Methallyl Chloride

[563-47-3]  · C4H7Cl  · Methallyl Chloride  · (MW 90.56)

(four-carbon alkylating agent and isobutyl halide equivalent;1 acetone carbenium ion equivalent and annulating agent;2 a nucleophile after conversion to an organometallic3)

Alternate Name: 3-chloro-2-methylpropene.

Physical Data: bp 71.5-72.5 °C; d 0.9165 g cm-3.

Form Supplied in: colorless liquid of 97-98% purity; 90% technical grade is also available (d 0.93 g mL-1).

Purification: may be distilled from P2O5 prior to use.

Handling, Storage, and Precautions: lachrymator; irritating to mucous membranes and a CANCER SUSPECT AGENT. Use in a fume hood.

Electrophilic Alkylation.

As an electrophile, methallyl chloride undergoes nucleophilic displacement by a variety of substrates including Grignard reagents,6 carbanions,7 enolates,8 carbonyl compounds,9 alkynes,10 alcohols,11 phenols,12 amines,13,14 amides,15 organoboranes,16 and cyanide17 to give the four-carbon alkylated product. The individual reagents, methallyl chloride, bromide, and iodide, should be considered as having unique reactivity profiles. For example, Methallyl Bromide is best suited for low temperature reactions (i.e. <-40 °C) with enolates.18 Under these conditions the chloride is too unreactive, whereas Methallyl Iodide leads to mixtures of non- and dialkylated products.

When alkylation is followed by hydrogenation, the net result is addition of an isobutyl group, analogous to alkylation with an isobutyl halide.1 Under standard catalytic hydrogenation conditions, isomerization to the more highly substituted alkene can also occur (eq 1).19 Hydrogenation over Wilkinson's catalyst (Chlorotris(triphenylphosphine)rhodium(I)) avoids isomerization and affords the saturated product.

Under acid-catalyzed conditions, methallyl chloride can be used for the Friedel-Crafts alkylation of benzene to give 1-chloro-t-butylbenzene.20

Annulation Reactions.

When the alkylation with methallyl iodide is coupled with an ozonolysis, the net effect is an alkylation with acetone.21 More often, alkylation is followed by ozonolysis and a base-catalyzed annulation process to generate a cyclopentenone (eq 2).2,22

While 2-Methoxyallyl Bromide offers an alternative to methallyl halides for both the acetonylation of anions and cyclopentenyl annulations, the instability of the reagent requires preparation prior to use. Methallyl chloride and bromide have the distinct advantage of being stable, commercially available compounds. Similarly, Isopropenyl Acetate is a comparable three carbon-annulating agent, but modest overall yields typically follow its use (see also Propargyl Chloride).

With a dicarboxylic acid ester, methallylation and cyclization may be carried out in such a way so as to generate a cyclohexenone system (eq 3).23

Methallyl chloride, after conversion to the Grignard reagent, has also been used for the benzoannulation of 2-hydroxymethylene ketones (eq 4).24

Sigmatropic Rearrangements.

Because of the allylic functionality, alkylation with methallyl halides often provides intermediates which are ideally constructed to undergo intramolecular rearrangement. Phenols may be efficiently alkylated with methallyl chloride in DMF to give the corresponding isopropenyl ether.12 Under thermal conditions, Claisen rearrangement of the ether provides the o-methallylphenol in high yield. When the reaction of an enolate with methallyl chloride gives mixtures of both C- and O-alkylated products, the Claisen rearrangement has been employed to afford solely the C-alkylated product.22a Similarly, the thio-Claisen rearrangement has been used to effect a-methallylation of a dithioester.25 This method has been further extended to include asymmetric induction in the thio-Claisen rearrangement of both dithioesters26 and thioamides.27 Alkylation on the oxygen of a chiral allylic alcohol allows for a [2,3]-sigmatropic Wittig rearrangement with this asymmetric induction (eq 5).11a

In the case of a chiral oxathianone, effective alkylation on sulfur requires use of the highly reactive methallyl triflate.5 Through the intermediacy of the ylide, [2,3]-sigmatropic rearrangement affords a diastereomeric mixture of substituted oxathianones (eq 6). By contrast, direct C-alkylation could be expected to be essentially nonselective, giving rise to a nearly equal mixture of diastereomers.

