Efficient Nitrogen Ring-Expansion Process Facilitated by in Situ Hemiketal Formation. An Asymmetric Schmidt Reaction

Abstract

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...

Reactions of Oxazolinium and Dihydrooxazinium Salts Prepared by an Azide Insertion Sequence: pH Control of Product Distribution

“…6 Although previously disclosed studies with acetone and 1b showed solely amide product in 86% yield when NaHCO 3 was used, 2 we have had difficulty in repeating this result. Current work to elucidate the effect of ketone and azide structures on the distribution of acyclic products is underway.…”

“…6 Only amide formation was observed in our previous studies with four-to six-membered ring ketones, using either base in the work-up. [2][3][4] The difference in transannular strain associated with the lactams (standard rings, 5-7 members) vs. lactones (medium rings, 8-11 members) formed in these cases most likely accounts for the absence of lactone production. In contrast, both products from the ring expansion of cycloheptanone contain medium-to-large rings and therefore, ring strain is likely to play a less dominant role in product selection.…”

“…More recently, we have demonstrated that imidate salts can also be generated in situ by the Lewis acid-promoted reactions of hydroxy azides with ketones. [2][3][4] The addition of nucleophiles to these imidate salts affords a range of products that includes amines, enamines and ω-substituted alkyl amides. 3 Globally, this mechanistically complex process can involve kinetic addition to the cationic center and proceed directly to product (path A) or involve displacement at the terminal carbon of the azido alcohol (starred, path B).…”

Oxidative Rearrangement of Cyclobutanone Derived <i>N</i>,<i>O</i>-Ketals Leading to Pyrrolidone Derivatives

“…The reaction represents an alternative to Schmidt reaction using hydroxyalkyl azides. [22][23][24][25][26][27][28] Studies of halogen-induced oxidative rearrangements of N,O-ketals were performed using 1a as a test substrate. Compound 1a was readily prepared by the condensation of cyclobutanone with a commercially available amino alcohol, 2-amino-3-phenylpropan-1-ol.…”

“…The iminium ether intermediate ii has ambident electrophilicity, and the C2 and C4 positions of the oxazoline ring can react with nucleophiles. [22][23][24][25][26][27][28][30][31][32][33] Methyl ether 3a′ is not produced, and therefore nucleophilic attack by MeOH on intermediate ii selectively occurs at the C2 position rather than the C4 position of the oxazoline ring, to give a possible intermediate iii, which affords alcohol 3a on aqueous work-up.…”