Palladium-catalyzed regioselective carbonylation of C-H bonds of N -alkyl anilines for synthesis of isatoic anhydrides

Article abstract of DOI:10.1021/ja308976x

A Pd-catalyzed regioselective C-H bond carbonylation of N-alkyl anilines for the synthesis of isatoic anhydrides has been developed. The key Pd-catalyst intermediate has been isolated and characterized. This novel Pd-catalyzed carbonylation reaction tolerates a wide range of functional groups and is a reliable method for the rapid elaboration of readily available N-alkyl anilines into a variety of substituted isatoic anhydrides under mild conditions.

Full text of DOI:10.1021/ja308976x

Communication
pubs.acs.org/JACS
Palladium-Catalyzed Regioselective Carbonylation of C−H Bonds of
N‑Alkyl Anilines for Synthesis of Isatoic Anhydrides
Zheng-Hui Guan,* Ming Chen, and Zhi-Hui Ren
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry &
Materials Science, Northwest University, Xi’an 710069, P. R. China
S
* Supporting Information
anhydride 2a, in 4% and 5% yields respectively, with 72%
recovery of N,N-dimethylaniline (eq 1). Importantly, the
ABSTRACT: A Pd-catalyzed regioselective C−H bond
carbonylation of N-alkyl anilines for the synthesis of isatoic
anhydrides has been developed. The key Pd-catalyst
intermediate has been isolated and characterized. This
novel Pd-catalyzed carbonylation reaction tolerates a wide
range of functional groups and is a reliable method for the
rapid elaboration of readily available N-alkyl anilines into a
variety of substituted isatoic anhydrides under mild
conditions.
carbonylation of the C−H bond of aniline was observed in
both products. Isatoic anhydrides are valuable chemicals and
versatile building blocks.21 Present methods for the synthesis of
isatoic anhydrides involve cyclization of anthranilic acid by highly
toxic chloroformate or triphosgene.22 The C−H carbonylation of
anilines for the synthesis of isastoic anhydrides would be an ideal
and environmentally friendly approach.
arbonylation reactions with CO have been and continue to
1
Cbe a very active area of research. Since the pioneering work
of Heck in 1974,2 carbonylations of aryl halides and
pseudohalides with CO have become one of the most common
methods for the addition of a carbonyl group to organic
molecules.3 In recent decades, much progress has been made in
C−H bond activation and functionalization.4 However, C−H
carbonylation has remained largely undeveloped.5 A break-
through in this area was made with the Pd-catalyzed carbon-
ylation of aromatic C−H bonds by Fujiwara et al., but the
reaction lacks regioselectivity and requires a large excess of the
arene as solvent.6
Since demethylation is required for N,N-dimethylaniline,23 we
moved to N-methylaniline. The yield of N-methyl isatoic
anhydride 2a improved dramatically to 40% (Table 1 entry 1).
Screening various oxidants, such as AgOAc, CuCl2, BQ, and
Oxone, revealed Cu(OAc)2 to be the most effective for the
Table 1. Optimization of Conditions for the Pd-Catalyzed
a
Carbonylation of N-Methyl Aniline
Recently, transition-metal-catalyzed chelation-assisted carbon-
ylation of C−H bonds for the synthesis of ketones, acids, amides,
and esters has been developed by Murai,7 Yu,8 Chatani,9 Orito,10
Lloyd-Jones and Booker-Milburn,11 our,12 and other
groups.13−19 Despite these advances, there is no efficient
protocol for C−H bond carbonylation to synthesize anhydrides
directly.8a As a class of powerful building blocks in organic
chemistry, the synthesis of anhydrides by C−H bond carbon-
ylation is high desirable.
Directing groups which could assist the ortho electrophilic
metalation of C−H bond are important in C−H bond
carbonylations.20 A small number of functional groups, such as
carboxy, amide, urea, pyridin-2-ylmethylamine, and azahetero-
cycles, have been explored for direct C−H bond carbonylation.
