Carbonylation of Aryl Chlorides with Oxygen Nucleophiles
TABLE 1. Optimization of Conditions for the Formation of
Phenyl Esters
previously reported methods for this important reaction lacked
substrate scope and required high pressures and/or temperatures.
Recently, we have described a procedure for the aminocarbo-
nylation of aryl chlorides that provides access to a wide variety
of amides.9 This new protocol operates at moderate temperatures
and requires only atmospheric carbon monoxide pressures; thus,
it can be readily applied under laboratory conditions.
Our development of these aminocarbonylation conditions
hinged on the discovery that sodium phenoxide was a uniquely
active basic additive. In situ IR spectroscopy studies revealed
that phenyl esters, which arose from initial nucleophilic attack
from phenoxide anion, were formed as intermediates and served
as acyl transfer agents in the ultimate formation of the amide
products (eq 1).
entry
[Pd]
nuc
base
solvent
yield (%)
1
2
3
4
5
6
7
8
9
Pd(OAc)2
dcppPdPhCla
dcppPdPhCla
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PhONa
PhONa
PhOH
PhOH
PhOH
PhOH
PhOH
PhOH
PhOH
none
none
DMSO
DMSO
DMSO
DMSO
DMSO
Tol
Bu2O
DMF
DMF
12b,c
54b
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
48b
52b
61b,d
0b,d
4b,d
75b,d
85d,e,f
a 2 mol % of dcpp ·2HBF4 used. b GC yield using dodecane as
internal standard. c 43% conversion. d K2CO3 flame dried. e PhOH
introduced as a solution in DMF that was dried over activated 3 Å MS.
f Isolated yield.
We recognized that phenyl esters could potentially serve as
useful acylating reagents for the production of other carboxylate
derivatives; a method for their direct production could be useful
in providing a reactive, yet isolable, acylating agent via
carbonylation. Such products would have utility both in the
production of libraries of carbonyl derivatives from a single
isolated carbonylation product and in the synthesis of carbonyl
products that incorporate nucleophilic components that are not
normally compatible with palladium-catalyzed conditions. Prior
to this work, the preparative formation of phenyl esters from
aryl chlorides was not known.10
Herein, we report optimized conditions for the production of
numerous phenyl esters via carbonylation of aryl chlorides.
These compounds can be readily isolated and subsequently
reacted with numerous nucleophiles to produce amides, esters,
and thioesters with varying substitution in good to excellent
yields under mild conditions. In addition, these studies have
also led us to explore the direct synthesis of carboxylic acids
and alkyl esters via carbonylation of aryl halides. In this regard,
we report improved conditions that allow the production of these
important products under user-friendly conditions (moderate
temperature and atmospheric pressure). Further, we report the
first conditions for atmospheric-pressure aryl chloride carbo-
nylation that are capable of preparing both methyl and ethyl
esters.
phonium salt dcpp·2HBF4.11 Under these conditions (NaOPh,
2 mol% Pd(OAc)2, 4 mol% dcpp ·2HBF4, 4 Å MS, DMSO),
only trace product and low conversion of the substrate were
observed after 6 h at 100 °C (Table 1, entry 1). Based upon
observations in our previous studies, we speculated that slow
reduction of the Pd(OAc)2 precatalyst was responsible for this
result. Accordingly, we examined the use of dcppPd(Ph)Cl ·tol
(1) as the precatalyst.9 This complex is structurally related to
intermediates in the putative catalytic cycle and, therefore, does
not require activation. With the use of 1 as the palladium source,
high conversions and moderate yields of the desired phenyl ester
were observed (entry 2). In contrast to our previous studies,
the use of K2CO3/PhOH in place of NaOPh led to similarly
good results (entry 3). More importantly, with PhOH as the
source of phenoxide, the combination of Pd(OAc)2 and
dcpp·2HBF4 proved to be an effective precatalyst, eliminating
the need for the use of 1 (entry 4).12 Examination of the solvent
(entries 5-8) revealed the need for highly polar media, with
DMF proving slightly better than DMSO. Even though molec-
ular sieves were used in the reaction, addition of MeI to the
reaction mixture prior to workup led to the formation of methyl
3-methyoxybenzoate, indicating that material was being lost as
the carboxylic acid due to adventitious moisture. More rigorous
exclusion of water13 resulted in the optimal conditions and
allowed isolation of phenyl 3-methoxybenzoate in 85% yield
using silica gel chromatography.
Results and Discussion
In order to examine the scope of this method, the transforma-
tion of a variety of aryl and heteroaryl chlorides was examined
(Table 2). Electron-deficient substrates performed well under
the optimized conditions. Both nitrile- and trifluoromethyl-
substituted aryl chlorides reacted smoothly to provide the
corresponding phenyl esters in high yields (entries 1-3).
We began our study of phenyl ester formation by examining
the conversion of 3-chloroanisole to phenyl 3-methoxybenzoate.
All reactions were conducted at atmospheric CO pressure in
septum-sealed glass test tubes. Initially, we investigated condi-
tions similar to those developed in our aminocarbonylation
method. The ligand bis(dicyclohexylphosphino)propane (dcpp)
was introduced as its commercially available, air-stable phos-
(11) Commercially available from Nippon Chemical Co. (103099-52-1).
Also see ref 9 for a convenient synthesis.
(12) We speculate that the proton on PhOH is required for successful
reduction of Pd(OAc)2 to Pd(0) under these conditions. For general discussions
regarding the reduction of Pd(OAc)2 in the presence of phosphine ligands, see:
(a) Ozawa, F.; Kubo, A.; Hayashi, T. Chem. Lett. 1992, 2177. (b) Amatore, C.;
Carre, E.; Jutand, A.; M’Barki, M. A. Organometallics 1995, 14, 1818.
(13) Better exclusion of water was achieved by flame-drying of the K2CO3
prior to use and introduction the hydroscopic phenol as a solution in DMF that
was predried over 3Å MS.
(9) Martinelli, J. R.; Clark, T. P.; Watson, D. A.; Munday, R. H.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2007, 46, 8460.
(10) A few studies have been published that report formation of aryl esters
using aryl bromides and iodides. For examples, see: (a) Ramesh, C.; Nakamura,
R.; Kubota, Y.; Miwa, M.; Sugi, Y. Synthesis 2003, 501. (b) Kubota, Y.; Nakada,
S.; Sugi, Y. Synlett 1998, 183. (c) Satoh, T.; Ikeda, M.; Miura, M.; Nomura, M.
J. Mol. Catal. A 1996, 111, 25.
J. Org. Chem. Vol. 73, No. 18, 2008 7097