Olefin exchange-mediated cyclopropanation of nitriles with homoallylic alcohols

Abstract

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 ...

Preparation and Some Synthetic Applications of 2-Hydroxyethyl-Substituted Cyclopropylamines

“…When the ramified alcohol 1b was used (entries 8 and 9), the cyclopropylamines 3h and 3i were obtained as an almost equivalent mixture of diastereomers. A lack of 1,3-diastereocontrol corroborates the results obtained by Cha et al 11,15 The presence of 2-hydroxyethyl group in 3 opens a straightforward entry into various aminocyclopropanecarboxylic acids. The synthetic utility of this reaction was exemplified by a short synthesis of a conformationally constrained glutamic acid derivative 4 from the amino alcohol 3d.…”

“…10 Very recently, the Cha group demonstrated that the intermolecular coupling of nitriles and homoallylic alcohols is possible by using this approach. 11 These results prompted us to report our own contribution in this field. We present an alternative reaction procedure and focus on some synthetic applications of this useful method.…”

Stereochemistry of the Kulinkovich Cyclopropanation of Nitriles

“…The aminocyclopropane products 9a−c / 9′a−c 11a−c , and 12b were obtained in modest yields from alcohols 5 , 6 , and 7 , respectively, whereas significant amounts of uncyclized ketones (e.g., 10a−c ) were also isolated in most cases . The latter products were reduced when TMSOTf was added . These examples represent the first successful cyclopropanation reactions of disubstituted alkenes with nitriles.…”

“…The use of a disubstituted alkene as the stereochemical probe was next extended to intermolecular cyclopropanation of nitriles by taking advantage of the directing effects of a homoallylic alcohol. We have recently shown that in situ formation of a temporary tether to the metal center is indispensable to the successful implementation of olefin-exchange mediated cyclopropanation to nitriles. , Coupling between ( E )-homoallylic alcohols 5 − 7 and nitriles 8a−c was thus examined under previously reported conditions (Table and Scheme ) . The aminocyclopropane products 9a−c / 9′a−c 11a−c , and 12b were obtained in modest yields from alcohols 5 , 6 , and 7 , respectively, whereas significant amounts of uncyclized ketones (e.g., 10a−c ) were also isolated in most cases .…”

“…For example, hydroxycyclopropanes (cyclopropanols) have been frequently utilized to exploit their facile ring cleavage. Kulinkovich and co-workers discovered an efficient method for preparing cyclopropanols from esters in 1989, and the Kulinkovich cyclopropanation has since been extended to other carboxylic acid derivatives such as amides and nitriles to afford the corresponding heteroatom-substituted cyclopropanes. − An olefin exchange variant of the Kulinkovich cyclopropanation involving a dialkoxytitanacyclopropane or titanium(II)-alkene complex has broadened the scope of the Kulinkovich reaction . An elegant deuterium labeling study by Casey and Strotman has established that the titanium homoenolate intermediates derived from esters undergo cyclization with retention of configuration at the Ti−C bond .…”