Efficient synthesis of α-aryl esters by room-temperature palladium-catalyzed coupling of aryl halides with ester enolates

Article abstract of DOI:10.1021/ja027643u

A catalytic amount of Pd(dba)₂ ligated by either carbene precursor N,N′-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazolium (1) or P(t-Bu)₃ mediated the coupling of aryl halides and ester enolates to produce α-aryl esters in high yields at room temperature. The reaction was highly tolerant of functionalities and substitution patterns on the aryl halide. Improved protocols for the selective monoarylation of tert-butyl acetate and the efficient arylation of α,α-disubstituted esters were developed with LiNCy₂ as base and P(t-Bu)₃ as ligand. In addition, tert-butyl esters, such as those of Naproxen and Flurbiprofen, were prepared from tert-butyl propionate and aryl bromides in high yields in the presence of Pd(dba)₂ and the hindered, saturated heterocyclic carbene ligand precursor.

Full text of DOI:10.1021/ja027643u

Published on Web 09/28/2002
Efficient Synthesis of r-Aryl Esters by Room-Temperature
Palladium-Catalyzed Coupling of Aryl Halides with Ester
Enolates
Morten Jørgensen, Sunwoo Lee, Xiaoxiang Liu, Joanna P. Wolkowski, and
John F. Hartwig*
Contribution from the Department of Chemistry, Yale UniVersity, P.O. Box 208107,
New HaVen, Connecticut 06520-8107
Received July 10, 2002
Abstract: A catalytic amount of Pd(dba)2 ligated by either carbene precursor N,N′-bis(2,6-diisopropylphenyl)-
4,5-dihydroimidazolium (1) or P(t-Bu)3 mediated the coupling of aryl halides and ester enolates to produce
R-aryl esters in high yields at room temperature. The reaction was highly tolerant of functionalities and
substitution patterns on the aryl halide. Improved protocols for the selective monoarylation of tert-butyl
acetate and the efficient arylation of R,R-disubstituted esters were developed with LiNCy2 as base and
P(t-Bu)3 as ligand. In addition, tert-butyl esters, such as those of Naproxen and Flurbiprofen, were prepared
from tert-butyl propionate and aryl bromides in high yields in the presence of Pd(dba)2 and the hindered,
saturated heterocyclic carbene ligand precursor.
Introduction
but these procedures were limited to aryl iodides and they gave
moderate yields of regioisomeric products.
A classic method to construct C-C bonds involves depro-
tonation R to a carbonyl group and addition of the resulting
nucleophile to electrophiles such as aldehydes, ketones, Michael
acceptors, and alkyl halides.1 Methods to attach enolate nu-
cleophiles to an aromatic ring, however, are more limited.2,3
Ketone enolates have been coupled with aryl radicals under
thermal4 and photolytic5 conditions. Aryllead(IV) species have
been coupled to cyanoacetates, malononitriles,6 â-keto esters,7
and malonates8 to give the R-arylated products, but stoichio-
metric amounts of lead are undesirable for most applications.
Barton used bismuth reagents to arylate ketones, diketones, and
â-keto esters,9 but only one of the three aryl groups is
transferred, and few of these reagents are commercially avail-
able. Cyanoacetates and malonates have also been arylated in
the presence of manganese,10,11 copper,12 and cerium13 salts,
Metal-catalyzed cross-coupling reactions have been used
widely to connect two sp2 carbon centers.14-17 The formation
of sp3-sp2 C-C bonds is less common, and high-yield examples
with reagents that display functional group tolerance are
generally limited to terminal or cyclic alkylboranes18,19 and -zinc
reagents.20,21 The coupling of iodo- and bromobenzene, as well
as vinyl bromides, with tert-butyl acetate in the presence of
stoichiometric NiBr2 and 25 mol % BuLi was reported a number
of years ago.22 Moreover, electrochemical, metal-mediated
enolate coupling reactions have been reported.23,24 These results
suggested that a metal-catalyzed route could be developed for
the arylation of ester enolates. Palladium-catalyzed coupling of
Reformatsky reagents25 and tin enolates26 was reported about
15 years ago, while a protocol involving a combination of copper
fluoride and silylketene acetal27 was developed more recently.
* To whom correspondence should be addressed. E-mail: john.hartwig@
yale.edu.
(14) Diederich, F.; Stang, P. J., Eds. Metal-Catalyzed Cross-coupling Reactions;
Wiley-VCH: New York, 1998.
(15) Suzuki, A. J. Organomet. Chem. 1999, 576, 147-168.
(16) Tsuji, J. Palladium Reagents and Catalysts. InnoVations in Organic
Chemistry, 5th ed.; John Wiley & Sons: New York, 1999.
(17) Bolm, C.; Hildebrand, J. P.; Muiz, K.; Hermanns, N. Angew. Chem., Int.
Ed. 2001, 40, 3284.
(18) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed.
2001, 40, 4544.
(19) Molander, G. A.; Yun, C.-S. Tetrahedron 2002, 58, 1465.
(20) Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T. J. Am.
Chem. Soc. 1984, 106, 158.
(21) Negishi, E. i. In Metal-Catalyzed Cross-coupling Reactions; Diederich, F.,
Stang, P. J., Eds.; Wiley-VCH: New York, 1998; Chapter 1.
(22) Millard, A. A.; Rathke, M. W. J. Am. Chem. Soc. 1977, 99, 4833.
(23) Durandetti, M.; Ne´de´lec, J.-Y.; Pe´richon, J. J. Org. Chem. 1996, 61, 1748.
(24) Conan, A.; Sibille, S.; D’Incan, E.; Pe´richon, J. Chem. Commun. 1990,
48.
(1) March, J. In AdVanced Organic Chemistry, 4th ed.; John Wiley & Sons:
New York, 2001; Chapters 10-16.
