Synthetic applications of Pd(II)-catalyzed C-H carboxylation and mechanistic insights: Expedient routes to anthranilic acids, oxazolinones, and quinazolinones

Article abstract of DOI:10.1021/ja9077705

A Pd(II)-catalyzed reaction protocol for the carboxylation of ortho-C-H bonds in anilides to form N-acyl anthranilic acids has been developed. This reaction procedure provides a novel and efficient strategy for the rapid assembly of biologically and pharmaceutically significant molecules, such as benzoxazinones and quinazolinones, from simple anilides without installing and removing an external directing group. The reaction conditions are also amenable to the carboxylation of N-phenyl pyrrolidinones. A monomeric palladacycle containing p-toluenesulfonate as an anionic ligand has been characterized by X-ray crystallography, and the crucial role of p-toluenesulfonic acid in the activation of C-H bonds in the presence of carbon monoxide is discussed. Identification of two key intermediates, a mixed anhydride and benzoxazinone formed by reductive elimination from organometallic Ar(CO)Pd(II)-OTs species, provides mechanistic evidence for a dual-reaction pathway.

Full text of DOI:10.1021/ja9077705

Published on Web 12/15/2009
Synthetic Applications of Pd(II)-Catalyzed C-H Carboxylation
and Mechanistic Insights: Expedient Routes to Anthranilic
Acids, Oxazolinones, and Quinazolinones
Ramesh Giri, Jonathan K. Lam, and Jin-Quan Yu*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, California 92037
Received September 13, 2009; E-mail: yu200@scripps.edu
Abstract: A Pd(II)-catalyzed reaction protocol for the carboxylation of ortho-C-H bonds in anilides to form
N-acyl anthranilic acids has been developed. This reaction procedure provides a novel and efficient strategy
for the rapid assembly of biologically and pharmaceutically significant molecules, such as benzoxazinones
and quinazolinones, from simple anilides without installing and removing an external directing group. The
reaction conditions are also amenable to the carboxylation of N-phenyl pyrrolidinones. A monomeric
palladacycle containing p-toluenesulfonate as an anionic ligand has been characterized by X-ray
crystallography, and the crucial role of p-toluenesulfonic acid in the activation of C-H bonds in the presence
of carbon monoxide is discussed. Identification of two key intermediates, a mixed anhydride and
benzoxazinone formed by reductive elimination from organometallic Ar(CO)Pd(II)-OTs species, provides
mechanistic evidence for a dual-reaction pathway.
1. Introduction
protocols are amenable to C-H activation conditions and
because both reactions (i.e., beginning with either C-X or
C-H bonds) proceed through similar organopalladium in-
termediates.4
Carbonylation of organic compounds is an attractive
synthetic goal since it utilizes carbon monoxide (CO) as a
carbon-atom source for the formation of a new carbon-carbon
(C-C) bond with concomitant introduction of a highly
oxidized functional group. Since the studies of Heck in 1974,
concerning the reaction of aryl and vinyl halides with CO,1
this reactivity has evolved to include organic triflates,
tosylates, mesylates, and fluorosulfonates as the substrates
to generate products such as carboxylic acids, esters, and
amides.2 A more straightforward strategy toward the con-
struction of these carbonylated molecules, however, would
be to utilize ubiquitous C-H bonds as a halide surrogate.3
As early as the 1980s, carbonylation of C-H bonds thus
emerged as a viable possibility since typical carbonylation
Arenes were first carbonylated by Fujiwara in 19804 with
Pd(OAc)2 under 15 atm of CO in an autoclave5 wherein the
arene substrates were used as solvent, providing carboxylic
acids with a 26-48% yield relative to Pd(OAc)2. The reaction
procedure proved to be compatible with heterocyclic systems
such as indoles, furans and thiophenes.6 Later, it was found
that the reaction was promoted by trifluoroacetic acid (TFA)
and benzene could be converted to benzoic acid under 1 atm
of CO at room temperature with catalytic amounts of
Pd(OAc)2 and K2S2O8 as the oxidant.7 While the reports by
Fujiwara demonstrated the impressive reactivity of Pd(II) in
carboxylating aryl C-H bonds, two major drawbacks largely
hampered the application of this catalytic reaction. First, a
large excess of arene, often used as a solvent, is required.
Second, there is a lack of control over regioselectivity when
substituted benzenes are used as the substrate. In fact, these
two problems are pervasive challenges in the field of C-H
activation and are often overcome through application of a
directing group approach. For example, Orito developed a
Pd(II)-catalyzed, alkylamine-directed regioselective carbo-
nylation of aryl C-H bonds in N-alkyl-ω-arylalkylamines
(1) (a) Schoenberg, A.; Bartoleti, I.; Heck, R. F. J. Org. Chem. 1974, 39,
3318–3326. (b) Schoenberg, A.; Heck, R. F. J. Org. Chem. 1974, 39,
3327–3331.
(2) (a) Munday, R. H.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem.
Soc. 2008, 130, 2754–2755. (b) Barnard, C. F. J. Organometallics
2008, 27, 5402–5422.
