Copper-catalyzed intramolecular C-H oxidation/acylation of formyl- N -arylformamides leading to indoline-2,3-diones

Article abstract of DOI:10.1021/ja103426d

A new, efficient Cu-catalyzed intramolecular C-H oxidation/acylation method has been developed for the synthesis of substituted indoline-2,3-diones (isatins). In the presence of CuCl₂ and O₂, a variety of formyl-N-arylformamides underwent the tandem reaction to afford the corresponding indoline-2,3-diones in moderate to good yields. It is noteworthy that the reaction serves as the first example of transition-metal-catalyzed transformation for the preparation of indoline-2,3-diones.

Full text of DOI:10.1021/ja103426d

Published on Web 06/14/2010
Copper-Catalyzed Intramolecular C-H Oxidation/Acylation of
Formyl-N-arylformamides Leading to Indoline-2,3-diones
Bo-Xiao Tang, Ren-Jie Song, Cui-Yan Wu, Yu Liu, Ming-Bo Zhou, Wen-Ting Wei, Guo-Bo Deng,
Du-Lin Yin, and Jin-Heng Li*
Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research, Ministry of Education,
Hunan Normal UniVersity, Changsha 410081, China
Received April 22, 2010; E-mail: jhli@hunnu.edu.cn
Table 1. Cyclization of N-Methyl-2-oxo-N-phenylacetamide (1a)a
Indoline-2,3-diones (isatins), an important class of hetero-
cycles, are commonly found in natural compounds, pharmaceu-
ticals, and dyes; they are also versatile synthetic blocks in organic
synthesis.1,2 Traditionally, there are two practical approaches
to their synthesis:1,3-6 one involves strong acid- (often H2SO4)
or base-mediated condensation of aniline with diethyl ketoma-
lonate (Martinet procedure),3 oxalyl chloride (Stolle´ procedure),4
or chloral hydrate (Sandmeyer procedure),5 and the other
entry
CuCl2 (mol %)
additive
T (°C)
time (h)
isolated yield (%)
involves introduction of substituents onto a preexisting aromatic
ring.6 Although these methods provided useful access to
substituted indoline-2,3-diones, there are noticeable drawbacks
associated with them, such as relatively harsh reaction conditions,
inaccessible substrates, and excess amount of acid or base
catalysts. Therefore, the design of general and direct strategies
for the preparation of indoline-2,3-diones, particularly involving
a transition-metal-catalyzed process, would be highly interesting.
Recently, direct acylation of aldehydes with the arene
π-systems Via transition-metal-catalyzed C-H activation has
been emerged as a powerful tool to give aryl ketones.7-9
However, only a few papers on this method have been published:
these have employed noble metal combined with ligand as the
catalytic systems and expensive aryl halides7 or arylboronic
acids8 as the arene π-system sources. Cheng and co-workers
have disclosed an alternative method that utilizes an arene sp2
C-H bond of 2-arylpyridines for Pd-catalyzed intermolecular
oxidative acylation with an aldehyde.9 However, their method
requires a chelation assistant for arene sp2 C-H bond activation
and is limited to aryl aldehydes. Here, we describe a new,
efficient route to indoline-2,3-diones by Cu-catalyzed intramo-
lecular C-H oxidation/acylation of formyl-N-arylformamides
using O2 as the terminal oxidant (eq 1).10 To the best of our
knowledge, it is the first example of the synthesis of indoline-
2,3-diones using a transition-metal-catalyzed process.
1
2
3
4
5
6
7
8
20
10
5
2
0
10
10
10
O2
O2
O2
O2
O2
air
argon
O2
100
100
100
100
100
100
100
80
4
4
90
89
86
66
0
58
<5
54
12
24
24
24
24
24
a Reaction conditions: 1a (0.2 mmol), CuCl2, additive (1 atm), and
THF (3 mL).
moderate yield was still achieved at 2 mol % of CuCl2 (entry
4). We noted that the reaction cannot take place without Cu
catalysis (entry 5). Using air as the terminal oxidant led to an
unsatisfactory yield (entry 6), and in argon only <5% yield was
observed (entry 7).13 The activity of substrate 1a was lowered
sharply at 80 °C (entry 8).
