Synlett 2014; 25(19): 2814-2815
DOI: 10.1055/s-0034-1379442
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© Georg Thieme Verlag Stuttgart · New York

Chloromethyllithium

Ashenafi Damtew Mamuye
a   Department of Pharmaceutical Chemistry - Division of Drug Synthesis, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria
b   Dipartimento di Chimica, Università di Sassari, I-07100-Sassari, Italy   Email: ashenafi.mamuye@univie.ac.at
› Author Affiliations
Further Information

Publication History

Publication Date:
05 November 2014 (online)

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]

Zoom Image
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


    • For seminal studies, see:
    • 1a Köbrich G, Akhtar A, Ansari F, Breckoff WE, Büttner H, Drischel W, Fischer RH, Flory K, Fröhlich H, Goyert W, Heinemann H, Hornke I, Merkle HR, Trapp H, Zündorf W. Angew. Chem. Int. Ed. 1967; 6: 41

    • For recent reviews, see:
    • 1b Pace V. Aust. J. Chem. 2014; 67: 311
    • 1c Capriati V, Florio S. Chem. Eur. J. 2010; 16: 4152
    • 1d Boche G, Lohrenz JC. W. Chem. Rev. 2001; 101: 697
    • 2a Sadhu KM, Matteson DS. Tetrahedron Lett. 1986; 27: 795
    • 2b Tarhouni R, Kirschleger B, Rambaud M, Villieras J. Tetrahedron Lett. 1984; 25: 835
    • 2c Matteson DS, Majumdar D. J. Am. Chem. Soc. 1980; 102: 7588
  • 3 Pace V, Holzer W, Verniest G, Alcántara AR, De Kimpe N. Adv. Synth. Catal. 2013; 355: 919 . See also ref. 2b
  • 4 Cantat T, Jacques X, Ricard L, Le Goff XF, Mézailles N, Le Floch P. Angew. Chem. Int. Ed. 2007; 46: 5947
  • 5 Sadhu KM, Matteson DS. Tetrahedron Lett. 1986; 27: 795
  • 6 Pace V, Castoldi L, Holzer W. Adv. Synth. Catal. 2014; 356: 1761
    • 7a Concellón JM, Rodríguez-Solla H, Simal C. Org. Lett. 2008; 10: 4457
    • 7b Concellón JM, Rodríguez-Solla H, Bernad PL, Simal C. J. Org. Chem. 2009; 74: 2452
    • 9a Nahm S, Weinreb SM. Tetrahedron Lett. 1981; 22: 3815
    • 9b Balasubramaniam S, Aidhen IS. Synthesis 2008; 3707
    • 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
  • 10 Pace V, Castoldi L, Holzer W. J. Org. Chem. 2013; 78: 7764
  • 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