Dichloromethyllithium

LiCHCl2

[2146-67-0]  · CHCl2Li  · Dichloromethyllithium  · (MW 90.87)

(reagent used for chlorocyclopropanation, nucleophilic dichloromethylation, ring expansion, a-chloro aldehyde preparation, a-hydroxy aldehyde preparation, chain homologation)

Physical Data: low temperature 13C and 6Li NMR data are available,1 as are matrix IR data.2

Preparative Methods: solutions of the title compound can be obtained by treatment of CH2Cl2 with n-Butyllithium in THF/ether/pentane (4:1:1) at -110 °C for 20 min;3 alternate conditions include n-BuLi-N,N,N,N-Tetramethylethylenediamine as the base in ether/THF (60:40) for 1 h at -90 °C.4 One may also deprotonate CH2Cl2 with amide bases at -100 to -78 °C.5

Handling, Storage, and Precautions: the reagent is generally stable from -110 to about -80 °C, depending on the solvent. There is evidence that carbenoids of this nature show greater thermal stability in THF than in ether.6 Solutions of LiCHCl2 in THF/ether mixtures of greater than about 20% (v/v) THF are quite stable for ~20 h at -74 °C.6a Further, transmetalation with Titanium Tetraisopropoxide is reputed to give a reagent with greater thermal stability,6e although subsequent reports confirming this have not appeared.

General Considerations.

Alkyllithiums bearing halogens on the a-carbon are frequently referred to as carbenoids, reflecting a major mode of reactivity. Good general reviews of such species are available.7 At very low temperatures, however, the reagent reacts like a typical alkyllithium. The reactivity of LiCHCl2 is mirrored by Dibromomethyllithium in many respects. It is noteworthy that LiCHCl2 has been used as a base in the generation of other carbenoids, including LiCHBr2.8

Cyclopropanations.

Unlike the carbenoids LiCHBr2, Tribromomethyllithium, and Trichloromethyllithium, LiCHCl2 has not been reported as a general precursor to chlorocarbene for use in cyclopropane synthesis. An apparently noncarbenic bromocyclopropanation of fulvenes has been described by Grohmann.9 When Lithium Diisopropylamide was slowly added to a THF solution of a fulvene and CH2Cl2 at -75 °C followed by slow warming to 0 °C, a mixture of cis- and trans-halospiro[2.4]heptadienes was formed (eq 1).

Alternatively, LiCHCl2 may be preformed and the fulvene added slowly at -95 °C. Evidence indicates a nucleophilic addition-displacement mechanism as opposed to a carbene reaction. A related reaction involving ring enlargement of silacycles has also been reported.10

Nucleophilic Dichloromethylation Reactions.

LiCHCl2 is an excellent reagent for incorporating the dichloromethyl group into molecules via nucleophilic displacement and addition reactions. Alkylation of primary alkyl halides proceeds well (eq 2).4,11 The reaction of the terminal dichlorides with 3 equiv of n-BuLi/THF at -30 to -40 °C results in production of the terminal alkynes in good yield (eq 3).

Carbonyl addition reactions are also quite facile. As with other a-haloorganolithiums, LiCHCl2 may be generated by deprotonation with lithium dicyclohexylamide in the presence of aldehydes and ketones to subsequently provide polyhalomethylcarbinol adducts in excellent yield (eq 4).12 The adducts may be trapped in situ by Chlorotrimethylsilane to provide silyl ethers13 which serve as precursors to terminal dichloroalkenes on treatment with n-BuLi in THF/ether/petroleum ether at -110 °C (eq 5).14

a-Chloro Ketones and Ring Expansions by Fritsch-Buttenberg-Wiechell Rearrangement.

