Two general routes to 1,4-disubstituted-2,3,4,5-tetrahydro- 1H-3-benzazepines

[structure] Two general routes to 1,4-disubstituted-2,3,4, 5-tetrahydro-1H-3-benzazepines are described. Both routes utilize an appropriately functionalized phenethylamino alcohol as the penultimate intermediate: the first route makes use of the reductive amination of a benzyl alkyl ketone with alpha-(aminomethyl)benzyl alcohol, while the second route utilizes the addition of a Grignard reagent to the oxazolidine derived from a substitued phenylacetaldehyde and alpha-(methylaminomethyl)benzyl alcohol. In all cases studied, the cis-1,4-disubstituted-2,3,4, 5-tetrahydro-1H-3-benzazepine was obtained as the major product.     

Azabicyclo chemistry II. Synthesis of 1,5-methano-2,3,4,5-tetrahydro-1H-2-benzazepines. B-norbenzomorphans

The syntheses of the B-norbenzomorphans, 1,5-methano-2,3,4,5-tetrahydro-1H-2-benzazepine (1a) and its N-methyl derivative (Ib) were accomplished. Phenylsuccinic anhydride (III) was cyclized to 3-carboxy-1-indanone (IVa), which was converted by the Arndt-Eistert method to the homologous methyl indanone-3-acetate (V). One experiment in the synthesis of V led to the by-products 3-carboxamido-1-indanone (IVd) and 3-(N-methylcarboxamido)-1-indanone (IVe), identified by physical and chemical means. Methyl 1-aminoindan-3-acetate (VII) was prepared by catalytic reduction of methyl indanone-3-acetate oxime (VI). Hydrolysis of VII afforded 1-aminoindan-3-acetic acid (VIII), which was cyclized with dicyclohexylcarbodiimide to 1,5-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one (IX). Reduction (lithium aluminum hydride) of IX gave amine Ia which was then methylated to Ib. The mass spectral fragmentation patterns of IX and Ia are discussed.     

The synthesis of some 7- and 7,8-substituted 2,3,4,5-tetrahydro-1H-3-benzazepines

The nitration of 2,3,4,5-tetrahydro-1H-3-benzazepine and its 3-methyl and 3-acetyl derivatives yields the corresponding 7-nitro derivatives which can be further transformed by classical procedures. The preparation of the ether cleavage products of the known 2,3,4,5-tetrahydro-7,8-dimethoxy-1H-3-benzazepine is also reported.     

A novel synthesis of aromatic methoxy and methylenedioxy substituted 2,3,4,5-tetrahydro-1H-3-benzazepines

A new synthesis of aromatic methoxy and methylenedioxy substituted 2,3,4,5-tetrahydro-1H-3-benzazepines is described. Suitably substituted phenethylamines and their α-methyl homologs in the form of their N-acetyl derivatives are chloromethylated, the resulting benzyl chlorides are reacted with cyanide and hydrolysis of the latter yields 2-(2-aminoethyl)phenylacetic acid derivatives. Thermal cyclization yields the corresponding lactams. Hydride reduction of these lactams furnishes the substituted 2,3,4,5-tetrahydro-1H-3-benzazepines which may be methylated on nitrogen by formaldehyde and hydrogen. By this sequence a number of previously unde-scribed compounds have been prepared.     

A general route to the synthesis of 1,5-methano- and 1,5-ethano- 2,3,4,5-tetrahydro-1H-3-benzazepines

A general approach to preparing 1,5-methano- (1) and 1,5-ethano-2,3,4,5-tetrahydro-1H-3-benzazepine (2) is discussed. This strategy involves converting an indanone or tetralone (4) to a cyanohydrin (3) which is subjected to hydrogenolysis followed by lactamization and reduction to provide bicyclic aryl piperidine (1) and bicyclic aryl homopiperidine (2).     

