Palladium-catalyzed decarboxylative coupling of isatoic anhydrides with arylboronic acids

Article abstract of DOI:10.1021/ol202609a

The decarboxylative coupling of isatoic anhydrides with arylboronic acids was realized for the first time in the presence of Pd₂(dba) ₃ and DPEphos, achieving aryl o-aminobenzoates with yields ranging from moderate to good. The efficiency of this procedure was demonstrated by good compatibility with fluoro, chloro, bromo, nitro, cyano, trifluoromethyl, formacyl, acetyl, thienyl, and naphthyl groups. Preliminary mechanistic experiments using deuterium labeling showed that the oxygen atom was derived from dioxygen.

Full text of DOI:10.1021/ol202609a

ORGANIC
LETTERS
2011
Vol. 13, No. 22
6114–6117
Palladium-Catalyzed Decarboxylative
Coupling of Isatoic Anhydrides with
Arylboronic Acids
Wei Lu, Jiuxi Chen,* Miaochang Liu, Jinchang Ding, Wenxia Gao, and Huayue Wu*
College of Chemistry & Materials Engineering, Wenzhou University, Wenzhou 325035,
P. R. China
jiuxichen@wzu.edu.cn; huayuewu@wzu.edu.cn
Received September 27, 2011
ABSTRACT
The decarboxylative coupling of isatoic anhydrides with arylboronic acids was realized for the first time in the presence of Pd2(dba)3 and
DPEphos, achieving aryl o-aminobenzoates with yields ranging from moderate to good. The efficiency of this procedure was demonstrated by
good compatibility with fluoro, chloro, bromo, nitro, cyano, trifluoromethyl, formacyl, acetyl, thienyl, and naphthyl groups. Preliminary
mechanistic experiments using deuterium labeling showed that the oxygen atom was derived from dioxygen.
Aryl benzoate derivatives are important building blocks
for the synthesis of natural products and pharmacologi-
cally active compounds.1 Recently, aryl benzoate deriva-
tives have been used as indicators of fragments of
chemiluminescent labels in the field of photochemistry.2
Traditional methods for the preparation of these com-
pounds involve esterification3 and transesterification
reactions4 as well as BaeyerÀVilliger oxidation reactions.5
However, the esterification and transesterification reac-
tions were often conducted under strongly acidic or basic
conditions, which might limit the scope of functional
groups and practicality of the reaction. The regiospecificity
of the BaeyerÀVilliger oxidation reaction depends on the
relative migratory ability of the substituents attached to
the carbonyl group, and in cases where the substituent
groups have similar migratory rates, the resulting products
will be mixtures with low regioselectivity. In 2008, we
developed the palladium-catalyzed aromatic esterification
of aldehydes with arylboronic acids.6 However, the yields
of the anticipated aryl benzoates were unsatisfactory.
Thus, we still consider it highly desirable to develop milder
and more efficient catalytic systems for the synthesisofaryl
benzoate derivatives.
(1) (a) Dhar, A.; Liu, S.; Klucik, J.; Berlin, K. D.; Madler, M. M.; Lu,
S; Ivey, R. T.; Zacheis, D.; Brown, C. W.; Nelson, E. C.; Birckbichler,
P. J.; Benbrook, D. M. J. Med. Chem. 1999, 42, 3602. (b) Moretto, A.;
Nicolli, A.; Lotti, M. Toxicol. Appl. Pharmacol. 2007, 219, 196. (c)
James, C.; Snieckus, V. J. Org. Chem. 2009, 74, 4080.
ꢀ
ꢀ
(2) Krzyminski, K.; Ozog, A.; Malecha, P.; Roshal, A. D.;
ꢀ
Wroblewska, A.; Zadykowicz, B.; Bzazejowski, J. J. Org. Chem. 2011,
76, 1072.
(3) (a) Fischer, E.; Speier, A. Chem. Ber. 1895, 28, 3252. (b) Chakraborti,
A. K.; Singh, B.; Chankeshwara, S. V.; Patel, A. R. J. Org. Chem.
2009, 74, 5967. (c) Kankanala, K.; Reddy, V.; Mukkanti, K.; Pal, S.
J. Fluorine Chem. 2009, 130, 505. (d) Krzyminski, K.; Roshal, A. D.;
Zadykowicz, B.; Bialk-Bielinska, A.; Sieradzan, A. J. Phys. Chem. A 2010,
114, 10550.
(4) (a) Oohashi, Y.; Fukumoto, K.; Mukaiyama, T. Bull. Chem. Soc.
Jpn. 2005, 78, 1508. (b) Zarchi, M. A. K.; Mirjalili, B. F.; Acal, A. K.
