Copper-catalyzed tandem oxidative cyclization of arylacetamides: Efficient access to N-functionalized isatins

Article abstract of DOI:10.1039/c3ra40657a

An efficient copper-catalyzed synthesis of N-substituted isatins has been developed in good yields from easily accessible arylacetamides. A wide range of electronically and structurally varied nitrogen fragments could be assembled through this tandem C-O/C-N bond-forming process by tuning the reaction conditions.

Full text of DOI:10.1039/c3ra40657a

RSC Advances
View Article Online
View Journal | View Issue
COMMUNICATION
Copper-catalyzed tandem oxidative cyclization of
arylacetamides: efficient access to N-functionalized
isatins3
Jie Sun,a Bingxin Liua and Bin Xu*ab
Cite this: RSC Advances, 2013, 3, 5824
Received 6th February 2013,
Accepted 1st March 2013
DOI: 10.1039/c3ra40657a
www.rsc.org/advances
An efficient copper-catalyzed synthesis of N-substituted isatins
has been developed in good yields from easily accessible
arylacetamides. A wide range of electronically and structurally
varied nitrogen fragments could be assembled through this
tandem C–O/C–N bond-forming process by tuning the reaction
conditions.
utilization of N,N-diarylamines with oxalyl chlorides,16 and by
ruthenium-catalyzed17 or indium(III) chloride–2-iodoxybenzoic
acid18 promoted oxidation of indoles. Recently, Li and co-workers
reported an efficient synthetic route to indoline-2,3-diones by
copper-catalyzed intramolecular C–H oxidation–acylation of for-
myl-N-arylformamides.19 However, some of these reactions suffer
from relatively harsh reaction conditions, poor yields and limited
diversification.
1H-Indole-2,3-dione (isatin) derivatives are of great pharmaceutical
interest with a wide range of biological and pharmacological
activities,1 which play an increasingly important role in drug
discovery. These compounds are structural units found in a vast
array of natural products,1d synthetic materials,1a,1d,2 and bioactive
molecules as anticancer,1c,3 anticonvulsant,4 anti-HIV,5 anti-
inflammatory and analgesic,6 antimicrobial,7 antioxidant,8 and
antiviral agents.9 Besides, isatins are synthetically versatile
substrates, which could be used as intermediates for the synthesis
of various heterocyclic compounds, such as isatoic anhydrides,
indoles, quinolines, and as precursors for the synthesis of
spirofused cyclic frameworks.1d Recently, the isatin derivative
sunitinib malate (SU11248) was approved by the FDA for the
treatment of renal cell carcinoma (RCC) and imatinib-resistant
gastrointestinal stromal tumor (GIST). Such characteristics have
made the molecules significant synthetic targets and, therefore,
have resulted in sustained interest in developing general and
direct methods for the preparation of this valuable structural
unit.1a,1d,2 Isatin was first obtained by Erdmann and Laurent in
1840 as a product from the oxidation of indigo dye by nitric and
chromic acids.10 Other improved synthetic methods to build this
useful scaffold include the N-alkylation or arylation of isatins with
alkyl halides,11 aryl boronic acids12 or triarylbismuth,13 microwave-
assisted modified Sandmeyer reactions of oximinoacetanilides,14
reaction of arynes with methyl 2-oxo-2-(arylamino)acetates,15
Metal-catalyzed intramolecular amidation reactions of arylace-
tamides usually lead to oxindoles in good to excellent yields
(Scheme 1), however, no generation of the corresponding
1H-indole-2,3-diones has been reported among these reactions.20
To continue our program aiming at the efficient construction of
heterocycles through a tandem reaction strategy,21 we herein
describe a copper-catalyzed tandem oxidative cyclization reaction,
whereby sequential C–O and C–N bonds are formed from easily
accessible ortho-bromo substituted arylacetamides to give
N-functionalized isatins in the presence of tetra-n-butylammonium
bromide (Scheme 1). To our knowledge, this reaction represents
the first efficient example of a one-pot synthesis of N-substituted
isatins through a tandem C–O/C–N bond-forming process.
