Methyl Propiolate

(1; R = Me)

[922-67-8]  · C4H4O2  · Methyl Propiolate  · (MW 84.08) (2; R = Et)

[623-47-2]  · C5H6O2  · Ethyl Propiolate  · (MW 98.11)

(a,b-unsaturated ester capable of undergoing Diels-Alder1 and other cycloaddition reactions,2 Michael additions,3 acetylide formation,4 halogen addition,5 and a variety of cyclization reactions to generate heterocycles6 and aromatics7)

Alternate Name: methyl propynoate.

Physical Data: (1) bp 104 °C; d 0.945 g cm-3. (2) bp 120 °C; d 0.968 g cm-3.

Form Supplied in: colorless oil; widely available.

Handling, Storage, and Precautions: methyl and ethyl propiolate are lachrymatory liquids; handle in a well-ventilated fume hood.

Diels-Alder Reactions.

Methyl and ethyl propiolate are effective dienophiles and enter into the Diels-Alder reaction with electron-rich (eq 1)8 and electron-neutral dienes (eq 2)9 as well as with heterodienes (eq 3).10 The regiochemical outcome of this transformation is in accord with standard HOMO-LUMO considerations.

Other Cycloaddition Reactions.

Methyl and ethyl propiolate are effective partners in [2 + 2] cycloadditions to afford cyclobutenes (eq 4).11 They also represent good dipolarophiles, undergoing [3 + 2] cycloadditions with a variety of 1,3-dipoles12 to generate five-membered heterocycles (eq 5).

Halogenation.

Methyl and ethyl propiolate are readily halogenated to afford versatile intermediates such as 3-bromopropiolate esters (eq 6),13 (Z)-haloacrylates (bromo,14 chloro,15 and iodo16) (eq 7), and 2,3-dihaloacrylates.17 In the latter case, the stereoselectivity depends on the reaction conditions; both (E)-18 and (Z)-19 dibromides can be prepared specifically (eq 8).

Conjugate Additions.

Conjugate additions to methyl and ethyl propiolate are well documented, particularly for heterocycle formation. Good Michael donors include thiols,20 salts of sulfinic acids (which generate potent dienophiles) (eq 9),21 enolate anions (eq 10),22 carbon nucleophiles (eq 11),23 and phenols.24 In general, heteronucleophiles afford (Z)-products and carbon nucleophiles give (E)-isomers.

Heterocycle Formation.

Amidines undergo intermolecular Michael addition followed by cyclization to generate pyrimidones (eq 12).25 Similar reactions with suitably substituted pyridinium salts afford indazoles (eq 13)26 and with hydrazines give pyrazolones.27 Dihydropyridines are prepared using the Michael addition of the elements of ammonia to methyl propiolate with concomitant condensation of the adduct with a simple aldehyde (eq 14).28 [3 + 2] Cyclizations generate pyrazoles,29 thiazoles,30 and oxazoles,31 among others. Benzofurans are prepared by either the palladium-32 or copper-catalyzed33 cyclization of an o-halophenol with ethyl propiolate (eq 15).

Acetylide Formation.

Acetylide anions, readily formed with either butyllithium or LDA, undergo nucleophilic addition to a variety of functional groups. These include epoxides,34 ketones,35 aldehydes,36 and carbon dioxide.37

Related Reagents.

2-Butynoic Acid; 3-Butyn-2-one; (E)-(Carboxyvinyl)trimethylammonium Betaine; 3,3-Diethoxy-1-propyne; Dimethyl Acetylenedicarboxylate; Propargyl Alcohol; Propargyl Aldehyde.


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11. (a) Graziano, M. L.; Iesce, M. R.; Cermola, F.; Cimminiello, G. JCS(P1) 1992, 1269. (b) Frank-Neumann, M.; Miesch, M.; Gross, L. TL 1990, 31, 5027. (c) Pasto, D. J.; Kong, W. JOC 1988, 53, 4807.
12. Padwa, A.; Chiacchio, U.; Venkatramanan, V. CC 1985, 1108.
13. Leroy, J. SC 1992, 22, 567.
14. Ma, S.; Lu, X.; Li, Z. JOC 1992, 57, 709.
15. (a) Ma, S.; Lu, X. CC 1990, 1643. (b) Ma, S.; Lu, X. OS 1993, 72, 112.
16. Marek, I.; Alexakis, A.; Normant, J-F. TL 1991, 32, 5329.
17. (a) Larson, S.; Luidhardt, T.; Pagni, R. M.; Kabalka, G. W. TL 1988, 29, 35. (b) Myers, A. G.; Dragovich, P. S. OS 1993, 72, 104.
18. Kodomari, M.; Sakomoto, T.; Yoshitomi, S. H. BCJ 1989, 62, 4053.
19. Myers, A. G.; Aluddin, M. M.; Fuhry, M. A. M.; Dragovich, P. S.; Finney, N. S.; Harrington, P. M. TL 1989, 30, 6997.
20. Kodomari, M.; Saitoh, G.; Yoshitomi, S. BCJ 1991, 64, 3485.
21. (a) Buss, A. D.; Hirst, G. C.; Parsons, P. J. CC 1987, 1836. (b) Hirst, G. C.; Parsons, P. J. OSC 1993, 8, 458.
22. Furber, M.; Taylor, R. J. K.; Burford, S. C. TL 1985, 26, 3285.
23. Linderman, R. J.; Griedel, B. D. JOC 1991, 56, 5491.
24. Brattesani, D. M.; Heathcock, C. H. JOC 1975, 40, 2165.
25. Stajer, G.; Szabo, A. E.; Bernath, G.; Sohar, P. JCS(P1) 1987, 237.
26. Boekelheide, V.; Fedoruk, N. A. JOC 1968, 33, 2062.
27. Heindel, N. D.; Kennewell, P. D.; Pfau, M. JOC 1970, 35, 80.
28. Chennat, T.; Eisner, U. JCS(P1) 1975, 926.
29. Regitz, M.; Martin, R. LA 1984, 1641.
30. Buffel, D. K.; Simons, B. P.; Deceuninck, J. A.; Hoornaert, G. J. JOC 1984, 49, 2165.
31. Wade, P. A.; Amin, N. V.; Yen, H.-K.; Price, D. T.; Huhn, G. F. JOC 1984, 49, 4595.
32. Arcadi, A.; Marinelli, F.; Cacchi, S. S 1986, 749.
33. Doad, G. J. S.; Barltrop, J. A.; Petty, C. M.; Owen, T. C. TL 1989, 30, 1597.
34. Takano, S.; Shimazaki, Y.; Moriya, M.; Ogasawara, K. CL 1990, 1177.
35. Krause, N. LA 1990, 603.
36. Garner, N.; Park, J. M. JOC 1990, 55, 3772.
37. Schmitt, M.; Bouguignon, J. J.; Wermuth, C. G.; Schott, D.; Rousseau, B.; Beaucourt, J. P. J. Labelled Compd. Radiopharm. 1989, 27, 23.

Gavin C. Hirst

Glaxo Research Institute, Research Triangle Park, NC, USA



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