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)

 
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Ashenafi Damtew Mamuye was born in Alem-Ketema, Ethiopia in 1984. He completed his B.Sc. in Applied Chemistry at the University of Gondar (2006) and received his M.Sc. in Medicinal Chemistry from Addis Ababa University (2009). He worked as teaching assistant from 2009 to 2011 in Ethiopia. In 2012 he joined the University of Sassari to undertake doctoral studies in Chemical Science and Technology under the supervision of Prof. Ugo Azzena. Starting from October 2013, he is a visiting PhD student at the University of Vienna under the supervision of Dr. Vittorio Pace and Prof. Wolfgang Holzer. His research focuses on α-substituted organolithiums (e.g. carbenoids), arene-catalyzed lithiation, and pyrazole chemistry.

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]

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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]


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Abstracts

(A) Carbonyl-type compounds have been homologated with lithium carbenoids. The addition of LiCH2Cl to an aldehyde or a ketone (2) after mild acidic treatment provides the corresponding halohydrin (3) in high yields. Interestingly, when the reaction is allowed to reach room temperature, an intramolecular nucleophilic displacement takes place, thus affording directly the epoxide 4.[5] The strategy has very recently been applied to cyclic α,β-unsaturated enones to access chloromethyl allylic alcohols in high yield.[6]

(B) Concellón and co-workers conveniently used a strategy for the preparation of β-chloro amines (7,7a) starting from activated N-arylsulfonamido imines 5.[7]

(C) Very recently Pace and co-workers reported the treatment of isocyanates 8 with LiCH2Cl to access versatile N-chloro acetamides 9 in high yields even in the presence of optically active starting materials which did not racemize during the process.[8]

(D) A general method for the synthesis of α-arylamino-α′-chloro ketones in the presence of various substituents on the nitrogen atom has been developed by Pace et al. who employed Weinreb amides[9] 10 as electrophilic starting materials for the chloromethylation.[3] Remarkably, the use of such amides could be successfully extended to the synthesis of α′-halo-α,β-unsaturated ketones 13 for which the use of esters provided exclusively the double addition products (i.e. carbinols).[10] In this regard, the high stability under the reaction conditions of tetrahedral intermediate 12a, formed upon the addition of chloromethyllithium to Weinreb amide 12, prevents the deleterious double addition of the reagent.

(E) Simpkins and co-workers realized an efficient synthesis of the key intermediate 15 needed for the total synthesis of fumagillol 16. Interestingly, the chloromethylation of the complex ketone 14 proceeded in good yield and dr. [11]

(F) Matteson pioneered the chemistry of monohalolithium carbenoids with boronic esters.[2c] Recently, Aggarwal reported the homologation of tertiary boronic esters 17 with chloromethyllithium followed by oxidation to produce the corresponding enantiopure alcohols 18. In addition, they rationalized that the formation of 18 or 19 depends on the intermediate complex formed from 17 and chloromethyllithium, which can undergo O-migration (giving 19) or C-migration.[12] By switching to LiCH2Br the undesired O-migration can be minimized.


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  • 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
    • 8a Pace V, Castoldi L, Holzer W. Chem. Commun. 2013; 49: 8383
    • 8b Pace V, Castoldi L, Mamuye AD, Holzer W. Synthesis 2014; 46: 2897
    • 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

  • 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
    • 8a Pace V, Castoldi L, Holzer W. Chem. Commun. 2013; 49: 8383
    • 8b Pace V, Castoldi L, Mamuye AD, Holzer W. Synthesis 2014; 46: 2897
    • 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

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Scheme 1 Ambiphilicity of chloromethyllithium