Arylation of esters catalyzed by the Pd(I) dimer {[P(t-Bu)]PdBr}

Article abstract of DOI:10.1021/ol8002578

Conditions for the coupling of bromoarenes with esters using a single base and catalyst with improved turnover numbers are described. These general conditions were made possible by using the Pd(l) catalyst {[P(f-Bu) ₃]PdBr}₂. Reactions of acetates, propionates, and isobutyrates are presented, and reactions of all three classes of esters on a 10 g scale are described.

Full text of DOI:10.1021/ol8002578

ORGANIC
LETTERS
2008
Vol. 10, No. 8
1545-1548
r
-Arylation of Esters Catalyzed by the
Pd(I) Dimer [P(t-Bu)3]PdBr
{
}
2
Takuo Hama and John F. Hartwig*
Department of Chemistry, Yale UniVersity, P.O. Box 208107, New HaVen, Connecticut
06520-8107, and Department of Chemistry, UniVersity of Illinois Urbana-Champaign,
Box 58-6, Urbana, Illinois 61801
jhartwig@uiuc.edu
Received February 4, 2008
ABSTRACT
Conditions for the coupling of bromoarenes with esters using a single base and catalyst with improved turnover numbers are described.
These general conditions were made possible by using the Pd(I) catalyst [P(t-Bu)3]PdBr 2. Reactions of acetates, propionates, and isobutyrates
are presented, and reactions of all three classes of esters on a 10 g scale are described.
{
}
The palladium-catalyzed R-arylation of carbonyl compounds
provides a simple method to conduct formal aromatic
substitution processes with alkali metal enolate nucleophiles.1-6
These reactions have been reported with palladium catalysts
containing hindered monodentate phosphines and N-hetero-
cyclic carbenes. The coupling of each class of carbonyl
compounds raises its own issues of selectivity, enolate
stability, and enolate basicity. Moreover, the R-arylation of
esters7-10 is challenging because of the potential that Claisen
condensation and decomposition of the ester enolates will
occur faster than cross-coupling. Thus, catalysts that react
rapidly under mild conditions are needed to create conditions
in which the rate of coupling exceeds the rate of condensation
and enolate decomposition. The need for fast rates places
particularly high demands on the catalyst when low loadings
of palladium are desired.
We recently reported a full account of the R-arylation of
esters in the presence of alkali metal amide bases.8 These
reactions occurred between enolates derived from acetates,
propionates and isobutyrates and a wide range of bromoare-
nes. However, the R-arylation of alkali metal enolates re-
quired different catalysts and different alkali metals, depend-
ing on the type of ester and the electronic property of the
bromoarene. For example, the arylation of tert-butyl acetate
and methyl isobutyrate occurred in high yields when using
lithium bases and P(t-Bu)3 as ligand, while the arylation of
tert-butyl propionate occurred in the highest yields when
using sodium bases and an N-heterocyclic carbene as ligand.
Moreover, the reactions of tert-butyl propionate tended to
occur in yields ranging from only 66% to 75% or with
catalyst loadings that ranged from 1 to 5 mol % for most
examples. The modest yields and high catalyst loadings for
the couplings of aryl bromides at the methylene position of
tert-butyl propionate were surprising because the yields, rates,
and catalyst loadings for the coupling of aryl bromides at
the methylene position of propiophenone are the most favor-
able of any coupling of ketone enolates studied thus far.11-14
(1) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 12382.
(2) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 1740.
(3) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108.
(4) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234.
(5) Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219, 211.
(6) Miura, M.; Satoh, T. In Palladium in Organic Synthesis; Springer:
Berlin/Heidelberg, 2005; Vol. 14.
(7) Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7996.
(8) Jørgensen, M.; Liu, X.; Wolkowski, J. P.; Hartwig, J. F. J. Am. Chem.
Soc. 2002, 124, 12557.
(9) Hama, T.; Liu, X.; Culkin, D.; Hartwig, J. F. J. Am. Chem. Soc.
2003, 125, 11176.
(10) Liu, X.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 5182.
10.1021/ol8002578 CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/22/2008