An initial study was performed by examining the reaction of 1a
in the presence of CuI, 1,10-Phen and TBAB in toluene using
pyridine as a base. However, this reaction gave only a trace
amount of N-benzylisatin (Table 1, entry 1). When using NaOH as
the base, a 39% yield of 3a could be isolated (entry 2). Amongst all
the other bases tested, K2CO3 proved to be the most efficient one
(entry 5), while K3PO4 and KOAc gave diminished yields (entries 3
and 4). Switching the solvent from toluene to dioxane, DMF,
acetonitrile or mesitylene gave decreased yields or trace amounts
of product (entries 6–9). An extensive screening concerning the
aDepartment of Chemistry, Shanghai University, Shanghai 200444, China.
E-mail: xubin@shu.edu.cn; Fax: +86-21-66132830; Tel: +86-21-66132830
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032, P R China
Electronic supplementary information (ESI) available: General experimental
3
procedures, characterization data and copies of the 1H and 13C NMR spectra for
all compounds. See DOI: 10.1039/c3ra40657a
Scheme 1 Tandem strategy on isatin ring synthesis.
5824 | RSC Adv., 2013, 3, 5824–5827
This journal is ß The Royal Society of Chemistry 2013

View Article Online
RSC Advances
Communication
Table 1 Condition optimizations of isatin synthesisa
Table 2 Substrate scope for the synthesis of N-alkyl substituted isatinsa
Time (h) Product Yieldb (%)
Entry Cu source Base
Solvent
Additive Ligand
Yieldb (%)
Entry
R
Alkyl
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuCl2
CuBr
CuI
CuI
CuI
CuI
CuI
CuI
/
Pyridine toluene
NaOH toluene
K3PO4 toluene
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
1,10-Phen ,5
1,10-Phen 39
1
2
3
4
5
6
H
Bn
Me
n-C3H7
n-C4H9
Me(CH2)11
i-Pr
c-Pr
c-Hex
Allyl
BnCH2
Furan-2-ylmethyl
HOCH2CH2
Bn
8
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
4a
74
67
64
61
58
75
69
68
72
50
69
60
61
65
46
57
27
1,10-Phen 59
1,10-Phen 65
1,10-Phen 74
1,10-Phen 52
1,10-Phen ,5
1,10-Phen ,5
1,10-Phen 51
1,10-Phen 56
1,10-Phen 30
TM-Phen 26
Bipyridine 39
12
12
16
12
6
12
8
8
4
4
6
KOAc
toluene
K2CO3 toluene
K2CO3 dioxane
K2CO3 DMF
K2CO3 CH3CN
K2CO3 mesitylene TBAB
K2CO3 toluene
K2CO3 toluene
K2CO3 toluene
K2CO3 toluene
K2CO3 toluene
K2CO3 toluene
K2CO3 toluene
K2CO3 toluene
K2CO3 toluene
K2CO3 toluene
K2CO3 toluene
K2CO3 toluene
7
8c
9
9
10
11
12
13
14
15
16
17
18
19
20
21
TBAB
TBAB
TBAB
TBAB
TBAB
10
11
12
13
14
15
16
17
5-OMe
4,5-diOMe Bn
4,5-diOMe n-C4H9
5-OTs
H
DACH
,5
6
16
2
Bu4NOAc 1,10-Phen ,5
Et4NBr 1,10-Phen 61
TBAB
TBAB
/
TBAB
TBAB
Bn
Ph
1,10-Phen 52c
1,10-Phen ,5
1,10-Phen 50
10
a
CuI
CuI
CuI
Reagents and conditions: 1 (0.25 mmol), CuI (10 mol%), 1,10-Phen
(20 mol%), K2CO3 (3.0 equiv.) and TBAB (1.4 equiv.) in toluene (2
mL), under air, at 100 uC, dried through a calcium chloride tube.
