Dimethyl Acetylenedicarboxylate

[762-42-5]  · C6H6O4  · Dimethyl Acetylenedicarboxylate  · (MW 142.11)

(an electron deficient symmetrical alkynic diester useful as a dienophile and dipolarophile in cycloaddition reactions;1 can undergo [2 + 2] cycloaddition;2 Michael acceptor;3 synthesis of phthalic acid derivatives4 and heteroaromatics5)

Alternate Name: DMAD.

Physical Data: bp 195-198 °C; bp 98 °C/20 mmHg; d 1.1564 g cm-3.

Solubility: sol common organic solvents, e.g. diethyl ether, ethyl alcohol, carbon tetrachloride.

Form Supplied in: commercially available liquid.

Handling, Storage, and Precautions: lachrymator and vesicant; avoid inhalation and contact with skin or eyes. Use in a fume hood.

As a Dienophile in the Diels-Alder Cycloaddition.

DMAD is a ubiquitous dienophile capable of facile cycloadditions with a wide variety of dienes. Much effort has been devoted to the development of dienes which retain additional functionality in the Diels-Alder adduct. New dienes are often reacted with DMAD in order to test their efficacy as a diene in the Diels-Alder reaction.6 DMAD is a liquid with a high boiling point and can be used as the Diels-Alder solvent. The number of possible stereoisomers is limited. Due to the symmetry of DMAD there are no regio or endo/exo isomers with respect to the dienophile. For this reason, DMAD is not useful for determining any regioselective biases of a diene. The triple bond gives rise to a double bond in which the product methyl esters are necessarily cis. A maximum of two stereoisomers are possible only if the two faces of the diene are either electronically7 or sterically8 nonequivalent, otherwise one isomer is produced. The two esters make the triple bond electron poor, and therefore well suited for normal electron demand Diels-Alder cycloadditions. A comparison of relative Diels-Alder reaction rates of common dienophiles, including DMAD, has been performed.9

Diels-Alder adducts from DMAD are 1,4-cyclohexadienes, which are prone to aromatization. In fact, the Diels-Alder/aromatization sequence constitutes a powerful protocol for the synthesis of phthalate derivatives (see below). Aromatization is facile when loss of a small molecule is possible. In many cases a benzenoid compound, not the initial Diels-Alder adduct, is directly isolated. Loss of an alcohol is common (eq 1).10

If loss of a small molecule is not possible, the diene adduct can be treated with oxidizing agents such as 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone.11 In the case of cyclic dienes, the initial adduct can undergo a retro-Diels-Alder reaction, extruding carbon dioxide,12 carbon monoxide,13 or ethylene14 to produce aromatic products (eqs 2-4).

Adducts possessing a [2.2.1] ring system, obtained from five-membered cyclic dienes such as furans15 and pyrroles,16 may fragment to gain aromaticity. DMAD has been exceedingly useful for the synthesis of a number of heteroaromatics such as indoles17 and furans.18 Electron deficient alkynes are well suited for the synthesis of pyrimidines from 1,3-diazabutadienes (eq 5).19

The cycloaddition of DMAD with anthracene20 has been used for the synthesis of an interesting new iodate phosphorolytic agent.21 DMAD has been used extensively in the development of o-quinodimethane equivalents (eq 6).22

Examples of higher order cycloadditions with DMAD are abundant. Extended conjugated cycloalkenes such as heptafulvene,23 fulvenes,24 azulenes,25 and indolizines26 have furnished higher order cycloadducts on treatment with DMAD.

As a Dipolarophile.

Not surprisingly, DMAD also undergoes cycloadditions with 1,3-dipoles. Cycloadditions with common 1,3-dipoles such as azides,27 diazo alkanes,28 nitrile imines,29 nitrile ylides,30 nitrile oxides,31 azomethine imines,32 azoxy compounds,33 azomethine ylides,34 and nitrones35 have been reported. As in the case of the Diels-Alder reaction, the number of stereoisomers obtained is limited (see above). When the faces of the dipole are not equivalent, DMAD can add stereoselectively.36 Two recent synthetically interesting examples of cycloaddition of DMAD with carbonyl ylides37 and azomethine ylides38 are illustrated (eqs 7 and 8).