We report our studies on the use of {[P(t-Bu)3]PdBr}215,16-18
as catalyst for the R-arylation of esters. This catalyst couples
bromoarenes with acetates, propionates, and isobutyrates in
was isolated in 91% yield (entry 2). Reactions con-
ducted with the combination of Pd(dba)2 and the air-stable
[HP(t-Bu)3]BF4 also occurred with good mass balance
of reactant and product, but the reaction did not occur to
completion with 0.25% palladium (entry 3). Reactions
catalyzed by the Pd(I) dimer occurred in 80% yield
with about 20% unreacted starting material in the pres-
ence of only 0.05% of Pd(I) dimer (0.1% palladium)
(entry 4). Considering the good reactivity and conven-
ience of handling the Pd(I) catalyst precursor, we in-
vestigated additional R-arylations of esters with this
system.
To determine if LiNCy2 or silylamide bases led to
R-arylations of tert-butyl propionate in the highest yield,
we compared reactions with lithium and sodium hexameth-
yldisilazide (HMDS) to those with LiNCy2 as base. As shown
in Scheme 1, the reaction with LiHMDS occurred in much
the presence of the same alkali metal amide base in each
16,18,19
case. This Pd(I) complex {[P(t-Bu)3]PdBr}2
has been
shown to be an exceptionally reactive catalyst or catalyst
precursor for the amination of aryl bromides and chlorides,18
for Suzuki couplings of aryl bromides,18,20 and for the
R-arylation of the zinc enolates of esters.9,21 In addition to
being highly reactive for cross-coupling, this complex is
commercially available and is convenient to use because it
is more stable to air than free P(t-Bu3). With this catalyst,
the R-arylations of the alkali metal enolates of esters occur
with turnover numbers that have been improved in many
cases. Reactions of each class of ester have been conducted
on a 10 gram scale.
Our initial studies to improve the R-arylation of esters
focused on catalyst compositions derived from P(t-Bu)3.
We tested catalysts containing this ligand because they
have been highly active for the R-arylation of the alkali
metal enolates of ketones, amides, and several classes of
esters4,10 and because the ligand is available in large
quantities.
Scheme 1a
Three different catalyst systems containing P(t-Bu)3 as
ligand have been typically used: the combination of
Pd(dba)2 or Pd2(dba)3 and P(t-Bu)3, a combination of these
22
Pd(0) precursors and [HP(t-Bu)3]BF4 instead of the free
phosphine, and the Pd(I) dimer {[P(t-Bu)3]PdBr}2. To
determine if the precursor affected the activity of the
catalyst toward the R-arylation of tert-butyl propionate,
we studied reactions of 4-bromo-tert-butylbenzene with
the lithium enolate of tert-butyl propionate (generated
from LiNCy2) in the presence of these three catalyst
systems.
a Reactions conducted with 1 mmol of bromoarene in 3 mL of
toluene. b Yields determined by GC-MS with dodecane as an
internal standard.
lower yield than the reaction with LiNCy2 under iden-
tical conditions. Either LiNCy2 or NaHMDS appear to be
suitable bases. In part because dicyclohexylamine is less
expensive than hexamethyldisilazane ($4.5/mol vs $15/mol),
further studies were conducted with commercial LiNCy2 as
base and reactions on larger scale were conducted with
LiNCy2 generated in situ from HNCy2 and BuLi.
The results of these experiments are summarized in Table
1. Reactions catalyzed by the combination of a 1:1 ratio of
Table 1. Comparison of Palladium Catalysts Containing
Tri-tert-Butylphosphinea
Table 2 summarizes the palladium-catalyzed coupling of
the lithium enolate of tert-butyl propionate with aryl
bromides in the presence of {[P(t-Bu)3]PdBr}2. The reaction
(11) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121,
1473.
(12) Viciu, M. S.; Germaneau, R. F.; Nolan, S. P. Org. Lett. 2002, 4,
4053.
(13) Singh, R.; Nolan, S. P. J. Organomet. Chem. 2005, 690, 5832.
(14) Ehrentraut, A.; Zapf, A.; Beller, M. AdV. Synth. Catal. 2002, 344,
209.
(15) Available from Johnson Matthey catalog no. PD-113.
(16) Dura-Vila, V.; Mingos, D. M. P.; Vilar, R.; White, A. J. P.; Williams,
D. J. J. Organomet. Chem. 2000, 600, 198.
(17) Vilar, R.; Mingos, D. M. P.; Cardin, C. J. Chem. Soc., Dalton Trans.
1996, 4313.
entry
Pd/ligand
yieldb (%)
1
2
3
4
0.1% Pd(dba)2/0.1% P(t-Bu)3
0.25% Pd(dba)2/0.25% P(t-Bu)3
0.25% Pd(dba)2/0.25% [HP(t-Bu)3]BF4
0.05% {[P(t-Bu)3]PdBr}2
75
91c
60
80
a Reactions conducted with 1 mmol of bromoarene in 3 mL of toluene.
b Determined by GC-MS with dodecane as an internal standard. c Isolated
yields (average of two runs).
(18) Stambuli, J. P.; Kuwano, R.; Hartwig, J. F. Angew. Chem., Int. Ed.
Engl. 2002, 41, 4746.
(19) Available from Johnson Matthey catalog no. PD-113.
(20) Prashad, M.; Mak, X. Y.; Liu, Y.; Repic, O. J. Org. Chem. 2003,
68, 1163.
(21) Hama, T.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2006,
128, 4976.
Pd(dba)2 and free P(t-Bu)3 occurred to about 75% conversion
and 75% yield with 0.1 mol % of palladium catalyst (entry
1). The reactionconducted with 0.25% of the same compo-
nents occurred to full conversion, and the coupled product
(22) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
1546
Org. Lett., Vol. 10, No. 8, 2008

