Palladium-catalyzed α-arylation of esters

Article abstract of DOI:10.1021/ja010797+

A new and simple one-pot procedure for the palladium-catalyzed intermolecular α-arylation of esters is described. A number of esters can be functionalized with a wide range of aryl bromides using Pd(OAc)₂ or Pd₂(dba)₃ and

Full text of DOI:10.1021/ja010797+

7996
J. Am. Chem. Soc. 2001, 123, 7996-8002
Palladium-Catalyzed R-Arylation of Esters
Wahed A. Moradi and Stephen L. Buchwald*
Contribution from the Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
ReceiVed March 27, 2001
Abstract: A new and simple one-pot procedure for the palladium-catalyzed intermolecular R-arylation of esters
is described. A number of esters can be functionalized with a wide range of aryl bromides using Pd(OAc)2 or
Pd2(dba)3 and bulky electron-rich o-biphenyl phosphines 1-3. Under the reaction conditions, using LiHMDS
as base, R-arylation proceeds at room temperature or at 80 °C with very good yields and high selectivities for
monoarylation. Important nonsteroidal antiinflammatory drug derivatives such as (()-naproxen tert-butyl ester
and (()-flurbiprofen tert-butyl ester can be prepared in 79% and 86% yield, respectively. The catalyst system
based on the di-tert-butylphosphine (2) is also active for the R-arylation of esters using aryl chlorides.
Furthermore, using (3) the R-arylation of trisubstituted ester enolates can be accomplished to provide compounds
that have quaternary centers.
Introduction
For the few catalytic R-arylations of esters, a Reformatsky
7a,b
8
9
reagent, silylketene acetals, aryl-Grignard reagents, R-halo-
The synthesis of R-aryl esters and their derivatives is of
interest in organic chemistry. In particular, R-aryl carboxylic
acids are integral structural components of several pharmaceu-
ticals with analgesic and antiinflammatory properties (e.g.,
ibuprofen, naproxen, ketoprofen, and flurbiprofen). These
compounds are able to reduce inflammation and pain by
inhibition of the cyclooxygenase system. Although the synthesis
of R-aryl esters has been a field of active research for years,
the development of a catalytic, economically reasonable, and
general protocol remains elusive.
Common strategies for the synthesis of R-aryl esters have a
number of disadvantages, including the need for special and
often toxic reagents, stoichiometric or large excesses of
substrates, harsh reaction conditions, or multiple steps. While
many of these methods are quite effective, their practicality is
diminished by the time needed to prepare the required stoichio-
metric reagents. Moreover, many of these methods do not use
an ester but instead a less readily available derivative.
1
0
11
12
carbonyl compound, silyl enol ether, or tin enolate is
required. Musco and Santi reported the palladium-mediated
coupling of trimethylsilylketene acetals with aryl triflates or
halides in the presence of toxic thallium acetate to provide alkyl
1
1
,2
8
a,b
2
-arylalkanoates in moderate to good yields.
Yamanaka
3
disclosed the palladium-catalyzed synthesis of ethyl aryl acetates
using aryl halides and ethoxy(trialkylstannyl)acetylenes to afford
ethoxy(ethynylalkylstannyl)acetylenes that, after solvolysis,
4
5
8c,d
provided ethylaryl acetates. Kuwajima and Urabe found that
tin enolates, generated in situ from silyl enol ethers in the
presence of tributyltin fluoride, undergo palladium-catalyzed
cross-coupling with aryl bromides to provide R-aryl ketones.13
Sulikowski extended Kuwajima and Urabe’s results to the
synthesis of aryl acetates by palladium-catalyzed cross-coupling
5
,7
8
e
of aryl bromides and copper(II) enolates. In this case, yields
are good, but the reaction is limited to the synthesis of R-aryl
acetates. Clearly a need exists for a general, inexpensive, and
practical synthesis of R-aryl esters.
(1) (a) Sonawane, H. R.; Bellur, N. S.; Ahuja, J. R.; Kulkarni, D. G.
Recently, Hartwig, Satoh, and our own group reported the
Tetrahedron Asymmetry 1992, 3, 163 and references therein. (b) Giordano,
C.; Castaldi, G.; Uggeri, F. Angew. Chem., Int. Ed. Engl. 1984, 23, 413.
14
palladium-catalyzed R-arylation of ketones. Hartwig subse-
quently reported an improved method based on PCy3 and P(t-
Bu)3. We have described the use of bulky, electron-rich
(
0
c) Stahly, B. C.; Lin, R. W.; Atkinson, E. E. Ethyl Corp., U.S. Patent
4.990.658, 1989; Chem. Abstr. 1991, 114, 246962. (d) Kawabe, M.;
Kojima, H. Daicel Chem. Ind., Japanese Patent 63.162.044, 1986; Chem.
Abstr. 1988, 109, 23149. (e) Stahly, G. P.; Starrett, R. M. In Chirality in
Industry II; Collins, A. N., Sheldrake, G. N., Crosby, J., Eds.; Wiley: New
York, 1997; p 22. (f) Arzoumanian, H.; Buono, G.; Choukrad, M. B.;
Petrignani, J.-F. Organometallics 1988, 7, 59. (g) Ohta, T.; Takaya, H.;
Kitamura, M.; Nagai, K.; Noyori, R. J. Org. Chem. 1987, 52, 3174, (h)
Alper, H.; Hamel, N. J. Am. Chem. Soc. 1990, 112, 2803. (i) Brunner, H.;
Schmidt, P. Eur J. Org. Chem. 2000, 11, 2119-2133. (j) Chelucci, G.;
Cabras, M. A.; Botteghi, M.; Marchetti, M. Tetrahedron Asymmetry 1994,
(6) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 1360.
(7) (a) Fauvarque, J. F.; Jutand, A. J. Organomet. Chem. 1979, 177, 273.
(b) Orsini, F.; Pelizzoni, F.; Vallarino, L. M. J. Organomet. Chem. 1989,
367, 375.
(8) (a) Carfagna, C.; Musco, A.; Sallese, G.; Santi, R.; Fiorani, T. J.
Org. Chem. 1991, 56, 261. (b) Galarini, R.; Musco, A.; Pontellini, R.; Santi,
R. J. Mol. Catal. 1992, 72, L11. (c) Sakamoto, T.; Kondo, Y.; Masumoto,
K.; Yamanaka, H. J. Chem. Soc., Perkin Trans. 1 1994, 235. (d) Sakamoto,
T.; Kondo, Y.; Masumoto, K.; Yamanaka, H. Heterocycles 1993, 36, 2509.
(e) Agnelli, F.; Sulikowski, G. A. Tetrahedon Lett. 1998, 39, 8807.
(9) Amano, T.; Yoshikawa, K.; Sano, T.; Ohuchi, Y.; Manzo, S.; Ishiguro,
M.; Fujita, Y. Synth. Commun. 1986, 16, 499.
5
, 299. (k) Consiglio, G.; Roncetti, L. Chirality 1991, 3, 341. (l) Hiyama,
T.; Wakasa, N.; Kusumoto, T. Synlett 1991, 569. For more refs see: Applied
Homogeneous Catalysis with Organometallic Compounds; Cornils, B.,
Herrmann, W. A., Eds.; VCH: Weinheim, Germany, 1996.
(2) Rieu, J.-P.; Boucherle, A.; Cousse, H.; Mouzin, G. Tetrahedron 1986,
4
1
1
2, 4095.