The intermediate lithioalkoxides have been treated with n-BuLi, which results in deprotonation of the halogen-containing carbon to generate another carbenoid intermediate (Scheme 1). Such species undergo synthetically useful carbene rearrangements. For example aldehyde-LiCHCl2 adducts undergo migration of hydrogen to provide one-carbon homologated a-chloro ketones in 50-70% overall yield (eq 6).15 Lithium Piperidide may also be used as the base in this process.15b Side products may include a-chloro aldehydes via migration of the alkyl group instead of hydrogen, although these tend to be minor products. Cyclic ketones undergo an analogous reaction, resulting in ring expanded a-chloro ketones (eq 7). Symmetrical acyclic ketones also undergo the transformation in good yield. A rough migratory aptitude order has been determined. An analogous series of reactions occurs with carbonyl-LiCHBr2 adducts (see Dibromomethyllithium).

Rearrangements to a-Chloro Aldehydes.

If the aldehyde-LiCHCl2 adducts (1) are heated in refluxing THF, the a-chloro aldehydes (3) are formed, presumably by ring opening of intermediate a-chlorooxiranes (2). Elimination of HCl from (3) results in a,b-unsaturated aldehydes in overall 50-80% yield (Scheme 2). Cyclic ketones also undergo the transformation in good yield.16

a-Hydroxy Aldehyde Preparation.

Hydrolysis of LiCHCl2-phenyl alkyl ketone adducts provides a-hydroxy aldehydes in moderate yield (eq 8).17 Oxidation of the aldehydes with Potassium Permanganate gives rise to the corresponding carboxylic acids in poor yield.

Reaction with Esters to Provide a,a-Dichloromethyl Ketones.

Esters undergo an addition-elimination process when treated with LiCHCl2 to provide a,a-dichloromethyl ketones in moderate yields (eq 9).18 Reaction with acyl chlorides gives dichloromethyl ketones, bis(dichloromethyl)carbinols, and/or a-chloro-b-(dichloromethyl)oxiranes, depending on the substrate and the reaction conditions.19

Chain Homologation of Boronic Esters.

LiCHCl2 is capable of chain elongating boronic esters to give a-chloroboronic esters, useful intermediates in synthesis. Treatment of a boronic ester, generally of the cyclic variety, with LiCHCl2 at low temperature and allowing it to stand at rt for a period of hours results in the familiar B -> C migration of an alkyl group in the ate complex (6), with expulsion of a chlorine resulting in a boronic ester (7) elongated by a chloromethylene group (Scheme 3). A variety of procedures were examined in order to optimize the process and it was concluded by Brown that in situ generation by deprotonating CH2Cl2 with LDA at 0 °C in the presence of the boronic ester was the method of choice for this homologation.5b Boronic esters (7) are quite stable intermediates which undergo facile displacement of the halide by nucleophiles with inversion of configuration, providing more highly functionalized boronic esters (eq 10).20

Use of optically active boronic esters provides the opportunity for asymmetric induction at the newly formed chiral carbon. Ate complexes of pinanediols undergo nearly enantiospecific Zinc Chloride catalyzed migration of alkyl groups, resulting in production of a new versatile chiral carbon.21 The utility of this technology can be seen in a synthesis of (+)-exo-brevicomin (9 -> 15) (Scheme 4). The final product was obtained contaminated with only 3% of an epimer, indicative of the stereospecificity of the three migration and two displacement steps. Subsequent reports state that LiCHBr2 gives better yields and diastereomeric ratios than LiCHCl2 in the migration step.22 Also, Br was found to be more readily displaced by LiOCH2Ph, enabling more efficient syntheses of small carbohydrates by an iterative approach.

Related Reagents.

Bromomethyllithium; Chloromethyllithium; Dibromomethyllithium; Tribromomethyllithium; Trichloromethyllithium.