(2) Abramovitch, R. A.; Barton, D. H. R.; Finet, J.-P. Tetrahedron 1988, 44,
3039.
(3) Elliott, G. I.; Konopelski, J. P. Tetrahedron 2001, 57, 5683.
(4) Scamehorn, R. G.; Hardacre, J. M.; Lukanich, J. M.; Sharpe, L. R. J. Org.
Chem. 1984, 49, 4881.
(5) Rossi, R. A.; Alonso, R. A. J. Org. Chem. 1980, 45, 1239.
(6) Kozgrod, R. P.; Morgan, J.; Pinhey, J. T. J. Aust. Chem. 1991, 44, 369.
(7) Pinhey, J. T.; Roue, B. A. J. Aust. Chem. 1980, 33, 113.
(8) Kopinski, R. P.; Pinhey, J. T.; Roue, B. A. J. Aust. Chem. 1984, 37, 1245.
(9) Barton, D. H. R.; Blazejewski, J.-C.; Charpiot, B.; Finet, J.-P.; Motherwell,
W. B.; Barros Papoula, M. T.; Sanforth, S. P. J. Chem. Soc., Perkin Trans.
1 1985, 2667.
(10) Citterio, A.; Santi, R.; Fiorani, T.; Strologo, S. J. Org. Chem. 1989, 54,
2703.
(11) Citterio, A.; Fancelli, D.; Finzi, C.; Pesce, L.; Santi, R. J. Org. Chem. 1989,
54, 2713.
(25) Fauvarque, J. F.; Jutland, A. J. Organomet. Chem. 1979, 177, 273.
(26) Kosugi, M.; Negishi, Y.; Kameyama, M.; Migita, T. Bull. Chem. Soc. Jpn.
1985, 58, 3383.
(12) Osuka, A.; Koybayashi, T.; Suzuki, T. Synthesis 1983, 67.
(13) Baciocchi, E.; Dell’Aira, D.; Ruzziconi, R. Tetrahedron Lett. 1986, 27,
2763.
(27) Agnelli, F.; Sulikowski, G. A. Tetrahedron Lett. 1998, 39, 8807.
9
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J. AM. CHEM. SOC. 2002, 124, 12557-12565
12557

A R T I C L E S
Jørgensen et al.
However, the scope of these reactions was narrow, the yields
were variable, and the procedures involved separate preparation
of zinc enolates, tin enolates, or silylketene acetals prior to the
arylation reaction in all three cases. The coupling of aryl boronic
acids with R-bromo acetates under Suzuki-Miyaura conditions
was reported recently by Goossen.28
Over the past few years, we and others have developed
palladium-catalyzed procedures for the R-arylation of ketones,29-38
malonates,31,34,39 and cyanoacetates,39 as well as the preparation
of oxindoles by an intramolecular amide R-arylation.40,41 The
coupling of aryl halides with ester enolates would provide easy
access to R-aryl esters, including precursors to R-aryl propionic
acids such as Ibuprofen, Ketoprofen, Naproxen, and Flurbipro-
fen, which are used extensively in the treatment of inflammatory
diseases and for the relief of pain.42,43
The palladium-catalyzed R-arylation of esters47 was reported
independently by Buchwald48 with biphenylphosphines and by
our group49 with both carbene and trialkylphosphine ligands.
Miura earlier reported three reactions of phenyl iodide or
bromide with methyl phenylacetate in low to modest yield with
PPh3-ligated palladium or ligandless palladium.36 Buchwald’s
procedure required 2 equiv of ester relative to the aryl halide,
and the coupling was conducted at elevated temperatures with
relatively high catalyst loadings (3 mol %, 70 °C). Miura’s
reactions were conducted at an even higher 100-130 °C. We
found that reactions with only a slight excess of ester occurred
at room temperature in the presence of 2 mol % Pd(dba)2 and
heterocyclic carbene precursor N,N′-bis(2,6-diisopropylphen-
yl)4,5-dihydroimidazolium (1) or P(t-Bu)3, but an excess of ester
and base was required for the arylation of R,R-disubstituted
esters. We now present a full account of the arylations of esters
with carbene precursor 1 and P(t-Bu)3. These studies produced
improved protocols that increased the scope and efficiency of
the arylation of tert-butyl acetate and R,R-disubstituted esters
and addressed mechanistic issues about the origin of the high
selectivity from the arylation of tert-butyl acetate.
Results and Discussion
1.1. Conditions for the r-Arylation of tert-Butyl Acetate
and Scope of the Coupling. Successful arylation of acetates
required careful selection of ester, solvent, base, and ligand.50
Because most acetate enolates are unstable, we focused our
effort on reactions of tert-butyl acetate that forms an enolate
that is stable in solution for several hours at room tempera-
ture.45,46 We initially tested a variety of ligands for the reaction
of this ester with 4-tert-butylbromobenzene in the presence of
alkali metal tert-butoxide and hexamethyldisilylamide bases,
which had been used previously for the arylation of ketones
and amides. Screening of the ligands was conducted with 2.3
equiv of base to ensure that the base or starting enolate would
not be fully quenched by the more acidic product during the
reaction. Reactions catalyzed by Pd(dba)2 and carbene ligand
precursor 1 occurred in quantitative yields without formation
of the diarylation product when this excess quantity of lithium
hexamethyldisilazide was used as base. These couplings oc-
curred in the highest yields in aromatic solvents. No product
was formed in ether solvents.
