Methyl Diazoacetate1

[6832-16-2]  · C3H4N2O2  · Methyl Diazoacetate  · (MW 100.09)

(cyclopropanation of alkenes;2,3 cyclopropenation of alkynes;4 addition to aromatic substrates;5,6 insertion into polar X-H bonds;7 condensation with carbonyls;8 1,3-dipolar cycloaddition with enamines9 and alkynes,10 yielding substituted pyrazolines and pyrazoles)

Physical Data: bp 39-43 °C/10 mmHg.

Solubility: sol diethyl ether, dichloromethane, chloroform, benzene.

Preparative Method: from methyl glycinate hydrochloride and sodium nitrite upon treatment with a 5% solution of sulfuric acid.11

Handling, Storage, and Precautions: extreme caution should be exercised in handling methyl diazoacetate since it is thermally unstable and has been found to detonate if heated rapidly or overheated (do not expose to temperatures >50 °C), emitting toxic fumes of NOx. Diazo esters are also toxic and should be handled in a well-ventilated fume hood.

Cyclopropanation.

Under catalytic conditions, methyl diazoacetate readily forms an ester carbenoid which adds to a variety of alkenes, yielding cyclopropyl esters. Dirhodium(II) Tetraacetate effectively catalyzes the addition of methyl diazoacetate to cis-2-octene.2 Substituted conjugated dienes can be selectively cyclopropanated with methyl diazoacetate.12 The observed regio- and stereoselectivity is determined by the choice of catalyst and the electronic characteristics of the diene. The enantioselective cyclopropanation of an alkene with methyl diazoacetate can be achieved with the use of a chiral catalyst.13 Methyl diazoacetate reacts under copper catalysis with the trimethylsilyl enol ether of cyclopentanone to give a silyloxycyclopropane. Treatment with a fluoride source yields a 1,4-keto ester (eq 1).14,15

2-(Trimethylsilyloxy)buta-1,3-diene can be cyclopropanated in a regioselective manner with methyl diazoacetate and Copper(II) Acetylacetonate. Subsequent nucleophilic addition of methanol yields methyl 6-methoxy-4-oxohexanoate in excellent yield (eq 2).16

A number of 6- or 7-functionalized 4-oxoalkanoates can be prepared utilizing this protocol with a variety of Michael adducts. Methyl diazoacetate addition to Allyltrimethylsilane followed by treatment with Tetra-n-butylammonium Fluoride yields methyl 4-pentenoate (eq 3).17 Cyclopropyl boronates18 and cyclopropyl amines19 can also be prepared from methyl diazoacetate under catalytic conditions.

The addition of the methyl diazoacetate-derived carbene to benzene gives rise to methyl cyclohepta-2,4,6-triene-1-carboxylate with a high degree of selectivity (eq 4).5 The rhodium-catalyzed addition to substituted phenyls yields an isomeric mixture of products. In addition to substituted phenyls, methyl diazoacetate can add to various aromatic hetrocycles.6

Cyclopropenation.

Cyclopropenyl esters are formed by the addition of methyl diazoacetate to various alkynes using Rh(OAc)2 as the catalyst.20 This cyclopropenation protocol is incompatible with alkynic alcohols (eq 5).4 The catalyzed insertion of methyl diazoacetate into the O-H bond successfully competes with cyclopropene formation. High enantioselectivity can be achieved in a cyclopropenation with the use of a chiral dirhodium(II) carboxylate.21

Insertion.

The insertion of methyl diazoacetate into the X-H bond (where X = S or O) is catalyzed efficiently with rhodium carboxylates.7,22 The catalyzed insertion into allyl alcohol yields an a-alkoxy ester (eq 6).23 Mild selectivity can be achieved over a competitive cyclopropanation with an appropriate catalyst.

Condensation.

Lewis acid-catalyzed addition of methyl diazoacetate to an aldehyde provides a convenient method for the preparation of a 1,3-dicarbonyl. Treatment of 2,3-O-isopropylidene-D-glyceraldehyde with methyl diazoacetate yielded methyl (4R)-4,5-O-isopropylidene-3-keto-4,5-dihydroxypentanoate in good yield (eq 7).24

1,3-Dipolar Cycloaddition.

The uncatalyzed 1,3-dipolar cycloaddition of methyl diazoacetate with a suitable dipolarophile yields a substituted pyrazoline or pyrazole.9,10,25 N-(1-Cyclohexenyl)pyrrolidine reacts with methyl diazoacetate, yielding a pyrazoline which eliminates pyrrolidine to give a pyrazole in excellent yield (eq 8).

