[18645-12-0]  · CH2ClLi  · Chloromethyllithium  · (MW 56.42)

(converts aldehydes or ketones to chlorohydrins or oxiranes;2-6 R1CO2R2 to RCOCH2Cl;2 B(OR)3 to ClCH2B(OR)2;1,7 RBY2 to RCH2BY2;7-9 ClSiR3 to ClCH2SiR310)

Physical Data: stable at -108 °C in the presence of LiBr; unstable at higher temperatures; unstable even at -130 °C in the absence of LiBr.11

Preparative Methods: preferably by addition of Methyllithium/Lithium Bromide or n-Butyllithium solution dropwise to a vigorously stirred solution of Chloroiodomethane and the substrate in THF cooled with a dry ice-acetone bath;3,4 inexpensive ClCH2Br in place of ClCH2I is almost as efficient;6,8 an alternative is Lithium wire, ClCH2Br, and substrate in THF with sonication.5

Handling, Storage, and Precautions: see n-Butyllithium; Chloroiodomethane. The reagent must be generated under an inert atmosphere of nitrogen or argon.


O-Lithio chlorohydrins are the initial products of the reaction of ClCH2Li with carbonyl compounds.2-6 If the reaction mixture is acidified promptly, before oxirane formation occurs, chlorohydrins can be isolated. The small body of literature data suggests that the most efficient and convenient procedure is the addition of an ether solution of methyllithium/lithium bromide to an equimolar mixture of chloroiodomethane and the carbonyl compound in THF at -78 °C (eq 1).4 Although BuI can be less convenient than the more volatile MeI to separate, BuLi is otherwise a satisfactory alternative to MeLi and yielded 97% of isolated chlorohydrin from cinnamaldehyde.4 Phenylacetaldehyde with its strongly acidic a-protons provided a severe test of generality and yielded 65% of chlorohydrin (eq 2).4

Sonication of benzaldehyde with lithium metal wire and ClCH2Br in THF at -50 °C has yielded 90% of the chlorohydrin (same transformation as eq 1).5

Although there is ordinarily no need to prepare the ClCH2Li in advance of adding the carbonyl reagent,4 older chlorohydrin preparations were done with preformed ClCH2Li (eq 3).2,3

Preformed ClCH2Li has converted ethyl benzoate, PhCO2Et, to chloroacetophenone, PhCOCH2Cl (61%).2

The reaction of BuLi with ClCH2Br, as well as that of MeLi with ClCH2I, in the presence of ketones has been used to produce O-lithio chlorohydrins, which were then lithiated and further transformed as described in the subsection b-lithio lithium alkoxides below.6


If a solution of O-lithio chlorohydrin initially formed from ClCH2Li and a carbonyl compound is allowed to stand at rt for a sufficient time, generally a few hours, ring closure to the oxirane results.2-6 These reactions are especially clean and nearly quantitative when ClCH2Li is generated from ClCH2I and MeLi/LiBr or BuLi in the presence of the carbonyl substrate in THF cooled with a dry ice-acetone bath (eqs 4-6).4

Sonication of acetophenone, ClCH2Br, and lithium metal wire in THF has yielded 82% of the oxirane (same net transformation as eq 4).6 Several other aldehydes and ketones were similarly converted to oxiranes in 72-91% yields. Reactions of ketones were carried out at -15 °C, aldehydes at -50 °C.

For an alternative reagent which costs less and converts carbonyl compounds to oxiranes faster and equally efficiently, see Bromomethyllithium.

Boronic Esters.

Addition of butyllithium to Triisopropyl Borate and ClCH2I in THF at -78 °C followed by treatment with anhydrous HCl yields diisopropyl (chloromethyl)boronate (eq 7), a useful synthetic intermediate (see Pinacol (Chloromethyl)boronate).7

With boronic esters, ClCH2Li adds to the boron atom to form a borate complex, which on warming to rt rearranges to form the homologous boronic ester (eqs 8 and 9).7 A chiral group was shown to migrate with retention of configuration (eq 10).7

The conditions for in situ generation of ClCH2Li have been explored with boronic esters as substrates. Less expensive ClCH2Br was found to work almost as well as ClCH2I (eq 11).8 It was also found that with ClCH2Br and R = 1-hexyl, addition of the BuLi at 0 °C resulted in a 47% yield, but temperatures between 0 °C and -78 °C were not tested.8

The reaction of eq 11 with ClCH2Br also yielded 89-91% with R = cyclopentyl, cyclohexyl, trans-2-methylcyclopentyl, trans-2-methylcyclohexyl, and exo-norbornyl.8 However, in view of the possible problems in separating starting material and product that differ by only one methylene unit, the nearly quantitative conversions achieved with ClCH2I may justify the extra cost.