Table 2. Improved Conditions for Palladium-Catalyzed
R-Arylation of tert-Butyl Propionate with Aryl Bromides
Table 3. R-Arylation of Methyl Isobutyrate with Aryl
Bromides in the Presence of {[P(t-Bu)3]PdBr}2
a Isolated yields (average of two runs) for reactions of 1 mmol of
bromoarene in 3 mL of toluene.
a Isolated yields (average of two runs) for reactions of 1 mmol of
bromoarene in 3 mL of toluene.
occurred with a variety of bromoarenes in high yields with
only 0.05%-0.25% of Pd(I) dimer (0.1%-0.5% palladium).
Entries 1-3 illustrate high yields for reactions of bromoare-
nes containing chloride and fluoride groups. Entry 4 shows
that the precursor to Naproxen is generated in high yield
with 0.2 mol % dimer (entry 4). Reactions of electron-rich
p-bromoanisole occurred in high yields (entry 5). Even the
reaction of the electron-rich and ortho-substituted 2-bro-
moanisole (entry 7) occurred in high yield. Most striking,
the reaction of the sterically hindered bromomesitylene
occurred in good yield with only 0.05 mol % {[P(t-Bu)3]-
PdBr}2 (0.1% palladium) (entry 8). In general, these yields
and turnover numbers are significantly higher than those
previously reported with the catalyst derived from an
N-heterocyclic carbene or with the catalyst generated from
Pd(dba)2 and P(t-Bu)3.8
required for the reactions of these heteroaryl bromides with
Pd(dba)2 and P(t-Bu)3 as catalyst.
The reactions of tert-butyl acetate also occurred in high
yield with low loadings of the dimeric palladium(I) catalyst.
These reactions are summarized in Table 4. The reaction of
Table 4. R-Arylation of tert-Butyl Acetate with Aryl Bromides
in the Presence of {[P(t-Bu)3]PdBr}2
Table 3 summarizes the coupling of aryl bromides with
methyl isobutyrate catalyzed by {[P(t-Bu)3]PdBr}2. These
reactions occurred with 0.05-0.5 mol % catalyst (0.1-1 mol
% palladium). The reactions occurred in high yield with
electron-neutral (entry 1) electron-poor (entries 2-4, 7, 8)
and electron-rich (entries 5, 6) bromoarenes. Entry 2 il-
lustrates the selectively at an aryl bromide over an aryl
chloride. Reactions of these hindered enolates did not occur
with ortho-substituted bromoarenes.
However, reactions of the lithium enolate of methyl
isobutyrate did occur with certain heteroaryl bromides
(entries 9, 10). For example, reactions with 2-bromopyridine
occurred in 71% yields with 0.5 mol % {[P(t-Bu)3]PdBr}2
(entry 9), and the reaction of 3-bromothiophene occurred in
75% yield with the same amount of catalyst (entry 10). These
reactions occur with much lower catalyst loading than was
a
Isolated yields (average of two runs) for reactions of 1 mmol of
bromoarene in 3 mL of toluene.
electron-neutral 4-bromo-tert-butylbenzene occurred in high
yields in the presence of only 0.2% {[P(t-Bu)3]PdBr}2 (entry
Org. Lett., Vol. 10, No. 8, 2008
1547

