Palladium-catalyzed arylation of malonates and cyanoesters using sterically hindered trialkyl- and ferrocenyldialkylphosphine ligands

Article abstract of DOI:10.1021/jo016226h

Palladium-catalyzed reactions of aryl bromides and chlorides with two common stabilized carbanions - enolates of dialkyl malonates and alkyl cyanoesters - are reported. An exploration of the scope of these reactions was conducted, and the processes were shown to occur in a general fashion. Using P(t-Bu)₃ (1), the pentaphenylferrocenyl ligand (Ph₅C₅)Fe(C₅H₄)P(t-Bu) ₂ (2), or the adamantyl ligand (1-Ad)P(t-Bu)₂ (3), reactions of electron-poor and electron-rich, sterically hindered and unhindered aryl bromides and chlorides were shown to react with diethyl malonate, di-tertbutyl malonate, diethyl fluoromalonate, ethyl cyanoacetate, and ethyl phenylcyanoacetate. Although alkyl malonates and ethyl alkylcyanoacetates did not react with aryl halides using these catalysts, the same products were formed conveniently in one pot from diethylmalonate by cross-coupling of an aryl halide in the presence of excess base and subsequent alkylation.

Full text of DOI:10.1021/jo016226h

J . Org. Chem. 2002, 67, 541-555
541
P a lla d iu m -Ca ta lyzed Ar yla tion of Ma lon a tes a n d Cya n oester s
Usin g Ster ica lly Hin d er ed Tr ia lk yl- a n d
F er r ocen yld ia lk ylp h osp h in e Liga n d s
Neil A. Beare and J ohn F. Hartwig*
Department of Chemistry, Yale University, P.O. Box 208107, New Haven, Connecticut 06520-8107
john.hartwig@yale.edu
Received October 22, 2001
Palladium-catalyzed reactions of aryl bromides and chlorides with two common stabilized
carbanionssenolates of dialkyl malonates and alkyl cyanoesterssare reported. An exploration of
the scope of these reactions was conducted, and the processes were shown to occur in a general
fashion. Using P(t-Bu)3 (1), the pentaphenylferrocenyl ligand (Ph5C5)Fe(C5H4)P(t-Bu)2 (2), or the
adamantyl ligand (1-Ad)P(t-Bu)2 (3), reactions of electron-poor and electron-rich, sterically hindered
and unhindered aryl bromides and chlorides were shown to react with diethyl malonate, di-tert-
butyl malonate, diethyl fluoromalonate, ethyl cyanoacetate, and ethyl phenylcyanoacetate. Although
alkyl malonates and ethyl alkylcyanoacetates did not react with aryl halides using these catalysts,
the same products were formed conveniently in one pot from diethylmalonate by cross-coupling of
an aryl halide in the presence of excess base and subsequent alkylation.
In tr od u ction
cyanoesters use either toxic or specialized reagents such
as bismuth,12 lead,13 chromium,14 or high valent iodonium
salts.15
The formation of carbon-carbon bonds by the addition
of stabilized carbanions to alkyl halides is one of the most
fundamental processes in synthetic organic chemistry.
In contrast, the reaction of stabilized carbanions with aryl
halides requires a catalyst or stoichiometric additive in
most cases and has been much less developed.1-3 Until
recently, reactions between aryl halides and enolates
derived from dialkyl malonates or cyanoacetates were
typically conducted with aryl iodides as the aryl electro-
phile and with stoichiometric amounts of copper addi-
tive.4,5 In 1993, the arylation of malonates and cyano-
esters was achieved using catalytic loadings of copper,
but the reaction again required aryl iodides, high tem-
peratures were used, and moderate yields were obtained.6
The only aryl bromides that have participated in this
copper chemistry have been ortho-substituted bromoben-
zoic acids.7,8 Aryl chlorides have been completely unre-
active. Another approach to the arylation of malonates
and cyanoesters involves the complexation of aryl bro-
mides or chlorides to a (cyclopentadienyl)iron moiety and
subsequent reaction of the anions of malonates and
cyanoesters to these activated aryl halides. However, this
method again requires stoichiometric amounts of metal,
and the metal was removed from the reaction product
by photolysis.9-11 Other arylations of malonates and
Only recently has this transformation shown more
synthetic potential. We reported two examples of the
palladium-catalyzed R-arylation of malonates and dem-
onstrated the first use of an aryl chloride substrate.16
Buchwald reported a further example of the reaction of
an aryl bromide with a malonate.17 Recently, we com-
municated the use of an assay based on FRET (fluores-
cence resonance energy transfer) for reaction discovery
and used the arylation of cyanoesters as a case study.18
Using this technique, we uncovered a catalyst and
procedure for the formation of R-aryl cyanoacetates and
R,R′-diarylated cyanoacetates in excellent yields under
mild conditions. This procedure employed catalytic load-
ings of palladium and sterically hindered, electron-rich
phosphine ligands. This approach followed the hypothesis
that such ligands should facilitate both the oxidative
additions of unreactive aryl chlorides and the reductive
eliminations from complexes with weakly donating lig-
ands, such as the anions of malonates and cyano-
esters.16,19-21
(10) Abd-El-Aziz, A. S.; Denus, C. R. J . Chem. Soc., Perkin Trans. 1
1993, 293.
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Motherwell, W. B.; Papoula, M. T. B.; Stanforth, S. P. J . Chem. Soc.,
Perkin Trans. 1 1985, 2667.
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J . J . Prakt. Chem. 1997, 339, 261.
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10.1021/jo016226h CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/29/2001

542 J . Org. Chem., Vol. 67, No. 2, 2002
Beare and Hartwig
A broad range of synthetically valuable materials is
derived from the products of the malonate and cyanoester
arylation. Decarboxylation provides arylacetic acids,22
which are common synthetic building blocks, and alky-
lation followed by decarboxylation generates higher
R-arylcarboxylic acid derivatives such as the family of
Profen drugs.23-26 Enantioselective enzymatic desymme-
trization of substituted malonates forms chiral, nonra-
cemic synthetic intermediates with one carboxylic acid
and one ester unit.27-31 Aryl malonates, themselves, have
been utilized as key components of enzyme inhibitors.32-34
In addition, these products serve as intermediates for the
preparation of enantiopure, differentially protected 1,3-
diols,35-37 as well as arylbarbituric acids.38,39 Aryl cyano-
acetates can be used to generate a variety of nitrogen-
containing products such as amino alcohols40 and â-amino
acids,41 while also being valuable as chiral shift rea-
gents.42-44
We report here a full account of the scope and limita-
tions of the new arylations of malonates and cyanoesters.
The scope of this reaction is broad and includes ortho-
substituted aryl halides, aryl chlorides that are activated
or deactivated, and a variety of malonate partners. In
some cases catalysts bearing ligands such as Ph5FcP(t-
Bu)3 or (1-Ad)P(t-Bu)3 gave higher yields than catalysts
bearing P(t-Bu)3, but most coupling processes could be
conducted with one of these three ligands. In addition,
it was necessary to suitably match the anionic base and
countercation with the pronucleophile to achieve high
yields.
F igu r e 1. Ligands used in the malonate and cyanoacetate
arylation.
reaction conditions for the arylation of malonates focused
on the coupling of diethyl malonate with bromobenzene.
We evaluated a variety of bases in combination with an
array of solvents. Several palladium sources were em-
ployed in 2 mol % quantities, and P(t-Bu)3 (1) was used
initially as ligand (Figure 1). This ligand has generated
efficient catalysts for the arylation of ketones.16 Moreover,
it had broadened the scope of aromatic C-N and C-O
bond formation to include weakly nucleophilic substrates
such as phenols and carbamates.45-47 The electronic
properties of malonate and cyanoester anions are likely
to control the scope of C-C coupling reactions in a similar
way that the electronic properties of phenoxides and
acidic nitrogen substrates control the scope of aromatic
carbon-heteroatom coupling. Therefore, we began our
studies toward the development of catalysts for arylation
of malonates and cyanoesters using this ligand.
We analyzed reactions at 70 °C using the readily
available bases Na3PO4, K3PO4, Na2CO3, Cs2CO3, NaH,
NaHMDS, LDA, and NaO-t-Bu. Reactions conducted with
alkoxide bases generated materials resulting from trans-
esterification of the starting malonate and product aryl-
malonate. Reactions containing NaH as base in THF
solvent gave the fastest reaction rates, providing com-
plete conversion of bromobenzene to the arylmalonate
product after 1 h. THF solvent was used to ensure
solubility of the malonate anion. K3PO4 was also a
suitable base and is more convenient to use under some
laboratory conditions. In this case, toluene was superior
to THF as solvent. Reactions containing this base were
somewhat slower, but still required only about 5 h for
full conversion. Considering the results with cyano-
acetates below and the suitability of NaH as base, we
were surprised to observe that reactions involving Na3-
PO4 were considerably slower than those involving K3-
PO4, as were reactions involving Na2CO3 and Cs2CO3. All
reactions with Na3PO4, Na2CO3, and Cs2CO3 failed to
provide complete conversion after 10 h. Throughout this
work both the cation and anion of the base influenced
rates and yield. With some classes of substrate and basic
anions, sodium cations produced the fastest rates and
highest yields, while in other cases, potassium as cation
gave better results. Thus, no trend of optimal cation was
observed, and in many cases the choice of base remains
empirical. No reaction was observed when using either
of the two stronger bases NaHMDS or LDA.
Resu lts a n d Discu ssion
1. Ar yla tion of Ma lon a tes. A. In itia l Eva lu a tion
of R ea ct ion Con d it ion s. Our initial exploration of
(21) Roy, A. H.; Hartwig, J . F. J . Am. Chem. Soc. 2001, 123, 1232.
(22) Matoishi, K.; Hanzawa, S.; Kakidani, H.; Sugai, T.; Ohta, H.
Chem. Commun. 2000, 1519.
(23) Harrington, P. J .; Lodewijk, E. Org. Proc. Res. Devel. 1997, 1,
72.
(24) Ugo, R.; Nardi, P.; Psaro, R.; Roberto, D. Gazz. Chim. Ital. 1992,
122, 511.
(25) Brunner, H.; Schmidt, P. Eur. J . Org. Chem. 2000, 2119.
(26) Brunner, H.; Schmidt, P. Z. Naturforsch., B: Chem. Sci. 2000,
55, 369.
(27) Schoffers, E.; Golebiowski, A.; J ohnson, C. R. Tetrahedron 1996,
52, 3769.
(28) Toone, E. J .; J ones, J . B. Tetrahedron: Asymmetry 1991, 2,
1041.
(29) Shunsaku, S.; Okada, H.; Nakamata, K.; Yamamoto, T.; Sekino,
F. Heterocycles 1996, 43, 1031.
(30) Patel, R.; Banerjee, A.; Chu, L.; Brozozowski, D.; Nanduri, V.;
Laszlo, L. J . J . Am. Oil Chem. Soc. 1998, 75, 1473.
(31) Ohno, M.; Otsuka, M. Org. React. 1989, 37, 1.
(32) Gao, Y.; Burke, T. R. Synlett 2000, 134.
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J . H.; Yang, D.; Burke, T. R. J . Med. Chem. 2000, 41, 911.
(34) Roedern, E. G.; Grams, F.; Brandstetter, H.; Moroder, L. J . Med.
Chem. 1998, 41, 339.
(35) Narisano, E.; Riva, R. Tetrahedron: Asymmetry 1999, 10, 1223.
(36) Guanti, G.; Narisano, E.; Riva, R. Tetrahedron: Asymmetry
1998, 9, 1859.
(37) Chenevert, R.; Desjardins, M. Can. J . Chem. 1994, 72, 2312.
(38) Knabe, J .; Buch, H. P.; Kirsch, G. A. Arch. Pharm. 1987, 320,
323.
(39) Meester, P. D.; J ovanovic, M. V.; Chu, S. S. C.; Biehl, E. R. J .
Heterocycl. Chem. 1986, 32, 337.
(40) Knabe, J .; Buchheit, W. Arch. Pharm. 1985, 318, 593.
(41) Abele, S.; Seebach, D. Eur. J . Org. Chem. 2000, 1.
(42) Shibata, N.; Suzuki, E.; Takeuchi, Y. J . Am. Chem. Soc. 2000,
122, 10728.
(43) Takeuchi, Y.; Iwashita, H.; Yamada, K.; Gotaishi, M.; Kurose,
N.; Koizumi, T.; Kabuto, K.; Kometani, T. Chem. Pharm. Bull. 1995,
43, 1668.
(44) Takeuchi, Y.; Konishi, M.; Hori, H.; Takahashi, T.; Kometani,
T.; Kirk, K. L. Chem. Commun. 1998, 365.
We also evaluated the optimum catalyst precursor and
metal:ligand ratio. In all cases Pd(dba)2 was a superior
precatalyst to Pd(OAc)2. Generally, [Pd(allyl)Cl]2 was an
equally effective precursor. In some cases, higher turn-
over numbers were observed using the allyl complex. Of
(45) Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J . F. J . Am.
Chem. Soc. 1999, 121, 3224.
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H.; Alcazar-Roman, L. M. J . Org. Chem. 1999, 64, 5575.
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hedron Lett. 2000, 41, 481.

Arylation of Malonates and Cyanoesters
J . Org. Chem., Vol. 67, No. 2, 2002 543
Ta ble 1. P r ep a r a tive Sca le Ar yla tion of Dieth yl Ma lon a tea
a
Reactions conducted in duplicate on a 1 mmol scale in THF using 1.1 equiv of diethyl malonate, 1.1 equiv of NaH, and 1.0 equiv of
aryl bromide. K3PO4 (3.0 equiv) used as base in toulene. c 0.050 mol % [(allyl)PdCl]2, 0.10 mol % ligand 4, 3.0 equiv of K3PO4, in toulene
b
at 100 °C for 12 h. Yields are an average of two runs.
course, no reaction was observed in the absence of
palladium. Unlike other palladium-catalyzed bond-form-
ing reactions using bulky alkylphosphines,16,46,48 the
palladium-to-ligand ratio was not a crucial factor in
determining reactivity. Both 1:1 and 1:2 ratios were
suitable, although use of a 1:2 ratio led to slightly faster
reaction rates. No reaction occurred with Pd(dba)2, [Pd-
(allyl)Cl]2 or Pd(OAc)2 in the absence of added phosphine
ligand.
with diethyl malonate. These results are presented in
Table 1. A broad scope of aryl bromides participated in
this reaction, as demonstrated by the results in entries
4, 7, 10, 12, and 15. Even reaction of the p-dialkylamino-
substituted aryl bromide in entry 10 gave over 85% yield.
Substrates with an ortho or pseudo-ortho substituent also
reacted under the standard conditions (entries 4, 5, and
9). o-Methoxybromobenzene, which is both electron-rich
and sterically hindered, gave over 85% yield of coupled
product (entry 4). Reaction of electron-poor substrates
such as those in entries 6, 13, 17, and 18 all occurred in
high yield.
B. Cou p lin g of Ar yl Br om id es w ith Dieth yl Ma l-
on a te. After optimization of the reaction conditions, we
investigated the scope of the coupling of aryl bromides
Some of these substrates can be sensitive to the
strongly basic conditions created by NaH. However, many
(48) Littke, A. F.; Dai, C.; Fu, G. C. J . Am. Chem. Soc. 2000, 122,
4020.

