Reactions of Cyclopropanone Acetals with Alkyl Azides:  Carbonyl Addition versus Ring-Opening Pathways

Abstract

The Lewis acid-mediated reactions of substituted cyclopropanone acetals with alkyl azides were found to strongly depend on the structure of the ketone component. When cyclopropanone acetal was treated with alkyl azides, N-substituted 2-azetidinones and ethyl carbamate products were obtained, arising from azide addition to the carbonyl, followed by ring expansion or rearrangement, respectively. When 2,2-dimethylcyclopropanone acetals were reacted with azides in the presence of BF 3 •OEt 2 , the products obtained were α-amino-α′-diazomethyl ketones, which arose from C2-C3 bond cleavage of the corresponding cyclopropanone, giving oxyallyl cations, that were captured by azides. Aryl-substituted cyclopropanone acetals, when subjected to these conditions, afforded [1,2,3] oxaborazoles exclusively, which were also the result of C2-C3 bond rupture, azide capture and then loss of nitrogen. In the reactions of n-hexyl-substituted cyclopropanone acetals with alkyl azides, a mixture of 2-azetidinones and regioisomeric [1,2,3]oxaborazoles were obtained. The reasons for the different behavior of the various systems is discussed.Cyclopropanones display unusual properties arising from the incorporation of the carbonyl group into a strained three-membered ring. 1 Initially, cyclopropanones attracted interest due to their role as intermediates in Favorskii rearrangements. 2 Since then, there have been numerous experimental and theoretical studies aimed at understanding the nature of cyclopropanone reactivity. 3 Inherently reactive, cyclopropanones are usually generated in situ from the corresponding hemiketals (or their derivatives), which are readily synthesized and easily handled (Scheme 1). 4 In general, the chemistry of cyclopropanones is dominated by ketone addition or ring-opening to form oxyallyl cations. 5 The latter species can be trapped with a nucleophile 6 or cyclized with a dipolarophile to give bicyclic ketones. 7In the 1970's, Wasserman et al. showed that cyclopropanones react with sodium azide, to afford β-lactams (Scheme 2). 8 This reaction presumably proceeds due to the release of strain upon ring expansion coupled with the generation of nitrogen as the byproduct. Our group has previously studied the intermolecular reaction of alkyl azides with cyclic ketones, which generally leads to ring-expanded lactams in a process reminiscent of the Schmidt reaction. 9 Following Wasserman, we were initially interested in reacting cyclopropanones with alkyl azides under Lewis acidic conditions as a means of synthesizing N-substituted β-lactams. In the course of this study, we discovered that the Lewis acid promoted reactions of azides and cyclopropanones provide a rich array of products that depend on the nature of the cyclopropanone substitution. Previously, we disclosed that the reactions of 2,2-dimethylcyclopropanone equivalents with azides provide α-amino-α2-diazomethyl ketones. 10 Herein, we describe the results of a broader investigation on the reactions of substituted cyclopropanones with alkyl azides. In s...

Enantioselective Synthesis of Cyclopropanone Equivalents and Application to the Formation of Chiral β‐Lactams

“…Considering the biological relevance of β‐lactam derivatives, a particularly attractive transformation we were prompted to study is the formal [3+1] cycloaddition of cyclopropanones with nitrene equivalents to afford β‐lactams. An analogous Schmidt‐type rearrangement had previously been reported by Aubé and co‐workers using (1‐ethoxycyclopropoxy)trimethylsilane in the presence of organoazides and BF 3 ⋅OEt 2 , although only unsubstituted achiral β‐lactam derivatives could be obtained in low to moderate yield . In that work, the relatively harsh conditions required for equilibration to cyclopropanone likely led to multiple decomposition pathways.…”

“…With general access to aw ide variety of highly reactive cyclopropanone precursors,w es ought to apply these substrates in strain-releasing rearrangements.C onsidering the biological relevance of b-lactam derivatives, [25] ap articularly attractive transformation we were prompted to study is the formal [3+ +1] cycloaddition of cyclopropanones with nitrene equivalents to afford b-lactams.A na nalogous Schmidt-type rearrangement had previously been reported by AubØ and coworkers using (1-ethoxycyclopropoxy)trimethylsilane in the presence of organoazides and BF 3 •OEt 2 , [26] although only unsubstituted achiral b-lactam derivatives could be obtained in low to moderate yield. [27,28] In that work, the relatively harsh conditions required for equilibration to cyclopropanone likely led to multiple decomposition pathways.Moreover,we sought to avoid organoazides in order to improve the applicability of the method on alarger scale.After evaluating various other nitrene equivalents, [11] it was found that simple hydroxylamines or their corresponding ethers could play the same role when the reaction was run in presence of aL ewis acid (Scheme 4).…”

Schmidt Rearrangement Reactions with Alkyl Azides

“…The highly ring strained cyclopropanone (which is conveniently stored and used as a mixed ketal) also undergoes Schmidt chemistry to afford N -substituted β -lactams along with ethyl carbamates in about a 1 : 1 ratio (Scheme 7.9 ). 23,24 Presumably, the β -lactam is formed via the typical ring expansion mechanism described above. Ethyl carbamates are more mechanistically intriguing, requiring the formal loss of ethylene and N 2 followed by recombination of a silylated isocyanate with ethanol.…”

Small Rings by Azide Chemistry

“…31,109 Simple azetidine -2 -ones 92 have also been obtained in moderate yield, along with carbamate esters 93 , from the boron trifl uoride catalyzed reaction of benzyl azides with a cyclopropanone acetal 91 . 110 The complex 94 has been suggested as an intermediate in the ring expansion reaction (Scheme 6.36 ).…”

“…Scheme 6.34 Triaziridines 108Scheme 6.35 Azetidin -2 -ones from 4 -azidopyrrol -2(5 H ) -ones 109Scheme 6.36 Azetidin -2 -ones from a cyclopropanone acetal110 …”