Two methods for direct ortho-arylation of benzoic acids

Article abstract of DOI:10.1021/ja071845e

Two new palladium-catalyzed methods for the direct ortho-arylation of free benzoic acids have been developed. The first method employs stoichiometric silver acetate for iodide removal, aryl iodide as the coupling partner, and acetic acid solvent. This method is applicable to the arylation of electron-rich to moderately electron-poor benzoic acids and tolerates chloride and bromide substituents on both coupling partners. The second method involves the use of aryl chloride, cesium carbonate base, n-butyl-di-1-adamantylphosphine ligand, and DMF solvent and is suitable for both electron-rich and electron-poor benzoic acids. Mechanistic studies of the second method point to the heterolytic C-H bond cleavage as the rate-determining step.

Full text of DOI:10.1021/ja071845e

Published on Web 07/25/2007
Two Methods for Direct ortho-Arylation of Benzoic Acids
Hendrich A. Chiong, Quynh-Nhu Pham, and Olafs Daugulis*
Contribution from the Department of Chemistry, UniVersity of Houston,
Houston, Texas 77204-5003
Received March 15, 2007; E-mail: olafs@uh.edu
Abstract: Two new palladium-catalyzed methods for the direct ortho-arylation of free benzoic acids have
been developed. The first method employs stoichiometric silver acetate for iodide removal, aryl iodide as
the coupling partner, and acetic acid solvent. This method is applicable to the arylation of electron-rich to
moderately electron-poor benzoic acids and tolerates chloride and bromide substituents on both coupling
partners. The second method involves the use of aryl chloride, cesium carbonate base, n-butyl-di-1-
adamantylphosphine ligand, and DMF solvent and is suitable for both electron-rich and electron-poor benzoic
acids. Mechanistic studies of the second method point to the heterolytic C-H bond cleavage as the rate-
determining step.
transition metals is not known.7a The reactions may be com-
plicated by decarboxylation.5 Direct arylation of aromatic
carboxylic acids would allow a one-step synthesis of 2-aryl-
benzoic acids. In contrast, the current methodology for the
conversion of benzoic acids to the 2-arylated derivatives requires
multiple steps (Scheme 1).7b-d
The carboxylate group may be removed after the arylation
reaction.8 It is well-known that transition-metal-catalyzed func-
tionalization of arenes not possessing directing groups often
results in the formation of regioisomer mixtures.9 This may be
avoided if the carboxylate substituent is used as a removable
directing group. A few reports that describe the regioselective
arylation of simple arenes rely on the use of either fluorine
substituents that act by acidifying the ortho-hydrogens or
substrates where the formation of regioisomers is not possible.10
The direct functionalization of ortho C-H bonds in benzoic
acids would have three important consequences: (1) achieve-
ment of the most direct functionalization of benzoic acids
forming 2-arylbenzoic acids, compounds that are of pharma-
1. Introduction
The selective functionalization of C-H bonds has attracted
a substantial interest due to potential shortening of synthetic
sequences.1 At present, development of the methods for sp2
C-H bond functionalization in directing-group containing
arenes and electron-rich heterocycles has received the most
attention. For a number of directing-group containing substances
the conversion of aromatic ortho-C-H bonds to C-C bonds
has been demonstrated. Compounds containing amide, pyridine,
oxazoline, imine, ketone, and phenol directing groups have been
ortho-arylated or alkylated under palladium, ruthenium, or
rhodium catalysis.2 We have developed a simple, palladium-
catalyzed method for the arylation of anilides, benzamides,
pyridines, and benzylamines.3 This reaction likely proceeds via
a Pd(II)-Pd(IV) catalytic cycle.4 Only a few reports have dealt
with the ortho-functionalization of free benzoic acids.5a,6 Direct
functionalization of C-H bonds in carboxylic acids is chal-
lenging. Stoichiometric ortho-metalation of carboxylic acids by
(1) Reviews: (a) Shilov, A. E.; Shul’pin, G. B. Chem. ReV. 1997, 97, 2879.
(b) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003, 345, 1077. (c)
Labinger, J. A.; Bercaw, J. E. Nature 2002, 417, 507. (d) Dyker, G. Angew.