(3) (a) Yu, J. Q.; Giri, R.; Chen, X. Org. Biomol. Chem. 2006, 4, 4041–
4047. (b) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439–
2463. (c) Daugulis, O.; Zaitsev, V. G.; Shabashov, D.; Pham, Q. N.;
Lazareva, A. Synlett 2006, 338, 2–3388. (d) Hartwig, J. F.; Cook,
K. S.; Hapke, M.; Incarvito, C. D.; Fan, Y. B.; Webster, C. E.; Hall,
M. B. J. Am. Chem. Soc. 2005, 127, 2538–2552. (e) Hartwig, J. F.
Nature 2008, 455, 314–322. (f) Du Bois, J. Chemtracts 2005, 18, 1–
13. (g) Periana, R. A.; Bhalla, G.; Tenn, W. J.; Young, K. J. H.; Liu,
X. Y.; Mironov, O.; Jones, C. J.; Ziatdinov, V. R. J. Mol. Catal.
AsChem. 2004, 220, 7–25. (h) Crabtree, R. H. J. Organomet. Chem.
2004, 689, 4083–4091. (i) Davies, H. M. L.; Beckwith, R. E. J. Chem.
ReV. 2003, 103, 2861–2903. (j) Stahl, S. S.; Labinger, J. A.; Bercaw,
J. E. Angew. Chem., Int. Ed. 1998, 37, 2180–2192. (k) Sen, A. Acc.
Chem. Res. 1998, 31, 550–557. (l) Shilov, A. E.; Shul’pin, G. B. Chem.
ReV. 1997, 97, 2879–2932. (m) Ryabov, A. D. Chem. ReV. 1990, 90,
403–424.
(4) Fujiwara, Y.; Kawauchi, T.; Taniguchi, H. J. Chem. Soc., Chem.
Commun. 1980, 220–221.
(5) Fujiwara, Y.; Takaki, K.; Taniguchi, Y. Synlett 1996, 591–599.
(6) (a) Itahara, T. Chem. Lett. 1983, 127–128. (b) Itahara, T. Chem. Lett.
1982, 1151–1152. (c) Ugo, R.; Chiesa, A.; Nardi, P.; Psaro, R. J. Mol.
Catal. 1990, 59, 23–31.
(7) (a) Taniguchi, Y.; Yamaoka, Y.; Nakata, K.; Takaki, K.; Fujiwara,
Y. Chem. Lett. 1995, 34, 5–346. (b) Lu, W. J.; Yamaoka, Y.;
Taniguchi, Y.; Kitamura, T.; Takaki, K.; Fujiwara, Y. J. Organomet.
Chem. 1999, 580, 290–294.
9
686 J. AM. CHEM. SOC. 2010, 132, 686–693
10.1021/ja9077705  2010 American Chemical Society

Synthetic Applications of Pd(II)-Catalyzed C-H Carboxylation
A R T I C L E S
Scheme 1. Anthranilic Acids as Precursors of Heterocyclic
Frameworks
Scheme 2. Examples of Drugs and Natural Products Arising from
Anthranilic Acids
serve as precursors for benzoxazinone natural products, which
display a variety of biological activities.16 In addition, readily
available acyl-protected aniline derivatives can be utilized
as substrates for their synthesis via carboxylation, in which
case the acyl protecting group is incorporated into the target
molecule, thereby avoiding additional steps which are gener-
ally required for the installation and removal of directing
groups in various C-H activation methodologies.17 In light
of their growing promise in drug discovery,18 diverse
synthetic methods have been developed with anthranilic acids
as one of the crucial constituents to access these heterocyclic
cores.19 The development of synthetic analogues is, unfor-
tunately, restricted to only a few targets due to the lack of
general procedures to prepare anthranilic acid derivatives.20
Herein, we disclose an unprecedented carboxylation reaction
of anilides using a C-H activation/CO insertion sequence
to give N-acyl-protected anthranilic acids. The use of simple
anilide substrates also allows for atom-economical, expedient,
and diversifying preparations of benzoxazinones and quinazoli-
nones from a combination of readily available starting
materials: anilines and benzoic acid derivatives (Scheme 1).
at 1 atm of CO to prepare benzolactams where the substrate
was used as the limiting reagent.8 Despite this new develop-
ment and other previous reports,9 Pd(II)-catalyzed C-H
activation/carbonylation under a CO environment remains an
outstanding challenge since Pd(II) catalysts are readily
reduced by CO10 and alternate catalytic systems are often
adopted.11 For example, Chan et al. have recently reported
an elegant Pd(II)-catalyzed esterification of sp2 C-H bonds
in a variety of aromatic substrates using diethyl azodicar-
boxylate as the ethoxycarbonylating reagent.11a
With our success in the Pd(II)-catalyzed regioselective
carboxylation of aryl and vinyl carboxylic acids under 1 atm
of CO,12 we embarked on extending the scope of this reaction
protocol to other molecular structures. We were specifically
interested in streamlining the protocol toward the synthesis
of molecules of biological and medicinal importance. As
such, we primarily focused our research on the construction
of anthranilic acid derivatives since they are widely utilized
in the synthesis of heterocyclic natural products and mol-
ecules of biological significance. Anthranilic acid derivatives
also constitute an essential motif in the heterocyclic frame-
work of quinazoline, quinoline, and acridinone alkaloids
(Scheme 1).13 These heterocyclic scaffolds are privileged
structures14 in medicinal chemistry, and therapeutic agents
with such cores are on the market or in clinical trials for the
treatment of cancer (Scheme 2).15 Moreover, anthranilic acids
2. Results
2.1. Preparation of Anthranilic Acid Derivatives. Early
investigations were discouraging since acetanilide 1 failed to
undergo ortho-carboxylation under the standard conditions
recently developed in our laboratory for carboxylic acids (Table
1, entry 1).12 It is well known from the pioneering works of
Tremont,21 de Vries,22 and Daugulis23 that anilides are amenable
to ortho-C-H cleavage with Pd(II) catalysts under a number
(8) Orito, K.; Horibata, A.; Nakamura, T.; Ushito, H.; Nagasaki, H.;
Yuguchi, M.; Yamashita, S.; Tokuda, M. J. Am. Chem. Soc. 2004,
126, 14342–14343.
