Synthetic Methods DOI: 10.1002/anie.200702713 An Efficient, Facile, and General Stereoselective Synthesis of Heterosubstituted Alkylidenecyclopropanes** Ahmad Masarwa, Amnon Stanger, and Ilan Marek* Dedicated to Professor Herbert Mayr on the occasion of his 60th birthday Over the last few decades, the chemistry of racemic methyl- enecyclopropane and alkylidenecyclopropane derivatives [1] in the presence of transition-metal catalysts has been explored extensively. [2] The reactive nature of these compounds is commonly attributed to the strained double bond. [3] The mode of ring opening (at the distal C3 À C4 bond or at the proximal C2ÀC3 bond) depends mainly on the choice of catalyst. [2c] The regioselectivity of the addition of an organo- metallic derivative RM across the exomethylene double bond C1ÀC2 depends on the nature of both the organometallic and the alkylidenecyclopropane derivative. [2] Furthermore, the presence of a carbon stereocenter on the cyclopropyl ring may lead to a transfer of chirality to the final product. [2] The presence of quaternary stereocenters in the alkylidenecyclo- propane would be particularly interesting, as insertion into the distal bond may be inhibited completely. Unfortunately, as a result of inherent difficulties with their preparation, the availability of enantiomerically enriched methylenecyclopro- panes and alkylidenecyclopropanes with quaternary stereo- centers is rather limited. [4] In this context, we reported the copper-catalyzed addition of Grignard reagents to enantio- merically pure cyclopropenyl alcohols 1 to give alkylidenecy- clopropane derivatives 2 with very high enantioselectivity [Eq. (1)]. [5] Alternatively, nonbonding interactions with substituents on the substrate may serve as the dominant stereochemical control element. In certain cases, reagents have been reported to preassociate with polar functional groups in the vicinity of the reactive center and to influence the stereochemical outcome of the process. Such interactions are frequently stronger than purely steric interactions and may lead to the opposite stereochemical outcome to that predicted on the basis of steric effects alone. Those cases in which such contrasteric selectivity has been observed have invariably involved substrates with polar functional groups and metal- based reagents. [6] In this context, a particularly interesting example would be the preparation of acetoxy-substituted alkylidenecyclopropane derivatives. Most of the methods known to date for the preparation of such compounds involve the reaction of an alkylidenecarbene with an enol ether, [7] the photolysis of a dithiolactone, [8] or the addition of tBuOH to 1,4-di-tert-butylmethylenecyclopropene. [9] To further enrich the chemistry of alkylidenecyclopro- panes in synthesis, in particular for the creation of quaternary stereocenters, we report herein the preparation of racemic and enantiomerically enriched alkylidene cyclopropane derivatives with polar functionalities through sigmatropic rearrangements. [10] Thus, racemic cyclopropenyl alcohols 1 were first transformed readily into cyclopropenyl acetate derivatives 3, the rearrangement of which fulfilled our expectations (Table 1). The [3,3] sigmatropic rearrangement of the tertiary allylic ester 3a proceeded under very mild conditions upon simple filtration through a column of silica gel (method A; Table 1, entry 1), upon heating at reflux in CH 2 Cl 2 (method B; Table 1, entry 2), or upon the addition of dry amberlyst-15, an acidic ion-exchange resin (method C; Table 1, entry 3). [11] In all cases, the desired rearrangement occurred to give the expected product 2-diphenylmethylene-1-methylcyclopropyl acetate (4a) in excellent yield. The relief of ring strain (an alkylidene cyclopropane is less strained than cyclopropene by 10.3 kcal mol À1 ) [12] is the driving force for rearrangement under such mild conditions. It was found that the substituent R 1 on the double bond of the cyclopropenyl acetate can be either alkyl or aryl (Table 1, entries 1–4), whereas the substituents R 2 and R 3 can be alkyl, aryl, or hydrogen atoms. When secondary alcohols were used (R 2 = H, R 3 = Ar), [13] the issue of the configuration of the double bond was raised. In almost all experiments, only the E isomer of the product was detected (as determined by NOE experiments). The E isomer results from a chairlike confor- mation A in the transition state in which the R 3 substituent [*] A. Masarwa, Prof. A. Stanger, Prof. I. Marek The Mallat Family Laboratory of Organic Chemistry Schulich Faculty of Chemistry and The Lise Meitner–Minerva Center for Computational Quantum Chemistry Technion—Israel Institute of Technology Haifa 32000 (Israel) Fax: (+ 972) 4-829-3709 E-mail: chilanm@tx.technion.ac.il [**] This research was supported by a grant from the German–Israeli Project Cooperation (DIP-F.6.2), by the Israel Science Foundation administrated by the Israel Academy of Sciences and Humanities (459/04), and by the Fund for the Promotion of Research at the Technion. I.M. is holder of the Sir Michael and Lady Sobell Academic Chair. Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author. Angewandte Chemie 8039 Angew. Chem. Int. Ed. 2007, 46, 8039 –8042 # 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim