Dibromomethyllithium

LiCHBr2

[37555-63-8]  · CHBr2Li  · Dibromomethyllithium  · (MW 179.77)

(reagent used for bromocyclopropanation, nucleophilic dibromomethylation, ring expansion, bromomethylenation, chain elongation)

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 Dibromomethane with slightly less than 1 equiv of Lithium Diisopropylamide in THF/ether (1:3) at -100 °C for 15 min.3 Amine-free solutions may be obtained by deprotonation of CH2Br2 with Dichloromethyllithium in THF at -100 °C.4

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.5 Further, transmetalation with Titanium Tetraisopropoxide is reputed to give a reagent with greater thermal stability,5e 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.6 At very low temperatures, however, the reagent reacts like a typical alkyllithium.

Cyclopropanations.

When a-haloorganolithium reagents are treated with alkenes, a rapid low temperature reaction takes place resulting from a-elimination of LiX to a carbene followed by cyclopropanation of the alkene (see also 2,2,2-Tribromoethyl Chloroformate, Trichloromethyllithium, and Dichloromethyllithium). This mode of reactivity has been reported for both LiCHBr2 and NaCHBr2 (eq 1).7 Yields were reported only for the organosodium reagent and were generally moderate. Details of this process were sketchy.

An apparently noncarbenic bromocyclopropanation of fulvenes has been described by Grohmann.8 When LDA was slowly added to a THF solution of a fulvene and CH2Br2 at -75 °C followed by slow warming to 0 °C, a mixture of cis- and trans-halospiro[2.4]heptadienes were formed (eq 2). 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.9

Nucleophilic Additions to Carbonyls and Subsequent Processes.

As with Tribromomethyllithium, Trichloromethyllithium, and Dichloromethyllithium, LiCHBr2 can be generated in the presence of aldehydes and ketones when a solution of CH2Br2 and the carbonyl compound in THF is treated with 2 equiv of lithium dicyclohexylamide at -78 °C (eq 3). Addition of LiCHBr2 to the carbonyls forms dibromocarbinols in excellent yield.10 Alternatively, LiCHBr2 may be generated by the LDA method followed by addition of the aldehyde or ketone.3a Such intermediates are quite versatile, undergoing a variety of synthetically useful transformations.

Preparation of Terminal Bromoalkenes.

Treatment of such dibromo alcohols with excess Zn dust and 2-6 equiv of HOAc (see Zinc-Acetic Acid) in CH2Cl2 at reflux provides the bromoalkene as a mixture of (E) and (Z) isomers.11 Overall yields for the two-step process are generally >40% (eq 4). Kobrich had previously reported similar alkene forming processes whereby elimination proceeds via the trimethylsilyl ether derivatives of the alcohol adducts (Scheme 1).12 Treatment with LDA at -100 °C promoted loss of TMS-OH and formation of terminal dibromoalkenes in good yield, while treatment with n-Butyllithium at the same temperature promoted Li-halogen exchange and elimination of TMSO-Li to give a mixture of monobromoalkenes.

Preparation of a,a-Dibromo Ketones.

The dibromo alcohols have been oxidized with the Swern reagent (Dimethyl Sulfoxide-Oxalyl Chloride), Pyridinium Dichromate, or Pyridinium Chlorochromate to the corresponding ketones in 44-60% yield (eq 5).13 A higher yield process is the direct addition of LiCHBr2 to esters, proceeding in 68-78% yield.14

Ring Expansions of Derived b-Oxidocarbenoids.

A facile ring expansion (Scheme 2) has been developed by Nozaki15 based on a well-known carbene rearrangement. Dibromo alcohols such as (1) can be treated with 2 equiv of n-BuLi in THF at low temperature to generate the alkoxycarbenoid (2). This can undergo a-elimination to the carbene (3) which undergoes ring-expanding rearrangement to enolate (4), eventually resulting in the ring-expanded ketone (5). Yields are good to excellent. There is some regioselectivity in the rearrangement step (eq 6).16 For example, the dibromo alcohol (6) provides the ketone (7) as the major product, resulting from migration of the more substituted center. This appears to be general, although there are clear temperature and solvent effects on the degree of regioselectivity.

In addition, cyclic conjugated enones undergo expansion by migration of the unsaturated group to give b,g-unsaturated cyclic ketones. However, there is a lack of regiospecificity with conjugated cyclopropyl ketones as substrates.17 An analogous ring expansion occurs if intermediate lithioalkoxides such as (8) are deprotonated with an amide base like Lithium 2,2,6,6-Tetramethylpiperidide (eq 7).18 In these cases the result is a ring expanded a-bromo ketone.

Ester Homologation.

Related to this rearrangement is an ester homologation process developed by Kowalski which proceeds without isolation of intermediates.19 In this procedure, LiCHBr2 is generated using LiTMP and is added to an ester at low temperature. A second addition of excess base promotes the collapse to the enolate (10) which undergoes Li-halogen exchange to the carbenoid (11). Fritsch-Buttenberg-Wiechell rearrangement of the derived (12) gives the ynolate (13) which is quenched into acidic ethanol, eventually giving the homologated ester (Scheme 3). Lactones also undergo the process. The intermediate ynolate (13) may be captured by silyl halides, resulting in one of the few methods of preparing ynol silyl ethers (14) (Scheme 4). Such species have been utilized in a stereoselective alkenation alternative to the Wadsworth-Emmons process (14) -> (15).20

Alkylation with Alkyl Halides.