J. Appl. Polym. Sci. 2010, 115, 237.
(5) (a) Olah, G. A.; Wang, Q.; Trivedi, N. J.; Prakash, G. K. S.
Synthesis 1991, 739. (b) Kotsuki, H.; Arimura, K.; Araki, T.; Shinohara,
T. Synlett 1999, 462. (c) Goodman, M. A.; Detty, M. R. Synlett 2006,
1100. (d) Yoshida, Y.; Murakami, K.; Yorimitsu, H.; Oshima, K. J. Am.
Chem. Soc. 2010, 132, 9236. (e) Murahashi, S.; Ono, S.; Imada, Y.
Angew. Chem., Int. Ed. 2002, 41, 2366.
Herein, we report a new method for the synthesis of aryl
o-aminobenzoates by Pd-catalyzed decarboxylative cou-
pling of isatoic anhydrides with arylboronic acids.
Initially, the reaction between isatoic anhydride 1a and
phenylboronic acid 2a was chosen as a model reaction to
screen the optimal reaction conditions, and the results are
listed in Table 1. Through the screening process, no target
productwas detectedusingNa2PdCl4 asthe Pdsourcewith
(6) Qin, C. M.; Wu, H. Y.; Chen, J. X.; Liu, M. C.; Cheng, J.; Su,
W. K.; Ding, J. C. Org. Lett. 2008, 10, 1537.
r
10.1021/ol202609a
Published on Web 10/20/2011
2011 American Chemical Society

a variety of parameters. However, we were delighted to
find that the yield could be improved to 18% when the
combination of Pd(OAc)2, tricyclohexylphosphine (PCy3),
and Na2CO3 was employed in THF under an O2 atmo-
sphere (Table 1, entry 1).
Table 1. Optimization of Reaction Conditionsa
Encouraged bythispromisingresult, wefurtheradjusted
reaction parameters including palladium catalysts, bases,
and solvents. Among the palladium sources used (e.g.,
PdCl2, PdCl2(PPh3)2, PdCl2(dppf), PdCl2(PhCN)2, PdCl2-
(cod), PdCl2(acac)2, Pd(PPh3)4, and Pd2(dba)3), Pd2(dba)3
exhibited the highest catalytic reactivity in 47% yield
(Table 1, entries 2À9). The choice of base was also vital
to the success of the catalytic reaction. Screening revealed
that the use of 1-methylpiperidine as base achieved the best
result. Other bases, including Na2CO3, NaOAc, Cs2CO3,
CsF, KF, tBuONa, Et2NH, Et3N, DABCO, 1-methylpyr-
rolidine, and 1-methylmorpholine, were less efficient
(Table 1, entries 9À20). Since phosphorus ligands always
play important roles in metal-catalyzed chemistry,7 we
then turned our attention to the screening of ligands
(Table 1, entries 21À28). We were pleased to discover
that only when the ligand changed to the bis[(2-
diphenylphosphino)phenyl] ether (DPEphos) did the yield
dramatically increase to 92% yield (Table 1, entries
21À28). Finally, we studied the solvent effect and found
that THF was superior to CH3NO2, 1,4-dioxane, xylene,
DMF, CH3CN, toluene, and sulfolane (Table 1, entries
28À35). In addition, the reaction failed to give the desired
product when the procedure was carried out under a N2
atmosphere. Therefore, the optimized conditions were de-
fined as follows: under an O2 atmosphere, Pd2(dba)3 (5 mol
%) as the catalyst, DPEphos (10 mol %) as the ligand, and
1-methylpiperidine (3 equiv) as the base in THF at 60 °C.
Having the optimized reaction conditions in hand, we
next investigated the scope and generality of the coupling
reaction using various arylboronic acids and isatoic anhy-
drides (Table 2). Initially, a variety of arylboronic acids
2bÀ2u were examined by the reaction with isatoic anhy-
dride 1a (Table 2, entries 1À21). The results demonstrated
that the optimal conditions were general for arylboronic
acids and were compatible with many functional groups,
including methyl, methoxy, fluoro, chloro, bromo, forma-
cyl, acetyl, nitro, cyano, trifluoromethyl, naphthyl, and
thienyl substituents on the phenyl moiety. For example,
arylboronic acids 2bÀ2h, with a methyl or methoxy group,
smoothly underwent the reaction in excellent yields,
although the o-methoxy substituents on the phenyl ring
decreased the substrate activity (Table 2, entries 1À8).
The electronic properties of the groups on the phenyl
ring of arylboronic acids had some effect on the reaction.
