Ring-retentive deprotonation of cyclopropene-3-carboxamides Ryan Kim, William M. Sherrill, Michael Rubin * Department of Chemistry, University of Kansas,1251 Wescoe Hall Drive, Lawrence, KS 66045-758, USA article info Article history: Received 10 December 2009 Received in revised form 27 April 2010 Accepted 28 April 2010 Available online 4 May 2010 abstract A remarkable stability of anionic species generated from cyclopropene-3-carboxamides toward ring- opening is demonstrated. The resulting cyclopropenyllithium species can be reacted with a range of electrophiles, which allows for efficient introduction of additional substituents at C1 of the strained ring. Ó 2010 Elsevier Ltd. All rights reserved. 1. Introduction Cyclopropene-3-carboxamides and closely related N-acyl derivatives are attractive pharmacophores 1 and practical versatile synthons, 2,3 which have lately become a focus of attention, primarily owing to the increasing interest in highly selective transformations of cyclopropenes. 4 The most recent advance- ments in this area include the employment of optically active cyclopropene-3-carboxamides and related imides in diaster- eoselective addition reactions; 5 synthesis of enantiomerically enriched cyclopropenes via the diastereomeric chromatographic separation, 6 parallel kinetic resolution, 7 and enantioselective desymmetrization. 8 It was also demonstrated that certain steri- cally hindered imide substituents can significantly stabilize the structure of otherwise very fragile mono-substituted cyclo- propenes. 9 Our group has recently demonstrated that the amide function at C3 of cyclopropene can be used to efficiently control the facial selectivity in additions of OeH and PeH entities to the cyclopropene double bond. 10 A practical synthetic approach to cyclopropene-3-carboxamides was also disclosed, 11 which allowed for efficient and scalable synthesis of these substrates. However, this methodology is limited to preparation of 1,2-unsubstituted cyclopropenes only. Accordingly, we sought complementary synthetic methods to further expand the scope of available cyclopropenylcarboxamides. Due to relatively high acidity of the C(sp 2 )eH bonds in cyclo- propenes, their deprotonation usually proceeds routinely providing a convenient tool for further functionalization of the double bond. However, electron-withdrawing substituents at C-3 are well known to promote facile ring-opening and rearrangement into a thermo- dynamically more stable propargyl anion 3 (Eq. 1). 12 Several ap- proaches have been developed to circumvent this unwanted process. Thus, Eckert-Maksic demonstrated that cyclic anion 2, generated from cyclopropene 1 by slow addition of a non-nucleo- philic base, can be efficiently intercepted with silyl- or germyl- chlorides. 13 This strategy was also employed by Fox 14 and Gevorgyan 15 to install a silyl protection at the double bond of cyclopropene-3-carboxylates. This protocol, however, cannot be used for selective installation of a single silyl group at the double bond of 1,2-unsubstituted cyclopropenes, and is inapplicable to reactions with carbon-based electrophiles. Recently, Fox disclosed a useful method for gener- ation of a dianionic carboxylate species 2 (EWG¼CO 2  ), which permitted efficient trapping of the cyclopropenyl anion with a wide range of electrophiles. 16 This dianionic species, however, required the presence of a stabilizing additive, an amine N-oxide, for efficient coupling with certain less reactive electrophiles. 16b Alternative methods for ring-retentive derivatization of cyclo- propene-3-carboxylic acids include Pd-catalyzed electrophilic arylation 17 and MoritaeBayliseHillman reaction 15 reported by Gevorgyan, as well as Lam’s Cu-catalyzed silylation 18 and fluoride- assisted stannylation 19 reactions. Herein, we demonstrate an effi- cient and chemoselective method for synthesis of trisubstituted cyclopropene-3-carboxamides (4, EWG¼CONR 2 ) via a ring- retentive deprotonation of cyclopropene-3-carboxamides (1), followed by trapping of the cyclopropenylmetal species with electrophilic reagents. EWG R base EWG R EWG R 1 2 3 (1) E EWG R E 4 * Corresponding author. Tel.: þ1 785 864 5071; fax: þ1 785 864 5396; e-mail address: mrubin@ku.edu (M. Rubin). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2010.04.123 Tetrahedron 66 (2010) 4947e4953