We showed recently that the rates and yields for reductive
elimination from arylpalladium enolate complexes were similar
for complexes of enolates derived from ketones, esters, or
amides.44 Because the coupling step occurred from complexes
of ketone and ester enolates with similar rates and yields and
R-arylations of ketones occurred in a general fashion,29-33,35-38
it seemed that a general coupling of ester enolates would occur
if the palladium enolate could be generated in high yield. Rathke
showed many years ago that tert-butyl esters generate more
stable enolates than less hindered alkyl esters.45,46 Thus, we
initiated our studies with tert-butyl acetate and propionate as
substrate. Effective arylation would require that the catalytic
coupling occur faster than any decomposition or condensation
of the alkali metal enolate. As a result, the recently developed,
highly efficient catalysts for coupling reactions proved critical
to the development of clean arylation of esters.
A few of the biaryldialkylphosphines developed by Buchwald
gave yields above 90% under similar conditions, but none we
tested were as effective as the carbene generated from 1.
Complexes of PCy(t-Bu)2, PCy2(t-Bu), and PAd2(n-Bu)51,52
catalyzed the coupling in slightly lower yields that ranged from
80 to 88%, while reactions catalyzed by complexes of P(t-
Bu)353,54 or several of the adamantyl ligands were less selective
for formation of the monoarylation product when this base was
used.55,56 Reactions attempted with carbene precursor 1 and tert-
(28) Goossen, L. J. Chem. Commun. 2001, 669.
(29) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 12382.
(30) Saughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem. 1998, 63,
6546.
(31) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473.
(32) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108.
(33) A° hman, J.; Wolfe, J. P.; Troutman, M. V.; Palucki, M.; Buchwald, S. L. J.
Am. Chem. Soc. 1998, 120, 1918.
(34) Fox, J. M.; Huang, X. H.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc.
2000, 122, 1360.
(35) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew. Chem., Int. Ed.
Engl. 1997, 36, 1740.
(36) Satoh, T.; Inoh, J.-I.; Kawamura, Y.; Kawamura, Y.; Miura, M.; Nomura,
M. Bull. Chem. Soc. Jpn. 1998, 71, 2239.
(47) Lloyd-Jones, G. C. Angew. Chem., Int. Ed. 2002, 41, 953.
(48) Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7996.
(49) Lee, S.; Beare, N. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 8410.
(50) Tables of data from screening of these reaction parameters are included in
the Supporting Information.
(37) Sole´, D.; Vallverdu´, L.; Peidro´, E.; Bonjoch, J. Chem. Commun. 2001, 1888.
(38) Sole´, D.; Vallverdu´, L.; Bonjoch, J. AdV. Synth. Catal. 2001, 343, 430.
(39) Beare, N. A.; Hartwig, J. F. J. Org. Chem. 2002, 67, 541.
(40) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402.
(41) Shaughnessy, K.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem. 1998, 63,
6546.
(51) Ehrentraut, A.; Zapf, A.; Beller, M. AdV. Synth. Catal. 2002, 344, 209.
(52) Zapf, A.; Ehrentraut, A.; Beller, M. Angew. Chem., Int. Ed. 2000, 39, 4153-
4155.
(42) Harrington, P. J.; E., L. Org. Process Res. DeV. 1997, 1, 72.
(43) Mongin, F.; Maggi, R.; Schlosser, M. Chimica 1996, 50, 650.
(44) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 5816.
(45) Rathke, M. W.; Lindert, A. J. Am. Chem. Soc. 1971, 93, 2318.
(46) Rathke, M. W.; Sullivan, D. F. J. Am. Chem. Soc. 1973, 95, 3050.
(53) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-
Roman, L. M. J. Org. Chem. 1999, 64, 5575.
(54) Watanabe, M.; Nishiyama, M.; Koie, Y. Tetrahedron Lett. 1999, 40, 8837-
8840.
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Efficient Synthesis of R-Aryl Esters
A R T I C L E S
Table 1. Arylation of tert-Butyl Acetate Catalyzed by Pd(dba)2 and Carbene Precursor 1
a P(t-Bu)3 was used as a ligand.
butoxide bases did not occur, and those conducted with
NaHMDS or KHMDS gave lower yields because of competing
diarylation (NaHMDS) and hydrodehalogenation (KHMDS).
Reactions conducted with dialkylamide bases and palladium
ligated by the carbene generated from 1 also occurred in low
yield.
using preformed enolate. Lower yields and lower selectivity for
the monoarylation product were observed from reactions
conducted by mixing the hexamethyldisilazide bases with ester
prior to addition of the same catalyst and aryl halide. Reaction
of the enolate from tert-butyl acetate and LiNCy2 in the presence
of catalysts generated from carbene precursor 1 or other ligands
tested originally with lithium hexamethyldisilazide base occurred
in significantly lower yield. Moreover, reactions of the enolate
generated from other alkylamide bases also occurred in lower
yields.
Table 2 summarizes the yields of reactions catalyzed by a
combination of Pd(dba)2 and P(t-Bu)3 in the presence of LiNCy2
as base. Reaction of 1.1 equiv of tert-butyl acetate with LiNCy2
at room temperature in toluene solvent, followed by addition
of a solution of this preformed enolate to the aryl bromide and
catalyst, generated the coupled product in high yield. In many
cases, consumption of the aryl bromide was complete within
minutes (vide infra), although the products were generally
isolated after 8-24 h. By this procedure, reactions in the
presence of 0.2-1.0 mol % of Pd(dba)2 and P(t-Bu)3 formed
the monoarylated product selectively at room temperature in
isolated yields that were generally higher than they were under
the conditions of reactions summarized in Table 1. Electron-
rich (entry 4) and electron-poor (entry 6) aryl halides generated
the products in high yields. In addition, fluorinated aryl bromides
gave the products in high yields (entry 5). These reactions did
not occur with pyridyl halides.
2. Arylation of tert-Butyl Propionate. The R-arylation of
tert-butyl propionate proceeded smoothly in the presence of the
catalyst generated from Pd(dba)2 and carbene precursor 1.