Chem., Int. Ed. 1999, 38, 1698. (e) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem.
ReV. 2002, 102, 1731. (f) Alberico, D.; Scott, M. E.; Lautens, M. Chem.
ReV. 2007, 107, 174.
(2) (a) Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.; Miyano, S.; Inoue, Y. Org.
Lett. 2001, 3, 2579. (b) Oi, S.; Ogino, Y.; Fukita, S.; Inoue, Y. Org. Lett.
2002, 4, 1783. (c) Oi, S.; Aizawa, E.; Ogino, Y.; Inoue, Y. J. Org. Chem.
2005, 70, 3113. (d) Tremont, S. J.; Rahman, H. U. J. Am. Chem. Soc. 1984,
106, 5759. (e) Kametani, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron
Lett. 2000, 41, 2655. (f) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford,
M. S. J. Am. Chem. Soc. 2005, 127, 7330. (g) Satoh, T.; Kawamura, Y.;
Miura, M.; Nomura, M. Angew. Chem., Int. Ed. 1997, 36, 1740. (h) Chen,
X.; Li, J.-J.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc.
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2006, 128, 12634. (j) Motti, E.; Faccini, F.; Ferrari, I.; Catellani, M.;
Ferraccioli, R. Org. Lett. 2006, 8, 3967.
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124, 11250. (b) Gooâen, L. J.; Paetzold, J. Angew. Chem., Int. Ed. 2004,
43, 1095. (c) Forgione, P.; Brochu, M.-C.; St-Onge, M.; Thesen, K. H.;
Bailey, M. D.; Bilodeau, F. J. Am. Chem. Soc. 2006, 128, 11350.
(6) (a) Miura, M.; Tsuda, T.; Satoh, T.; Pivsa-Art, S.; Nomura, M. J. Org.
Chem. 1998, 63, 5211. (b) Giri, R.; Maugel, N.; Li, J.-J.; Wang, D.-H.;
Breazzano, S. P.; Saunders, L. B.; Yu, J.-Q. J. Am. Chem. Soc. 2007, 129,
3510. (c) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9, 1407.
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Cain, P. A. J. Org. Chem. 1994, 59, 4042. Lithiation cross coupling
methodologies: (b) Eaddy, J. F. Org. Prep. Proced. Int. 1995, 27, 367. (c)
Ciske, F. L.; Jones, W. D., Jr. Synthesis 1998, 1195. A recent, more direct
arylation via o-lithiation of unprotected benzoic acid: (d) Tilly, D.; Samanta,
S. S.; Castanet, A.-S.; De, A.; Mortier, J. Eur. J. Org. Chem. 2006, 174.
(8) Gooâen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662.
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(b) Shabashov, D.; Daugulis, O. Org. Lett. 2005, 7, 3657. (c) Zaitsev, V.
G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154. (d)
Shabashov, D.; Daugulis, O. Org. Lett. 2006, 8, 4947. (e) Lazareva, A.;
Daugulis, O. Org. Lett. 2006, 8, 5211.
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L.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 14047.
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9
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J. AM. CHEM. SOC. 2007, 129, 9879-9884
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A R T I C L E S
Chiong et al.
Scheme 1. Benzoic Acid Arylation
ceutical and other interest;11 (2) possibility of subsequent
decarboxylation; this sequence would be synthetically equivalent
to regioselective arylation of unfunctionalized arenes; and (3)
possibility of tandem reaction development by using carboxylate
functionality in subsequent Heck and Suzuki couplings.12
We decided to investigate benzoic acid arylation by aryl
iodides under Pd(II)-Pd(IV) catalytic cycle conditions and by
aryl chlorides under Pd(0)-Pd(II) catalytic cycle conditions.
The Pd(II)-Pd(IV) catalytic cycle would allow tolerance of
halide substituents on both the benzoic acid and aryl iodide.
