From anilines to isatins: Oxidative palladium-catalyzed double carbonylation of C-H bonds

Article abstract of DOI:10.1002/anie.201410321

A novel palladium-catalyzed C-H double carbonylation introduces two adjacent carbonyl groups for the synthesis of isatins from readily available anilines. The reaction proceeds under atmospheric pressure of CO with high regioselectivity and without any additives. Density functional theory investigations indicate that the palladium-catalyzed double carbonylation catalytic cycle is plausible.

Full text of DOI:10.1002/anie.201410321

Angewandte
Chemie
DOI: 10.1002/anie.201410321
Heterocycle Synthesis
From Anilines to Isatins: Oxidative Palladium-Catalyzed Double
À
Carbonylation of C H Bonds**
Wu Li, Zhengli Duan, Xueye Zhang, Heng Zhang, Mengfan Wang, Ru Jiang, Hongyao Zeng,
Chao Liu, and Aiwen Lei*
À
Abstract: A novel palladium-catalyzed C H double carbon-
ylation introduces two adjacent carbonyl groups for the
synthesis of isatins from readily available anilines. The reaction
proceeds under atmospheric pressure of CO with high
regioselectivity and without any additives. Density functional
theory investigations indicate that the palladium-catalyzed
double carbonylation catalytic cycle is plausible.
Isatin (indoline-2,3-dione) is a well-known natural prod-
P
alladium-catalyzed carbonylation for the construction of
uct which is present in bioactive compounds, synthetic
intermediates, and pharmaceuticals.[4] Many isatin derivatives
exhibit a broad range of biological activities such as anti-
cancer,[5] anticonvulsant,[6] antifungal,[7] anti-HIV,[8] and anti-
inflammatory,[9] and others.[10] Although a number of methods
have been established for the construction of such structures,
the reported synthetic methods of isatins often require
substrate pre-functionalization, multiple steps, and starting
materials which are not readily available.[11] Most importantly,
most of the methods are not atom economical as only a part of
the reagent used for the introduction of carbonyl group is
retained. Given the importance of the isatin skeleton,
development of direct and economic strategies, as well as
control of the regioselectivity has attracted considerable
attention from synthetic chemists.
carbonyl compounds has received considerable attention in
recent years.[1] In contrast to the well-known palladium-
catalyzed process of introducing one carbonyl group into
organic compounds, palladium-catalyzed double carbonyla-
tion as a powerful tool for the preparation of organic
compounds with two adjacent carbonyl groups, has remained
largely undeveloped. In fact, palladium-catalyzed double
carbonylation is limited to the use of aromatic halides or vinyl
halides.[2] In comparison, the direct utilization of aromatic
À
C H bonds in double carbonylation would be more appeal-
ing. Thus far, no direct oxidative double carbonylation of
À
C H bonds for introducing two adjacent carbonyl groups in
the synthesis of heterocyclic compounds has been devel-
oped.[3] Herein, we report a palladium-catalyzed double
À
carbonylation of a C H bond ortho to an amino group and
it involves the use of commercially available anilines for the
synthesis of isatins [Eq. (1)].