(16) (a) Hsieh, P. W.; Chang, F. R.; Chang, C. H.; Cheng, P. W.; Chiang,
L. C.; Zeng, F. L.; Lin, K. H.; Wu, Y. C. Bioorg. Med. Chem. Let.
2004, 14, 4751–4754. (b) Krantz, A.; Spencer, R. W.; Tam, T. F.;
Liak, T. J.; Copp, L. J.; Thomas, E. M.; Rafferty, S. P. J. Med. Chem.
1990, 33, 464–479.
(9) For the carbonylation of C-H bonds by other metals, see: (a) Mori,
Y.; Tsuji, J. Tetrahedron 1971, 27, 3811–3819. (b) Kunin, A. J.;
Eisenberg, R. J. Am. Chem. Soc. 1986, 108, 535–536. (c) Moore, E.;
Pretzer, W. R.; O’Connell, J. H.; LaBounty, L.; Chou, L.; Grimmer,
S. S. J. Am. Chem. Soc. 1992, 114, 5888–5890. (d) Choi, J.-C.;
Kobayashi, Y.; Sakakura, T. J. Org. Chem. 2001, 66, 5262–5263. (e)
Funk, J. K.; Yennawar, H.; Sen, A. HelV. Chim. Acta 2006, 89, 1687–
1695. (f) Imoto, S.; Uemura, T.; Kakiuchi, F.; Chatani, N. Synlett 2007,
170–172.
(17) (a) Giri, R.; Chen, X.; Yu, J.-Q. Angew. Chem. Int. Ed. 2005, 44,
2112. (b) Giri, R.; Liang, J.; Lei, J. G.; Li, J. J.; Wang, D. H.; Chen,
X.; Naggar, I. C.; Guo, C.; Foxman, B. M.; Yu, J.-Q. Angew. Chem.,
Int. Ed. 2005, 44, 7420. (c) Giri, R.; Wasa, M.; Breazzano, S. P.; Yu,
J.-Q. Org. Lett. 2006, 8, 5685.
(18) Tilloquin, F. Phytochem. ReV. 2007, 6, 65–79.
(19) (a) Pereira, M. D.; Thiery, V.; Besson, T. Tetrahedron 2007, 63, 847–
854. (b) Gil, C.; Brase, S. Chem.sEur. J. 2005, 11, 2680–2688. (c)
Griffin, R. J.; Srinivasan, S.; Bowman, K.; Calvert, A. H.; Curtin,
N. J.; Newell, D. R.; Pemberton, L. C.; Golding, B. T. J. Med. Chem.
1998, 41, 5247–5256.
(10) Moiseev, I. I. Pure Appl. Chem. 1989, 61, 1755–1762.
(11) For the use of diethyl azodicarboxylate as the ethoxycarbonylating
reagent, see: (a) Yu, W. Y.; Sit, W. N.; Lai, K. M.; Zhou, Z. Y.;
Chan, A. S. C. J. Am. Chem. Soc. 2008, 130, 3304–3306. For
carboxylation with CO2, see: (b) Reference 5. (c) Sugimoto, H.;
Kawata, I.; Taniguchi, H.; Fujiwara, Y. J. Organomet. Chem. 1984,
266, C44–C46. For carboxylation with formic acid, see: (d) Shibahara,
F.; Kinoshita, S.; Nozaki, K. Org. Lett. 2004, 6, 2437–2439. (e)
Sakakibara, K.; Yamashita, M.; Nozaki, K. Tetrahedron Lett. 2005,
46, 959–962.
(20) (a) Kamal, A.; Shankaraiah, N.; Markandeya, N.; Reddy, C. S. Synlett
2008, 129, 7–1300. (b) Zhou, Z. L.; Kher, S. M.; Cai, S. X.;
Whittemore, E. R.; Espitia, S. A.; Hawkinson, J. E.; Tran, M.;
Woodward, R. M.; Weber, E.; Keana, J. F. W. Bioorg. Med. Chem.
2003, 11, 1769–1780.
(12) Giri, R.; Yu, J. Q. J. Am. Chem. Soc. 2008, 130, 14082–14083.
(13) Michael, J. P. Nat. Prod. Rep. 2008, 25, 166–187.
(14) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103,
893–930.
(21) Tremont, S. J.; Rahman, H. U. J. Am. Chem. Soc. 1984, 106, 5759–
5760.
(22) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer,
P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. J. Am. Chem.
Soc. 2002, 124, 1586–1587.
(15) For example, Raltitrexed (Tomudex, marketed for colorectal cancer),
Ispinesib (phase II for solid tumors), and Tempostatin (phase II for
bladder cancer).
(23) Zaitsev, V. G.; Daugulis, A. J. Am. Chem. Soc. 2005, 127, 4156–
4157.
9
J. AM. CHEM. SOC. VOL. 132, NO. 2, 2010 687

A R T I C L E S
Giri et al.