Aryl chlorides are now routinely used for C-C bond creation
under Pd(0)-Pd(II) catalytic cycle conditions.13 As a conse-
quence, use of cheaper ArCl in C-H bond functionalization
should also be possible if appropriate ligands are used. Only a
few examples of intermolecular C-H/C-Cl bond couplings
have been reported so far.14 We report here two complementary
methods for direct palladium-catalyzed ortho-arylation of ben-
zoic acids by (1) aryl iodides/AgOAc and (2) aryl chlorides/
Cs2CO3/n-butyl-di-1-adamantylphosphine.15 The decarboxyl-
ation of the arylated benzoic acid is also reported. Additionally,
we report here the mechanistic studies of the arylation processes.
silver acetate and catalytic palladium acetate afforded a 52%
yield of the corresponding arylacetic acid (eq 1).
The formation of this byproduct can be minimized by
employing shorter reaction times and lower temperature. The
arylation of benzoic acids proceeds with both electron-poor
(entries 1, 3, 4, Table 1) and electron-rich (entries 2, 5, 6) aryl
iodides. Chloride and bromide are tolerated on the coupling
partners (entries 3 and 4). Both electron-rich and moderately
electron-poor benzoic acids can be arylated. ortho-Substituted
aryl iodides are unreactive, and attempted arylation of 2-furoic
acid resulted in the formation of an intractable mixture.
2.2. Arylation Employing Aryl Chlorides. The second
method required substantially more optimization. The reactions
were optimized with respect to solvent, phosphine ligand, and
the presence of molecular sieves. The best results were obtained
in dry DMF in the presence of molecular sieves.16 Wet DMF
in the presence of wet molecular sieves resulted in slower
reactions, omission of molecular sieves resulted in incomplete
reactions, and no reaction was observed in DMA. A number of
ligands that are routinely used for palladium-catalyzed ArCl
coupling reactions were tested in phenylation of 2-naphthoic
acid (Table 2). Use of trioctylphosphine, tri-p-tolylphosphine,
and triphenylphosphine as ligands did not lead to efficient
catalysis. Substantial conversions to product were observed with
tricyclohexylphosphine, di-tert-butylmethylphosphine, and tert-
butyldicyclohexylphosphine.
The best results were obtained with n-butyl-di-1-adaman-
tylphosphine15 that was used in all subsequent reactions. Aryl
bromides are also reactive, but because there are no substantial
advantages in their use, all reactions were run with aryl
chlorides.
Electron-poor benzoic acids react well, and it is possible to
couple them with both electron-poor (entries 1-2, 4, 6, 9, 13;
Table 3) and electron-rich (entry 3, 5, 11, 14) aryl chlorides.
This result is somewhat surprising given that palladation is often
slower for electron-deficient compounds.17
2. Results
2.1. Arylation Employing Aryl Iodides. Our initial efforts
toward benzoic acid arylation employing aryl iodides and silver
acetate focused on the use of acetic acid or trifluoroacetic acid
as solvents under conditions previously utilized in our laboratory
for anilide, benzamide, and benzylamine arylation.3 The reac-
tions proceed in both cases, but decarboxylation was observed
to be faster in trifluoroacetic acid. The best results were obtained
by using about 3.5 equiv of acetic acid as a solvent, although
arylacetic acid byproduct was observed at longer reaction times.
Heating 5-iodo-m-xylene with acetic acid in the presence of
(11) (a) Lewis, M. C.; Hodgson, G. L.; Shumaker, T. K.; Namm, D. H.
Atherosclerosis 1987, 64, 27. (b) Adamski-Werner, S. L.; Palaninathan, S.
K.; Sacchettini, J. C.; Kelly, J. W. J. Med. Chem. 2004, 47, 355.
(12) Review: Zapf, A. Angew. Chem., Int. Ed. 2003, 42, 5394.
(13) Review: (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41,
4176. (b) Huser, M.; Youinou, M.-T.; Osborn, J. A. Angew. Chem., Int.
Ed. 1989, 28, 1386. (c) Ben-David, Y.; Portnoy, M.; Milstein, D. J. Am.
Chem. Soc. 1989, 111, 8742. (d) Herrmann, W. A.; Brossmer, C.; O¨ fele,
K.; Reisinger, C.-P.; Priermeier, T.; Beller, M.; Fischer, H. Angew. Chem.,
Int. Ed. 1995, 34, 1844. (e) Littke, A. F.; Fu, G. C. J. Org. Chem. 1999,
64, 10. (f) Zapf, A.; Beller, M. Chem.sEur. J. 2000, 6, 1830. (g) Koike,
T.; Mori, A. Synlett 2003, 1850. (h) Hills, I. D.; Fu, G. C. J. Am. Chem.