544 J . Org. Chem., Vol. 67, No. 2, 2002
Beare and Hartwig
Ta ble 2. Rea ction of Dieth yl Ma lon a te w ith Ar yl
Ch lor id esa
of these substrates gave high yields under appropriately
modified conditions. For example, high yields for reaction
of the acetophenone derivative in entry 17 were observed
when employing K3PO4 as base and toluene as solvent
instead of NaH as base in THF solvent. The origin of this
requirement is not straightforward because the malonate
is much more acidic than the methyl ketone. The ester
in entry 6, the benzophenone in entry 18, and dioxolane-
containing substrate in entry 19 gave high yields for
reactions containing the phosphate, but not for those
containing the hydride base. In addition 2-bromo-6-
methoxynaphthalene and 1-bromo-3-fluorobiphenyl
smoothly underwent coupling with diethyl malonate
using K3PO4 as base to give precursors to the com-
mercially important drugs Naproxen and Flurbiprofen,
respectively (entries 11 and 20). In these cases, increased
amounts of hydrodehalogenation products were observed
when using NaH as base.
Although not investigated in detail, the malonate
arylation also occurred when using substantially lower
catalyst loadings than the standard conditions of 2 mol
% catalyst. As shown in entry 3, the reaction of diethyl
malonate with bromobenzene occurred in high yield with
0.05 mol % of the precursor [(allyl)PdCl]2 at 100 °C.
Higher turnover numbers were observed under these
conditions than when using NaH as base.
C. Cou p lin g of Ar yl Ch lor id es w ith Dieth yl Ma l-
on a te. Significant success has been observed recently in
the coupling of aryl chlorides in a number of pro-
cesses.16,19,49-57 These substrates are, of course, less
reactive for palladium-catalyzed processes than are aryl
bromides, but are less expensive and available in more
derivatives from commercial sources. With the catalysts
containing sterically hindered electron-rich phosphine
ligands, the reactions of aryl chlorides with diethyl
malonate occurred smoothly in many cases. These results
are summarized in Table 2. In these cases, K3PO4 was a
more effective base than was NaH. Although high
conversions were observed when using P(t-Bu)3 as ligand,
arene that was formed from hydrodehalogenation was a
significant side product. The source of the hydrogen is
unclear, and we do not understand at this time the
difference in selectivity as a function of halide. However,
use of either the pentaphenylferrocenyl phosphine, (Ph5C5)-
Fe(C5H4)P(t-Bu)2 (2),58 or the adamantyl phosphine, (1-
Ad)P(t-Bu)2(3)18 (see Figure 1), instead of P(t-Bu)3, al-
lowed for coupling of aryl chlorides in high yields.
Electron-rich (entries 3-5), electron-poor (entry 6) and
sterically hindered substrates (entries 8 and 9) were
suitable coupling partners when using ligand 2. Although
catalysts comprised of adamantyl ligand 3 were effective
for reactions of many aryl chlorides, this catalyst system
a
Reactions conducted in duplicate on a 1 mmol scale in toulene
using 1.1 equiv of diethyl malonate, 1.0 equiv of aryl chloride and
3.0 equiv of K3PO4. Yields are an average of two runs.
produced roughly 50% of the product from hydrodehalo-
genation during coupling of the dioxolane in entry 5 or
the ortho-substituted aryl chlorides.
D. Cou p lin g of Ar yl Ha lid es w it h Di-ter t-b u t yl
Ma lon a te. It is well-known that tert-butyl esters are
more readily deprotected than related methyl or ethyl
versions. Earlier, the authors’ group used palladium
complexes of the sterically hindered 1,1′-bis(di-tert-bu-
tylphosphino)ferrocene (4) as catalysts for the coupling
of di-tert-butyl malonate with chlorobenzene. Because we
successfully conducted the reaction of diethyl malonate
with a wide variety of aryl halides using ligands 1-3,
we investigated whether di-tert-butyl malonate would
display as broad or broader a scope in its coupling with
bromo- and chloroarenes than did diethyl malonate.
A large number of aryl bromides and chloride reagents
were suitable for coupling with di-tert-butyl malonate
(Table 3). As observed for reactions of diethyl malonate,
Pd(dba)2 and [(allyl)PdCl]2 were useful precatalysts, but
Pd(OAc)2 generated catalysts of much lower activity.
With di-tert-butyl malonate as substrate, NaO-t-Bu proved
to be an effective base. Reactions containing NaH as base
also occurred in high yields. In contrast to reactions of
diethyl malonate, the reaction of di-tert-butyl malonate
with bromobenzene using K3PO4 as base failed to give
complete conversion, even after extended periods of
heating.
(49) Stauffer, S.; Hauck, S. I.; Lee, S.; Stambuli, J .; Hartwig, J . F.
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Tetrahedron Lett. 1999, 40, 1237.
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L. J . Org. Chem. 2000, 65, 1158.
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Using NaH as base and P(t-Bu)3 as ligand, the cross-
coupling reactions of a diverse range of aryl bromides
occurred in high yields (entries 1-7). The use of this
commercially available ligand instead of the bisphosphine
4 allowed for the arylation of di-tert-butyl malonate with

Arylation of Malonates and Cyanoesters
J . Org. Chem., Vol. 67, No. 2, 2002 545
Ta ble 3. Ar yla tion of Di-ter t-Bu tylm a lon a tea
a
Reactions conducted in duplicate on a 1 mmol scale in THF using 1.1 equiv of di-tert-butyl malonate, 1.1 equiv of NaH, and 1.0 equiv
of aryl halide. 1.0 mol % [(allyl)PdCl]2, 1.1 equiv of NaOt-Bu in dioxane, 45 °C, 8 h. c Stirred for 12 h. 1.0 mol % [(allyl)PdCl]2, 1.1
equiv of NaOt-Bu used as base in dioxane at 100 °C for 12 h. e 2.0 mol % Pd(dba)2, 1.1 equiv of NaOt-Bu used as base in dioxane at 100
°C for 12 h. Yields are an average of two runs.
b
d
chlorobenzene (entry 8) in a somewhat higher yield (88%
versus 80%).16 As did aryl bromides, a large variety of
aryl chlorides successfully coupled with the anion of di-
tert-butyl malonate (entries 8-12). For reactions of these
aryl halides, NaO-t-Bu was superior to NaH as base.
Reactions containing NaH as base formed nearly equal
amounts of hydrodehalogenated arene and coupled prod-
uct. In contrast, reactions containing NaO-t-Bu formed
little hydrodehalogenation product and generated high
yields of di-tert-butyl arylmalonates.
E. Cou p lin g of Ar yl Ha lid es w ith F lu or om a lo-
n a tes. Fluorinated materials are increasingly studied
because of their importance as pharmaceutical candi-
dates.59,60 2-Aryl-2-fluoromalonates serve as key inter-
mediates for the preparation of optically active, differ-
entially protected 2-aryl-1,3-propanediols after desym-
metrization with lipases.35,36 These synthetic intermedi-
ates are generally prepared from either 2-aryl-2-fluoro-
acetates,61 electrophilic fluorination of aryl malonates,62
or nucleophilic substitution using fluoroarenes activated
by chromium and the enolate of 2-fluoromalonate.14 The
direct formation of the sp2-sp3 bond by arylation of
2-fluoromalonate is rare and limited to reactions of metal
arene complexes.14 Because diethyl 2-fluoromalonate is
isosteric with diethyl malonate, we suspected that these
substrates would undergo the palladium-catalyzed ary-
lation process.
The results of reactions between diethyl 2-fluoromalo-
nate and aryl bromides are presented in Table 4. As
observed from our studies with diethyl and di-tert-butyl
malonates, catalysts derived from Pd(OAc)2 were less
reactive than were those from Pd(dba)2. Both K3PO4 and
NaH were suitable bases, although reactions containing
K3PO4 as base required substantially longer times for
complete generation of the coupled product (entry 1).
F . Lim ita tion s of th e Cou p lin g of Ar yl Ha lid es
w ith Ma lon a tes. The limitations of the catalytic aryla-
tion of malonates were principally the reactions of pyridyl
halides and halobenzonitriles as electrophiles and diethyl
alkylmalonates as nucleophiles. No conversion was ob-
served when attempting the reaction of 2-, 3-, or 4-bro-
mopyridine with diethyl or di-tert-butylmalonate. The
origin of this absence of reactivity is unclear. Catalysts
comprised of P(t-Bu)3 can catalyze the amination of
pyridines,63 and we have observed clean reaction of
bromopyridines with imine-protected glycinates.64 More-
over, complexes with electron-poor, palladium-bound aryl
groups generally undergo faster reductive elimination
than do those with electron-rich aryl groups.65 The 2- and
(59) Ojima, I.; McCarthy, J . R.; Welch, J . T. Biomedical Frontiers
of Fluorine Chemistry; American Chemical Society: Washington, D.
C., 1996; Vol. 639, p 356.
(60) Hintermann, L.; Togni, A. Angew. Chem., Int. Ed. 2000, 39,
4359.
(61) Fukuyama, Y.; Matoishi, K.; Iwasaki, M.; Takizawa, E.; Miyaza-
ki, M.; Ohta, H.; Hanzawa, S.; Kakidani, H.; Sugai, T. Biosci.,
Biotechnol., Biochem. 1999, 63, 1664.
(62) Banks, E. R.; Lawrence, N. J .; Popplewell, A. J . J . Chem. Soc.,
Chem. Commun. 1994, 343.
(63) Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett. 1998,
39, 617.
(64) Lee, S.; Beare, N. A.; Hartwig, J . F. J . Am. Chem. Soc. 2001,
123, 8410.
(65) Driver, M. S.; Hartwig, J . F. J . Am. Chem. Soc. 1997, 119, 8232.

546 J . Org. Chem., Vol. 67, No. 2, 2002
Beare and Hartwig
Ta ble 4. P a lla d iu m -Ca ta lyzed Ar yla tion of Dieth yl
F lu or om a lon a tea
Ta ble 5. On e-P ot P r ep a r a tion of Dieth yl
2-Ar yl-2-m eth ylm a lon a tesa
a
Reactions conducted in duplicate on a 1 mmol scale in toulene
using 1.0 equiv of diethyl malonate, 4.5 equiv of K3PO4, and 1.1
equiv of aryl bromide, and 3.0 equiv CH3I added after consumption
b
of malonate. 0.5 mol % Pd2(dba)3 used. Yields are an average of
two runs.
a
Reactions conducted in duplicate on 1 mmol scale in THF using
1.1 equiv Diethyl fluoromalonate, 1.1 equiv of NaH and 1.0 equiv
b
of aryl bromide. 3.0 equiv of K3PO4 used as base, 14 h required
2. Ar yla tion of Cya n oa ceta tes. A. Rea ction s of
Eth yl Cya n oa ceta te. A number of aryl bromides and
chlorides reacted with ethyl cyanoacetate using bulky
trialkyl phosphines and loadings of palladium as low as
0.1 mol %. In contrast to the findings on the arylation of
diethyl malonate, Na3PO4 was the most effective base for
the arylation of cyanoacetates. When we used NaH as
base, no product was formed, and when we used K3PO4
the product was generated slowly. The poor solubility of
the sodium or potassium salts of ethyl cyanoacetate in
the tetrahydrofuran, dioxane, toluene, and acetonitrile
solvents we investigated may be responsible for the low
reactivity when using strong bases. Deprotonation of the
cyanoacetate with NaH quickly generated a thick sus-
pension. Perhaps the low levels of enolate present in the
reaction media when using Na3PO4 as base allows the
cyanoester anion to react with the catalyst before it
aggregates and precipitates. Alternatively, coordinated
cyanoacetate, and not free substrate, is deprotonated by
this base.
for completion. Yields are an average of two runs.
4-pyridyl groups are certainly less electron-donating
substituents than a simple phenyl. The lack of reactivity
of halobenzonitriles is equally perplexing. Amination of
4-bromo- and chlorobenzonitrile occurred cleanly when
using catalysts generated from Pd(dba)2 and P(t-Bu)3,63
but the malonate arylation using these substrates gave
low conversions. Again, the cyano group should accelerate
the reductive elimination step. The lack of reactivity of
alkyl-substituted diethylmalonates is more easily ratio-
nalized. Steric hindrance could inhibit formation of the
C-bound malonate anion complexes. Moreover, â-hydro-
gen elimination can occur from these species. When
reaction did occur at elevated temperatures, products
from apparent â-hydrogen elimination and Michael ad-
dition to a transient methylene diethylmalonate inter-
mediate66 were observed.
Although alkyl-substituted diethylmalonates have not
participated in the palladium-catalyzed arylation process,
sequential arylation and alkylation formed these prod-
ucts. Using an excess of K3PO4 base, we developed a one-
pot process involving palladium-catalyzed arylation fol-
lowed by simple alkylation (Table 5). In a typical
experiment, the arylation reaction was run at 70 °C using
excess base, and methyl iodide was added after the
malonate was consumed. These products formed from
sequential arylation and alkylation were isolated in
excellent yields. For some purposes the products can be
used to form acetic acid derivatives, such as the Profen
drugs, by decarboxylation. As mentioned in the Introduc-
tion, the products can also be used to generate optically
active building blocks by known enzymatic desymmetri-
zations.27-31
Examples of the arylation of ethyl cyanoacetate are
presented in Table 6. The selective monoarylation of ethyl
cyanoacetate with an aryl bromide was achieved in a
general fashion using 4 mol % P(t-Bu)3 or pentaphenyl-
ferrocenyl 2 as ligand and either 2 mol % Pd(dba)2 or 1
mol % [Pd(allyl)Cl]2 as the palladium source.
Reactions of aryl bromides bearing electron-withdraw-
ing substituents using catalysts ligated by P(t-Bu)3 were
significantly different from those of electron-neutral or
electron-rich aryl bromides. Reactions of these substrates
generated, in varying amounts, the diarylated product
in competition with the major monoarylation product.
This difference in reactivity as a function of electronics
was particularly evident during reactions of 3- and
4-bromobenzotrifluoride. Reaction of the meta-substituted
trifluoride produced the desired monoarylated product
(66) Pivsa-Art, S.; Fukui, Y.; Miura, M.; Nomura, M. Bull. Chem.
Soc. J pn. 1996, 69, 2039.