Table 1. Optimization of Reaction Conditions
been reported by Lloyd-Jones, Booker-Milburn, and co-workers
in a urea-directed ortho-carbonylation26 and 1,2-dicarboamina-
tion of dienes via ortho-C-H activation of phenylurea deriva-
tives.27
A variety of anilides underwent carboxylation in good to
excellent yields to give N-acyl anthranilic acids (Table 2). While
HOAc/dioxane (2:1) was the solvent of choice for acetanilide
and a few other substrates (Table 2, entries 1, 3, 7), dioxane
was the best solvent for the majority of substrates (Table 2,
entries 2, 5, 6, 8-11), and HOAc/toluene (2:1) provided higher
product yields for substrates 5 and 15. Addition of 0.5 equiv of
NaOAc is essential for the best product yields with substrates
9-12 (Table 2, entries 8-11), as significantly less product
(30-40%) was obtained in the absence of NaOAc. This result
indicates that the formation of Pd-OAc species is beneficial
for the C-H activation step.
Substituents on the arene ring also exhibited significant steric
and electronic effects on reactivity. Ortho-substituted acetanil-
ides, in general, afforded lower product yields than meta- and
para-substituted derivatives (Table 2, entries 1, 2, 7). The
carboxylation reaction proceeded efficiently with electron-rich
substrates, which is consistent with an electrophilic palladation
mechanism.28 The reaction tolerates a variety of oxygenated
substrates, and excellent product yields are consistently obtained
(Table 2, entries 8-11). Excellent levels of regioselectivity were
observed in the carboxylation of meta-substituted anilides, in
which cases carboxylation of the more hindered C-H bonds
was not observed (Table 2, entries 3, 6, 8, 10, 11). The
carboxylation protocol is also amenable to N-phenyl pyrrolidi-
none 15. However, electron-deficient substrates containing
halogens gave less than 20% products. Due to the importance
of the availability of a halogen on the aryl ring for further
transformations, we developed an improved catalytic system to
overcome this limitation by using Pd(OTf)2(CH3CN)4 as the
catalyst (Table 2, entries 12, 13). Substrates bearing strong
electron-withdrawing groups such as p-NO2 and p-COOMe
afforded less than 10% products under the current carboxylation
conditions. Intermolecular competition experiments containing
a 1:1 mixture of electron-rich and electron-deficient substrates
1 and 13, respectively, also showed that the latter is much less
reactive (see the Experimental Section for details).
entry
R
oxidant
additive
solvent
dioxane
TFA
% yielda
b
1
2
3
4
5
6
7
8
9
Me Ag2CO3 K2CO3/NaOAc
0
c
Me none
Me BQ
Me BQ
Me BQ
Me BQ
Me BQ
Me BQ
Me BQ
none
none
80
32
d,e
TFA
d
p-TsOH (0.5 equiv)
p-TsOH (0.5 equiv)
p-TsOH (0.5 equiv)
p-TsOH (0.5 equiv)
p-TsOH (0.5 equiv)
p-TsOH (0.5 equiv)
p-TsOH (0.5 equiv)
TfOH
HOAc/dioxane (2:1)
HOAc/toluene (2:1) 86
dioxane
HOAc
toluene
DCE
t-BuOH
dioxane
dioxane
90
70
60
70
60
65
<10
<10
<10
0
10 Me BQ
11 Me BQ
12 Me BQ
13 Me BQ
HBF4
(()-camphor sulfonic acid dioxane
p-TsOH (0.5 equiv)
p-TsOH (0.5 equiv)
14
H
BQ
dioxane
dioxane
15 t-Bu BQ
0
a
1H NMR yields. b 120 °C, 18 h. See ref 12. c 1 equiv of Pd(OAc)2
d Isolated yields. e 25 °C.
of conditions;21-24 however, ortho-C-H activation of aceta-
nilide 1 was initially unsuccessful in the presence of CO
(Scheme 3). It became evident to us that the presence of CO
impedes the C-H activation process and effects the reduction
of Pd(OAc)2 to Pd(0) in both stoichiometric and catalytic
experiments.10
To overcome this problem, we searched for reaction condi-
tions that would promote the cleavage of C-H bonds over the
reduction of Pd(OAc)2. Highly electrophilic cationic Pd(II)
species generated under strongly acidic conditions are known
to be more reactive toward C-H activation;7b thus, we began
our investigation with the reaction of acetanilide 1 with
stoichiometric Pd(OAc)2 in TFA under 1 atm of CO. Gratify-
ingly, the reaction proceeded at room temperature, and N-
acetylanthranilic acid 1a was obtained in 80% yield (Table 1,
entry 2). The reaction could also be run catalytically with 10
mol % Pd(OAc)2 using 1 equiv of benzoquinone (BQ) as the
terminal oxidant, affording product 1a, albeit in meager yield
(Table 1, entry 3). Further optimization of the reaction conditions
in the presence of different acids established that the reaction
was most productive using a solvent mixture of acetic acid
(HOAc)/dioxane (2:1) in the presence of 0.5 equiv of p-
toluenesulfonic acid monohydrate (p-TsOH·H2O) while heating
at 60 °C. Other acids are not effective, suggesting the counter-
anion TsO- is crucial for this reaction (Table 1, entries 11-13).
N-Acetylanthranilic acid 1a was obtained in 90% isolated yields
(Table 1, entry 4).25 The carboxylation also proceeds in a variety
of other solvents in good yields under these conditions (Table
1, entries 5-10). The crucial effect of p-toluenesulfonic acid
in assisting in the cleavage of acetanilide ortho-C-H bonds by
Pd(II) was first realized by de Vries, van Leeuwen, and co-
workers in 2002.22 Recently, a similar effect of p-TsOH has
2.2. Syntheses of Benzoxazinones and Quinazolinones. We
were excited to find that this newly developed carboxylation
protocol could be extended to benzanilide substrates 16-18.