/
30
1,10-Phen 25d
b
c
Isolated yields. At 120 uC in o-xylene (2 mL).
a
Reaction conditions: 1a (0.25 mmol), [Cu] (10 mol%), ligand (20
mol%), base (3.0 equiv.) and additive (1.4 equiv.) in solvent (1 mL),
for 10 h, at 100 uC, open to air, dried through a calcium chloride
tube. DACH = diaminocyclohexane, 1,10-Phen = 1,10-phenanthroline,
TBAB = tetra-n-butylammonium bromide, TM-Phen = 3,4,7,8-
reason may be due to its steric factor and resulted in a lower
reactivity in this reaction. Substrates bearing benzyl (3a), allyl (3i),
phenethyl (3j) or furfuryl (3k) groups illustrated better reactivities
in this reaction, and produced isatins efficiently. Substrate 1l with
hydroxy functionality was readily incorporated and produced 3l
selectively in good yield, without observing any by-products via the
intra- or inter-molecular nucleophilic attack of oxygen.
Remarkably clean reactions were observed with the functionalized
molecules bearing methoxyl (3m and 3n) or tosyl (3p) substitu-
tions on the aryl ring, whereas in the case of the N-butyl group the
attached substrate gave a slightly complicated reaction (3o).
However, when 2-(2-bromophenyl)-N-phenylacetamide (2a) was
used under the optimized reaction, only 27% yield of the desired
isatin product (4a) could be generated (entry 17).
To address this limitation and further explore the generality
and scope of this approach, an extensive screening of copper
catalysts and ligands together with solvents, bases and additives
was carried out next, and we found that N-phenyl substituted
isatin product 4a could be achieved in the presence of CuI, 1,10-
Phen and TBAB using 3.0 equivalents of KOAc as the base in
b
c
tetramethyl-1,10-phenanthroline. Isolated yields. At 90 uC.
d
Under nitrogen.
copper resources (entries 10 and 11), ligands (entries 12–14),
additive (entries 15 and 16) and temperature (entry 17) revealed
that the use of TBAB as an additive in toluene at 100 uC under air
is the best choice, and afforded 3a in 74% yield (entry 5). Trace
amounts of isatin product were detected in the absence of CuI
(entry 18), and a decreased yield could be afforded without using
an additive (entry 19) or a ligand (entry 20), which indicated that
both the catalyst and ammonium salt were crucial for this
oxidative cyclization reaction.21e,22 The reaction became sluggish
under nitrogen and a low yield was obtained (entry 21).
With the optimized reaction conditions in hand, we then
extended the reaction to the synthesis of a range of N-alkyl
substituted isatins. As illustrated in Table 2, a wide variety of
substitution patterns and functionalities are tolerated. Substrates
bearing N-alkyl or cycloalkyl substituents reacted smoothly, and
afforded the corresponding isatins in moderate to good yields (3a–
3p). A slight decrease in the yield of the isatins was observed when
the aliphatic chain length on the N-substituent was varied (3b–3e).
Employment of the N-isopropyl substrate performed well and gave
3f in 75% yield. The N-cycloalkyl group containing substrates with
various ring sizes participated smoothly in the reaction with
comparable efficiency (3g and 3h), although elevated temperature
was needed for the substrate with a cyclohexyl group (3h); the
dioxane (see Table S1 in the ESI for details). Under the optimized
3
conditions, the reaction proceeded smoothly and a series of N-aryl
containing substrates could be tolerated as shown in Table 3.
