Synthesis of 1-(pyridin-4-yl)-3,6-diazahomoadamantane and its derivatives

Abstract

Condensation of 1-(pyridin-4-yl)propan-2-one with 1, 3,6,8-tetraazatricyclo[4.4.1.1 3,8 ]dodecane gave 1-( pyridin-4-yl)-3,6-diazahomoadamantan-9-one as intermediate product in the synthesis of 1-(pyridin-4-yl)-3,6-diazahomoadamantane and its derivatives having functional substituents at the bridging carbon atom in the homoadamantane skeleton.We previously [1] developed a procedure for the condensation of methyl ketones with 1, 3,6,8-tetraazatricyclo[4.4.1.1 3,8 ]dodecane, which ensured synthesis of 3,6-diazahomoadamantane derivatives substituted at the bridgehead position [2-5]; Wolff-Kishner reduction of the latter gave a number of 3,6-diazahomoadamantane derivatives having aliphatic and aromatic substituents. No analogous compounds with heteroaromatic substituents were reported. We synthesized 1-(pyridin-4-yl)-3,6-diazahomoadamantan-9-one (II) using 1-(pyridin-4-yl)propan-2-one (I) as initial methyl ketone; it was prepared by acylation of 4-methylpyridine with acetyl chloride according to the procedure described in [6]. The condensation of ketone I with 1, 3,6,8-tetraazatricyclo[4.4.1.1 3,8 ]dodecane gave compound II in more than 40% yield (Scheme 1).The structure of 1-(pyridin-4-yl)-3,6-diazahomoadamantan-9-one (II) was confirmed by spectral data. Its 1 H NMR spectrum contained a set of signals typical of diazahomoadamantane skeleton. It included two AB systems arising from the NCH 2 C protons, a multiplet from the ethylene fragment (NCH 2 CH 2 N), and a broadened singlet from one proton in the bridgehead position. Protons in the pyridine ring resonated as two symmetric doublets in the region δ 7.11-8.25 ppm. In the IR spectrum we observed an absorption band at 1695 cm -1 due to stretching vibrations of the carbonyl group. Compound II displayed the molecular ion peak (m/z 243) in the mass spectrum.Ketone II was converted into the corresponding hydrazone III, and the latter was reduced according to Wolff-Kishner to obtain 1-(pyridin-4-yl)-3,6-diazahomoadamantane (IV) in 76% yield. Heating of hydrazone III with alkali was accompanied by formation of a considerable amount of 4-(3,6-diazahomoadamantan-1-yl)pyridin-2-ol (V). The IR spectrum of IV lacked absorption band assignable to stretching vibrations of C=N bond (which is typical of hydrazone III). Absorption bands belonging to vibrations of the pyridine ring were observed at 1590 and 1530 cm -1 . By reduction of II with NaBH 4 we obtained 1-(pyridin-4-yl)-3,6-diazahomoadamantan-9-ol (VI), and acylation of VI afforded 1-(pyridin-4-yl)-3,6-diazahomoadamantan-9-yl acetate (VII). In the IR spectrum of VII we observed no absorption band at 3203 cm -1 typical of stretching vibrations of the OH group in initial alcohol VI, and ester carbonyl band appeared at 1730 cm -1 .1-(Pyridin-4-yl)-3,6-diazahomoadamantan-9-amine (IX) was synthesized by reduction of 1-(pyridin-4-yl)-3,6-diazahomoadamantan-9-one oxime (VIII) with

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

“…IR spectrum, ν, cm -1 : 1700 (C=O), 1590 (pyridine). 1 1-Methyl-8-(pyridin-2-yl)-3,6-diazahomoadamantan-9-ol (VII). Sodium tetrahydridoborate, 0.15 g (3.96 mmol), was added in small portions under continuous stirring to 0.5 g (1.9 mmol) of ketone II in 10 ml of methanol.…”

“…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).…”

Synthesis of 3,6-diazahomoadamantane

“…Heating of 9-phenyl-3,6-diazahomoadamantan-9-ols with Raney nickel resulted in reduction of the hydroxy group with formation of 9-phenyl-3,6-diazahomoadamantanes.By condensation of methyl ketones with 1,3,6,8-tetraazatricyclo[4.4.1.1 3,8 ]dodecane [1] and subsequent Wolff-Kishner reduction of the resulting 3,6-diazahomoadamantan-9-ones we obtained a number of 3,6-diazahomoadamantane derivatives substituted at the bridgehead position [2][3][4]. In the present communication we report on the synthesis of 3,6-diazahomoadamantane in a similar way.…”

Oximes of Seven-Membered Heterocyclic Compounds Containing Two Heteroatoms

“…The classical method for the synthesis of 1,3-and 1,4-diazepane [1] oximes is based on the reaction of diazepane ketones with hydroxylamine hydrochloride in the presence of Na 2 CO 3 / EtOH [2], aqueous NaHCO 3 / i-PrOH [2,3], aqueous NaOH [4] or pyridine in ethanol / MS 4 Å [5]. 1,4-Diazepane oximes 2 were obtained in the two-step reaction from Boc-protected 1,4-diazepanone 1 in the presence of P 4 S 10 / hexamethyl disiloxane and then by treatment with hydroxylamine in methanol [6].…”