(10) (a) Durandetti, M.; P e´ richon, J.; N e´ d e´ lec, J.-Y. J. Org. Chem. 1997,
62, 7914 and references therein. (b) Durandetti, M.; N e´ d e´ lec, J.-Y.; P e´ richon,
J. J. Org. Chem. 1996, 61, 1748.
(11) Tamao, K.; Zembayashi, M.; Kumada, M. Chem. Lett. 1976, 1239.
(12) Kosugi, M.; Hagiwara, I.; Sumiya, T.; Migita, T. Bull. Chem. Soc.
Jpn. 1984, 57, 242.
(
3) Williams, K. M.; Day, R. O.; Breit, S. N. AdV. Drug Res. 1993, 24,
21-198.
(
4) (a) Brooks, P. M.; Day, R. O. New Engl. J. Med. 1991, 324, 1716-
725. (b) Vane, J. R.; Botting, R. M. Inflamm. Res. 1995, 44, 1-10.
(5) For a survey of methods that give R-aryl esters see references cited
in footnotes 6-12.
(13) Kuwajima, I.; Urabe, H. J. Am. Chem. Soc. 1982, 104, 6831.
1
0.1021/ja010797+ CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/27/2001

Palladium-Catalyzed R-Arylation of Esters
J. Am. Chem. Soc., Vol. 123, No. 33, 2001 7997
o-biphenyl phosphines which constitute a significant improve-
ment from our initial system. This catalyst system demonstrated
Table 1. Palladium-Catalyzed R-Arylation of tert-Butyl Acetate
Using Ligand 1 and LiHMDS at Room Temperaturea
6
a good functional group tolerance and a high selectivity for
ketones with two enolizable positions wherein the less substi-
tuted position is arylated. In addition, this protocol was extended
to the arylation of nitroalkanes, malonate esters, and 1,3-
6
diketones. We have also disclosed an enantioselective variant
15
of our initial system using the Pd/BINAP catalyst.
The use of bulky, electron-rich o-biphenyl phosphine ligands
-3 for the R-arylation of esters was a desirable extension of
other palladium-catalyzed cross-coupling processes. On the
basis of our success with other catalyzed cross-coupling
reactions, particularly ketone arylation, we chose to explore the
palladium-catalyzed arylation of esters.
1
1
6
a
Reaction conditions: 1.0 equiv of aryl bromide, 2.3 equiv of tert-
2
butyl acetate, 2.5 equiv of LiHMDS, 3.0 mol % Pd(OAc) , and 6.3
mol % ligand 1. 2 mL of toluene was added per 0.5 mmol of aryl
bromide. b Isolated yield. c The reaction temperature was 80 °C.
counterions (i.e., more covalent M-O bonds).17 That Li-O
bonds are more covalent than Na-O bonds has ample precen-
Results
1
8
dent.
Initial attempts to couple 1-bromo-4-tert-butylbenzene with
tert-butyl acetate using sodium hexamethyldisilazane (NaH-
MDS) as base and a catalyst derived from 1 and Pd(OAc)2 gave
a mixture of mono- and diarylated products (4 and 5) along
with significant amounts of the Claisen product 6 (eq 1). The
mixture of 4 and 5 was obtained in 46% yield.
With a catalyst combination employing 1 as ligand, LiHMDS
as base, and toluene as solvent it was possible to carry out the
reaction at room temperature, and doing so, the formation of
the diarylation product (e.g., 5) was suppressed. As shown in
Entry 1 of Table 1, the reaction of 2-bromonaphthalene and
tert-butyl acetate at room temperature for 1 h in toluene with
LiHMDS as base, 3 mol % Pd(OAc)2 and ligand 1 gave the
desired product in 84% yield.
One limitation of the method is that it was necessary to use
2
.3 equiv of ester and 2.5 equiv of LiHMDS to effect complete
conversion of the aryl bromide. A significant part of the ester
was consumed via Claisen condensation. We assume that, in
many instances, the product may exist in deprotonated form
1
4e
prior to the quenching of the reaction mixture. Attempts to
use less base and ester under these conditions were unsuccessful
as the reaction did not go to completion. The use of sodium
tert-butoxide as base under the same conditions gave no
conversion of the aryl bromide. We found that either Pd(OAc)2
or Pd2(dba)3 could be used as the catalyst precursor. The most
general catalyst system was comprised of the commercially
available ligand 1, Pd(OAc)2, and LiHMDS in toluene. This
To search for better conditions, we screened a number of
reaction variables including temperature, base, and ligands. We
found that lithium hexamethyldisilazane (LiHMDS) was the
most effective base for the R-arylation of esters. In contrast to
what we had observed with NaHMDS, reactions with LiHMDS
gave only traces of diarylated product. We note that this is the
first time that we have witnessed a situation in which a reaction
(16) For C-N coupling reactions employing these ligands, see: (a)
Harris, M. C.; Buchwald, S. L. J. Org. Chem. 2000, 65, 5327-5333. (b)
Zhang, X. X.; Sadighi, J. P.; Mackewitz, T. W.; Buchwald, S. L. J. Am.
Chem. Soc. 2000, 122, 7606-7607. (c) Plante, O. J.; Buchwald, S. L.;
Seeberger, P. H. J. Am. Chem. Soc. 2000, 122, 7148-7149. (d) Old, D.
W.; Harris, M. C.; Buchwald, S. L. Org. Lett. 2000, 2, 1403-1406. (e)
Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J. J.; Buchwald, S. L. J. Org.
Chem. 2000, 65, 1158-1174. (f) Wolfe, J. P.; Buchwald, S. L. Angew.
Chem., Int. Ed. Engl. 1999, 38, 2413-2416. (g) Old, D. W.; Wolfe, J. P.;
Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 9722-9723. (h) For C-O
coupling reactions, see: Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J.
P.; Sadighi, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369-
4378. (i) For R-arylation see ref 6. For the C-C coupling reaction employing
these ligands, see: (j) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald,
S. L. J. Am. Chem. Soc. 1999, 121, 9550-9561. (k) Wolfe, J. P.; Buchwald,
S. L. Angew. Chem., Int. Ed. Engl. 1999, 38, 2413-2416. For the synthesis
of these ligands, see: (l) Tomori, H.; Fox, J. M.; Buchwald, S. L. J. Org.
Chem. 2000, 65, 5334-5341.
+
protocol using a Li counterion gave superior results to one
+
employing a Na counterion. This result is consistent with
previous findings that the selective monoalkylation of dianions
+
+
derived from â-diketones is favored on moving from K to Na
(
14) (a) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119,
1
1108. (b) See reference 6. (c) Hamann, B. C.; Hartwig, J. F. J. Am. Chem.
Soc. 1997, 119, 12382. (d) Shaughnessy, K. H.; Hamann, B. C.; Hartwig,
J. F. J. Org. Chem. 1998, 63, 6546. (e) Kawatsura, M.; Hartwig, J. F. J.
Am. Chem. Soc. 1999, 121, 1473. (f) Satoh, T.; Kawamura, Y.; Miura, M.;
Nomura, M. Angew. Chem., Int. Ed. Engl. 1997, 36, 1740. (g) Satoh, T.;
Inoh, J.-I.; Kawamura, Y.; Kawamura, Y.; Miura, M.; Nomura, M. Bull.
Chem. Soc. Jpn. 1998, 71, 2239.
(17) Hampton, K. G.; Harris, T. M.; Hauser, C. R. J. Org. Chem. 1963,
28, 1946.
(
15) Åhman, J.; Wolfe, J. P.; Troutman, M. V.; Palucki, M.; Buchwald,
(18) Schlosser, M. In Organometallics in Synthesis: A Manual; Schlosser,
M., Ed.; Wiley: Chichester, 1994; Chapter 1.