A series of substrates with different substituents on both the
nitrogen atom and the aromatic ring of 1 were examined (Table
2). While treatment of 2-oxo-N-phenylacetamide with CuCl2 and
O2 afforded a trace amount of the desired product 2b, both
N-benzyl and N-allyl substrates gave the target products 2c and
2d in 80% and 74% yields, respectively. To our delight, several
functional groups, such as methyl, methoxy, fluoro, chloro,
acetyl, phenyl, and thiophen-2-yl groups, on the aromatic moiety
were well-tolerated, giving the corresponding products 2e-p in
moderate to good yields. For methyl-substituted substrates, the
order of activity is meta > para > ortho in terms of yields
(2e-h). We found that substituents at the para position affected
the reaction: the electron-donating or weak electron-withdrawing
groups worked well and furnished the targets products 2i-k,n
in moderate yields, but the electron-withdrawing groups, acetyl
and CF3 groups, lowered the yields to 50% (2l) and 30% (2m
obtained at 40 mol % of CuCl2). Notably, substrates with a meta
substituent gave a mixture of 3-acylated and 6-acylated products
with the ratio of 1.6:1 (2f/f′ or 2o/o′). The introduction of olefin,
heterocycles, or carbocycles into this system makes this meth-
Our investigation began with the reaction of N-methyl-2-oxo-
N-phenylacetamide (1a) under the reported Pd7,9 or other
conditions,11 but it failed. After a series of trials, we found that
substrate 1a could be successfully cyclized with 20 mol % of
CuCl2 and 1 atm of O2 in THF at 100 °C, affording the desired
product 2a in 90% yield (entry 1, Table 1).12 Identical yields
were obtained using either 10 or 5 mol % of CuCl2, the latter
requiring prolonged time (entries 2 and 3). Gratifyingly, a
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8900 J. AM. CHEM. SOC. 2010, 132, 8900–8902
10.1021/ja103426d  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. CuCl2/O2-Catalyzed Synthesis of Indoline-2,3-diones (2)a
Scheme 2. Some Controlled Experiments
Scheme 3. A Possible Mechanism
a Reaction conditions: 1a (0.2 mmol), CuCl2 (10 mol %), O2 (1
atm), and THF (3 mL) at 100 °C. b CuCl2 (20 mol %). c CuCl2 (40
mol %).
Scheme 1. Kinetic Isotope Effect Experiments
Figure 1. Data of in situ FTIR analysis during the reaction of Cu complex
under air atmosphere.
odology more useful for the preparation of pharmaceuticals and
nature products (2p-r).
As expected, a Friedel-Crafts product 4, together with 2a, was
isolated when CuOTf or Cu(OTf)2 was used for catalysis in argon.16
We reason that product 4 can be readily oxidized, resulting in 2a.13
These results suggest that the present reaction proceeds not Via a
Friedel-Crafts process.
The same values of the inter- and intramolecular kinetic
isotope effects (kH/kD ) 1.5) imply that this reaction does not
proceed Via a chelation-assisted C-H bond cleavage (Scheme
1).10,14 The intramolecular kinetic isotope effect also indicates
that the mechanism of the C-H activation is not compatible
with the SEAr mechanism14 or the free radical mechanism.15
Moreover, the free radical mechanism can be ruled out because
this reaction is not affected by two radical inhibitors, 1,1-
diphenylethylene or TEMPO.7e,15 The kinetic isotope effect (kH/
kD ) 2.4) was observed by comparison with the rates of 1a and
the monodeuterated aldehyde substrate 1a-D by FTIR analysis,
suggesting that aldehyde C-H bond cleavage is the rate-limiting
step.7e
Consequently, a possible mechanism as outlined in Scheme
3 was proposed on the basis of the present results.7-10,13-16,18
The C-H bond activation of aldehyde from the Cu complex 3
affords intermediate A with the aid of O2. Intermediate A then
undergoes the sp2 arene C-H bond activation to yield CuIII
intermediate B.10c,d,18 Reductive elimination of intermediate B
gives the product 2 and CuI species. Intermediates A and B are
supported by the CdO stretch data of in situ FTIR analysis
(Figure 1
Interestingly, a Cu complex (3) was obtained when CuCl2 reacted
with substrate 1a under an argon atmosphere (Scheme 2). However,
it was sensitive to oxygen and readily decomposed to 2a in air.13
):7e,19 Generally, 1783 cm-1 is a CdO stretch in a four-
membered ring, 1750 cm-1 is a CdO stretch in a five-membered
ring (indoline-2,3-dione), and 1730 cm-1 is a CdO stretch in a
9
J. AM. CHEM. SOC. VOL. 132, NO. 26, 2010 8901

C O M M U N I C A T I O N S
Scheme 4. Application to the One-Pot Synthesis of Polyethers
(3) (a) Guyot, A.; Martinet, J. Compt. Rend. 1913, 166, 1625. (b) Martinet,
J. Compt. Rend. 1918, 166, 851. (c) Bonnefoy, J.; Martinet, J. Compt. Rend.
1921, 172, 220.