Synthesis of nitro-substituted 4-methyl-2,3-dihydro- and 2,3,4,5-tetrahydro-1H-1,5-benzo-2-diazepinones

The nitration of 4-methyl-2,3-dihydro-1H-1,5-benzo-2-diazepinone gives the 7 nitro derivative. The 8-nitro isomer was obtained from 4-nitro-1,2-phenylenediamine. The catalytic hydrogenation of the nitrobenzodiazepinones gives the 7- and 8-amino derivatives. The nitrobenzodiazepinones exist in the enol form in alkaline media.     

Substituted 2,3,4,5-tetrahydro-1H-3-benzazepine and 2,3,4,5-tetrahydro-1H-naphth[1,2-d] azepine derivatives

The multi-step synthetic procedures to prepare a number of 2,3,4,5-tetrahydro-1H-benzazepine derivatives 1 through a series of intermediates are described. The condensation of arylaldehydes 2 with 2-nitropropanes 3 gave nitroalcohols 4 which were reduced to alcohol amines 5 . The condensation of 5 with arylacetaldehydes 6 gave imino derivatives 7 which on reduction with borohydride gave secondary amines 8 . By employing different methods, alcohol amines 5 were condensed with arylacetic acids 9 to give amides 10 which were then reduced to amines 8 . On treatment with mineral acids, amines 8 were cyclized to the target compounds 1 . Biological activities of 1 are also briefly discussed.     

Complete 1H and 13C NMR spectral assignment of N-aralkylsulfonamides, N-sulfonyl-1,2,3,4-tetrahydroisoquinolines and N-sulfonyl-2,3,4,5-tetrahydro-1H-2-benzazepines. Conformational analysis of N-[((3',4'-dichlorophenyl)methyl)sulfonyl]-3-methyl-2,3,4,5-tetrahydro-1H-2-benzazepin

The complete and unambiguous assignment of the 1H NMR and 13C NMR spectra of 26 N-aralkylsulfonamides, N-sulfonyl-1,2,3,4-tetrahydroisoquinolines and N-sulfonylbenz[c]azepines was performed on the basis of APT, DEPT, homonuclear (gs-COSY) and 1H-detected heteronuclear one-bond (gs-HMQC) and long-range (gs-HMBC) correlation experiments. The methylated 2,3,4,5-tetrahydro-1H-2-benzazepine derivative 26 adopts a chair conformation as determined by 1H-1H coupling analysis and gamma-gauche effects. This is supported by a single-crystal X-ray structure analysis.     

An efficient three-component one-pot approach to the synthesis of 2,3,4,5-tetrahydro-1H-2-benzazepines by means of rhodium-catalyzed hydroaminomethylation

We have developed a novel and efficient three-component one-pot, catalytic approach for the synthesis of 2,3,4,5-tetrahydro-1H-2-benzazepines, using a rhodium catalyst that does not require phosphine. The isolated yields are excellent and the protocol tolerates anilines of diverse basicity.     

Synthesis of N-acyl-4-methyl-7(8)nitro-2,3,4,5-tetrahydro-1H-1-5-benzodiazepin-2-ones and their spectral properties

The conditions were studied o f mono- and diacylation of 7(8)-nitro-2, 3, 4, 5-tetrahydro-1H-1, 5-benzodiazepin-2ones. It was found that under mild conditions (lower temperatures, weak acylating agents), the 7-nitro isomers are acylated only at the 5 -position; increase in the temperature or treatment with an active acylating agent gives the 1,5-diacyl derivatives. Under mild conditions the 8-nitro isomer is not acylated, while under more rigorous conditions a mixture of mono- and diacylated products is formed.Translated from Khimiya Geterotsiklicheskikh Soedinenii, Vol. 30, No. 1, pp. 99–105, January, 1994.     

Synthesis and dynamic stereochemistry of 1,5-disubstituted 2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-ones

The 1-isopropyl and 1-benzyl derivatives of 1,5-tetrahydrobenzodiazepin-2-one were synthesized by alkylation under the conditions of phase-transfer catalysis. The inversion of the heterocycle was studied by PMR spectroscopy, and the free energies of activation were determined.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 254–258, February, 1986.     

