Asymmetric Schmidt Reaction of Hydroxyalkyl Azides with Ketones

Abstract

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.

Recent Advances in the Mitsunobu Reaction: Modified Reagents and the Quest for Chromatography‐Free Separation

“…The products available via the Mitsunobu reaction have been expanded or the procedure has been improved to include styrene oxides with a high level of stereoretention, [32] oxetanes, [29] lactones from hindered chiral alcohols with retention of configuration, [73] aldehydes from 1,1-disubstituted-1,2-diols, [85] carbamate esters, [57,86,87] γ-lactams from amino alcohols, [88] primary amines, [89] tertiary benzylamines, [40] alkylated hydrazines, [90] nitriles, [41,61] isocyanates, [31] thiocyanates, [91] hydroxyalkyl azides, [69,92] and cisor trans-1,2-diazides from epoxides or trans-diols. [93] Hydra- zine derivatives can be obtained directly from the azodicarboxylate and an alcohol, [94] vinylhydrazinecarboxylates from ketones in the presence of dimethyl azodicarboxylate, [95] and hydrazylmethyl uracil derivatives from N 3 -benzyluracil, TMAD, and N-hydroxymethylphthalimide.…”

Schmidt Rearrangement Reactions with Alkyl Azides

“…25,31 Thus, when the chiral hydroxyalkyl azide shown was treated with 4 -tert -butylcyclohexanone in the presence of BF 3 · OEt 2 followed by basic hydrolysis, a mixture of lactams 19a and 19b was formed in modest yield (Scheme 7.14 ). The stereochemical rationale for the observed stereoselectivity involves equatorial addition of azide to the oxonium ion (supported by ab initio calculations).…”

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.…”