(4) (a) Stolle´, R. J. Prakt. Chem. 1922, 106, 137. (b) Stolle´, R. Ber. Bunsenges.
Dtsch. Chem. 1913, 46, 3915.
(5) (a) Sandmeyer, T. HelV. Chim. Acta 1919, 2, 234. (b) Prinz, W.; Kayle,
A.; Levy, P. R. J. Chem. Res. (S) 1978, 168. (c) Pinto, A. C.; Lapis,
A. A. M.; da Silva, B. V.; Bastos, R. S.; Dupont, J.; Neto, B. A. D.
Tetrahedron Lett. 2008, 49, 5639.
(6) (a) Erdmann, O. L. J. Prakt. Chem. 1840, 19, 321. (b) Laurent, A. Ann.
Chim. Phys. 1840, 3, 393. (c) Erdmann, O. L. J. Prakt. Chem. 1841, 24, 1.
(d) Laurent, A. J Prakt Chem 1842, 25, 430. (e) Gericke, H. J. Prakt. Chem.
1865, 96, 177. (f) Forrer, C. Ber. Bunsenges. Dtsch. Chem. 1884, 17, 976.
A review: (g) Yadav, J. S. Synthesis 2007, 693.
six-membered ring. Moreover, the results of the HRMS (ESI)
analysis also support the formation of intermediates
A
(7) (a) Satoh, T.; Itaya, T.; Miura, M.; Nomura, M. Chem. Lett. 1996, 823. (b)
Huang, Y.-C.; Majumdar, K. K.; Cheng, C.-H. J. Org. Chem. 2002, 67,
1682. (c) Ko, S.; Kang, B.; Chang, S. Angew. Chem., Int. Ed. 2005, 44,
455. (d) Ruan, J.; Saidi, O.; Iggo, J. A.; Xiao, J. J. Am. Chem. Soc. 2008,
and B.13
This novel methodology was also applied to the one-pot synthesis
of polyethers 5 and 6, a motif in enzyme mimics, receptor site
models, and selective ionophores,17 through a C-H oxidation/
acylation reaction followed by bis-addition with ethyl propiolate
(Scheme 4).
In summary, we have developed a novel copper-catalyzed
intramolecular C-H oxidation/acylation protocol using two C-H
bonds as the reaction partners and O2 as the terminal oxidant.
Importantly, the reaction could be a valuable method for
preparing substituted indoline-2,3-diones with high tolerance of
functional groups. The mechanism was also discussed according
to the kinetic isotope effect experiments, in situ FTIR, and
HRMS (ESI) analysis.
´
130, 10510. (e) Alvarez-Bercedo, P.; Flores-Gaspar, A.; Correa, A.; Martin,
R. J. Am. Chem. Soc. 2010, 132, 466.
(8) Pucheault, M.; Darses, S.; Genet, J.-P. J. Am. Chem. Soc. 2004, 126,
15356.
(9) Jia, X.; Zhang, S.; Wang, W.; Luo, F.; Cheng, J. Org. Lett. 2009, 11,
3120.
(10) A limited number of transformations have been developed for conversion
of the arene sp2 C-H bonds to the C-C bonds using inexpensive copper
catalysis: (a) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 6968. (b)
Inamoto, K.; Hasegawa, C.; Hiroya, K.; Doi, T. Org. Lett. 2008, 10, 5147.
(c) Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008,
130, 8172. (d) Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593. (e)
Mizuhara, T.; Inuki, S.; Oishi, S.; Fujii, N.; Ohno, H. Chem. Commun.
2009, 3413. (f) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2008, 130,
1128. (g) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2009, 131, 17052.
(h) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42,
1074.
(11) IPy2BF4/HBF4: (a) Barluenga, J.; Trincado, M.; Rubio, E.; Gonza´lez,
J. M. Angew. Chem., Int. Ed. 2006, 45, 3140AlCl3 or SeO2: (b) Fusn,
R. C.; Talbott, R. L. J. Org. Chem. 1961, 26, 2674. BF3 ·Et2O or PPA:
(c) Benincori, T.; Fusco, R.; Sannicolo, F. Gazz. Chim. Ital. 1990, 120,
635.