Related Reagents.

Diazoacetaldehyde; Diazoacetone; Dimethyl Diazomalonate; Ethyl Diazoacetate.


1. (a) Adams, J.; Spero, D. M. T 1991, 47, 1765. (b) Carbene Chemistry; Kirmse, W.; Ed.; Organic Chemistry; Academic: New York, 1971; Vol. 1. (c) Diazo Groups Properties and Synthesis; Regitz, M.; Maas, G, Ed.; Academic: New York, 1986. (d) The Chemistry of Diazonium and Diazo Groups; Patai, S., Ed.; The Chemistry of Functional Groups; Wiley: New York, 1978; Parts 1 and 2.
2. Hubert, A. J.; Noels, A. F.; Anciaux, A. J.; Petiniot, N.; Teyssie P. JOC 1980, 45, 695.
3. Kutney, J. P.; Choudhury, M. K.; Decesare, J. M.; Jacobs, H.; Singh, A. K.; Worth, B. R. CJC 1981, 59, 3162.
4. Petiniot, N.; Anciaux, A. J.; Noels; A. F.; Hubert, A. J.; Teyssie, Ph. TL 1978, 1239.
5. (a) Anciaux, A. J.; Demonceau, A.; Hubert, A. J.; Noels, A. F.; Petiniot, N.; Teyssie P. CC 1980, 765. (b) Anciaux, A. J.; Demonceau, A.; Hubert, A. J.; Noels, A. F.; Warin, R.; Teyssie P. JOC 1981, 46, 873.
6. Kurihara, T.; Kawasaki, E; Nasu, K. H 1983, 20, 1913.
7. Paulissen, R.; Hayez, E.; Hubert, A. J.; Teyssie, P. TL 1974, 607.
8. Medvedeva, A. S. Demina, M. M.; Borisova, A. I.; Margorskaya, O. I.; Kalikhman, I. D.; Bodskaya, E. I.; Vyazankin, N. S. JOM 1982, 231, 109.
9. Reissig, H. U.; Huisgen, R. AG 1979, 91, 346 (CA 1979, 90, 203 944s).
10. Mass, G.; Regitz, M.; Moll, U.; Rahm, R.; Krebs, F.; Hector, R.; Stang, P. J.; Crittell, C. M.; Williamson, B. L. T 1992, 48, 3527.
11. Womack, E. B.; Nelson, A. B. In Organic Synthesis; Horning, E. C.; Ed.; Wiley: New York, 1955; Vol. 3, p 392.
12. Demonceau, A.; Noels, A. F.; Anciaux, A. J.; Hubert A. J.; Teyssie, P. BSB 1984, 93, 949.
13. Reissig, H. U.; Kunz, T. TL 1989, 2079.
14. Reissig, H. U.; Hirsch, E. AG 1980, 92, 839 (CA 1981, 94, 30 221f).
15. (a) Reissig, H. U.; Reichelt, I.; Kunkel, E. LA 1984, 512 (CA 1984, 101, 72 794p). (b) Reissig, H. U.; Radunz, H. E.; Schneider, G.; Riethmueller, A. LA 1990, 705 (CA 1990, 113, 59 810u).
16. Reissig, H. U.; Zschiesche, R.; Grimm, E. L. JOC 1985, 50, 5543.
17. Reissig, H. U.; Reichelt, I. LA 1984, 828 (CA 1984, 100, 209 980x).
18. (a) Carboni, B.; Fontani, P.; Vaultier, M.; Carrie, R. TL 1989, 4815. (b) Carboni, B.; Fontani, P.; Vaultier, M.; Mass, G. S 1991, 605.
19. Reissig, H. U.; Paulini, K. LA 1991, 455 (CA 1991, 115, 9263p)
20. Shapiro, E. A.; Kalinin, A. V.; Nefedov, O. M. OPP 1992, 24, 517.
21. Doyle, M. P.; Protopopova, M. N. JACS 1992, 114, 2755.
22. Hlavacek, J.; Kral, V. CCC 1992, 57, 525.
23. Noels, A. F.; Demonceau, A.; Petiniot, N.; Hubert, A. J.; Teyssie, P. T 1982, 38, 2733.
24. Lopez-Herrera, F. J.; Valpuesta-Fernandez, M.; Garcia-Claros, S. T 1990, 46, 7165.
25. (a) Sandhu, J. S.; Boruah, R. C. S 1982, 677. (b) Sandhu, J. S, Devi, P. CC 1983, 990.

James J. Droste & James E. Audia

Eli Lilly and Co., Indianapolis, IN, USA



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