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The stereochemistry of the Kulinkovich cyclopropanation of nitriles with alkenes has been examined by employing (E)-disubstituted alkenes and deuterium-labeled homoallylic alcohols as a stereochemical probe. An intramolecular cyclopropanation proceeds with preservation of the olefin configuration. On the other hand, intermolecular counterparts occur with both preservation and reversal of the olefin configuration, which corresponds to retention and inversion of configuration at the Ti–C bond, respectively, in the cyclopropane-forming step. These uncommon stereochemical outcomes contrast with that of the Kulinkovich cyclopropanation of tertiary amides.

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We report herein olefin exchange-mediated cyclopropanation of nitriles with homoallylic alcohols. The use of homoallylic alcohols is central to the successful implementation. KeywordsCyclopropanation; Aminocyclopropane; Titanium; Nitrile; Homoallylic alcohols Since Kulinkovich and co-workers discovered an efficient cyclopropanation of carboxylic esters in 1989, 1 the Kulinkovich reaction has been extended to other carboxylic acid derivatives to provide convenient access to heteroatom-substituted cyclopropanes. 2 For example, the Szymoniak group developed the preparation of aminocyclopropanes by adaptation of the Kulinkovich reaction to nitriles with aid of a Lewis acid. 3a The successful cyclopropanation reactions of nitriles with homologs other than the ethyl Grignard reagent and an intramolecular version of unsaturated nitriles by the action of the cyclohexyl Grignard reagent were also reported. 3,4,5a Addition of a Lewis acid is typically required to promote ring closure, but is unnecessary in the case of intramolecular reactions or in the presence of a suitable chelating substituent. 4 A variant involving the use of diethylzinc and lithium iodide also appeared. 5b,c In contrast, attempts to implement the olefin exchange-mediated procedure 6 to intermolecular coupling of nitriles and α-olefins (such as 1-hexene, 1-octene, etc) proved to be futile, presumably because the low-valent titanium species reacts with the nitrile prior to olefin exchange. 3d,4,7a,b We report herein the first example of an intermolecular Kulinkovich cyclopropanation between nitriles and homoallylic alcohols.Over the years, we examined low-valent titanium-mediated cyclopropanation reactions of several carboxylic acid derivatives, such as esters, amides, carbonates, imides, nitriles, vinylogous esters and amides, N-acylpyrroles, etc. under previously developed ligand (olefin) exchange conditions. Initial investigations on nitriles were unsuccessful under these conditions, and the high affinity of nitriles for low-valent titanium species was presumed to thwart the requisite olefin exchange. 7a Other laboratories also made similar observations, and competition between intra-and intermolecular cyclopropanation reactions of ω-vinyl tethered nitriles were particularly informative. 3d,4,8 Nitriles are indeed more reactive substrates than esters and amides in the Kulinkovich reactions, and the greater reactivity of nitriles has allowed chemoselective preparation of functionalized aminocyclopropanes bearing esters and amides.© 2008 Elsevier Ltd. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the ...