Palladium-catalyzed-arylattion of esters With chloroarenes

Article abstract of DOI:10.1021/ol800258u

Palladium-catalyzed α-arylations of esters with chloroarenes are reported. The reactions of chloroarenes with the sodium enolates of tert-butyl propionate and methyl isobutyrate occur in high yields with 0.2-1 mol % of {[P(f-Bu)₃]PdBr}₂

Full text of DOI:10.1021/ol800258u

ORGANIC
LETTERS
2008
Vol. 10, No. 8
1549-1552
Palladium-Catalyzed
Esters with Chloroarenes
r-Arylation of
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
Palladium-catalyzed
butyl propionate and methyl isobutyrate occur in high yields with 0.2
r
-arylations of esters with chloroarenes are reported. The reactions of chloroarenes with the sodium enolates of tert-
1 mol % of [P(t-Bu)3]PdBr or the combination of Pd(dba)2 and
−
{
}
2
P(t-Bu)3 as catalyst. The reactions of chloroarenes with the Reformatsky reagent of tert-butyl acetate were most challenging but occurred in
high yields for chlorobenzene and electron-poor chloroarenes catalyzed by 1 mol % of Pd(dba)2 and pentaphenylferrocenyl di-tert-butylphosphine
(Q-phos).
The palladium-catalyzed R-arylation of esters (eq 1) has
become a convenient route to form benzylic esters.1-4 Such
reactions between bromoarenes and the enolates of esters
occur in high yields in the presence of palladium catalysts
bearing sterically hindered, electron-rich phosphine or car-
bene ligands. The accompanying paper14 reports reactions
of bromoarenes in the presence of a dimeric palladium(I)
catalyst that form R-aryl esters in high yields with good
substrate scope with low loadings of palladium. However,
few reactions between chloroarenes and the enolates of esters
have been reported.5,6
toluene, chloroanisole, and 4-chlorodiphenyl ether as the
haloarene using 2.3 equiv of lithium enolate and 3 mol %
of palladium at 80 °C.5 No examples of reactions of
chloroarenes that could form benzyne intermediates or that
contained functional groups that could interfere with the
coupling process were reported.
The authors’ laboratory reported the reactions of chloro-
arenes with the sodium enolate of tert-butyl propionate in
the presence of 1 mol % palladium catalyst containing a
hindered N-heterocyclic ligand.6 This reaction required only
a slight excess of the enolate and was conducted at room
temperature, but only reactions of chlorobenzene were
studied.
Thus, reactions of chloroarenes with the enolates of
isobutyrates and acetates are not known, and reactions of
chloroarenes possessing varied electronic properties and
pendant functional groups are limited. The coupling of
chloroarenes with the enolates of esters is challenging
because of the combination of higher temperatures required
for coupling of chloroarenes and low stability of the enolates
of esters at elevated temperatures. To address this problem,
catalysts with high reactivity are needed.
Buchwald and Moradi reported four arylations of esters
with chloroarenes. These were conducted with tert-butyl
propionate and ethyl phenylacetate as the ester and chloro-
(1) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234.
(2) Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219, 211.
(3) Fox, J. M.; Huang, X. H.; Chieffi, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 1360.
(4) Lloyd-Jones, G. C. Angew. Chem., Int. Ed. 2002, 41, 953.
(5) Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7996.
(6) Jorgensen, M.; Lee, S.; Liu, X.; Wolkowski, J. P.; Hartwig, J. F. J.
Am. Chem. Soc. 2002, 124, 12557.
10.1021/ol800258u CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/22/2008