The methallyl group has also seen utility in a diastereoselective intramolecular ene cyclization, whereby Lewis acid catalysis provides a moderate yield of the indolizidine (eq 7).14

Nucleophilic Reactions.

As a halide, methallyl chloride can be converted to a wide variety of organometallic species for subsequent use as a nucleophile. This includes the methallyl organometallics of magnesium,3,28 cerium,29 lithium,30 manganese,31 mercury,32 tin,33 and zinc.34 The p-(2-methallyl)nickel bromide complex has found utility in the reaction with various electrophiles.35 Because of the nonbasic nature of the reagent, this is the preferred method of preparation for compounds such as methallylbenzene (eq 8),4 where the nonconjugated product is desired. An alternate approach, the reaction of a methallyl halide with phenylmagnesium bromide, is complicated by both double bond isomerization and rearrangement.

Finally, the a-halomethallyllithium species can be generated in situ via the Lithium Diisopropylamide deprotonation of methallyl chloride.36 The resulting allyl carbanion undergoes exclusive a-alkylation with primary bromides (secondary bromides give unacceptable yields) to give alkylated products which retain both the chloride and the double bond functionality (eq 9).

The above lithiated intermediate also reacts with Diethylaluminum Chloride to give a g-chloromethallylaluminum species.37 This in turn reacts stereoselectively with aldehydes to provide cis-substituted epoxides, via an intermediate syn-chlorohydrin.