Arylation of Malonates and Cyanoesters
J . Org. Chem., Vol. 67, No. 2, 2002 547
Ta ble 6. Ar yla tion of Eth yl Cya n oa ceta tea
a
Reactions conducted in duplicate on a 1 mmol scale in toluene using 1.0 equiv of ethyl cyanoacetate, 1.0 equiv of aryl halide, and 3.0
b
equiv of Na3PO4. 1.0 mol % [Pd(allyl)Cl]2 used at 100 °C for 12 h. Yields are an average of two runs.
in good yield (entry 3), but reactions of the para-
substituted trifluoride produced a mixture of the mono-
and diarylated product. Although lowering of the reaction
temperature and varying the ligand:metal ratio had no
noticeable effect on this selectivity, a change in ligand
solved this problem of selectivity. Reactions of electron-
poor aryl halides, such as those in Table 6, entries 4-6,
with ethyl cyanoacetate catalyzed by complexes of pen-
taphenylferrocenyl ligand 2 provided good yields of the
monoarylcyanoacetate product.
Catalysts generated from P(t-Bu)3 were more effective
for the arylation of ethyl cyanoacetate using aryl chlo-
rides than they were for the arylation of malonates using
aryl chlorides. All of the aryl halides in entries 7-12 of
Table 6 had generated large amounts of hydrodehaloge-
nation product during reactions with diethyl malonate,
but they gave high yields for reaction with ethyl cyano-
acetate. Although P(t-Bu)3 was a generally effective
ligand for reactions of ethyl cyanoacetate with aryl
chlorides, pentaphenylferrocenyl ligand 2 again improved
yields in certain cases. For example, hydrodehalogenation
products were formed in 10-20% yield when coupling
3,4-methylenedioxyphenyl chloride or 2-chloroanisole
with ethyl cyanoacetate catalyzed by complexes of
P(t-Bu)3. In contrast, the same reactions catalyzed by
Pd(dba)2 and pentaphenylferrocenyl 2 formed less arene,
and the desired products were isolated in 86% and 81%
yield (entries 11 and 12).
substrates, cyanoacetates did not couple with pyridyl
halides or halobenzonitriles. In addition, 4-haloacetophe-
none, 4-halobenzophenone, and methyl 4-halobenzoate
did not react with ethyl cyanoacetate. Reactions of very
hindered aryl halides such as bromomesitylene also did
not occur. Ethyl alkylcyanoacetates, like diethyl alkyl-
malonates, were unreactive toward aryl halides.
B. Ar yla tion of Eth yl Ar ylcya n oa ceta tes. As de-
scribed above, we observed the diarylation of cyanoac-
etates as a side reaction in some couplings of electron-
poor aryl halides with ethyl cyanoacetate. Thus, we
investigated whether these diaryl products could be
formed purposefully in high yield. Examples of the
formation of quaternary diaryl-substituted products are
presented in Table 7. Both symmetrical (entries 1 and
2) and unsymmetrical diaryl cyanoacetates were readily
synthesized. A broad spectrum of aryl bromides coupled
with ethyl phenylcyanoacetate or ethyl p-anisylcyano-
acetate as nucleophile to give the diaryl cyanoester
products in excellent yield.
Except for reactions of ortho-substituted aryl halides,
the scope of the arylation of ethyl phenylcyanoacetate
was even more extensive than that for arylation of the
parent ethyl cyanoacetate. As expected, aryl bromides
(entries 6, 8, and 10) and aryl chlorides (entries 11 and
12) that coupled with ethyl cyanoacetate also coupled
with the ethyl arylcyanoacetates. In addition, several aryl
bromides that were not suitable substrates for reaction
with ethyl cyanoacetate were suitable substrates for
reaction with ethyl phenylcyanoacetate. For example,
4-bromobenzophenone (entry 5), 4-bromoacetophenone
The limitations of the catalytic arylation of ethyl
cyanoacetate were somewhat greater than were those for
the arylation of malonates. As observed for malonate

548 J . Org. Chem., Vol. 67, No. 2, 2002
Beare and Hartwig
Ta ble 7. Gen er a tion of Dia r yla ted Cya n oa ceta tesa
lent yields. Yet, substrates with ortho substituents were
less reactive toward the ethyl arylcyanoacetate than they
were toward the parent ethyl cyanoacetate. No reaction
was observed between the phenyl cyanoacetate and
2-bromotoluene, and no reaction was observed between
ethyl o-tolylcyanoacetate and 4-bromobenzotrifluoride.
A similar arylation of dialkyl arylmalonates was not
observed. Reaction of diethyl malonate with 2 equiv of
bromobenzene formed only the monophenylmalonate and
left the second equivalent of phenyl bromide unreacted.
Furthermore, all attempts to couple diethyl phenylmalo-
nate with aryl bromides were unsuccessful. Although the
pKa values of diethyl malonate and ethyl cyanoacetate
are similar, the values for the monoaryl versions of these
materials are substantially different. Ethyl phenylcy-
anoacetate has a pKa that is roughly five units lower than
that of the ethyl cyanoacetate,67 while diethyl phenyl-
malonate has a pKa value that is roughly six units higher
than that of the diethyl malonate.68 Thus, the phenyl-
substituted, stabilized nucleophile that is further from
the ketone enolate basicity undergoes the coupling reac-
tion more readily. Ketones, including R-aryl ketones,
undergo palladium-catalyzed R-arylation in a general
fashion. Thus, this difference in reactivity between
arylcyanoacetates and arylmalonates is more likely to
result from steric effects than electronic effects.
Con clu sion s: Over a ll Rea ction Scop e a n d Rela -
tion sh ip to P a lla d iu m -Ca ta lyzed C-X Bon d F or m a -
tion . Because the malonates and cyanoesters used in
these reactions display the same oxidation level at the
three central carbons, we discuss here the overall scope
of the reaction using malonates and cyanoesters inter-
changeably. For coupling with electron-poor aryl bro-
mides, the use of malonates is more straightforward than
the use of cyanoacetates. No diarylation is observed, and
ligand 2 is not necessary. In the coupling of malonates
with aryl chlorides, di-tert-butyl malonate reacts in the
most general fashion using ligand 1. Reactions of di-tert-
butylmalonate occurred in high yield using 1 as ligand
and NaH, or in some cases NaO-t-Bu, as base. In
contrast, it was necessary to use ligands 2 or 3 to prevent
hydrodehalogenation of the chloroarene when using
diethyl malonate. Fluoromalonates also reacted with aryl
halides in high yield, in this case to form products with
fluorine-substituted, quaternary centers. The scope for
reactions of cyanoacetates was not as broad as that for
reactions of malonates, but many reactions did occur
smoothly. Besides introducing functionality containing
nitrogen directly into the product of coupling with aryl
halides, the coupling of cyanoacetates reported here
provides products with diaryl-substituted quaternary
carbons. Formation of analogous diarylmalonates did not
occur. Finally, a straightforward, one-pot procedure for
formation of dialkyl alkylarylmalonates was developed
using a sequence of palladium-catalyzed arylation with
excess base and subsequent addition of an alkyl halide.
We presume that this process would be equally effective
for reactions of cyanoacetates, considering that the
alkylation step is commonplace.
a
Reactions conducted in duplicate on 1.0 mmol scale in toulene
using 1.0 equiv of aryl cyanoacetate, 1.1 equiv of aryl halide, and
b
Strong parallels can be found between the palladium-
catalyzed, base-mediated arylations reported here and
amine or alkoxide arylations. The coupling of amines with
3.0 equiv of Na3PO4. 0.5 equiv of ethyl cyanoacetate, 1.1 equiv
of aryl bromide, 4 mol % Pd(dba)2, 8 mol % 1. c Stirred at 100 °C
d
for 16 h. Reaction required 20 h. Yields are an average of two
runs.
(67) Bordwell, F. G.; Branca, J . C.; Bares, J . E.; Filler, R. J . Org.
Chem. 1988, 53, 780.
(68) Zaugg, H. E.; Schaefer, A. D. J . Am. Chem. Soc. 1965, 87, 7.
(entry 7), and methyl 4-bromobenzoate (entry 9) reacted
to form the products with a quaternary carbon in excel-

Arylation of Malonates and Cyanoesters
J . Org. Chem., Vol. 67, No. 2, 2002 549
Dioxane was purchased as anhydrous grade and stored in a
drybox. Toluene and tetrahydrofuran were distilled from
sodium and benzophenone and were stored in a drybox. Pd-
(dba)2 was prepared according to the literature procedure and
[(allyl)PdCl]2, P(t-Bu)3, and Pd2(dba)3‚CHCl3 were purchased
from Strem Chemicals. The following ligands were prepared
using literature procedures or slightly modified variations
thereof: 2,18 3,18 4,18 5,75 and 6.76
Gen er a l P r oced u r e for th e Ar yla tion of Dieth yl Ma lo-
n a te w ith Ar yl Br om id es (Ta ble 1). Method A: To a screw-
capped vial containing diethyl malonate (1.1 mmol) was added
tetrahydrofuran (1.0 mL) followed by NaH (1.1 mmol). Upon
evolution of hydrogen (ca.2 min), aryl bromide (1.0 mmol), P(t-
Bu)3 (0.040 mmol), Pd(dba)2 (0.020 mmol), and tetrahydrofuran
(2.0 mL) were added. The vial was sealed with a cap containing
a PTFE septum and removed from the drybox. The homoge-
neous reaction mixture was stirred at 70 °C and monitored
by GC. After complete conversion of the aryl halide, the crude
reaction was filtered through a plug of Celite and concentrated
in vacuo. The residue was purified by chromatography on silica
gel (1:2 dichloromethane/hexanes).
Method B: To a screw-capped vial containing diethyl
malonate (1.1 mmol) and aryl bromide (1.0 mmol) were added
P(t-Bu)3 (0.040 mmol), Pd(dba)2 (0.020 mmol), and K3PO4 (3.0
mmol) followed by toluene (3.0 mL). The vial was sealed with
a cap containing a PTFE septum and removed from the drybox.
The heterogeneous reaction mixture was stirred at 70 °C and
monitored by GC. After complete conversion of the aryl halide,
the crude reaction was filtered through a plug of Celite and
concentrated in vacuo. The residue was purified by chroma-
tography on silica gel (1:2 dichloromethane/hexanes).
aryl halides occurs with either aromatic or sterically
hindered alkylphosphines, but the coupling of less basic
substrates, such as such as alcohols and phenols, with
unactivated aryl halides occurs more readily with the
most sterically hindered of the alkylphosphine lig-
ands.45,58,69 The reason for this catalyst requirement in
the coupling of alcohols and phenols is the slow reductive
elimination to form ethers as a result of the lower basicity
of the alkoxide relative to the amido ligand.65,70,71
The rates for reductive elimination of R-aryl carbonyl
compounds are also connected, at least roughly, with the
electronic properties of the carbonyl substrate. The
coupling of ketones with aryl halides can be conducted
with either arylphosphines72,73 or sterically hindered
alkylphosphines,16,17 but they occur more rapidly when
conducted with the alkylphosphines. However, malonate
and cyanoester arylations require at this time the steri-
cally hindered alkylphosphines. We have shown recently
that arylpalladium monocarbonyl enolate complexes li-
gated by 1,2-bis(diphenylphosphino)benzene (DPPBz)
undergo reductive elimination at similar rates. However,
reductive elimination of these enolate complexes was
slower than reductive elimination of the analogous
arylpalladium methyl complex,74 and, most important for
the work here, reductive elimination of the analogous
arylpalladium complex of a malonate anion did not occur
at all. Thus, sterically hindered ligands, such as those
used in the work described here, accelerate reductive
elimination and overcome the unfavorable electronic
properties of these substrates. In addition, these hindered
ligands promote oxidative addition. Thus, the catalysts
described here lead to reaction of weakly basic malonates
and cyanoesters with aryl bromides and even unactivated
aryl chlorides.
Dieth yl 2-P h en ylm a lon a te (Ta ble 1, En tr y 1).16 Method
A of the above general procedure was followed using bro-
mobenzene (157 mg, 1.00 mmol) and diethyl malonate (176
mg, 1.10 mmol). The reaction mixture was purified by column
chromatography on silica gel (1:2 dichloromethane/hexanes)
to give the desired product (204 mg, 87%) as a colorless oil:
1H NMR (CDCl3) δ 7.43-7.34 (m, 5H), 4.62 (s, 1H), 4.27-4.18
(m, 4H), 1.27 (t, 7.2 Hz, 6H). 13C{1H} NMR (CDCl3) δ 168.17,
132.81, 129.27, 128.59, 128.20, 61.80, 57.96, 14.01.
Dieth yl 2-(2-Meth oxyp h en yl)m a lon a te (Ta ble 1, En tr y
4).77 Method A of the above general procedure was followed
using 2-bromoanisole (188 mg, 1.01 mmol) and diethyl malo-
nate (176 mg, 1.10 mmol). The reaction mixture was purified
by column chromatography on silica gel (1:2 dichloromethane/
hexanes) to give the desired product (233 mg, 87%) as a
colorless oil: 1H NMR (CDCl3) δ 7.34-7.28 (m, 2H), 6.99-6.95
(m, 1H), 6.90-6.88 (m, 1H), 5.11 (s, 1H), 4.28-4.17 (m, 4H),
3.82 (s, 3H), 1.26 (t, 7.2 Hz, 6H). 13C{1H} NMR (CDCl3) δ
168.63, 156.89, 129.43, 129.33, 121.87, 120.67, 110.66, 61.60,
55.61, 51.28, 14.06.
Dieth yl 2-(2-Meth ylp h en yl)m a lon a te (Ta ble 1, En tr y
5).5 Method A of the above general procedure was followed
using 2-bromotoluene (174 mg, 1.01 mmol) and diethyl malo-
nate (176 mg, 1.10 mmol). The reaction mixture was purified
by column chromatography on silica gel (1:2 dichloromethane/
hexanes) to give the desired product (208 mg, 82%) as a
colorless oil: 1H NMR (CDCl3) δ 7.41-7.37 (m, 1H), 7.24-7.17
(m, 3H), 4.87 (s, 1H), 4.29-4.17 (m, 4H), 2.34 (s, 3H), 1.26 (t,
7.2 Hz, 6H). 13C{1H} NMR (CDCl3) δ 168.40, 136.48, 131.65,
130.50, 128.82, 128.11, 126.33, 61.76, 54.39, 19.77, 14.04.
Dieth yl 2-(4-Meth oxyca r bon ylp h en yl)m a lon a te (Ta ble
1, En tr y 6). Method A of the above general procedure was
followed using methyl 2-bromobenzoate (217 mg, 1.01 mmol)
and diethyl malonate (177 mg, 1.11 mmol). The reaction
mixture was purified by column chromatography on silica gel
(1:1 dichloromethane/hexanes) to give the desired product (276
mg, 93%) as a colorless oil: 1H NMR (CDCl3) δ 8.04 (d, 8.4
Hz, 2H), 7.50 (d, 8.2 Hz, 2H), 4.66 (s, 1H), 4.25-4.22 (m, 4H),
3.92 (s, 3H), 1.27 (t, 6.8 Hz, 6H). 13C{1H} NMR (CDCl3) δ
Exp er im en ta l Section
Gen er a l Meth od s. Reactions were conducted using stan-
dard drybox techniques. 1H and 13C NMR spectra were
recorded on
a Bruker DPX 400 MHz spectrometer with
tetramethylsilane or residual protiated solvent used as a
reference and coupling constants reported in hertz (Hz).
Elemental analyses were performed by Robertson Microlabs,
Inc., Madison, NJ , and by Atlantic Microlabs, Inc., Norcross,
GA. Chromatographic purifications were performed by flash
chromatography using silica gel (200-400 mesh) from Natland
International Corporation. Yields for final products in all
tables refer to isolated yields and are the average of at least
two runs. Spectroscopic data and combustion analyses are
reported for all new compounds. Previously reported products
were isolated in greater than 95% purity as determined by 1H
NMR and capillary gas chromatography (GC). All 13C NMR
spectra were proton decoupled. GC analyses were performed
on a HP-6890 instrument using a DB-1301 narrow bore
column for high-temperature ramp applications (max. 120 °C/
min). GCMS spectra were recorded on a HP5890 instrument
equipped with a HP5971A Mass Spectral Analyzer using a
HP-1 methyl silicone column. All reagents and bases were
purchased from Aldrich and used without further purification.
(69) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J . P.; Sadighi, J .
P.; Buchwald, S. L. J . Am. Chem. Soc. 1999, 121, 4369.
(70) Mann, G.; Driver, M. S.; Hartwig, J . F. J . Am. Chem. Soc. 1998,
120, 827.
(71) Widenhoefer, R. A.; Buchwald, S. L. J . Am. Chem. Soc. 1998,
120, 6504.
(72) Hamann, B. C.; Hartwig, J . F. J . Am. Chem. Soc. 1997, 119,
12382.
(73) Palucki, M.; Buchwald, S. L. J . Am. Chem. Soc. 1997, 119,
11108.
(75) Tomori, H.; Fox, J . M.; Buchwald, S. L. J . Org. Chem. 2000,
65, 5334.
(76) Butler, I. R.; Cullen, W. R.; Kim, T. J .; Rettig, S. J .; Trotter, J .
Organometallics 1985, 4, 972.
(74) Culkin, D. A.; Hartwig, J . F. J . Am. Chem. Soc. 2001, 123, 5816.

