An asymmetric equivalent of the Schmidt reaction permits stereocontrol in ring expansions of symmetrical cyclohexanones. The procedure involves the reaction of chiral 1,2- and 1,3-hydroxyalkyl azides with ketones under acid catalysis; the initial reaction affords an iminium ether that can be subsequently opened with base. A systematic study of this reaction is reported, in which ketone substrates, chiral hydroxyalkyl azides, and reaction conditions are varied. Selectivities as high as ca. 98:2 are possible for the synthesis of substituted caprolactams, with up to 1,7-stereoselection involved in the overall process. The fact that either possible migrating carbon is electronically identical provides an unusual opportunity to study a ring-expansion reaction controlled entirely by stereoelectronic factors. The mechanism of the reaction and the source of its stereoselectivity are also discussed.

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The regiochemistry of ring expansions of 2-substituted cyclic ketones using 1,2-azidoethanol and 1,3-azidopropanol was examined. It was determined that the reactions of ketones with an adjacent methyl or ethyl group are generally unselective, but that bulkier substituents lead to preferential migration of the more highly substituted carbon. In addition, it was found that ketones bearing inductively electron-withdrawing substituents (OMe, Ph, Br) undergo selective migration of the less highly substituted carbon. For some substrates, alternative reaction pathways were also identified.

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We recently reported an intramolecular version of the Schmidt reaction' in which hydrazoic acid was replaced by an alkyl azide connected to the reactive ketone.2 This is an unusual example of intramolecularity because the analogous H+-promoted intermolecular reaction does not succeed at alL3 Given the potential utility of a general method for the intermolecular insertion of an N-alkyl group adjacent to a ketone, other conditions to effect the direct reaction of ketones with alkyl azides were examined. Of several Lewis acids tried, only TiCL was effe~tive.~ However, this reaction tumed out to be severely limited, with poor (<20%) yields being obtained when even modestly substituted cyclohexanones or, most curiously, cyclopentanones of any stripe were used. In addition, the need for such a strong Lewis acid could be a drawback in reactions of multifunctional substrates.One immediately evident solution to this problem was to utilize a tethering substituent that would temporarily connect the two reactive groups and be subsequently r e m~v e d .~ Although meritorious, this approach would entail the addition of minimally two steps to a synthetic sequence in attaching and removing the tethering group. An alternative approach is suggested in Scheme 1. Utilization of an azido alcohol such as 2-azidoethanol (1) presents an activated ketone with two potential nucleophiles. Our previous work has shown that direct attack by azide is possible but only marginally effective. Instead, hemiketal formation could occur, followed by dehydration to generate the oxonium ion shown. At this point, intramolecular attack of the azide on the carbocation is possible, following our own precedent2 and that of Pearson and coworkers.6 Migration of one of the alkyl groups with concomitant loss of NZ would then afford an iminium ether species that, upon addition of water, would give the formal product of direct insertion of the azide end of 1 into the ketone.This idea was attractive because the tether which renders the ketone and azide intramolecular would be generated in situ and not require additional steps for its installation and removal. Previously, Boyer and co-workers had found that hydroxy azides could be reacted with aromatic aldehydes only, affording oxazolines or dihydrooxazines as the products in good yields; however, this HzSO4-promoted reaction failed with ketones.'~~ These authors attributed the success of hydroxy azides relative to simple alkyl azides to greater acid stability of the former species (due to hydrogen bonding) and did not consider the (1) Reviews of the Schmidt reaction: (a) Wolff, H. ( 5 ) For a successful example of this strategy, see: Stork, G.; Chan, T. Y.; Brealt, G. A. 1 H0-l Y 0 N. R R mechanism shown above in Scheme 1 .g Herein, we report that this strategy provides an effective and broad approach to multifunctional lactam synthesis and that using chiral azido alcohols leads to the first known examples of an asymmetric Schmidt reaction.The examples shown in Table 1 are representative. Although several Lewis ac...