a-Diazoacetophenone1

[3282-32-4]  · C8H6N2O  · a-Diazoacetophenone  · (MW 146.16)

(precursor to carbenes and carbenoids;2 reagent for preparation of sulfonium,3 oxonium,4 and pyridinium5 ylides; 1,3 dipole for heterocycle synthesis;6 reagent for Lewis acid or transition metal-mediated insertion reactions;7 reagent for cyclopropanation of alkenes8 and for aromatic annulation9)

Physical Data: pale yellow rods, mp 49-50 °C.

Solubility: sol ether, THF; slightly sol pentane.

Form Supplied in: not commercially available.

Preparative Methods: an improved method of synthesis of diazo ketones has been recently published, via acylation of the lithium enolate of the ketone with 2,2,2-Trifluoroethyl Trifluoroacetate and subsequent reaction with Methanesulfonyl Azide.10 Alternatively, acylation of diazomethane with aroyl chlorides in the presence of triethylamine provides a general method for the synthesis of aromatic diazo ketones.11

Handling, Storage, and Precautions: diazoacetophenone is a skin irritant; therefore direct contact should be avoided. Diazoacetophenone has shown microbial mutagenicity.

Ylide Formation.

Diazoacetophenone (and other diazo ketones) react under copper catalysis with sulfides to form sulfonium ylides, which may be trapped with electron-deficient alkenes for cyclopropanation (eq 1).3a Sulfonium ylides are also available by acid-catalyzed reaction with sulfides, followed by base treatment.3b Applied to cyclic sulfides, the ylides so formed can undergo [2,3]-rearrangement, allowing for ring expansion (eq 2).3c

In a similar fashion, oxonium ylides, formed by rhodium(II)-catalyzed decomposition of diazoacetophenone in the presence of methyl allyl and methyl propargyl ethers, undergo [2,3]-rearrangement to provide methoxy keto alkenes (eq 3)4a and allenes (eq 4).4b Rhodium(II) perfluorobutyrate is often the preferred catalyst to minimize competing cyclopropanation.

Decomposition of diazoacetophenone in the presence of 2-(methylthio)pyridine affords the pyridinium ylide, which undergoes 1,3-dipolar cycloadditions with a variety of dipolarophiles (eq 5).5

Heterocycle Formation.

Diazoacetophenone reacts with nitriles under Lewis acid (eq 6) or transition metal (eq 7) catalysis to afford oxazoles.6a,b

Alternatively, diazoacetophenone reacts with unsaturated nitriles and esters under pyridine catalysis to yield pyrazolines. The nitrile-derived pyrazolines undergo alkoxide-induced elimination of HCN to afford the 3-benzoylpyrazoles (eq 8).6c A variety of activated alkenes, including enamines,6d and vinyltriphenylphosphonium salts,6e can be readily converted to the corresponding pyrazolines and pyrazoles with diazoacetophenone (eq 9). Additionally, treatment of formamidines with diazoacetophenone affords the 4-benzoyl-1,2,3-triazole (eq 10).12

Insertion Reactions.

Diazoacetophenone (and other diazo ketones) reacts with a variety of compounds containing acidic X-H bonds under Lewis acid and transition metal catalysis. Included are alcohols,7a thiols,7b and trialkylsilanes (eq 11).7c The latter forms a general synthesis of a-silylacetophenone (and a-silyl ketones). In similar fashion, diazoacetophenone reacts with trialkylboranes affording, selectively, the (E)-enol boronates (eq 12).7d

Cyclopropanation.

Diazoacetophenone is effective in transition metal-mediated cyclopropanation of a variety of alkenic compounds. For electron-deficient alkenes, molybdenum catalysts favor cyclopropane formation over competing pyrazoline formation (eq 13).8a Reaction with vinylboronic acid esters follows in similar fashion, with Palladium(II) Acetate as the catalyst of choice for the formation of benzoylcyclopropylboronic acid esters (eq 14).8b

Aromatic Annulation.

Diazo ketones have been utilized in a novel aromatic annulation protocol. The use of diazoacetophenone in this fashion allows for the conversion of alkynes into naphthol derivatives (eq 15).9

Related Reagents.

Diazoacetaldehyde; Diazoacetone; Ethyl Diazoacetate; Methyl Diazoacetate.


1. Regitz, M.; Maas, G. Diazo Compounds: Properties and Synthesis; Academic: Orlando, 1986.
2. Doyle, M. P.; Devia, A. H.; Bassett, K. E.; Terpstra, J. W.; Mahapatro, S. N. JOC 1987, 52, 1619.
3. (a) Quintana, J.; Torres, M.; Serratosa, F. T 1973, 29, 2065. (b) Flowers, W. T.; Holt, G.; Hope, M. A. JCS(P1) 1974, 1116. (c) Vedejs, E.; Hagen, J. P.; Roach, B. L.; Spear, K. L. JOC 1978, 43, 1185.
4. (a) Doyle, M. P.; Bagheri, V.; Harn, N. K. TL 1988, 29, 5119. (b) Doyle, M. P.; Bagheri, V.; Claxton, E. E. CC 1990, 46.
5. Padwa, A.; Austin, D. J.; Precedo, L.; Zhi, L. JOC 1993, 58, 1144.
6. (a) Doyle, M. P.; Buhro, W. E.; Davidson, J. G.; Elliot, R. C.; Hoekstra, J. W.; Oppenhuizen, M. JOC 1980, 45, 3657. (b) Ibata, T.; Fukushima, K. CL 1992, 2197. (c) Doyle, M. P.; Colsman, M. R.; Dorow, R. L. JHC 1983, 20, 943. (d) Huisgen, R.; Reissig, H-U.; Huber, H.; Voss, S. TL 1979, 2987. (e) Schweizer, E. E.; Labaw, C. S. JOC 1973, 36, 3069.
7. (a) Yates, P. JACS 1952, 74, 5376. (b) Bagheri, V.; Doyle, M. P.; Taunton, J.; Claxton, E. E. JOC 1988, 53, 6158. (c) McKervey, M. A.; Ratananukul, P. TL 1983, 24, 117. McKervey, M. A.; Ratananukul, P. TL 1982, 23, 2509. (d) Pasto, D. J.; Wojtkowski, P. W. JOC 1971, 36, 1790. Mukaiyama, T.; Inomata, K.; Muraki, M. JACS 1973, 95, 967. Hooz, J.; Bridson, J. N. JACS 1973, 95, 603. Masamune, S.; Mori, S.; Van Horn, D.; Brooks, D. W. TL 1979, 1665.
8. (a) Doyle, M. P.; Dorow, R. L.; Tamblyn, W. H. JOC 1982, 47, 4059. (b) Fontani, P.; Carboni, B.; Vaultier, M.; Maas, G. S 1991, 605.
9. Danheiser, R. L.; Brisbois, R. G.; Kowalczyk, J. J.; Miller, R. F. JACS 1990, 112, 3093.
10. Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S. Z. JOC 1990, 55, 1959.
11. Bridson, J. N.; Hooz, J. OS 1973, 53, 35.
12. Regitz, M.; Schoder, W. S 1985, 178.

James E. Audia & James J. Droste

Eli Lilly, Indianapolis, IN, USA



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