Soc. 2004, 126, 13178. (i) Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc.
2004, 126, 13028. (j) Ackermann, L.; Born, R. Angew. Chem., Int. Ed.
2005, 44, 2444. (k) Marion, N.; Navarro, O.; Mei, J.; Stevens, E. D.; Scott,
N. M.; Nolan, S. P. J. Am. Chem. Soc. 2006, 128, 4101.
(14) (a) Dyker, G.; Heiermann, J.; Miura, M. AdV. Synth. Catal. 2003, 345,
1127. (b) Ackermann, L. Org. Lett. 2005, 7, 3123. (c) Lafrance, M.; Rowley,
C. N.; Woo, T. K.; Fagnou, K. J. Am Chem. Soc. 2006, 128, 8754. (d)
Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc.
2006, 128, 581. (e) Chiong, H. A.; Daugulis, O. Org. Lett. 2007, 9, 1449.
(15) Ehrentraut, A.; Zapf, A.; Beller, M. Synlett 2000, 1589.
Both electron-poor (entry 13) and electron-rich (entry 14) aryl
chlorides can be coupled with electron-rich benzoic acids.
However, the combination of an electron-rich aryl chloride and
an electron-rich benzoic acid is occasionally problematic due
(16) Steinhoff, B. A.; King, A. E.; Stahl, S. S. J. Org. Chem. 2006, 71, 1861.
(17) (a) Bruce, M. I.; Goodall, B. L.; Stone, F. G. A. J. Chem. Soc., Dalton
Trans. 1978, 687. (b) Ryabov, A. D.; Sakodinskaya, I. K.; Yatsimirsky, A.
K. J. Chem. Soc., Dalton Trans. 1985, 2629.
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ortho-Arylation of Benzoic Acids
A R T I C L E S
Table 1. Arylation of Benzoic Acids by Aryl Iodidesa
Figure 1. ORTEP view of triethylammonium 3-fluoro-2,6-bis(4-trifluo-
romethyl-phenyl)benzoate. Thermal ellipsoids are 40% equiprobability
envelopes.
is the ester group (entries 6-8). Benzoic acid is diarylated
(entries 9, 10). In general, 2- or 3-substituted benzoic acids are
monoarylated, presumably due to steric interference of the
substituent. It is well-known that the palladation of sterically
hindered positions is unfavorable.18 The exception is 3-fluo-
robenzoic acid, which is diarylated, presumably due to the small
size of the fluorine substituent (entries 4, 5). There are two
possible regiochemical outcomes of 3-fluorobenzoic acid dia-
rylation. The fluorine can act as a directing group by increasing
the acidity of the ortho-hydrogen substituent,10b or the carboxyl-
ate can direct the arylation. The X-ray crystallographic analysis
of the diarylation product triethylammonium salt verified that
the carboxylic acid group had directed the arylation (Figure 1).
2-Chlorotoluene was unreactive, and 4-chloroanisole suffered
substantial hydrodehalogenation with all benzoic acids tested.
Halogens other than fluorine are not compatible with the reaction
conditions in contrast with the ArI/AgOAc method. For
example, the coupling of 1,4-dichlorobenzene with 3-trifluo-
romethylbenzoic acid afforded 2-phenyl-5-trifluoromethylben-
zoic acid as the major product.
a ArCO2H (1 mmol), iodoarene (3 equiv), Pd(OAc)2 (5 mol %), AgOAc
(1.3 equiv), AcOH (0.2 mL), 4.5-7 h. Yields are isolated yields and are
the average of three or four runs. See the Supporting Information for details.