Due to the unsaturation remaining in the [3 + 2] adducts obtained with DMAD, aromatization and sigmatropic rearrangements are common. Adducts from a-diazo ketones tend to undergo 1,5-acyl sigmatropic rearrangements (eq 9).39

Simple fragmentations of the [3 + 2] adducts are also common. Reaction of DMAD with quinoxaline 4-oxide gives a pyrrole compound (eq 10).40 The initial [3 + 2] adduct fragments and incorporates a second molecule of DMAD.

Cyclization with extended dipoles is known. Benzothiazole undergoes Michael addition with DMAD to form a 1,4-dipole intermediate which subsequently cyclizes with a second molecule of DMAD (eq 11).41 1,4-Thiazepines have been constructed via cyclization of DMAD with a 1,5-dipole (eq 12).42

[2 + 2] Cycloaddition.

DMAD readily undergoes [2 + 2] cycloadditions with enamines, often at ambient temperatures, to form cyclobutene compounds.43 In many cases these compounds are not isolated and tend to fragment to form 1,3-dienamines.44 When the enamine is cyclic the ring is enlarged by two carbon atoms (eq 13).45 This chemistry has successfully been carried out on a range of enamine substrates including indoles,46 quinolines,47 and vinylogous imides (enamino lactams).48 The cycloaddition with enamines is compatible with a wide range of functionalities (eq 14).49

1,1-Dimethoxyalkenes,50 enol ethers,51 and silyl enol ethers52 undergo Lewis acid mediated [2 + 2] cycloaddition with DMAD to afford cyclobutene compounds. In the case of silyl enol ethers the [2 + 2] adducts can generate fragmentation products analogous to the enamine substrates. The common isolation of simple Michael adducts and strong solvent dependency on yield is solid evidence for a stepwise mechanism involving dipolar intermediates.53

As a Michael Acceptor.

A wide variety of nucleophiles undergo 1,4-addition with DMAD. There are examples where carbon,54 oxygen,55 nitrogen,56 and halogen57 nucleophiles undergo simple Michael addition, thus making DMAD useful for the synthesis of a great number of substituted alkenes. A predominance of the (Z)-isomer (methyl esters trans) is most common.58 Frequently, the initial Michael adducts cyclize; this presents a facile route to heterocycles and especially heteroaromatics. With amine nucleophiles the resultant enamines (or vinylogous urethanes) often cyclize onto nearby electrophilic centers. The process is especially efficient when a five- or six-membered ring can be formed. Thus vinylogous amides yield pyridines on treatment with DMAD, whereas a-amino ketones give pyrroles (eqs 15 and 16).59

Alternatively, a nearby nucleophile in the Michael adduct may attack the ester moiety of DMAD. This process is facile when five- or six-membered rings can be formed (eq 17).60

If there are no proton sources to quench the enolate formed by the Michael addition, cyclization onto a nearby electrophilic center is possible. Thus treatment of the benzyl anion of 5-pyrimidinecarboxylate with DMAD affords a quinazoline (eq 18).61

Alternatively, the enolate could undergo another Michael addition, incorporating a second molecule of DMAD which then cyclizes (see dipolar reactions, eq 11). DMAD reacts with p-toluenethiosulfonate at rt to form tetramethyl thiophenetetracarboxylate in good yield (eq 19).62 Interestingly, phenylacetylene, diphenylacetylene, or 3-phenyl-2-propynoate did not give any thiophenes. Apparently only alkynes with two electron-withdrawing groups will work.

1,4-Addition of radicals to DMAD are also known.63 Michael addition of the t-butoxy radical,64 selenyl radicals,65 and the isopropyl radical66 (eq 20) have recently been studied.

DMAD has been used in a palladium-catalyzed annulation with aryl halides.67

Related Reagents.

Methyl Propiolate.