The ortho-C-H bond of the aniline fragment in benzanilide
was carboxylated selectively in the presence of C-H bonds on
the benzoyl ring29 to give N-benzoylanthranilic acids 16a-18a
in 73-96% yield (Scheme 4), which could be cyclized by
treating with Ac2O to afford the corresponding benzoxazinones
16b-18b in one pot (Scheme 5).30 Furthermore, N-benzoylan-
thranilic acids 16a and 17a could be treated with PCl3 in the
(26) While our work on the synthesis of benzoxazinones and quinazolinones
via the activation of ortho-C-H bonds in aniline derivatives was in
progress, Lloyd-Jones, Booker-Milburn, and co-workers reported a
C-H carbonylation protocol using phenylurea as the directing
group: Houlden, C. E.; Hutchby, M.; Bailey, C. D.; Ford, J. G.; Tyler,
S. N. G.; Gagne, M. R.; Lloyd-Jones, G. C.; Booker-Milburn, K. I.
Angew. Chem., Int. Ed. 2009, 48, 1830–1833.
(24) (a) Horino, H.; Inoue, N. J. Org. Chem. 1981, 46, 4416–4422. (b)
Yang, S. D.; Li, B. J.; Wan, X. B.; Shi, Z. J. J. Am. Chem. Soc. 2007,
129, 6066–6067. (c) Wang, G.-W.; Yuan, T.-T.; Wu, X.-L. J. Org.
Chem. 2008, 73, 4717–4720.
(27) Houlden, C. E.; Bailey, C. D.; Ford, J. G.; Gagne´, M. R.; Lloyd-
Jones, G. C.; Booker-Milburn, K. I. J. Am. Chem. Soc. 2008, 130,
10066–10067.
(25) Formation of dicarboxylated product was not observed. The exclusive
monoselectivity is due to the lack of reactivity of the electron-deficient
arenes in the carboxylated products. Furthermore, bis-chelation of
Pd(II) catalyst with the acetyl and the newly generated carboxyl groups
also makes it difficult for the Pd(II) to reach the remaining ortho-C-
H bonds.
(28) Mart´ın-Matute, B.; Mateo, C.; Ca´rdenas, D. J.; Echavarren, A. M.
Chem.sEur. J. 2001, 7, 2341–2348.
(29) Kametani, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron Lett.
2000, 41, 2655.
9
688 J. AM. CHEM. SOC. VOL. 132, NO. 2, 2010

Synthetic Applications of Pd(II)-Catalyzed C-H Carboxylation
A R T I C L E S
Scheme 3. Interference by CO on Ortho-C-H Cleavage by Pd(OAc)2
Table 2. Ortho-Carboxylation of Anilides via C-H Activationa b
,
a 10 mol % Pd(OAc)2, 0.5 equiv of p-TsOH·H2O, 1 equiv of benzoquinone, 1 atm of CO, HOAc/dioxane (2:1), 60 °C (entries 1, 4-6, 8, 10, and 11)
or 80 °C (entries 2, 3, 7, 9, and 12-14), 18 h (entries 3-6 and 14), 24 h (entries 1, 2, and 7-11), or 36 h (entries 12 and 13), Hi-Vac valve Schlenk
tube. b Isolated yields. c Dioxane was used as a solvent. d HOAc/toluene (2:1) was used as a solvent. e 0.5 equiv of NaOAc was used as an additive. f 15
mol % Pd(OTf)2(MeCN)4 was used.
presence of aniline to generate quinazolinones 16c-e and
Scheme 4. Ortho-Carboxylation of Benzanilides via C-H Activation
17c-e, respectively, in high yields (85-96%) (Scheme 6).31,32
These reaction sequences showcase the utility of our C-H bond
carboxylation protocol in the rapid synthesis of natural product
analogues and biologically active molecules from readily
available aniline derivatives.
2.3. Mechanistic Consideration and Catalytic Cycle. During
the course of our investigation, we also characterized a
cyclopalladated intermediate complex and carried out further
experiments in order to gain insight into the role of p-TsOH
(30) Afsah, S. A.; Ahmad, J.; Purbey, R.; Kumar, A. Asian J. Chem. 2003,
15, 552–554.
(31) Xue, S.; McKenna, J.; Shieh, W.-C.; Repic, O. J. Org. Chem. 2004,
69, 6474–6477.
9
J. AM. CHEM. SOC. VOL. 132, NO. 2, 2010 689

A R T I C L E S
Giri et al.
with either an authentic sample or a product generated in situ.34
Simultaneous operation of both catalytic cycles is also plausible
under the catalytic reaction conditions. Finally, benzoquinone
reoxidizes Pd(0) to Pd(OTs)2 in the presence of p-TsOH.35
Scheme 5. Syntheses of Benzoxazinones via C-H Activation of
Benzanilides
Under non-anhydrous conditions, a suspension of palladacycle
1b in dioxane or CH2Cl2 reacts quantitatively with CO at room
temperature to produce N-acetylanthranilic acid 1a (Scheme 10).
Carboxylation could also be carried out directly by stirring a
solution of acetanilide 1 with stoichiometric amounts of
Pd(OAc)2 and p-TsOH·H2O under 1 atm of CO to give
N-acetylanthranilic acid 1a in nearly quantitative yield (90%).