Results of the R-arylation of tert-butyl propionate are shown in
Table 3. Reactions in the presence of NaHMDS as base occurred
in higher yields than did those containing LiHMDS. In general,
reactions of the enolate of tert-butyl propionate formed from
LiNCy2 prior to addition of catalyst and aryl halide formed the
desired product in lower yields than did reactions of the ester
in the presence of hexamethyldisilazide base. However, certain
reactions did occur in higher yields when the preformed enolate
of tert-butyl propionate was used. For example, the reaction of
tert-butyl propionate with p-(trifluoromethyl)bromobenzene pro-
The scope of the coupling of tert-butyl acetate with aryl
bromides in the presence of Pd(dba)2 and carbene precursor 1
as catalyst and HMDS as base is shown in Table 1. Reactions
of this ester with alkyl- and aryl-substituted aryl bromides
occurred in high yields (entries 1-4). Electron-rich o- and
p-bromoanisoles, as well as the less electron-rich m-bromoani-
sole, reacted with tert-butyl acetate to give the coupled product
in high yield under these conditions (entry 5). Electron-
withdrawing fluoro- and trifluoromethyl groups on the aryl
bromide were also tolerated (entries 6 and 7). The reaction
occurred in high yield with bromonaphthalenes, as shown in
entry 8. The most hindered aryl halides reacted in higher yields
with a catalyst bearing P(t-Bu)3. For example, bromomesitylene
reacted with tert-butyl acetate in higher yield in the presence
of this catalyst than in the presence of catalysts bearing the
carbene from 1 (entry 3). tert-Butyl acetate did not couple with
pyridyl halides in the presence of this combination of base and
catalyst.
1.2. Improved Conditions for the r-Arylation of tert-Butyl
Acetate. During our studies described below on ester arylations
that form fully substituted carbon centers, we uncovered a
protocol that improved significantly the R-arylation of tert-butyl
acetate. Reactions of aryl halides with the lithium enolate of
tert-butyl acetate generated prior to addition of the palladium
catalyst and aryl halide occurred with high selectivity for
monoarylation of tert-butyl acetate and with less catalyst, ester,
and base. However, these improved reactions also required
careful selection of ligand and base. It was critical to generate
the enolate with LiNCy2 as base and to conduct the coupling
process with P(t-Bu)3 as ligand to observe high yields when
(55) Stambuli, J. P.; Stauffer, S. R.; Shaughnessy, K. H.; Hartwig, J. F. J. Am.
Chem. Soc. 2001, 123, 2677.
(56) Stauffer, S. R.; Lee, S.; Stambuli, J. P.; Hauck, S. I.; Hartwig, J. F. Org.
Lett. 2000, 2, 1423.
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A R T I C L E S
Jørgensen et al.
Table 2. Arylation of the Enolate of tert-Butyl Acetate Formed from LiNCy2 in the Presence of Pd(dba)2 and P(t-Bu)3 as Ligand
Table 3. Arylation of tert-Butyl Propionate Catalyzed by Pd(dba)2
and Carbene Precursor
butylbromobenzene produced, as a side product, the silylamine
from C-N coupling. The reaction even produced this product
when the more hindered LiN(SiMePh2)2 and LiN(SiMe2Ph)2
were used as base.40 Wide ranges of solvents and ligands were
tested, but the C-N coupling of this base57 was suppressed
effectively only when 2.0 equiv of the ester and 3.0 equiv of
base were used in toluene solvent and the combination of Pd-
(dba)2 and P(t-Bu)3 was used as catalyst. Reactions of enolates
generated from sodium and potassium hydride, alkoxide, or
amide bases generally occurred with low conversions, except
for those generated from NaHMDS. Reactions in the presence
of this base gave mainly arene.
The use of specific lithium amide bases allowed for the
arylation of R,R-disubstituted esters to be conducted without
competing C-N coupling and without excess of ester or base.
A series of lithium amides were tested for the reaction of methyl
isobutyrate with 4-tert-butylbromobenzene because LiN(i-Pr)-
Cy is effective at generating isolable ester enolates.45,46 Lithium
amides had not been useful bases for previous couplings of
enolates with aryl halides. Yet, the coupling occurred rapidly
when LDA was used to generate the enolate and formed 76%
a 1.3 equiv of preformed enolate from reaction with LiNCy2 was used.
yield of coupled product, although the reaction proceeded to
only 90% conversion in the presence of 1 mol % catalyst. Arene
was formed in 14% yield. Reactions in the presence of LiN(i-
ceeded in high yield when the lithium enolate was formed from
Pr)Cy were less selective and also did not proceed to completion.
LiNCy2 prior to addition of aryl halide and catalyst. In contrast,
Reactions in the presence of 2,2,6,6-tetramethylpiperazide
no reaction occurred between tert-butyl propionate and this aryl
occurred to full completion, but only 71% yield of product was
halide in the presence of NaHMDS as base and even 5 mol %
formed. Finally, reactions of the enolate of methyl isobutyrate
catalyst. Moreover, no reaction occurred with the sodium enolate
generated from LiNCy2 completely consumed the aryl halide
generated from NaNCy2 prior to addition of aryl halide and
and formed the arylated ester in an excellent 93% yield with
catalyst.
only 7% arene. This reaction occurred most readily in arene
3.1. Development of Reaction Conditions for the Arylation
solvents. Reactions in pentane and cyclohexane did not proceed
to completion, and arene was the major product from reactions
in ether solvent. No reaction occurred in Et3N.
