The synthesis of new spiro derivatives of tetrahydro‐2‐benzazepine was accomplished and their nitration, bromination, allylation, acetylation, formylation and oxidation reactions were studied. Nitration and bromi‐nation of 5‐methyl(1,5‐dimethyl)‐1,2,4,5‐tetrahydrospiro[3H‐2‐benzazepine‐3,1‐cycloalkane] took place regioselectively on position C‐8 of the phenyl ring. A nitrone was obtained for the first time in the title series. The structures of the compounds were established by ir and nmr spcctroscopy.
Nitroderivatives 9a-g have been prepared with great C-8 regioselectivity by allowing the corresponding 1,2,4,5-tetrahydrospiro[3H-2-benzazepine-3,1'-cycloalkanes] 8a-g to react with potassium nitrate and concentrated H 2 SO 4 . The oxidative reaction of a nitrogen-carbon bond in spirobenzazepines 8 and 9 was performed with H 2 O 2 and catalytic amounts of sodium tungstate at room temperature affording nitrones 10a-d in moderate to high yields. Stereochemical assignments for all the 2-benzazepine derivatives obtained were derived from a full analysis of the 1 H NMR spectroscopic data and an X-ray crystallographic analysis of 1,5-dimethyl-8-nitro-1,2,4,5-tetrahydrospiro[3H-2-benzazepine-3,1'-cyclohexane] 9c. These data indicate that the 2-benzazepines 8-11 in solution present the azepine ring preferably in the chair conformation, with the methyl substituent at C-5 disposed equatorially.
The reaction between allylmagnesium bromide and imines 5a-l leads to the corresponding 4-substituted 4-N-benzylaminobut-1-enes 6a-l, which were oxidized in a regioselective manner to the alkenylnitrones 7a-l. The intramolecular 1,3-dipolar cycloaddition of these nitrones gave 2-spiroannulated or 2-substituted 6-exo-phenyl-1-aza-7-oxabicyclo[2.2.1]heptanes 8a-j. Reductive cleavage of the N-O bond of the obtained bicycles afforded the diverse substituted 4-hydroxypiperidines 9a-h in good yields. This stereoselective approach allowed the preparation of all-cis-4-hydroxy-6-phenyl-2-nonylpiperidine (9i), a close analogue of dendrobatid frog alkaloid 241D.Substituted piperidines play an important role in heterocyclic chemistry from the chemical, biological and medicinal points of view. The piperidine ring system occurs in many alkaloids of both the plant and animal kingdom. 1,2 During the last 20-30 years, considerable effort has been directed towards the study, isolation and total synthesis of quinolizidines, indolizidines and piperidines such as epilasubine II (1), 3 allopumiliotoxin 323B (2), and histrionicotoxin 283A (3). 4,5 The structures 1 and 2 contain a substituted 4-hydroxypiperidine nucleus and the latter possesses a remarkable spiropiperidinecyclohexanol system. Moreover, relatively simple monocyclic 4-hydroxypiperidines such as piperidine 214D (4) (cis,cis-4-hydroxy-2-methyl-6-nonylpiperidine) has been discovered 6 and synthesized 7-9 (Figure). Special interest has been generated by those hydroxypiperidines which display important physiological properties such as cardiotonic, 4 tranquilizing (haloperidol analogues), and analgesic (promedol derivatives) activities. 10Despite the development of general methods for the synthesis of the above heterocycles, there are few examples where the accessible substituted 4-aminobut-1-enes (homoallylic amines) serve as starting materials to synthesize diverse 2,6-disubstituted 4-hydroxypipepiridines, including 2-spiropiperidine ring. Hoffman and coworkers 11 disclosed that the conversion of N-(homoallyl)-hydroxylamines to the N-(3-alkenyl)nitrones followed by intramolecular cycloaddition reaction afforded the 1-aza-7-oxabicyclo[2.2.1]heptanes, 12 principal precursors of 2,6-disubstituted 4-hydroxypiperidines. This methodology allowed the synthesis of alkaloid 1. 13 It is also noteworthy that this nitrone strategy was developed for the preparation of all-cis-2,3,6-trisubstituted piperidines, which in turn were used in the total synthesis of carpamic acid. 14
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