1. (a) Seebach, D.; Siegel, H.; Gabriel, J.; Hassig, R. HCA 1980, 63, 2046. (b) Heinzer, J.; Oth, J. F. M.; Seebach, D. HCA 1985, 68, 1848. (c) Seebach, D.; Hassig, R.; Gabriel, J. HCA 1983, 66, 308.
2. (a) Andrews, L.; Carver, T. G. J. Phys. Chem. 1968, 72, 1743. (b) Hatzenbuhler, D. A.; Andrews, L.; Cary, F. A. JACS 1975, 97, 187.
3. (a) Kobrich, G.; Flory, K.; Drischel, W. AG(E) 1964, 3, 513.
4. Villieras, J.; Perriot, P.; Normant, J. F. BSF(2) 1977, 765.
5. (a) Taguchi, H.; Yamamoto, H.; Nozaki, H. JACS 1974, 96, 3010. (b) Taguchi, H.; Yamamoto, H.; Nozaki, H. BCJ 1977, 50, 1588. (c) Brown, H. C.; Singh, S. M.; Rangaishenvi, M. V. JOC 1986, 51, 3150.
6. (a) Kobrich, G.; Merkle, H. R.; Trapp, H. TL 1965, 969. (b) Kobrich, G.; Merkle, H. R. CB 1966, 99, 1782. (c) Kobrich, G.; Trapp, H. CB 1966, 99, 670. (d) Kobrich, G.; Breckoff, W. E.; Heinemann, H.; Akhtar, A. JOM 1965, 3, 492. (e) Kauffmann, Fobker, R.; Wensing, M. AG(E) 1988, 27, 943.
7. (a) Siegel, H. Top. Curr. Chem. 1982, 106, 55. (b) Taylor, K. G. T 1982, 38, 2751. (c) Kobrich, G. AG(E) 1967, 6, 41.
8. (a) Kobrich, G.; Fischer, R. H.; CB 1968, 101, 3208 and 3219.
9. Amaro, A.; Grohmann, K. JACS 1975, 97, 3830.
10. Matsumoto, K.; Oshima, K.; Utimoto, K. TL 1990, 31, 6055.
11. (a) Villieras, J.; Perriot, P.; Normant, J. F. S 1979, 502.
12. (a) Taguchi, H.; Yamamoto, H.; Nozaki, H. JACS 1974, 96, 3010. (b) Taguchi, H.; Yamamoto, H.; Nozaki, H. BCJ 1977, 50, 1588.
13. Kobrich, G.; Grosser, J.; Werner, W. CB 1973, 106, 2610.
14. (a) Kobrich, G.; Entmayr, P. CB 1976, 109, 2175. (b) Villieras, J.; Bacquet, C.; Normant, J. F. BSF(2) 1974, 1731. (c) Villieras, J.; Bacquet, C.; Normant, J. F. JOM 1975, 97, 355.
15. (a) Villieras, J.; Bacquet, C.; Normant, J. F. JOM 1972, 40, Cl. (b) Villieras, J.; Bacquet, C.; Normant, J. F. JOM 1975, 97, 325. (c) Taguchi, H.; Yamamoto, H.; Nozaki, H. TL 1972, 4661. (d) Taguchi, H.; Yamamoto, H.; Nozaki, H. BCJ 1977, 50, 1592. (e) Kobrich, G.; Grosser, J. CB 1973, 106, 2626.
16. Taguchi, H.; Tanaka, S.; Yamamoto, H.; Nozaki, H. TL 1973, 2465.
17. Blumbergs, P.; LaMontagne, M. P.; Stevens, J. I. JOC 1972, 37, 1248.
18. Bacquet, C.; Villieras, J.; Normant, J. F. CR(C) 1974, 278, 929.
19. Kobrich, G.; Grosser, J. CB 1975, 108, 328.
20. Matteson, D. S.; Majumdar, D. OM 1983, 2, 1529.
21. Matteson, D. S.; Sadhu, K. M.; Peterson, M. L. JACS 1986, 108, 810.
22. (a) Matteson, D. S.; Peterson, M. L. JOC 1987, 52, 5116. (b) Matteson, D. S.; Beedle, E. C. TL 1987, 28, 4499.

Kim F. Albizati

University of California, San Diego, CA, USA



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