S. L. J. Am. Chem. Soc. 1998, 120, 1918.

7998 J. Am. Chem. Soc., Vol. 123, No. 33, 2001
Moradi and Buchwald
Table 2. Palladium-Catalyzed R-Arylation of R-Alkyl Estersa
procedure proved to be general for the R-arylation of tert-butyl
acetate with a variety of aryl bromides (Table 1). In all cases
examined, only traces of diarylation products were observed.
We note that the use of esters derived from smaller alcohols
(e.g., ethyl) led to reduced yields in many instances.
It should be noted that the vinylation of tert-butyl acetate is
also possible under the same conditions. The reaction of
â-bromostyrene and tert-butyl acetate gave the corresponding
â,γ-unsaturated ester in 66% yield (Table 1, entry 6). It is
interesting that even in the presence of excess strong base,
isomerization to the R,â-unsaturated ester did not predominate.
After our success with the synthesis of R-aryl acetates, we
turned our attention to the preparation of R-aryl propionic esters
(
eq 2). That class of compounds is important as many non-
steroidal antiinflammatory and analgesic drugs are based on
R-aryl propionic acids and their derivatives.1
,2
The R-arylation of tert-butyl propionate with a variety of aryl
bromides was examined and was found to proceed in good yield
either at room temperature or at 80 °C (see Table 2). For
example, the combination of 2-bromonaphthalene and 2.3 equiv
of tert-butylpropionate using 3 mol % Pd(OAc)2, 6.3 mol % 1,
and 2.5 equiv of LiHMDS as base gave, after 15 min at 80 °C,
the desired product in 92% yield (entry 1). The only significant
byproduct (10-20%) observed in this R-arylation process was
the Claisen product of the corresponding tert-butyl ester. Using
this catalyst system, a number of aryl bromides were converted
to products in very good to excellent yields.
a
Reaction conditions: 1.0 equiv of aryl bromide, 2.3 equiv of ester,
2
.5 equiv of LiHMDS, 3.0 mol % Pd(OAc) , and 6.3 mol % ligand 1.
2
b
2 mL of toluene was added per 0.5 mmol of aryl bromide. Isolated
yield. c Ligand 3 was used.
As shown in Table 2, the reaction has a good level of
generality and tolerates trifluoromethyl and o-vinyl groups as
well as 2,6-disubstitution. Also shown is that ethyl esters can
be utilized and quaternary centers can be formed, albeit in
moderate yields (Table 2, entries 12 and 13).
The reaction described in Table 2, entry 1 was also carried
out at room temperature using PPh3, BINAP, PCy3, and P(t-
Bu)3 as ligands. Only P(t-Bu)3 gives the desired R-aryl ester in
any significant amount, but the reactions were much slower and
resulted in lower yield than those using 1. We note, however,
that no attempt was made to optimize the process using any of
these ligands.
One goal of the ester R-arylation was the development of an
efficient method for the preparation of several non-steriodal
antiinflammatories (Table 2, entries 8, 9, and 10). Using the
simple protocol described, (()-naproxen tert-butyl ester can be
prepared in 79% yield (Table 2, entry 10) and (()-flurbiprofen
tert-butyl ester in 86% yield (Table 2, entry 8). Reaction of the
tert-butyl ester of flurbiprofen with TFA in dichloromethane at
We were also interested in extending the scope of the
arylation process to include methyl or ethyl esters. Our initial
attempts to use ethyl phenylacetate under reaction conditions
similar to those described above at room temperature were
unsuccessful; unreacted aryl bromide was recovered. However,
the same reaction proceeded cleanly in only 10 min when the
reaction temperature was increased to 80 °C. As is evident from
the results shown in Table 3, the method is quite effective in a
number of instances and produces the desired products in very
good yields. Moreover, a variety of functional groups (Cl, NMe2,
t
CO2NEt2, and CO2 Bu) were tolerated as illustrated (Table 3,
entries 3-6 and 8). From these results it is evident that, at least
for stabilized ester enolates, ethyl and methyl esters are
satisfactory substrates.
The only byproduct in all of the reactions described in Table
3
was that of Claisen condensation of the starting ester. Despite
the usefulness of the catalyst system derived from Pd(OAc)2
and ligand 1 for the preparation of many R-aryl esters, not all
combinations of substrates were effectively transformed. The
coupling product of ethyl phenylacetate with N,N-dimethyl-4-
bromoaniline was obtained in only 49% yield with Pd(OAc)2
40 °C provided the free carboxylic acid in 96% yield. Our
method is quite competitive with the other methods of synthe-
sizing flubiprofen described in the literature.19
(Table 3, entry 4). The combination of 1.5 mol % Pd2(dba)3
and 2, however, gave the desired product in 90% yield and was
complete in only 10 min at 80 °C.
(
19) Schlosser, M.; Geneste, H. Chem. Eur. J. 1998, 4, 1969 and
references therein.

Palladium-Catalyzed R-Arylation of Esters
J. Am. Chem. Soc., Vol. 123, No. 33, 2001 7999
Table 3. Palladium-Catalyzed R-Arylation of Ethyl Phenyl Acetate
Table 4.a R-Arylation of Esters Using Aryl Chlorides and Ligand 2
at 80 °C
a
Using Ligand 1
a
Reaction conditions: 1.0 equiv of aryl chloride, 2.3 equiv of ester,
2
.5 equiv of LiHMDS, 1.5 mol % Pd
2 3
(dba) , and 6.3 mol % ligand 2.
2
mL of toluene was added per 0.5 mmol of aryl chloride. The reaction
b
temperature was 80 °C. Isolated yield.
The described method has the advantage of simplicity and
employs a one-pot procedure to obtain R-aryl esters in high
yields from commercially available starting materials. Of special
importance is that the use of LiHMDS as the base is a key factor
in obtaining monoarylated product in a selective manner. In
addition to the efficacy of our catalyst system, these conditions
exhibited good functional group compatibility. The reactions
proceed at room temperature to 80 °C with 3 mol % palladium
catalyst in good to excellent yields and with high selectivity
for monoarylation.
a
Reaction conditions: 1.0 equiv of aryl bromide, 2.3 equiv of ethyl
2
phenylacetate, 2.5 equiv of LiHMDS, 3.0 mol % Pd(OAc) , and 6.3
mol % ligand 1. 2 mL of toluene was used per 0.5 mmol of aryl
bromide. The reaction temperature was 80 °C. Isolated yield. c 1.5
b
Experimental Section
2 3
mol % Pd (dba) and 6.3 mol % ligand 2 were used.
General Considerations. All reactions were carried out in glassware
that was flame-dried under vacuum and cooled under argon. Flash
chromatography was performed on Silicycle ultrapure silica gel (230-
Because aryl chlorides are relatively inexpensive and therefore
attractive for industrial applications, attempts were made to
apply our method for aryl bromides to the R-arylation of ethyl
phenylacetate with aryl chlorides. We found that di-tert-
butylphosphine ligand 2 is much more effective for this purpose
than is 1. To demonstrate the efficacy of the ligand 2/Pd2(dba)3
catalyst system, we have prepared the compounds shown in
Table 4 from aryl chlorides. While activated esters such as ethyl
phenylacetate give very good results (Table 4, entries 1 and 2),
tert-butyl propionate gave only moderate yields of the desired
product. As before, Claisen condensation of tert-butyl propionate
was the predominant side reaction.