of r,r-Disubstituted Esters. A match of the steric bulk of the
substrate with that of the ligand allowed for our initial formation
of quaternary carbons by ester arylation, and the use of LiNCy2
as base produced our most efficient arylations of R,R-disubsti-
Thus, we tested a wide range of ligands for the reaction of
isobutyrate with 4-tert-butylbromobenzene in the presence of
LiNCy2 base in toluene solvent. The highest yields of the desired
of LiHMDS generated a mixture of products that included those
tuted esters. Reactions of tert-butyl isobutyrate in the presence
product were obtained when employing bulky trialkylphosphine
ligands such as P(t-Bu)3, 1-adamantyldi-tert-butylphosphine ((1-
Ad)P(t-Bu)2), (1-Ad)2P(t-Bu), or ferrocenyldi-tert-butylphos-
phines. Poor yields and conversions were observed when the
less bulky PCy3, PCy(t-Bu)2, PCy2(t-Bu), and P(2-Ad)(t-Bu)2
were used. The carbene precursors that we tested generated poor
formed from coupling of the silylamide with the aryl halide,57
but reactions of methyl isobutyrate occurred to form the
R-arylated material as the major product. With 1-2 equiv of
base, however, the reaction of methyl isobutyrate with 4-tert-
(57) Lee, S.; Jørgensen, M.; Hartwig, J. F. Org. Lett. 2001, 3, 2729.
9
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Efficient Synthesis of R-Aryl Esters
A R T I C L E S
Table 4. Scope of the Arylation of Methyl Isobutyrate
a This aryl halide was used as the HCl salt. A 2.3 equiv amount of LiNCy2 was used. b2:1 ratio of products from R- and â-arylation of the ester; 48% yield
of pure R-isomer was isolated.
yields of the R-arylation of methyl isobutyrate. The most
convenient and effective combination of palladium and ligand
was Pd(dba)2 and P(t-Bu)3.53,57,58 The yield was independent
of the ratio of ligand to palladium (ranging from 0.33:1 to 3:1),
and the rate was similarly fast when an excess or an equimolar
amount of ligand relative to Pd(dba)2 was used.
In contrast to reactions of tert-butyl acetate and propionate,
reactions of methyl isobutyrate occurred with heterocyclic aryl
bromides such as bromoquinoline and bromopyridines, -thio-
phenes, and -furans (entries 15-18), although more catalyst was
required than for reactions of bromoarenes. The reactions of
all the heterocyclic aryl bromides gave a single product, except
for the reaction of methyl isobutyrate with 2-bromothiophene.
In this case, products from coupling of the heteroaryl bromide
to the R- and â-positions of the ester were observed in a 2:1
ratio. The latter product probably forms by rearrangement of
the hindered palladium enolate to a less hindered homoenolate,
followed by reductive elimination. This migration could occur
by â-hydrogen elimination and reinsertion of the olefin into the
metal hydride to form a primary alkyl. We suggest that this
sequence is observed only during reaction of bromothiophene
because reductive elimination of coupled product from the
electron-rich thiophenylpalladium enolate intermediate is slower
than it is from the analogous intermediates formed from aryl
or other heteroaryl bromides.
3.2. Scope of the Arylation of r,r-Disubstituted Esters.
Methyl isobutyrate was chosen as the benchmark substrate to
examine the scope of the reaction with a wide range of aryl
bromides. These results are summarized in Table 4. Because
competing decomposition of the ester enolates could control
the amount of required catalyst, we evaluated the minimum
amount that would give suitably fast reactions. A wide range
of electron-neutral and electron-donating substituents were
tolerated on the aryl bromide (entries 1-3, 5-8). The biphenyl
and naphthyl bromides that would generate protected Flurbi-
profen and Naproxen analogues gave high yields of the coupled
product (entries 4 and 16). In addition, biologically attractive
amino, dioxolane, and fluoro functionalities were tolerated.
Although dibromoarenes could not be selectively monofunc-
tionalized, chlorobromoarenes generated the monofunctionalized
chloro-substituted product in high yield (entries 9 and 10).
Although (trifluoromethyl)arenes were suitable substrates, bro-
mobenzaldehydes, methyl or tert-butyl bromobenzoates, and
bromobenzonitrile generated product mixtures. Bromobenzophen-
one and the ethylene glycol acetal of bromobenzaldehydes,
however, reacted in good yields (entries 13 and 14).
Reactions of several other esters were studied to evaluate the
scope of the ester component (Table 5). The slightly more
hindered methyl 2-methylbutyrate was as reactive as methyl
isobutyrate. The isolated yields were high in all cases, and the
amount of catalyst required for full conversion of the aryl
bromide was lower than 0.5 mol %. Reactions of the more
hindered, but more acidic, methyl 2-phenylpropionate also
occurred in good yields by the standard protocol. A slightly
higher catalyst loading of 1 mol % was required, but the coupled
product was formed in good to excellent yields with various
(58) Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett. 1998, 39, 617.
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A R T I C L E S
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Table 5. Scope of the Coupling of R,R-Disubstituted Methyl and Benzyl Esters
a 1.5 equiv of ester and 1.8 equiv of LiNCy2 were employed.
aryl bromides. Cyclic esters such as methyl cyclohexylcarboxyl-
ate reacted similarly to acyclic systems. Again, a slightly higher
catalyst loading of 0.5-1.0 mol % was required, but electron-
neutral, -rich, and -poor aryl bromides, as well as biphenyl
bromides and bromonaphthalenes, reacted with this ester in high
yields in all cases.
Because benzyl esters are more conveniently converted to
carboxylic acids than methyl esters, we evaluated reactions of
benzyl isobutyrate (entries 17-22 of Table 5). In contrast to
the 1.1 equiv of methyl isobutyrate, 1.5 equiv of the benzyl
esters was required to obtain good yields; reactions containing
less ester occurred in lower yields or with incomplete conversion
of the aryl halide. Yet, the palladium-catalyzed arylation of these
benzyl esters afforded the desired product in high yields when
1.5 equiv of ester and 1 mol % catalyst were used. The slightly
lower reactivity of this benzyl ester is consistent with a
deceleration of the reaction as the size of the substituent on the
oxygen of an R,R-disubstituted ester is increased.
formation of the coupled product in high yield in just 10 min
at room temperature when the enolate was generated from 1.1
equiv of methyl isobutyrate and 1.3 equiv of LiNCy2 in toluene.
