenyl)-3-benzazocine (III), has been achieved and catalytic hydro-genation has been found to be effective for the debenzylation of quaternary ammonium salts.     

Studies on the syntheses of analgesics. Part XXXVI. Synthesis of 1,2,3,4,5,6-ilexahydro-2,6-methano-6-phenyl-2 henzazocine [studies on the syntheses of heterocyclic compounds. Part D XI]

An attempt to obtain 2,3,4,5,6,7-hexahydro-lH2,7-methano-9-methoxy-3-rnethyl-7-phenyl-2,3-benzodiazonine (II) by the Pictet-Spengler reaction of 2,3,4,5,6,7-hexahydro-lH-4-(3-meth-oxyphenyl)-l-methyl-4-phenyl-1,2-diazepine (XI) prepared through several steps from 1-(3-methoxyphenyl)phenylaeetonitrile (IV) resulted instead, in the formation of 1,2,3,4,5,6-hexa-hydro-2,6-methano-8-methoxy-6-phenyl-2-benzazocine (XIV).     

Syntheses of analgesics. Part XXX.. Conformational studies of diastereoisomeric quaternary ammonium salts of 1,2,3,4,5,6-Hexahydro-2,6-methano-3-benzazocines

The configuration of the quaternary ammonium salts (Va and Vb) from 3-benzyl-1,2,3,4,5,6-hexahydro-8-hydroxy-6,11-dimethyl-2,6-methano-3-benzazocine. (II) and 3-methyl-2-butenyl bromide was determined spectroscopically. Moreover, configurational studies on 3-benzyl (VIa and VIb) and 3-(3-methyl-2-butenyl)benzazocinium bromides (VIIa and VIIb) were also achieved.     

Studies on the synthesis of analgesics. Part 51. Synthesis of 4-(1-oxo-2-isoindolinyl)phenyl derivatives. [Studies on the syntheses of heterocyclic compounds. Part 779]

In order to examine their effect on carrageenin-induced edema in rats, 4-(1-oxo-2-isoindolinyl)-phenyl derivatives were synthesized. 2-Hydroxy-3-[4-(1-oxo-2-isoindolinyl)phenyl]butyramide was found to be more effective than phenylbutazone.     

Studies on the syntheses of analgesics. Part XXXIX . Synthesis of 1,2,3,4,5,6- Hexahydro-8-hydroxy -2,6-methane-3,6,1 1-trimethyl-2,3-benzo|g| diazocine and 1,2,3,4,5,10,11,12-Octahydro-7-hydroxy-1,5-dimethylpyridazino|2,3-b| isoquinoline |studies on the syntheses of heterocyclic compounds. Part LXI |

1,2,3,4,5,6-Hexahydro-8-hydroxy-2,6-methano-3,6,1 1-trimethyl-2,3-benzo |g| diazocine (IV) and 1,2,3,4,5,10,11,12-octahydro-7-hydroxy-1,5-dimethylpyridazino |2,3-b| isoquinoline (VI) were synthesized from a common intermediate, 3-(3-methoxyphenyl)-2-butanone (VII), through several steps. Reaction of VII with ethyl bromoacetate gave the mixture of ethyl 4-keto-3-(3-methoxyphenyl)-3-methylpentanoate (XIV) and ethyl 4-keto-5-(3-methoxyphenyl)hexanoate (XV) which were hydrolyzed and condensed with methylhydrazine to give the 4,5-dihydro-5-(3-methoxyphenyl)-2,5,6-trimethyl- (XVIII) and 4,5-dihydro-6-(3-methoxy-α-methylbenzyl)-2-methylpyridazine-3(2H)one (XIX). Reduction of XVIII and XIX followed hy cyclization afforded the 2,3-benzo |g| diazocine (XXII) and the pyridazino |2,3-b| isoquinoline (XXIII) which on treatment with 47% hydrobromine acid afforded the phenolic bases (IV and VI), respectively. The mass spectrum of IV, VI, XXII and XXIII was also discussed.     