Generally, the arylboronic acids possessing electron-do-
nating groups produce the corresponding aryl o-amino-
benzoates 3ab, 3ad, 3ae, and 3ag with higher yields
a Unless otherwise noted, the reaction conditions were as follows: 1a
(0.4 mmol), 2a (1.2 mmol), indicated Pd source (5 mol %), ligand (10 mol
%), base (1.2 mmol), dry solvent (2.5 mL), 60 °C, 24 h, O2. b Isolated
yield. c 2-Amino-N,N-diethylbenzamide was obtained in 72% yield.
(Table 2, entries 2, 4, 5, and 7). Electron-withdrawing
arylboronic acids, which are less nucleophilic, and hence
transmetalate more slowly than their electron-neutral ana-
logues, are prone to homocoupling and protodeborona-
tion side reactions.8 However, in our catalytic system,
p-(trifluoromethyl)phenylboronic acid 2i, m-nitrophenyl-
boronic acid 2j, and p-cyanophenylboronic acid 2k reacted
with 1a to afford the respective compounds 3ai, 3aj, and
3ak in moderate to good yields (Table 2, entries 9À11).
Notably, the fluoro, chloro, and bromo moieties
(commonly used for cross-coupling reactions) in arylboro-
nic acids 2lÀ2o were all tolerated and afforded a novel
route to compounds 3al, 3am, 3an, and 3ao in good yields,
(7) (a) Tolman, C. A. Chem. Rev. 1977, 77, 313. (a) Braga, A. A. C.;
Morgon, N. H.; Ujaque, G.; Liedos, A.; Maseras, F. J. Organomet.
Chem. 2006, 691, 4459. (b) Braga, A. A. C.; Morgon, N. H.; Ujaque, G.;
Maseras, F. J. Am. Chem. Soc. 2005, 127, 9298. (c) Littke, A. F.; Fu,
G. C. Angew. Chem., Int. Ed. 2002, 41, 4176. (d) Eichenseher, S.;
Delacroix, O.; Kromm, K.; Hampel, F.; Gladysz, J. A. Organometallics
2005, 24, 245.
(8) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J.
Am. Chem. Soc. 2005, 127, 4685.
Org. Lett., Vol. 13, No. 22, 2011
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making further elaborations of the corresponding biaryl
products possible (Table 2, entries 12À15). Moreover,
substrates 2p and 2q, possessing the active formacyl or
acetyl group, were tolerated well (Table 2, entries 16 and 17).
It is noteworthy that biarylboronic acids such as 4-phe-
nylphenylboronic acid 2r, 1-naphthylboronic acid 2s, and
2-naphthylboronic acid2talsogavethe corresponding 3ar,
3as, and 3at in 99%, 86%, and 84% yields, respectively
(Table 2, entries 18À20). Although the heteroatoms in the
heteroarylboronic acids may coordinate to palladium, 2u
was still a good partner for the coupling reaction, and the
corresponding coupling product 3au was isolated in 85%
yield (Table 2, entry 21).
Table 2. Scope of Arylboronic Acids and Isatoic Anhydrides in
the Pd-Catalyzed Coupling Reactiona
Next, the decarboxylative coupling reactions of phenyl-
boronic acids with several benzo-substituted isatoic anhy-
drides were investigated. As expected, the groups on the
phenyl ring of isatoic anhydrides, such as methyl, chloro,
nitro, and fluoro, were quite compatible under the opti-
mized reaction conditions. Benzo-substituted isatoic anhy-
drides possessing electron-donating (1bÀ1c) and electron-
withdrawing (1dÀ1g) groups on the phenyl ring provided
the corresponding aryl o-aminobenzoates in good yields
(Table 2, entries 22À29). However, benzo-substituted
isatoic anhydride containing a strong electron-withdraw-
ing group (;NO2) on the benzene ring, such as 5-nitroi-
satoic anhydride (1h), achieved the corresponding desired
products 3ha and 3hb in slightly lower yields (Table 2,
entries 30À31). N-Methylisatoic anhydride 1e delivered
the corresponding 3ea and 3eb in relatively low yields
(Table 2, entries 32À33).
Finally, treatment of an alkylboronic acid such as
methylboronic acid 2v or cyclopropylboronic acid 2w with
1a under the optimized conditions afforded the desired
product 3av and 3aw in 37% and 33% yields, respectively
(Scheme 1).
