An Approach to Azabicyclo[n.3.1]alkanes by Double Mannich Reaction

Abstract

Chlorotrimethylsilane-promoted double Mannich annulation of ketones using N,N-bis(methoxymethyl)benzylamine has been explored. It has been shown that the structure of the substrate drastically influenced the outcome of the reaction. The method allows azabicyclo[n.3.1]alkane derivatives (n = 2-5) to be obtained in good yields.

gem‐Difluoro‐3‐azabicyclo[3.n.1]alkanes and Their Derivatives – Bicyclic Fluorinated Piperidine Isosteres for Drug Discovery

“…According to the synthetic plan shown above (Scheme 1, B ), the preparation of key intermediates 3 started with the known MeSiCl 3 ‐promoted double Mannich annulation of ketones 1 a – e or β‐ketoesters 1 f – i upon reaction with N , N ‐bis(methoxymethyl)benzylamine [19,25–27] . Intermediate bicyclic ketones 2 were transformed into corresponding difluorinated species upon action of SF 4 in HF using the protocol optimized by Mykhailiuk and co‐workers [19] .…”

“…According to the synthetic plan shown above (Scheme 1, B), the preparation of key intermediates 3 started with the known MeSiCl 3 -promoted double Mannich annulation of ketones 1 a-e or β-ketoesters 1 f-i upon reaction with N,N-bis(methoxymethyl)benzylamine. [19,[25][26][27] Intermediate bicyclic ketones 2 were transformed into corresponding difluorinated species upon action of SF 4 in HF using the protocol optimized by Mykhailiuk and co-workers. [19] Purification of the crude products with fractional distillation under reduced pressure resulted in amines 3 a-i (up to 150 g in a single run) and did not require any further optimization of the reaction conditions (Figure 2).…”

Double Mannich reaction with ketones as a route to heterocyclic systems: A mini review

“…These compounds are bispidinone derivatives, where one nitrogen atom in bispidinone has been replaced with oxygen, sulfur, selenium, or phosphorus. A variety of 3,7‐DHBCN‐9‐ones with different substituents have been synthesized by a double Mannich reaction of 1‐hetera‐4‐cyclohexanones with a primary amine and aldehyde [27, 30, 73]. The 3‐oxa‐7‐azabicyclo[3.3.l]nonan‐9‐ones ( 90 ) [70, 74, 75] and 92a – d [76], have been prepared by double Mannich reaction with the appropriate tetrahydro‐4 H ‐pyran‐4‐one (Scheme 19).…”

“…The synthesis of the asymmetric 3,7-DABCN-9-ones (84) [16, 39b, 66, 68-70] A variety of 3,7-DHBCN-9-ones with different substituents have been synthesized by a double Mannich reaction of 1-hetera-4-cyclohexanones with a primary amine and aldehyde [27,30,73]. The 3-oxa-7-azabicyclo[3.3.l]nonan-9-ones (90) [70,74,75] and 92a-d [76], have been prepared by double Mannich reaction with the appropriate tetrahydro-4H-pyran-4-one (Scheme 19).…”

“…Chlorotrimethylsilane‐promoted double Mannich reaction of ketones ( 29c , d ) using N , N ‐bis(methoxymethyl)alkylamine ( 31 , R = benzyl, R′ = Me) allows azabicyclo[n.3.1]alkane derivatives ( 32a , b ) to be obtained in good yields [27]. A similar reaction of 29c , d with ( 31 , R = alkyl, R′ = Et), afforded 3‐azabicyclic ketones 32c–i [28].…”