Studies on the syntheses of analgesics. Part 50. Synthesis of optically active 2-[4-(1-oxo-2-isoindolinyl)phenyl]propanoic acid. [Studies on the syntheses of heterocyclic compounds. Part 742]

2-[4-(1-Oxo-2-isoindolinyl)phenyl]propanoic acid ( 1 ) having a potent analgesic and anti-inflammatory activity could be obtained by three methods, which were found to provide extremely useful ways for the synthesis of 1 from the industrial point of view. (E)- and (Z)-Isomers of 2-butenoic acid and oxiranecarboxylic acid derivatives as the intermedaites in the synthesis of 1 were separated and characterized. Furthermore, the optical resolution of (±)-2-[4-(1-oxo-2-isoindolinyl)phenyl]propanoic acid was successfully achieved using cinchonidine as a resolution reagent.     

Studies on the syntheses of heterocyclic compounds. Part CCCXV erythrinan and related compounds. II . An alternative synthesis of cis-16-hydroxy-15-methoxyerythrinan-8-one and its mass spectrum

Phenolic cyclization of 2-ethoxycarbonylmethylidenecyclohexanone (IV) with 3-hydroxy-4-methoxyphenethylamine (V) were performed in the process of finding a synthetic approach to dihydroerysolidine (I). Thus, 16-hydroxy-15-methoxyerythrinan-6-ene-8-one (VI) and 16-hydroxy-15-methoxyerythrinan-7-ene-8-one (VII) were synthesized, both of which were hydrogenated in the presence of Adams platinum to give the same product (XI). Furthermore, on the basis of the mass spectra of XI and XII, these compounds were assumed to be stereoisomeric at the C₅- and C₆-positions.     

Studies on the syntheses of heteroeyelie compounds. Part DV. Cyclization products of i-substituted 2-benzyl-1,2,5,6-tetrahydropyridines [syntheses of analgesics. Part XXXV]

Treatment of 1,2,5,6-tetrahydro-2-(4-hydroxy- and/or 4-methoxybenzyl)-3,4-dimethyl-I-(3-methyl-2-butenyl)pyridines (IV and V) and 2-(4-methoxybenzyl)-3,4-dimethyl-1-(3-methyl-2-butenyl)-4-piperidinol (X) with acid afforded 9-(4-hydroxy- and/or 4-methoxybenzyl)-4,4,5,6-tetramethyl-1-azabicyelo[3,3,1]non-6-ene (XIII and XIV). In contrast, the corresponding 1-allyl-substituted derivatives VI, VII, and XI were converted into the expected 3-allyl-1,2,3,4,5,6-hexahydro-8-hydroxy- and/or 8-methoxy-6,11-dimethyl-2,6-methano-3-benzazocine (II and III).     

Total synthesis of (±)-obaberine [studies on the syntheses of heterocyclic compounds. Part CCCXLIX ]

Cyclization of one of two cyclic bisamides (III and IX), followed by reduction and successive methylation, gave our expected bis-coclaurine derivatives, one of which was identical with O-methyloxyacanthine, namely natural obaberine (I).     

Studies on the syntheses of azole derivatives. Part VIII. Photolysis of N-aryl-N-benzylearbamoyl azides [studies on the syntheses of heterocyclic compounds. Part CDXV

Photolysis of N-benzyl-N-phenylearbamoylazide (IVc) afforded 1-benzy 1-2-benzimidazolinone (Ic), 2-benzimidazolinone (IIe), 4-benzy 1-2-benzimidazolinone (IIe), and 5-benzy1-2-benzimidazo-linone (IIf)- The same reaction of N-benzyl-N-(4-chlorophenyl) carbamoyl azide (IVd) gave 3-benzyl-1-(phenylhydrazocarbonyl)-2-benzimidazolinone (VIb) besides the above four products. In the case of N-benzyl-4-(4-butoxyphenyl)carbamoyl azide (IVe), 1-benzy1-5-butoxy-2-benz-imidazolinone (1e), 5-butoxy-2-benzimidazolinone (IId), 5-benzy1-2-benzimidazolinone (IIf), and 4-benzy1-6-butoxy-2-benzimidazolinone (IIg).     

Studies on the synthesis of heterocyclic compounds. Part X. One-step route to 1,2-dimethyl-3-R-5-salicyloylimino-3-pyrazolines

This communication outlines the development of a direct synthetic route to 1,2-dimethyl-3-R-5-salicyloyl-imino-3-pyrazolines, starting from readily available 3(5)-aminopyrazoles 1a, b, c and methyl salicylate. The structures of the new compounds 3a, b, c were determined on the basis of analytical and spectroscopic data as well as on the acid hydrolysis products.