Substrates containing electron-donating (4b–4g), or bearing ortho-
(4b and 4c), meta- (4d), and para- groups (4e–4g) proceeded
efficiently with moderate to good yields. However, substrates with
electron-withdrawing groups showed relatively low reactivity (4h–
4j). The reaction was not limited to simple benzene-containing
This journal is ß The Royal Society of Chemistry 2013
RSC Adv., 2013, 3, 5824–5827 | 5825

View Article Online
Communication
RSC Advances
Table 3 Substrate scope for the synthesis of N-aryl substituted isatinsa
Entry
R
Aryl
Time (h) Product Yieldb (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
Ph
10
10
10
10
10
10
10
12
12
12
6
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4a
75
47
47
61
64
64
62
33
34
23
61
51
14
2-MeC6H4
2-OMeC6H4
3-MeC6H4
4-MeC6H4
4-OMeC6H4
4-OEtC6H4
4-BrPh
4-ClPh
4-CO2EtC6H4
Naphthalen-1-yl
Scheme 2 Formation of N-substituted isatins.a
9
10
11
12
13c
5-OMe Ph
Ph
6
12
applications for bioactive compounds are currently under
investigation in our laboratory and will be reported in due course.
H
a
Reagents and conditions: acetamide (0.25 mmol), CuI (10 mol%),
1,10-Phen (20 mol%), KOAc (3.0 equiv.) and TBAB (1.4 equiv.) in 1,4-
dioxane (2 mL), under air, at 100 uC, dried through a calcium
Acknowledgements
b
c
chloride tube. Isolated yields. 2-(2-Chlorophenyl)-
N-phenylacetamide (2m) was used.
We are grateful to the National Natural Science Foundation of
China (No. 21272149) for financial support of this work. The
authors thank Prof. Hongmei Deng (Laboratory for
Microstructures, SHU) for NMR support.
aromatics, but the naphthyl substrate also gave the desired
product in 61% yield (4k) and substitution on the aryl ring was
also tolerated during the reaction (4l). It should be noted that the
less reactive chloro-substituted substrate, 2-(2-chlorophenyl)-
N-phenylacetamide (2m), gave product 4a in only 14% yield (entry
13). Furthermore, when we used 1a as the substrate under these
conditions, a 52% yield of 3a was isolated.
To clarify the mechanism, the reaction intermediate 5 was
isolated in 34% yield after reacting for 12 h from N-allyl
substituted amide 1i under Conditions A, together with 39%
isolated yield of isatin product 3i (Scheme 2). Furthermore, the
isolated intermediate 5 could be further transformed to 3i in 90%
yield under the same conditions. The two-step reaction could
afford isatin 3i in about 70% overall yield from 1i, which is
comparable with the result of the one-step reaction in 72% yield
(Table 2, entry 9). Similarly, for the formation of N-phenyl
substituted isatins, compound 6 could be the key intermediate
during the reaction under Conditions B (Scheme 2). Based on
these results, we envisioned that the benzylic oxidation followed
by the cyclic amidation process is the major pathway to afford the
target isatins.
Notes and references
1 For selective reviews on bioactivity of isatins, see: (a) J. F. M. Da
Silva, S. J. Garden and A. C. Pinto, J. Braz. Chem. Soc., 2001, 12,
273; (b) S. N. Pandeya, S. Smitha, M. Jyoti and S. K. Sridhar, Acta
Pharm., 2005, 55, 27; (c) K. L. Vine, L. Matesic, J. M. Locke,
M. Ranson and D. Skropeta, Anti-Cancer Agents Med. Chem.,
2009, 9, 397; (d) G. S. Singh and Z. Y. Desta, Chem. Rev., 2012,
112, 6104.
2 (a) W. C. Sumpter, Chem. Rev., 1944, 34, 393; (b) F. D. Popp, Adv.
Heterocycl. Chem., 1975, 18, 1; (c) M. G. A. Shvekhgeimer, Chem.
Heterocycl. Compd., 1996, 32, 249.
3 (a) X. K. Wee, W. K. Yeo, B. Zhang, V. B. C. Tan, K. M. Lim, T.
E. Tay and M.-L. Go, Bioorg. Med. Chem., 2009, 17, 7562; (b) V.
R. Solomon, C. Hu and H. Lee, Bioorg. Med. Chem., 2009, 17,
7585.