The search for new directing groups which are synthetically
versatile is still a challenging task. We have found that
synthetically versatile secondary anilines can be used for ortho
C−H bond carbonylation. Here, we report a Pd-catalyzed N-
alkyl amino directed carbonylation of C−H bonds for the
synthesis of isatoic anhydrides.
b
entry
additive
solvent
MeCN
T (°C)
yield (%)
1
100
100
100
100
100
100
100
100
100
60
40
71
76
60
80
68
65
20
37
85
68
2
NaI
Bu4NI
I2
MeCN
MeCN
MeCN
MeCN
DMSO
DMF
3
4
5
KI
6
KI
7
KI
8
KI
toluene
1,4-dioxane
MeCN
MeCN
9
KI
10
KI
c
11
KI
60
a
Reaction conditions: 1a (0.2 mmol), Pd(OAc)2 (5 mol %), oxidant
(2.2 equiv), MI (0.2 equiv), CO (1 atm), solvent (2 mL). Isolated
b
c
yield. Cu(OAc)2 (0.5 equiv), CO/O2 (5:1) 1 atm.
We began our study with the Pd-catalyzed carbonylation of
anilines using N,N-dimethylamino as the directing group. The
carbonylation product 2′ was formed along with isatoic
Received: September 10, 2012
Published: October 10, 2012
© 2012 American Chemical Society
17490
dx.doi.org/10.1021/ja308976x | J. Am. Chem. Soc. 2012, 134, 17490−17493

Journal of the American Chemical Society
Communication
a
Table 2. Scope of Pd-Catalyzed Carbonylation of N-Methyl Anilines for the Synthesis of Isatoic Anhydrides
a
Reaction conditions: aniline 1 (0.2 mmol), Pd(OAc)2 (5 mol %), Cu(OAc)2 (2.2 equiv), KI (0.2 equiv), CH3CN (2 mL), CO (1 atm), 60 °C.
Isolated yields. At room temperature. Pivalic acid (1.0 equiv) was added. CO/O2 (2:1) (3 atm).
b
c
d
e
transformation (see Supporting Information (SI), Table S1). To
further improve the reaction outcome, iodide compounds which
have been shown to improve the efficiency of Pd-catalyzed
carbonylations were also screened (Table 1, entries 2−5).12b,24
KI was found to be the most effective and gave the desired
product 2a in 80% yield (Table 1, entry 5).25 Other solvents such
as DMSO, DMF, toluene, and 1,4-dioxane are inferior to
CH3CN in the reaction (Table 1, entries 6−9). Finally, the
reaction temperature was also varied, and 60 °C gave the best
yield (see SI Table S1). It should be noted that the isatoic
anhydride 2a could also be obtained in 68% yield using only a
catalytic amount of Cu(OAc)2 (50 mol %) under 1 atm of CO/
O2 (5:1) (Table 1, entry 11).
With the optimized reaction conditions established, the scope
of the reaction was investigated (Table 2). This new carbon-
ylation reaction displayed high functional group tolerance and
proved to be a quite general methodology. Anilines with methyl,
methoxyl, fluoro, and sensitive functional groups such as chloro,
bromo, and formyl (aldehyde) and strong electron-withdrawing
groups such as nitro, acetyl, and ester groups all gave the
corresponding substituted isatoic anhydrides in good to high
yields. Generally, the electron-rich substrates showed more
reactivity, which is consistent with an electrophilic palladation
mechanism.8,11 Dimethyl, methoxyl, or dimethoxyl substituted
anilines were converted to corresponding isatoic anhydrides in
good yields at rt (Table 1, entries 4−6). When pivalic acid was
used as an additive, isatoic anhydrides bearing electron-
withdrawing groups were afforded in high yields under 3 atm
of CO/O2 (2:1) (Table 1, entries 7−14). The steric effect was
observed in the transformation. Ortho-substituted anilines gave
low yields of the corresponding isatoic anhydrides.8b,11a But the
steric effect improves the regioselectivity of the carbonylation of
meta-substituted anilines, in which case only less sterically
hindered products were obtained (Table 2, entries 3−4, 6, 10−
11). Similarly, the isatoic anhydride 2o from the carbonylation of
2-naphthylamine 1o was observed as the only product in 68%
yield (Table 1, entry 15). Although the indoline 1p was inert to
the transformation, the carbonylation of tetrahydroquinoline 1q
proceeded smoothly to give the tricyclic isatoic anhydride in 75%
yield (Table 1, entries 16−17).
