Ethyl 4-Chloroacetoacetate1

(1a; R = Et)

[638-07-3]  · C6H9ClO3  · Ethyl 4-Chloroacetoacetate  · (MW 164.60) (1b; R = Me)

[32807-28-6]  · C5H7ClO3  · Methyl 4-Chloroacetoacetate  · (MW 150.57) (1c; R = i-Pr)

[41051-20-1]  · C7H11ClO3  · Isopropyl 4-Chloroacetoacetate  · (MW 178.63) (1d; R = t-Bu)

[74530-56-6]  · C8H13ClO3  · t-Butyl 4-Chloroacetoacetate  · (MW 192.66)

(highly functionalized four-carbon building block for organic synthesis1)

Physical Data: (1a) mp -8.5 °C; bp 95 °C/10 mmHg; fp 92 °C; d 1.212 g cm-3. (1b) mp 14 °C; bp 50 °C/1 mmHg; fp 107 °C; d 1.287 g cm-3. (1c) mp 10 °C; bp 64 °C/1.65 mmHg; fp 86 °C; d 1.152 g cm-3. (1d) bp 101 °C/15 mmHg; fp 41 °C; d 1.130 g cm-3.

Form Supplied in: the alkyl 4-chloroacetoacetates are colorless liquids.

Solubility: sol most organic solvents. The ethyl ester (1a) is 12% enolized in the pure liquid, and highly enolized (60% in CCl4) in nonpolar solvents.2

Preparative Methods: the industrial production of the esters is made exclusively by chlorination of diketene followed by reaction of the intermediate acid chloride with the corresponding alcohol.3

Handling, Storage, and Precautions: these reagents are lachrymators of moderate toxicity; use in a fume hood.

Reactivity.

The 4-chloroacetoacetates with their four reactive carbon centers offer diverse synthetic possibilities, and their reactions may be subdivided into those occurring at the 1-, 2-, 3-, or 4-positions, and various combinations of these with di- and trifunctional reagents to give ring formation.

Reactions at the 1-Position.

Reactions of nucleophiles at this position are of minor importance. Hydrolysis produces 4-chloroacetoacetic acid which on nitrosation gives 3-chloropyruvaldoxime, useful for the synthesis of 6-substituted pteridines.4

Reactions at the 2-Position.

Electrophiles readily react at position 2. Chlorination with Sulfuryl Chloride represents a good route for the synthesis of 3-chlorotetronic acid.5 Nitrosation is best carried out under acidic conditions to form the (Z)-oxime (2). This may be isolated6 or reacted directly in situ with thiourea to form the 2-aminothiazole (3) (eq 1),7 which is an important intermediate for the side chain synthesis of many b-lactam antibiotics.

The combined effect of trimethyl orthoformate (see Triethyl Orthoformate) and aniline results in the formation of the N-substituted methylene compound (4) (eq 2).8

In the reaction with fluorosulfonyl isocyanate (see Chlorosulfonyl Isocyanate), initial attack occurs at the oxygen atom and then at higher temperatures the enol-carbamate intermediate rearranges to give the 2-substituted product (5). This on further heating decarboxylates to yield the acetoacetamide (6) (eq 3),9 useful for the preparation of acesulpham sweetener analogs.

With less reactive electrophiles the enolate salt of (1a) is used (e.g. alkylation10). If deprotonation of (1a) (pKa 9.7) is incomplete then dimerization occurs through intermolecular self-alkylation to give 2,5-dialkoxycarbonylcyclohexane-1,4-dione.11 Aldehydes condense in the Knoevenagel reaction and the intermediate unsaturated ketones (7) are used in the Hantzsch synthesis of dihydropyridines (8) (eq 4).12

Reactions at the 3- and 4-Positions.

In general, soft nucleophiles react at position 4 and hard nucleophiles react at position 3. For selective reactions at position 4 it may be necessary to protect position 3.

Reactions at Position 4.

Aliphatic13a and aromatic13b thiolate anions and Potassium Thiocyanate13c substitute readily, but with anionic oxygen nucleophiles the substitution is made on the acetoacetate enolate. The 4-t-butoxy derivative is used for the preparation of ethyl 4-t-butoxy-3-hydroxybutanoate (9), a versatile chiral building block (eq 5).14

Substitution with tertiary amines proceeds readily, and the reaction with Trimethylamine provides a synthetic route to carnitine.15 Substitution with primary and secondary amines is best made after protection of the 3-position.

Reaction at Position 3.

Asymmetric reduction of the keto group is accomplished using the Noyori process,16a which allows synthesis of either the (R)- or (S)-4-chloro-3-hydroxybutanoate more efficiently than with biological methods.16b After formation of the acetal (10), selective substitution with hydroxylamine at the 1-position gives a synthetic route17 to the isoxazole pantherine (11) (eq 6).

Acetal (10) can be directly converted to (E)-4-chloro-3-methoxy-2-butenoic acid ester (12). This compound is the reagent of choice for selective substitution at position 4.18 With primary amines, cyclization to form tetramic acids (13) occurs (eq 7).

In contrast, the reaction of alkyl 4-chloroacetoacetates with weakly basic primary and secondary amines yields enamines;19 the enamines from primary amines cyclize to give tetronic acids.20 Enol ether (12) reacts with phosphites to produce Horner-Emmons reagents, useful for carbon chain extension after ylide generation with Sodium Hydride.18

Ring-Closure Reactions.

When alkyl 4-chloroacetoacetates react with bifunctional reagents, various ring closures yielding heterocycles occur.

Retention of the Chloromethyl Group.

