[920-37-6]  · C3H2ClN  · 2-Chloroacrylonitrile  · (MW 87.51)

(ketene equivalent for use in the Diels-Alder reaction1 and other cycloaddition reactions; undergoes Michael additions and radical additions)

Physical Data: mp -65 °C; bp 88-89 °C; d 1.096 g cm-3.

Solubility: sol most organic solvents other than pure hydrocarbons.

Form Supplied in: neat colorless liquid.

Analysis of Reagent Purity: 1H NMR, 13C NMR.

Handling, Storage, and Precautions: highly toxic; use only in a fume hood. Reagent can be absorbed through the skin. Always wear gloves when handling this reagent.

[4 + 2] Cycloaddition Reactions.

2-Chloroacrylonitrile is a reasonably good dienophile for the Diels-Alder reaction. It reacts thermally with a variety of cyclic dienes such as cyclopentadiene2 and cyclohexadiene.2,3 Most often the initial cycloadducts are hydrolyzed immediately to produce the corresponding ketones (eq 1). In this fashion, 2-chloroacrylonitrile, along with 2-Acetoxyacrylonitrile, is one of the most popular ketene equivalents for use in the Diels-Alder reaction.1 In the case of substituted cyclohexadienes the starting diene is often an unconjugated 1,4-diene which under the reaction conditions isomerizes to the reactive 1,3-diene and produces the desired Diels-Alder adduct (eq 2).4

Once again the product a-chloro nitrile is hydrolyzed to produce the bicyclo[2.2.2]octanone. The hydrolysis reaction is usually carried out with either Potassium Hydroxide in DMSO2,5 or with Sodium Sulfide in refluxing ethanol.6

Copper salts have been used to catalyze the Diels-Alder reaction of 2-chloroacrylonitrile.6 Most notable is the successful cycloaddition of the thermally sensitive substituted cyclopentadiene (1) (eq 3).6a,b Use of copper(II) fluoroborate allowed the reaction to take place at 0 °C. This ultimately produced ketone (2), an important intermediate in the early syntheses of prostaglandins. Diels-Alder reactions between furans and 2-chloroacrylonitrile have also been achieved via copper catalysis (eq 4).6d Interestingly, the base-catalyzed hydrolysis of adduct (3) produced the amide (4) instead of the expected ketone. There have been other instances in which the intermediate a-chloronitrile yields products other than the hydrolyzed ketone.7

As seen from the above examples, cyclic dienes are usually used in conjunction with 2-chloroacrylonitrile.8 Such dienes include substituted cyclohexadienes,4,7a-d,9 substituted cyclopentadienes,6a-c,7e hydroxypyrones,10 fulvenes,11 furans,6d,12 and isobenzofurans.13 Other dienes which give [4 + 2] cycloadducts with 2-chloroacrylonitrile include vinyl heterocycles14 and a few acyclic dienes.15 It has been stated that thermal cycloadditions are limited to 140 °C due to polymerization of the chloroacrylonitrile above this temperature.3 In addition to the aforementioned Cu2+ catalysis, Zinc Iodide,12b triorganotin cations,12e and high pressure12a,f have been used to accelerate the cycloaddition reactions of 2-chloroacrylonitrile and furans.

In addition to 2-chloroacrylonitrile and 2-Acetoxyacrylonitrile, other ketene equivalents have been developed.1 These include acrylonitrile,2 2-aminoacrylonitrile,16a 2-methylthioacrylonitrile,16b 2-chloroacryloyl chloride,17a,b 2-bromoacrolein,17c vinyl boronates,4,18a vinylboranes,18b nitroethylene,19 and vinyl sulfoxides.20 One comparative study found that 2-chloroacrylonitrile was both more reactive and more regioselective than either 2-acetoxyacrylonitrile or dibutyl vinyl boronate.4 Chiral vinyl sulfoxides have been explored as possible chiral ketene equivalents.17c,20

Other Cycloaddition Reactions.

