Diazoacetone1

[2684-62-0]  · C3H4N2O  · Diazoacetone  · (MW 84.09)

(cyclopropanation of alkenes,2 furans,3 and oxy alkenes;4 condensation with carbonyls5,6 and organoboranes;7 1,3-dipolar cycloaddition with acrylates8 and alkynes,9 yielding substituted pyrazolines and pyrazoles)

Physical Data: bp 49 °C/13 mmHg.

Solubility: sol diethyl ether, THF, DME, methanol, cyclohexane, benzene.

Preparative Methods: diazoacetone is not commercially available, but can be prepared from Acetyl Chloride and Diazomethane.10 An alternative method for preparation involves an alkaline acyl cleavage of 3-diazo-2,4-pentanedione.11

Handling, Storage, and Precautions: diazo ketones are known to be unstable at elevated temperatures (>50 °C) and should be handled in a fume hood. The health risks associated with diazoacetone have not been evaluated. At low temperatures diazoacetone can be stored without significant decomposition.

Cyclopropanation.

The metal-catalyzed decomposition of diazoacetone generates a reactive carbenoid species which readily adds to a variety of alkenes. This reaction can give rise to a cyclopropyl ketone in moderate yield or subsequently furnish a rearranged product. The catalyzed reaction between diazoacetone and a suitable alkene is often carried out neat or with cyclohexane as the solvent. The generation of the keto carbenoid with anhydrous Copper(II) Sulfate in cyclohexene is accompanied by rapid addition to the alkene (eq 1).2 Diazoacetone addition to 1-ethoxycyclohexene is catalyzed efficiently with Copper Bronze at 90 °C for 2 h. Aqueous acid hydrolysis and ring opening yields a 1,4-diketone.12 Addition of diazoacetone to furan, also catalyzed by copper bronze, furnishes a cross-conjugated dicarbonyl (eq 2).3

The catalyzed reaction of diazoacetone with the trimethylsilyl enol ether of cyclohexanone affords a regiospecific silyl enol ether formed through a silatropic retro-aldol (eq 3).13 Cyclopropanation of a methyl enol ether in the presence of copper bronze yields a b-methoxycyclopropyl ketone.14 Subsequent acid hydrolysis yields a 1,4-keto aldehyde (eq 4). The catalytic reaction between diazoacetone and 1-methoxy-1,3-butadiene provides only mild regioselectivity, with the predominant formation of the nonoxygenated cyclopropane.15

In addition to alkenes, diazoacetone can undergo catalytic insertion into a number of carbenoid acceptors. A substituted dihydrofuran is synthesized by the Copper(II) Acetylacetonate-catalyzed insertion of diazoacetone into a ketene dimethyl acetal.16 A benzyl ketone is obtained by the Rh2(O2CCF3)4-catalyzed addition of diazoacetone to benzene.17 Cyclopropenes are formed through either catalytic or photolytic insertion into alkynes.18,19

Condensation.

Treatment of diazoacetone with Silver(I) Oxide in diethyl ether generates a diazomethyl carbon nucleophile that adds to most electrophiles in moderate to poor yields.20 An improved result is seen with the condensation between diazoacetone and a ketone or aldehyde, conveniently effected under basic conditions to yield an a-diazo-b-hydroxycarbonyl.5 1,3-Diketones can be readily formed by the addition of 1-diazo-1-lithioacetone to an aldehyde followed by a catalytic transformation with Rh2(OAc)4 (eq 5).21 This condensation process is quite efficient with excellent yields obtained for a variety of aldehydes. 1-Diazo-1-lithioacetone also reacts with lactones and thiolactones to give the corresponding diazo alcohol or diazo thiol. The respective 2-substituted 3-oxepanone or 2-substituted 3-thiopanone is formed upon heating in benzene with a catalytic amount of Rh2(OAc)4 (eq 6).6,22

The addition of diazoacetone to an organoborane provides a convenient method for a three-carbon homologation of an alkene, via an organoborane, to a ketone or regiospecific enol borane.7,23 This enol borane can be mono a-alkylated with certain electrophiles in the presence of lithium dimethylaminoethoxide (eq 7). Di- and polyalkylation products are not observed, nor is alkylation of the methyl terminus.

An a-alkoxy ketone or an a-thioketone is prepared by the insertion of the keto carbenoid of diazoacetone into the O-H or S-H bond of an alcohol or thiol.24,25

1,3-Dipolar Cycloaddition.

