[16714-78-6]  · C4H6Cl2O  · 1,4-Dichloro-2-butanone  · (MW 141.00)

(reactive electrophile, precursor for 1,4-disubstituted 2-butanones and 2-butenones)

Alternate Name: 2-chloroethyl chloromethyl ketone.

Physical Data: bp 65 °C/3 mmHg; vap. d 4.9 g cm-3.1

Solubility: freely sol organics; may react with amides, amines, alcohols, sulfoxides, water.

Form Supplied in: neat liquid.

Analysis of Reagent Purity: IR, UV, NMR (d 3.08, 2H, t, J = 6 Hz; 3.71, 2H, t, J = 6 Hz; 4.00 ppm, 2H, s).2

Preparative Methods: can be prepared by the Friedel-Crafts acylation of ethylene with Chloroacetyl Chloride catalyzed by Aluminum Chloride4 or the treatment of 2-chloropropionyl chloride with Diazomethane followed by concentrated HCl.5 The Friedel-Crafts process can be used with other alkenes and acid chlorides to yield a,b-dichloroalkyl ketones.4

Handling, Storage, and Precautions: highly irritating to the skin, eyes, and mucous membranes via oral inhalation and skin contact. A lacrimator type of military poison. Dangerous; when heated to dec, burns and emits highly toxic fumes of chlorides.3 Use in a fume hood.

Alkylation Reactions.

The title reagent (1) can react at either of the halide positions or at the carbonyl. With weak nucleophiles such as alkoxide,6 acetate,6 thiolate,7 or phthalimide,8 (1) yields (2) or (3). Compound (2) can be converted into (3) with base treatment. Diamine (2) (X = NH2) has been converted into histamine (eq 1).8 The carbonyl group of (1) is the electrophilic site in reactions with organolithium or Grignard reagents. The intermediate alkoxide can be converted into a diorganolithio trianion which can be trapped with several electrophiles (eq 2).9

Enones such as (3) have found extensive use as the dienophiles in Diels-Alder reactions.10 They should also be valuable 2p electron components in other cycloadditions. Compound (1) was used to generate (3) (X = Cl) in situ for a Robinson annulation with b-dicarbonyls (eq 3).11 The normal aldol product is trapped in about 50% yield to afford an epoxy ketone. This process has been called epoxyannulation. Other examples of epoxyannulation have included treatment of enolates with 2-Chloroacrylonitrile12a or 1-butadienylsulfonium salts12b and the cyclization of o-ketosulfonium salts.12c,d

The other major use of (1) has been to construct functionalized azoles. Although only thiazoles13 (eq 4) appear to have been reported, oxazoles and imidazoles should be available from (1) since other chloromethyl ketones yield all of these azoles.14

1. Heilbron, Dictionary of Organic Compounds, 5th ed.; 1st suppl.; Chapman & Hall: New York, 1983; p 158.
2. Champaign, E.; et al. CED 1967, 12, 454.
3. Sax, N. I. Dangerous Properties of Industrial Materials, 5th ed.; Van Nostrand-Reinhold: New York, 1979; p 564.
4. (a) Catch, J. R.; Elliott, D. F.; Hey, D. H.; Jones, E. R. H. JCS 1948, 278. (b) Baddeley, G.; Taylor, H. T.; Pickles, W. JCS 1953, 124.
5. Carroll, R. H.; Smith, G. B. JACS 1933, 55, 370.
6. (a) Arbuzov, Y. A.; Korolev, A. M. ZOB 1962, 32, 3674 (CA 1963, 58, 112 34b). (b) Arbuzov, Y. A.; Dyatkin, B. L.; Shevelev, S. A. DOK 1957, 112, 261 (CA 1957, 51, 12 053h).
7. (a) Thyagarajan, B. S.; Majumdar, K. C.; Bates, D. K. JHC 1975, 12, 59. (b) Lattrell, R. LA 1974, 1361.
8. Jakobiec, T. CA 1960, 54, 14 234f.
9. Barluenga, J.; Fernandez, J. R.: Yus, M. S 1985, 10, 977.
10. Arbuzov, Y. A.; Dyatkin, B. L. DOK 1956, 111, 1249 (CA 1957, 51, 9503i).
11. Danishefsky, S.; Koppel, G. A. CC 1971, 367.
12. (a) White, D. R. CC 1975, 95. (b) Garst, M. E., Arrhenius, P. JOC 1983, 48, 16. (c) Crandall, J. K.; Magaha, H. S.; Widener, R. K.; Tharp, G. A. JOC 1982, 47, 5372. (d) Garst, M. E.; McBride, B. J.; Johnson, A. T. JOC 1983, 48, 8.
13. (a) Naito, Y.; et al. CPB 1991, 39, 2323. (b) Ueda, I.; Morino, D.; Takimoto, K. Eur. Patent Appl. 32 058, 1981 (CA 1981, 95, 169 217y).
14. Paquette, L. A. Modern Heterocyclic Chemistry; Benjamin: New York, 1968; pp 192-3.

Michael E. Garst

Allergan, Irvine, CA, USA

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