Scheme 1. Reaction of Alkylboronic Acid with Isatoic
Anhydride
To elucidate the mechanism of this coupling reaction,
the following control experiments were performed under
our standard conditions as shown in Scheme 2. According
to relevant reports in the literature9 and our recent
report,10 we initially thought that the oxygen atom of
3aa might be derived from water present in the solvent
a Unless otherwise noted, the reactions conditions were as follows:
isatoic anhydride 1 (0.4 mmol), arylboronic acid 2 (1.2 mmol), Pd2(dba)3
(5 mol %), DPEphos (10 mol %), 1-methylpiperidine (1.2 mmol), dry
THF (2.5 mL), 60 °C, 24 h, O2. b Isolated yield.
(9) (a) Simon, J.; Salzbrunn, S.; Prakash, G. K. S.; Petasis, N. A.;
Olah, G. A. J. Org. Chem. 2001, 66, 633. (b) Xu, J.; Wang, X.; Shao, C.;
Su, D.; Cheng, G.; Hu, Y. Org. Lett. 2010, 12, 1964.
(10) Zheng, X. W.; Ding, J. C.; Chen, J. X.; Gao, W. X.; Liu, M. C.;
Wu, H. Y. Org. Lett. 2011, 13, 1726.
and in the ambient environment. Therefore, we carried out
the reaction of isatoic anhydride 1a with phenylboronic
6116
Org. Lett., Vol. 13, No. 22, 2011

Scheme 2. Isotope Labeling Studies
Scheme 3. Plausible Mechanism
acid 2a in the presence of 18OH2 in dry THF under our
standard conditions [eq 1]. However, 3aa was obtained in
87% yield, and no 3aa-18O was detected. To understand
the mechanism more clearly, labeling studies were con-
ducted using 18O2 [eq 2]. Surprisingly, the reaction pro-
ceeded smoothly under an 18O2 atmosphere to provide the
aryl o-aminobenzoate product 3aa-18O containing 18O in
91% yield. The 18O-atom-containing product 3aa-18O was
determined by GC/MS and HRMS (ESI) analysis. This
result confirmed that dioxygen took part in this reaction
and was essential for the transformation. Finally, the
reaction of 2-aminobenzoic acid11 withphenylboronic acid
2a failed to deliver the desired product 3aa.
We therefore propose a plausible formation mechanism
of aryl o-aminobenzoate derivatives (Scheme 3) based on
the results above and relevant reports in the literature.12À14
It is known that the reaction of [Pd2(dba)3] with oxygen
affords the reactive palladiumÀperoxo species [(η2-O2)PdL2]
complex Ain the presence of ligand.13 Jutand, Amatore and co-
workers investigated the transmetalation between the [(η2-O2)
PdL2] complex A and ArB(OH)2, and a fast reaction gener-
ated the trans-[ArPd(OH)L2] complex B.14 Next, decarbox-
ylation and transmetalation of trans-[ArPd(OH)L2] complex
B in the presence of isatoic anhydride 1 would result in the
liberation of carbon dioxide and the formation of the corre-
sponding Pd(II) intermediate C, which undergoes reductive
elimination to give the desired product 3 and regenerates the
starting Pd(0).
In summary, an unprecedented palladium-catalyzed
decarboxylative coupling of isatoic anhydrides with aryl-
boronic acids was developed. The present method affords
only the o-amino benzoate derivatives as products; how-
ever, these compounds, as anthranilic acid derivatives, are
important structural motifs in natural products, and this
new process provides a straightforward method to access
these compounds. Preliminary mechanistic experiments
using deuterium labeling showed that dioxygen took part
in this reaction and was essential for the transformation.
Further efforts to expand the scope of the chemistry and
studies of the detailed mechanism are currently underway
in our laboratories.
Acknowledgment. We thank the National Natural
Science Foundation of China (Nos. 21102105 and 21072153)
for financial support.
(11) Isatoic anhydride was converted presumably to 2-aminobenzoic
acid in the presence of water, please see: Chiu, S.-J.; Chou, C.-H.
Tetrahedron Lett. 1999, 40, 9271.
(12) Liu, Q.; Li, G.; He, J.; Liu, J.; Li, P.; Lei, A. Angew. Chem., Int.
Ed. 2010, 49, 3371.
(13) Stahl, S. S.; Thorman, J. L.; Nelson, R. C.; Kozee, M. A. J. Am.
Chem. Soc. 2001, 123, 7188.
(14) Adamo, C.; Amatore, C.; Ciofini, I.; Jutand, A.; Lakmini, H.
Supporting Information Available. Experimental pro-
cedures along with copies of spectra.Thismaterialisavailable
free of charge via the Internet at http://pubs.acs.org.
J. Am. Chem. Soc. 2006, 128, 6829 and references cited therein.
Org. Lett., Vol. 13, No. 22, 2011
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