Notably, while the acetate-bridged palladacycle 1i prepared from
acetanilide 1 in the absence of p-TsOH was also carboxylated
efficiently under 1 atm of CO at room temperature,24a the
stoichiometric reaction starting directly with acetanilide and
Pd(OAc)2 failed to afford any product in the absence of p-TsOH
(Scheme 10). These experiments indicate that p-TsOH is critical
for the activation of C-H bonds under a CO environment.
and the mechanism of acetanilide carboxylation. Treatment of
acetanilide 1 with 1 equiv of Pd(OAc)2 in the presence of 1
equiv of p-TsOH·H2O in CH2Cl2 or dioxane at 40 °C instantly
gave a faint yellow cyclopalladated intermediate in quantitative
yield. Its structure is consistent with the dimeric complex 1b
as determined by 1H and 13C NMR (Scheme 7). Complex 1b is
insoluble in organic solvents such as diethyl ether and CH2Cl2
and partially dissolves in THF but with the loss of dimeric
integrity to give an off-white monomer 1c with the incorporation
of one solvent molecule as a ligand. The monomer 1c was
crystallized from THF at room temperature, and its structure
was confirmed by X-ray crystallography. Interestingly, a similar
structure has been observed by 1H NMR; however, the p-
toluenesulfonate anion is not directly coordinated to the Pd(II)
center in the crystal structure.26,33
3. Summary
We have developed a Pd(II)-catalyzed reaction protocol for
the direct ortho-carboxylation of anilides to form N-acyl
anthranilic acids. We have also characterized by X-ray crystal-
lography a monomeric palladacycle containing p-toluene-
sulfonate as a ligand, formed from the cyclometalation of
acetanilide. Further mechanistic investigations have revealed the
involvement of a mixed anhydride and benzoxazinone as key
intermediates, formed by reductive elimination from an
Ar(CO)Pd(II)-OTs species, which lead to the generation of a
carboxylic acid product after hydrolysis with traces of H2O. The
reaction conditions can also be applied to the carboxylation of
N-phenyl pyrrolidinones. This reaction protocol allows us to
rapidly generate an array of biologically active benzoxazinone
and quinazolinone derivatives from simple anilides without
installing and removing an external directing group.
The structure of 1c lends support to a number of mechanistic
hypotheses. First, the presence of OTs in 1b and 1c suggests
that the OTs anion is likely to be attached to Pd(II) in the form
of L2Pd(OTs)X on the C-H activation step, thereby enhancing
the reactivity. Second, the C-H insertion intermediate 1c or
1d inserts CO to generate palladacycle 1e, which then undergoes
reductive elimination with p-toluenesulfonate to give a mixed
anhydride species 1f (Scheme 8, catalytic cycle A). Alterna-
tively, intermediate 1e could release a molecule of p-TsOH via
enolization of the acidic N-H bond to generate a second
intermediate 1g, which subsequently undergoes reductive elimi-
nation to generate benzoxazinone 1h (Scheme 8, catalytic cycle
B). The final carboxylic acid product 1a arises from the
subsequent hydrolysis of these anhydride and benzoxazinone
intermediate products by water present in the reaction system
(Scheme 8).12 Operation of these dual-reaction pathways was
supported by the observation of a 1:1 mixture of the mixed
anhydride 1f and benzoxazinone 1h when a reaction of dimeric
palladacycle 1b with carbon monoxide was carried out in a
glovebox under anhydrous conditions in CD2Cl2 (Scheme 9).
4. Experimental Section
4.1. General Information. Solvents were obtained from Acros
and used directly without further purification. Infrared spectra were
recorded on a Perkin-Elmer FT-IR spectrometer. 1H and 13C NMR
spectra were recorded on a Varian instrument (400 and 100 MHz,
respectively) and internally referenced to the SiMe4 signal. High-
resolution mass spectra for new compounds were recorded at the
Mass Spectrometry Facilities, The Scripps Research Institute. X-ray
crystallographic analysis of palladacycle 1c was done at the X-ray
crystallography facility, Department of Chemistry and Biochemistry,
University of California, San Diego. Palladium acetate, sodium
acetate, and p-toluenesulfonic acid monohydrate were purchased
from Sigma-Aldrich. Aniline derivatives were purchased from
Acros, Sigma-Aldrich, and Alfa-Aesar. Acetanilides 3, 6, 11, 12
and benzanilides 17, 18 were prepared according to the literature
procedure.36 Carbon monoxide (99% purity) was purchased from
Airgas.
1
The formation of these products was confirmed by H NMR
and GC-MS analysis of the reaction mixture and comparison
(32) For other reports on the synthesis of heterocyclic compounds via C-
H bond activation, see: (a) Kuninobu, Y.; Tokunaga, Y.; Kawata, A.;
Takai, K. J. Am. Chem. Soc. 2006, 128, 202–209. (b) Me´ry, D.;
Aranzaes, J. R.; Astruc, D. J. Am. Chem. Soc. 2006, 128, 5602–5603.
(c) Kuninobu, Y.; Nishina, Y.; Nakagawa, C.; Takai, K. J. Am. Chem.
Soc. 2006, 128, 12376–12377. (d) Yotphan, S.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 2452–2453. (e) Jordan-
Hore, J. A.; Johansson, C. C. C.; Gulias, M.; Beck, E. M.; Gaunt,
M. J. J. Am. Chem. Soc. 2008, 130, 16184–16186. (f) Coulter, M. M.;
Dornan, P. K.; Dong, V. M. J. Am. Chem. Soc. 2009, 131, 6932–
6933.