Cyclizations with hard dinucleophiles can occur between positions 1 and 3. Thus amidines yield pyrimidines21 and carbamates give oxazinones.23 In this category is the von Pechmann reaction with phenols, which produces coumarins.22 Ring closure between positions 3 and 2 occurs with Chloroacetaldehyde under basic conditions to produce 3-alkoxycarbonyl-2-chloromethylfuran,24 and the Hantzsch synthesis of dihydropyridines also falls in this category.

Loss of the Chloromethyl Group.

The reactions of alkyl 4-chloracetoacetate enolates with isocyanates and isothiocyanates give 2-aminofuranones25 and 2-aminothiophenones,26 respectively. Ring formation between the reactive 3- and 4-positions is well documented, whereby the soft nucleophilic center reacts at position 4. Amides, thioamides, and thiourea give the corresponding 4-oxazolyl- and 4-thiazolylacetic acid esters,27 and 2-aminothiophenol produces a 3,4-dihydro-2H-1,4-benzothiazine.28 Also, direct formation of an indole by reaction of an N-benzylaniline with (1) has been reported.29

Related Reagents.

Also available by bromination of diketene are the corresponding 4-bromoacetoacetates (methyl ester [17790-81-7]; ethyl ester [13176-46-0]), which find similar use in synthesis.1 The 4-iodo- and 4-fluoroacetoacetates are known, but they are of minor importance. See also Acetoacetic Acid; Diketene; Ethyl Acetoacetate; Ethyl 4-(Triphenylphosphoranylidene)acetoacetate; 2,2,6-Trimethyl-4H-1,3-dioxin-4-one.


1. (a) 4-Haloacetoacetic acid Derivatives; Lonza: Visp, Switzerland, 1990. (b) Clemens, R. J. CRV 1986, 241 (c) Beilsteins Handbuch der Organischen Chemie; Springer: Berlin; Vol. 3; H 663, E1 233, E2 426, E3 1207, E4 1550.
2. Rappoport, Z. The Chemistry of Enols; Wiley: New York, 1990; p 365.
3. Lonza AG; U.S. Patent 4 473 508, 1984 (CA 1985, 102, 5715).
4. Taylor, E. C.; Portnoy, R. C. JOC 1973, 33, 806.
5. Lonza AG; Eur. Patent 153 615, 1985 (CA 1986, 104, 148 723).
6. Taylor, E. C.; Dumas, D. J. JOC 1982, 47, 116.
7. Lonza AG; Eur. Patent Appl. 45 005, 1982 (CA 1982, 96, 217 829).
8. Wolfbeis, O. S. CB 1981, 114, 3471.
9. Clauss, K. LA 1980, 494.
10. Takeda; Eur. Patent Appl. 52 299, 1982 (CA 1982, 97, 182 093).
11. Lonza AG; Ger. Offen. 2 313 329, 1973 (CA 1973, 79, 146 065).
12. Gandolfi, C. A.; Frigerio, M.; Zaliani, A.; Riva, C.; Palmisano, G.; Pilati, T. TL 1988, 29, 6335.
13. (a) Int. Flavours: U.S. Patent 4 521 613, 1985 (CA 1985, 103, 87 515). (b) Campaigne, E.; Kim, S. C. JHC 1983, 20, 1697. (c) Perrone, E.; Alpegiani, M.; Giudici, F.; Bedeschi, A.; Pellizzato, R; Nannini, G. JHC 1984, 21, 1097.
14. Seebach, D.; Eberle, M. S 1986, 37.
15. Lonza AG; Ger. Offen. 2 542 196, 1976 (CA 1976, 85, 6052).
16. (a) Noyori, R.; Kitamura, M.; Ohkuma, T.; Takaya, H. TL 1988, 29, 1555. (b) Sih, C. J.; Zhou, B.; Gopalan, A. S., Van Middlesworth, F; Shieh, W.-R. JACS 1983, 105, 5925.
17. Eugster, C. H.; Good, R.; Gagneux, A. R.; Häfliger, F.; Geigy, J. R.; Basle, S. A. TL 1965, 2077.
18. McGarrity, J. F.; Duc, L.; Meul, T.; Warm, A. S 1992, 391.
19. Boosen, K. J. HCA 1977, 60, 1256.
20. Momose, T.; Toyooka, N.; Nishi, T.; Takeuchi, Y. H 1988, 27, 1907.
21. Lonza AG; Ger. Offen. 2 120 247, 1971 (CA 1972, 76, 72 539).
22. Kato, T.; Kimura, H.; Sato, H; Tsuchiya, C.; Chiba, T. CPB 1982, 30, 552.
23. Washburne, S. S.; Park, K. K. TL 1976, 243.
24. Bisagni, E.; Rivalle, C. BSF(2) 1974, 519
25. Georgiev, V. St.; Mack, R. A; Zazulak, W. I.; Radov, L. A.; Baer, J. E.; Stewart, J. D.; Elzer, P. H.; Kinsolving, C. R. JMC 1988, 31, 1910.
26. Faull, A. W.; Hull, R. JCS(P1) 1981, 1078.
27. (a) Sohda, T.; Mizuno, K.; Momose, Y.; Ikeda, H.; Fujita, T.; Meguro, K. JMC 1992, 35, 2617. (b) Hardy, K. D.; Harrington, F. P.; Stachulski, A. V. JCS(P1) 1984, 1227.
28. Trapani, G.; Latrofa, A.; Franco, M.; Liso, G. FES 1990, 45, 577.
29. Cheng, J. F.; Nishiyama, S.; Yamamura, S. CL 1990, 1591.

Barry Jackson

Lonza, Visp, Switzerland



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