Recently, we showed that the Pd(I) complex {[P(t-Bu)3]-
7
PdBr}2 is highly active for cross-coupling.8 Although this
Table 1. Arylation of Sodium Enolate of tert-Butyl Propionate
complex contains unusual Pd(I) centers, this complex appears
to be readily reduced to form the key Pd(PtBu3) intermediate.
We also showed that the palladium catalyst containing
pentaphenylferrocenyl di-tert-butylphosphine (Q-phos)9,10 is
highly active toward the R-arylation of esters with bromo-
arenes.11
with Chloroarenes
Here, we report that reactions of chloroarenes with the
alkali metal enolates of esters catalyzed by {[P(t-Bu)3]PdBr}2
or the combination of Pd(dba)2 and P(t-Bu)3 occur in high
yield with a range of esters and chloroarenes and that
reactions of chloroarenes with Reformatsky reagents occurs
when catalyzed by Pd(dba)2 and P(t-Bu)3. These results
illustrate that practical couplings of these chloroarenes can
be conducted with ester enolates.
Conditions for the palladium-catalyzed reactions of tert-
butyl propionate were investigated first. These studies
focused initially on the reaction of this enolate with chloro-
benzene in toluene in the presence of the Pd(I) complex
{[P(t-Bu)3]PdBr}2. Two different types of alkali metal
enolates were evaluated: the lithium enolate generated from
LiNCy2, which formed high yields of R-aryl esters from
reactions of bromoarenes, and the sodium enolate generated
from NaHMDS, which one might expect to be more reactive
than the lithium enolate. As shown in eq 2, the reaction of
chlorobenzene with the sodium enolate of tert-butyl propi-
onate in the presence of only 0.2 mol % {[P(t-Bu)3]PdBr}2
at room temperature occurred to form the R-aryl ester product
in quantitative yield.
a Isolated yields (average of two runs) for reactions of 1 mmol
of chloroarene in 3 mL of toluene. b Product from reaction with aryl
bromide.
mol % of palladium using either catalyst system (entries 1
and 2). Reactions of the more electron-rich 2- and 4-chloro-
anisole were conducted using the catalyst generated from 1
mol % Pd(dba)2 and 1 mol % P(t-Bu)3 or 0.4 mol %
{[P(t-Bu)3]PdBr}2 (0.8 mol % palladium) (entries 3, 4, 5,
and 6). Entries 3 and 4 show that the reactions of
4-chloroanisole occur in higher yield when conducted with
{[P(t-Bu)3]PdBr}2 as precatalyst.5 These conditions required
only 1.2 equiv of the enolate and occurred at room temper-
ature with only 0.8-1 mol % palladium. Entries 5 and 6
illustrate that the same trend in catalyst activity was observed
for reactions of the ortho-substituted, electron-rich 2-chloro-
anisole. Finally, reactions of the more electron-poor m-
chloroanisole (entries 7 and 8) occurred in only 41% yield
in the presence of the catalyst generated from 1 mol % Pd-
(dba)2 and 1 mol % P(t-Bu)3, but in a higher 75% yield with
only 0.4 mol % of the Pd(I) precatalyst {[P(t-Bu)3]PdBr}2.
Entries 9-13 illustrate reactions conducted at the mildly
elevated temperature of 60 °C. Again, yields were higher
for reactions conducted with the Pd(I) precatalyst {[P(t-Bu)3]-
PdBr}2. No diarylation was observed even at 60 °C. In
contrast to the reactions of the chloroanisoles, these reactions
occurred to about 80-90% conversion with 0.15-0.2 mol
% of {[P(t-Bu)3]PdBr}2, and some N-aryl disilylamine was
observed as a side product. Nevertheless, the isolated yields
of R-aryl ester were high in most cases.
Table 1 summarizes reactions between chloroarenes and
the sodium enolate of tert-butyl propionate. Reactions were
conducted using two different catalyst systems bearing
P(t-Bu)3. One system was generated by mixing Pd(dba)2 and
P(t-Bu)3. The other system was generated from the Pd(I)
precatalyst {[P(t-Bu)3]PdBr}2. These reactions occurred in
good yields at room temperature or 60 °C. Products from
diarylation of the ester were not observed.
Reactions of the sodium enolate of tert-butyl propionate
with chlorobenzene occurred in high yields with only 0.4
Reactions of the hindered 2-chloro-m-xylene occurred at
60 °C with 0.4 mol % palladium (entries 9 and 10). When
conducted with 0.4 mol % Pd(dba)2 and 0.4 mol % P(t-Bu)3,
this reaction occurred in only 42% yield (entry 9), but when
conducted with the same loading of {[P(t-Bu)3]PdBr}2 as
catalyst, it occurred in 81% yield (entry 10). Chloroarenes
containing fluoride substituents also underwent arylation in
good yield, in this case using only 0.15 mol % {[P(t-Bu)3]-
(7) Vilar, R.; Mingos, D. M. P.; Cardin, C. J. J. Chem. Soc., Dalton
Trans. 1996, 4313.
(8) Stambuli, J. P.; Kuwano, R.; Hartwig, J. F. Angew. Chem., Int. Ed.
2002, 41, 4746.
(9) Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J. F. J. Am. Chem. Soc.
2000, 122, 10718.
(10) Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem.
2002, 67, 5553.
(11) Hama, T.; Liu, X.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc.
2003, 125, 11176.
1550
Org. Lett., Vol. 10, No. 8, 2008