Boracyclane Ring Expansion.

Boracyclanes of ring sizes 5-11 undergo efficient ring expansion when treated with ClCH2Li generated in situ (eq 12).9 Since these compounds are easily converted to carbocycles via the reaction with LiCCl2OMe, which inserts a carbonyl group in place of BOMe, and since the 7-membered borepane can be prepared fairly directly from 1,5-hexadiene via a hydroboration route, this chemistry affords an efficient route to medium-sized rings.9


Addition of butyllithium to mixtures of ClCH2Br and various chlorosilanes in THF at -60 to -70 °C (-78 °C cooling bath) yields (chloromethyl)silanes.10 A typical example is illustrated in eq 13. Similar conditions were used to prepare Ph3GeCH2Cl, Ph3SnCH2Cl, and Ph3PbCH2Cl.10

b-Lithio Lithium Alkoxides.

These are indirect derivatives of ClCH2Li and ketones which can be produced via lithiation of O-lithio chlorohydrins with Lithium Naphthalenide and related reagents (eq 14).6 If warmed to rt, b-lithio lithium alkoxides eliminate Li2O to form alkenes. At -78 °C, b-lithio lithium alkoxides react with variety of electrophiles EX to form C-substituted derivatives. Examples of EX and E included D2O, D; MeSSMe, SMe; CO2, CO2H; BrCH2CH=CH2, CH2CH=CH2; and cyclohexanone, 1-hydroxycyclohexyl. Overall yields were generally in the useful range, 50-95%, for any of the processes described.6

Related Reagents.

1-Chloroethyllithium has been prepared at -115 °C from MeCHClBr and s-BuLi and reacted with benzaldehyde to form the corresponding oxirane (60%, cis/trans ratio 2:1).3 Similarly prepared MeCH2CHClLi with cyclohexanone yielded the chlorohydrin (70%), and Me2CClLi with benzaldehyde yielded the oxirane (42%).3 See also Bromomethyllithium; Dimethylsulfonium Methylide; Dibromomethyllithium; Dichloromethyllithium; Tribromomethyllithium; Trichloromethyllithium.

1. (a) Matteson, D. S. ACR 1988, 21, 294. (b) Matteson, D. S. CRV 1989, 89, 1535. (c) Matteson, D. S. T 1989, 45, 1859. (d) Matteson, D. S. The Chemistry of the Metal-Carbon Bond, Hartley, F.; Patai, S., Eds.; Wiley: New York, 1987; Vol 4, pp 307-409.
2. Tarhouni, R.; Kirschleger, B.; Rambaud, M.; Villieras, J. TL 1984, 25, 835.
3. (a) Villieras, J.; Tarhouni, R.; Kirschleger, B.; Rambaud, M. BSF 1985, 825. (b) Villieras, J.; Kirschleger, B.; Tarhouni, R.; Rambaud, M. BSF 1986, 470.
4. Sadhu, K. M.; Matteson, D. S. TL 1986, 27, 795.
5. Einhorn, C.; Allavena, C.; Luche, J. L. CC 1988, 333.
6. (a) Barluenga, J.; Fernández-Simón, J. L.; Concellón, J. M.; Yus, M. CC 1987, 915. (b) Barluenga, J.; Fernández-Simón, J. L.; Concellón, J. M.; Yus, M. JCS(P1) 1988, 3339.
7. Sadhu, K. M.; Matteson, D. S. OM 1985, 4, 1687.
8. Brown, H. C.; Singh, S. M.; Rangaishenvi, M. V. JOC 1986, 51, 3150.
9. Brown, H. C.; Phadke, A. S.; Rangaishenvi, M. V. JACS 1988, 110, 6263.
10. Kobayashi, T.; Pannell, K. H. OM 1991, 10, 1960.
11. (a) Villieras, J.; Rambaud, M.; Kirschleger, B.; Tarhouni, R. BSF 1985, 837. (b) Köbrich, G.; Fischer, R. H. T 1968, 24, 4343.

Donald S. Matteson

Washington State University, Pullman, WA, USA

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.