Synthesis of Nitrogenated Heterocycles by Asymmetric Transfer Hydrogenation of N-(tert-Butylsulfinyl)haloimines

Abstract

Highly optically enriched protected nitrogenated heterocycles with different ring sizes have been synthesized by a very efficient methodology consisting in the asymmetric transfer hydrogenation of N-(tert-butylsulfinyl)haloimines followed by treatment with a base to promote an intramolecular nucleophilic substitution process. N-Protected aziridines, pyrrolidines, piperidines and azepanes bearing aromatic, heteroaromatic and aliphatic substituents have been obtained in very high yields and diastereomeric ratios up to > 99:1. The free heterocycles can be easily obtained by a simple and mild desulfinylation procedure. Both enantiomers of the free heterocycles can be prepared with the same good results by changing the absolute configuration of the sulfur atom of the sulfinyl group.

tert-Butanesulfinamides as Nitrogen Nucleophiles in Carbon–Nitrogen Bond Forming Reactions

“…By contrast, five-membered ring formation by displacement of a halide leaving group is far more usual and has been implemented in several ways (Scheme 2). It has been accomplished either at 50°C by treatment with KOH in H 2 O/THF [17] or tBuOK in iPrOH, [13] or at room temperature in THF using LiHMDS [18] (see the formation of 6), KHMDS, [19] or a combination of NaH and a crown ether additive (15-Crown-5). [20] As illustrated with 7, the latter conditions are tolerant of functionalized substrates.…”

“…[13] racemization makes them privileged intermediates to carry out N-functionalization without losing the chiral information on the sulfur atom. Strategies for N-alkylation and N-acylation have been developed as well as aza-Michael reactions.…”

“…For instance, the formation of tetrahydroisoquinolines such as 10 has been achieved in DMF at room temperature, [24] and 3-substituted piperidines like 11 have been prepared in DMSO at 80°C. [25] Finally, even though ring closure to afford seven-membered rings is not always straightforward, [18b] azepane formation has been reported by intramolecular displacement of a bromide following deprotonation with KHMDS, [13] as in the case of 12, as well as by displacement of a tosylate leaving group using NaH (formation of 13). [26] A notable aspect of these intramolecular N-alkylation reactions is that it is possible to embed them in one-pot tandem sequences that entail the addition of an organometallic reagent on a N-tert-butanesulfinyl imine and the subsequent ring closure of the metal amide produced.…”

Catalytic Asymmetric Transfer Hydrogenation of Imines: Recent Advances

“…The reaction was not possible for n = 1, because the starting imine could not be prepared due to the elimination of hydrogen chloride from the carbonyl precursor under basic conditions. The desulfinylation of products 35 under acidic conditions afforded the corresponding deprotected heterocycles in an essentially enantiomerically pure form …”

Recent Developments in Asymmetric Aziridination

“…[32] This methodology consisted in an asymmetric ruthenium-catalyzed transfer hydrogenation of N-(tert-butylsulfinyl)haloimines followed by treatment with a base to promote an intramolecular nucleophilic substitution process. [32] This methodology consisted in an asymmetric ruthenium-catalyzed transfer hydrogenation of N-(tert-butylsulfinyl)haloimines followed by treatment with a base to promote an intramolecular nucleophilic substitution process.…”