PdBr}2 at 60 °C (entry 11). The reation of 4-chlorobro-
mobenzene occurred in high yield at the bromide (entries
12 and 13).
Table 3. Arylation of Sodium Enolate of Methyl Isobutyrate
with Chloroarenes
Reactions of electron-poor chloroarenes presented the
greatest limitation. For example, reactions of the electron-
poor 4-chloro-trifluoromethylbenzene in the presence of 0.2
mol % Pd(I) dimer or 0.4 mol % Pd(dba)2 and P(t-Bu)3 as
catalyst at room temperature did not give detectable amounts
of the coupled product, and only 30% of coupled product
from the reaction at 60 °C was observed by GC-MS.
Reactions with higher loadings of palladium were not studied.
The lower conversions for reactions of electron-poor aryl
chlorides are in contrast with typical trends for palladium-
catalyzed processes. We do not have a clear explanation for
the lower reactivity of these arenes toward the R-arylation
of esters.
We were also able to develop conditions for the coupling
of the enolate of methyl isobutyrate with chloroarenes.
Initially, reactions of chlorobenzene with enolates generated
from several alkali metal amide bases were evaluated in the
presence of 0.1 mol % of the Pd(I) precatalyst {[P(t-Bu)3]-
PdBr}2 in toluene solvent (Table 2). No conversion of
Table 2. Optimized Conditions for Reactions of Methyl
Isobutyrate and Chlorobenzene
a Isolated yields (average of two runs) for reactions of 1 mmol of
chloroarene in 3 mL of toluene. b Product from reactions of aryl bromide.
The examples in Table 3 encompass reactions of electron-
neutral, electron-rich, and electron-poor chloroarenes. Reac-
tions of the sodium enolate of methyl isobutyrate with
chlorobenzene occurred in high yield with 0.2 mol % of
palladium (entries 1 and 2). The reaction of 4-chlorotoluene
occurred in good yield in the presence of 0.4 mol % Pd-
(dba)2 and 0.4 mol % P(t-Bu)3 (entry 3) or 0.2 mol % of the
Pd(I) dimer (0.4 mol % palladium, entry 4). Reactions of 4-
and 3-chlorofluorobenzene also occurred in high yields with
0.4 mol % palladium (entries 5-8). Reactions of the electron-
rich 4-chloroanisole occurred in 69 and 73% yield with the
two catalyst systems (entries 9 and 10), and reaction of the
less electron rich 3-chloroanisole occurred in a somewhat
higher 77% and 74% yield with the two catalysts (entries
11 and 12). No coupled product was observed from reactions
of this hindered enolate with o-chloroanisole in the presence
of either of these catalyst systems.
Reactions of electron-poor chloroarenes also occurred
using both catalysts. The reaction of this enolate with
4-chloro benzotrifluoride occurred in acceptable yield when
catalyzed by either 0.4 mol % Pd(dba)2 and 0.4 mol %
P(t-Bu)3 (entry 13) or 0.2 mol % {[P(t-Bu)3]PdBr}2 (entry
14). Reactions of 3-trifluoromethyl chlorobenzene occurred
in high yields with both catalysts (entries 15 and 16).
Like the sodium enolate of tert-butyl propionate, the
enolate of methyl isobutyrate reacted selectively with the
bromide of bromo chlorobenzene (entries 19 and 20). Unlike
entry
base
T (°C)
yielda (%)
1
2
3
4
5
LiNCy2
rt
rt
60
100
100
0
0
NaHMDS
NaHMDS
LiNCy2
trace
trace
90
NaHMDS
a Determined by GC-MS with dodecane as an internal standard.
chlorobenzene was observed from reaction of either the
lithium or sodium enolates at room temperature (entries 1
and 2), and low conversions were observed at 60 °C (entries
3 and 4). However, the reaction of the sodium enolate at
100 °C occurred in high yields (entry 5), even with only 0.1
mol % of the Pd(I) dimer.
Reactions of the sodium enolate of methyl isobutyrate with
chloroarenes in the presence of the combination of Pd(dba)2
and P(t-Bu)3 or {[P(t-Bu)3]PdBr}2 as catalyst are summarized
in Table 3. These reactions were conducted at 100 °C with
only 0.2-0.4 mol % of palladium. In general, reactions with
the Pd(I) dimer occurred in higher yields than those with
Pd(dba)2 and P(t-Bu)3, but the difference in yield was smaller
than the difference in yields of the reactions of tert-butyl
propionate using the two catalysts. The major side product
of these reactions was the N-aryl bis-trimethylsilylamime
from the known12 palladium-catalyzed reaction of the base
with the chloroarene.
(12) Lee, S.; Jorgensen, M.; Hartwig, J. F. Org. Lett. 2001, 3, 2729.
Org. Lett., Vol. 10, No. 8, 2008
1551

