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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Am Chem Soc. Author manuscript; available in PMC 2010 April 22.
Published in final edited form as:
PMCID: PMC2765507

Directed Carbozincation Reactions of Cyclopropene Derivatives

Directed carbometallation reactions of cyclopropenes are powerful reactions for the construction of functionalized cyclopropanes1—structures that have manifold applications in synthesis.2 A number of effective carbomagnesation procedures have been described in recent years,3 but a limitation has been the reactivity of Grignard reagents toward many functional groups. Most conspicuous has been the intolerance toward the ester functions of cyclopropenes (1) that are available from transition metal-catalyzed reactions of alkynes with α-diazo esters (Scheme 1).4 Described herein are carbozincation reactions of cyclopropenes that are directed by ester or oxazolidinone substituents. This straightforward approach to cyclopropane synthesis proceeds with a stereochemical outcome that is complementary to that generally observed in catalytic cyclopropanation reactions of diazo compounds with alkenes.5

Scheme 1
Directed carbozincation of readily available cyclopropenes

It is well established that Cu-complexes can catalyze the conjugate addition reactions of organozinc reagents, and mechanistic proposals have invoked the cooperative action of Cu and Zn (Scheme 2a).6 As cycloprop-2-ene carboxylates are homologs of α,β-unsaturated carbonyl compounds, it was hypothesized that esters would direct the carbozincation of cyclopropenes by analogy (Scheme 2b). Work by Gevorgyan, Rubin and Orchin has established that esters can be used as syn-directing groups7 in catalytic hydroboration reactions7a and in hydroformylation7b-d reactions of cyclopropenes. Pioneering work by Negishi8 and Nakamura9 has established that allylzinc reagents add to cyclopropene derivatives. Nakamura has described an enantioselective Fe-catalyzed system for the addition of diorganozinc reagents to cyclopropenone ketals,3c and Richey has described additions of Et2Zn to spiro[2.5]oct-1-enes.10 However, facially selective carbozincations of cyclopropenes were unknown.

Scheme 2
Scheme for Cu-catalyzed (a) conjugate addition, and (b) directed carbozincation reactions of cyclopropenes.

From an optimization study directed toward the preparations of 3a-c, it was determined that additions of diorganozinc reagents could be effectively catalyzed by a variety of Cu(I) salts (see Supporting Information). CuI and CuCN were the most effective catalysts, and led to carbometallation products with excellent selectivity. Low conversions were observed and large excesses of organozinc reagents were required for additions carried out in the absence of a catalyst. An exception was 4b, which was formed in high yield with or without a catalyst. Solvent choice was an essential parameter: toluene was most effective, whereas the use of THF or diethyl ether lead to carbometallation products with low diastereoselectivity. The reactions with Ph2Zn were most effective in terms of reagent economy: 3c was obtained in 83% and 70% yields with 1.0 equiv and 0.6 equiv of Ph2Zn, respectively (Table 1). Larger amounts of Me2Zn (4.0 equiv) and Et2Zn (2.5 equiv) were required for optimal reactivity, as decreasing the amount of these organozinc reagents led to lower yields and increased side product formation.

Table 1
Cu-catalyzed directed carbozincation

The carbozincation protocols were successfully applied to cyclopropenes 2a-d to give cyclopropane products 3-6 in good yields and excellent diastereoselectivities (Table 1). Additions to 2-alkylsubstituted cyclopropene carboxylates 2c-d also proceeded with excellent regioselectivity11 to produce quaternary-center-containing cyclopropanes 5a-c and 6a-c. Stereospecific reactions of cyclopropylzinc adducts from 2a were successful12 with I2 or allyl bromide to give adducts 3d-e.

As only a limited number of dialkylzinc reagents are commercially available, in situ protocols for generating diorganozinc species13 were investigated. As shown in Table 2, (o-tolyl)2Zn, i-Pr2Zn, and vinyl2Zn were prepared from the corresponding Grignard reagents and ZnCl2. Carbozincation adducts were quenched with water to give products 7a-7c with >93:7 diastereoselectivity.

Table 2
Carbometallation with diorganozinc reagents formed in situ

It was also demonstrated that acyloxazolidinone auxilaries can direct carbozincation reactions of cyclopropenes. This was particularly important for derivatives of the parent cycloprop-2-ene carboxylic acid, as ester derivatives of this acid are unstable.14 However, oxazolidinone derivatives such as 8 are readily available and stable to longterm storage.14 Carbometallation reactions of 8 proceed with high diastereoselectivity to give adducts 9a-d (Scheme 3).

Scheme 3
Oxazolidinone directed carbozincation reactions

Also investigated were additions of diorganozinc reagents to a chiral oxazolidinone derivative of 3-phenylcycloprop-2-ene carboxylic acid (Scheme 4). After optimization, it was found that the combination of CuBr•Me2S and MgBr2•OEt2 was selective for the addition of Et2Zn to cyclopropene 10. After aqueous quench, 11a is formed with >95% diastereoselectivity (4 diastereomers are possible). Capture by I2 and allyl bromide provided 11b and 11c, respectively. Compound 11a could be converted to the corresponding methyl ester in 60% yield by Sm(OTf)3 mediated methanolysis (see Supporting Information).

Scheme 4
Chiral auxiliary control of carbometallation by Et2Zn

In summary, a diastereoselective procedure has been developed for the Cu-catalyzed addition of diorganozinc reagents to cyclopropene substrates. Ester and oxazolidinone functions direct the addition of a variety of nucleophiles with excellent facial selectivity. The regioselectivity is also high for carbozincation reactions of 2-alkyl substituted cycloprop-2-ene carboxylate esters. The resulting cyclopropylzinc reagents can be captured via stereospecific reactions with electrophiles. The scope of the method is broadened by the ability to utilize organozinc reagents that have been generated in situ from Grignard reagents. Chiral oxazolidinone auxilaries are effective in controlling the diastereoselectivity of carbometallation reactions.

Supplementary Material








This work was supported by NIH grant GM068640. We thank Glenn P. A. Yap for crystallography.


Supporting Information Available: Full experimental details and 1H, 13C NMR spectra are provided, and Stereochemical assignments are described. This material is available free of charge via the Internet at


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