Radical Chain Reactions of α-Azido-β-keto Esters with Tributyltin Hydride. A Novel Entry to Amides and Lactams through Regiospecific Nitrogen Insertion

Abstract

A variety of acyclic and carbocyclic α-azido-β-keto esters have been readily prepared from the parent dicarbonyl compounds, and their radical chain reactions with tributyltin hydride have been investigated. These reactions normally result in efficient production of alkoxycarbonyl-substituted amides and lactams and thence provide a new, useful method for regiospecific nitrogen insertion of keto ester compounds. The likely mechanism entails initial addition of tributylstannyl radical to the azido moiety to give a stannylaminyl radical, which readily undergoes intramolecular three-membered cyclization onto the ketone group to form an alkoxyl radical. The alkoxyl radical then undergoes regiospecific β-scission to form a stable ring-opened radical that is eventually reduced by tributyltin hydride to propagate the chain. With certain substrates, concomitant deazidation occurs to an important extent. This process, which is unusually observed in radical reactions of alkyl azides, is ascribed to addition of the stannyl radical to the terminal azido nitrogen; subsequent fragmentation of the ensuing 1,3-triazenyl adduct gives stannyl azide and a deazidated alkyl radical, resonance-stabilized by the adjacent carbonyl groups. The radical reactions of 2-azido-2-(ethoxycarbonyl)-l-tetralone with allyltributylstannane and allyltriphenylstannane have also been investigated with the (missed) aim to achieve nitrogen insertion and concomitant allylation.

Ring‐Expansion Reactions in the Synthesis of Macrocycles and Medium‐Sized Rings

“…179!180)w hich allowed generation of the nitrogen centred radicali nt he presence of ak etone. The mechanism of ring expansion is similart ot he Dowd-Beckwith reaction and is driven by the formation of the more stable tertiary radical 182.S urprisingly,g iven the efficiency with which this methodp rovides access to mediumr ing lactams, it has received little attention from the synthetic community [75] and it could be arguedt hat nitrogen centred radical ring expansion remains an underused and underexplored area. [76]…”

Synthesis and Consecutive Reactions of α-Azido Ketones: A Review

“…These reactions result in the efficient preparation of alkoxycarbonyl-substituted amides and lactams and hence provide a useful route for regiospecific nitrogen addition to keto ester compounds. Hence through free radical nitrogen insertion reaction, Benati [31] reported in 1999 the synthesis of amides and lactams by the reaction of α-azido-β-keto esters 105 with tributyltin hydride (Bu 3 SnH) (Scheme 44).…”

Radical Chemistry with Azides

“…77 Radical cyclization of tributylstannylaminyl radicals generated from azides to carbonyl compounds, 109 nitriles and alkenes 110 are reported. 111 The same reaction can be used for the conversion of α -azidoα -methylacetylacetate to α -aminoacid under radical reduction with Bu 3 SnH (Scheme 8.42 , bottom). 110 A one -atom ring -expansion of α -azidoketones allows to prepare lactams according to Benati (Scheme 42, top).…”