1), and the reaction of 4-fluorobromobenzene occurred in
good yield at the bromide with only 0.4 mol % catalyst (entry
2). In addition, the coupling of this enolate occurred in good
yields with both electron-rich and electron-poor bromoarenes.
Like the reactions of the enolate of tert-butyl propionate,
the reaction of the lithium enolate of tert-butyl acetate with
the electron-rich aryl bromide (entry 3) occurred with less
catalyst than the reaction of the electron-poor aryl bromide
(entry 4). These data are comparable to those reported
previously with the combination of Pd(dba)2 and P(t-Bu)3
as catalyst.
0 °C to generate the enolate. The enolate was generated in
one reaction vessel at 0 °C by slow addition of the ester to
LiNCy2 in toluene solvent. A toluene solution of the
bromoarene and catalyst was then added to this solution at
room temperature. Stirring of this solution at room temper-
ature for 4 h, followed by quenching, extraction, and
distillation, led to the isolation of 7.9-8.6 g (79-86% yields)
of the R-aryl esters.
Three aspects of the catalyst loading warrant comment.
First, the amount of catalyst needed for the R-arylation of
methyl isobutyrate is only 0.1 mol %, and the amount of
palladium needed for reaction of the propionate is only 0.8
mol %. Second, the amount of ligand is equal to the amount
of palladium and is easily removed. Third, less catalyst was
required for the reactions on larger scale than was required
for reactions on a 1 mmol scale. In particular, full conversion
was observed for the arylation of tert-butyl propionate on a
10 g scale in the presence of 0.05% catalyst, but full
conversion to the R-aryl ester was not observed with this
amount of catalyst when conducting the reaction on a 1 mmol
scale.
With a particularly active catalyst for the R-arylation of
esters, we sought to develop procedures to conduct this
chemistry conveniently on a scale larger than the typical 1
mmol scale used to demonstrate reaction scope. To do so,
reactions of tert-butyl acetate, tert-butyl propionate, and
methyl isobutyrate were conducted with 40 mmol of bro-
moarene as limiting reagent in the presence of the catalyst
generated from {[P(t-Bu)3]PdBr}2 (Scheme 2). Arylation of
all three esters required less than 1% catalyst loading (0.4%
In summary, we have shown that the coupling of esters at
methyl, methylene and methine positions occurs with a
variety of bromoarenes with practical loadings of palladium
and ligand when conducted with the dimeric Pd(I) species
{[P(t-Bu)3]PdBr}2 as catalyst. The reactions occur under mild
conditions and can be conducted easily without a drybox
and on substantial scale.
Scheme 2
Acknowledgment. We thank the NIH (GM-58108) for
support of this work and Johnson-Matthey for palladium
complexes. We thank Ryan DeLuca from the University of
Illinois at Urbana-Illinois for checking experimental proce-
dures and help with text editing.
Supporting Information Available: Experimental pro-
cedures and characterization of reaction products. This
information is available free of charge via the Internet at
http://pubs.acs.org.
palladium for arylation of the acetate, 0.08% palladium for
arylation of the propionate, and 0.1% palladium for arylation
of the isobutyrate).
These reactions were conducted without the use of a
drybox in toluene solvent at temperatures equal to or above
OL8002578
1548
Org. Lett., Vol. 10, No. 8, 2008