Synthesis of 1-amino-5-phenyl-4,5-dihydro-3H-2-benzazepines and the isomeric 2-amino-1-benzazepines

The title amidines (1 and 2) were synthesized. A synthesis of lactam 10 free of isomeric 4 is described. An interesting rate difference in displacement of thiomethyl ether intermediates 5 and 11 with amines was observed.     

Synthesis and study of structure of 5-formyl-substituted 2,3,4,5-tetrahydro-1H-1, 5-benzodiazepin-2-ones

A series of 5-formyl derivatives was synthesized by formylation of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-ones with a mixture of formic acid and acetic anhydride. The structure of their rotation isomers was studied by PMR spectroscopy.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 957–961, July, 1988.     

Synthesis of 2-substituted 1-benzyl-2,3,4,5-tetrahydro-1-benzazepines by palladium catalysis. Observation of a competitive β-hydride elimination pathway

A synthetic route to 1-benzyl-tetrahydro-1-benzazepine is reported, which also permits access to analogous structures with alkyl and aryl substituents at position-2 of the aliphatic ring. Palladium catalysis is utilized in two of the three steps, constructing the seven-membered rings effectively from 2-bromoiodobenzene. Competitive β-hydride elimination was observed in the attempted carbonnitrogen bond formation with a sterically bulky substrate (when R=tert-butyl).     

Regioselective alkylation of 2-alkyl-5,6,7,8-tetrahydro-3h-cycloheptimidazol-4-ones and 2-alkyl-3h-cycloheptimidazol-4-ones

Regioselective alkylation of 2-alkyl-5,6,7,8-tetrahydro-3H-cycloheptimidazol-4-one (1) and 2-alkyl-3H-cycloheptimidazol-4-one (2) was investigated. 3-[2'-(1-tert-Butyl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-2-propyl-5,6,7,8-tetrahydro-1H-cycloheptimidazol-4-one (6) was preferentially obtained under the conditions by using NaH in DMF or THF. On the other hand, 3-[2'-(1-tert-butyl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-2-propyl-5,6,7,8-tetrahydro-3H-cycloheptimidazol-4-one (5), the synthetic intermediate compound of Pratosartan, was obtained selectively in the presence of n-Bu(4)NBr in toluene by using aqueous sodium hydroxide as a base. In this reaction, it was found that the concentration of the alkaline solution influences its regioselectivity. This selectivity was observed even for aldehyde and ester derivatives.     

Synthesis and anti-TMV activity of novel N-(3-alkyl-1H-pyrazol-4-yl)-3-alkyl-4-substituted-1H-pyrazole-5-carboxamides

In order to investigate the biological activity of novel bis-pyrazole compounds,a series of N-（3-alkyl-5-（N-methylcarbamyl）- 1H-pyrazol-4-yl）-3-alkyl-4-substituted-1H-pyrazole-5-carboxamides were designed and synthesized with ethyl 3-alkyl-1H-pyrazole -5-carboxylate 1 as starting materials.N-Methyl-3-alkyl-4-amino-1H-pyrazole-5-carboxamides 6 were obtained from 1 via 5 steps.3-Alkyl-4-substitued-1H-pyrazole-5-carboxyl chlorides 4a,4b,11a,11b,11c or 12 were also obtained from 1 via several steps.Target compounds 7a-7g were obtained after the reaction of 6 with the above 1H-pyrazole-5-carboxyl chlorides.Preliminary bioassay showed some compounds possessing good inactivation effect against TMV（tobacco mosaic virus）.Compound 7a showed higher activity superior to ningnanmycin at a concentration of 5.0×10^-4 g/mL and equal activity at 1.0×10^-4 g/mL;7b and 7c showed equal activity to virazole both at concentrations of 5.0×10^-4 g/mL and 1.0×10^-4 g/mL.