1. (a) Dellaria, J. F.; Santarsiero, B. D. TL 1988, 29, 6079. (b) Manjunatha, S. G.; Rajappa, S. CC 1991, 372.
2. Sarett, L. H.; Johns, W. F.; Beyler, R. E.; Lukes, R. M.; Poos, G. I.; Arth, G. E. JACS 1953, 75, 2112.
3. (a) Stork, G.; Grieco, P. A.; Gregson, M. TL 1969, 1393. (b) Rosini, G.; Geier, M.; Marotta, E.; Petrini, M.; Ballini, R. T 1986, 42, 6027. (c) Duhamel, L.; Ancel, J.-E. T 1992, 48, 9237.
4. Semmelhack, M. F.; Helquist, P. M. OSC 1988, 6, 722.
5. Tahir, S. H.; Olmstead, M. M.; Kurth, M. J. TL 1991, 32, 335.
6. (a) Tamao, K.; Iwahara, T.; Kanatani, R.; Kumada, M. TL 1984, 25, 1909. (b) Chattopadhyay, A.; Mamdapur, V. R. CI(L) 1986, 491. (c) Snowden, R. L.; Linder, S. M.; Muller, B. L.; Schulte-Elte, K. H. HCA 1987, 70, 1858.
7. (a) Lansbury, P. T.; Bebernitz, G. E.; Maynard, S. C.; Spagnuolo, C. J. TL 1985, 26, 169. (b) Polo, C.; Ramos, V.; Torroba, T.; Bossio, R.; Marcaccini, S.; Pepino, R. H 1990, 31, 811.
8. (a) Evans, D. A.; Bartroli, J. TL 1982, 23, 807. (b) Baker, M. V.; Ghitgas, C.; Haynes, R. K.; Hilliker, A. E.; Lynch, G. J.; Sherwood, G. V.; Yeo, H.-L. TL 1984, 25, 1625. (c) Rao, E. S.; Yadav, J. S. IJC(B) 1986, 25B, 1174. (d) Ruggeri, R. B.; Heathcock, C. H. JOC 1987, 52, 5745. (e) Najera, C.; Yus, M. JOC 1989, 54, 1491. (f) Ihara, M.; Takahashi, M.; Niitsuma, H.; Taniguchi, N.; Yasui, K.; Fukumoto, K. JOC 1989, 54, 5413. (g) Najdi, S.; Reichlin, D.; Kurth, M. J. JOC 1990, 55, 6241.
9. (a) Boatman, S.; Hauser, C. OSC 1973, 5, 767. (b) Rao, V. B.; George, C. F.; Wolff, S.; Agosta, W. C. JACS 1985, 107, 5732. (c) Rosini, G.; Marotta, E.; Petrini, M.; Ballini, R. T 1985, 41, 4633. (d) Hackett, S.; Livinghouse, T. CC 1986, 75.
10. Jeffery, T. TL 1989, 30, 2225.
11. (a) Tsai, D. J.-S.; Midland, M. M. JACS 1985, 107, 3915. (b) Mori, K.; Miyake, M. T 1987, 43, 2229.
12. Brown, E. G.; Cambie, R. C.; Holroyd, S. E.; Johnson, M.; Rutledge, P. S.; Woodgate, P. D. TL 1989, 30, 4735.
13. Ben Cheikh, R.; Chaabouni, R.; Laurent, A.; Milson, P.; Nafti, A. S 1983, 685.
14. Dike, S. Y.; Mahalingam, M.; Kumar, A. TL 1990, 31, 4641.
15. (a) Kaura, A. C.; Maycock, C. D.; Stoodley, R. J. CC 1980, 34. (b) Knapp, S.; Gibson, F. S.; Choe, Y. H. TL 1990, 31, 5397.
16. Hara, S.; Satoh, Y.; Suzuki, A. CL 1982, 1289.
17. Lynn, J. W.; Roberts, R. L.; Kilsheimer, J. R. JOC 1961, 26, 4300.
18. Fray, A. H.; Kaye, R. L.; Kleinman, E. F. JOC 1986, 51, 4828.
19. Dugger, R. W.; Ralbovsky, J. L.; Bryant, D.; Commander, J.; Massett, S. S.; Sage, N. A.; Selvidio, J. R. TL 1992, 33, 6763.
20. (a) Calcott, W. S.; Tinker, J. M.; Weinmayr, V. JACS 1939, 61, 1010. (b) Smith, W. T.; Sellas, J. T. OSC 1963, 4, 702.
21. Meyers, A. I.; Lefker, B. A. JOC 1986, 51, 1541.
22. See also: (a) Miyano, M.; Dorn, C. R. JOC 1972, 37, 268. (b) Brown, E.; Ragault, M. TL 1973, 1927. (c) Evans, D. A.; Sims, C. L.; Andrews, G. C. JACS 1977, 99, 5453. (d) McMurry, K. E.; Farina, V.; Scott, W. J.; Davidson, A. H.; Summers, D. R.; Shenvi, A. JOC 1984, 49, 3803. (e) Brown, E.; LeBreton, J. TL 1986, 27, 2595.
23. Kigoshi, H.; Imamura, Y.; Niwa, H.; Yamada, K. JACS 1989, 111, 2302.
24. (a) Tius, M. A.; Ali, S. JOC 1982, 47, 3163. (b) Tius, M. A.; Kannangara, G. S. K. OS 1992, 71, 158.
25. Metzner, P.; Pham, T. N.; Vialle, J. T 1986, 42, 2025.
26. Beslin, P.; Perrio, S. T 1991, 47, 6275.
27. Reddy, K. V.; Rajappa, S. TL 1992, 33, 7957.
28. Bogdanovic, B.; Nikolaus, J.; Kinzelmann, H.-G. CB 1990, 123, 1507.
29. Imamoto, T.; Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.; Mita, T.; Hatanaka, Y.; Yokoyama, M. JOC 1984, 49, 3904.
30. Fraenkel, G.; Winchester, W. R. JACS 1989, 111, 3794.
31. Cahiez, G.; Chavant, P. Y. TL 1989, 30, 7373.
32. Larock, R. C.; Lu, Y. JOC 1993, 58, 2846.
33. Cai, J.; Davies, A. G. JCS(P1) 1992, 3383.
34. Shono, T.; Ishifune, M.; Kashimura, S. CL 1990, 449.
35. (a) Corey, E. J.; Semmelhack, M. F. JACS 1967, 89, 2755. (b) Hegedus, L. S.; Waterman, E. L.; Catlin, J. JACS 1972, 94, 7155. (c) Hegedus, L. S.; Wagner, S. D.; Waterman, E. L.; Siirala-Hansen, K. JOC 1975, 40, 593. (d) Hegedus, L. S.; Evans, B. R.; Korte, D. E.; Waterman, E. L.; Sjoberg, K. JACS 1976, 98, 3901.
36. MacDonald, T. L.; Narayanan, B. A.; O'Dell, D. E. JOC 1981, 46, 1504.
37. Hosomi, A.; Kohra, S.; Tominaga, Y.; Ando, M.; Sakurai, H. CPB 1987, 35, 3058.

Mark A. Krook

The Upjohn Company, Kalamazoo, MI, USA

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