[78-85-3]  · C4H6O  · Methacrolein  · (MW 70.10)

(used in cycloaddition reactions, aldol reactions; undergoes both 1,2- and 1,4-additions)

Alternate Name: 2-methylpropenal.

Physical Data: mp -81 °C; bp 69 °C; vapor pressure 121 mmHg at 20 °C; d 0.837 g cm-3.

Solubility: miscible with water, alcohol, ether.

Form Supplied in: colorless liquid; widely available. Drying: fractional distillation (freshly distilled methacrolein turns cloudy within 1 or 2 h at rt; this can be prevented by the addition of 1% hydroquinone).1

Handling, Storage, and Precautions: methacrolein is extremely flammable, and a severe irritant and lachrymator. Use in a fume hood.

Diels-Alder Reactions.

Methacrolein (1) has been widely used in Diels-Alder reactions, where it most commonly functions as the dienophile2 (eq 1); X = Me, CO2Me, OMe;2a O2CNMe2;2b CH2CO2Me2c).

Methacrolein also undergoes a Diels-Alder reaction with itself to produce a dimer (eq 2).1

When treated with electron-rich alkenes, generally in the presence of a Lewis acid, methacrolein undergoes a hetero-Diels-Alder reaction (eq 3).3

There are numerous examples in which chiral Lewis acid catalysts have been used to obtain enantioselective [4 + 2] cycloadditions.4 A few of these are listed in Table 1 as applied to the reaction of methacrolein with cyclopentadiene (eq 4).5

Nucleophilic 1,2-Additions.

The reactions of methacrolein with Grignard reagents (eq 5),6a organozincs (eq 6),7 alkyllithiums,8 and lithium,9 tin,10 and boron11 enolates yield, selectively, the products from 1,2-addition. These allylic alcohols are useful intermediates for a number of transformations, including formation of allyl vinyl ethers which then undergo Claisen rearrangements (eq 5).6,8a,12

Reaction of methacrolein with lithium enolates of hindered aryl esters yields selectively the threo aldol products (eq 7).9c

The reaction of the boron enolate of a chiral imide with methacrolein allows for the selective synthesis of syn aldol products (eq 8), which can be elaborated into a-amino acids.11f

A useful extension of the Evans methodology allows the selective preparation of either the anti aldol or the syn aldol products from the same substrate by simply changing the reaction conditions (eq 9).11c

Other 1,2-additions to methacrolein lead to the formation of acetals (eq 10),13 imines (eq 11),14 cyano ethers (eq 12),15a cyano esters (eq 13),15b and acyl silanes (eq 14).16

Nucleophilic 1,4-Additions.

Nucleophilic 1,4-addition of amines,17 thiols,18 and phosphorus reagents19 to methacrolein leads to a wide variety of products in high yield (eqs 15-19).

The 1,4-addition of alkaline Hydrogen Peroxide, with careful control of the pH, occurs in good yield to give a-methylglycidaldehyde.20 The 1,4-addition of alcohols to methacrolein is less successful (however, a synthetically useful example is shown in eq 20).21

Unlike a,b-unsaturated ketones, a,b-unsaturated aldehydes such as methacrolein give poor yields of 1,4-addition products with carbon nucleophiles due to the preference for 1,2-addition to the carbonyl. Two important exceptions are the reactions with trialkylboranes (eq 21),22 and the copper-catalyzed addition of Grignard reagents (eq 22).23 Significantly, the latter procedure has been greatly improved by the addition of Chlorotrimethylsilane and Hexamethylphosphoric Triamide.23