LiCHBr2 reacts well with alkyl bromides, iodides, and other active alkylating agents at low temperature to provide dibromoalkanes in good yield (eq 8).21

Chain Homologation of Boronic Esters.

LiCHBr2 is capable of chain elongating boronic esters to give a-bromoboronic esters, useful intermediates in synthesis. Treatment of a boronic ester, generally of the cyclic variety, with LiCHBr2 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 (17) with expulsion of bromine to form a boronic ester (18) elongated by a bromomethylene group (Scheme 5). Boronic esters (18) are quite stable intermediates which undergo facile displacement of the halide by nucleophiles with inversion of configuration, providing more highly functionalized boronic esters.22

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.23 It was found that LiCHBr2 gives better yields and diasteromeric ratios than LiCHCl2 in the migration step.24 Also, Br was found to be more readily displaced by LiOCH2Ph, enabling more efficient syntheses of small carbohydrates by an iterative approach. This is illustrated in the first few steps of a synthesis of (+)-ribose, (19) -> (21), which proceed in excellent yield and stereoselectivity (Scheme 6).

Related Reagents.

Bromomethyllithium; Chloromethyllithium; Dichloromethyllithium; 2,2,2-Tribromoethyl Chloroformate; 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) Villieras, J.; Bacquet, C.; Masure, D.; Normant, J. F. BSF(2) 1975, 1797. (b) Takahashi, A.; Shibasaki, M. JOC 1988, 53, 1227.
4. (a) Kobrich, G.; Fischer, R. H. T 1968, 24, 4343. (b) Kobrich, G.; Fischer, R. H. CB 1968, 101, 3208 and 3219. (c) Villieras, J.; Bacquet, C.; Masure, D.; Normant, J. F. JOM 1973, 50, C7.
5. (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, T.; Fobker, R.; Wensing, M. AG(E) 1988, 27, 943.
6. (a) Siegel, H. Top. Curr. Chem. 1982, 106, 55. (b) Taylor, K. G. T 1982, 38, 2751. (c) Kobrich, G. AG(E) 1972, 11, 473. (d) Kobrich, G. AG(E) 1967, 6, 41.
7. Martel, B.; Hiriart, J. M. AG(E) 1972, 11, 326.
8. Amaro, A.; Grohmann, K. JACS 1975, 97, 3830.
9. Matsumoto, K.; Oshima, K.; Utimoto, K. TL 1990, 31, 6055.
10. (a) Taguchi, H.; Yamamoto, H.; Nozaki, H. JACS 1974, 96, 3010. (b) Taguchi, H.; Yamamoto, H.; Nozaki, H. BCJ 1977, 50, 1588.
11. (a) Williams, D.; Nishitani, K.; Bennett, W.; Sit, S. Y. TL 1981, 22, 3745. (b) Niwa, H.; Yoshida, Y.; Hasegawa, T.; Yamada, K. CL 1985, 1687.
12. Kobrich, G.; Entmayr, P. CB 1976, 109, 2175.
13. (a) Takahashi, A.; Shibasaki, M. JOC 1988, 53, 1227. (b) Bacquet, C.; Villieras, J.; Normant, J. F. CR(C) 1974, 929.
14. Kowalski, C.; Haque, M. S. JOC 1985, 50, 5140.
15. (a) Taguchi, H.; Yamamoto, H.; Nozaki, H. JACS 1974, 96, 6510. (b) Taguchi, H.; Yamamoto, H.; Nozaki, H. BCJ 1977, 50, 1592.
16. (a) Taguchi, H.; Yamamoto, H.; Nozaki, H. TL 1976, 2617. (b) Nagao, K.; Chiba, M.; Yoshimura, I.; Kim, S.-W. CPB 1981, 29, 2733.
17. Ward, H. D.; Teager, D. S.; Murray, Jr., R. K. JOC 1992, 57, 1926.
18. Villieras, J.; Bacquet, C.; Normant, J. F. JOM 1975, 97, 325.
19. (a) Kowalski, C. J.; Fields, K. W. JACS 1982, 104, 321. (b) Kowalski, C. J.; Haque, M. S.; Fields, K. W. JACS 1985, 107, 1429. (c) Kowalski, C. J.; Lal, G. S.; Haque, M. S. JACS 1986, 108, 7127.
20. Kowalski, C. J.; Sakdarat, S. JOC 1990, 55, 1977.
21. (a) Kauffmann, T.; Ilchmann, G.; Konig, R.; Wensing, M. CB 1985, 118, 391. (b) Villieras, J.; Rambaud, M.; Kirschleger, B.; Tarhouni, R. BSF(2) 1985, 837. (c) Refs. 4c and 3a.
22. Matteson, D. S.; Majumdar, D. OM 1983, 2, 1529.
23. Matteson, D. S.; Sadhu, K. M.; Peterson, M. L. JACS 1986, 108, 810.
24. (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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