(34) For the preparation of benzoxazinone 1h, see: (a) Nagase, T.; Mizutani,
T.; Ishikawa, S.; Sekino, E.; Sasaki, T.; Fujimura, T.; Ito, S.; Mitobe,
Y.; Miyamoto, Y.; Yoshimoto, R.; Tanaka, T.; Ishihara, A.; Takenaga,
N.; Tokita, S.; Fukami, T.; Sato, N. J. Med. Chem. 2008, 51, 4780–
4789. (b) The mixed anhydride 1f was prepared in situ. See
Experimental Section for details.
(35) Popp, B. V.; Stahl, S. S. Top. Orgmet. Chem. 2007, 22, 149–189.
(36) (a) Fang, Y. Q.; Lautens, M. J. Org. Chem. 2008, 73, 538–549. (b)
Lyon, M. A.; Lawrence, S.; Williams, D. J.; Jackson, Y. A. J. Chem.
Soc., Perkin Trans. 1999, 1, 437–442.
(33) Rauf, W.; Thompson, A. L.; Brown, J. M. Chem. Commun. 2009,
3874–3876.
9
690 J. AM. CHEM. SOC. VOL. 132, NO. 2, 2010

Synthetic Applications of Pd(II)-Catalyzed C-H Carboxylation
A R T I C L E S
Scheme 6. Syntheses of Quinazolinones via C-H Activation of Benzanilides
Scheme 7. Formation of 1b and 1c
Scheme 8. Dual-Reaction Pathways of Catalytic Carboxylation in the Presence of H2O
Scheme 9. Stoichiometric Reaction of Palladacycle 1b with CO under Anhydrous Conditions
4.2. General Procedure for Preparation of Anthranilic Acid
Derivatives. HOAc/dioxane (2:1, 1 mL) was added to a mixture of
Pd(OAc)2 (11.2 mg, 0.05 mmol), anilide (0.5 mmol), p-toluene-
sulfonic acid monohydrate (47.5 mg, 0.25 mmol), and benzoquinone
(54.0 mg, 0.5 mmol) in a 50 mL Hi-Vac valve Schlenk tube.
Dioxane (1 mL) was used as a solvent for substrates 3, 6, 7, 9-14,
16-18, and HOAc/toluene (2:1, 1 mL) was used as a solvent for
substrates 5 and 15. NaOAc (20.5 mg, 0.25 mmol) was used as an
additive for substrates 9-12 and 16-18. The Schlenk tube was
degassed under high vacuum and filled with carbon monoxide from
a balloon at room temperature. (Note: The use of a fresh CO-filled
balloon is crucial for reproducibility of the results and high product
yields.) The reaction mixture was heated at 60 °C (substrates 2,
5-7, 9, 11, 12) or 80 °C (substrates 3, 4, 8, 10, 13-18) in an oil
bath with vigorous stirring. After 18-36 h (18 h, substrates 4-7,
15; 24 h, substrates 2, 3, 8-12, 16-18; 36 h, substrates 13, 14),
the reaction was cooled to room temperature, and the solvent was
removed in a rotary evaporator. The residue was dissolved in
saturated NaHCO3 (2 mL) and washed with CH2Cl2 (1 mL × 3),
and the aqueous fraction was acidified with dropwise addition of 6
N HCl at 0 °C and extracted with ethyl acetate (2 mL × 5). The
ethyl acetate fraction was washed with water (2 mL × 3) and dried
over Na2SO4, and the solvent was removed in a rotary evaporator.
The product was purified by silica gel column chromatography using
9
J. AM. CHEM. SOC. VOL. 132, NO. 2, 2010 691

A R T I C L E S
Giri et al.
Scheme 10. Reaction of Palladacycles 1b and 1i with CO
The product was purified by silica gel column chromatography with
gradient elution from 2% to 10% ethyl acetate in hexanes with 2%
increments.
4.5. Formation and Characterization of Palladacycles 1b and
1c. A solution of acetanilide (27 mg, 0.2 mmol), p-toluenesulfonic
acid monohydrate (38 mg, 0.2 mmol), and Pd(OAc)2 (45 mg, 0.2
mmol) in CH2Cl2 or dioxane (2 mL) was heated at 40 °C for 1 min
(CH2Cl2) or 10 min (dioxane). The mixture was filtered to afford
a pale yellow solid which was dried under vacuum (82 mg, 99%).
The complex was characterized as a dimer 1b by 1H and 13C NMR:
1H NMR (400 MHz, CD3OD) δ 2.30 (s, 3H), 2.36 (s, 3H),
6.89-6.97 (m, 3H), 7.12 (t, J ) 8.0 Hz, 1H), 7.23 (d, J ) 8.0 Hz,
2H), 7.75 (d, J ) 8.0 Hz, 2H), 11.47 (s, 1H); 13C NMR (100 MHz,
CD3OD) δ 21.5, 21.5, 22.1, 115.1, 115.2, 118.1, 118.2, 125.0, 127.7,
128.0, 130.6, 132.8, 132.9, 134.0, 142.5, 144.1, 168.7, 168.8.
The pale yellow solid was dissolved partially in THF (1 mL)
at 60 °C, and the suspension was then filtered through a Cameo
3N syringe filter (0.45 µm, 3 mm) (Osmonics Inc.) in a glass
sample vial. The complex was crystallized as yellow prisms 1c
in 24 h at room temperature. The complex 1c was characterized
by X-ray crystallography.
a gradient elution starting at 10% ethyl acetate in hexanes containing
5% acetic acid and ending at 30% ethyl acetate in hexanes
containing 5% HOAc (10:5:85 to 30:5:65 EtOAc/HOAc/hexanes)
with 5% increments unless stated otherwise.