1. Stoner, G. G.; McNulty J. S. JACS 1950, 72, 1531.
2. (a) Wu, P-L.; Chu, M.; Fowler, F. W. JOC 1988, 53, 963. (b) Mikami, K.; Terada, M.; Motoyama, Y.; Nakai, T. TA 1991, 2, 643. (c) Stevens, R. V.; Cherpeck, R. E.; Harrison, B. L.; Lai, J.; Lapalme, R. JACS 1976, 98, 6317. (d) Posner, G. H.; Nelson, T. D.; Kinter, C. M.; Johnson, N. JOC 1992, 57, 4083. (e) Posner, G. H.; Vinader, V.; Afarinkia, K. JOC 1992, 57, 4088. (f) Kozikowski, A. P.; Huie, E. M. JACS 1982, 104, 2923. (g) Brandes, E.; Grieco, P. A.; Garner, P. CC 1988, 500. (h) Petrzilka, M.; Grayson, J. I. S 1981, 753.
3. (a) Danishefsky, S.; Bednarski, M. TL 1984, 25, 721. (b) Conrads, M.; Mattay, J. CB 1991, 124, 1425. (c) Yamamoto, Y.; Suzuki, H.; Moro-Oka, Y. CL 1986, 73.
4. (a) Corey, E. J.; Loh, T. P.; Roper, T. D.; Azimioara, M. D.; Noe, M. C. JACS 1992, 114, 8290. (b) Hong, Y.; Kuntz, B. A.; Collins, S. OM 1993, 12, 964. (c) Mikami, K.; Terada, M.; Motoyama, Y.; Nakai, T. TA 1991, 2, 643. (d) Sartor, D.; Saffrich, J.; Helmchen, G.; Richards, C. J.; Lambert, H. TA 1991, 2, 639. (e) Takasu, M.; Yamamoto, H. SL 1990, 194. (f) Rebiere, F.; Riant, O.; Kagan, H. B. TA 1990, 1, 199.
5. (a) Bao, J.; Wulff, W. D.; Rheingold, A. L. JACS 1993, 115, 3814. (b) Kobayashi, S.; Murakami, M.; Harada, T.; Mukaiyama, T. CL 1991, 8, 1341. (c) Furata, K.; Shimizu, S.; Miwa, Y.; Yamamoto, H. JOC 1989, 54, 1481. (d) Kaufmann, D.; Boese, R. AG(E) 1990, 545. (e) Bir, G.; Kaufmann, D. TL 1987, 28, 777. (f) Hashimoto, S.; Komeshima, N.; Koga, K. CC 1979, 437.
6. Trust, R. I.; Ireland, R. E. OSC 1988, 6, 606.
7. Hayashi, M.; Kaneko, T.; Oguni, N. JCS(P1) 1991, 25.
8. (a) Cohen, T.; Lin, M.-T. JACS 1984, 106, 1130. (b) McCullough, D. W.; Bhupathy, M.; Piccolino, E.; Cohen, T. T 1991, 47, 9727.
9. (a) Hayashi, T. TL 1991, 32, 5369. (b) Luengo, J. I.; Koreeda, M.; TL 1984, 25, 4881. (c) Heathcock, C. H.; Pirrung, M. C.; Montgomery, S. H.; Lampe, J. T 1981, 4087.
10. (a) Evans D. A.; Sheppard, G. S. JOC 1990, 55, 5192. (b) Paterson, I.; Tillyer, R. D. TL 1992, 33, 4233.
11. (a) Vulpetti A.; Bernardi, A.; Gennari, C.; Goodman, J.; Paterson, I. T 1993, 49, 685. (b) Evans, D. A.; Ng, H. P.; Clark, S. J.; Rieger, D. L. T 1992, 48, 2127. (c) Walker, M. A.; Heathcock, C. H. JOC 1991, 56, 5747. (d) Reno, D. S.; Lotz, B. T.; Miller, M. J. TL 1990, 31, 827. (e) Paterson, I.; McClure, C. K.; Schumann, R. C. TL 1989, 30, 1293. (f) Evans, D. A.; Weber, A. E. JACS 1987, 109, 7151.
12. (a) Paterson, I.; Hulme, A. N.; Wallace, D. J. TL 1991, 32, 7601. (b) Heathcock, C. H.; Jarvi, E. T.; Rosen, T. TL 1984, 25, 243.
13. Scriabine, I. BSF(2) 1961, 1194.
14. (a) Smith, C. W.; Norton, D. G.; Ballard, S. A. JACS 1953, 75, 3316. (b) Uyehara, T.; Suzuki, I.; Yamamoto, Y. TL 1990, 31, 3753.
15. (a) Krepski, L. R.; Jensen, K. M.; Heilmann, S. M.; Rasmussen, J. K.; Lynch, L. E. SC 1986, 16, 617. (b) Nishizawa, M.; Adachi, K.; Hayashi, Y. CC 1984, 24, 1637.
16. Reich, H. J.; Eisenhart, E. K. JOC 1984, 49, 5282.
17. (a) Moe, O. A.; Warner, D. T. JACS 1949, 71, 1251. (b) Marko, I. E.; Chesney, A. SL 1992, 275.
18. (a) Paterson, I.; Laffan, D.; Rawson, D. J. TL 1988, 29, 1461. (b) Vedejs, E.; Buchanan, R. A.; Conrad, P. JACS 1989, 111, 8421. (c) Nakazawa, T.; Shibazaki, M.; Itabashi, K. NKK 1987, 45.
19. (a) Evans, D. A.; Hurst, K. M.; Takacs, J. M. JACS 1978, 100, 3467. (b) Okamoto, Y. CL 1984, 87. (c) Hashimoto, T.; Maeta, H.; Matsumoto, T, Morooka, M.; Ohba, S.; Suzuki, K. SL 1992, 4, 340.
20. Payne, G. B. JACS 1959, 81, 4901.
21. Merger, F.; Hettinger, P.; Lange, A. Ger. Patent 3 321 517, 1984 (CA 1985, 102, 148 738s).
22. (a) Brown, H. C.; Kabalka, G. W.; Rathke, M. W.; Rogic, M. M. JACS 1968, 90, 4165. (b) Koster, R.; Zimmermann, H. J.; Fenzl, W. LA 1976, 1116.
23. Horiguchi, Y.; Matsuzawa, S.; Nakamura, E.; Kuwajima, I. TL 1986, 27, 4025.

Brian A McKittrick

Schering-Plough Research Institute, Kenilworth, NJ, USA

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