Synthesis and properties of 3-substituted 3-azabicyclo-[3.3.1]nonan-9-amines

Abstract

Catalytic hydrogenation of 3-benzyl-and 3-tert-butoxycarbonyl-3-azabicyclo[3.3.1]nonan-9-one oximes over Raney nickel gave the corresponding 3-substituted 3-azabicyclo[3.3.1]nonan-9-amines which were converted into amides via reactions with acetyl and chloroacetyl chlorides and maleic and succinic anhydrides, into Schiff bases by condensation with benzaldehyde and 4-chlorobenzaldehyde, and into isothiocyanates by treatment with thiophosgene in the presence of K 2 CO 3 . 3-Benzyl-and 3-tert-butoxycarbonyl-3-azabicyclo-[3.3.1]nonan-9-yl isothiocyanates readily reacted with methanol, aniline, and sodium azide to produce methyl thiocarbamate, thiourea, and dihydrotetrazole-5-thione derivatives having a 3-azabicyclo[3.3.1]nonane fragment.In continuation of our studies on 3-azabicyclo-[3.3.1]nonane derivatives [1, 2] as potential biologically active compounds [3], in the present work we synthesized for the first time some 3-substituted 3-azabicyclo[3.3.1]nonan-9-amines having a primary amino group and obtained a number of their derivatives at the amino group. The optimal procedure for the synthesis of 3-azabicyclo[3.3.1]nonan-9-amines IIa and IIb is catalytic reduction of the corresponding accessible 3-azabicyclo[3.3.1]nonan-9-one oximes Ia and Ib [2] with hydrogen over Raney nickel. This procedure ensured smooth formation of target amines IIa and IIb in 73-76% yield (Scheme 1).3370-3360 cm -1 due to stretching vibrations of N-H bonds. In the 1 H NMR spectra of IIa and IIb, the NH 2 protons resonated as a broadened singlet at δ 4.23 ppm, and a new signal appeared in the region δ 3.62-3.80 ppm due to 9-H (no such signal was observed in the spectra of the initial compounds).Diverse chemical transformations of amines IIa and IIb provided additional proofs for their structure and demonstrated wide potential of their application in organic synthesis for the preparation of new compounds having an azabicyclic fragment. Amines IIa and IIb readily reacted with acetyl and chloroacetyl chlorides in the presence of triethylamine, as well as with maleic and succinic anhydrides on heating in anhydrous chloroform. As a result, N-substituted amides III-VI were obtained. Maleamic and succinamic acid derivatives Va, Vb, VIa, and VIb were subjected to intramolecular cyclization on heating in acetic anhydride. We thus isolated the corresponding N-substituted maleimides VIIa and VIIb and succinamides VIIIa and VIIIb (Scheme 2).Schiff bases IXa, IXb, Xa, and Xb were synthesized by condensation of amines IIa and IIb with benzaldehyde and 4-chlorobenzaldehyde on heating in boiling anhydrous ethanol. Compounds IXa, IXb, Xa, and Xb are promising as intermediate products in organic synthesis. Their reduction with sodium tetrahydridoborate afforded secondary aromatic amines

Intramolecular Schmidt reaction of tert-butyl 3-(3-azidopropyl)-4-oxopiperidine-1-carboxylate as a synthetic route to saturated fused aza heterocycles

“…Compound VIII turned out to be a convenient intermediate product for the synthesis of various N-substituted derivatives. Successive treatment of dihydrochloride VIII with triethylamine and such electrophiles as acetic anhydride, methanesulfonyl chloride, benzoyl chloride, and phenyl isocyanate under the conditions described in [16,17] gave the corresponding amides IX-XII (Scheme 4). The reaction of VIII with benzaldehyde in the presence of sodium triacetoxy(hydrido)borate [18] led to the formation of N-benzyl derivative XIII.…”