Synthesis of 1‐azabicyclo[3.3.1]nonadienes by intramolecular cyclization of 1‐(3‐oxo‐2‐phenylbutyl)tetrahydropyridines

Abstract

Intramolecular cyclization reactions were performed with 1-(3-0~0-2-phenylbutyl)-1,2,5,6-tetrahydropyridine derivatives 6a-h in sulfuric acid to give 3,6-diphenyl-substituted 1-azabicyclo(3.3. llnonadienes 9. The intermediate carbinols 7a-f and 8b, c could be isolated. Carrying out the reaction in methanesulfonic acid stereoselectivity was found in the formation of carbinols with preferential production of derivatives 7 . Some of the compounds 9 show remarkable dopamine uptake inhibition.As a part of our research program on new memory-enhancing agents various substituted 1-azabicyclic derivatives were synthesized by intramolecular electrophilic cyclization between differently generated oxocarbenium and a conjugated C=C bond, because several 1-azabicyclic systems are known to show affinity to either the m~scarinic[~l of 5HT3 receptorL5I. Later, among the different types of compounds synthesized other activities were found as well. Thus, e. g. some 4,6-diaryl-substituted 1 -azabicyclo-[3.3.l]nona-3,6-dienes (e. g. 2 in Scheme 1) show remarkable antifungal and antibacterial effects[*]. Cationic cyclization between a benzylic cation and a conjugated C=C bond afforded another type Scheme 2 Y 4% 4% 8b.e 6a-h 7a-f ~~ of diaryl-substituted 1-azabicyclononenes where one of the aryl groups is in 3-position to the bridgehead nitrogen atomr61. Scheme 1 1 (R=H,Me, n=l) 2 (R=H. Me, n=1) 5 (X=H, CI) 3 (R=H, n=O) (R=H. n=O)From different structure-activity considerations we expected from this substitution pattern, involved in an azabicyclic ring system, dopamine uptake inhibitory potential. Therefore the synthesis of diaryl-substituted I-azabicyclo[3.3. llnonadines 9 (Scheme 2) was aimed at.Our previous work suggested that rac-N-(3-oxo-3-phenylpropyl or -phenacyl)-substituted tetrahydropyridine derivatives of type 1 or 3 (X = H, halogen, methyl, methoxy, nitro; Y = H, m-or phalogen, methyl) can be cyclized with strong mineral acids in a modified Prins reaction to give azabicyclic derivatives 2 or 4 re-~pectively[~.~.'] (Scheme 1). We assume that the protonated carbonyl group provides an oxocarbenium ion, which is responsible for the electrophilic attack on the conjugated double bond. We also con-clude that the oxocarbenium ion, stabilized by the adjacent phenyl group, is required for a successful ring closure, because no cyclization could be observed with ketone S'].Nevertheless, the success with the Prins-type cyclizations of 1 and 3 prompted us to try the same reaction with ketones 6 to obtain the desired 3,6-diphenyl-substituted 1-azabicyclo[3.3. llnona-3,6-dienes 9 (Scheme 2). When compounds 1 were treated with about 80% sulfuric acid the expected azabicyclic dienes 9 were formed in moderate yield. As a consequence of the reaction conditions, additional sulfonation occurred on the dialkoxy-substituted 3-phenyl group in derivatives 9g, h. According to the 'H-NMR spectra of the latter compounds the site of the sulfonation is the less hindered ortho-phenyl position and the compounds exist in solution as 1 : 1 mixture of two rot...