4 F. Palluotto, A. Carotti, G. Casini, F. Campagna, G. Genchi,
M. Rizzo and S. G. B. De, Bioorg. Med. Chem., 1996, 4, 2091.
5 V. S. Pawar, D. K. Lokwani, S. V. Bhandari, K. G. Bothara, T.
S. Chitre, T. L. Devale, N. S. Modhave and J. K. Parikh, Med.
Chem. Res., 2011, 20, 370.
In conclusion, we have developed an efficient method for the
straightforward synthesis of N-substituted isatins from easily
accessible arylacetamides. A wide range of electronically and
structurally varied nitrogen fragments could be introduced
through this tandem C–O/C–N bond-forming process. Compared
with other reported methods, the current approach provides a very
simple and convenient route. The produced N-substituted isatins
and their derivatives are present as the key structural motif in
many marketed drugs, and will find their application in medicinal
chemistry. Further studies on the substrate scope and synthetic
6 M. E. Matheus, F. d. A. Violante, S. J. Garden, A. C. Pinto and P.
D. Fernandes, Eur. J. Pharmacol., 2007, 556, 200.
7 (a) A. H. Abdel-Rahman, E. M. Keshk, M. A. Hanna and S.
M. El-Bady, Bioorg. Med. Chem., 2004, 12, 2483; (b) A. Patel,
S. Bari, G. Talele, J. Patel and M. Sarangapani, Iran. J. Pharm.
Res., 2006, 5, 249.
8 A. Andreani, S. Burnelli, M. Granaiola, A. Leoni, A. Locatelli,
R. Morigi, M. Rambaldi, L. Varoli, M. A. Cremonini, G. Placucci,
R. Cervellati and E. Greco, Eur. J. Med. Chem., 2010, 45, 1374.
5826 | RSC Adv., 2013, 3, 5824–5827
This journal is ß The Royal Society of Chemistry 2013

View Article Online
RSC Advances
Communication
9 L.-R. Chen, Y.-C. Wang, Y. W. Lin, S.-Y. Chou, S.-F. Chen, L.
T. Liu, Y.-T. Wu, C.-J. Kuo, T. S.-S. Chen and S.-H. Juang, Bioorg.
Med. Chem. Lett., 2005, 15, 3058.
10 (a) O. L. Erdmann, J. Prakt. Chem., 1840, 19, 321; (b) A. Laurent,
Ann. Chim. Phys., 1840, 3, 393.
20 For some examples using Pd: (a) J. P. Wolfe, R. A. Rennels and
S. L. Buchwald, Tetrahedron, 1996, 52, 7525; (b) B. H. Yang and
S. L. Buchwald, Org. Lett., 1999, 1, 35; (c) A. van den
Hoogenband, J. A. J. den Hartog, J. H. M. Lange and J.
W. Terpstra, Tetrahedron Lett., 2004, 45, 8535; (d) R. R. Poondra
and N. J. Turner, Org. Lett., 2005, 7, 863; (e) Y. Kitamura,
A. Hashimoto, S. Yoshikawa, J.-I. Odaira, T. Furuta, T. Kan and
11 D. D. Bhragual, N. Kumar and S. Drabu, J. Chem. Pharm. Res.,
2010, 2, 345.
12 (a) P. Y. S. Lam, G. Vincent, C. G. Clark, S. Deudon and P.