Presumably, similar results would be observed from reactions
initiated with the air stable HBF4 salt of P(t-Bu)3, which is now
commercially available.59 A 1:1 ratio of the commercially
60
available and air-stable Pd[P(t-Bu)3]2 and Pd(dba)2 and the-
air stable palladium(I) species [PdBrP(t-Bu)3]261,62 also generated
active catalysts. Reactions catalyzed by these two systems were
approximately four times slower, but the reaction yields were
similar. Reactions catalyzed by Pd[P(t-Bu)3]2 alone formed the
coupled product, but the selectivity was lower and the reaction
required a longer time of 2 h.
5.1. Comments on the Relationship between pKa of the
Base and Selectivity. Dialkylation of alkali metal enolates is
commonly observed,63 but diarylation of the alkali metal
enolates from the palladium-catalyzed coupling occurs for
different reasons. The enolate of the coupling product is more
4. Conditions for Convenient Use of P(t-Bu)3 as Ligand.
Conditions were developed for convenient arylation of esters
in the presence of catalysts generated from the air-sensitive P(t-
Bu)3. First, 1 mol % of the catalyst was generated by adding
P(t-Bu)3 by syringe from a commercially available stock solution
in toluene. This procedure generated a catalyst that induced
(59) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
(60) Littke, A.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 12, 4020.
(61) Vilar, R.; Mingos, D. M. P.; Cardin, C. J. J. Chem. Soc., Perkin Trans.
1996, 4313.
(62) Dura-Vila, V.; Mingos, D. M. P.; Vilar, R.; White, A. J. P.; Williams, D.
J. J. Organomet. Chem. 2000, 600, 198.
(63) Streitwieser, A.; Kim, Y. J.; Wang, D. Z. R. Org. Lett. 2001, 3, 2599.
9
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Efficient Synthesis of R-Aryl Esters
A R T I C L E S
Scheme 1
stable than the starting enolate. Moreover, the palladium enolate
intermediates are less aggregated than the alkali metal enolates64
and are most likely monomeric. The palladium-catalyzed
coupling of acetate enolates involves multiple equilibria. The
ratio of the two enolates generated from the starting and product
esters is substantially different at different stages of the reaction
and can be substantially different when bases are used that have
conjugate acids with different pKa values.
The pKa data that are relevant to the equilibria of enolates in
the coupling process are available in THF65 and DMSO.66,67
Values for the same substrate in THF and DMSO are often
within 2-3 pKa units of each other, with the value in THF
generally the higher of the two. Our catalytic reactions were
conducted in the less polar solvent toluene in which pKa values
will be even higher and ion pairs will not be solvent separated.
Thus, the literature pKa values can help interpret results but do
not provide quantitative predictions on the population of species
in the reaction solutions.
The pKa of hexamethyldisilazane in THF is 25.8.65 The pKa
of tert-butyl acetate in DMSO is 30.3, and the pKa of tert-butyl
phenylacetate in DMSO is 23.6.67 Thus, it is likely that reactions
conducted with 1 equiv of LiHMDS base will be initiated with
only small concentrations of the acetate enolate, and the
silylamide base will be quenched by the coupled product in
toluene solvent. These data suggest that 1 equiv of base to
starting ester will be consumed at 50% conversion and that the
product will be the dominant enolate in solution after 33%
conversion. If an excess of base is used, then some starting
enolate will be present throughout the reaction and the major
product is formed from this more basic, less hindered enolate.
We do not have a detailed explanation for the higher selectivity
observed from reactions conducted with lithium hexamethyl-
disilazide versus those conducted with sodium hexamethyl-
disilazide.
Dialkylamines have pKa values in DMSO that exceed 40.66
Thus, mixing of tert-butyl acetate and this base will generate
the enolate quantitatively. This complete formation of enolate
contrasts with the partial formation of enolate from the silyl-
amide bases and tert-butyl acetate. We were surprised to find
that 1.2 equiv of the enolate provided the product from
monoarylation with high selectively. If proton exchange is faster
than the palladium-catalyzed chemistry, then reaction with 1
equiv of enolate would consume the starting enolate at 50%
conversion. Thus, the difference in pKa values requires that the
acetate enolate be roughly 108 times more reactive than the
phenylacetate enolate or that proton transfer between esters be
slower than the coupling process.
More substituted arylpalladium enolates undergo faster reduc-
tive elimination.44 Thus, a greater population of palladium
acetate enolate or faster formation of this intermediate must
account for the difference in reactivity if equilibration of the
alkali metal enolates has occurred. Although this trend in
stability has been observed,44 the stabilities of primary and
secondary alkyls have been measured previously,68 and the
magnitude of the difference in stability of the palladium enolates
required by the conditions of enolate equilibration is too large.
Thus, the high selectivity must arise from different rates for
transmetalation of the tert-butyl acetate vs tert-butyl phenylac-
etate enolates if the proton transfer equilibrium is fully
established. We tested these relative rates by studying a single
turnover. Reaction of [(1-Ad)P(t-Bu)2]Pd(Ph)(Br)69 with a 1:1
mixture of the enolates gave a 5:1 ratio of products instead of
the 18:1 ratio observed from the catalytic reactions conducted
with this ligand. Moreover, reactions of [(1-Ad)P(t-Bu)2]Pd-
(Ph)(Br) with the lithium enolate of tert-butyl acetate and with
the enolate of tert-butyl phenylacetate both gave the coupled
product essentially instantaneously.