In addition to [4 + 2] cycloadditions, 2-chloroacrylonitrile also undergoes [2 + 3]21,22 and [2 + 2]23 cycloaddition reactions. In particular, 2-chloroacrylonitrile is a good dipolarophile and has produced cycloadducts with nitrones21 and a number of different azomethine ylides.22 In the case of nitrones the cycloadducts have been hydrolyzed to isoxazolidinones; thus 2-chloroacrylonitrile once again functions as a ketene equivalent in these reactions (eq 5).21c Chiral nitrones have been found to undergo stereoselective cycloaddition reactions and have been used in the synthesis of chiral amino acids21c and carbapenem derivatives.21a

Michael Additions and Radical Additions.

As with other acrylonitriles, 2-chloroacrylonitrile is an excellent acceptor of nucleophiles23e,24 and nucleophilic radicals.25 In a number of instances24a,b,25b,e the initial addition product can undergo a further cyclization, in which case 2-chloroacrylonitrile functions as a convenient two-carbon annulating agent. Such an annulation is illustrated for both a polar addition (eq 6)24b and a radical addition (eq 7).25b 2-Chloroacrylonitrile has been used extensively in the homologation of nucleophilic radicals25a,c,f and, in keeping with the captodative effect,25d has been shown to react 10-15 times faster than acrylonitrile.25a,d