550 J . Org. Chem., Vol. 67, No. 2, 2002
Beare and Hartwig
167.59, 166.72, 137.61, 130.00, 129.84, 129.43, 62.09, 57.88,
52.23, 14.00. Anal. Calcd for C15H18O6: C, 61.22; H, 6.16.
Found: C, 61.50: H, 5.94.
Dieth yl 2-(4-Tr iflu or om eth ylp h en yl)m a lon a te (Ta ble
1, En tr y 13).80 Method A of the above general procedure was
followed using 4-bromobenzotrifluoride (226 mg, 1.00 mmol)
and diethyl malonate (178 mg, 1.11 mmol). The reaction
mixture was purified by column chromatography on silica gel
(1:2 dichloromethane/hexanes) to give the desired product (271
mg, 89%) as a colorless oil: 1H NMR (CDCl3) δ 7.63 (d, 8.4
Hz, 2H), 7.55 (d, 8.4 Hz, 2H), 4.68 (s, 1H), 4.29-4.17 (m, 4H),
1.27 (t, 7.2 Hz, 6H). 13C{1H} NMR (CDCl3) δ 167.54, 136.64,
130.49 (q, 32.5 Hz), 129.83, 125.55 (q, 3.7 Hz), 124.02 (q, 272.2
Hz), 62.18, 57.71, 14.00.
Dieth yl 2-(2-Na p h th yl)m a lon a te (Ta ble 1, En tr y 14).81
Method A of the above general procedure was followed using
2-bromonaphthalene (212 mg, 1.02 mmol) and diethyl malo-
nate (176 mg, 1.10 mmol). The reaction mixture was purified
by column chromatography on silica gel (1:2 dichloromethane/
hexanes) to give the desired product (266 mg, 91%) as a
colorless oil: 1H NMR (CDCl3) δ 7.85-7.81 (m, 4H), 7.56 (dd,
8.6, 1.6 Hz, 1H), 7.49-7.46 (m, 2H), 4.79 (s, 1H), 4.29-4.17
(m, 4H), 1.26 (t, 7.2 Hz, 6H). 13C{1H} NMR (CDCl3) δ 168.21,
133.19, 132.98, 130.26, 128.64, 128.30, 128.00, 127.63, 126.72,
126.34, 126.23, 61.88, 58.08, 14.03.
Dieth yl 2-(3,4-Meth ylen ed ioxyp h en yl)m a lon a te (Ta ble
1, En tr y 15). Method A of the above general procedure was
followed using 4-bromo-1,2-(methylenedioxy)benzene (202 mg,
1.00 mmol) and diethyl malonate (177 mg, 1.11 mmol). The
reaction mixture was purified by column chromatography on
silica gel (1:2 dichloromethane/hexanes) to give the desired
product (231 mg, 82%) as a colorless oil: 1H NMR (CDCl3) δ
6.96 (d, 1.6 Hz, 1H), 6.81 (dd, 8.0, 1.6 Hz, 1H), 6.77 (d, 8.0 Hz,
1H), 5.96 (s, 2H), 4.52 (s, 1H), 4.27-4.15 (m, 4H), 1.27 (t, 7.2
Hz, 6H). 13C{1H} NMR (CDCl3) δ 168.25, 147.82, 147.62,
126.31, 122.96, 109.58, 108.21, 101.23, 61.84, 57.45, 14.03.
Anal. Calcd for C14H16O6: C, 59.99; H, 5.75. Found: C, 60.01:
H, 5.80.
Dieth yl 2-(4-Bip h en yl)m a lon a te (Ta ble 1, En tr y 16).82
Method A of the above general procedure was followed using
4-bromobiphenyl (232 mg, 1.00 mmol) and diethyl malonate
(176 mg, 1.10 mmol). The reaction mixture was purified by
column chromatography on silica gel (1:2 dichloromethane/
hexanes) to give the desired product (283 mg, 91%) as a
colorless oil: 1H NMR (CDCl3) δ 7.60-7.56 (m, 4H), 7.49-7.41
(m, 4H), 7.36-7.32 (m, 1H), 4.66 (s, 1H), 4.30-4.17 (m, 4H),
1.28 (t, 7.2 Hz, 6H). 13C{1H} NMR (CDCl3) δ 168.16, 141.11,
140.56, 131.76, 129.68, 128.77, 127.43, 127.34, 127.12, 61.87,
57.62, 14.02.
Diet h yl 2-(4-Acet ylp h en yl)m a lon a t e (Ta b le 1, E n t r y
17).5 Method B of the above general procedure was followed
using 4-bromoacetophenone (201 mg, 1.01 mmol) and diethyl
malonate (177 mg, 1.11 mmol). The reaction mixture was
purified by column chromatography on silica gel (2:1 dichloro-
methane/hexanes) to give the desired product (250 mg, 89%)
as a colorless oil: 1H NMR (CDCl3) δ 7.98-7.95 (m, 2H), 7.53-
7.50 (m, 2H), 4.68 (s, 1H), 4.29-4.17 (m, 4H), 2.61 (s, 3H), 1.27
(t, 7.2 Hz, 6H). 13C{1H} NMR (CDCl3) δ 197.66, 167.54, 137.79,
136.81, 129.64, 128.58, 62.11, 57.84, 26.69, 14.00.
Dieth yl 2-(4-Ben zoylp h en yl)m a lon a te (Ta ble 1, En tr y
18). Method B of the above general procedure was followed
using 4-bromobenzophenone (261 mg, 1.00 mmol) and diethyl
malonate (176 mg, 1.10 mmol). The reaction mixture was
purified by column chromatography on silica gel (2:1 dichlo-
romethane/hexanes) to give the desired product (313 mg, 92%)
as a colorless oil: 1H NMR (CDCl3) δ 7.83-7.80 (m, 4H), 7.62-
7.57 (m, 1H), 7.56-7.53 (m, 2H), 7.51-7.46 (m, 2H), 4.71 (s,
1H), 4.31-4.18 (m, 4H), 1.28 (t, 7.2 Hz, 6H). 13C{1H} NMR
(CDCl3) δ 196.20, 167.61, 137.37, 137.33, 137.10, 132.55,
130.29, 130.06, 129.36, 128.32, 62.11, 57.86, 14.01. Anal. Calcd
for C20H20O5: C, 70.57; H, 5.92. Found: C, 70.77: H, 6.05.
Dieth yl 2-(4-Meth oxyp h en yl)m a lon a te (Ta ble 1, En tr y
7).5 Method A of the above general procedure was followed
using 4-bromoanisole (189 mg, 1.01 mmol) and diethyl malo-
nate (176 mg, 1.10 mmol). The reaction mixture was purified
by column chromatography on silica gel (1:2 dichloromethane/
hexanes) to give the desired product (245 mg, 91%) as a
colorless oil: 1H NMR (CDCl3) δ 7.35-7.31 (m, 2H), 6.91-6.87
(m, 2H), 4.55 (s, 1H), 4.27-4.15 (m, 4H), 3.79 (s, 3H), 1.26 (t,
7.2 Hz, 6H). 13C{1H} NMR (CDCl3) δ 168.46, 159.46, 130.39,
124.90, 114.00, 61.75, 57.13, 55.25, 14.03.
Dieth yl 2-(4-F lu or op h en yl)m a lon a te (Ta ble 1, En tr y
8).78 Method A of the above general procedure was followed
using 4-bromofluorobenzene (175 mg, 1.00 mmol) and diethyl
malonate (176 mg, 1.10 mmol). The reaction mixture was
purified by column chromatography on silica gel (1:2 dichlo-
romethane/hexanes) to give the desired product (203 mg, 80%)
as a colorless oil: 1H NMR (CDCl3) δ 7.41-7.37 (m, 2H), 7.08-
7.03 (m, 2H), 4.59 (s, 1H), 4.28-4.16 (m, 4H), 1.26 (t, 7.2 Hz,
6H). 13C{1H} NMR (CDCl3) δ 168.06, 162.65 (d, 247.2 Hz),
131.04 (d, 8.3 Hz), 128.59 (d, 3.5 Hz), 115.54 (d, 22.5 Hz), 61.94,
57.10, 14.01.
Dieth yl 2-(1-Na p h th yl)m a lon a te (Ta ble 1, En tr y 9).5
Method A of the above general procedure was followed using
1-bromonaphthalene (207 mg, 1.00 mmol) and diethyl malo-
nate (176 mg, 1.10 mmol). The reaction mixture was purified
by column chromatography on silica gel (1:2 dichloromethane/
hexanes) to give the desired product (240 mg, 84%) as a
colorless oil: 1H NMR (CDCl3) δ 7.98 (d, 8.4 Hz, 1H), 7.90 (d,
7.6 Hz, 1H), 7.86 (d, 8.0 Hz, 1H), 7.59-7.48 (m, 4H), 5.44 (s,
1H), 4.29-4.23 (m, 4H), 1.27 (t, 7.2 Hz, 6H). 13C{1H} NMR
(CDCl3) δ 168.49, 133.88, 131.60, 129.28, 129.00, 128.89,
127.03, 126.68, 125.80, 125.40, 122.80, 61.93, 54.44, 14.03.
Dieth yl 2-(4-Dim eth yla m in op h en yl)m a lon a te (Ta ble 1,
En tr y 10).79 Method A of the above general procedure was
followed using 4-bromo-N,N-dimethylaniline (200 mg, 1.00
mmol) and diethyl malonate (176 mg, 1.10 mmol). The reaction
mixture was purified by column chromatography on silica gel
(1:2 dichloromethane/hexanes) to give the desired product (249
mg, 89%) as a colorless oil: 1H NMR (CDCl3) δ 7.27-7.25 (m,
2H), 6.71-6.69 (m, 2H), 4.50 (s, 1H), 4.26-4.14 (m, 4H), 2.94
(s, 6H), 1.26 (t, 7.6 Hz, 6H). 13C{1H} NMR (CDCl3) δ 168.82,
150.30, 129.90, 120.32, 112.37, 61.57, 57.09, 40.46, 14.06.
Dieth yl 2-(6-Meth oxyn a p h th a len -2-yl)m a lon a te (Ta ble
1, En tr y 11).24 Method B of the above general procedure was
followed using 2-bromo-6-methoxynaphthalene (238 mg, 1.00
mmol) and diethyl malonate (176 mg, 1.10 mmol). The reaction
mixture was purified by column chromatography on silica gel
(1:2 dichloromethane/hexanes) to give the desired product (283
mg, 89%) as a colorless oil: 1H NMR (CDCl3) δ 7.76 (m, 1H),
7.74-7.69 (m, 2H), 7.51 (dd, 8.8, 1.6 Hz, 1H), 7.13 (dd, 8.8,
2.4 Hz, 1H), 7.11 (d, 2.4 Hz, 1H), 4.75 (s, 1H), 4.28-4.16 (m,
4H), 3.88 (s, 3H), 1.25 (t, 7.2 Hz, 6H). 13C{1H} NMR (CDCl3)
δ 168.35, 158.03, 134.24, 129.50, 128.70, 128.40, 127.99,
127.25, 127.14, 119.09, 105.56, 61.80, 57.93, 55.27, 14.03.
Dieth yl 2-(4-P h en oxyp h en yl)m a lon a te (Ta ble 1, En tr y
12). Method A of the above general procedure was followed
using 4-bromobiphenyl ether (249 mg, 1.00 mmol) and diethyl
malonate (176 mg, 1.10 mmol). The reaction mixture was
purified by column chromatography on silica gel (1:2 dichlo-
romethane/hexanes) to give the desired product (292 mg, 89%)
as a colorless oil: 1H NMR (CDCl3) δ 7.38-7.31 (m, 4H), 7.13-
7.09 (m, 1H), 7.04-7.01 (m, 2H), 7.00-6.96 (m, 2H), 4.59 (s,
1H), 4.28-4.16 (m, 4H), 1.27 (t, 7.2 Hz, 6H). 13C{1H} NMR
(CDCl3) δ 168.26, 157.42, 156.68, 130.70, 129.80, 127.34,
123.60, 119.31, 118.53, 61.87, 57.22, 14.05. Anal. Calcd for
C
19H20O5: C, 69.50; H, 6.14. Found: C, 69.55: H, 6.12.
(80) Hammond, G. B.; Plevey, R. G.; Sampson, P.; Tatlow, J . C. J .
Fluorine Chem. 1988, 40, 81.
(81) Guanti, G.; Narisano, E.; Podgorski, T.; Thea, S.; Williams, A.
Tetrahedron 1990, 46, 7081.
(82) Cavalleri, B.; Bellasio, E.; Vigevani, A.; Testa, E. Farmaco, Ed.
Sci. 1969, 24, 451.
(77) Setsune, J .; Ueda, T.; Shikata, K.; Matsukawa, K.; Iida, T.;
Kitao, T. Tetrahedron 1986, 42, 2647.
(78) Djakovitch, L.; Kohler, K. J . Organomet. Chem. 2000, 606, 101.
(79) Ghosh, S.; Pardo, S. N.; Salomon, R. G. J . Org. Chem. 1982,
47, 4692.