1. (a) Carruthers, W. Cycloaddition Reactions in Organic Synthesis; Pergamon: Oxford, 1990. (b) Bastide, J.; Henri-Rousseau, O. Chemistry of Functional Group, The Chemistry of Triple-Bonded Functional Groups; Patai, S.; Rappoport, Z., Eds; Wiley: Chichester, 1983; Suppl. C, Part 1, pp 447-522.
2. Cook, A. G. Enamines: Synthesis, Structure and Reactions, 2nd ed.; Cook, A. G., Ed.; Dekker: New York, 1988; pp 384-389.
3. Hendrickson, J. B.; Rees, R.; Templeton, J. F. JACS 1964, 86, 107.
4. Wenkert, E.; Johnston, D. B. R.; Dave, K. G. JOC 1964, 29, 2534.
5. (a) Muchowski, J. M.; Scheller, M. E. TL 1987, 28, 3453. (b) Belloir, P. F.; Laurent, A.; Mison, P. S 1986, 683.
6. (a) Tada, M.; Schimizu, T. BCJ 1992, 65, 1252. (b) Murase, M.; Hosaka, T.; Yoshida, S.; Tobinaga, S. CPB 1992, 40, 1343. (c) Kanomata, N.; Kawaji, H.; Nitta, M. JOC 1992, 57, 618.
7. Halterman, R. L.; McCarthy, B. A.; McEvoy, M. A. JOC 1992, 57, 5585.
8. (a) Fessner, W. D.; Grund, C.; Prinzbach, H. TL 1991, 32, 5935. (b) Paquette, L. A.; Shen, C. C. JACS 1990, 112, 1159.
9. Sauer, J. AG 1961, 73, 545.
10. (a) Heffner, R. J.; Joullié, M. M. SC 1991, 21, 2231. (b) Danishefsky, S.; Kitahara, T. JACS 1974, 96, 7807.
11. Paquette, L. A.; Melega, W. P.; Kramer, J. D. TL 1976, 4033.
12. Jackson, P. M.; Moody, C. J. T 1992, 48, 7447.
13. (a) Brown, R. F. C.; Choi, N.; Eastwood, F. W. TL 1992, 35, 3787. (b) Eicher, T.; Abdesaken, F.; Franke, G.; Weber, J. L. TL 1975, 3915.
14. Rama Rao, A. V.; Reddy, R. G. TL 1992, 28, 4061.
15. (a) Krutôsiková, A.; Hanes, M. CCC 1992, 57, 1487. (b) Bloomer, J. L.; Lankin, M. E. TL 1992, 33, 2769.
16. Sha, C. K.; Liu, J. M.; Chiang, R. K.; Warg, S. L. H 1990, 31, 603.
17. Gribble, G. W.; Keavey, D. J.; Davis, D. A.; Saulnier, M. G.; Pelcman, B.; Barden, T. C.; Sibi, M. P.; Olson, E. R.; Belbruno, J. J. JOC 1992, 57, 5878.
18. Aken, K. V.; Hoornaert, G. CC 1992, 895.
19. Guman, A.; Muchowski, J. M.; Romero, M.; Talamas, F. X. TL 1992, 33, 3449.
20. Paquette, L. A.; Bay, E. JACS 1984, 106, 6693.
21. Moss, R. A.; Zhang, H. TL 1992, 33, 4291.
22. (a) Greco, M. N.; Rasmussen, C. R. JOC 1992, 57, 5532. (b) Ando, K.; Hatano, C.; Akadegawa, N.; Shigihara, A.; Takayama, H. CC 1992, 870. (c) Ruiz, N.; Pujol, M. D.; Guillaumet, G.; Coudert, G. TL 1992, 33, 2965. (d) Mertzanos, G. E.; Stephanidou-Stephanatou, J.; Tsolenidis, C. A.; Alexandrou, N. E. TL 1992, 33, 4499.
23. Doering, W. E.; Wiley, D. W. T 1960, 11, 183.
24. Liu, C. Y.; Ding, S. T. JOC 1992, 57, 4539.
25. Hafner, K.; Knaup, G. L.; Lindner, H. J. BCJ 1988, 61, 155.
