Synthesis of Chiral Methylenecyclopropane Derivatives

Abstract

Diastereoisomerically pure methylenecyclopropane and methylenecyclopropane carbinol derivatives were easily prepared, in a single-pot operation, from 1,1,2-tribromocyclopropane via a three-component reaction.In the past decades, methylenecyclopropanes (MCP), which are highly strained but stable molecules, have been extensively studied. 1 They are of synthetic interest due to the multiple possibilities for reaction either of one of the three strained bonds (two proximal and one distal bonds) in the cyclopropane ring and by the nature of the reactive exomethylene double bond. 1 Particular attention has been paid to the metal-catalyzed reaction (Cu, 2 Pd, 3 Ni, 4 Pt, 5 Rh, 6 Sn, 7 Mg 8 ) of methylenecyclopropane for the construction of more elaborated carbon skeleton. However, most of these transformations were based on racemic methylenecyclopropanes as very few methods were reported for the preparation of chiral methylenecyclopropanes. 1c,9 On the other hand, Padwa has reported the reaction of 1-phenylsulfonyl-2,3,3-trimethylcyclopropene 1 with n-BuLi followed by alkylation with various electrophiles to produce the corresponding arylsulfonyl-substituted methylenecyclopropanes 2 as the exclusive product (Scheme 1). 10 Scheme 1The product 2 has been rationalized by a removal of the acidic proton with a strong base followed by alkylation via the formation of the allyllithium species. As cyclopropene derivatives are easily prepared and that their usefulness has been increased significantly by recent developments from our group 11 and others, 12 we though to combine the isomerization reaction described above with an easy source of chirality. In this regard, we recently found that the chiral sulfinyl group was the best chiral inductor for controlling the metallotropic equilibrium of allyl species, even for the creation of chiral quaternary centers. 13 In this letter, we would like to disclose our preliminary results for the preparation of chiral methylenecyclopropane derivatives, in a three-component condensation reaction from 1,1,2-trihalogenocyclopropanes, chiral sulfinyl ester and electrophiles. Cyclopropenyllithium 4 is obtained from 1,1,2-tribromocyclopropane 3 (prepared by reaction of 2-bromo-3-methyl-2-butene derivative with bromoform in the presence of cetrimide as phase-transfer catalyst) 14 by a successive 1,2-dehalogenation reaction followed by a halogen-lithium exchange as described in Scheme 2. Then, after addition of (-)-menthyl-(S)-p-toluenesulfinate, 15 the corresponding cyclopropenyl sulfoxide is formed as intermediate. Then, we found after several optimizations, that the optimal condition for the in situ formation of the allyl species 7 was obtained by a deprotonation reaction of the cyclopropenyl sulfoxide 6 with cyclopropenyllithium 4 itself with concomitant formation of the volatile 1,2,2-trimethylcyclopropene derivative. Therefore, two equivalents of 4 are necessary for the completion of the reaction (Scheme 2). After addition of water, the corresponding chiral methylenecyclopropane is obtained in ...

Sigmatropic rearrangements of cyclopropenylcarbinol derivatives. Access to diversely substituted alkylidenecyclopropanes

“…Another approach relies on the reaction of cyclopropenylmethyl organometallic species C with electrophiles through an S E 2’ process leading to substituted alkylidenecyclopropanes D (Scheme 1, reaction 2). Examples of those transformations include the carboxylation of a (trimethylsilylmethyl)cyclopropene in the presence of a fluoride promoter [22], and also the addition of electrophiles to (lithiomethyl)cyclopropenes generated by lithiation of the corresponding methylcyclopropenylsulfone [23] or -sulfoxide [24]. More recently, the addition of cyclopropenylmethylboronates to aldehydes was also reported [25].…”