Acknowledgment. We thank the NCET (No. NCET-06-0711),
NSFC (No. 20872112), and Hunan Provincial Innovation Founda-
tion For Postgraduate (CX2009B104) for financial support.
(12) See the Supporting Information for details (Table S1).
(13) See the controlled experiments in the Supporting Information (Scheme
S1). The decomposition of the Cu salt 3 process was monitored in situ
by FTIR and HRMS (ESI) analysis (Figure S1), and no Friedel-Crafts
Supporting Information Available: Experimental procedures and
spectral data for all products 2,4-6. This material is available free of
charge via the Internet at http://pubs.acs.org.
product
4 was determined by comparison with the standard
sample 4.
(14) (a) Jones, W. D. Acc. Chem. Res. 2003, 36, 140. (b) Pinto, A.; Neuville,
L.; Retailleau, P.; Zhu, J. Org. Lett. 2006, 8, 4927. (c) Jones, W. D.; Feher,
F. J. J. Am. Chem. Soc. 1986, 108, 4814. (d) Jones, W. D.; Feher, F. J.
Acc. Chem. Res. 1989, 22, 91.
(15) (a) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc.
2006, 128, 6790. (b) Chen, X.; Dobereiner, G.; Hao, X.-S.; Giri, R.; Maugel,
N.; Yu, J.-Q. Tetrahedron 2009, 65, 3085.
References
(1) For reviews, see: (a) Sumpter, W. C. Chem. ReV. 1944, 34, 393. (b) Popp,
F. D. AdV. Heterocycl. Chem. 1975, 18, 1. (c) da Silva, J. M.; Garden,
S. J.; Pinto, A. C. J. Braz. Chem. Soc. 2001, 12, 273.
(2) For selected papers, see: (a) Guo, Y.; Chen, F. Zhongcaoyao 1986, 17, 8;
Chem. Abstr. 1986, 104, 213068f. (b) Yoshikawa, M.; Murakami, T.;
Kishi, A.; Sakurama, T.; Matsuda, H.; Nomura, M.; Matsuda, H.; Kubo,
M. Chem. Pharm. Bull. 1998, 46, 886. (c) Gil-Turners, M. S.; Hay, M. E.;
Fenical, W. Science 1989, 116. (d) Medvedev, A. E.; Clow, A.; Sandler,
M.; Glover, V. Biochem. Pharmacol. 1996, 52, 385. (e) Koguchi, Y.;
Kohno, J.; Nisshio, M.; Takahashi, K.; Okuda, T.; Ohnuki, T.;
Komatsubara, S. J. Antibiot. 2000, 53, 105. (f) Itoh, J.; Han, S. B.;
Krische, M. J. Angew. Chem., Int. Ed. 2009, 48, 6313. (g) Franz, A. K.;
Dreyfuss, P. D.; Schreiber, S. L. J. Am. Chem. Soc. 2007, 129, 1020.
(h) Ding, X.-Q.; Lindstrom, E.; Hakanson, R. Pharmacol. Toxicol. 1997,
81, 232.
(16) Poulsen, T. B.; Jørgensen, K. A. Chem. ReV. 2008, 108, 2903.
(17) Gokel, G. W.; Korzenniowski, S. H. Macrocyclic Polyether Synthesis;
Springer Verlag: New York, 1982.
(18) (a) Zhang, S.-L.; Liu, L.; Fu, Y.; Guo, Q.-X. Organometallics 2007, 26,
4546. (b) Ribas, X.; Jackson, D. A.; Donnadieu, B.; Mah´ıa, J.; Parella, T.;
Xifra, R.; Hedman, B.; Hodgson, K. O.; Llobet, A.; Stack, T. D. P. Angew.
Chem., Int. Ed. 2002, 41, 2292.
(19) (a) Hu, Y.; Liu, J.; Lu¨, Z.; Luo, X.; Zhang, H.; Lan, Y.; Lei, A. J. Am.
Chem. Soc. 2010, 132, 3153. (b) Liu, Q.; Lan, Y.; Liu, J.; Li, G.; Wu,
Y.-D.; Lei, A. J. Am. Chem. Soc. 2009, 131, 10201.
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