In recent years, we have developed copper-catalyzed
methods for the arylation of amides,9 amines,9,10 nitrogen-
containing heterocycles,9,11 hydrazides,9,12 and phenols.13 The
arylation of activated methylene compounds mediated by
copper salts is a well-established process, dating back to the
development of the Hurtley reaction in 1929.14 There have
since been numerous reports of variants of this process,15
but in general high yields are only obtained with aryl halides
bearing electron-withdrawing groups or ortho substituents
capable of coordinating to copper. These reactions are usually
run in nonvolatile and/or highly toxic solvents (e.g., DMSO
or HMPA). Furthermore, it is often necessary to prepare the
enolate (by deprotonation of the malonate using sodium
hydride or a sodium alkoxide) prior to coupling. Perhaps
least attractive is that in nearly all cases stoichiometric or
even excess amounts of copper salts must be used. In 1993,
Miura et al. reported a copper-catalyzed arylation of mal-
onitrile, ethyl cyanoacetate, and acetylacetone using unhin-
dered aryl iodides.16 However, their system requires harsh
conditions (DMSO, 120 °C) under which malonate esters
are prone to decomposition (via ester hydrolysis and
subsequent rapid decarboxylation). Konopelski and co-
workers have recently developed a copper-catalyzed mal-
onate arylation,17 but the substrate scope is limited (only
o-halophenols and o-haloanisoles are reactive) and the air-
sensitive CuBr must be used. To date, therefore, there have
been no general methods affording R-aryl malonates that
employ catalytic amounts of copper. Because of the potential
of such compounds as important synthetic intermediates and
therapeutic agents, we set out to develop a general and mild
catalytic method that would provide ready access to a wide
variety of R-aryl diesters that could be further manipulated
to a myriad of desirable products.
An important initial goal of our investigations was to find
a base other than sodium hydride (or alkoxide) that would
effect the desired reaction. Soluble organic bases such as
triethylamine, N-ethyldiisopropylamine (Hunig’s base), and
DBU (diazabicyclo[5.4.0]undec-7-ene) completely inhibit the
reaction, likely by saturating the coordination sphere of
copper.18 Upon screening commonly used inorganic bases,
it was found that the use of Cs2CO3 is crucial to the success
of the reaction. K3PO4 was considerably less effective, while
K2CO3 and Na2CO3 did not afford any reaction at all.
With the best base determined, the effects of various
additives to the reaction were surveyed. Among the effective
ligands discovered, we found that phenols expedite the
reaction and in general allow for the lower reaction temper-
atures required to circumvent excessive product decomposi-
tion. The use of phenol itself resulted in a significant amount
of diaryl ether formation,13 while phenols bearing large ortho
substituents (tBu, iPr) slowed the malonate arylation reaction
considerably. It was found that 2-phenylphenol (o-hydroxy-
biphenyl) does not hinder the desired reaction from proceed-
ing, but C-O bond formation occurs to only a very small
extent. Furthermore, from a practical standpoint, 2-phenyl-
phenol is a practically odorless, crystalline solid that is
considerably less toxic than most other phenols. In fact, its
sodium salt has been used as a preservative for citrus fruits
for decades,19 and thus it is extremely inexpensive and
available from a plethora of commercial sources.
By heating a mixture of aryl iodide, Cs2CO3, and diethyl
malonate in THF (70 °C) in the presence of catalytic amounts
of copper(I) iodide and 2-phenylphenol under an inert
atmosphere (Scheme 1), the corresponding R-aryl malonate
Scheme 1. Arylation of Diethyl Malonate
(7) (a) Fauvarque, J. F.; Jutand, A. J. Organomet. Chem. 1979, 177, 273.
(b) Carfagna, C.; Musco, A.; Sallese, G.; Santi, R.; Fiorani, T. J. Org. Chem.
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Masumoto, K.; Yamanaka, H. J. Chem. Soc., Perkin Trans. 1 1994, 235.
(f) Terao, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron Lett. 1998,
39, 6203. (g) Agnelli, F.; Sulikowski, G. A. Tetrahedron Lett. 1998, 39,
8807. (h) Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc., 2001, 123,
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123, 8410.
(8) (a) Ciufolini, M. A.; Qi, H.-B.; Browne, M. E. J. Org. Chem. 1988,
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101.
(9) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7727.
(10) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077.
(11) Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron Lett.
1999, 40, 2657.
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(13) Marcoux, J.-F.; Doye, S.; Buchwald, S. L. J. Am. Chem. Soc. 1997,
119, 10539.
(14) Lindley, J. Tetrahedron 1984, 40, 1433 and references therein.
(15) (a) Setsune, J.; Matsukawa, K.; Wakemoto, H.; Kitao, T. Chem.
Lett. 1981, 367. (b) Setsune, J.; Matsukawa, K.; Kitao, T. Tetrahedron Lett.
1982, 23, 663. (c) Osuka, A.; Kobayashi, T.; Suzuki, H. Synthesis 1983,
67. (d) Setsune, J.; Ueda, T.; Shikata, K.; Matsukawa, K.; Iida, T.; Kitao,
T. Tetrahedron 1986, 42, 2647. (e) Ugo, R.; Nardi, P.; Psaro, R.; Roberto,
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can be obtained in good to excellent yields (Table 1). A
2-fold excess of diethyl malonate (relative to iodide) is
necessary to drive the reaction to completion in a reasonable
amount of time. We found that this reaction can be run at
higher temperatures using only a slight excess of malonate;
however, these reaction conditions lead to unacceptable
amounts (typically ∼10%) of the decarboxylated product.
The malonate arylation proceeds smoothly using a diverse
array of aryl iodides, including electron-rich (entry 8) and
heterocyclic (entry 6). Even the sterically hindered 2-iodo-
isopropylbenzene (entry 4) can be converted to the desired
product, although 10 mol % CuI and 15 mol % 2-phenyl-
phenol are required to facilitate complete conversion. Im-
portantly, palladium-incompatible functional groups are well
(17) (a) Konopelski, J. P.; Hottenroth, J. M.; Oltra, H. M.; Ve´liz, E. A.;
Yang, Z.-C. Synlett 1996, 609. (b) Hang, H. C.; Drotleff, E.; Elliott, G. I.;
Ritsema, T. A.; Konopelski, J. P. Synthesis 1999, 398.
(18) Miura has made a similar observation in his system; see ref 16.
(19) Johnson, G. D.; Harsy, S. G.; Geronimo, J.; Wise, J. M. J. Agric.
Food. Chem. 2001, 49, 2497.
270
Org. Lett., Vol. 4, No. 2, 2002