MAGNESIUM ETHYL MALONATE 1

Magnesium Ethyl Malonate1 O

O
O
O O
Mg2+ +
EtO O H3O
O (3)
DMF, 60 C, 4 h CO2 94%

O CO2Et CO2Et
Mg2+
EtO O
O O
1. (1), DMF, 80 C
[64679-38-5] C5 H6 MgO4 (MW 154.42) (4)
2. AcOH, 100 C, 18 h
InChI = 1/C5H8O4.Mg/c1-2-9-5(8)3-4(6)7;/h3,8H,2H2,1H3, 81%
CO2Et
(H,6,7);/q;+2/p-2/b5-3+;/fC5H6O4.Mg/h8h;/q-2;m
InChIKey = LCJYBSLHGBKLHC-GRFIJMJEDS (1)
CO2Et
NO2 (5)
Ph NO2
(reagent for conjugate addition to ,-unsaturated carbonyl com- 85%
Ph
pounds followed by in situ decarboxylation to give 1,5 keto-
esters;2 conjugate addition to other functionality;2 acylation of O O
active esters1,3 )
(1)
(6)
Alternate Name: MEM. 56%
Cl
Physical Data: high melting solid salt; ethanol complex.
CO2Et
Solubility: sol DMF; slightly sol THF.
Form Supplied in: off-white solid or slurry in THF.
Analysis of Reagent Purity: 1 H NMR. O O (1) EtO2C O O
Drying: azeotrope with benzene or toluene; high vacuum. (7)
77%
Handling, Storage, and Precautions: hygroscopic solid; stable O O O O
for at least several weeks as a solid or slurry in dry THF. EtO2C EtO2C

Introduction. Magnesium ethyl malonate (1) undergoes Acylations. Magnesium ethyl malonate adds the acetic es-
conjugate addition reactions with ,-enones and other activated ter residue to activated carboxylic acid derivatives, acid chlo-
alkenes,2 as well as acylation of active esters.1,3 Decarboxylation rides (eq 8),1,3a acyl imidazolides (eqs 912),1,3bf and mixed
occurs upon neutralization with acetic acid or during workup, anhydrides (eq 11).3b Decarboxylation is more facile after acyla-
affording a single-step addition of an acetic ester residue. Ethyl tion with (1) than after conjugate addition and does not require
Malonate reacts with magnesium metal turnings in ethanol to give prolonged treatment after neutralization with acetic acid.
(1), a basic salt, complexed with 1 equiv of ethanol (eq 1) or with
isopropylmagnesium bromide to form a bromide complex.1 O CO2Et
R COCl (1), THF R
O (8)
CH2Cl2
R R R R
CO2H Mg, EtOH O
Mg2+ (1)
70 C, 2 h O O
CO2Et EtO O
CO2Et
(1) N N (1), THF
(9)
O N reflux, 4 h O N
Dilithio ethyl malonate undergoes alkylation with alkyl halides
and subsequent decarboxylation (eq 2).4 Little or no reaction Ph Ph
occurs with ketones or enones.
O
1. CDI, THF
O RX
R R
(10)
Li+ RCH2CO2Et (2) 2. (1), 18 h, rt
O CO2H
EtO Li+
O CO2Et
R = H (91%), Ph (78%)
Conjugate Additions. As the magnesium salt, (1) gives ex-
O O
clusive conjugate, 1,4 addition to ,-enones, probably due to CO2Et
the reversibility of 1,2-addition (eq 3).2 Steric hindrance at either R
(1), THF
the - or -position can inhibit addition of (1) and starting mate- (11)
rt, 18 h N
rial is then recovered.2 Conjugate addition of (1) to 6-methyl-2- N
cyclohexenone occurs with stereoselection (axial attack) (eq 4).5 O O
Other ,-unsaturated electron-withdrawing groups give conju- R = OCO2Et (50%), N N (73%)
gate addition with (1) (eqs 57).2,6