Arylation of Malonates and Cyanoesters
J . Org. Chem., Vol. 67, No. 2, 2002 551
Dieth yl 2-[3-(1,3-Dioxola n e)p h en yl]m a lon a te (Ta ble 1,
En tr y 19). Method B of the above general procedure was
followed using 2-(3-bromophenyl)-1,3-dioxolane (229 mg, 1.00
mmol) and diethyl malonate (176 mg, 1.10 mmol). The reaction
mixture was purified by column chromatography on silica gel
(2:1 dichloromethane/hexanes) to give the desired product (256
mg, 83%) as a colorless oil: 1H NMR (CDCl3) δ 7.50-7.36 (m,
4H), 5.81 (s, 1H), 4.63 (s, 1H), 4.26-4.16 (m, 4H), 4.15-3.98
(m, 4H), 1.25 (t, 7.2 Hz, 6H). 13C{1H} NMR (CDCl3) δ 167.98,
138.32, 132.92, 130.04, 128.65, 127.59, 126.36, 103.40, 65.28,
61.84, 57.87, 14.00. Anal. Calcd for C16H20O6: C, 62.33; H, 6.54.
Found: C, 62.27: H, 6.53.
Dieth yl 2-(2-F lu or obip h en yl-4-yl)m a lon a te (Ta ble 1,
En tr y 20).24 Method B of the above general procedure was
followed using 4-bromo-2-fluorobiphenyl (251 mg, 1.00 mmol)
and diethyl malonate (176 mg, 1.10 mmol). The reaction
mixture was purified by column chromatography on silica gel
(1:2 dichloromethane/hexanes) to give the desired product (371
mg, 91%) as a colorless oil: 1H NMR (CDCl3) δ 7.55-7.52 (m,
2H), 7.45-7.41 (m, 3H), 7.38-7.36 (m, 1H), 7.28 (d, 1.6 Hz,
1H), 7.24 (dd, 6.0, 1.6 Hz, 1H), 4.64 (s, 1H), 4.30-4.19 (m, 4H),
1.29 (t, 7.2 Hz, 6H). 13C{1H} NMR (CDCl3) δ 167.69, 159.51
(d, 248.3 Hz), 135.31, 129.99 (d, 2.9 Hz), 128.47, 128.46, 127.83,
125.35 (d, 3.3 Hz), 117.14 (d, 24.4 Hz), 62.08, 57.35, 14.03.
Gen er a l P r oced u r e for th e Ar yla tion of Dieth yl Ma lo-
n a te w ith Ar yl Ch lor id es (Ta ble 2). To a screw-capped vial
containing diethyl malonate (1.1 mmol) and aryl chloride (1.0
mmol) were added phosphine (0.040 mmol), Pd(dba)2 (0.020
mmol), and K3PO4 (3.0 mmol) followed by toluene (3.0 mL).
The vial was sealed with a cap containing a PTFE septum and
removed from the drybox. The heterogeneous reaction mixture
was stirred at 100 °C and monitored by GC. After complete
conversion of the aryl halide, the crude reaction was filtered
through a plug of Celite and concentrated in vacuo. The residue
was purified by chromatography on silica gel (1:2 dichloro-
methane/hexanes).
Dieth yl 2-(2,4-Dim eth ylp h en yl)m a lon a te (Ta ble 2, En -
tr y 9). The above general procedure was followed using
2-chloro-p-xylene (141 mg, 1.00 mmol) and diethyl malonate
(176 mg, 1.10 mmol). The reaction mixture was purified by
column chromatography on silica gel (1:2 dichloromethane/
hexanes) to give the desired product (228 mg, 86%) as a
colorless oil: 1H NMR (CDCl3) δ 7.19 (s, 1H), 7.07 (d, 8.0 Hz,
1H), 7.03-7.01 (m, 1H), 4.83 (s, 1H), 4.29-4.17 (m, 4H), 2.31
(s, 3H), 2.29 (s, 3H), 1.27 (t, 7.2 Hz, 3H). 13C{1H} NMR (CDCl3)
δ 168.50, 135.78, 133.32, 131.36, 130.38, 129.36, 128.90, 61.71,
54.35, 21.06, 19.29, 14.04.
Gen er a l P r oced u r e for th e Ar yla tion of Di-ter t-bu tyl
Ma lon a te (Ta ble 3). Method A: Into a screw-capped vial
containing di-tert-butyl malonate (1.1 mmol) was added tet-
rahydrofuran (1.0 mL), followed by NaH (1.1 mmol). After the
evolution of hydrogen was complete (ca. 2 min), aryl bromide
(1.0 mmol), phosphine (0.040 mmol), Pd(dba)2 (0.020 mmol),
and additional tetrahydrofuran (2.0 mL) were added. The vial
was sealed with a cap containing a PTFE septum and removed
from the drybox. The homogeneous reaction mixture was
stirred at 70 °C and monitored by GC. After complete conver-
sion of the aryl bromide, the crude reaction was filtered
through a plug of Celite and concentrated in vacuo. The residue
was purified by chromatography on silica gel (1:2 dichlo-
romethane/hexanes).
(177 mg, 1.10 mmol). The reaction mixture was purified by
column chromatography on silica gel (1:2 dichloromethane/
hexanes) to give the desired product (204 mg, 87%) as a white
solid: 1H NMR (CDCl3) δ 7.39-7.30 (m, 5H), 4.43 (s, 1H), 1.46
(s, 18H). 13C{1H} NMR (CDCl3) δ 167.47, 133.47, 129.31,
128.40, 127.86, 81.96, 60.08, 27.87.
Di-ter t-bu tyl 2-(2-Meth oxyp h en yl)m a lon a te (Ta ble 3,
En tr y 2). Method A of the above general procedure was
followed using 2-bromoanisole (187 mg, 1.00 mmol) and di-
tert-butyl malonate (238 mg, 1.10 mmol). The reaction mixture
was purified by column chromatography on silica gel (1:2
dichloromethane/hexanes) to give the desired product (264 mg,
82%) as a white solid: 1H NMR (CDCl3) δ 7.38-7.35 (m, 1H),
7.29-7.25 (m, 1H), 6.97-6.94 (m, 1H), 6.88-6.86 (m, 1H), 4.94
(s, 1H), 3.80 (s, 3H), 1.47 (s, 18H). 13C{1H} NMR (CDCl3) δ
167.87, 156.95, 129.23, 128.93, 122.63, 120.51, 110.57, 81.59,
55.54, 53.06, 27.91. Anal. Calcd for C18H26O5: C, 67.06; H, 8.13.
Found: C, 67.30: H, 8.23.
Di-ter t-bu tyl 2-(4-Meth oxyp h en yl)m a lon a te (Ta ble 3,
En tr y 3). Method B of the above general procedure was
followed using 4-bromoanisole (145 mg, 1.01 mmol), di-tert-
butyl malonate (238 mg, 1.10 mmol), and [Pd(allyl)Cl]2 (3.4
mg, 0.0093 mmol). The reaction mixture was purified by
column chromatography on silica gel (1:2 dichloromethane/
hexanes) to give the desired product (278 mg, 85%) as a white
solid: 1H NMR (CDCl3) δ 7.31 (d, 8.8 Hz, 2H), 6.88 (d, 8.8 Hz,
2H), 4.37 (s, 1H), 3.79 (s, 3H), 1.46 (s, 18H). 13C{1H} NMR
(CDCl3) δ 167.75, 159.20, 130.41, 125.62, 113.82, 81.84, 59.24,
55.21, 27.88. Anal. Calcd for C18H26O5: C, 67.06; H, 8.13.
Found: C, 67.00: H, 7.79.
Di-ter t-bu tyl 2-(2-Meth ylp h en yl)m a lon a te (Ta ble 3,
En tr y 4). Method A of the above general procedure was
followed using 2-bromotoluene (171 mg, 1.00 mmol) and di-
tert-butyl malonate (238 mg, 1.10 mmol). The reaction mixture
was purified by column chromatography on silica gel (1:4
dichloromethane/hexanes) to give the desired product (266 mg,
87%) as a white solid: 1H NMR (CDCl3) δ 7.43-7.38 (m, 1H),
7.23-7.15 (m, 3H), 4.70 (s, 1H), 2.32 (s, 3H), 1.47 (s, 18H).
13C{1H} NMR (CDCl3) δ 167.69, 136.45, 132.41, 130.33, 128.59,
127.73, 126.11, 81.92, 56.33, 27.89, 19.81. Anal. Calcd for
C
18H26O4: C, 70.56; H, 8.55. Found: C, 70.58: H, 8.36.
Di-ter t-b u t yl 2-(3,4-Met h ylen ed ioxyp h en yl)m a lon a t e
(Ta ble 3, En tr y 6). Method A of the above general procedure
was followed using 4-bromo-1,2-(methylenedioxy)benzene (206
mg, 1.00 mmol) and di-tert-butyl malonate (238 mg, 1.10
mmol). The reaction mixture was purified by column chroma-
tography on silica gel (1:2 dichloromethane/hexanes) to give
the desired product (292 mg, 85%) as a colorless oil: 1H NMR
(CDCl3) δ 6.95-6.94 (m, 1H), 6.79 (m, 1H), 6.77 (d, 8.0 Hz,
1H), 5.95 (s, 2H), 4.34 (s, 1H), 1.47 (s, 18H). 13C{1H} NMR
(CDCl3) δ 167.53, 147.63, 147.34, 127.05, 122.99, 109.63,
108.09, 101.09, 82.00, 59.57, 27.88. Anal. Calcd for C18H24O6:
C, 64.27; H, 7.19. Found: C, 60.01: H, 5.80.
Di-ter t-bu tyl 2-(4-Dim eth ylam in oph en yl)m alon ate (Ta-
ble 3, En tr y 7). Method A of the above general procedure was
followed using 4-bromo-N,N-dimethylaniline (203 mg, 1.01
mmol) and di-tert-butyl malonate (238 mg, 1.10 mmol). The
reaction mixture was purified by column chromatography on
silica gel (1:1 dichloromethane/hexanes) to give the desired
product (299 mg, 88%) as a white solid: 1H NMR (CDCl3) δ
7.26-7.22 (m, 2H), 6.72-6.69 (m, 2H), 4.32 (s, 1H), 2.93 (s,
6H), 1.46 (s, 18H). 13C{1H} NMR (CDCl3) δ 168.08, 150.15,
129.93, 121.21, 112.42, 81.53, 59.19, 40.54, 27.91. Anal. Calcd
for C19H29NO4: C, 68.03; H, 8.71; N, 4.18. Found: C, 68.04:
H, 8.82: N, 4.04.
Di-ter t-b u t yl 2-(4-Tr iflu or om et h ylp h en yl)m a lon a t e
(Ta ble 3, En tr y 10). Method B of the above general procedure
was followed using 4-chlorobenzotrifluoride (143 mg, 1.00
mmol), di-tert-butyl malonate (238 mg, 1.10 mmol), and [Pd-
(allyl)Cl]2 (3.7 mg, 0.010 mmol). The reaction mixture was
purified by column chromatography on silica gel (1:2 dichlo-
romethane/hexanes) to give the desired product (255 mg, 83%)
as a white solid: 1H NMR (CDCl3) δ 7.62 (d, 8.2 Hz, 2H), 7.53
(d, 8.2 Hz, 2H), 4.51 (s, 1H), 1.47 (s, 18H). 13C{1H} NMR
(CDCl3) δ 166.82, 137.40, 130.14 (q, 32.5 Hz), 129.86, 125.36
Method B: Into a screw-capped vial containing di-tert-butyl
malonate (1.1 mmol) and aryl chloride (1.0 mmol) were added
P(t-Bu)3 (0.040 mmol), Pd(dba)2 (0.020 mmol) or [Pd(allyl)Cl]2
(0.010 mmol), and NaO-t-Bu (1.2 mmol) followed by dioxane
(3.0 mL). The vial was sealed with a cap containing a PTFE
septum and removed from the drybox. The heterogeneous
reaction mixture was stirred at the required temperature and
monitored by GC. After complete conversion of the aryl halide,
the crude reaction was filtered through a plug of Celite and
concentrated in vacuo. The residue was purified by chroma-
tography on silica gel (1:2 dichloromethane/hexanes).
Di-ter t-bu t yl 2-P h en ylm a lon a t e (Ta b le 3, E n t r y 1).16
Method A of the above general procedure was followed using
bromobenzene (157 mg, 1.00 mmol) and di-tert-butyl malonate