Table 2. Ligand Optimizationa
It was also demonstrated that the arylation products can be
decarboxylated by using the method developed by Gooâen and
co-workers.8 2-(3,5-Bis(trifluoromethyl)phenyl)-5-methylben-
zoic acid was decarboxylated in the presence of CuO/quinoline
in NMP to afford 3,5-bis(trifluoromethyl)-4′-methylbiphenyl in
86% yield (eq 2). Two roles can be envisioned for the
entry
phosphine
conversion, %
1
2
3
4
5
6
7
8
9
tricyclohexylphosphine
di-tert-butylmethylphosphine-HBF4
tri-n-octylphosphine
46
58
7
triphenylphosphine
1
tert-butyldicyclohexylphosphine
n-butyl-di-1-adamantylphosphine
tri-p-tolylphosphine
1,3-bis(diphenylphosphino)propane
none
57
65
2
7
<1
carboxylate. First, it can be used as a directing group, allowing
the functionalization of the benzoic acid moiety. Second, if
desired, the carboxylate group can be removed, allowing the
regioselectiVe synthesis of bi- and polyphenyls. This would be
attractive as arylation of arenes that do not contain directing
groups is problematic due to the possibility of regioisomer
a Pd(OAc)2 (5 mol %), 2-naphthoic acid (0.5 mmol), chlorobenzene (0.75
mmol), phosphine ligand (10 mol %), Cs2CO3 (1.1 mmol), molecular sieves
3 Å (155 mg), and anhydrous DMF (2.5 mL), 145 °C, 24 h. Conversion
determined by GC analysis using hexadecane internal standard.
to product decarboxylation or aryl halide hydrodehalogenation.
The arylation of 2- and 3-phenylbenzoic acids proceeds well
affording the m- and p-terphenyl derivatives (entries 11, 12).
The nitro group is compatible with the reaction conditions, as
(18) Review: (a) Ryabov, A. D. Synthesis 1985, 233. (b) Kalyani, D.; Dick, A.
R.; Anani, W. Q.; Sanford, M. S. Org. Lett. 2006, 8, 2523.
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A R T I C L E S
Chiong et al.
Table 3. Arylation of Benzoic Acids by Aryl Chloridesa
a ArCO2H (0.5 mmol), chloroarene (2-3 equiv), Pd(OAc)2 (5 mol %), n-BuAd2P (10 mol %), Cs2CO3 (2.2 equiv), MS 3 Å (155 mg), DMF (2.5 mL),
c
24 h, 145 °C. Yields are isolated yields. See the Supporting Information for details. bIsolated as the dimethyl ester after treatment with TMSCHN2. 2-
Phenylbenzoic acid (10%) also isolated.
formation, unless unsubstituted benzene or very specifically
substituted arenes are used.10 The current examples of both
palladium- and iridium-catalyzed or promoted functionalization
of monosubstituted benzenes result in the formation of regio-
isomer mixtures that are difficult to separate due to similar
chromatographic properties.9
2.3. Mechanistic Considerations. 2.3.1. Arylation by Aryl
Iodides. There are several possible mechanistic pathways for
this reaction (Scheme 2). The reaction may proceed by a Pd(II)-
Pd(IV) mechanism (Scheme 2A). Cyclometallation followed by
oxidative addition of ArI would afford a Pd(IV) intermediate.
Fast reductive elimination would produce the arylated carboxylic
acid and regenerate Pd(II) species. Alternatively, a Pd(0)-Pd-
(II) mechanism may be considered (Scheme 2B). After reduction
of Pd(II) to Pd(0)19 oxidative addition of aryl iodide would
afford arylpalladium iodide. Cyclometallation followed by
reductive elimination would produce the arylated carboxylic acid
and regenerate a Pd(0) species. To distinguish between these
possibilities, 2-naphthoic acid was reacted with 3-iodotoluene
in the presence of a 20 mol % palladium source (Scheme 2C).
If palladium acetate was used, about one turnover to the arylated
product was observed. Reactions in the presence of Pd2dba3 or
Pd(PtBu3)2 did not afford tolylnaphthoic acid. This result points
to a Pd(II)-Pd(IV) catalytic cycle; however, a σ-bond metathesis
mechanism suggested by Tremont cannot be excluded.2d
2.3.2. Arylation by Aryl Chlorides. As mentioned before,
the arylation reaction proceeds well with both electron-rich and
electron-poor benzoic acids. The palladation reactions often pro-
ceed faster for electron-rich arenes.17 Recent work by Echavarren
(19) A reviewer suggested that a Pd(0)-Pd(II) catalytic cycle might be accessed
by cyclometallation of the substrate followed by reductive elimination of
o-acetoxyarenecarboxylic acid. Under the conditions of Scheme 2C the
formation of 1-hydroxy-2-naphthoic, 3-hydroxy-2-naphthoic, 1-acetoxy-
2-naphthoic, and 3-acetoxy-2-naphthoic acids was not observed (GC
analysis of crude reaction mixtures; comparison with authentic samples).