While the yields given in Table 4 are moderate, to the best
of our knowledge, they represent the first examples of the
palladium-catalyzed R-arylation of an ester using an aryl
chloride.
Ligands 1-3 possess a fine balance of steric and electronic
properties that allow for significantly accelerated oxidative
addition while facilitating, or at least not inhibiting, the other
steps in the catalytic cycle. Although mechanistic investigations
have not been carried out, we expect that the key steps are
similar to the proposed mechanism of the palladium-catalyzed
R-arylation of ketones.15
4
00 mesh). Elemental analyses were performed by Atlantic Microlabs,
Inc, Norcross, GA. Toluene was distilled from molten sodium under
an atmosphere of nitrogen. Alternatively, toluene was purchased from
J. T. Baker in CYCLE-TAINER solvent delivery kegs, and vigorously
purged with argon for 2 h. Toluene was further purified by passing it
through two packed columns of neutral alumina and copper(II) oxide
under argon pressure. Esters and aryl halides were purchased from
commercial sources and used without purification. Palladium acetate,
tris(dibenzylideneacetone)dipalladium(0), and sodium hexamethyldi-
silazane (NaHMDS) were purchased from Strem Chemical, Inc. Lithium
hexamethyldisilazane (LiHMDS) and sodium tert-butoxide were pur-
chased from Aldrich Chemical Co., and the bases were stored under
nitrogen in a Vacuum Atmospheres glovebox. All materials were
weighed in the air, except for LiHMDS and NaHMDS, which were
weighed and added to the reaction flask in a glovebox. IR spectra
reported in this paper were obtained by placing neat samples directly
on the DiComp probe of an ASI REACTIR in situ IR instrument.
Alternatively, IR spectra in this paper for several compounds were
recorded on a Perkin-Elmer FT-IR 1600. Yields in tables refer to
isolated yields of compounds estimated to be 95% pure as determined
1
by H NMR, GC, and, in most cases, combustion analysis. Compounds
that are described more than once in the same table were completely
characterized once. Other samples of these compounds were character-
ized by comparing their 1H NMR spectra to those of the fully
characterized product, and their purity was confirmed by GC analysis.
General Procedure. An oven-dried, resealable Schlenk tube con-
taining a stirbar was capped with a rubber septum, flame-dried under
vacuum, and then backfilled with argon and cooled to room temperature.
Conclusion
We have thus extended the palladium-catalyzed R-arylation
method to the R-arylation of esters. The lack of a straightforward
way to prepare R-aryl esters can be solved, in many instances,
using bulky electron-rich o-biphenyl phosphines 1-3.
The tube was then charged with Pd(OAc) (3.4 mg, 15 µmol) and 1
2
(12.4 mg, 31.5 µmol). The tube was sealed and brought into a nitrogen-
filled glovebox where lithium bis(trimethylsilyl)amide (209 mg, 1.25

8
000 J. Am. Chem. Soc., Vol. 123, No. 33, 2001
Moradi and Buchwald
3H, J ) 6.90 Hz), 1.29 (s, 9H) ppm; 13C NMR (C
, 75 MHz) δ
mmol) was added. The Schlenk tube was removed from the box and
the mixture was dissolved in toluene (2 mL) and stirred for 10 min at
room temperature. The ester (1.15 mmol) was added dropwise to this
solution at -10 °C under argon, and the mixture was stirred for an
additional 10 min to complete the formation of the enolate. The aryl
bromide (0.5 mmol) was added at -10 °C and then the reaction mixture
was allowed to warm to room temperature and stirred for the time
specified. In some cases the temperature was increased to 80 °C. After
cooling, if necessary, the reaction mixture was filtered through a plug
of 5 g of silica gel using 150 mL of toluene as eluent and then
concentrated under reduced pressure, and the residue was chromato-
graphed on silica gel.
6 6
D
173.8, 139.7, 134.5, 133.4, 128.9, 128.5, 128.3, 126.8, 126.6, 126.4,
-
1
126.2, 80.4, 47.3, 28.3, 19.3 ppm; IR (neat, cm ) ν 3048, 2966, 2919,
1719, 1596, 1449, 1390, 1367, 1320, 1255, 1208, 1149. Anal. Calcd
for C17H O : C, 79.65; H, 7.86. Found: C, 79.41; H, 7.94.
20 2
tert-Butyl r-(2-methylphenyl)propionate (Table 2, entry 2): The
general procedure was followed. The reaction was carried out at 80 °C
1
for 2 h. The yield was 90 mg (82%). H NMR (C
D
6 6
, 300 MHz) δ
7.40 (m, 1H), 7.11-6.98 (m, 3H), 3.77 (q, 1H, J ) 7.20 Hz), 2.20 (s,
1H), 1.39 (d, 3H, J ) 7.20 Hz), 1.28 (s, 9H) ppm; 13C NMR (C
, 75
MHz) δ 174.0, 140.7, 136.1, 131.0, 127.3, 127.0, 127.0, 80.2, 43.0,
6
D
6
-
1
28.4, 20.2, 18.6 ppm; IR (neat, cm ) ν 3074, 2971, 2937, 1721, 1487,
tert-Butyl (naphthalen-2-yl)acetate (Table 1, entry 1): The general
procedure was followed. The reaction was carried out at room
temperature for 1 h. The yield was 102 mg (84%). Mp 45-46 °C; H
1453, 1390, 1358, 1333, 1254, 1214, 1151, 1088, 1054. Anal. Calcd
for C14H O : C, 76.32; H, 9.15. Found: C, 76.49; H, 9.20.
20 2
1
tert-Butyl r-(3-trifluoromethylphenyl)propionate (Table 2, entry
NMR (C
6
D
6
, 300 MHz) δ 7.60-7.57 (m, 4H), 7.40-7.36 (m, 1H),
3): The general procedure was followed. The reaction was carried out
1
3
1
7
.27-7.20 (m, 2H), 3.51 (s, 2H), 1.34 (s, 9H); C NMR (C
6
D
6
, 75
at 80 °C for 1 h. The yield was 111 mg (81%). H NMR (C
6 6
D , 300
MHz) δ 170.6, 134.4, 133.3, 133.2, 128.7, 128.6, 128.4, 128.3, 128.1,
MHz) δ 7.60 (s, 1H), 7.25-7.19 (m, 2H), 6.93-6.88 (m, 1H), 3.36 (q,
26.6, 126.2, 80.7, 43.5, 28.5 ppm; IR (neat, cm-1) ν 3054, 2978, 2930,
1H, J ) 7.20 Hz), 1.24 (s, 9H), 1.24 (d, 3H, J ) 7.20 Hz) ppm;
6 6
NMR (C D , 75 MHz) δ 172.9, 143.0, 131.5-131.1 (m), 129.6, 127.1,
13
C
1
1
719, 1633, 1598, 1455, 1385, 1390, 1365, 1295, 1256, 1145. Anal.
Calcd for C16H O
18 2
: C, 79.31; H, 7.49. Found: C, 79.51; H, 7.39.
125.2 (q, J ) 3.8 Hz), 124.3 (q, J ) 3.8 Hz), 123.5, 80.9, 46.9, 28.3,
19.1 ppm; 19F NMR (C
D , 282 MHz) δ -62.7; IR (neat, cm ) ν
-1
tert-Butyl (6-methoxynaphthalen-2-yl)acetate (Table 1, entry
6 6
2
): The general procedure was followed. The reaction was carried out
2978, 2919, 2849, 1725, 1449, 1455, 1360, 1331, 1255, 1214, 1143,
1
at room temperature for 4 h. The yield was 122 mg (90%). H NMR
17 3 2
1073. Anal. Calcd for C14H F O : C, 61.30; H, 6.25. Found: C, 61.13;
(
1
(
1
C
6
D
6
, 300 MHz) δ 7.58-7.51 (m, 2H), 7.46-7.41 (m, 2H), 7.17 (m,
H, 6.22.
