Alkylation of N,N-Dibenzylaminoacetonitrile: From Five- to Seven- Membered Nitrogen-Containing Heterocyclic Systems

The syntheses of several alkaloids and nitrogen-containing compounds including N-Boc-coniine (14b), pyrrolizidine (1), 6-coniceine (2), and pyrrolo[1,2a]azepine (3) are described. New C-C bonds in the alpha position relative to the nitrogen atom were formed by the alkylation of metalated alpha-aminonitriles 4 and 6a-c with alkyl iodides possessing the requisite size and functionality. In all of the reported cases, the pyrrolidine ring was formed in the aqueous medium through a favorable 5-exo-tet process involving a primary or a secondary amino group and a terminal 6-leaving group. Conversely, the azepane ring was efficiently formed in N,N-dimethylformamide (DMF), as the preferred aprotic solvent, through an unreported 7-exo-tet cyclization process involving a more nucleophilic sodium amide and a terminal mesylate borne by a saturated six carbon chain unit. In this way, we successfully synthesized pyrrolo[1,2a]azepane 3 and 2-propyl-azepane 14c in good yields from inexpensive and readily available materials without tedious separation methods.

Automated summary

The syntheses of several alkaloids and nitrogen-containing compounds were described in this study, including N-Boc-coniine (14b), pyrrolizidine (1), 6-coniceine (2), and pyrrolo[1,2a]azepine (3). New C-C bonds in the alpha position relative to the nitrogen atom were formed through alkylation reactions. The pyrrolidine ring was formed in an aqueous medium, while the azepane ring was efficiently formed in N,N-dimethylformamide (DMF) as the solvent, using a 7-exo-tet cyclization process.