[3018-12-0]  · C2HCl2N  · Dichloroacetonitrile  · (MW 109.94)

(used in synthesis of a-chloro- and a,a-dialkyl-substituted nitriles;1 building block for synthesis of pyrimidines2 and pyridines;3 undergoes Darzens reaction with aldehydes and ketones4)

Physical Data: bp 110-112 °C; d 1.369 g cm-3.

Solubility: insol H2O; sol hexane, benzene, EtOH, ether, acetone, CH2Cl2.

Form Supplied in: colorless liquid; commercially available.

Handling, Storage, and Precautions: lachrymator; avoid inhalation of vapors or skin contact; flammable (toxic fumes); possible mutagen. Store under N2. Since Cl2CHCN is a byproduct of drinking water disinfection with chlorine, its toxicity has been studied in detail.5 Use in a fume hood.

Alkylation of dichloroacetonitrile with trialkylboranes (eq 1) (R = primary or secondary alkyl) affords a-chloro nitriles or a,a-dialkyl-substituted nitriles in good yield.1 The use of the hindered phenoxide base (pK 11.7) is advantageous because it minimizes self-condensation of both starting nitrile and the product. Since nitriles are readily hydrolyzed to acids, this procedure represents an alternative to the classical malonic ester synthesis.6

Treatment of 2-amino aromatic nitriles with Cl2CHCN affords either 4-chloro- or 4-aminopyrimidines depending on the substrate (eq 2).2 Halogenated pyridines are obtained via the copper-catalyzed addition of Cl2CHCN to methacrolein (eq 3).3 The first step of eq 3 represents a special case of the more general reaction in which copper salt-catalyzed addition of Cl2CHCN to alkenes yields a variety of 2,4-dichlorobutyronitriles,7 via an oxidation-reduction chain mechanism.

Aldehydes and ketones condense with Cl2CHCN in the presence of alkoxide bases at -78 °C to afford isolable a,a-dichloro-b-hydroxy nitriles in good yield (eq 4).4 At higher temperatures the chloroglycidimidates are obtained. Analogous reactions utilizing nonnucleophilic bases allow retention of the nitrile functionality.4,8

Reaction of Cl2CHCN with Hydrogen Cyanide (or, more safely, with Acetone Cyanohydrin) yields a versatile enamino nitrile which can form Schiff bases, be acylated, react with thiolates and alkoxides, and (in two steps) form amino-substituted oxazoles (eq 5).9

The dimerization of Cl2CHCN in the presence of HCl gives an N-(a-chloroalkenyl)alkylamidine hydrochloride, which upon treatment with Phosgene provides an unusual 4(3H)-pyrimidinone (eq 6).10 Novel selenium-containing heterocycles are available via Diels-Alder cyclization of selenoaldehydes prepared in good yield from Cl2CHCN (eq 7).11

Related Reagents.

Dibromoacetonitrile; Ethyl Dibromoacetate; Methyl Dichloroacetate.

1. Nambu, H.; Brown, H. C. JACS 1970, 92, 5790.
2. Shishoo, C. J.; Devani, M. B.; Bhadti, V. S.; Jain, K. S.; Ananthan, S. JHC 1990, 27, 119.
3. Pews, R. G.; Lysenko, Z. JOC 1985, 50, 5115.
4. Coutrot, P. BSF(2) 1974, 1965.
5. Hayes, J. R.; Condie, L. W., Jr.; Borzelleca, J. F. Environ. Health Perspect. 1986, 69, 183 (CA 1987, 106, 97 552z).
6. House, H. O. Modern Synthetic Reactions, 2nd ed.; Benjamin: Menlo Park, CA, 1972; pp 510-518, 756-761.
7. Murai, S.; Tsutsumi, S. JOC 1966, 31, 3000.
8. Arseniyadis, S.; Kyler, K. S.; Watt, D. S. OR 1984, 31, 1-364, esp. p 61.
9. Matsumura, K.; Saraie, T.; Hashimoto, N. CPB 1976, 24, 912, 924.
10. (a) Grundmann, C.; Weisse, G.; Seide, S. LA 1952, 577, 77. (b) Yanagida, S.; Fujita, T.; Ohoka, M.; Katagiri, I.; Komori, S. BCJ 1973, 46, 292, 299.
11. Segi, M.; Kato, M.; Nakajima, T. TL 1991, 32, 7427.

Gordon L. Bundy

The Upjohn Company, Kalamazoo, MI, USA

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