1. Ranganathan, S.; Ranganathan, D.; Mehrotra, A. K. S 1977, 289.
2. Freeman, P. K.; Balls, D. M.; Brown, D. J. JOC 1968, 33, 2211.
3. Kreiger, H.: Nakajima, F. Suom. Kemistil. 1969, 42, 314 (CA 1969, 71, 112496p).
4. Evans, D. A.; Scott, W. L.; Truesdale, L. K. TL 1972, 121.
5. Paasivirta, J.; Kreiger, H. Suom. Kemistil. 1965, B38, 182 (CA 1966, 64, 4965g).
6. (a) Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W. JACS 1969, 91, 5675. (b) Corey, E. J.; Koelliker, U.; Neuffer, J. JACS 1971, 93, 1489. (c) Goering, H. L.; Chang, C.-S. JOC 1975, 40, 2565. (d) Vieira, E.; Vogel, P. HCA 1982, 65, 1700.
7. (a) Damiano, J.; Geribaldi, S.; Torri, G.; Azzaro, M. TL 1973, 2301. (b) Yamada, Y.; Kimura, M.; Nagaoka, H.; Ohnishi, K. TL 1977, 2379. (c) Clark, R. S. J.; Holmes, A. B.; Matassa, V. G. TL 1989, 30, 3223. (d) Clark, R. S. J.; Holmes, A. B.; Matassa, V. G. JCS(P1) 1990, 1389. (e) Bull, J. R.; Grundler, C.; Niven, M. L. CC 1993, 217.
8. Fringuelli, F.; Taticchi, A. Dienes in the Diels-Alder Reaction; Wiley: New York, 1990.
9. (a) Mirrington, R. N.; Greyson, R. P. CC 1973, 598. (b) Munai, A.; Sato, S.; Masamune, T. CL 1981, 429. (c) Oku, A.; Hasegawa, H.; Shimazu, H.; Nishimura, J.; Harada, T. JOC 1981, 46, 4152.
10. Corey, E. J.; Kozikowski, A. P. TL 1975, 2389.
11. (a) Sakai, K.; Kobori, T. TL 1981, 22, 115. (b) Siegel, H. S 1985, 798. (c) Nzabamwita, G.; Kolani, B.; Jousseaume, B. TL 1989, 30, 2207.
12. (a) Kotsuki, H.; Nishizawa, H. H 1981, 16, 1287. (b) Brion, F. TL 1982, 23, 5299. (c) Schuda, P. F.; Bennett, J. M. TL 1982, 23, 5525. (d) Moursoundis, J.; Wege, D. AJC 1983, 36, 2473. (e) Nugent, W. A.; McKinney, R. J.; Harlow, R. L. OM 1984, 3, 1315. (f) Kotsuki, H.; Mori, Y.; Ohtsuka, T.; Nishizawa, H.; Ochi, M.; Matsuoka, K. H 1987, 26, 2347.
13. Makhlouf, M. A.; Rickborn, B. JOC 1981, 46, 2734.
14. (a) Sasaki, T.; Ishibashi, Y.; Ohno, M. JCR(S) 1984, 218. (b) Ohmura, H.; Motoki, S. BCJ 1984, 57, 1131. (c) Alexandre, C.; Rouessac, F.; Tabti, B. TL 1985, 26, 5453. (d) Pindur, U.; Eitel, M.; Abdoust-Houshang, E. H 1989, 29, 11.
15. (a) Kozikowski, A. P.; Hiraga, K.; Springer, J. P.; Wang, B. C.; Xu, Z. B. JACS 1984, 106, 1845. (b) Gordon, P. F. CA 1985, 102, 131717m. (c) Baldwin, J. E.; Otsuka, M.; Wallace, P. M. T 1986, 42, 3097.
16. (a) Boucher, O.-L.; Stella, L. T 1985, 41, 875. (b) Boucher, O.-L.; Stella, L. T 1986, 42, 3871.
17. (a) Corey, E. J.; Ravindranathan, T.; Terashima, S. JACS 1971, 93, 4326. (b) Van Tamelen, E. E.; Zawacky, S. R. TL 1985, 26, 2833. (c) Corey, E. J.; Loh, T.-P. JACS 1991, 113, 8966.
18. (a) Matteson, D. S.; Waldbillig, J. O. JOC 1963, 28, 366. (b) Singleton, D. A.; Martinez, J. P.; Watson, J. Y. TL 1992, 33, 1017.
19. (a) Bartlett, P. A.; Green, F. R.; Webb, T. R. TL 1977, 33. (b) Ranganathan, D.; Rao, C. B.; Ranganathan, S.; Mehrotra, A. K.; Iyengar, R. JOC 1980, 45, 1185. (c) Mehta, G.; Subrahmanyam, D. JCS(P1) 1991, 395.
20. Maignan, C.; Raphael, R. A. T 1983, 39, 3245. Lopez, R.; Carretero, J. C. TA 1991, 2, 93.
21. (a) Freer, A.; Overton, K.; Tomanek, R. TL 1990, 1471. (b) Kurasawa, Y.; Kim, H. S.; Katoh, R.; Kawano, T.; Takada, A.; Okamoto, Y. JHC 1990, 27, 2209. (c) Keirs, D.; Moffat, D.; Overton, K.; Tomanek, R. JCS(P1) 1991, 1041.
22. (a) Benages, I. A.; Albonica, S. M. JOC 1978, 43, 4273. (b) Pierini, A. B.; Cardozo, M. G.; Montiel, A. A.; Albonica, S. M.; Pizzorno, M. T. JHC 1989, 26, 1003. (c) Bonneau, R.; Liu, M. T. H.; Lapouyade, R. JCS(P1) 1989, 1547. (d) Jones, R. C. F.; Nichols, J. R.; Cox, M. T. TL 1990, 31, 2333.
23. (a) Scheeren, H. W.; Frissen, A. E. S 1983, 794. (b) De Cock, C.; Piettre, S.; Lahousse, F.; Janousek, Z.; Merenyi, R. Viehe, H. G. T 1985, 41, 4183. (c) Shimo, T.; Somekawa, K.; Wakikawa, Y.; Uemura, H.; Tsuge, O.; Imada, K.; Tanabe, K. BCJ 1987, 60, 621. (d) Schuster, D. I.; Heibel, G. E.; Brown, P.; Turro, N. J.; Kumar, C. V. JACS 1988, 110, 8261. (e) Quendo, A.; Rousseau, G. SC 1989, 19, 1551. (f) Narasaka, K.; Hayashi, Y.; Shimadzu, H.; Niihata, S. JACS 1992, 114, 8869.
24. (a) Bergmann, E. D.; Ginsburg, D.; Pappo, R. OR 1959, 10, 179. (b) White, D. R. JCS(C) 1975, 95. (c) Joucla, M.; Fouchet, B.; Hamelin, J. T 1985, 41, 2707.
25. (a) Giese, B. AG(E) 1983, 22, 753. (b) Henning, R.; Urbach, H. TL 1983, 24, 5343. (c) Giese, B.; Horler, H. T 1985, 41, 4025. (d) Ito, O.; Arito, Y.; Matsuda, M. JCS(P2) 1988, 869. (e) Srikrishna, A.; Hemamalini, P. JCS(P1) 1989, 2511. (f) Barton, D. H. R.; Chern, C. Y.; Jaszberenyi, J. C. TL 1992, 33, 5017.

Patrick G. McDougal

Reed College, Portland, OR, USA

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