attempts to use this transient copper enolate intermediate in
various conceivable reactions.5 By analogy to the copper enolate
chemistry, we envisaged that the Reformatsky reagent could
be formed from the zinc ethyl malonate species which would
be readily prepared from the reaction of potassium ethyl
malonate (2) with a zinc(II) salt, and further reaction with a
nitrile would form a â-amino acrylate product (Scheme 1).
The Decarboxylative Blaise Reaction
Jae Hoon Lee, Bo Seung Choi, Jay Hyok Chang,
Hee Bong Lee, Joo-Yong Yoon, Jaeick Lee, and
Hyunik Shin*
Chemical DeVelopment DiVision, LG Life Sciences, Ltd./R&D,
104-1, Moonji-dong, Yusong-gu, Daejeon 305-380, Korea
SCHEME 1
ReceiVed August 13, 2007
Initially it was found that when a mixture of zinc chloride
(1.0 equiv), potassium ethyl malonate (2, 1.5 equiv), and
benzonitrile in the polar aprotic solvents such as N-methylpyr-
rolidone (NMP) or DMF was heated at 90 °C, decarboxylation
of the zinc ethyl malonate species gave ethyl acetate as the
exclusive product. Since it is known that the rate of decarboxy-
lation is dependent on the polarity of the medium,6 we tested
the reaction in less polar media, which changed the profile of
the reaction dramatically. In chlorinated solvents such as 1,2-
dichloroethane (DCE) or chloroform, complete reaction was
achieved in 18 h (Table 1, entries 3 and 4). On the other hand,
ethereal solvents such as THF and dioxane showed limited
conversion (entries 5 and 6).
With the optimal reaction medium determined, diverse metal
salts were investigated for the decarboxylative Blaise reaction
in DCE (Table 2). Among them, Zn(II), Cu(II), Ni(II), and In-
(III) salts showed moderate to excellent reactivity. Zinc chloride,
bromide, or acetate (entries 1, 2, and 3) showed similar excellent
reactivity, 98% conversion in 18 h, whereas zinc stearate (entry
4) showed marginal conversion; use of zinc triflate and oxide
(entries 5 and 6) resulted in no conversion. Indium chloride or
bromide (entries 9 and 10) exerted excellent reactivity, com-
parable to that of zinc. Cupric chloride and nickel bromide
(entries 7 and 8) showed moderate reactivity, 73% conversion
and 42% conversion in 100 h, respectively.
Reaction of aryl nitriles with potassium ethyl malonate in
the presence of zinc chloride and a catalytic amount of
Hu¨nig’s base provided â-amino acrylates in moderate to good
yield. Compared to the classical Blaise reaction, this reaction
is safer (endothermic), devoid of lachrymatory reagent, and
is possible with 0.5-1.0 equiv of zinc chloride.
The Blaise reaction was introduced to synthetic organic
chemists a century ago as an important method for the
preparation of â-keto esters and â-amino acrylates by the
reaction of the Reformatsky reagent with nitrile compounds.
However, in spite of its straightforward introduction of versatile
functionalities, this reaction has been under-exploited due to
its narrow scope, low yields, and the formation of side products.1
Although these shortcomings were significantly improved by
several modifications of the original protocol,2 there is still room
for further refinements, particularly in eliminating the use of
excess zinc metal, in avoiding the use of lachrymatory bro-
moacetate, and in suppression of the self-condensation side
products of bromoacetate. In that context, we were intrigued
by the feasibility of the decarboxylative3 Blaise reaction that
would obviate the need for both zinc metal and bromoacetate.
Although there are several reports4 that the decarboxylation
of malonic acid was accelerated by Cu(I) salts, there are scant
In spite of having optimized both the metal salts and reaction
medium, we encountered occasional problems such as an
unpredictable induction period of up to a few hours, and poor
overall reproducibility of the reaction. The former issue was
resolved by the addition of Hu¨nig’s base (N,N-diisopropylethy-
lamine): addition of 0.1 to 1.0 equiv of Hu¨nig’s base consis-
tently initiated the reaction as the reaction mixture reached
(1) (a) Blaise, E. E. C. R. Acad. Sci. 1901, 132, 478 and 978. (b) Cason,
J.; Rinehart, K. L., Jr.; Thornton, S. D., Jr. J. Org. Chem. 1953, 18, 1594.
(c) Kagan, H. B.; Suen, Y.-H. Bull. Chim. Soc. Fr. 1966, 1819. (d) Konrad,
J.; Jezo, I. Chem. ZVesti 1980, 34, 125.
(2) (a) Hannick, S. M.; Kishi, Y. J. Org. Chem. 1983, 48, 3833. (b)
Shin, H.; Choi, B. S.; Lee, K. K.; Choi, H.-w.; Chang, J. H.; Lee, K. W.;
Nam, D. H.; Kim, N.-S. Synthesis 2004, 2629. (c) Narkunan, K.; Uang,
B.-J. Synthesis 1998, 1713. (d) Lee, A. S.-Y.; Cheng, R.-Y.; Pan, O.-G.
Tetrahedron Lett. 1997, 38, 443. (e) Choi, B. S.; Chang, J. H.; Choi, H.-
w.; Kim, Y. K.; Lee, K. K.; Lee, K. U.; Lee, J. H.; Heo, T.; Nam, D. H.;
Shin, H. Org. Process Res. DeV. 2005, 9, 311.
(3) For an excellent recent review on the transition metal-catalyzed
decarboxylative addition of enolates, see: Tunge, J. A.; Burger, E. C. Eur.
J. Org. Chem. 2005, 1715.
(5) Recently a decarboxylative aldol reaction catalyzed by Cu(II) species
has been disclosed by the Shair group. See: (a) Lalic, G.; Aloise, A. D.;
Shair, M. D. J. Am. Chem. Soc. 2003, 125, 2852. (b) Magdziak, D.; Lalic,
G.; Lee, H. M.; Fortner, K. C.; Aloise, A. D.; Shair, M. D. J. Am. Chem.
Soc. 2005, 127, 7284. (c) Fortner, K. C.; Shair, M. D. J. Am. Chem. Soc.
2007, 129, 1032. For a heterobimetallic version, see: (d) Lou, S.; Westbrook,
J. A.; Schaus, S. E. J. Am. Chem. Soc. 2004, 126, 11440.
(4) (a) Toussaint, O.; Capdevielle, P.; Maumy, M. Synthesis 1986, 1029.
(b) Darensbourg, D. J.; Holtcamp, M. W.; Khandelwal, B.; Reibenspies, J.
H. Inorg. Chem. 1994, 33, 531.
(6) Please refer to ref 4b.
10.1021/jo701743m CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/30/2007
J. Org. Chem. 2007, 72, 10261-10263
10261