552 J . Org. Chem., Vol. 67, No. 2, 2002
Beare and Hartwig
(q, 3.5 Hz), 124.12 (q, 272.1 Hz), 82.37, 59.85, 27.85. Anal.
Calcd for C18H23F3O4: C, 59.99; H, 6.43. Found: C, 59.99: H,
6.46.
for C17H23FO4: C, 65.79; H, 7.47; F, 6.12. Found: C, 65.96:
H, 7.37: F, 6.26.
Dieth yl 2-F lu or o-2-(2-n a p h th yl)m a lon a te (Ta ble 4, En -
tr y 5).35 The above general procedure was followed using
2-bromonaphthalene (209 mg, 1.01 mmol) and diethyl fluoro-
malonate (195 mg, 1.10 mmol). The reaction mixture was
purified by column chromatography on silica gel (1:2 dichlo-
romethane/hexanes) to give the desired product (236 mg, 77%)
as a colorless oil: 1H NMR (CDCl3) δ 8.09 (d, 1.6 Hz, 1H), 7.89-
7.82 (m, 3H), 7.69 (dd, 8.8, 2.0 Hz, 1H), 7.54-7.48 (m, 2H),
4.34 (q, 7.2 Hz, 4H), 1.31 (t, 7.2 Hz, 6H). 13C{1H} NMR (CDCl3)
δ 165.64 (d, 25.5 Hz), 133.45, 132.56, 130.50 (d, 21.6 Hz),
128.58, 128.11 (d, 1.1 Hz), 127.61, 127.07, 126.58, 125.16 (d,
10.3 Hz), 123.06 (d, 7.3 Hz), 94.28 (d, 211.6 Hz), 63.08, 13.94.
Gen er a l P r oced u r e for th e Sequ en tia l Ar yla tion /Alk y-
la tion of Dieth yl Ma lon a te (Ta ble 5). Into a screw-capped
vial containing diethyl malonate (1.0 mmol) and aryl bromide
(1.1 mmol) were added P(t-Bu)3 (0.040 mmol), Pd(dba)2 (0.020
mmol), and K3PO4 (4.5 mmol) followed by toluene (2.0 mL).
The vial was sealed with a cap containing a PTFE septum and
removed from the drybox. The heterogeneous reaction mixture
was stirred at 70 °C and monitored by GC. After complete
conversion of the aryl bromide, iodomethane (2.0 mmol) was
injected and the thick slurry was stirred at 70 °C until all of
the arylmalonate was converted. The crude reaction was
filtered through a plug of Celite and concentrated in vacuo.
The residue was purified by chromatography on silica gel (1:2
dichloromethane/hexanes).
Diet h yl 2-Met h yl-2-p h en ylm a lon a t e (Ta b le 5, E n t r y
1).83 The above general procedure was followed using bro-
mobenzene (174 mg, 1.11 mmol), diethyl malonate (161 mg,
1.01 mmol), and iodomethane (0.130 µL, 2.09 mmol). The
reaction mixture was purified by column chromatography on
silica gel (1:2 dichloromethane/hexanes) to give the desired
product (225 mg, 89%) as a colorless oil: 1H NMR (CDCl3) δ
7.39-7.25 (m, 5H), 4.26-4.19 (m, 4H), 1.86 (s, 3H), 1.25 (t,
7.2 Hz, 6H). 13C{1H} NMR (CDCl3) δ 171.54, 138.36, 128.14,
127.55, 127.42, 61.68, 58.79, 22.37, 13.97.
Dieth yl 2-Meth yl-2-(4-m eth oxyph en yl)m alon ate (Table
5, En tr y 2).15 The above general procedure was followed using
2-bromoanisole (213 mg, 1.14 mmol), diethyl malonate (162
mg, 1.01 mmol), and iodomethane (0.130 µL, 2.09 mmol). The
reaction mixture was purified by column chromatography on
silica gel (1:2 dichloromethane/hexanes) to give the desired
product (257 mg, 91%) as a colorless oil: 1H NMR (CDCl3) δ
7.33-7.29 (m, 2H), 6.89-6.85 (m, 2H), 4.28-4.16 (m, 4H), 3.79
(s, 3H), 1.85 (s, 3H), 1.25 (t, 7.2 Hz, 6H). 13C{1H} NMR (CDCl3)
δ 171.79, 158.86, 130.23, 128.66, 113.47, 61.63, 57.98, 55.21,
22.18, 13.99.
Dieth yl 2-Meth yl-2-(4-tr iflu or om eth ylph en yl)m alon ate
(Ta ble 5, En tr y 3). The above general procedure was followed
using 4-bromobenzotrifluoride (174 mg, 1.11 mmol), diethyl
malonate (161 mg, 1.01 mmol), and iodomethane (0.130 µL,
2.09 mmol). The reaction mixture was purified by column
chromatography on silica gel (1:2 dichloromethane/hexanes)
to give the desired product (289 mg, 90%) as a colorless oil:
1H NMR (CDCl3) δ 7.61 (d, 8.4 Hz, 2H), 7.52 (d, 8.4 Hz, 2H),
4.30-4.19 (m, 4H), 1.89 (s, 3H), 1.26 (t, 7.2 Hz, 6H). 13C{1H}
NMR (CDCl3) δ 170.95, 142.30, 129.84 (q, 32.5 Hz), 128.10,
125.13 (q, 3.7 Hz), 124.10, (q, 272.06 Hz), 62.07, 58.79, 22.28,
13.97. Anal. Calcd for C15H17F3O4: C, 56.60; H, 5.38. Found:
C, 56.77: H, 5.27.
Dieth yl 2-Meth yl-2-(6-m eth oxyn a p h th a len -2-yl)m a lo-
n a te (Ta ble 5, En tr y 4).26 The above general procedure was
followed using 2-bromo-6-methoxynaphthalene (264 mg, 1.11
mmol), diethyl malonate (162 mg, 1.01 mmol), and iodo-
methane (0.130 µL, 2.09 mmol). The reaction mixture was
purified by column chromatography on silica gel (1:2 dichlo-
romethane/hexanes) to give the desired product (301 mg, 90%)
as a colorless oil: 1H NMR (CDCl3) δ 7.72-7.70 (m, 3H), 7.48
(dd, 8.8, 2.0 Hz, 1H), 7.14 (dd, 9.0, 2.4 Hz, 1H), 7.11 (d, 2.4
Di-ter t-bu tyl 2-(2,5-Dim eth ylp h en yl)m a lon a te (Ta ble
3, En tr y 12). Method B of the above general procedure was
followed using 4-chloro-p-xylene (142 mg, 1.01 mmol), di-tert-
butyl malonate (238 mg, 1.10 mmol), and Pd(dba)2 (11.5 mg,
0.0200 mmol). The reaction mixture was purified by column
chromatography on silica gel (1:2 dichloromethane/hexanes)
to give the desired product (285 mg, 88%) as a white solid:
1H NMR (CDCl3) δ 7.20 (s, 1H), 7.05 (d, 8.0 Hz, 1H), 7.00 (d,
7.6 Hz, 1H), 4.66 (s, 1H), 2.31 (s, 3H), 2.26 (s, 3H), 1.48 (s,
18H). 13C{1H} NMR (CDCl3) δ 167.80, 135.44, 133.28, 132.15,
130.19, 129.18, 128.47, 81.83, 56.31, 27.91, 21.11, 19.31. Anal.
Calcd for C19H28O4: C, 71.22; H, 8.81. Found: C, 71.21: H,
8.89.
Gen er a l P r oced u r e for th e Ar yla tion of Dieth yl 2-F lu -
or om a lon a te (Ta ble 4). Into a screw-capped vial containing
diethyl 2-fluoromalonate (1.1 mmol) was added tetrahydrofu-
ran (1.0 mL), followed by NaH (1.1 mmol). After complete
evolution of hydrogen (ca. 2 min), aryl bromide (1.0 mmol),
P(t-Bu)3 (0.040 mmol), Pd(dba)2 (0.020 mmol), and tetrahy-
drofuran (2.0 mL) were added. The vial was sealed with a cap
containing a PTFE septum and removed from the drybox. The
homogeneous reaction mixture was stirred at 70 °C and
monitored by GC. After complete conversion of the aryl halide,
the crude reaction was filtered through a plug of Celite and
concentrated in vacuo. The residue was purified by chroma-
tography on silica gel (1:2 dichloromethane/hexanes).
Diet h yl 2-F lu or o-2-p h en ylm a lon a t e (Ta b le 4, E n t r y
1).35 The above general procedure was followed using bro-
mobenzene (157 mg, 1.00 mmol) and diethyl fluoromalonate
(196 mg, 1.10 mmol). The reaction mixture was purified by
column chromatography on silica gel (1:2 dichloromethane/
hexanes) to give the desired product (219 mg, 86%) as a
colorless oil: 1H NMR (CDCl3) δ 7.61-7.58 (m, 2H), 7.43-7.41
(m, 3H), 4.34 (q, 7.2 Hz, 4H), 1.32 (t, 7.62 Hz, 6H). 13C{1H}
NMR (CDCl3) δ 165.60 (d, 25.8 Hz), 133.13 (d, 22.0 Hz), 129.42
(d, 1.2 Hz), 128.30 (d, 1.1 Hz), 125.65 (d, 8.8 Hz), 94.05 (d,
200.1 Hz), 63.02, 13.92.
Dieth yl 2-F lu or o-2-(4-m eth oxyp h en yl)m a lon a te (Ta ble
4, En tr y 2).82 The above general procedure was followed using
4-bromoanisole (187 mg, 1.00 mmol) and diethyl fluoromalo-
nate (195 mg, 1.10 mmol). The reaction mixture was purified
by column chromatography on silica gel (1:2 dichloromethane/
hexanes) to give the desired product (244 mg, 86%) as a
colorless oil: 1H NMR (CDCl3) δ 7.52-7.48 (m, 2H), 6.95-7.91
(m, 2H), 4.38-4.27 (m, 4H), 3.82 (s, 3H), 1.31 (t, 7.2 Hz, 6H).
13C{1H} NMR (CDCl3) δ 165.85 (d, 26.1 Hz), 160.36, 127.25
(d, 8.4 Hz), 125.19 (d, 22.7 Hz), 113.71, 93.99 (d, 199.5 Hz),
62.94, 55.31, 13.95.
Dieth yl 2-F lu or o-2-(4-m eth oxyca r bon ylp h en yl)m a lo-
n a te (Ta ble 4, En tr y 3). The above general procedure was
followed using methyl 4-bromobenzoate (215 mg, 1.00 mmol)
and diethyl fluoromalonate (195 mg, 1.10 mmol). The reaction
mixture was purified by column chromatography on silica gel
(1:2 dichloromethane/hexanes) to give the desired product (262
mg, 84%) as a colorless oil: 1H NMR (CDCl3) δ 8.10-8.07 (m,
2H), 7.71-7.69 (m, 2H), 4.34 (q, 7.2 Hz, 4H), 3.93 (s, 3H), 1.31
(t, 7.2 Hz, 6H). 13C{1H} NMR (CDCl3) δ 166.44, 165.07 (d, 25.6
Hz), 137.57, (d, 21.9 Hz), 131.08, 129.47 (d, 1.3 Hz), 125.77 (d,
9.2 Hz), 93.81 (d, 202.0 Hz), 63.30, 52.33, 13.91. Anal. Calcd
for C15H17FO6: C, 57.69; H, 5.49. Found: C, 57.67: H, 5.59.
Dieth yl 2-Flu or o-2-(4-ter t-bu tylph en yl)m alon ate (Table
4, En tr y 4). The above general procedure was followed using
1-bromo-4-tert-butylbenzene (217 mg, 1.02 mmol) and diethyl
fluoromalonate (196 mg, 1.10 mmol). The reaction mixture was
purified by column chromatography on silica gel (1:2 dichlo-
romethane/hexanes) to give the desired product (275 mg, 87%)
as a colorless oil: 1H NMR (CDCl3) δ 7.52-7.49 (m, 2H), 7.44-
7.41 (m, 2H), 4.38-4.27 (m, 4H), 1.32 (s, 9H), 1.32 (t, 7.2 Hz,
6H). 13C{1H} NMR (CDCl3) δ 165.76 (d, 26.0 Hz), 152.46 (d,
1.2 Hz), 130.15 (d, 22.1 Hz), 125.45 (d, 8.4 Hz), 125.36 (d, 9.8
Hz), 94.11 (d, 199.6 Hz), 62.94, 34.66, 31.20, 13.95. Anal. Calcd
(83) Easton, C. J .; Lincoln, S. F.; May, L. B.; Papageorgiou, J . Aust.
J . Chem. 1997, 50, 451.

