Synthesis of Di-(N-tropinonyl)alkanes and Di-(N-tropinonyl)benzenes

Abstract

Tropane alkaloids have received a great deal of attention because of their remarkable pharmaceutical significance. Therefore a variety of synthetic approaches to tropane alkaloids have been investigated. Especially, a series of tropanes showed anticonvulsant activity against pentylenetetrazol-induced convulsions in mice and antiarrhythmic activity in rabbit previously treated with ouabain. *Corresponding Author. E-mail : As a part of a research program related to the synthetic study of pharmacologically interesting tropane compounds, we now report the synthesis of di-(N-tropinonyl)benzenes and di-(N-tropinonyl)alkanes in the reaction of phenylenediamines (or diaminoalkanes) with 2,5-dimethoxytetrahydrofuran, and acetonedicarboxylic acid at 0 C. Earlier we reported the synthesis of N-substituted nortropinones in the reaction of amines with 2,5-dimethoxytetrahydrofuran, and acetonedicarboxylic acid. A representative experimental procedure for the synthesis of 1,4-di-(8-azabicyclo[3,2,1]octan-3-onyl)benzene (7) is as follows: A mixture of 2,5-dimethoxytetrahydrofuran (6.6 g, 0.05 mol), acetonedicarboxylic acid (5.84 g, 0.04 mol), water (20 mL), and c-HCl (0.5 mL) was stirred for 30 min. p-Phenylenediamine (2.16 g, 0.02 mol) in water (10 mL) was added by using a dropping funnel at 0 C. After the reaction mixture was stirred under N2 at room temperature for 22 h, a crude brown solid was precipitated. The reaction mixture was diluted with water (20 mL) and neutralized with saturated NaHCO3 solution. The neutralized solution was extracted with dichloromethane (100 mL × 3). The organic layer was dried (Na2SO4), filtered and concentrated. The residue was chromatographed on a silica gel (n-hexane : ethyl acetate = 1 : 3, v/v) to yield 7 (4.47 g, 69%) as a brown crystalline solid. H-NMR showed a singlet at δ 4.49 for four protons of C1 and C5, a doublet at δ 1.78 for four protons of C6n and C7n, a doublet at δ 2.17 for four protons of C6x and C7x, a doublet at δ 2.22 (H-2(4)α, J = 3 Hz). for four protons of C2α and C4α, and a doublet at δ 2.70 (H-2(4)α, J = 10 Hz) for four protons of C2β and C4β. Aromatic protons were at δ 6.89 as a singlet.