13
H), 6.89 (m, 1H), 3.52 (s, 2H), 3.36 (s, 3H), 1.34 (s, 9H); C NMR
tert-Butyl r-(2-vinylphenyl)propionate (Table 2, entry 4): The
general procedure was followed. The reaction was carried out at 80 °C
for 2 h. The yield was 90 mg (77%). H NMR (C
C
6
D
6
, 75 MHz) δ 170.9, 158.4, 134.5, 130.8, 129.9, 129.9, 128.6,
-
1
1
28.5, 127.6, 119.7, 106.3, 80.6, 55.2, 43.4, 28.5 ppm; IR (neat, cm
)
D
6 6
, 300 MHz) δ
ν 3056, 2977, 2908, 1720, 1631, 1610, 1476, 1385, 1365, 1331, 1262,
212, 1158, 1020; HRMS for C17 272.1407, found 272.1413.
tert-Butyl (4-methylphenyl)acetate (Table 1, entry 3): The
general procedure was followed. The reaction was carried out at room
7.39-7.36 (m, 2H), 7.11-6.99 (m, 3H), 5.50 (dd, 1H, J ) 17.39, 1.50
Hz), 5.16 (dd, 1H, J ) 11.09, 1.50 Hz), 3.92 (q, 1H, J ) 7.20 Hz),
1.39 (d, 3H, J ) 7.20 Hz), 1.27 (s, 9H) ppm; 13C NMR (C D , 75
1
20 3
H O
20
6
6
MHz) δ 173.8, 139.7, 137.4, 135.5, 128.7, 127.6, 127.4, 127.2, 116.9,
-
1
1
80.4, 43.0, 28.4, 18.9 ppm; IR (neat, cm ) ν 3060, 2966, 2931, 2872,
725, 1625, 1484, 1455, 1390, 1331, 1320, 1250, 1220, 1155. Anal.
Calcd for C H O : C, 77.55; H, 8.68. Found: C, 77.39; H, 8.59.
temperature for 4 h. The yield was 83 mg (81%). H NMR (C
6 6
D , 300
1
MHz) δ 7.15 (d, 2H, J ) 8.10 Hz), 6.95 (d, 2H, J ) 8.10 Hz), 3.37 (s,
1
3
2
1
H), 2.07 (s, 3H), 1.32 (s, 3H) ppm; C NMR (C
6
D
6
, 75 MHz) δ 170.9,
15 20
2
-
1
36.7, 132.7, 129.8, 129.7, 80.3, 42.9, 28.3, 21.3 ppm; IR (neat, cm
)
tert-Butyl r-(2,6-dimethylphenyl)propionate (Table 2, entry 5):
ν 3007, 2974, 2923, 1725, 1505, 1446, 1362, 1294, 1252, 1134.
tert-Butyl (4-fluorophenyl)acetate (Table 1, entry 4): The general
The general procedure was followed. The reaction was carried out at
1
8
0 °C for 2 h. The yield was 80 mg (68%). H NMR (C
D
6 6
, 300 MHz)
δ 6.98-6.88 (m, 3H), 3.93 (q, 1H, J ) 7.20 Hz), 2.22 (s, 6H), 1.40 (d,
procedure was followed. The reaction was carried out at room
3H, J ) 7.20 Hz), 1.29 (s, 9H) ppm; 13C NMR (C D , 75 MHz) δ
1
temperature for 6 h. The yield was 74 mg (71%). H NMR (C
6
D
6
, 300
6
6
1
74.1, 139.7, 136.5, 129.6, 127.0, 80.1, 42.1, 28.3, 20.9, 15.9 ppm; IR
MHz) δ 6.96-6.91 (m, 2H), 6.78-6.71 (m, 2H), 3.20 (s, 2H), 1.30 (s,
-
1
1
3
(neat, cm ) ν 3005, 2971, 2938, 2878, 1723, 1681, 1580, 1462, 1360,
3
H) ppm; C NMR (C
6 6
D , 75 MHz) δ 170.4, 164.2, 161.0, 131.4 (d,
19
1243, 1162. Anal. Calcd for C H O : C, 76.88; H, 9.46. Found: C,
J ) 7.92 Hz), 115.7 (d, J ) 21.21 Hz), 80.7, 42.3, 28.4 ppm; F NMR
(C D , 282 MHz) δ -116.6; IR (neat, cm ) ν 3045, 2979, 2933, 1732,
6 6
607, 1510, 1392, 1368, 1257, 1225, 1144; HRMS for C12
Na] 233.0948, found 233.0957.
15 22
2
-1
76.71; H, 9.64.
tert-Butyl r-(2-isopropylphenyl)propionate (Table 2, entry 6):
1
+
H15FO
2
[M
+
The general procedure was followed. The reaction was carried out at
1
8
0 °C for 2 h. The yield was 109 mg (88%). H NMR (C
D
6 6
, 300
tert-Butyl (2-methylphenyl)acetate (Table 1, entry 5): The general
procedure was followed. The reaction was carried out at 80 °C for 10
MHz) δ 7.44-7.41 (m, 1H), 7.19-7.14 (m, 1H), 7.12-7.03 (m, 2H),
3.92 (q, 1H, J ) 6.90 Hz), 3.17 (sep, 1H, J ) 6.90 Hz), 1.41 (d, 3H,
J ) 6.60 Hz), 1.28 (s, 9H), 1.24 (d, 3H, J ) 6.60 Hz), 1.13 (d, 3H, J
1
min. The yield was 79 mg (78%). H NMR (C
6
D
6
, 300 MHz) δ 7.15-
7
9
1
2
.12 (m, 2H), 7.05-6.98 (m, 2H), 3.37 (s, 2H), 2.16 (s, 3H), 1.30 (3,
H) ppm; C NMR (C D , 75 MHz) δ 170.6, 137.3, 134.4, 130.8,
6 6
30.8, 127.7, 126.6, 80.4, 41.3, 28.5, 20.2 ppm; IR (neat, cm ) ν 3065,
977, 2930, 1732, 1495, 1456, 1392, 1367, 1335, 1256, 1144; HRMS
) 6.90 Hz) ppm; 13C NMR (C
D
, 75 MHz) δ 174.2, 146.3, 139.5,
1
3
6
6
-1
127.7, 127.3, 126.7, 126.0, 80.1, 41.7, 29.3, 28.2, 24.7, 24.1, 19.6 ppm;
-
1
IR (neat, cm ) ν 3060, 2966, 2872, 1725, 1490, 1449, 1390, 1361,
+
1325, 1249, 1214, 1149. Anal. Calcd for C16
24 2
H O : C, 77.38; H, 9.74.
for C13H O
18 2
[M + Na] 229.1199, found 229.1209.
Found: C, 77.36; H, 9.82.