Our initial efforts focused on the double carbonylation of
N-methyl-4-methylaniline (1a; Table 1). We were pleased to
observe the desired product under the combined reaction
Table 1: Reaction optimization for the palladium-catalyzed double
carbonylation of N-methyl-4-methylaniline.[a]
[*] W. Li, Z. Duan, X. Zhang, H. Zhang, M. Wang, R. Jiang, Dr. C. Liu,
Prof. A. Lei
College of Chemistry and Molecular Sciences
Wuhan University, Wuhan 430072, Hubei (P.R. China)
E-mail: aiwenlei@whu.edu.cn
Homepage: http://aiwenlei.whu.edu.cn/Main_Website/
Prof. A. Lei
Entry Catalyst
Oxidant
Solvent
Yield [%][b]
State Key Laboratory for Oxo Synthesis and Selective Oxidation,
Lanzhou Institute of Chemical Physics
Chinese Academy of Sciences, 730000, Lanzhou (P.R. China)
1
2
3
4
5
6
7
8
9
[PdCl2(PPh3)2]
Cu(OPiv)2
Cu(OPiv)2
Cu(OPiv)2
Cu(OPiv)2
DMSO
toluene
DMF
54
trace
trace
[PdCl2(PPh3)2]
[PdCl2(PPh3)2]
[PdCl2(PPh3)2]
[PdCl2(MeCN)2] Cu(OPiv)2
Pd(OAc)2
[PdCl2(PPh3)2]
[PdCl2(PPh3)2]
[PdCl2(PPh3)2]
Dr. H. Zeng
DMSO/tol (1:1) 70 (70)[c]
DMSO/tol (1:1) 21
DMSO/tol (1:1) 16
College of Chemistry, Leshan Normal University
Leshan, Sichuan, 614000 (P.R. China)
Cu(OPiv)2
[**] This work was supported by the 973 Program (2011CB808600,
2012CB725302), the National Natural Science Foundation of China
(21390400, 21025206, 21272180 and 21302148), the Research Fund
for the Doctoral Program of Higher Education of China
Cu(OPiv)2/O2 DMSO/tol (1:1) trace[d]
O2
Cu(OAc)2
DMSO/tol (1:1) trace
DMSO/tol (1:1) 41
(20120141130002), and the Program for Changjiang Scholars and
Innovative Research Team in University (IRT1030). The support of
the Program of Introducing Talents of Discipline to Universities of
China (111Program) is also appreciated.
[a] Reaction conditions: 1a (0.20 mmol), catalyst (0.01 mmol), oxidant
(0.40 mmol), and solvent (1.0 mL) under 1 atm CO at 1008C for 24 h.
[b] Determined by NMR spectroscopy using CH2Br2 as an internal
standard. [c] Yield of isolated product. [d] 0.04 mmol Cu(OPiv)2 was
employed. DMF=N,N-dimethylformamide, DMSO=dimethyl sulfox-
ide, OPiv=trimethylacetate, tol=toluene.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201410321.
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conditions of [PdCl2(PPh3)2] and Cu(OPiv)2 in DMSO at
1008C under 1 atm CO (entry 1). Under these reaction
conditions, a 54% yield (determined by NMR spectroscopy)
of 2a was obtained in 24 hours. Only trace amounts of product
was obtained while using DMF or toluene as the solvent
(entries 2 and 3). Further optimization of the reaction
conditions showed that the reaction was most productive
when a mixed solvent of DMSO/toluene (1:1) was used
(entry 4). The use of other palladium(II) pre-catalysts, such as
[PdCl2(MeCN)2] and Pd(OAc)2 resulted in much lower yields
(entries 5 and 6). Only trace amounts of the desired product
was detected when decreasing the loading of Cu(OPiv)2 to
a catalytic amount and using O2 as the terminal oxidant
(entry 7), and no product was detected when using O2 as the
sole oxidant (entry 8). This outcome may arise because
anilines are easily decomposed under aerobic conditions at
high temperature. It should be noted that Cu(OAc)2 was less
effective for this reaction compared with Cu(OPiv)2 (entry 9).
Actually, under the reaction conditions used in entry 9 of
Table 1 the N-acetylation of aniline was detected through
GC-MS and the acetyl group was believed to be generated
from Cu(OAc)2. The acylation of substrate was completely
inhibited when Cu(OPiv)2 was used as the oxidant. Further-
more, the solubility of Cu(OPiv)2 is better compared to that of
Cu(OAc)2 in organic solvents, and could be considered as
another promotion to the reaction.