26. (a) Blake, A. J.; Dick, J. W.; Leaver, D.; Strachan, P. JCS(P1) 1991, 2991. (b) Matsumoto, K.; Uchida, T.; Yoshida, H.; Toda, M.; Kakehi, A. JCS(P1) 1992, 2437.
27. Prabahar, J. K.; Shanmugasundaram, P.; Ananthanarayanan, C.; Ramakrishnan, V. T. Indian J. Heterocycl. Chem. 1992, 1, 157.
28. (a) Frampton, C. S.; Majchrzak, M. W.; Warkentin, J. CJC 1991, 69, 373. (b) Majchrzak, M. W.; Békhazi, M.; Tse-Sheepy, I.; Warkentin, J. JOC 1989, 54, 1842. (c) Birkhahn, M.; Hohlfeld, R.; Massa, W.; Schmidt, R.; Lorberth, J. JOM 1980, 192, 47.
29. (a) Baruah, A. K.; Prajapati, D.; Sandhu, J. S. T 1988, 44, 1241. (b) Tewari, R. S.; Dixit, P. D.; Parihar, P. JHC 1982, 19, 1573.
30. (a) Ibata, T.; Fukushima, K. CL 1992, 2197. (b) Berée, F.; Marchand, E.; Morel, G. TL 1992, 33, 6155. (c) Bossio, R.; Marcaccini, S.; Paoli, P.; Pepino, R.; Polo, C. H 1990, 31, 1855. (d) Wipf, P.; Prewo, R.; Bieri, J. H.; Germain, G.; Heimgartner, H. HCA 1988, 71, 1177. (e) Frank-Neumann, M.; Buchecker, C. TL 1972, 937.
31. (a) Yokoyama, M.; Sujino, K.; Irie, M.; Yamazaki, N.; Hiyama, T.; Yamada, N.; Togo, H. JCS(P1) 1991, 2801. (b) Yokoyama, M.; Yamada, N. TL 1989, 30, 3675.
32. (a) Noguchi, M.; Kiriki, Y.; Tsuruoka, T.; Mizui, T.; Kajigaeshi, S. BCJ 1991, 64, 99. (b) Thesis, W.; Bethäuser, W.; Regitz, M. CB 1985, 118, 28. (c) Diez-Barra, E.; Pardo, C.; Elguero, J.; Arriau, J. JCS(P2) 1983, 1317. (d) Burger, K.; Schickaneder, H.; Zettl, C.; Dengler, O. LA 1982, 1730.
33. (a) Huisgen, R.; Gambra, F. P. CB 1982, 115, 2242. (b) Huisgen, R; Gombra, F. P. TL 1982, 23, 55.
34. (a) Padwa, A.; Austin, D. J.; Precedo, L.; Zhi, L. JOC 1993, 58, 1144. (b) Vedejs, E.; Piotrowski, D. W. JOC 1993, 1341. (c) de Pablo, M. S.; Gandásegui, T.; Vaquero, J. L.; Navió, G.; Alvarez-Builla, J. T 1992, 48, 8793. (d) Pandey, G.; Lakshmaiah, G.; Kumaraswamy, G. CC 1992, 1313. (e) Padwa, A.; Ku, H. JOC 1979, 44, 255.
35. (a) Purwono, B.; Smalley, R. K.; Porter, T. C. SL 1992, 231. (b) Hippeli, C.; Reissig, H. O. LA 1990, 475. (c) Bennett, G. A.; Mullen, G. B.; Georgiev, V. St. HCA 1989, 72, 1718.
36. Anslow, A. S.; Harwood, L. M.; Phillips, H.; Watkins, D.; Wong, L. F. TA 1991, 2, 1343.
37. Wender, P. A.; Mascarenas, J. L. TL 1992, 33, 2115.
38. Padwa, A.; Dean, D. C.; Hertzog, D. L.; Nadler, W. R.; Zhi, L. T 1992, 48, 7565.
39. (a) Jefferson, E.; Warkentin, J. JACS 1992, 114, 6318. (b) Katner, A. S. JOC 1973, 38, 825.
40. (a) Kurasaw, Y.; Katoh, R.; Takada, A.; Kim, H. S.; Okamoto, Y.; JHC 1992, 29, 1001. (b) Fukuchi, M.; Okamoto, M.; Takada, A.; Kim, H. S.; Okamoto, Y. JHC 1992, 29, 1009.
41. McKillop, A.; Sayer, T. S. B. TL 1975, 3081.