4
-Phenylbut-3-enoic acid tert-butyl ester (Table 1, entry 6): The
tert-Butyl r-(4-biphenyl)propionate (Table 2, entry 7): The
general procedure was followed. The reaction was carried out at room
1
general procedure was followed. The reaction was carried out at 80 °C
temperature for 1 h. The yield was 72 mg (66%). H NMR (C
6 6
D , 300
1
for 30 min. The yield was 122 mg (86%). H NMR (C
6 6
D , 300 MHz)
MHz) δ 7.20-7.18 (m, 3H), 7.11-6.98 (m, 2H), 6.37-6.20 (m, 2H),
.97 (d, 2H, J ) 6.30 Hz), 1.36 (s, 9H); 1 C NMR (C
3
δ 7.44-7.40 (m, 4H), 7.34-7.30 (m, 2H), 7.22-7.08 (m, 3H), 3.58
2
1
6 6
D
, 75 MHz) δ
70.6, 137.9, 133.6, 129.1, 127.9, 127.0, 123.3, 80.6, 40.2, 28.6 ppm;
13
(
q, 1H, J ) 7.20 Hz), 1.44 (d, 3H, J ) 7.20 Hz), 1.32 (s, 9H) ppm;
C
-
1
NMR (C , 75 MHz) δ 173.7, 141.6, 141.2, 140.6, 129.4, 128.6, 128.0,
6 6
D
IR (neat, cm ) ν 3062, 3028, 2983, 2926, 1721, 1602, 1493, 1441,
390, 1361, 1293, 1259, 1145. Anal. Calcd for C14 : C, 77.03;
H, 8.31. Found: C, 76.98; H, 8.43.
-1
1
2
1
27.7, 127.7, 80.4, 47.0, 28.4, 19.6 ppm; IR (neat, cm ) ν 3049, 3025,
978, 2931, 2872, 1725, 1601, 1519, 1484, 1455, 1384, 1361, 1337,
255, 1214, 1149, 1072. Anal. Calcd for C19 : C, 80.82; H, 7.85.
1
18 2
H O
22 2
H O
tert-Butyl r-(naphthalen-2-yl) propionate (Table 2, entry 1): The
Found: C, 81.12; H, 8.04.
tert-Butyl r-(2-fluoro-4-biphenyl)propionate (Table 2, entry 8):
The general procedure was followed. The reaction was carried out at
general procedure was followed. The reaction was carried out at room
1
temperature for 17 h. The yield was 108 mg (84%). Mp 81-82 °C; H
6 6
NMR (C D , 300 MHz) δ 7.68 (m, 1H), 7.62-7.57 (m, 3H), 7.48-
1
8
0 °C for 20 min. The yield was 128 mg (86%). Mp ) 59-60 °C; H
7
.44 (m, 1H), 7.27-7.19 (m, 2H), 3.69 (q, 1H, J ) 6.90 Hz), 1.49 (d,
NMR (C
1
6 6
D , 300 MHz) δ 7.47-7.44 (m, 2H), 7.20 (m, 1H), 7.16 (m,
H), 7.15 (m, 2H), 7.12-7.07 (m, 1H), 7.04-7.00 (m, 1H), 3.45 (q,
(
20) Amin, H. B.; Taylor, R. J. Chem. Soc., Perkin Trans. 2 1978, 1095-
1
3
1
098.
1H, J ) 7.20 Hz), 1.35 (d, 3H, J ) 7.20 Hz), 1.30 (s, 9H) ppm; C

Palladium-Catalyzed R-Arylation of Esters
NMR (C , 75 MHz) δ 173.1, 162.2, 158.9, 143.6 (d, J ) 7.70 Hz),
J. Am. Chem. Soc., Vol. 123, No. 33, 2001 8001
6
D
6
Ethyl r-phenyl-r-(2,6-dimethylphenyl)acetate (Table 3, entry
1
1
4
9
1
36.3 (d, J ) 1.36 Hz), 131.4 (d, J ) 4 Hz), 129.7 (d, J ) 2.94 Hz),
2): The general procedure was followed. The reaction was carried out
1
29.0, 128.2, 124.1 (d, J ) 3.24 Hz), 116.0 (d, J ) 23.47 Hz), 80.8,
at 80 °C for 2 h. The yield was 95 mg (71%). H NMR (C
D
6 6
, 300
1
9
6.7, 28.4, 19.3 ppm; F NMR (C
6
D
6
, 282 MHz) δ -118.14 (t, J )
MHz) δ 7.28-7.24 (m, 2H), 7.14-7.11 (m, 2H), 7.10-7.06 (m, 2H),
7.07-7.00 (m, 2H), 6.96-6.94 (m, 1H), 5.45 (s, 1H), 3.94 (m, 2H),
.03 Hz); IR (neat, cm-1) ν 3059, 3033, 2978, 2934, 2876, 1728, 1624,
582, 1562, 1484, 1455, 1418, 1368, 1334, 1255, 1147, 1075. Anal.
2.18 (s, 6H), 0.85 (t, 3H, J ) 6.90 Hz) ppm; 13C NMR (C
D
, 75 MHz)
6
6
2
Calcd for C19H21FO : C, 75.97; H, 7.05. Found: C, 76.11; H, 7.12.
δ 172.8, 138.3, 137.9, 136.5, 129.8, 129.4, 128.8, 127.9, 127.2, 61.2,
-
1
5
1
1.8, 21.5, 14.5 ppm; IR (neat, cm ) ν 3048, 2966, 2919, 1731, 1595,
20 2
490, 1466, 1443, 1366, 1366, 1178, 1026. Anal. Calcd for C18H O :
tert-Butyl r-(4-diphenoxy)propionate (Table 2, entry 9): The
general procedure was followed. The reaction was carried out at 80 °C
1
C, 80.56; H, 7.51. Found: C, 80.65; H, 7.61.
for 2 h. The yield was 107 mg (71%). H NMR (C
6
D
6
, 300 MHz) δ
Ethyl r-phenyl-r-(3-chlorophenyl)acetate (Table 3, entry 3): The
7
6
1
1
.17-7.13 (m, 3H), 7.05-6.97 (m, 2H), 6.93-6.88 (m, 4H), 6.86-
general procedure was followed. The reaction was carried out at 80 °C
.80 (m, 1H), 3.48 (q, 1H, J ) 7.20 Hz), 1.38 (d, 3H, J ) 7.20 Hz),
1
1
3
for 1 h. The yield was 108 mg (79%). H NMR (C D , 300 MHz) δ
.31 (s, 9H) ppm; C NMR (C
6
6
D , 75 MHz) δ 173.7, 158.1, 157.0,
6
6
7
.46 (t, 1H, J ) 1.80 Hz), 7.28-7.25 (m, 2H), 7.13-6.97 (m, 5H),
6.76 (t, 1H, J ) 7.79 Hz), 4.83 (s, 1H), 3.87 (t, 2H, J ) 6.89 Hz), 0.83
t, 3H, J ) 6.89 Hz) ppm; 13C NMR (C
, 75 MHz) δ 171.8, 141.8,
39.1, 135.1, 130.4, 129.5, 129.3, 129.2, 128.0, 127.5, 61.6, 57.4, 14.5
36.9, 130.4, 129.5, 123.7, 119.6, 119.6, 80.4, 46.6, 28.4, 19.6 ppm;
-
1
IR (neat, cm ) ν 3070, 3038, 2977, 2932, 2874, 1727, 1590, 1506,
489, 1456, 1367, 1334, 1240, 1148, 1072. Anal. Calcd for C19
C, 76.48; H, 7.43. Found: C, 76.36; H, 7.47.
(
1
6 6
D
1
22 3
H O :
-
1
ppm; IR (neat, cm ) ν 3063, 3028, 2981, 2937, 1735, 1594, 1573,
496, 1475, 1454, 1367, 1311, 1192, 1152, 1027. Anal. Calcd for
: C, 69.95; H, 5.50. Found: C, 70.05; H, 5.52.