With the optimized reaction conditions in hand, the
substrate scope was studied (Scheme 1). The isatin 2b was
obtained in 62% yield by direct double carbonylation under
the optimized reaction conditions. The sole product 2c was
produced in moderate yield by reaction at the less hindered
ortho position of N-methyl-3-methyl aniline. The reaction of
an N-methyl aniline bearing either a tert-butyl or phenyl
group proceeded well to give the corresponding products 2d
and 2e with high yields. 3,5-Dimethyl-substituted N-methyl
aniline smoothly led to 2 f in 68% yield. 3,4-Dimethyl-
substituted N-methyl aniline was converted into the corre-
sponding isatin in good yields (2g). Substituents such as
chloro and fluoro were well tolerated, and the corresponding
products could be isolated successfully (2h–j). Furthermore,
various kinds of N-alkyl substituents such as ethyl, n-hexyl,
and isobutyl were also investigated and provided the desired
products in moderate to good yields (2k–m). Cyclopropyl and
allyl groups were also well tolerated (2n,o). In addition,
tetrahydroquinoline proceeded smoothly to give the double
carbonylation product 2p in 38% yield.
Scheme 1. Palladium-catalyzed oxidative double carbonylation of
N-alkyl anilines for the synthesis of isatins. Reaction conditions:
1 (0.20 mmol), [PdCl2(PPh3)2] (0.01 mmol), Cu(OPiv)2 (0.40 mmol),
and DMSO/toluene (0.5 mL/0.5 mL) under 1 atm CO at 1008C for
24 h. Yields are those of isolated and purified products.
To further demonstrate the utility of this method for
organic synthesis and to confirm its efficiency in the complex
molecules preparation, we explored strategies for the prep-
aration of drug-type derivatives. N-Benzyl isatins can be
successfully achieved under basic conditions using alkyl
chlorides and bromides. Although conventional heating is
used to generate N-benzyl products, the base lability of the
isatin nucleus and use of starting materials which are not
readily available would be considered a limitation of such
protocols. We were pleased to find that the desired N-benzyl
isatins could be successfully obtained with highly chemo-
selectivity and good yields under our reaction conditions (2q–
u; Scheme 2). Not surprisingly, the expected double carbon-
Scheme 2. Palladium-catalyzed oxidative double carbonylation for the
synthesis of isatins. Reaction conditions: 1 (0.20 mmol), [PdCl2(PPh3)2]
(0.01 mmol), Cu(OPiv)2 (0.40 mmol), and DMSO/toluene (0.5 mL/
0.5 mL) under 1 atm CO at 1008C for 24 h. Yields are those of isolated
and purified products. [a] Pivalic acid (2.0 equiv) was added.
2
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ylation products N-phenylpropyl, N-phenoxypropyl, and
N-naphthalen-2-ylmethyl isatins (2v–x) were obtained
smoothly in high yields.
N-Benzylated isatin oximes have gained much attention in
the pharmaceutical industry because of their inhibitory effects
of the mitogen-activated kinase JNK3.[12] The N-benzyl isatins
were further transformed into the target inhibitory active
N-benzyl isatin oximes in excellent yields (Scheme 3).[13]
membered cyclic carbamoyl intermediate (D), which is
followed by a reductive elimination reaction to give the
product 2. Finally, the Pd0 species is reoxidized to the PdII
catalyst in the presence of Cu(OPiv)2. Finally, density func-
tional theory investigations have elucidated the mechanism of
À
À
the direct oxidative palladium-catalyzed C H/N H double
carbonylation (see the Supporting Information). Density
functional theory results indicate that the double carbon-
ylation catalytic cycle in the Scheme 4 is favorable.
In conclusion, we have developed the first direct oxidative
À
À
palladium-catalyzed C H/N H double carbonylation which
introduces adjacent carbonyl groups for the direct synthesis of
isatins. This transformation offers a general process for
converting readily available substrates into potentially
useful compounds. Density functional theory investigations
indicate that the palladium-catalyzed double carbonylation of
À
C H is favorable. Studies into the substrate scope and
mechanism are ongoing in our laboratory and will be reported
in the near future. Hopefully, these studies will inspire the
development of oxidative double carbonylation for the
synthesis of various heterocycles.
