Dimethyl Bromomalonate

(1; R = Me)

[868-26-8]  · C5H7BrO4  · Dimethyl Bromomalonate  · (MW 211.02) (2; R = Et)

[685-87-0]  · C7H11BrO4  · Diethyl Bromomalonate  · (MW 239.08) (3; R = t-Bu)

[15960-79-9]  · C11H19BrO4  · Di-t-Butyl Bromomalonate  · (MW 295.20)

(cyclopropanation of Michael acceptors;1,2 synthesis of vinylogous urethanes from thioamides via the Eschenmoser sulfide contraction3-5)

Physical Data: (1) bp 112.5-113 °C/15 mmHg.6 (2) bp 150-152 °C/25 mmHg.6 (3) bp 120-125 °C/11 mmHg.7

Form Supplied in: (1) technical grade, ~90% purity; (2) technical grade, 85-95% purity, contains varying amounts of diethyl malonate and diethyl dibromomalonate.

Analysis of Reagent Purity: (1) 1H NMR (CDCl3) d 3.85 (6H, s), 4.87 (1H, s);8 (2) 1H NMR (CCl4) d 1.34 (6H, t, J = 7 Hz), 4.28 (4H, q, J = 7 Hz), 4.72 (1H, s); IR (CCl4) 1750 cm-1; (3) 1H NMR (CDCl3) d 1.45 (18H, s), 4.6 (1H, s);9 13C NMR (CDCl3) d 27.4, 45.4, 83.5, 163.3;9 IR (KBr) 1756 cm-1;9 IR (CCl4) 1765, 1740 cm-1;10 IR (film) 1735 cm-1.4

Preparative Methods: (1): by treatment of Malonic Acid with Bromine in diethyl ether followed by esterification with HCl in methanol;11 by electrolytic bromination of dimethyl malonate with Magnesium Bromide or Copper(II) Bromide and Sodium Methoxide in acetonitrile-water at 2-3 °C.12 (2): by light-induced bromination of Diethyl Malonate with bromine in carbon tetrachloride;13 by treatment of diethyl malonate with bromotrichloromethane and 1,8-Diazabicyclo[5.4.0]undec-7-ene in benzene at 0 °C.14 (3): by bromination of Malonic Acid with bromine in diethyl ether at rt followed by sulfuric acid catalyzed esterification with Isobutene in diethyl ether at rt;7 by bromination of di-t-butyl malonate with bromine and Calcium Carbonate in chloroform at rt followed by reflux;7 by lithiation of di-t-butyl malonate with n-Butyllithium in THF at -78 °C followed by addition of bromine and allowing reaction to warm to rt;10 by lithiation of di-t-butyl malonate with n-butyllithium in THF at -78 °C, addition of Chlorotrimethylsilane, warming to rt, and treatment of the resulting trimethylsilyl ketene acetal solution with bromine in carbon tetrachloride.4

Cyclopropanation.

Bromomalonates react with Michael acceptors (a,b-unsaturated aldehydes, ketones, esters, and nitriles) under basic conditions to yield cyclopropane-1,1-dicarboxylic esters (eqs 1 and 2). Sodium1,15 or potassium alkoxides,10 1,1,3,3-Tetramethylguanidine,10 Potassium Carbonate,16 Diisopropylethylamine,2 and Cesium Fluoride or Potassium Fluoride17 have been used as bases in this reaction.

Eschenmoser Sulfide Contraction.

Thioamides react with bromomalonates under mild conditions to give vinylogous urethanes (eq 3).3,4,5 In some cases, the addition of a phosphine is unnecessary because the intermediates spontaneously extrude sulfur.3,5 The Battersby group has made extensive use of this process, followed by ester hydrolysis and decarboxylation, as a method for introduction of a methyl group in studies of vitamin B12 biosynthesis.4,18 Use of 2-13C labeled di-t-butyl bromomalonate (prepared from 13CH3CO2H) allows introduction of a 13C-labeled methyl group.18d

N-, O-, and S-Alkylation.

Amino-, aryloxy-, and thiomalonates can be prepared by alkylation of amines,7,8,11,19 phenols,6,20 and thiols,21 respectively, with bromomalonates (eq 4).

Other Applications.

MnIII-promoted radical additions of dimethyl bromomalonate to alkenes give (b-bromoalkyl)malonates (eq 5).22 A Wittig-type alkenation of aldehydes can be accomplished with Tri-n-butylstibine and bromomalonates (eq 6).23 Bromomalonates can also serve as oxidizing agents, probably by acting as Br+ donors (eq 7).24


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19. (a) Balsiger, R. W.; Fischer, R. W.; Hirt, R.; Giovannini, E. HCA 1953, 36, 708. (b) Lattrell, R.; Lohaus, G. LA 1974, 921. (c) de Jong, F.; van Zon, A.; Reinhoudt, D. N.; Torny, G. J.; Tomassen, H. P. M. RTC 1983, 102, 164. (d) Venuti, M. C.; Jones, G. H.; Alvarez, R.; Bruno, J. J. JMC 1987, 30, 303. (e) Maier, L. PS 1988, 36, 1. (f) Heckendorn, R. HCA 1990, 73, 1700.
20. (a) Kraus, R.; Spiteller, G. Biol. Mass Spectrom. 1991, 20, 53. (b) Gabriel, G.; Pickles, R.; Tyman, J. H. P. JCR(S) 1989, 348.
21. Hakimelahi, G. H.; Just, G. TL 1980, 21, 2119.
22. Nédélec, J. Y.; Nohair, K. SL 1991, 659.
23. Chen, C.; Huang, Y.-Z.; Shen, Y.; Liao, Y. HC 1990, 1, 49.
24. (a) Docken, A. M. JOC 1981, 46, 4096. (b) Kavinde, M. N.; Kelkar, R. M.; Paradkar, M. V. SC 1993, 23, 961.

William J. Frazee

Zeneca Pharmaceuticals, Wilmington, DE, USA



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