Furthermore, different alkyl substituents on the anilines were
also investigated (Table 3). N-Ethyl, propyl, or cyclohexyl
17491
dx.doi.org/10.1021/ja308976x | J. Am. Chem. Soc. 2012, 134, 17490−17493

Journal of the American Chemical Society
Communication
a
conducted under a CO atmosphere in the absence of Cu(OAc)2
(Scheme 2). A palladium complex whose structure is consistent
Table 3. Pd-Catalyzed Carbonylation of N-Alkyl Anilines
Scheme 2. Formation and Characterization of Palladium
Intermediate
a
with A by 1H NMR and mass spectrometry analysis was obtained
in 60% yield.26 This complex is poorly soluble in common
organic solvents. To confirm the structure of the palladium
complex A, it was converted to the more soluble PPh3
coordinated palladium complexes B and C. The structures of B
and C were then characterized by X-ray crystallography, thus
confirming A is a CO coordinated palladium hydroxide
dimer.26,27 Treating the palladium dimer A with Cu(OAc)2
(2.2 equiv) in the presence of KI (1.0 equiv) in CH3CN under
a CO atmosphere gave the isatoic anhydride 2a in 78% yield.
Therefore, the palladium dimer A should be a key intermediate in
the reaction.
Reaction conditions: aniline 1 (0.2 mmol), Pd(OAc)2 (5 mol %),
Cu(OAc)2 (2.2 equiv), KI (0.2 equiv), CH3CN (2 mL), CO (1 atm),
60 °C. Isolated yields.
b
substituted anilines could be used and provided the correspond-
ing carbonylation products in moderate to good yields (Table 3,
entries 1−3). Even N-benzylaniline 1u gave the isatoic anhydride
2u as the product in 72% yield (eq 2).
Therefore, a tentative mechanism for this carbonylation is
proposed in Scheme 3. Electrophilic palladation of the C−H
Scheme 3. Tentative Mechanism of the Reaction
To demonstrate the synthetic utility of this reaction, the isatoic
anhydride 2a which was synthesized by catalytic amounts of
Pd(OAc)2/Cu(OAc)2 under a CO/O2 atmosphere was easily
transformed into N-methylanthranilic acid 3, ethyl 2-
(methylamino)benzoate 4, or 2-(methylamino)benzamide 5 in
high yields (Scheme 1).
To gain insight into the mechanism of the reaction, a
stoichiometric reaction of Pd(OAc)2 with N-methylaniline was
Scheme 1. Subsequent Decarboxylative Transformations
bond of N-methyl aniline 1 by Pd(OAc)2 under a CO
atmosphere forms a dimeric palladium intermediate A. Insertion
of CO to intermediate A followed by a reductive elimination
reaction gives N-methylanthranilic acid C28 and Pd(0). Pd(0)
was assumed to be oxidized by Cu(OAc)2 to generate the
Pd(OAc)2 catalyst. Then, metathesis of N-methylanthranilic acid
C and Pd(OAc)2 produces the intermediate D. Coordination
17492
dx.doi.org/10.1021/ja308976x | J. Am. Chem. Soc. 2012, 134, 17490−17493

Journal of the American Chemical Society
Communication
(8) (a) Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14082. (b) Giri,
R.; Lam, J. K.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 686. (c) Yoo, E. J.;
Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 17378. (d) Lu, Y.; Leow,
D.; Wang, X.; Engle, K. M.; Yu, J.-Q. Chem. Sci. 2011, 2, 967.
(9) (a) Inoue, S.; Shiota, H.; Fukumoto, Y.; Chatani, N. J. Am. Chem.
Soc. 2009, 131, 6898. (b) Hasegawa, N.; Charra, V.; Inoue, S.;
Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc. 2011, 133, 8070.
(c) Chatani, N.; Yorimitsu, S.; Asaumi, T.; Kakiuchi, F.; Murai, S. J. Org.
Chem. 2002, 67, 7557. (d) Asaumi, T.; Matsuo, T.; Fukuyama, T.; Ie, Y.;
Kakiuchi, F.; Chatani, N. J. Org. Chem. 2004, 69, 4433.
and insertion of CO to D affords intermediate E. Nucleophilic
attack of the amino group on the acylpalladium moiety gives the
isatoic anhydride 2 and Pd(0).8d,14 Finally, Pd(0) was reoxidized
by Cu(OAc)2 to regenerate the Pd(OAc)2 catalyst.
