Bromomethane1

CH3Br

[74-83-9]  · CH3Br  · Bromomethane  · (MW 94.95)

(methylates C, N, O, P, S, Se, and Te nucleophiles; forms metal-Me systems which act as bases or which attack >C=O, -C&tbond;N)

Alternate Name: methyl bromide.

Physical Data: mp -93.66 °C; bp 3.56 °C; d 1.732 g cm-3 (0 °C).

Solubility: miscible with most organic solvents, sparingly with aqueous media.

Form Supplied in: colorless mobile liquid.

Purification: gas passed through conc. H2SO4 and dried with P2O5.

Handling, Storage, and Precautions: usually available in cylinders or as a solution in Et2O or MTBE. Potent alkylating agent; high toxicity. Use in a fume hood.

Introduction.

CH3Br is usually prepared by the bromination of methane1a or by the interaction of MeOH with Hydrogen Bromide.1b Methyl bromide is the archetypal alkylating agent, either directly as a source of Med+ or through organometallic intermediates giving Med-. The alkyl group may also undergo substitution, usually selectively (e.g. bromination; 90% of the bromide is converted, giving a mixture of CH2Br2 and CHBr3 (96:4, using [Br2]/[CH3Br] = 10:1)).1a

Methylating Agent.

CH3Br reacts readily with many nucleophiles including C-, O-, N-, and S-based systems; increased reactivity is often achieved through formation of the conjugate base (e.g. ROH -> RO-). In this way, 2,3-dimethylcyclohexanone provides 2,2,3-trimethylcyclohexanone (eq 1).2

Ru-coordinated dibenzotetrathiacyclodecane dianion is methylated at the position a to sulfur,3 and bridged annulene dianions (e.g. 1) are correspondingly attacked.4 Unsubstituted or monosubstituted malonic esters are methylated in the absence of solvent, forming the carbanion by adding NaOEt and distilling out the EtOH.5

Other carbanions which may be methylated include the perfluoro-2-methylpentyl carbanion6 and lithiated phenanthrene-9-carbamate, which provides the 10-Me analog.7 Superacids (Tetrafluoroboric Acid, Boron Trifluoride, or Trifluoromethanesulfonic Acid) allow the carbonylation of MeCl or MeBr, giving a mixture of AcOH and AcOMe; this process is cheaper than those involving Rh catalysis.8

Asymmetric induction is achieved in the methylation of enones of a-aryl-substituted ketones, esters, and lactones by using chiral phase-transfer catalysts derived from cinchonine, cinchonidine, or their dihydro analogs.9 Similarly, CpFe(CO)(PPh3)(COCH2R) is deprotonated (n-Butyllithium) to form exclusively the (E)-enolate; alkylation of this substitutes the a-position of the acyl ligand. The greatest stereoselectivity of attack is shown by more bulky electrophiles.10 A study of the methylation of lithiated silacyclopentenes reflects many uses of MeBr as a small electrophile which shows little influence by steric factors. Thus the allylic carbanion formed when silacyclopentene (2) (Ar = p-t-BuC6H4; R = RŽ = H) reacts with t-Butyllithium is deuterated (D2O) or methylated (MeBr) at the a-position (eq 2) (R = D or Me), whereas Triisopropylsilyl Chloride attacks at the g-position to give the rearranged product (3) (R = H, RŽ = i-Pr3Si).11

The methylation of aminobenzothiazoles (MeBr-DMF) on nitrogen exemplifies the use of aprotic solvents to encourage alkylation; it is accompanied by formylation at C-2 in these substrates.12 [Mo(N2)2(Et2PCH2CH2PEt2)2] reacts with MeBr to provide the N,N-dimethylhydrazine derivative [Mo(NNMe2)2(Et2PCH2CH2PEt2)2]Br.13

Organometallic Reagents.

The Grignard reagent Methylmagnesium Bromide is formed readily and quantitatively in Et2O. The reaction with carbon-11 CO2 is the first step in a synthesis of Me11CH2I via labelled EtOH in a convenient one-pot process (eq 3).14

Similar reactions with carbonyl compounds15a are widely used to incorporate methyl groups, while the corresponding processes often occur with great diastereoselectivity.15b The ring opening of epoxides proceeds in good yield with no loss of chirality both in systems such as (4) (Z = SO, SO2, CO2R) with RMgBr + CuI in Et2O-THF at -60 °C which provide EtCH(OH)CH2Z (eq 4)16 and in the reaction between either (R)- or (S)-glycidol with (RMgBr + 2LiCl/CuCl2) in THF at -5 °C when, for example, (S)-glycidol gives (S)-butane-1,2-diol in 70% yield and with 97% ee (eq 5).17

Related Reagents.

Chloromethane; Iodomethane.


1. (a) Jackisch, P. F. Kirk-Othmer Encyclopedia of Chemical Technology; Wiley: New York, 1993; Vol. 4, p 567. (b) Segall, J.; Shorr, L. M.; Adda, M. Fr. Patent 2 631 335, 1989 (CA 1990, 113, 77 676j). (c) Segall, J.; Shorr, L. M. Eur. Patent Appl. 446 537, 1991 (CA 1991, 115, 207 506h).
2. Kawanobe, T.; Iwamoto, M.; Kojo, K. Jpn. Patent 61 243 034, 1986 (CA 1987, 106, 138 669p).
3. Sellmann, D.; Waeber, M.; Huttner, G.; Zsolnai, L. ICA 1986, 118, 49.
4. Muellen, K.; Muel, T.; Schade, P.; Schmichler, H.; Voegel, E. JACS 1987, 109, 4992.
5. Steffan, K. D. Ger. Patent 3 737 377, 1989 (CA 1989, 111, 214 126e).
6. Dmowski, W.; Wozniacki, R. JFC 1987, 36, 385.
7. Fu, J. M.; Sharp, M. J.; Snieckus, V. TL 1988, 29, 5459.
8. Bagno, A.; Bukala, J.; Olah, G. A. JOC 1990, 55, 4284.
9. Nerinckx, W.; Vandewalle, M. TA 1990, 1, 265.
10. Brown, S. L.; Davies, S. G.; Foster, D. F.; Seeman, J. I.; Warner, P. TL 1986, 27, 623.
11. Horvath, R. C.; Chan, T. H. JOC 1987, 52, 4489.
12. Lucky, Ltd., Jpn. Patent 01 207 282, 1989 (CA 1990, 112, 118 811z).
13. Hussain, W.; Leigh, G. J.; Ali, H. P.; Pickett, C. J. JCS(D) 1988, 553.
14. Laangstroem, B.; Antoni, G.; Gullberg, P.; Halldin, C.; Naagren, K.; Rimland, A.; Svaerd, H. Appl. Radiat. Isot. 1986, 37, 1141.
15. (a) Grummitt, O.; Becker, E. I., OSC 1963, 4, 771. (b) e.g. Denmark, S. E.; Weber, T.; Piotrowski, D. W. JACS 1987, 109, 2224.
16. Tanikaga, R.; Hosoya, K.; Kaji, A. CC 1986, 836.
17. Kutsuki, H.; Maemoto, S.; Hasegawa, J.; Oohashi, T. Jpn. Patent 01 146 835, 1989 (CA 1990, 112, 20 674g).

Roger Bolton

University of Surrey, Guildford, UK



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