Scheme 3. Preparation of N-benzyl isatin oximes.
Notably, this reaction could be run on gram scale, and the
desired product 2a was obtained in 67% yield by using
3 mol% [PdCl2(PPh3)2] [Eq. (2)], thus demonstrating the
scalability of this reaction.
Received: October 21, 2014
Revised: November 26, 2014
Published online: && &&, &&&&
À
Keywords: C H activation · carbonylation · heterocycles ·
oxidation · palladium
.
[1] a) K. Orito, A. Horibata, T. Nakamura, H. Ushito, H. Nagasaki,
M. Yuguchi, S. Yamashita, M. Tokuda, J. Am. Chem. Soc. 2004,
126, 14342 – 14343; b) B. Gabriele, G. Salerno, M. Costa, Top.
Organomet. Chem. 2006, 18, 239 – 272; c) E. M. Beccalli, G.
Broggini, M. Martinelli, S. Sottocornola, Chem. Rev. 2007, 107,
5318 – 5365; d) S. Zheng, X. Peng, J. Liu, W. Sun, C. Xia, Helv.
Chim. Acta 2007, 90, 1471 – 1476; e) S.-Z. Zheng, X.-G. Peng, J.-
M. Liu, W. Sun, C.-G. Xia, Chin. J. Chem. 2007, 25, 1065 – 1068;
f) A. Brennfꢀhrer, H. Neumann, M. Beller, Angew. Chem. Int.
Ed. 2009, 48, 4114 – 4133; Angew. Chem. 2009, 121, 4176 – 4196;
g) C. E. Houlden, M. Hutchby, C. D. Bailey, J. G. Ford, S. N.
Tyler, M. R. Gagne, G. C. Lloyd-Jones, K. I. Booker-Milburn,
Angew. Chem. Int. Ed. 2009, 48, 1830 – 1833; Angew. Chem.
2009, 121, 1862 – 1865; h) E. J. Yoo, M. Wasa, J. Q. Yu, J. Am.
Chem. Soc. 2010, 132, 17378 – 17380; i) Q. Liu, H. Zhang, A. Lei,
Angew. Chem. Int. Ed. 2011, 50, 10788 – 10799; Angew. Chem.
2011, 123, 10978 – 10989; j) X. F. Wu, H. Neumann, M. Beller,
Chem. Soc. Rev. 2011, 40, 4986 – 5009; k) P. Xie, Y. Xie, B. Qian,
H. Zhou, C. Xia, H. Huang, J. Am. Chem. Soc. 2012, 134, 9902 –
9905; l) Z. H. Guan, M. Chen, Z. H. Ren, J. Am. Chem. Soc.
2012, 134, 17490 – 17493; m) S. Luo, F. X. Luo, X. S. Zhang, Z. J.
Shi, Angew. Chem. Int. Ed. 2013, 52, 10598 – 10601; Angew.
Chem. 2013, 125, 10792 – 10795; n) A. McNally, B. Haffemayer,
B. S. Collins, M. J. Gaunt, Nature 2014, 510, 129 – 133; o) B.
Gabriele, R. Mancuso, G. Salerno, Eur. J. Org. Chem. 2012,
6825 – 6839; p) R. Giri, J. Q. Yu, J. Am. Chem. Soc. 2008, 130,
14082 – 14083; q) R. Giri, J. K. Lam, J. Q. Yu, J. Am. Chem. Soc.
2010, 132, 686 – 693.
A possible mechanism for this reaction has been outlined
À
in Scheme 4. First, aryl N H activation by the palladium
complex forms the intermediate A from 1. Then, coordination
and insertion of CO into A affords the carbamoyl intermedi-
ate B.[14] Then B undergoes another CO insertion to give the
À
intermediate C. The C H activation of C generates a six-
[2] a) T. Kobayashi, M. Tanaka, J. Organomet. Chem. 1982, 233,
C64 – C66; b) M. Tanaka, T.-A. Kobayashi, T. Sakakura, J.