Ethyl r-phenyl-r-(4-N,N-dimethylaminophenyl)acetate (Table 3,
entry 4): The general procedure was followed. The reaction was carried
out at 80 °C for 10 min. Pd (dba) (1.5 mol %) and 2 (6.3 mol %)
were used. The yield was 127 mg (90%). H NMR (C
tert-Butyl r-(6-methoxynaphthalen-2-yl)propionate (Table 2,
entry 10): The general procedure was followed. The reaction was
carried out at room temperature for 15 h. The yield was 113 mg (79%).
1
16 2
C H15ClO
1
Mp ) 72-73 °C; H NMR (C
6
D
6
, 300 MHz) δ 7.60 (m, 1H), 7.56-
7
3
1
1
2
1
7
.53 (m, 1H), 7.49-7.42 (m, 2H), 7.14-7.10 (m, 1H), 6.86 (m, 1H),
2
3
.67 (q, 1H, J ) 7.20 Hz), 3.33 (s, 3H), 1.48 (d, 3H, J ) 7.20 Hz),
1
1
3
6 6
D , 300 MHz)
.27 (s, 9H) ppm; C NMR (C
6 6
D , 75 MHz) δ 174.0, 158.5, 137.3,
δ 7.49-7.45 (m, 2H), 7.39-7.33 (m, 2H), 7.17-7.11 (m, 2H), 7.07-
7.02 (m, 1H), 6.57-6.52 (m, 2H), 5.07 (s, 1H), 3.97 (q, 2H, J ) 7.20
34.6, 130.0, 129.9, 127.8, 126.9, 126.8, 119.7, 106.2, 80.3, 55.1, 47.2,
8.3, 19.4 ppm; IR (neat, cm ) ν 2979, 2939, 1721, 1607, 1505, 1488,
451, 1389, 1368, 1266, 1158, 1027. Anal. Calcd for C18
5.50; H, 7.74. Found: C, 75.30; H, 7.90.
-1
Hz), 2.47 (s, 6H), 0.91 (t, 3H, J ) 7.20 Hz) ppm; 13C NMR (C
D
, 75
6
6
22 3
H O : C,
MHz) δ 173.2, 150.4, 140.9, 130.1, 129.4, 129.0, 127.6, 127.5, 113.4,
-
1
6
1
1.1, 57.1, 40.6, 14.5 ppm; IR (neat, cm ) ν 3027, 2980, 2901, 2802,
tert-Butyl r-(naphthalen-2-yl)butyrate (Table 2, entry 11): The
general procedure was followed. The reaction was carried out at 80 °C
732, 1613, 1520, 1495, 1453, 1348, 1309, 1226, 1189, 1149, 1028.
Anal. Calcd for C18H21NO : C, 76.30; H, 7.47. Found: C, 76.21; H,
2
1
for 2 h. The yield was 109 mg (81%). H NMR (C
6
D
6
, 300 MHz) δ
.74 (m, 1H), 7.63-7.56 (m, 3H), 7.54-7.50 (m, 1H), 7.28-7.19 (m,
H), 3.53 (t, 1H, J ) 7.80 Hz), 2.29-2.15 (m, 1H), 1.88-1.74 (m,
7
.47.
7
2
1
Ethyl r-phenyl-r-(4-N,N-diethylcarbamoylphenyl)acetate (Table
3
, entry 5): The general procedure was followed. The reaction was
H), 1.30 (s, 9H), 0.88 (t, 3H, J ) 7.50 Hz) ppm; 1 C NMR (C
3
D , 75
6 6
1
carried out at 80 °C for 1 h. The yield was 149 mg (88%). H NMR
MHz) δ 173.3, 138.2, 134.4, 133.5, 128.9, 128.5, 128.3, 127.5, 126.7,
(C
6
D
6
, 300 MHz) δ 7.33-7.23 (m, 6H), 7.11-6.95 (m, 4H), 4.95 (s,
H), 3.88 (q, 2H, J ) 6.90 Hz), 3.23 (bs, 2H), 2.77 (bs, 2H), 0.96 (br,
H), 0.84 (t, 3H, J ) 6.90 Hz), 0.62 (br, 3H) ppm; 13C NMR (C
5 MHz) δ 172.2, 170.5, 140.6, 139.5, 137.5, 129.3, 129.2, 127.9, 127.6,
1
2
1
8
26.6, 126.2, 80.5, 55.3, 28.3, 27.7, 12.8 ppm; IR (neat, cm-1) ν 3042,
1
3
7
6
1
970, 2921, 2873, 1722, 1625, 1595, 1449, 1449, 1389, 1364, 1341,
6 6
D ,
256, 1153. Anal. Calcd for C18
0.21; H, 8.17.
22 2
H O : C, 79.96; H, 8.20. Found: C,
-
1
1.6, 57.7, 14.6 ppm; IR (neat, cm ) ν 2976, 2935, 1732, 1631, 1472,
Ethyl r-methyl-r-(4-methylphenyl)butyrate (Table 2, entry
2): The general procedure was followed. The reaction was carried
455, 1428, 1381, 1366, 1309, 1287, 1190, 1152, 1096, 1022. Anal.
1
Calcd for C21
-(Ethoxycarbonylphenylmethyl)benzoic acid tert-butyl ester
Table 3, entry 6): The general procedure was followed. The reaction
3
H25NO : C, 74.31; H, 7.42. Found: C, 74.05; H, 7.51.
out at 80 °C for 30 min. Ligand 3 was used. The yield was 53 mg
4
1
(
(
2
(
48%). H NMR (C
m, 2H), 3.93 (q, 2H, J ) 7.20 Hz), 2.24-2.10 (m, 1H), 2.03 (s, 3H),
.01-1.89 (m, 1H), 1.52 (s, 3H), 0.89-0.77 (m, 6H) ppm; 13C NMR
, 75 MHz) δ 176.1, 142.0, 136.4, 129.7, 126.7, 60.9, 50.9, 32.8,
6 6
D , 300 MHz) δ 7.30-7.25 (m, 2H), 7.00-6.98
(
1
was carried out at 80 °C for 30 min. The yield was 128 mg (75%). H
NMR (C , 300 MHz) δ 8.07-8.03 (m, 2H), 7.33-7.26 (m, 4H),
.13-6.99 (m, 3H), 4.95 (s, 1H), 3.91 (q, 2H, J ) 7.20 Hz), 1.44 (s,
6
D
6
6 6
C D
7
9
1
8
-
1
2
2.9, 21.4, 14.6, 9.9 ppm; IR (neat, cm ) ν 2975, 2937, 2880, 1728,
13
6 6
H), 0.86 (t, 3H, J ) 7.20 Hz) ppm; C NMR (C D , 75 MHz) δ
1
514, 1460, 1381, 1306, 1235, 1144, 1101, 1049. Anal. Calcd for
71.9, 165.6, 144.2, 139.3, 131.9, 130.5, 129.3, 129.3, 129.2, 127.9,
C
14
H O
20 2
: C, 76.32; H, 9.15. Found: C, 76.32; H, 9.32.
tert-Butyl r-methyl-r-(4-naphthalen-2-yl)butyrate (Table 2, entry
3): The general procedure was followed. The reaction was carried
out at 40 °C for 17 h. Ligand 3 was used. The yield was 69 mg (54%).
-1
0.4, 61.6, 57.8, 28.6, 14.6 ppm; IR (neat, cm ) ν 3062, 2978, 2933,
1735, 1712, 1610, 1520, 1495, 1454, 1367, 1293, 1256, 1191, 1162,
1
1117, 1020. Anal. Calcd for C H O : C, 74.09; H, 7.11. Found: C,
21
24
4
73.92; H, 7.21.