4.3. General Procedure for Preparation of Benzoxaziones.
Benzoxazinones were prepared according to the literature proce-
dure30 starting from the crude reaction mixture of the corresponding
N-benzoylanthranilic acids. The carboxylation reaction was carried
out in 0.2 mmol scale according to the general procedure. Solvent
was then removed in a rotary evaporator, and acetic anhydride (10
mL) was added. The reaction mixture was stirred at 60 °C for 4 h.
Benzoxazinones were obtained after the removal of excess solvent
in a rotary evaporator and silica gel column chromatography using
5% ethyl acetate in hexanes. The benzoxazinones can also be
prepared from the pure N-benzoylanthranilic acids in quantitative
yields using the same procedure but without the need for chro-
matographic purification.
4.4. General Procedure for Preparation of Quinazolinones.
Quinazolinones were prepared according to the literature proce-
dure31 starting from the corresponding N-benzoylanthranilic acids.
Aniline (0.4 mmol) was added to a solution of N-benzoylanthranilic
acid derivative (0.2 mmol) in CH3CN (1.0 mL) at room temperature,
followed by PCl3 (0.4 mmol). The reaction mixture was warmed
to 50 °C and stirred for 18 h, and then it was cooled to room
temperature and diluted with EtOAc. The mixture was quenched
by the addition of 1 N aqueous HCl solution. The organic layer
was separated, washed with 10% aqueous NaHCO3 solution, and
dried over MgSO4. The solvent was removed in a rotary evaporator.
4.6. Competition Experiment. Dioxane (1 mL) was added to a
mixture of Pd(OAc)2 (11.2 mg, 0.05 mmol), acetanilide 1 (33.8
mg, 0.25 mmol), p-bromoacetanilide 13 (53.5 mg, 0.25 mmol),
p-toluenesulfonic acid monohydrate (47.5 mg, 0.25 mmol), and
benzoquinone (54.0 mg, 0.5 mmol) in a 50 mL Hi-Vac valve
Schlenk tube. The Schlenk tube was degassed under high vacuum
and filled with carbon monoxide from a balloon at room temper-
ature. The reaction mixture was heated at 80 °C. After 3 h, the
reaction was cooled to room temperature, and the solvent was
removed in a rotary evaporator. The residue was dissolved in
saturated NaHCO3 (2 mL) and washed with CH2Cl2 (1 mL × 3),
and the aqueous fraction was acidified with dropwise addition of 6
N HCl at 0 °C and extracted with ethyl acetate (2 mL × 5). The
ethyl acetate fraction was washed with water (2 mL × 3) and dried
over Na2SO4, and the solvent was removed in a rotary evaporator.
1
The product was analyzed by H NMR. The product yields of 1a
(31%) and 13a (5%) were determined relative to the remaining
starting materials.
4.7. Identification of Products after Reductive Elimination
from a Pd(II) Intermediate. In a glovebox, palladacycle 1b (82.4
mg, 0.1 mmol) was weighed into a NMR tube with a J-Young valve
and suspended in anhydrous CD2Cl2 (1.0 mL). The NMR tube was
taken out of the glovebox, frozen in liquid N2, evacuated, and filled
with 1 atm CO. The tube was tightly screw-capped and slowly
warmed to room temperature with shaking, at which point the
suspension turned black. The suspension was shaken for 10 min,
brought into the glovebox, and filtered through a tight pad of cotton
into another NMR tube with a J-Young valve. The clear solution
1
was analyzed by H NMR and GC-MS. A 1:1 ratio of two new
products arising from acetanilide 1 was observed, along with the
formation of p-TsOH (see the 1H NMR spectra below). The
formation of benzoxazinone 1h was confirmed by comparison of
1
the H NMR spectrum of the reaction mixture with that of the
authentic sample of benzoxazinone 1h and by the observation of
M+ ion at 161 corresponding to the retention time of benzoxazinone
1h at 6.63 min when an aliquot of the reaction mixture was analyzed
by GC-MS.
Moreover, when a sample of benzoxazinone 1h (10 mg) was
1
added to the reaction mixture, intensities of one set of H NMR
peaks corresponding to benzoxazinone 1h were enhanced.
Similarly, when a sample of the mixed anhydride 1f, generated
in situ from a mixture of 1:1:1 molar ratios of p-TsCl,
N-acetylanthranilic acid 1a, and triethylamine in anhydrous
CD2Cl2, was added to the reaction mixture, the intensities of
Figure 1. Crystal structure of 1c.
9
692 J. AM. CHEM. SOC. VOL. 132, NO. 2, 2010

Synthetic Applications of Pd(II)-Catalyzed C-H Carboxylation
A R T I C L E S
the remaining set of 1H NMR peaks were enhanced (see the
Supporting Information for details).
Supporting Information Available: Detailed experimental
procedures, characterization of new compounds, and X-ray
crystallographic data for 1c. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank The Scripps Research Institute
and the U.S. National Science Foundation (NSF CHE-0910014)
for financial support, the Camille and Henry Dreyfus Foundation
for a New Faculty Award, and the A. P. Sloan Foundation for a
Fellowship.
JA9077705
9
J. AM. CHEM. SOC. VOL. 132, NO. 2, 2010 693