Chem. Soc. Chem. Commun. 1985, 837; c) F. Ozawa, H. Soyama,
H. Yanagihara, I. Aoyama, H. Takino, K. Izawa, T. Yamamoto,
A. Yamamoto, J. Am. Chem. Soc. 1985, 107, 3235 – 3245; d) M.
Scheme 4. Proposed mechanism for the palladium-catalyzed double
À
carbonylation of a C H bond.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
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3
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.
Angewandte
Communications
Tanaka, T.-A. Kobayashi, T. Sakakura, H. Itatani, S. Danno, K.
Zushi, J. Mol. Catal. 1985, 32, 115 – 118; e) F. Ozawa, N.
Kawasaki, H. Okamoto, T. Yamamoto, A. Yamamoto, Organo-
metallics 1987, 6, 1640 – 1651; f) T. Sakakura, H. Yamashita, T.
Kobayashi, T. Hayashi, M. Tanaka, J. Org. Chem. 1987, 52, 5733 –
5740; g) I. Pri-Bar, H. Alper, Can. J. Chem. 1990, 68, 1544 – 1547;
h) Y. Uozumi, T. Arii, T. Watanabe, J. Org. Chem. 2001, 66,
5272 – 5274; i) D. U. Nielsen, K. Neumann, R. H. Taaning, A. T.
Lindhardt, A. Modvig, T. Skrydstrup, J. Org. Chem. 2012, 77,
6155 – 6165.
Sabde, K. Bothara, A. Madgulkar, Bioorg. Med. Chem. 2010, 18,
3198 – 3211; d) Y.-L. Liu, F.-M. Liao, Y.-F. Niu, X.-L. Zhao, J.
Zhou, Org. Chem. Front. 2014, 1, 742 – 747; e) K. C. Rice, B. J.
Boone, A. B. Rubin, T. J. Rauls, J. Med. Chem. 1976, 19, 887 –
892; f) A. Boucherif, Q. Q. Yang, Q. Wang, J. R. Chen, L. Q. Lu,
W. J. Xiao, J. Org. Chem. 2014, 79, 3924 – 3929.
[11] a) R. Stollꢁ, Ber. Dtsch. Chem. Ges. 1913, 46, 3915 – 3916; b) T.
Sandmeyer, Helv. Chim. Acta 1919, 2, 234 – 242; c) P. G. Gass-
man, B. W. Cue, T.-Y. Luh, J. Org. Chem. 1977, 42, 1344 – 1348;
d) F. Ozawa, H. Yanagihara, A. Yamamoto, J. Org. Chem. 1986,
51, 415 – 417; e) P. Hewawasam, N. A. Meanwell, Tetrahedron
Lett. 1994, 35, 7303 – 7306; f) B. X. Tang, R. J. Song, C. Y. Wu, Y.
Liu, M. B. Zhou, W. T. Wei, G. B. Deng, D. L. Yin, J. H. Li, J.
Am. Chem. Soc. 2010, 132, 8900 – 8902; g) D. C. Rogness, R. C.
Larock, J. Org. Chem. 2011, 76, 4980 – 4986; h) P.-C. Huang, P.
Gandeepan, C.-H. Cheng, Chem. Commun. 2013, 49, 8540 –
8542; i) Y. Zi, Z. J. Cai, S. Y. Wang, S. J. Ji, Org. Lett. 2014, 16,
3094 – 3097; j) A. Ilangovan, G. Satish, J. Org. Chem. 2014, 79,
4984 – 4991.
[12] a) J. Cao, H. Gao, G. Bemis, F. Salituro, M. Ledeboer, E.
Harrington, S. Wilke, P. Taslimi, S. Pazhanisamy, X. Xie, M.