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ortho-Arylation of Benzoic Acids
A R T I C L E S
Scheme 2. Illustration of Two Possible Reaction Mechanisms: Pd(II)/Pd(IV) and Pd(0)/Pd(II)
Scheme 3. Intra- vs Intermolecular KIE
Scheme 4. Proposed Catalytic Cycle
substituent. In the arylation of fluorobenzene derivatives,
preferential reaction is observed at positions ortho to fluorine
that are more acidic.10b
Both inter- and intramolecular deuterium isotope effects were
obtained for the reaction of p-tolyl chloride and benzoic acid
(Scheme 3). The intramolecular and intermolecular isotope
effects are the same, 4.4. The magnitude of the isotope effect
is close to the one observed by Echavarren20a and is within the
expected range for turnover-limiting C-H bond cleavage.20b It
may be concluded that the exchange of benzoate on the
palladium center is rapid compared with the C-H cleavage step.
Given the magnitude of the isotope effect, insensitivity of
reaction to electronic properties of benzoic acid, and lack of
selectivity in the monoarylation of 3-fluorobenzoic acid, we
believe that the most likely mechanism for the C-H bond
cleavage is the one proposed by Macgregor21 and Echavarren.20a
The reaction is initiated by reduction of Pd(II) to Pd(0) (Scheme
4). Oxidative addition of aryl chloride to Pd(0) is facilitated by
an electron-rich, bulky ligand. The halide in the coordination
sphere of palladium may be replaced by the benzoate followed
by the rate-limiting C-H bond cleavage step. The initial
formation of an agostic complex is favored by electron-rich
C-H bonds.21 This may explain the slight predominance of
arylation at the more electron-rich position of 3-fluorobenzoic
and Fagnou has shown that for electron-poor fluoroarenes
complete inversion of reactivity may be achieved.10b,20a Acces-
sibility of this mechanistic pathway is dependent on the acidity
of the C-H bond that is being functionalized. To evaluate the
mechanism of the benzoic acid ortho-arylation, several experi-
ments were carried out. First, 3-fluorobenzoic acid was arylated
under the usual reaction conditions with p-tolyl chloride. The
reaction was stopped at very low conversion, before the
formation of the diarylation product was observed (eq 3). Low
(20) (a) Garcia-Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M.
J. Am. Chem. Soc. 2006, 128, 1066. (b) Reactions proceeding by
electrophilic aromatic substitution mechanisms typically have kH/kD of
around 1. Zollinger, H. AdV. Phys. Org. Chem. 1964, 2, 163.
(21) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am. Chem. Soc.
2005, 127, 13754.
selectivity of the arylation was observed, with preferential
arylation (1:1.4) observed at the para-position to the fluorine
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A R T I C L E S
Chiong et al.
dichloromethane (2 × 1 mL). The filtrate was concentrated under
reduced pressure, and the residue was suspended in 5% aqueous KOH.
The mixture was extracted with dichloromethane (3 × 10 mL) after
which the aqueous layer was acidified with concentrated HCl to pH )
2 followed by extraction with dichloromethane (3 × 10 mL). After
filtering through a pad of Celite the dichloromethane layer was
concentrated to a volume of about 2 mL. The mixture was adsorbed
on silica gel and was subjected to flash chromatography (hexanes then
dichloromethane-ethyl acetate 95:5). After the removal of the solvent
and trituration with hexanes, the residue was dried under reduced
pressure (50 °C) to give the product.
acid. The deprotonation step, on the other hand, may be more
facile for more acidic protons allowing the arylation of electron-
poor benzoic acids. The equilibrium isotope effect for the agostic
bond formation is expected to be relatively small (less than 2).22
As a consequence, it appears that the deprotonation of the agostic
complex is the overall rate-determining step of the reaction.