42. Kakehi, A.; Ito, S.; Hakui, J. CL 1992, 777.
43. Acheeson, R. M.; Wright, N. D.; Tasker, P. A. JCS(P1) 1972, 2918.
44. (a) Brannock, K. C.; Burpitt, R. D.; Goodlett, V. W.; Thweatt, J. G. JOC 1963, 28, 1464. (b) Reinhoudt, D. N.; Kouwenhoven, C. G. TL 1973, 3751. (c) Acheson, R. M.; Paglietti, G. CC 1973, 665.
45. Huebner, C. F.; Dorfman, L.; Robinson, M. M.; Donoghue, E.; Pierson, W. G.; Strachan, P. JOC 1963, 28, 3134.
46. (a) Acheson, R. M.; Bridson, J. N.; Cameron, T. S. JCS 1972, 968; (b) Plieninger, H.; Wild, D. CB 1966, 99, 3070.
47. Lehman, P. G. TL 1972, 4863.
48. Heinicke, G. W.; Morella, A. M.; Orban, J.; Prager, R. H.; Ward, A. D. AJC 1985, 38, 1847.
49. Matsunaga, H.; Sonoda, M.; Tomioka, Y.; Yamazaki, M. CPB 1986, 34, 396.
50. Graziano, M. L.; Lesce, M. R.; Cermola, F.; Cimminiello, G. JCS(P1) 1992, 1269.
51. Wang, Y. W.; Fang, J. M.; Wang, Y. K.; Wang, M. H.; Ko, T. Y.; Cherng, Y. J. JCS(P1) 1992, 1209.
52. Clark, R. D.; Untch, K. G. JOC 1979, 44, 248.
53. Aue, H. A.; Thomas, D. JOC 1975, 40, 2360.
54. Parmer, R. H; Ghosal, S. C.; Kou, G. A. R. JCS 1961, 1804.
55. (a) Ireland, R. E.; Obrecht, D. M. HCA 1986, 69, 1273. (b) Yokoyama, M.; Sujino, K.; Irie, M.; Togo, H. TL 1991, 32, 7269.
56. Heindel, N. D.; Bechara, I. S.; Kennewell, P. D.; Molnar, J.; Ohnmacht, C. J.; Lemke, S. M.; Lemke, T. F. JMC 1968, 11, 1218.
57. Johnson, A. W. Chemistry of the Acetylenic Compounds; Longmans, Green: New York, 1950; Vol. II, pp 199-266.
58. Hendrickson, J. B.; Rees, R. JACS 1961, 83, 1250.
59. James, D. S.; Fanta, P. E. JOC 1962, 27, 3346.
60. (a) Padwa, A.; MacDonald, J. G. JHC 1987, 24, 1225. (b) Reimlinger, H.; Jacquier, R.; Daunis, J. CB 1971, 104, 2702.
61. Wada, A.; Yamamoto, H.; Ohki, K.; Nagai, S.; Kanatomo, S. JHC 1992, 29, 911.
62. Kutateladze, T. G.; Kice, J. L. JOC 1992, 57, 5270.
63. Amiel, Y. Chemistry of Functional Groups, The Chemistry of Triple-Bonded Functional Groups; Patai, S.; Rappoport, Z., Eds; Wiley: Chichester, 1983; Suppl. C, Part 1, pp 341-382.
64. Bottle, S.; Bosfield, W. K.; Jenkins, I. D.; Skelton, B. W.; White, A. H.; Rizzardo, E.; Solomon, D. H. JCS(P2) 1991, 1001.
65. (a) Kataoka, T.; Yoshimatsu, M.; Shimizu, H.; Hori, M. TL 1990, 31, 5927. (b) Kataoka, T.; Yoshimatsu, M.; Noda, Y.; Sato, T.; Shimizu, H.; Hori, M. JCS(P1) 1993, 121.
66. Curran, D. P.; Dooseop, K. T 1991, 47, 6171.
67. (a) Dyker, G. JOC 1993, 58, 234. (b) Sakakibara, T.; Tanaka, Y.; Yamasaki, S. I. CL 1986, 797.

John E. Stelmach & Jeffrey D. Winkler

University of Pennsylvania, Philadelphia, PA, USA

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