Jacobs, J. Green, Bioorg. Med. Chem. Lett. 2009, 19, 2891 – 2895;
b) R. E. Dolle, B. L. Bourdonnec, K. Worm, G. A. Morales, C. J.
Thomas, W. Zhang, J. Comb. Chem. 2010, 12, 765 – 806.
[13] N. Sin, B. L. Venables, X. Liu, S. Huang, Q. Gao, A. Ng, R.
Dalterio, R. Rajamani, N. A. Meanwell, J. Heterocycl. Chem.
2009, 46, 432 – 442.
[3] Li and coworkers reported
a palladium-catalyzed double
carbonylation of indoles with amines, in this work, I2 was
selected to oxidatively functionalize indole C(3)-H. Q. Xing, L.
Shi, R. Lang, C. Xia, F. Li, Chem. Commun. 2012, 48, 11023 –
11025.
[4] a) W. C. Sumpter, Chem. Rev. 1944, 34, 393 – 434; b) G. S. Singh,
Z. Y. Desta, Chem. Rev. 2012, 112, 6104 – 6155.
[5] K. Han, Y. Zhou, F. Liu, Q. Guo, P. Wang, Y. Yang, B. Song, W.
Liu, Q. Yao, Y. Teng, P. Yu, Bioorg. Med. Chem. Lett. 2014, 24,
591 – 594.
[6] M. P. Verma, S. N. Pandeya, K. N. Singh, J. P. Stables, Acta
Pharm. 2004, 54, 49 – 56.
[7] Z. H. Chohan, H. Pervez, A. Rauf, K. M. Khan, C. T. Supuran, J.
Enzyme Inhib. Med. Chem. 2004, 19, 417 – 423.
[8] T. Jiang, K. L. Kuhen, K. Wolff, H. Yin, K. Bieza, J. Caldwell, B.
Bursulaya, T. Tuntland, K. Zhang, D. Karanewsky, Y. He,
Bioorg. Med. Chem. Lett. 2006, 16, 2109 – 2112.
[9] C. R. R. Prakash, S. Raja, G. Saravanan, Int. J. Pharm. Sci.
Biotechnol. 2010, 1, 105.
[14] a) K. Orito, M. Miyazawa, T. Nakamura, A. Horibata, H. Ushito,
H. Nagasaki, M. Yuguchi, S. Yamashita, T. Yamazaki, M.
Tokuda, J. Org. Chem. 2006, 71, 5951 – 5958; b) W. Li, C. Liu,
H. Zhang, K. Ye, G. Zhang, W. Zhang, Z. Duan, S. You, A. Lei,
Angew. Chem. Int. Ed. 2014, 53, 2443 – 2446; Angew. Chem.
2014, 126, 2475 – 2478.
[10] a) M. K. Uddin, S. G. Reignier, T. Coulter, C. Montalbetti, C.
Granas, S. Butcher, C. Krog-Jensen, J. Felding, Bioorg. Med.
Chem. Lett. 2007, 17, 2854 – 2857; b) Y. Lai, L. Ma, W. Huang, X.
Yu, Y. Zhang, H. Ji, J. Tian, Bioorg. Med. Chem. Lett. 2010, 20,
7349 – 7353; c) V. Pawar, D. Lokwani, S. Bhandari, D. Mitra, S.
4
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Communications
Heterocycle Synthesis
W. Li, Z. Duan, X. Zhang, H. Zhang,
M. Wang, R. Jiang, H. Zeng, C. Liu,
A. Lei*
&&&& — &&&&
Two at once: A novel palladium-catalyzed
regioselectivity and without any additives.
À
C H double carbonylation introduces
Density functional theory investigations
indicate that the palladium-catalyzed
double carbonylation catalytic cycle is
plausible.
From Anilines to Isatins: Oxidative
Palladium-Catalyzed Double
two adjacent carbonyl groups for the
synthesis of isatins from readily available
anilines. The reaction proceeds under
atmospheric pressure of CO with high
À
Carbonylation of C H Bonds
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!