1
6 6
H NMR (C D , 300 MHz) δ 7.80 (m, 1H), 7.66-7.57 (m, 3H), 7.52-
Ethyl r-phenyl-r-(naphthalen-2-yl)acetate (Table 3, entry 7):
7
2
.48 (m, 1H), 7.28-7.20 (m, 2H), 3.94 (q, 2H, J ) 7.20 Hz), 2.32-
.20 (m, 1H), 2.10-1.98 (m, 1H), 1.62 (s, 3H), 0.86-0.81 (m, 6H)
The general procedure was followed. The reaction was carried out at
1
8
6 6
0 °C for 3 h. The yield was 128 mg (88%). H NMR (C D , 300
1
3
ppm; C NMR (C
6
D
6
, 75 MHz) δ 175.9, 142.3, 134.3, 133.1, 128.8,
MHz) δ 7.74 (m, 1H), 7.49-7.41 (m, 4H), 7.35-7.32 (m, 2H), 7.18-
1
9
1
28.7, 128.1, 126.6, 126.4, 125.6, 125.4, 61.1, 51.4, 32.6, 22.8, 14.6,
.9 ppm; IR (neat, cm ) ν 3048, 2978, 2931, 2884, 1725, 1595, 1502,
455, 1378, 1302, 1231, 1137, 1126, 1090, 1026. Anal. Calcd for
6
)
1
1
.92 (m, 5H), 5.10 (s, 1H), 3.88 (q, 2H, J ) 7.20 Hz), 0.84 (t, 3H, J
-
1
13
6 6
7.20 Hz) ppm; C NMR (C D , 75 MHz) δ 172.5, 139.8, 137.3,
34.3, 133.5, 129.5, 129.2, 129.0, 128.3, 128.1, 127.8, 127.6, 126.7,
C
17
H O
20 2
: C, 79.65; H, 7.86. Found: C, 79.60; H, 8.08.
Ethyl r-phenyl-r-(4-methylphenyl)acetate (Table 3, entry 1):
The general procedure was followed. The reaction was carried out at
-1
26.5, 61.5, 58.1, 14.6 ppm; IR (neat, cm ) ν 3049, 2972, 1734, 1597,
1507, 1490, 1452, 1366, 1306, 1153, 1029. Anal. Calcd for C20
18 2
H O :
C, 82.73; H, 6.25. Found: C, 82.62; H, 6.34.
1
8
0 °C for 30 min. The yield was 108 mg (85%). H NMR (C
D
6 6
, 300
Methyl r-methoxyphenyl-r-(naphthalen-2-yl)acetate (Table 3,
MHz) δ 7.42-7.41 (m, 2H), 7.33-7.30 (m, 2H), 7.16-7.09 (m, 3H),
entry 8): The general procedure was followed. The reaction was carried
1
7
7
7
6
1
.05-7.00 (m, 1H), 6.96-6.93 (m, 1H), 5.03 (s, 1H), 3.93 (q, 2H, J )
out at 80 °C for 30 min. The yield was 127 mg (83%). H NMR (C
6 6
D ,
13
.20 Hz), 2.05 (s, 3H), 0.88 (t, 3H, J ) 7.20 Hz) ppm; C NMR (C
6
D
6
,
300 MHz) δ 7.83 (m, 1H), 7.60-7.49 (m, 4H), 7.34-7.28 (m, 2H),
5 MHz) δ 172.5, 140.1, 137.1, 136.9, 129.8, 129.3, 129.2, 129.1, 127.6,
1.3, 57.6, 21.4, 14.5 ppm; IR (neat, cm-1) ν 3027, 2980, 2923, 1737,
600, 1513, 1494, 1453, 1367, 1366, 1185, 1150, 1028. Anal. Calcd
7.23-7.18 (m, 2H), 6.77-6.72 (m, 2H), 5.16 (s, 1H), 3.35 (s, 3H),
13
3.25 (s, 3H) ppm; C NMR (C
D
6 6
, 75 MHz) δ 173.2, 159.7, 137.6,
134.3, 133.4, 131.6, 130.6, 129.0, 128.7, 128.3, 128.0, 127.6, 126.7,
-1
for C17H O
19 2
: C, 80.28; H, 7.13. Found: C, 80.68; H, 7.26.
126.5, 57.1, 55.2, 52.2 ppm; IR (neat, cm ) ν 3055, 3000, 2950, 2835,

8002 J. Am. Chem. Soc., Vol. 123, No. 33, 2001
Moradi and Buchwald
1
1
1
736, 1609, 1582, 1510, 1462, 1434, 1369, 1303, 1251, 1156, 1033,
007. Anal. Calcd for C20 : C, 78.41; H, 5.92. Found: C, 78.31;
for 5 h. The yield was 66 mg (56%). H NMR (C
6 6
D , 300 MHz) δ
18 3
H O
7.23-7.18 (m, 2H), 6.77-6.72 (m, 2H), 3.53 (s, 1H, J ) 7.20 Hz),
1
3
H, 6.04.
3.27 (s, 3H), 1.42 (d, 3H, J ) 7.20 Hz), 1.31 (s, 9H) ppm; C NMR
(C , 75 MHz) δ 174.0, 159.4, 134.2, 129.1, 114.6, 80.2, 55.2, 46.5,
28.4, 19.6 ppm; IR (neat, cm ) ν 2976, 2934, 2836, 1727, 1612, 1584,
Ethyl r-phenyl-r-(methoxyphenyl)acetate (Table 4, entry 2): The
6 6
D
-1
general procedure was followed. The reaction was carried out at 80 °C
for 1 h. The yield was 129 mg (87%). H NMR (C
1
6
D
6
, 300 MHz) δ
1513, 1457, 1392, 1367, 1248, 1149, 1036. Anal. Calcd for C14
20 3
H O :
7
7
.41-7.37 (m, 2H), 7.32-7.27 (m, 2H), 7.12-7.10 (m, 2H), 7.05-
.00 (m, 1H), 6.75-6.70 (m, 2H), 5.00 (s, 1H), 3.94 (q, 2H, J ) 7.20
C, 71.16; H, 8.53. Found: C, 71.13; H, 8.57.
1
3
Acknowledgment. We gratefully acknowledge the National
Institute of Health (GM 46059) for funding, and also thank
Pfizer and Merck for additional unrestricted support. WAM
thanks the Deutsche Forschungsgemeinschaft (DFG) for a
postdoctoral fellowship. We gratefully acknowledge Dr. J. M.
Fox for the preparation of the ligands.
Hz), 3.26 (s, 3H), 0.89 (t, 3H, J ) 7.20 Hz) ppm; C NMR (C
MHz) δ 172.8, 159.6, 140.4, 131.9, 130.5, 129.3, 129.1, 127.7, 114.7,
6 6
D , 75
-
1
6
2
1
1.4, 57.2, 55.2, 14.6 ppm; IR (neat, cm ) ν 3061, 3018, 2985, 2920,
832, 1730, 1610, 1582, 1506, 1495, 1457, 1452, 1364, 1299, 1250,
174, 1146, 1027. Anal. Calcd for C17H O : C, 75.53; H, 6.84.
18 3
Found: C, 75.65; H, 6.84.
tert-Butyl r-(methoxyphenyl)propionate (Table 4, entry 3): The
general procedure was followed. The reaction was carried out at 80 °C
JA010797+