Reductive elimination followed by fast ligand exchange affords
the product.
3. Summary
We have developed two methods for direct ortho-arylation
of benzoic acids. The first method involves the use of catalytic
palladium acetate, stoichiometric silver acetate, and an aryl
iodide coupling partner. This method is tolerant of chloride and
bromide substitution and most likely proceeds through a Pd-
(II)-Pd(IV) coupling cycle. Moderately electron-poor to electron-
rich benzoic acids are reactive, and aryl iodides of any electronic
properties may be used. The second method involves the use
of catalytic palladium in combination with n-butyl-di-1-ada-
mantylphosphine, cesium carbonate base, and an aryl chloride
coupling partner. The reaction requires the presence of molecular
sieves. Benzoic acids of any electronic properties are reactive.
Inter- and intramolecular isotope effects for the benzoic acid
arylation by aryl chlorides have been determined and were found
to be the same with a magnitude of 4.4 pointing toward
heterolytic C-H bond cleavage as the turnover-limiting step.
4.2. General Procedure for Coupling of Chloroarenes with
Benzoic Acids. Outside the glovebox a 2-dram vial equipped with a
magnetic stir bar was charged with Pd(OAc)2 (5 mol %), ArCO2H (0.5
mmol), and chloroarene (2-3 equiv). The vial was flushed with argon,
capped, and placed inside a glovebox. To this mixture was added
n-butyl-di-1-adamantylphosphine (10 mol %), Cs2CO3 (2.2 equiv),
molecular sieves 3 Å (155 mg), and anhydrous DMF (2.5 mL). The
sealed vial was taken out of the glovebox, stirred at room temperature
for 2 h, and placed in a preheated oil bath (145 °C) for 24 h. The
reaction mixture was cooled to room temperature and quenched with
15% aqueous HCl (4 mL). The resulting suspension was extracted with
ethyl acetate (3 × 3 mL), and the organic layer was filtered through a
pad of Celite. The filtrate was concentrated under vacuum to a volume
of about 2 mL. The mixture was adsorbed on silica gel and subjected
to flash chromatography (hexanes then CH2Cl2-EtOAc 95:5). The
CH2Cl2-EtOAc fraction was concentrated, and the residue was
triturated with distilled water (3 × 2 mL) and dried under reduced
pressure. The residue, after trituration with hexanes (2 × 2 mL) and/
or purification by preparative HPLC and drying under reduced pressure
(50 °C), yielded the product.
4. Experimental Section
4.1. General Procedure for Coupling of Iodoarenes with Benzoic
Acids. Without special precautions, a 2-dram vial equipped with a
magnetic stir bar was charged with Pd(OAc)2 (5 mol %), silver acetate
(1.3 equiv), ArCO2H (1 equiv), iodoarene (3 equiv), and acetic acid
(200 µL per mmol of ArCO2H). The sealed vial was placed in a
preheated oil bath (100-130 °C) and heated until all benzoic acid
starting material had been consumed as determined by TLC or GC
(ca. 4.5 to 7 h). The reaction mixture was allowed to cool to room
temperature, diluted with dichloromethane (2 mL), and filtered through
a pad of Celite. The reaction vessel and Celite pad were rinsed with
Acknowledgment. We thank the Welch Foundation (Grant
No. E-1571) for supporting this research. Q.P. is grateful to
University of Houston for an undergraduate research scholarship
(PURS). We thank Dr. James Korp for collecting and solving
the X-ray structures. We also thank Prof. Maurice Brookhart
for helpful comments.
Supporting Information Available: Detailed experimental
procedures and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(22) (a) Brookhart, M.; Green, M. L. H.; Wong, L.-L. Prog. Inorg. Chem. 1988,
36, 1. (b) Jones, W. D. Acc. Chem. Res. 2003, 36, 140. However, a
substantial isotope effect (kH/kD ) 3.0) observed in the palladium-catalyzed
dimerization of arylacetylenes was explained by an agostic interaction. (c)
Rubina, M.; Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 11107.
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