In summary, we have developed a novel palladium-catalyzed
C−H bond carbonylation of N-alkyl anilines for the synthesis of
isatoic anhydrides. The mechanism was investigated, and a key
intermediate was isolated and characterized. This novel
palladium-catalyzed carbonylation reaction tolerates a wide
range of functional groups and is a reliable method for the
rapid elaboration of readily available N-alkyl anilines into a
variety of substituted isatoic anhydrides under mild conditions.
Further scope and mechanistic studies of the reaction are
underway in our laboratory and will be reported in due course.
(10) Orito, K.; Horibata, A.; Nakamura, T.; Ushito, H.; Nagasaki, H.;
Yuguchi, M.; Yamashita, S.; Tokuda, M. J. Am. Chem. Soc. 2004, 126,
14342.
(11) (a) 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. (b) Wrigglesworth, J. W.; Cox, B.; Lloyd-
Jones, G. C.; Booker-Milburn, K. I. Org. Lett. 2011, 13, 5326.
(12) (a) Guan, Z.-H.; Ren, Z.-H.; Spinella, S. M.; Yu, S.; Liang, Y.-M.;
Zhang, X. J. Am. Chem. Soc. 2009, 131, 729. (b) Guan, Z.-H.; Lei, H.;
Chen, M.; Ren, Z.-H.; Bai, Y.; Wang, Y.-Y. Adv. Synth. Catal. 2012, 354,
489.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures; mechanistic studies; X-ray structures
of 2a, B, C; and spectral data for all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(13) Li, H.; Cai, G.-X.; Shi, Z.-J. Dalton Trans. 2010, 39, 10442.
(14) (a) Haffemayer, B.; Gulias, M.; Gaunt, M. J. Chem. Sci. 2011, 2,
́
312. (b) Lopez, B.; Rodriguez, A.; Santos, D.; Albert, J.; Ariza, X.; Garcia,
AUTHOR INFORMATION
Corresponding Author
guanzhh@nwu.edu.cn
Notes
■
J.; Granell, J. Chem. Commun. 2011, 47, 1054.
(15) Du, Y.; Hyster, T. K.; Rovis, T. Chem. Commun. 2011, 47, 12074.
(16) Wu, X.-F.; Anbarasan, P.; Neumann, H.; Beller, M. Angew. Chem.,
Int. Ed. 2010, 49, 7316.
(17) (a) Zhang, H.; Liu, D.; Chen, C.; Liu, C.; Lei, A. Chem.Eur. J.
2011, 17, 9581. (b) Zhang, H.; Shi, R.; Gan, P.; Liu, C.; Ding, A.; Wang,
Q.; Lei, A. Angew. Chem., Int. Ed. 2012, 51, 5204.
(18) (a) Lang, R.; Wu, J.; Shi, L.; Xia, C.; Li, F. Chem. Commun. 2011,
47, 12553. (b) Lang, R.; Shi, L.; Li, D.; Xia, C.; Li, F. Org. Lett. 2012, 14,
4130.
(19) (a) Chen, H.; Cai, C.; Liu, X.; Li, X.; Jiang, H. Chem. Commun.
2011, 47, 12224. (b) Xie, P.; Xie, Y.; Qian, B.; Zhou, H.; Xia, C.; Huang,
H. J. Am. Chem. Soc. 2012, 134, 9902.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(NSFC-21272183, 21002077) and Fund of New Scientific Stars
of Shanxi Province (2012KJXX-26) for financial support. We also
thank Prof. Biao Wu, Huai-Ming Hu (NWU) and Dr. Yongliang
Shao (LZU) for X-ray crystallographic assistance.
(20) (a) Dupont, J.; Consorti, C. S.; Spenser, J. Chem. Rev. 2005, 105,
2527. (b) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc.
̈
REFERENCES
■
Rev. 2011, 40, 4740. (c) Ackermann, L. Chem. Rev. 2011, 111, 1315.
(d) Bosque, R.; Maseras, F. Eur. J. Inorg. Chem. 2005, 4040.
(21) (a) D’Souza, A. M.; Spiccia, N.; Basutto, J.; Jokisz, P.; Wong, L. S.-
M.; Meyer, A. G.; Holmes, A. B.; White, J. M.; Ryan, J. H. Org. Lett. 2011,
13, 486. (b) Beutner, G. L.; Kuethe, J. T.; Yasuda, N. J. Org. Chem. 2007,
72, 7058. (c) Coppola, G. M.; Hardtmann, G. E.; Pfister, O. R. J. Org.