K. Jadhav, Tetrahedron Lett., 2001, 42, 3415; (b) M. J. Konkel,
M. Packiarajan, H. Chen, U. P. Topiwala, H. Jimenez, I.
J. Talisman, H. Coate and M. W. Walker, Bioorg. Med. Chem.
Lett., 2006, 16, 3950; (c) M. G. Bursavich, A. M. Gilbert,
S. Lombardi, K. E. Georgiadis, E. Reifenberg, C. R. Flannery and
E. A. Morris, Bioorg. Med. Chem. Lett., 2007, 17, 5630; (d)
R. Romagnoli, P. G. Baraldi, O. Cruz-Lopez, D. Preti, J. Bermejo
´
K. Tanaka, Synlett, 2006, 115; (f) K. Flyren, L. O. Bergquist, V.
M. Castro, C. Fotsch, L. Johansson, D. J. St. Jean Jr, L. Sutin and
M. Williams, Bioorg. Med. Chem. Lett., 2007, 17, 3421. For some
examples using Cu: (g) T. Kukosha, N. Trufilkina and
M. Katkevics, Synlett, 2011, 2525; (h) R. Harada, N. Nishida,
S. Uchiito, Y. Onozaki, N. Kurono, H. Senboku, T. Masao,
T. Ohkuma and K. Orito, Eur. J. Org. Chem., 2012, 366; (i)
T. Kukosha, N. Trufilkina, S. Belyakov and M. Katkevics,
Synthesis, 2012, 44, 2413. For an example using Ag: (j)
M. Kawase, T. Kitamura and Y. Kikugawa, J. Org. Chem.,
1989, 54, 3394.
´
and F. Estevez, ChemMedChem, 2009, 4, 1668.
13 D. M. T. Chan, Tetrahedron Lett., 1996, 37, 9013.
14 M. M. Hossain, R. M. Islam, S. K. Saha and M. K. Islam,
Tetrahedron Lett., 2010, 51, 1155.
15 D. C. Rogness and R. C. Larock, J. Org. Chem., 2011, 76, 4980.
16 (a) A. V. Shindikar, F. Khan and C. L. Viswanathan, Eur. J. Med.
Chem., 2006, 41, 786; (b) P. Moser, A. Sallmann and
I. Wiesenberg, J. Med. Chem., 1990, 33, 2358; (c) R. Sarges, H.
R. Howard, B. K. Koe and A. Weissman, J. Med. Chem., 1989, 32,
437.
17 S. Chen, Z. Liu, E. Shi, L. Chen, W. Wei, H. Li, Y. Cheng and
X. Wan, Org. Lett., 2011, 13, 2274.
18 J. S. Yadav, B. V. S. Reddy, C. S. Reddy and A. D. Krishna,
Synthesis, 2007, 693.
21 (a) C. Sun and B. Xu, J. Org. Chem., 2008, 73, 7361; (b) W. Ye,
J. Mo, T. Zhao and B. Xu, Chem. Commun., 2009, 3246; (c) T.-
K. Zhao and B. Xu, Org. Lett., 2010, 12, 212; (d) C. Wang, C. Sun,
F. Weng, M. Gao, B. Liu and B. Xu, Tetrahedron Lett., 2011, 52,
2984; (e) J. Shao, X. Huang, S. Wang, B. Liu and B. Xu,
Tetrahedron, 2012, 68, 573; (f) J. Shao, X. Huang, X. Hong, B. Liu
and B. Xu, Synthesis, 2012, 44, 1798; (g) B. Liu, X. Hong, D. Yan,
S. Xu, X. Huang and B. Xu, Org. Lett., 2012, 14, 4398; (h) S. Xu,
X. Huang, X. Hong and B. Xu, Org. Lett., 2012, 14, 4614; (i) G. Li,
Z. Ding and B. Xu, Org. Lett., 2012, 14, 5338.
´
22 B. Orlinska, J. Zawadiak and D. Gilner, Appl. Catal., A, 2005,
19 B.-X. Tang, R.-J. Song, C.-Y. Wu, Y. Liu, M.-B. Zhou, W.-T. Wei,
G.-B. Deng, D.-L. Yin and J.-H. Li, J. Am. Chem. Soc., 2010, 132,
8900.
287, 68.
This journal is ß The Royal Society of Chemistry 2013
RSC Adv., 2013, 3, 5824–5827 | 5827