Synthesis of 1‐Azabicyclo[3.3.1]nona‐3,6‐diene Derivatives by a Modified Prins Reaction

Abstract

Intramolecular electrophilic cyclization reactions were performed with l-(3-oxo-3-phenylpropyl)-1,2,5,6-tetrahydropyridine derivatives l a -p in strong acids to give 4,6-diphenylsubstituted 1-azabicyclo[3.3. llnonadienes 2a-p. Some qualitative observations were made on substituents and reaction conditions influencing the ring closure reaction. Naphthylsubstituted starting compounds 3a, b were converted into pentacyclic compounds 4a, b which represent a new ring system, suggesting the occurrence of a carbenium ion intermediate in the ring closure reaction. Some of the compounds 2a-p show remarkable antifungal and antibacterial effects.The 1-azabicyclo[3.3. llnonane ring system, also called isogranatanine skeleton, was synthesized earlier by Dieckmann condensation ['] and an intramolecular alkylation as well [*]. Later, derivatives of this ring system were prepared also by an intramolecular electrophilic cyclization of l-allyl-1,2,5,6-tetrahydropyridine compounds in acidic medium. In this reaction the acid obviously protonates the trialkyl-substituted double bond in the N-substituent and the resulting carbenium ion serves as the electrophile in the ring closure reacti~n[~.~]. While the above-mentioned methods offer a limited possibility of introducing different substituents into the azabicyclic system we were interested in finding methods which would allow the introduction of a wider variety of different functionalities. Therefore, we investigated other types of intramolecular electrophilic cyclization reactions with differently substituted 1,2,5,6-tetrahydropyridine derivatives. From a biological point of view we aimed at synthesizing new types of 1 -azabicycloalkanes and related derivatives. Among the former there are well known examples of muscarinic agonists which might have a beneficial effect on certain deseases associated with memory irnpairmentr5].As part of this synthetic program successful intramolecular cyclization reactions of 1,2,5,6-tetrahydropyridines containing an acetal moiety in the side chain resulted in new types of 1 -azabicycloalkene derivatives bearing hydroxy and aryl groupd6]. Using in situ generated iminium ions, we could also obtain 1,4-diazabicyclo[4.3. lldecene derivative~ [~]. In the present paper we describe the synthesis of the l-azabicyclo[3.3.l]nona-3,6-diene ring system bearing two aryl substituents.Under the conditions of the Prins reaction[*] treatment of 1 -(3-0~0-3-phenylpropy1)-4-phenyl-1,2,5,6-tetrahydropyridines 1 with sulfuric acid afforded 4,6-diphenyl-l-azabicyclo[3.3.1]nona-3,6-diene derivatives 2 in moderate yields

The Pharmacology of GYKI‐46 903, a New Cognition Enhancer

“…The compound was synthesized in the frame of extended research work (21,22,68) with azabicyclic compounds, originally aimed at finding muscarinic ligands. The synthesis of the compound is summarized in Fig.…”

4,6-Diaryl-7-methoxycarbonyl-1-azabicyclo[3.3.1]nonene Isomers by benzyl cation initiated cyclization

“…Oxidation of the secondary hydroxyl group in 5 with different methods resulted only in decomposition, therefore a Prins type ring closure of the corresponding ketone, on the analogy of our earlier method [2], had to be neglected. On the other hand when the diastereomeric mixture 5 was treated with 83% sulfuric acid a ring closure reaction occured and a mixture of 6 and 7, the 6,7-trans-diaxial and -diequatorial azabicyclic products were formed as a result of an intramolecular electrophilic cyclization with the obviously formed benzyl cations A and B. Conjugated carbon-carbon double bond, as cyclization terminator (internal nucleophile) in benzyl cation initiated cyclizations, has not been used before [8], therefore cyclization reaction of the above type may be of interest.…”