Thus, we tested the alternative hypothesis that the catalytic
reaction is faster than proton transfer. The proton transfer
between the enolate of tert-butyl acetate generated from LiNCy2
and tert-butyl phenylacetate required hours. The half-life of this
process was on the order of 0.5-1 h. In contrast, the catalytic
coupling was shown to be complete within 15 min when the
reaction progress was checked by GC. We confirmed these
relative rates by conducting reactions with one ester and the
enolate of a second ester together (Scheme 1). The catalytic
reaction of the enolate of tert-butyl acetate with 4-bromo-tert-
butylbenzene in the presence of 1 equiv of added tert-butyl
phenylacetate occurred with 14:1 selectivity for reaction with
the acetate enolate. In contrast, reaction of the enolate of tert-
butyl phenylacetate with 4-bromo-tert-butylbenzene in the
presence of tert-butyl acetate occurred with 50:1 selectivity for
reaction with the phenylacetate enolate. These data confirm that
the product is generated from the starting enolate and that the
palladium-catalyzed coupling process is faster than proton
transfer between the enolates.
5.2. Effect of Amine on the Arylation of Esters. The
difference between the reactivity of enolates formed from
LiNCy2 and LDA in the R-arylation of methyl isobutyrate was
unexpected because a similar enolate would be formed.70 Yet,
ligands affect the solvation71 and the mechanism by which
LiHMDS participates in acid-base reactions.72 Thus, a brief
set of experiments was conducted to investigate the potential
effect of the neutral amine on the reactivity of the ester enolate.
(64) Streitwieser, A.; Juaristi, E.; Kim, Y. J.; Pugh, J. K. Org. Lett. 2000, 2,
3739.
(65) Fraser, R. R.; Mansour, T. S.; Savard, S. J. Org. Chem. 1985, 50, 3232.
(66) Bordwell, F. G.; Drucker, G. E.; Fried, H. E. J. Org. Chem. 1981, 46, 632.
(67) Bordwell, F. G.; Fried, H. E. J. Org. Chem. 1981, 46, 4327.
(68) Buchanan, J. M.; Stryker, J. M.; Bergman, R. G. J. Am. Chem. Soc. 1986,
108, 1537-1550.
(69) Stambuli, J. P.; Bu¨hl, M.; Hartwig, J. F. J. Am Chem. Soc. 2002, 124,
9346.
(70) Autrecht, K. B.; Collum, D. B. J. Org. Chem. 1996, 61, 8674.
(71) Lucht, B. L.; Collum, D. B. Acc. Chem. Res. 1999, 32, 1035.
(72) Sun, X.; Kenkre, S. L.; Remenar, J. F.; Gilchrist, J. H.; Collum, D. B. J.
Am. Chem. Soc. 1997, 119, 4765.
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A R T I C L E S
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Deprotonation of the ester with lithium tetramethylpiperazide
(LiTMP), followed by addition of diisopropylamine, dicyclo-
hexylamine, or N-isopropylcyclohexylamine, generates the same
enolate aggregates as when the enolate is generated from LDA,
LiNCy2, or LiN(i-Pr)Cy alone because of the hindrance of
LiTMP. The enolates generated from addition of LiTMP,
followed by HNCy2 or HN(i-Pr)2, reacted in yields more similar
to those observed from reactions of the enolates generated from
LiNCy2 or LiN(i-Pr)2 than from reactions of the enolates
generated from LiTMP alone. These results suggested that the
presence of the amine in the enolate aggregate influenced the
palladium chemistry. However, reaction of the enolate formed
from LiTMP and Cy(i-Pr)NH occurred in higher yields than
those of the enolate generated from LiN(i-Pr)Cy alone. Perhaps,
an impurity present in the noncrystalline LiN(i-Pr)Cy influenced
the reaction when this base was used alone to form the
enolate.73,74
5.3. Comments on Ligand Effects. The high activity of
palladium catalysts generated from strongly electron-donating
trialkylphosphines or N-heterocyclic carbenes toward C-C and
C-N bond-forming reactions stems, in part, from the ability of
these ligands to stabilize the zerovalent palladium species and
to promote oxidative addition.75-77 In many cases high yields
also rely on the ability of these ligands to promote reductive
elimination.78-80 Both the high overall activity and the high
selectivity for reductive elimination over â-hydrogen elimination
are important for successful coupling of ester enolates. Although
we cannot explain the influence on activity of subtle steric
differences among related ligands, it is clear that less active
catalysts generated the product in lower yield even at long
reaction times. Fast rates for the coupling are crucial for the
arylation of esters because the catalytic process must occur faster
than competing decomposition of the ester enolate. In addition,
most of the enolate intermediates can undergo â-hydrogen
elimination. Complexes of several ligands simply catalyzed the
reduction of aryl halides in the presence of the enolate. Thus,
the sterically hindered ligands that create catalysts for coupling
with broad scope must be efficient at promoting reductive
elimination at the expense of â-hydrogen elimination, even when
the enolate is similar in structure to a tertiary alkyl. Tertiary
alkyls have generally undergone homolysis or â-hydrogen
elimination more often than they have undergone productive
processes such as reductive elimination.81
tion and Claisen condensations of the ester enolate. A catalyst
generated from Pd(dba)2 and the N-heterocyclic carbene precur-
sor 1 in the presence of LiHMDS mediated the coupling of tert-
butyl acetate, and the same catalyst in the presence of NaHMDS
mediated the coupling of tert-butyl propionate. However, we
found that enolates of tert-butyl acetate and R,R-disubstituted
esters formed from lithium dicyclohexylamide prior to addition
of catalyst and aryl halide reacted in higher yields to form aryl
acetic acid esters and products with quaternary carbons. In these
cases catalysts generated from Pd(dba)2 and P(t-Bu)3 were most
active.
