Chloromethyllithium

Introduction

Chloromethyllithium (LiCH₂Cl) is a synthetically useful reagent belonging to the category of carbenoids, which are known to exhibit an ambiphilic behavior ranging from nucleophilic (at low temperatures) to electrophilic (at higher temperatures). This fact can be deduced by the resonance structures represented in Scheme [1], in which the extreme ionization of the polar bonds could lead, in principle, to the carbanionic (1a) or carbocationic (1b) species.[1] Chloromethyllithium can be prepared via a halogen–lithium exchange reaction on a given dihalomethane. Iodo- and bromo-chloromethane (ICH₂Cl and BrCH₂Cl) are the ideal precursors jointly with methyllithium–lithium bromide complex or n-butyllithium.[2] It is highly unstable except at very low temperatures (–78 °C or below); however, performing the reaction in the presence of the electrophile (i.e. Barbier-type conditions) allows to realize efficient processes. The presence of lithium halides and the use of ethereal-type solvents (THF or diethyl ether) had beneficial effects on its stability.[3]

Scheme 1 Ambiphilicity of chloromethyllithium

Interestingly, Le Floch and co-workers showed that by replacing the two hydrogens with electron-withdrawing groups, it is possible to dramatically improve the stability of the corresponding carbenoid.[4]

• References


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For recent reviews, see:
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• 3 Pace V, Holzer W, Verniest G, Alcántara AR, De Kimpe N. Adv. Synth. Catal. 2013; 355: 919 . See also ref. 2b
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• 5 Sadhu KM, Matteson DS. Tetrahedron Lett. 1986; 27: 795
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• 9c Pace V, Castoldi L, Alcántara AR, Holzer W. RSC Adv. 2013; 3: 10158

For a highlight on the activation strategies of amides towards organometallics, see:
• 9d Pace V, Holzer W, Olofsson B. Adv. Synth. Catal. 2014; in press (DOI: 10.1002/adsc.201400630)
• 9e Pace V, Holzer W. Aust. J. Chem. 2013; 66: 507
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• 11 Hutchings M, Moffat D, Simpkins NS. Synlett 2001; 661
• 12 Sonawane RP, Jheengut V, Rabalakos C, Larouche-Gauthier R, Scott HK, Aggarwal VK. Angew. Chem. Int. Ed. 2011; 50: 3760