Avoid Skin Contact with All Reagents

2 MAGNESIUM ETHYL MALONATE

OHC O
1. (1), DMF CO2H 1. Mg(OEt)2
60 C, 3 d R1 CO2Me
R2 (15)
CO2Me 2. R2COIm R1
N 2. AcOH, 80 C, 2 d
O R1 = H, Me
OHC CO2Et
CO2Et
Related Reagents. Bis(trimethylsilyl) Malonate; Diethyl-
+ (12)
Ethoxymagnesiomalonate; Diethyl Malonate; 2,2-Dimethyl-1,3-
N N
dioxane-4,6-dione; Ethyl Bromozincacetate; Ethyl Lithioac-
O O
31% 38%
etate; Ethyl Lithio(trimethylsilyl)acetate; Ethyl Malonate; Ethyl
Trimethylsilylacetate; Ethyl Trimethylsilyl Malonate.

Electrophiles such as (methylthio)alkylideniminium salts react

with (1) to give the expected addition products (eq 13).7 1. (a) Ireland, R.; Marshall, J., J. Am. Chem. Soc. 1959, 81, 2907. (b) Bram,
G.; Vilkas, M., Bull. Soc. Chem. Fr. 1964, 945.
2. (a) McMurry, J. E.; Andrus, W. A.; Musser, J. H., Synth. Commun. 1978,
(1), DMF 8, 53. (b) Fang, J. M., J. Org. Chem. 1982, 47, 3464. (c) Bailey, W. F.;
CO2Et (13) Nurmi, T. T.; Patricia, J. J.; Wang, W., J. Am. Chem. Soc. 1987, 109, 2442.
+N SMe 89% N
(d) Bailey, W. F.; Khanolkar, A. D., J. Org. Chem. 1990, 55, 6058.

Me I Me 3. (a) Pollet, P.; Gelin, S., Synthesis 1978, 142. (b) Hankovszky, H. O.;
Hideg, K.; Lex, L.; Kulcsar, G.; Halasz, H. A., Can. J. Chem. 1982, 60,
1432. (c) Batty, D.; Crich, D., J. Chem. Soc., Perkin Trans. 1 1992, 3205.
Analogous Magnesium Malonates. The neutral magnesium (d) Houghten, R. A.; Simpson, R. A.; Hanson, R. N.; Rapoport, H., J. Org.
carboxylate salt of S-thioethyl methylthiomalonate has been pre- Chem. 1979, 44, 4536. (e) Schroeder, M. C.; Kiely, J. S.; Johnson, D. R.;
Szoteck, D. L.; Domagala, J. M. Stickney, T. M.; Michel, A.; Kampf, J. M.,
pared and added to acyl imidazolides (eq 14).8 The methyl ester
J. Heterocycl. Chem. 1992, 29, 1481. (f) Gumieniak, J.; Andruszkiewicz,
analog of (1) is also reactive (eq 15).8 R.; Borowski, E., Pol, J. Chem. 1984, 58, 881.
4. McMurry, J. E.; Musser, J. H., J. Org. Chem. 1975, 40, 2556.
O 5. Bohlmann, F.; Suding, H., Liebigs Ann. Chem. 1985, 160.
CO2H R N 6. (a) Schlessinger, R. H.; Wood, J. L., J. Org. Chem. 1986, 51, 2621.
N
1 equiv Mg(OEt)2 (b) Denmark, S. E.; Weber, E. J., Helv. Chim. Acta 1983, 66, 1655.
SEt
Mg2+ O2C 7. Gugelchuk, M. M.; Hart, D. J.; Tsai, Y. M., J. Org. Chem. 1981, 46, 3671.
SEt
O O 2 8. Brooks, D. W.; Lu, L. D.-L.; Masamune, S., Angew. Chem., Int. Ed. Engl.
2 equiv 1979, 18, 72.
O O
(14) Alex Andrus
R SEt
Applied Biosystems, Foster City, CA, USA

A list of General Abbreviations appears on the front Endpapers