Arylation of Malonates and Cyanoesters
J . Org. Chem., Vol. 67, No. 2, 2002 553
Hz, 1H), 4.31-4.19 (m, 4H), 3.91 (s, 3H), 1.96 (s, 3H), 1.26 (t,
7.2 Hz, 6H). 13C{1H} NMR (CDCl3) δ 171.70, 157.99, 133.76,
133.44, 129.74, 128.40, 126.67, 126.50, 125.65, 118.88, 105.38,
61.72, 58.70, 55.31, 22.25, 14.01.
ethyl cyanoacetate (123 mg, 1.09 mmol), ligand 7 (14 mg, 0.020
mmol), and Pd(dba)2 (6.0 mg, 0.010 mmol). The reaction
mixture was purified by column chromatography on silica gel
(1:3 dichloromethane/hexanes) to give the desired product (213
mg, 82%) as a colorless oil: 1H NMR (CDCl3) δ 7.71-7.69 (m,
2H), 7.63-7.60 (m, 2H), 4.80 (s, 1H), 4.27 (dq, 7.2, 1.2 Hz, 2H),
1.30 (t, 7.2 Hz, 3H). 13C{1H} NMR (CDCl3) δ 164.28, 133.81,
131.66 (q, 33.0 Hz), 128.55, 126.38 (q, 3.7 Hz), 123.68 (q, 272.3
Hz), 115.00, 63.78, 43.52, 13.89.
Gen er a l P r oced u r e for th e Ar yla tion of Eth yl Cy-
a n oa ceta te (Ta ble 6). Method A: Into a screw-capped vial
containing ethyl cyanoacetate (1.1 mmol) and aryl bromide (1.0
mmol) were added phosphine (0.040 mmol), Pd(dba)2 (0.020
mmol) or [Pd(allyl)Cl]2 (0.010 mmol), and Na3PO4 (3.0 mmol),
followed by toluene (3.0 mL). The vial was sealed with a cap
containing a PTFE septum and removed from the drybox. The
heterogeneous reaction mixture was stirred at 70 °C and
monitored by GC. After complete conversion of the aryl
bromide, the crude reaction was filtered through a plug of
Celite and concentrated in vacuo. The residue was purified
by chromatography on silica gel (1:3 dichloromethane/hex-
anes).
Method B: Into a screw-capped vial containing ethyl cy-
anoacetate (1.1 mmol) and aryl chloride (1.0 mmol) were added
P(t-Bu)3 (0.040 mmol), [Pd(allyl)Cl]2 (0.010 mmol), and Na3-
PO4 (3.0 mmol), followed by toluene (3.0 mL). The vial was
sealed with a cap containing a PTFE septum and removed
from the drybox. The heterogeneous reaction mixture was
stirred at 100 °C and monitored by GC. After complete
conversion of the aryl chloride, the crude reaction was filtered
through a plug of Celite and concentrated in vacuo. The residue
was purified by chromatography on silica gel (1:3 dichloro-
methane/hexanes).
Eth yl 2-(2-Meth ylp h en yl)cya n oa ceta te (Ta ble 6, En tr y
1).84 Method A of the above general procedure was followed
using 2-bromotoluene (172 mg, 1.00 mmol), ethyl cyanoacetate
(125 mg, 1.11 mmol), P(t-Bu)3 (40 µL, 1.0 M in toluene, 0.040
mmol), and [Pd(allyl)Cl]2 (3.7 mg, 0.010 mmol). The reaction
mixture was purified by column chromatography on silica gel
(1:3 dichloromethane/hexanes) to give the desired product (180
mg, 88%) as a colorless oil: 1H NMR (CDCl3) δ 7.47-7.45 (m,
1H), 7.32-7.22 (m, 3H), 4.89 (s, 1H), 4.31-4.19 (m, 2H), 2.40
(s, 3H), 1.28 (t, 7.2 Hz, 3H). 13C{1H} NMR (CDCl3) δ 165.03,
136.23, 131.24, 129.34, 128.93, 128.62, 127.05, 115.90, 63.25,
41.06, 19.42, 13.92.
Eth yl 2-(4-P h en oxyp h en yl)cya n oa ceta te (Ta ble 6, En -
tr y 2). Method A of the above general procedure was followed
using 4-bromobiphenyl ether (250 mg, 1.00 mmol), ethyl
cyanoacetate (125 mg, 1.10 mmol), P(t-Bu)3 (40 µL, 1.0 M in
toluene, 0.040 mmol), and Pd(dba)2 (11.5 mg, 0.0200 mmol).
The reaction mixture was purified by column chromatography
on silica gel (1:3 dichloromethane/hexanes) to give the desired
product (247 mg, 88%) as a colorless oil: 1H NMR (CDCl3) δ
7.42-7.34 (m, 4H), 7.17-7.13 (m, 1H), 7.05-6.99 (m, 4H), 4.69
(s, 1H), 4.31-4.20 (m, 2H), 1.29 (t, 7.2 Hz, 3H). 13C{1H} NMR
(CDCl3) δ 165.06, 158.41, 156.17, 129.95, 129.42, 124.18,
124.07, 119.55, 118.91, 115.74, 63.34, 43.00, 13.91. Anal. Calcd
for C17H15NO3: C, 72.58; H, 5.37; N, 4.98. Found: C, 72.80:
H, 5.37: N, 4.93.
Eth yl 2-(4-Bip h en yl)cya n oa ceta te (Ta ble 6, En tr y 5).87
Method A of the above general procedure was followed using
4-bromobiphenyl (233 mg, 1.00 mmol), ethyl cyanoacetate (124
mg, 1.10 mmol), ligand 7 (28 mg, 0.040 mmol), and Pd(dba)2
(11.6 mg, 0.0200 mmol). The reaction mixture was purified
by column chromatography on silica gel (1:3 dichloromethane/
hexanes) to give the desired product (234 mg, 88%) as a
colorless oil: 1H NMR (CDCl3) δ 7.64-7.62 (m, 2H), 7.58-7.56
(m, 2H), 7.54-7.52 (m, 2H), 7.46-7.43 (m, 2H), 7.39-7.35 (m,
1H), 4.76 (s, 1H), 4.31-4.20 (m, 2H), 1.29 (t, 7.2 Hz, 3H). 13C-
{1H} NMR (CDCl3) δ 164.98, 142.19, 139.91, 128.91, 128.83,
128.33, 127.99, 127.84, 127.12, 115.68, 63.40, 43.40, 13.91.
Eth yl 2-(2-Na p h th yl)cya n oa ceta te (Ta ble 6, En tr y 6).6
Method A of the above general procedure was followed using
2-bromonaphthalene (208 mg, 1.00 mmol), ethyl cyanoacetate
(123 mg, 1.09 mmol), ligand 8 (6.0 mg, 0.020 mmol), and Pd-
(dba)2 (6.0 mg, 0.010 mmol). The reaction mixture was purified
by column chromatography on silica gel (1:3 dichloromethane/
hexanes) to give the desired product (214 mg, 89%) as a
colorless oil: 1H NMR (CDCl3) δ 7.94 (s, 1H), 7.89-7.82 (m,
3H), 7.55-7.50 (m, 3H), 4.88 (s, 1H), 4.29-4.20 (m, 2H), 1.26
(t, 7.2 Hz, 3H). 13C{1H} NMR (CDCl3) δ 165.00, 133.21, 133.16,
129.35, 128.07, 127.76, 127.51, 127.21, 127.08, 126.96, 124.81,
115.75, 63.38, 43.90, 13.89.
Eth yl 2-P h en ylcyan oacetate (Table 6, En tr y 7).84 Method
B of the above general procedure was followed using 4-chlo-
robenzene (112 mg, 1.00 mmol) and ethyl cyanoacetate (124
mg, 1.10 mmol). The reaction mixture was purified by column
chromatography on silica gel (1:3 dichloromethane/hexanes)
to give the desired product (162 mg, 86%) as a colorless oil:
1H NMR (CDCl3) δ 7.49-7.42 (m, 5H), 4.73 (s, 1H), 4.29-4.21
(m, 2H), 1.29 (t, 7.2 Hz, 3H). 13C{1H} NMR (CDCl3) δ 165.00,
129.97, 129.34, 129.23, 127.91, 115.70, 63.32, 43.73, 13.88.
Eth yl 2-(4-F lu or op h en yl)cya n oa ceta te (Ta ble 6, En tr y
9).84 Method B of the above general procedure was followed
using 4-chlorobenzotrifluoride (131 mg, 1.01 mmol) and ethyl
cyanoacetate (125 mg, 1.11 mmol). The reaction mixture was
purified by column chromatography on silica gel (1:3 dichlo-
romethane/hexanes) to give the desired product (172 mg, 83%)
as a colorless oil: 1H NMR (CDCl3) δ 7.48-7.43 (m, 2H), 7.15-
7.09 (m, 2H), 4.70 (s, 1H), 4.31-4.20 (m, 2H), 1.29 (t, 6.8 Hz,
3H). 13C{1H} NMR (CDCl3) δ 165.00, 163.21 (d, 249.1 Hz),
130.01 (d, 8.4 Hz), 125.94, 116.64 (d, 21.9 Hz), 115.67, 64.00,
43.20, 14.11.
Eth yl 2-(2,5-Dim eth ylp h en yl)cya n oa ceta te (Ta ble 6,
En tr y 10).10 Method B of the above general procedure was
followed using 4-chloro-p-xylene (141 mg, 1.00 mmol) and ethyl
cyanoacetate (124 mg, 1.10 mmol). The reaction mixture was
purified by column chromatography on silica gel (1:3 dichlo-
romethane/hexanes) to give the desired product (190 mg, 87%)
as a colorless oil: 1H NMR (CDCl3) δ 7.27 (s, 1H), 7.12-7.07
(m, 2H), 4.85 (s, 1H), 4.31-4.18 (m, 2H), 2.34 (s, 3H), 2.33 (s,
3H), 1.28 (t, 7.2 Hz, 3H). 13C{1H} NMR (CDCl3) δ 165.17,
136.74, 133.0, 131.10, 130.06, 129.13, 128.63, 116.05, 63.19,
40.98, 20.88, 18.93, 13.92.
Eth yl 2-(3-Tr iflu or om eth ylph en yl)cyan oacetate (Table
6, En tr y 3).85 Method A of the above general procedure was
followed using 3-bromobenzotrifluoride (225 mg, 1.00 mmol),
ethyl cyanoacetate (124 mg, 1.10 mmol), P(t-Bu)3 (40 µL, 1.0
M in toluene, 0.040 mmol), and Pd(dba)2 (11.5 mg, 0.0200
mmol). The reaction mixture was purified by column chroma-
tography on silica gel (1:3 dichloromethane/hexanes) to give
the desired product (211 mg, 82%) as a colorless oil: 1H NMR
(CDCl3) δ 7.73-7.68 (m, 3H), 7.60-7.56 (m, 1H), 4.79 (s, 1H),
4.31-4.24 (m, 2H), 1.30 (t, 7.2 Hz, 3H). 13C{1H} NMR (CDCl3)
δ 164.36, 131.91 (q, 33.0 Hz), 131.46, 131.04, 130.05, 126.27
(q, 4.1 Hz), 124.99 (q, 3.9 Hz), 123.59 (q, 273.3 Hz), 115.09,
63.80, 43.46, 13.88.
Eth yl 2-(3,4-Meth ylen ed ioxyp h en yl)cya n oa ceta te (Ta -
ble 6, En tr y 11). Method B of the above general procedure
was followed using 4-chloro-1,2-(methylenedioxy)benzene (157
mg, 1.00 mmol) and ethyl cyanoacetate (124 mg, 1.10 mmol).
The reaction mixture was purified by column chromatography
on silica gel (1:3 dichloromethane/hexanes) to give the desired
Eth yl 2-(4-Tr iflu or om eth ylph en yl)cyan oacetate (Table
6, En tr y 4).86 Method A of the above general procedure was
followed using 4-bromobenzotrifluoride (226 mg, 1.01 mmol),
(84) Uno, M.; Seto, K.; Ueda, W.; Masuda, M.; Takahashi, S.
Synthesis 1985, 506.
(85) Suzuki, H.; Kobayashi, T.; Yoshida, Y.; Osuka, A. Chem. Lett.
1993, 193.
(86) Nakamura, I.; Tsukada, N.; Al-Masum, M.; Yamamoto, Y.
Chem. Commun. 1997, 16, 1583.
(87) J uby, P. F.; Goodwin, W. R.; Hudyma, T. W.; Partyka, R. A. J .
Med. Chem. 1972, 15, 1306.

