Preparation of 2-azabicyclo[3.3.1]nonan-3-ones by a Radical C-Carbonylation of Methylcyclo-Hexylamines

Abstract

The search for a rational method for the synthesis of 2-azabicyclo[3.3.1]nonane, needed for pharmaceutical studies, has led us to the idea that the -C-carbonylation of tertiary alkylamines and the synthesis of lactams can be effected similarly to the radical C-carboxylation of branched alkanes [1, 2]. Remote -carbonylation of alkanols is associated with a 1,5-H transfer on a generated alkoxyl radical [3-6]. As a result, a -hydroxylalkyl radical is formed which reacts with carbon monoxide to give the corresponding acyl radical. This stage is reversible hence a high pressure of the carbon monoxide is needed to ensure the cyclization. The only limitation of such -CH-functionalization reactions of alkanols in a singleelectron oxidation process (e.g., by the action of Pb(OAc)4) is that tertiary alcohols can not be used [7]. Under the conditions given above a -CH-functionalization of the tert-alkylamines can be accomplished, however further oxidation of the substrate occurs [8]. In a modified method for generating -aminoand -amidoalkyl radicals it was necessary to use not only an oxidant but also iodine [4]. However, this variation is inapplicable to amines 1a,b since it can lead to -C-iodination and the subsequent formation of a pyrrolidine ring [4]. Azacyclization using NBS also proceeds via formation of an aminoalkyl bromide intermediate [9] and is not applicable to carbonylation. Hence, despite the expected oxidative side reactions, we had to use Pb(OAc)4 in the presence of K2CO3 by analogy with the study [1]. The amine 1b has a fixed axial amino group and presumably can ensure the 1,5-H transfer on an aminyl radical. Analysis of the reaction mixture of amines 1a,b has shown that, in fact, the corresponding 2-azabicyclo[3.3.1]nonanes 4a,b are formed, but in the case of amine 1a the yield of bicycle 4a relative to the other reaction products is 19% (68% conversion) while the yield of bicycle 4b in the reaction of amine 1b is only 6% (52% conversion). Such result can only be explained by a more rapid azacyclization of radical B due to stabilized conformation that is optimal for formation of bicycle 2b. This is confirmed by the domination of the products of in situ oxidation of amine 2b (imine 3b in 11% and lactam 7b in 22% yields) when an excess of