Dimethyl Diazomalonate1

[6773-29-1]  · C5H6N2O4  · Dimethyl Diazomalonate  · (MW 158.13)

(carbene or carbenoid precursor;1 cyclopropanation;2 synthesis of oxazoles3 and furans;4 ring expansion;5 deoxygenation of epoxides;6 alkenation;7 C-glycosidation;8 etherification9)

Physical Data: bp 60-61 °C/2 mmHg.

Solubility: sol ether, THF, halocarbon and hydrocarbon solvents.

Form Supplied in: not commercially available.

Preparative Methods: diazomalonates are generally prepared by diazo transfer reaction of malonates and sulfonyl azides.10a A recent modification employs polystyrene-supported trialkylammonium azide (generated in situ) under phase-transfer catalysis conditions and allows for facile isolation.10b

Handling, Storage, and Precautions: dimethyl diazomalonate has been utilized more extensively than has diethyl diazomalonate due to the explosion hazard of the latter. Nonetheless, care should be taken in preparation and handling of dimethyl diazomalonate. Storage at low temperature is recommended. The decomposition of dimethyl diazomalonate evolves nitrogen and can result in high pressures.

Cyclopropanation.

Decomposition of dimethyl diazomalonate by direct photolysis or by transition metal catalysis in the presence of alkenes leads to cyclopropanation (eq 1).2a The use of alkynes to trap the carbenoid species affords cyclopropenes (eq 2).2b Rhodium(II) acetate-catalyzed reaction with allenes allows ready access to methylenecyclopropanes, which form the basis for a methylenecyclopentane annulation protocol (eq 3).2c

Synthesis of Oxazoles and Furans.

Dimethyl diazomalonate reacts with a variety of nitriles in the presence of rhodium(II) acetate to afford 2-substituted 5-methoxy-4-methoxycarbonyl-1,3-oxazoles (eq 4).3 This reaction is fairly general in scope, although cyclopropanation and insertion can be competing processes.

In contrast to the direct photolytic cyclopropanation of alkynes with dimethyl diazomalonate, benzophenone-sensitized photolysis in the presence of alkynes affords furans as the major products in moderate yields (eq 5).4a

An alternative furan synthesis is based upon allylic C-H insertion upon reaction with a ketone-derived enol ether.4b Reduction and hydrolysis affords the furan (eq 6). With aldehyde-derived enol ethers, copper(I) induced reaction with dimethyl diazomalonate yields an alkoxycyclopropane diester, whose reduction, hydrolysis, and oxidation affords a spiro-b-methylene-g-lactone (eq 7).

Ring Expansion.

Sulfonium ylides can be prepared from sulfides and dimethyl diazomalonate under rhodium(II) or copper catalysis. Subsequent [2,3] or [1,2] rearrangement of the ylides derived from cyclic sulfides allows for ring expansion. Examples include the synthesis of cis-thiacyclooctene (eq 8),5a dihydrothiazinones (eq 9),5b and homocephems (eq 10).5c

Deoxygenation of Epoxides.

In the presence of catalytic rhodium(II) acetate, dimethyl diazomalonate deoxygenates epoxides under neutral conditions (eq 11).6 This reaction tolerates functionality such as ketones, esters, alkyl and silyl ethers and halogen substituents, although alcohols and aldehydes undergo competing insertion reactions.

Alkenation.

Alkenation of thiolactones can be achieved by rhodium(II) acetate-catalyzed reaction with dimethyl diazomalonate (eq 12).7a Recently, an efficient alternative alkenation protocol has been demonstrated to be applicable to a variety of ketones and aldehydes by reaction with Tri-n-butylstibine and dimethyl diazomalonate in the presence of Copper(I) Bromide (eq 13).7b This process is proposed to occur via tributylstibonium bis(methoxycarbonyl)methylide.

C-Glycosidation.

Reaction of phenyl thioglycosides with dimethyl diazomalonate in the presence of rhodium(II) acetate allows for the construction of C-glycosyl linkages in moderate yields under neutral conditions (eq 14).8a The methodology is applicable to both thiofuranosides and thiopyranosides. A related insertion process allows for a mild carbon extension of 4-phenylthioazetidinones (eq 15).8b

Etherification.

Rhodium(II) acetate-catalyzed O-H insertion of dimethyl diazomalonate is exceedingly facile, resulting in an efficient, neutral etherification in the presence of other sensitive functionality (eq 16).9


1. (a) Regitz, M.; Maas, G. Diazo Compounds: Properties and Synthesis; Academic: Orlando, 1986. (b) Peace, B. W.; Wulfman, D. S. S 1973, 137. See also Adams, J.; Spero, D. M. T 1991, 47, 1765.
2. (a) Wulfman, D. S.; Peace, B. W.; Steffen, E. K. CC 1971, 1360. (b) Maier, G.; Wolf, B. S 1985, 871; see also Ref. 4a. (c) Singleton, D. A.; Huval, C. C.; Church, K. M.; Priestley, E. S. TL 1991, 32, 5765.
3. Connell, R.; Scavo, F.; Helquist, P.; Akermark, B. TL 1986, 27, 5559.
4. (a) Hendrick, M. E. JACS 1971, 93, 6337. (b) Wenkert, E.; Alonso, M. E.; Buckwalter, B. L.; Chou, K. J. JACS 1977, 99, 4778.
5. (a) Vedejs, E.; Hagen, J. P.; Roach, B. L.; Spear, K. L. JOC 1978, 43, 1185. (b) Crow, W. D.; Gosney, I.; Ormiston, R. A. CC 1983, 643. (c) Morin, J. M.; Spry, D. O.; Elzey, T. K.; Kinnick, M. D.; Paschal, J. W.; Snyder, N. J. H 1990, 31, 1423.
6. Martin, M. G.; Ganem, B. TL 1984, 25, 251.
7. (a) Honda, T.; Ishige, H.; Araki, J.; Akimoto, S.; Hirayama, K.; Tsubuki, M. T 1992, 48, 79. See also Takano, S.; Tomita, S.; Takahashi, M.; Ogasawara, K. S 1987, 1116. (b) Liao, Y.; Huang, Y.-Z. TL 1990, 31, 5897.
8. (a) Kametani, T.; Kawamura, K.; Honda, T. JACS 1987, 109, 3010. (b) Prassad, K.; Kneussel, P.; Schulz, G.; Stutz, P. T 1982, 23, 1247. Kametani, T.; Kanaya, N.; Mochizuki, T.; Honda, T. H 1982, 19, 1023.
9. (a) Ganem, B.; Ikota, N.; Muralidharan, V. B.; Wade, W. S.; Young, S. D.; Yukimoto, Y. JACS 1982, 104, 6787. (b) Paulissen, R.; Reimlinger, H.; Hayez, E.; Hubert, A. J.; Teyssie, P. TL 1973, 2233.
10. (a) Regitz, M. S 1972, 351. (b) Kumar, S. M. SC 1991, 21, 2121.

James E. Audia & James J. Droste

Eli Lilly & Company, Indianapolis, IN, USA



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