Chem. 1976, 41, 825. (d) Lu, W.; Chen, J.; Liu, M.; Ding, J.; Gao, W.;
Wu, H. Org. Lett. 2011, 13, 6114.
(1) (a) Wu, X.-F.; Neumann, H.; Beller, M. Chem. Soc. Rev. 2011, 40,
4986. (b) Liu, Q.; Zhang, H.; Lei, A. Angew. Chem., Int. Ed. 2011, 50,
10788. (c) Brennfuhrer, A.; Neumann, H.; Beller, M. Angew. Chem., Int.
̈
Ed. 2009, 48, 4114. (d) Barnard, C. F. J. Organometallics 2008, 27, 5402.
(2) (a) Schoenberg, A.; Bartoleti, I.; Heck, R. F. J. Org. Chem. 1974, 39,
3318. (b) Schoenberg, A.; Heck, R. F. J. Org. Chem. 1974, 39, 3327.
(c) Schoenberg, A.; Heck, R. F. J. Am. Chem. Soc. 1974, 96, 7761.
(3) (a) Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E.-i., Meijere, de A., Eds.; Wiley: New York, 2002; Vol. 2, p
2309. (b) Transition Metals for Organic Synthesis, 2nd ed.; Beller, M.,
Bolm, C., Eds.; Wiley-VCH: Weinheim, 2004. (c) Grigg, R.; Mutton, S.
P. Tetrahedron 2010, 66, 5515.
(22) Brouillette, Y.; Martinez, J.; Lisowski, V. Eur. J. Org. Chem. 2009,
3487.
(23) Mutet, C.; Pfeffer, M. J. Organomet. Chem. 1979, 171, C34.
(24) (a) Fukuoka, S.; Chono, M.; Kohno, M. J. Org. Chem. 1984, 49,
1458. (b) Valli, V. L. K.; Alper, H. Organometallics 1995, 14, 80.
(25) For KI effect on the carbonylation, see Supporting Information.
(26) Palladacycles are usually observed in dimeric, see: (a) Zhao, X.;
Yeung, C. S.; Dong, V. M. J. Am. Chem. Soc. 2010, 132, 5837. (b) Yeung,
C. S.; Zhao, X.; Borduas, N.; Dong, V. M. Chem. Sci. 2010, 1, 331.
(c) Borduas, N.; Lough, A. J.; Dong, V. M. Inorg. Chim. Acta 2011, 369,
247. (d) 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 For dinuclear ruthenium catalytic intermediate, see ref
9a, b.
(4) (a) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010,
110, 624. (b) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293.
(c) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45,
788. (d) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(e) Shilov, A. E.; Shul’pin, G. B. Chem. Rev. 1997, 97, 2879. (f) Cho, S.
H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068.
(g) Ryu, J.; Shin, K.; Park, S. H.; Kim, J. Y.; Chang, S. Angew. Chem., Int.
Ed. 2012, 51, 9904. (h) Kwak, J.; Kim, M.; Chang, S. J. Am. Chem. Soc.
2011, 133, 3780.
(5) Wu, X.-F.; Neumann, H. ChemCatChem 2012, 4, 447.
(6) (a) Fujiwara, Y.; Kawauchi, T.; Taniguchi, H. J. Chem. Soc., Chem.
Commun. 1980, 220. (b) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem.
Res. 2001, 34, 633.
(27) See Supporting Information for details.
(28) N-Methylanthranilic acid C can be converted to N-methyl isatoic
anhydride 2a in 88% yield under the standard conditions.
(7) (a) Chatani, N.; Asaumi, T.; Ikeda, T.; Yorimitsu, S.; Ishii, Y.;
Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 2000, 122, 12882. (b) Chatani,
N.; Fukuyama, T.; Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 1996, 118,
493. (c) Fukuyama, T.; Chatani, N.; Tatsumi, J.; Kakiuchi, F.; Murai, S. J.
Am. Chem. Soc. 1998, 120, 11522.
17493
dx.doi.org/10.1021/ja308976x | J. Am. Chem. Soc. 2012, 134, 17490−17493