the reactions of the propionate enolate at 60 °C, some side
product (ca. 10-15%) was observed from the reaction of
the aryl bromide with excess amide base. No product from
the reaction of both the bromide and chloride was observed.
Reactions of heteroaryl chlorides were also evaluated
briefly. The reaction of the sodium enolate of methyl
isobutyrate with 2-chloropyridine formed the coupled product
in 66% yield when the catalyst was generated from 0.4 mol
% Pd(dba)2 and 0.4 mol % P(t-Bu)3 (entry 17) and in a
slightly higher 71% yield when catalyzed by 0.2 mol %
({[P(t-Bu)3]PdBr}2 entry 18). The same reactions with
3-chloropyridine occurred to low conversion.
Table 4. R-Arylation of Isolated Reformatsky Reagent of
tert-Butyl Acetate with Chloroarenes
The reations of chloroarenes with the alkali metal enolates
of tert-butyl acetate were more challenging to develop than
the reactions of the propionates and isobutyrates, and we
have not developed conditions that produced more than 10%
of the coupled product from reactions of chloroarenes with
the alkali metal enolates of this ester. We presume this
difficulty results from the low stability of the acetate enolate,
relative to that of the more substituted propionate and
isobutyrate enolates.
To overcome this problem, we studied reactions of
chloroarenes with zinc enolates of acetates.13 Because the
catalyst system generated from Pd(dba)2 and Q-phos was
the most general for the coupling of zinc enolates of esters
with bromoarenes,13 reactions of chlorobenzene with this
enolate were conducted in the presence of this catalyst. Even
with 3 mol % of palladium and a reaction temperature of 70
°C, no coupled product was generated from the reactions of
zinc enolates generated by quenching the sodium or lithium
enolate of tert-butyl acetate with zinc chloride.
a Isolated yield (average of two runs) for reactions of 0.5 mmol of
chloroarene in 2 mL of THF.
of these reactions was narrower than of the reactions of
chloroarenes with the alkali metal enolates of propionates
and isobutyrates, but several examples of this process with
electron-neutral and electron-poor chloroarenes occurred in
high yield. For example, the reaction of chlorobenzene
occurred in 95% yield (entry 1), and the reactions of electron-
poor chloroarenes containing reactive functional groups
(entries 2-4) occurred in high yields. No side products were
observed for these reactions.
Unfortunately, reactions of electron-rich chloroarenes, such
as 4-chloroanisole, reactions of ortho-substituted chloro-
arenes, such as 2-chloroanisole or 2-chloro-m-xylene, and
reactions of heteroaryl chlorides, such as 2-chloropyridine
and 3-chloropyridine, occurred in less than 50% yields.
Future studies are needed to address the scope of the coupling
of the enolates of tert-butyl acetate with chloroarenes.
In summary, the use of highly active catalysts and reaction
conditions involving the sodium enolates has extended the
R-arylation of esters to reactions with chloroarenes. The
reactions of chloroarenes with the sodium enolates of tert-
butyl propionate and tert-butyl isobutyrate occurred in high
yields in the presence of palladium catalysts bearing
P(t-Bu)3. Although reactions of the sodium enolates of tert-
butyl acetate with chloroarenes did not occur, reactions of
the Reformatsky reagent of tert-butyl acetate with electron-
netural and electron-poor chloroarenes occurred. The reac-
tions of chloroarenes with the propionate and isobutyrate
enolates occurred in the highest yields in the presence of
the Pd(I) dimer as precatalyst, and the turnover numbers for
these processes are high for this type of coupling.
However, the coupling of the Reformatsky reagent of tert-
butyl acetate generated from the R-bromo acetate occurred
in high yield. As shown in Scheme 1, reactions of chlo-
Scheme 1
a Isolated yield (average of two runs) for reactions of 0.5 mmol
of chlorobenzene in 2 mL of THF.
Acknowledgment. We thank the NIH (GM-58108) for
support of this work and Johnson-Matthey for a gift of
palladium complexes.
robenzene with the Reformatsky reagent of tert-butyl acetate
occurred in the presence of the catalyst generated from Pd-
(dba)2 and Q-phos but did not occur in substantial yield in
the presence of the Pd(I) complex {[P(t-Bu)3]PdBr}2.
Table 4 summarizes the reactions of chloroarenes with this
zinc enolate catalyzed by Pd(dba)2 and Q-phos. The scope
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.
(13) Hama, T.; Liu, X.; Culkin, D.; Hartwig, J. F. J. Am. Chem. Soc.
2003, 125, 11176.
(14) Hama, T.; Hartwig, J. F. Org. Lett. 2008, 10, 1545.
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