Synthesis of 1-methyl-8-(pyridin-2-yl)-3,6-diazahomoadamantane and its derivatives

Abstract

Condensation of 1-(pyridin-2-yl)butan-2-one with 1, 3,6,8-tetraazatricyclo[4.4.1.1 3, 8 ]dodecane gave 1-methyl-8-(pyridin-2-yl)-3,6-diazahomoadamantan-9-one as intermediate product in the synthesis of 1-methyl-8-(pyridin-2-yl)-3,6-diazahomoadamantane and its derivatives with various functional groups at the bridging carbon atom.We previously reported on the synthesis of 1-(pyridin-4-yl)-3,6-diazahomoadamantane and its derivatives having functional groups at the bridging carbon atom, starting from 4-methylpyridine [1]. In continuation of our studies on the synthesis of pyridinyl-substituted diazahomoadamantanes [2, 3] from methylpyridines, we synthesized 1-(pyridin-2-yl)butan-2-one (I) from 2-methylpyridine according to the procedure described in [4], and compound I was brought into condensation with 1, 3,6,8-tetraazatricyclo[4.4.1.1 3,8 ]-dodecane to obtain 1-methyl-8-(pyridin-2-yl)-3,6-diazahomoadamantan-9-one (II) (Scheme 1). The 1 H NMR spectrum of compound II contained a group of signals typical of diazahomoadamantane skeleton. It included two AB systems from the NCH 2 C fragments and a multiplet belonging to protons in the ethylene bridge. Protons in the pyridine ring resonated as four multiplets in the region δ 7.13-8.59 ppm. Protons in the methyl group on the bridgehead carbon atom gave a singlet at δ 1.00 ppm. In the IR spectrum of II we observed absorption bands due to stretching vibrations of the carbonyl group (1700 cm -1 ) and pyridine ring (1590 cm -1 ).Compound II was converted into 1-methyl-8-(pyridin-2-yl)-3,6-diazahomoadamantane (IV) according to Kishner-Wolff through the corresponding hydrazone III (Scheme 2); the yield of IV was 67%. The reaction of ketone II with hydroxylamine hydrochloride gave oxime V which was reduced with hydrogen in statu nascendi (generated from Ni-Al alloy, 1 : 1, by the action of aqueous alkali). As a result, 1-methyl-8-(pyridin-2-yl)-3,6-diazahomoadamantan-9-amine (VI) was isolated in 75% yield. The reduction of diazahomoadamantanone II with sodium tetrahydridoborate produced 1-methyl-8-(pyridin-2-yl)-3,6-diazahomoadamantan-9-ol (VI) which was converted into the corresponding acetate VIII (Scheme 2). EXPERIMENTALThe IR spectra were recorded in KBr on a Bruker IFSv spectrometer. The 1 H NMR spectra were meas-