Experimental Section
General Methods. Reactions were conducted using standard drybox
techniques. However, P(t-Bu)3 is available as a solution in toluene or
as an air-stable HBF4 salt (Strem), lithium hexamethyldisilazide is
available as a solution in hexanes, sodium hexamethyldisilazide is
available as a solution in toluene (Aldrich), and Pd(dba)2 can be weighed
in air without decomposition. Thus, addition of these reagents to a
degassed solution of toluene and aryl halide using standard syringe
techniques provides an alternative procedure to those described below.
When tested, equivalent yields by GC were obtained without use of
the drybox. 1H and 13C NMR spectra were recorded at 400 MHz with
tetramethylsilane or residual protiated solvent used as a reference, and
coupling constants are reported in Hertz (Hz). Chromatographic
purifications were performed by flash chromatography on 200-400
mesh silica gel. 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
1
by H NMR and capillary gas chromatography (GC). All 13C NMR
spectra were proton decoupled. GC analyses were performed with a
DB-1301 narrow-bore column and 120 °C/min temperature ramps.
GCMS spectra were obtained using an HP-1 methyl silicone column.
All reagents and bases were purchased from Aldrich and used without
further purification. Pd(dba)282 and NaNCy283 were prepared according
to literature procedures. Toluene was distilled from sodium and
benzophenone and stored in a drybox.
General Procedure for the Arylation of Esters in the Presence
of LiHMDS or NaHMDS. To a screw-capped vial containing carbene
precursor 1 or P(t-Bu)3 (0.0050 mmol), Pd(dba)2 (0.0050 mmol), and
LiHMDS (2.3 mmol, for tert-butyl acetate) or NaHMDS (2.3 mmol,
for tert-butyl propionate) were added aryl halide (1.0 mmol) and ester
(1.1 mmol) followed by toluene (2.5 mL). The vial was sealed with a
cap containing a PTFE septum and removed from the drybox. The
heterogeneous reaction mixture was stirred at room temperature and
monitored by GC. Upon consumption of aryl halide, the crude reaction
was diluted with Et2O and was quenched with aqueous NH4Cl. The
organic phase was washed with a saturated NaCl solution, dried over
MgSO4, filtered, and concentrated at reduced pressure. The organic
solution was concentrated in vacuo. The residue was then purified by
chromatography on silica gel using 5% ethyl acetate in hexanes, unless
otherwise stated.
Conclusion
Two sets of conditions that allow for the effective coupling
of ester enolates and aryl halides in the presence of palladium
catalysis have been uncovered. Reactions of acetates and
propionates occurred when protected as the tert-butyl esters
because this hindered group suppresses competing decomposi-
(73) Perez, D. G.; Nudelman, N. S. J. Org. Chem. 1988, 53, 408.
(74) Nudelman, N. S.; Garc´ıa Lin˜ares, C. E. J. Org. Chem. 2000, 65, 1629.
(75) McGuinness, D. S.; Green, M. J.; Cavell, K. J.; Skelton, B. W.; White, A.
H. J. Organomet. Chem. 1998, 557, 93.
(76) McGuinness, D. S.; Cavell, K. J.; Skelton, B. W.; White, A. H. Organo-
metallics 1999, 18, 1569.
General Procedure for the Arylation of Esters in the Presence
of LiNCy2. A solution of the ester (1.1 mmol, 1.5 mmol for benzyl
esters) in toluene (2 mL) was added to a vial containing 1.3 equiv (1.8
equiv for benzyl esters) of LiNCy2 (1.3 mmol). The solution was stirred
for 10 min before it was transferred to a screw-capped vial containing
a catalytic amount of Pd(dba)2 and the aryl or heteroaryl halide (1.0
(77) Alcazar-Roman, L. M.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 12905.
(78) Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J. F. J. Am. Chem. Soc. 2000,
122, 10718-10719.
(79) Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am. Chem.
Soc. 1999, 121, 3224-3225.
(80) Roy, A. H.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 1232.
(81) Hayashi, T.; Konishi, M.; Yokota, K.-i.; Kumada, M. Chem. Lett. 1980,
767.
(82) Ukai, T.; Kawazura, H.; Ishii, Y.; Bonnet, J. J.; Ibers, J. A. J. Organomet.
Chem. 1974, 65, 253.
(83) Barr, D.; Dawson, A. J.; Wakefield, B. J. Chem. Commun. 1992, 204.
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12564 J. AM. CHEM. SOC. VOL. 124, NO. 42, 2002

Efficient Synthesis of R-Aryl Esters
A R T I C L E S
mmol). Finally, P(t-Bu)3 was added from a 0.5 M toluene stock solution.
The vial was fitted with a PFTE septum and removed from the drybox.
The reaction mixture was stirred at room temperature. The solvent was
evaporated under vacuum, and the crude product mixture was purified
over silica gel using 5% ethyl acetate in hexanes as the eluent.
Alternatively, the crude product mixture was extracted with dichlo-
romethane (10 mL) and 5% aqueous hydrochloric acid (10 mL). The
precipitate was removed by filtration, and the organic layer was
extracted with 5% aqueous hydrochloric acid (10 mL) and water (10
mL) before it was dried over MgSO4 and concentrated. The residue
was filtered through a plug of silica gel, and eluted with 5% ethyl acetate
in hexane unless otherwise stated.
Acknowledgment. We thank the NIH (Grant GM58108) for
support of this work and Johnson-Matthey for a gift of palladium
chloride. We thank Professor David B. Collum for helpful
discussions and suggestions.
Supporting Information Available: Tables of data from
varying reaction parameters, conditions for isolation, spectral
and analytical data, and literature references for all reaction
products. This material is available free of charge via the Internet
at http://pubs.acs.org.
JA027643U
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