Diazoacetone can undergo an uncatalyzed 1,3-dipolar cycloaddition with a variety of dipolarophiles to yield pyrazoles or pyrazolines.8,9,26 Reaction with an a-substituted acrylate under mild conditions yields a 3,5,5-trisubstituted pyrazoline in good yield (eq 8).27

Related Reagents.

Diazoacetaldehyde; a-Diazoacetophenone; Ethyl Diazoacetate; Methyl Diazoacetate.


1. (a) Adams, J.; Spero, D. M. T 1991, 47, 1765. (b) Carbene Chemistry; Kirmse, W., Ed.; Academic: New York, 1971; Vol. 1. (c) The Chemistry of Diazonium and Diazo Groups; Patai, S. Ed.; Wiley: New York, 1978; Part 1 and Part 2. (d) Regitz, M.; Maas, G. Diazo Groups Properties and Synthesis; Academic: New York, 1986.
2. Sorm, F.; Sneberk; V.; Ratusky, J.; Novak, J. CCC 1957, 22, 1836 (CA 1959, 51, 10 508e).
3. Sorm, F.; Novak, J. CCC 1958, 23, 1126 (CA 1960, 52, 4480h).
4. Wenkert, E. ACR 1980, 13, 27.
5. (a) Wenkert, E.; McPherson, A. C. JACS 1972, 94, 8084. (b) Schollkopf, U.; Banhidai, B.; Frasnelli, H.; Meyer, R.; Beckhaus, H. LA 1974, 1767 (CA 1975, 82, 155 228x).
6. Moody, T. J.; Davies, M. J.; Taylor, R. J. SL 1990, 93.
7. Hooz, J.; Linke, S. JACS 1968, 90, 5936.
8. Guha, P. C.; Muthanna, M. S. CB 1938, 71, 2665 (CA 1940, 32, 49695).
9. Rodina, L. L.; Bulusheva, V. V.; Ekimova, T. G.; Korobitsyna, I. K. ZOR 1974, 10, 55 (CA 1974, 80, 146 070w).
10. Arndt, F.; Amende, J. CB 1928, 61, 1122 (CA 1929, 24, 3985).
11. Wolff, L. LA 1912, 394, 23 (CA 1912, 7, 787).
12. Wenkert, E.; McPherson, C. A.; Sanchez, E. L.; Webb, R. SC 1973, 3, 255.
13. Coates, R. M.; Sandefur, L. O.; Smillie, R. D. JACS 1975, 97, 1619.
14. Wenkert, E.; Buckwalter, B. L.; Craveiro, A. A.; Sanchez, E. L.; Sathe, S. S. JACS 1978, 100, 1267.
15. Wenkert, E.; Goodwin, T. E.; Ranu, B. C. JOC 1977, 42, 2137.
16. Scarpati, R.; Iesce, R. M.; Graziano, L. M. JHC 1986, 23, 553.
17. McKervey, A. M.; Russell, N. D.; Twohig, F. M. JCS(C) 1985, 491.
18. Vidal, M.; Vincens, M.; Arnaud, P. BSF(2) 1972, 657 (CA 1972, 76, 152 986h).
19. Nefedov, O. M.; Dolgii, I. E.; Baidzhigitova; E. A. IZV 1975, 2842 (CA 1976, 84, 121 933z).
20. Schollkopf, U.; Rieber, N. CB 1969, 102, 488 (CA 1969, 70, 86 980z).
21. (a) Pellicciari, R.; Fringuelli, R.; Sisani, E. JCS(P1) 1981, 2566. (b) Eguchi, Y.; Sasaki, F.; Takashima, Y.; Nakajima, M.; Ishikawa, M. CPB 1991, 39, 795.
22. Moody, T. J.; Taylor, R. J. T 1990, 46, 6501.
23. (a) Masamune, S.; Mori, S.; Van Horn, D.; Brooks, D. W. TL 1979, 1665. (b) Hooz, J.; Oudenes, J. SC 1980, 10, 139.
24. Sorm, F.; Jarolim, V. CCC 1973, 39, 587.
25. McKervey, A. M.; Ratananukul, P. TL 1982, 2509.
26. Sabate-Alduy, C.; Bastide, J.; Bercot, P. BSF(2) 1976, 1841 (CA 1977, 87, 23 137k).
27. Ghandour, N. E.; Soulier, J. CR(C) 1971, 272, 243 (CA 1971, 74, 111 964q).

James J. Droste & James E. Audia

Eli Lilly, Indianapolis, IN, USA



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