554 J . Org. Chem., Vol. 67, No. 2, 2002
Beare and Hartwig
product (191 mg, 82%) as a colorless oil: 1H NMR (CDCl3) δ
6.93-6.90 (m, 2H), 6.83-6.80 (m, 1H), 6.00 (s, 2H), 4.62 (s,
1H), 4.30-4.19 (m, 2H), 1.29 (t, 7.2 Hz, 3H). 13C{1H} NMR
(CDCl3) δ 165.07, 148.46, 148.44, 123.33, 121.76, 115.75,
108.79, 108.25, 101.68, 63.34, 43.31, 13.92. Anal. Calcd for
C12H11NO4: C, 61.80; H, 4.75; N, 6.01. Found: C, 62.08: H,
4.62: N, 6.13.
Eth yl 2-(2-Meth oxyp h en yl)cya n oa ceta te (Ta ble 6, En -
tr y 12).84 Method B of the above general procedure was
followed using 2-chloroanisole (143 mg, 1.01 mmol) and ethyl
cyanoacetate (125 mg, 1.11 mmol). The reaction mixture was
purified by column chromatography on silica gel (1:3 dichlo-
romethane/hexanes) to give the desired product (191.4 mg,
87%) as a colorless oil: 1H NMR (CDCl3) δ 7.40-7.35 (m, 2H),
7.03-6.99 (m, 1H), 6.93 (d, 8.0 Hz, 1H), 5.03 (s, 1H), 4.30-
4.22 (m, 2H), 3.86 (s, 3H), 1.29 (t, 7.2 Hz, 3H). 13C{1H} NMR
(CDCl3) δ 165.19, 156.48, 130.73, 129.44, 121.11, 119.11,
115.92, 111.12, 62.97, 55.72, 38.18, 13.97.
(q, 7.2 Hz, 2H), 1.35 (t, 7.2 Hz, 3H). 13C{1H} NMR (CDCl3) δ
166.73, 139.91, 135.23, 131.01 (q, 32.9 Hz), 129.48, 129.41,
128.82, 127.94, 126.30 (q, 3.8 Hz), 123.84 (q, 272.4 Hz), 118.28,
64.27, 58.71, 14.02. Anal. Calcd for C18H14F3NO2: C, 64.86;
H, 4.23; F, 17.10; N, 4.20. Found: C, 65.04: H, 4.28: F,
17.35: N, 4.27.
Eth yl 2-P h en yl-2-(4-m eth oxyp h en yl)cya n oa ceta te (Ta -
ble 7, En tr y 4).88 The above general procedure was followed
using 4-bromoanisole (207 mg, 1.10 mmol) and ethyl 2-phen-
ylcyanoacetate (190 mg, 1.01 mmol). The reaction mixture was
purified by column chromatography on silica gel (1:2 dichlo-
romethane/hexanes) to give the desired product (288 mg, 97%)
as a colorless oil: 1H NMR (CDCl3) δ 7.41-7.36 (m, 5H), 7.33-
7.29 (m, 2H), 6.92-6.89 (m, 2H), 4.36-4.31 (m, 2H), 3.80 (s,
3H), 1.31 (t, 7.2 Hz, 3H). 13C{1H} NMR (CDCl3) δ 167.42,
159.84, 136.10, 129.26, 128.91, 128.86, 127.88, 127.70, 63.61,
58.11, 55.34, 13.89.
Eth yl 2-(4-Ben zoylph en yl)-2-ph en ylcyan oacetate (Table
7, En tr y 5). The above general procedure was followed using
4-bromobenzophenone (289 mg, 1.11 mmol) and ethyl 2-phen-
ylcyanoacetate (189 mg, 1.00 mmol). The reaction mixture was
purified by column chromatography on silica gel (2:1 dichlo-
romethane/hexanes) to give the desired product (335 mg, 91%)
as a colorless oil: 1H NMR (CDCl3) δ 7.84-7.80 (m, 4H), 7.62-
7.58 (m, 1H), 7.56-7.53 (m, 2H), 7.51-7.46 (m, 2H), 7.45-
7.40 (m, 5H), 4.38 (q, 7.2 Hz, 2H), 1.34 (t, 7.2 Hz, 3H). 13C{1H}
NMR (CDCl3) δ 195.69, 166.65, 139.88, 137.97, 136.97, 135.17,
132.82, 130.43, 130.05, 129.22, 129.16, 128.42, 128.12, 127.84,
118.23, 64.00, 56.69, 13.89. Anal. Calcd for C24H19NO3: C,
78.03; H, 5.18; N, 3.79. Found: C, 77.66: H, 5.28: N, 3.65.
Eth yl 2-(4-Bip h en yl)-2-p h en ylcya n oa ceta te (Ta ble 7,
En tr y 6). The above general procedure was followed using
4-bromobiphenyl (256 mg, 1.10 mmol) and ethyl 2-phenylcy-
anoacetate (189 mg, 1.00 mmol). The reaction mixture was
purified by column chromatography on silica gel (1:2 dichlo-
romethane/hexanes) to give the desired product (307 mg, 90%)
as a colorless oil: 1H NMR (CDCl3) δ 7.62-7.55 (m, 4H), 7.49-
7.32 (m, 10H), 4.35 (q, 7.2 Hz, 2H), 1.31 (t, 7.2 Hz, 3H). 13C-
{1H} NMR (CDCl3) δ 167.15, 141.79, 139.86, 135.76, 134.70,
128.98, 128.97, 128.87, 128.41, 128.20, 127.93, 127.55, 127.10,
118.69, 63.74, 58.51, 13.88. Anal. Calcd for C23H19NO2: C,
80.92; H, 5.61; N, 4.10. Found: C, 80.87: H, 5.82: N, 4.21.
Eth yl 2-(4-Acetylp h en yl)-2-p h en ylcya n oa ceta te (Ta ble
7, En tr y 7). The above general procedure was followed using
4-bromoacetophenone (259 mg, 1.30 mmol) and ethyl 2-phen-
ylcyanoacetate (223 mg, 1.18 mmol). The reaction mixture was
purified by column chromatography on silica gel (2:1 dichlo-
romethane/hexanes) to give the desired product (341 mg, 94%)
as a colorless oil: 1H NMR (CDCl3) δ 8.00-7.97 (m, 2H), 7.54-
7.51 (m, 2H), 7.43-7.38 (m, 5H), 4.37 (q, 7.2 Hz, 2H), 2.61 (s,
3H), 1.33 (t, 7.2 Hz, 3H). 13C{1H} NMR (CDCl3) δ 197.18,
166.59, 140.55, 137.27, 135.16, 129.22, 129.16, 128.79, 128.41,
127.80, 118.17, 64.00, 58.65, 26.72, 13.87. Anal. Calcd for
C19H17NO3: C, 74.25; H, 5.58; N, 4.56. Found: C, 74.46: H,
5.44: N, 4.58.
Eth yl 2-[3-(1,3-Dioxola n e)p h en yl]-2-p h en ylcya n oa ce-
ta te (Ta ble 7, En tr y 8). The above general procedure was
followed using 2-(3-bromophenyl)-1,3-dioxolane (260 mg, 1.13
mmol) and ethyl 2-phenylcyanoacetate (189 mg, 1.00 mmol).
The reaction mixture was purified by column chromatography
on silica gel (2:1 dichloromethane/hexanes) to give the desired
product (311 mg, 92%) as a colorless oil: 1H NMR (CDCl3) δ
7.57-7.56 (m, 1H), 7.53-7.50 (m, 1H), 7.43-7.36 (m, 7H), 5.79
(s, 1H), 4.34 (q, 7.2 Hz, 2H), 4.10-3.98 (m, 4H), 1.30 (t, 7.2
Hz, 3H). 13C{1H} NMR (CDCl3) δ 166.98, 139.00, 135.83,
135.80, 129.02, 128.95, 128.87, 127.97, 127.12, 126.15, 118.57,
103.13, 65.32, 63.75, 58.75, 13.85. Anal. Calcd for C20H19NO4:
C, 71.20; H, 5.68; N, 4.15. Found: C, 70.91: H, 5.59: N, 4.00.
Eth yl 2-(4-Ca r bom eth oxyp h en yl)-2-p h en ylcya n oa ce-
ta te (Ta ble 7, En tr y 9). The above general procedure was
followed using methyl 4-bromobenzoate (239 mg, 1.11 mmol)
Eth yl 2,2-(Bis-4-tr iflu or om eth ylp h en yl)cya n oa ceta te
(Ta ble 6, En tr y 1). Into a screw-capped vial containing ethyl
cyanoacetate (57 mg, 0.50 mmol) and 4-bromobenzotrifluoride
(248 mg, 1.10 mmol) were added P(t-Bu)3 (40 µL, 1.0 M in
toluene, 0.040 mmol), Pd(dba)2 (11.5 mg, 0.0200 mmol), and
Na3PO4 (500 mg, 3.05 mmol), followed by toluene (3.00 mL).
The vial was sealed with a cap containing a PTFE septum and
removed from the drybox. The heterogeneous reaction mixture
was stirred at 70 °C until GC analysis indicated the reaction
was complete (12 h). After this time, the crude reaction was
filtered through a plug of Celite and concentrated in vacuo.
The residue was purified by chromatography on silica gel (1:2
dichloromethane/hexanes) to give the product (192 mg, 96%)
as a colorless oil: 1H NMR (CDCl3) δ 7.71-7.69 (m, 4H), 7.56-
7.53 (m, 4H), 4.40 (q, 7.2 Hz, 2H), 1.35 (t, 7.2 Hz, 3H). 13C-
{1H} NMR (CDCl3) δ 165.98, 138.90, 131.62 (q, 33.1 Hz),
128.48, 126.22 (q, 3.5 Hz), 123.53 (q, 272.4 Hz), 117.46, 64.50,
58.24, 13.87. Anal. Calcd for C19H13F6NO2: C, 56.87; H, 3.27;
N, 3.49. Found: C, 56.95: H, 3.41: N, 3.62.
Eth yl 2,2-(Bis-4-m eth oxyp h en yl)cya n oa ceta te (Ta ble
6, En tr y 2). Into a screw-capped vial containing ethyl cy-
anoacetate (60 mg, 0.53 mmol) and 4-bromoanisole (215 mg,
1.15 mmol) were added P(t-Bu)3 (40 µL, 1.0 M in toluene, 0.040
mmol), Pd(dba)2 (11.5 mg, 0.0200 mmol), and Na3PO4 (496 mg,
3.02 mmol), followed by toluene (3.00 mL). The vial was sealed
with a cap containing a PTFE septum and removed from the
drybox. The heterogeneous reaction mixture was stirred at 70
°C until GC analysis indicated the reaction was complete (12
h). After this time, the crude reaction was filtered through a
plug of Celite and concentrated in vacuo. The residue was
purified by chromatography on silica gel (1:2 dichloromethane/
hexanes) to give the product (167.0 mg, 97%) as a colorless
oil: 1H NMR (CDCl3) δ 7.32-7.29 (m, 4H), 6.92-6.88 (m, 4H),
4.33 (q, 7.2 Hz, 2H), 3.81 (s, 6H), 1.31 (t, 7.2 Hz, 3H). 13C{1H}
NMR (CDCl3) δ 167.69, 159.80, 129.18, 128.02, 119.08, 114.19,
63.53, 57.46, 55.35, 13.92. Anal. Calcd for C19H19NO4: C, 70.14;
H, 5.89; N, 4.31. Found: C, 70.36: H, 5.98: N, 4.30.
Gen er a l P r oced u r e for th e Ar yla tion of Eth yl Ar ylcy-
a n oa ceta tes (Ta ble 7). Into a screw-capped vial containing
ethyl arylcyanoacetate (1.0 mmol) and aryl bromide (1.1 mmol)
were added P(t-Bu)3 (0.040 mmol), Pd(dba)2 (0.020 mmol), and
Na3PO4 (3.0 mmol), followed by toluene (3.0 mL). The vial was
sealed with a cap containing a PTFE septum and removed
from the drybox. The heterogeneous reaction mixture was
stirred at 70 °C and monitored by GC. After complete conver-
sion of the ethyl arylcyanoacetate, the crude reaction was
filtered through a plug of Celite and concentrated in vacuo.
The residue was purified by chromatography on silica gel (1:2
dichloromethane/hexanes).
Eth yl 2-P h en yl-2-(4-tr iflu or om eth ylp h en yl)cya n oa c-
eta te (Ta ble 7, En tr y 3). The above general procedure was
followed using 4-bromobenzotrifluoride (249 mg, 1.10 mmol)
and ethyl 2-phenylcyanoacetate (188 mg, 0.990 mmol). The
reaction mixture was purified by column chromatography on
silica gel (1:2 dichloromethane/hexanes) to give the desired
product (308.1 mg, 93%) as a colorless oil: 1H NMR (CDCl3) δ
7.70-7.66 (m, 2H), 7.59-7.56 (m, 2H), 7.47-7.40 (m, 5H), 4.39
(88) Kozyrod, R. P.; Morgan, J .; Pinhey, J . T. Aust. J . Chem. 1991,
44, 369.

Arylation of Malonates and Cyanoesters
J . Org. Chem., Vol. 67, No. 2, 2002 555
and ethyl 2-phenylcyanoacetate (193 mg, 1.02 mmol). The
reaction mixture was purified by column chromatography on
silica gel (2:1 dichloromethane/hexanes) to give the desired
product (307 mg, 93%) as a colorless oil: 1H NMR (CDCl3) δ
8.08-8.06 (m, 2H), 7.52-7.49 (m, 2H), 7.42-7.38 (m, 5H), 4.37
(q, 7.2 Hz, 2H), 3.92 (s, 3H), 1.32 (t, 7.2 Hz, 3H). 13C{1H} NMR
(CDCl3) δ 166.62, 166.19, 140.45, 135.23, 130.72, 130.09,
129.20, 129.14, 128.20, 127.84, 118.22, 63.97, 56.69, 52.36,
13.87. Anal. Calcd for C19H17NO4: C, 70.58; H, 5.30; N, 4.33.
Found: C, 70.46: H, 5.40: N, 4.49.
Eth yl 2-(4-Flu or op h en yl)-2-p h en ylcya n oa ceta te (Ta ble
7, En tr y 10). The above general procedure was followed using
4-bromofluorobenzene (193 mg, 1.10 mmol) and ethyl 2-phen-
ylcyanoacetate (191 mg, 1.00 mmol). The reaction mixture was
purified by column chromatography on silica gel (1:2 dichlo-
romethane/hexanes) to give the desired product (257 mg, 90%)
as a colorless oil: 1H NMR (CDCl3) δ 7.42-7.36 (m, 7H), 7.10-
7.04 (m, 2H), 4.35 (q, 7.2 Hz, 2H), 1.31 (t, 7.2 Hz, 3H). 13C-
{1H} NMR (CDCl3) δ 167.05, 162.80 (d, 249.4 Hz), 135.68,
131.79, 131.76, 130.03 (d, 8.5 Hz), 129.09, 127.81, 118.56,
Eth yl 2-(4-Meth oxyp h en yl)-2-(4-tr iflu or om eth ylp h en -
yl)cya n oa ceta te (Ta ble 7, En tr y 13). The above general
procedure was followed using 4-bromobenzotrifluoride (248 mg,
1.10 mmol) and ethyl 2-(4-methoxy)phenylcyanoacetate (221
mg, 1.00 mmol). The reaction mixture was purified by column
chromatography on silica gel (1:2 dichloromethane/hexanes)
to give the desired product (333 mg, 91%) as a colorless oil:
1H NMR (CDCl3) δ 7.66 (d, 8.4 Hz, 2H), 7.55 (d, 8.4 Hz, 2H),
7.33-7.29 (m, 2H), 6.95-6.92 (m, 2H), 4.36 (q, 7.2 Hz, 2H),
3.82 (s, 3H), 1.32 (t, 7.2 Hz, 3H). 13C{1H} NMR (CDCl3) δ
166.85, 160.15, 140.14, 131.13 (q, 33.0 Hz), 129.13, 128.60,
126.92, 125.89 (q, 3.5 Hz), 123.72 (q, 272.3 Hz), 118.31, 114.54,
64.02, 57.92, 55.41, 13.89. Anal. Calcd for C19H16F3NO3: C,
62.81; H, 4.44; N, 3.86. Found: C, 62.92: H, 4.45: N, 3.79.
E t h yl 2-(4-Met h oxyp h en yl)-2-(2-n a p h t h yl)cya n oa ce-
ta te (Ta ble 7, En tr y 15). The above general procedure was
followed using 2-bromonaphthalene (239 mg, 1.15 mmol) and
ethyl 2-(4-methoxy)phenylcyanoacetate (221 mg, 1.01 mmol).
The reaction mixture was purified by column chromatography
on silica gel (1:2 dichloromethane/hexanes) to give the desired
product (310 mg, 89%) as a colorless oil: 1H NMR (CDCl3) δ
7.92 (d, 1.6 Hz, 1H), 7.86-7.81 (m, 3H), 7.55-7.48 (m, 2H),
7.45 (dd, 8.8, 2.0 Hz, 1H), 7.36-7.32 (m, 2H), 6.93-6.89 (m,
2H), 4.36 (q, 7.2 Hz, 2H), 3.80 (s, 3H), 1.32 (t, 7.2 Hz, 3H).
13C{1H} NMR (CDCl3) δ 167.41, 159.89, 133.22, 133.00, 132.83,
129.36, 128.89, 128.40, 127.70, 127.60, 127.23, 127.15, 126.82,
125.19, 118.89, 114.28, 63.67, 58.26, 55.35, 13.92. Anal. Calcd
for C22H19NO3: C, 76.50; H, 5.54; N, 4.06. Found: C, 76.26:
H, 5.67: N, 4.07.
115.91 (d, 21.9 Hz), 63.82, 58.14, 13.87. Anal. Calcd for C17H14
-
FNO2: C, 72.07; H, 4.98; N, 4.94. Found: C, 72.18: H, 5.06:
N, 4.88.
Eth yl 2,2-Dip h en ylcya n oa ceta te (Ta ble 7, En tr y 11).89
The above general procedure was followed using chlorobenzene
(124 mg, 1.10 mmol) and ethyl 2-phenylcyanoacetate (191 mg,
1.01 mmol) at 100 °C. The reaction mixture was purified by
column chromatography on silica gel (1:2 dichloromethane/
hexanes) to give the desired product (233 mg, 87%) as a
colorless oil which solidified on standing: 1H NMR (CDCl3) δ
7.41-7.37 (m, 10H), 4.35 (q, J ) 6.8 Hz, 2H), 1.31 (t, J ) 6.8
Hz, 3H). 13C{1H} NMR (d4-MeOD) δ 168.54, 137.51, 130.23,
130.20, 129.18, 120.03, 64.94, 60.42, 14.29.
Ack n ow led gm en t. We thank the NIH (GM 58108)
for support of this work and J ohnson-Matthey for a gift
of palladium salts. We also thank Motoi Kawatsura for
some initial experiments on the arylation of diethyl
malonate.
(89) Bockmuehl, M.; Ehrhart, G. J ustus Liebigs Ann. Chem. 1949,
52, 78.
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