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Dimethylzinc-Initiated Radical Reactions

Accounts of Chemical Research2008Vol. 42(2), pp. 345–355

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Tito Akindele, Ken‐ichi Yamada, Kiyoshi Tomioka

Abstract

Developments in modern organic synthesis owe much to the field of radical chemistry. Mild reaction conditions, high selectivity, good functional group tolerance and high product yield are features that have made reactions involving radical species indispensable tools for synthetic chemists. In part, the discovery of new radical initiators has led to the efficiency that now characterizes most radical reactions. This Account describes our investigations of radical reactions initiated by dimethylzinc. In 2001, we unexpectedly observed this reaction while investigating the amidophosphane-copper-catalyzed asymmetric addition of dimethylzinc to N-sulfonyl imines with tetrahydrofuran (THF) as reaction solvent. However, instead of adding the desired methyl group to the N-sulfonyl imine, we produced the THF adduct in excellent yield. This result laid the foundation for our discovery of novel modes of reactivity. Further investigations of the unexpected addition reaction revealed that a trace amount of air was needed for reaction progress, indicating that radical intermediates were involved. Indeed, controlled injection of air into the reaction flask by a syringe pump through a sodium hydroxide tube afforded the products in good to excellent yield. In addition, the reaction proved to be chemoselective for a C=N bond over a C=O bond, as well as for 1,4-addition over 1,2-addition. We developed asymmetric variants of the radical addition reaction of ethers to imines using chiral N-sulfinyl imines to produce the adducts in reasonably high stereoselectivity (up to 11:1). A 93:7 diastereomeric ratio of the adduct was obtained when bis(8-phenylmenthyl) benzylidenemalonate was used in the radical addition of ethers to C=C bonds. Interestingly, in the presence of dimethylzinc and air, arylamines, alkoxyamines, and dialkylhydrazines react with THF to give amino alcohols, oximes, and hydrazones, respectively, in moderate to high yields. We performed a tin-free intermolecular addition of functionalized primary alkyl groups, generated from their corresponding iodides, to N-sulfonyl imines using dimethylzinc, air, boron trifluoride diethyl etherate, and a catalytic amount of copper(II) triflate. Direct C-H bond cleavage from cycloalkanes was also feasible in the presence of dimethylzinc, air, and boron trifluoride diethyl etherate to give the corresponding cycloalkyl radicals, which were suitable nucleophiles for N-sulfonyl imines. In all of the above reactions, dimethylzinc was a superior radical initiator than other conventional initiators such as dibenzoyl peroxide, diethylzinc, and triethylborane. We hope the coming decades will witness the report of other novel radical initiators that would complement the reactivity modes of existing ones.

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Abstract

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