N-heterocyclic carbene-palladium(II)-1-methylimidazole complex catalyzed α-arylation of oxindoles with aryl chlorides and aerobic oxidation of the products in a one-pot procedure

Article abstract of DOI:10.1021/ol400186b

NHC-Pd(II)-Im complex 1 was found to be an effective catalyst for the α-arylation of unprotected oxindoles with aryl chlorides to give products 4 in 44-98% yields under a N₂ atmosphere. Furthermore, if the reactions were first performed under conditions identical to those for the α-arylation reaction for 12 h and then exposed to air for another 3 h, 3-aryl-3-hydroxy-2-oxindoles 5 can be obtained in 49-84% yields in a one-pot procedure.

Full text of DOI:10.1021/ol400186b

ORGANIC
LETTERS
2013
Vol. 15, No. 6
1254–1257
N‑Heterocyclic Carbene-Palladium(II)-1-
Methylimidazole Complex Catalyzed
r‑Arylation of Oxindoles with Aryl
Chlorides and Aerobic Oxidation of
the Products in a One-Pot Procedure
Zheng-Kang Xiao, Hui-Ying Yin, and Li-Xiong Shao*
College of Chemistry and Materials Engineering, Wenzhou University, Chashan
University Town, Wenzhou, Zhejiang Province 325035, People’s Republic of China
Shaolix@wzu.edu.cn
Received January 21, 2013
ABSTRACT
NHC-Pd(II)-Im complex 1 was found to be an effective catalyst for the r-arylation of unprotected oxindoles with aryl chlorides to give products
4 in 44À98% yields under a N2 atmosphere. Furthermore, if the reactions were first performed under conditions identical to those for the
r-arylation reaction for 12 h and then exposed to air for another 3 h, 3-aryl-3-hydroxy-2-oxindoles 5 can be obtained in 49À84% yields in a one-pot
procedure.
During the past years, palladium-catalyzed R-arylation
reactions of carbonyl compounds have become versatile
methods for the formation of new carbonÀcarbon bonds.1
Among them, since its first discovery, the palladium-
catalyzed direct R-arylation of oxindoles has proven to
be an important reaction and has attracted considerable
attention2 because the 3-substituted oxindole derivatives
are frequently found in many natural products and
compounds with biological activity.3 Meanwhile, the
3-substituted 3-hydroxy-oxindoles are also attractive due to
their prevalence in many alkaloid natural compounds
and compounds with pharmaceutical and biological activity.4
However, the previously reported palladium-catalyzed
R-arylation of oxindoles is still hampered as a practical
method mainly due to the following reasons: (1) expensive,
air-sensitive, electron-rich, and sterically hindered phos-
phine ligands are mandatory to facilitate such a transfor-
mation; (2) some require high catalyst loadings; (3) some
require the preprotection of the free NÀH of oxindoles.
Therefore, development of an alternative method for the
R-arylation of oxindoles still remains a challenge. During
the past two decades, N-heterocyclic carbenes (NHCs)
and their metal complexes have attracted much atten-
tion because of their significant advantages over their
phosphine counterparts in air, thermal, and moisture
stability. Consequently, NHC-Pd complexes have proven
to be effective catalysts in the formation ofcarbonÀcarbon
(1) For recent reviews on the R-arylation reaction, please see:
(a) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082–1146. (b) Johansson,
C. C. C.; Colacot, T. J. Angew. Chem., Int. Ed. 2010, 49, 676–707.
(2) (a) Altman, R. A.; Hyde, A. M.; Huang, X.-H.; Buchwald, S. L.
J. Am. Chem. Soc. 2008, 130, 9613–9620. (b) Durbin, M. J.; Willis, M. C.
Org. Lett. 2008, 10, 1413–1415. (c) Taylor, A. M.; Altman, R. A.;
Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 9900–9901. (d) Li,
P.-F.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 6396–6400.
(e) Yang, Y.-Y.; Moinodeen, F.; Chin, W.; Ma, T.; Jiang, Z.-Y.; Tan,
C.-H. Org. Lett. 2012, 14, 4762–4765.
(3) (a) Jensen, B. S. CNS Drug Rev. 2002, 8, 353–360. (b) Marti, C.;
Carreira, E. M. Eur. J. Org. Chem. 2003, 2209–2219. (c) Lin, H.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 36–51. (d) Scheidt,
K. A.; Galliford, C. V. Angew. Chem., Int. Ed. 2007, 46, 8748–8758.
(4) For recent selected reviews, please see: (a) Trost, B. M.; Brennan,
M. K. Synthesis 2009, 3003–3025. (b) Peddibhotla, S. Curr. Anal. Chem.
Curr. Bioact. Compd. 2009, 5, 20–38. (c) Badillo, J. J.; Hanhan, N. V.;
Franz, A. K. Curr. Opin. Drug Discovery Dev. 2010, 13, 758–776.
r
10.1021/ol400186b
Published on Web 03/01/2013
2013 American Chemical Society

and carbonÀheteroatom bonds.5 Despite the progress of
NHC-Pd complexes in organic synthesis, however, to the
best of our knowledge, NHC-Pd complex catalyzed
R-arylation of oxindoles has not been reported to date.
Therefore, on the basis of our success in the well-defined
and easily prepared N-heterocyclic carbene-Pd(II)-1-
methylimidazole [NHC-Pd(II)-Im] complex 1 catalyzed
carbonÀcarbon and carbonÀnitrogen bond formation
reactions using aryl chlorides as the substrates,6 and as
a continuation of our investigations on the R-arylation
reaction of ketones,6a herein, we wish to report the first
example of phosphine-free, NHC-Pd complex catalyzed
R-arylation of oxindoles with aryl chlorides and the
further unprecedented aerobic oxidation of the correspond-
ing products to 3-aryl-3-hydroxy-oxindoles in a one-pot
procedure.
Table 1. Optimization for the Reaction Conditions
entrya
base
solvent
yield/%b
Using oxindole 2a (1.3 mmol) and chlorobenzene 3a
(1.0 mmol) as the substrates, NHC-Pd(II)-Im complex 1
(1.0 mol %) as the catalyst, and toluene (2.0 mL) as the
solvent, we initially compared a variety of bases for this
reaction performed at 100 °C for 12 h. Typical results are
shown in Table 1. It was found that the bases drastically
affected the reaction. For example, a moderate yield (78%)
of product 4a can be achieved when KOtBu was used as the
base (Table 1, entry 1), while, in the presence of all other
bases such as NaOtBu, Cs2CO3, NaOH, KOH, K2CO3,
and Na2CO3, no reaction occurred (Table 1, entries 2À7).
The solvents also drastically affected the reaction. For
example, almost no reaction occurred when other solvents
such as DMSO, DMF, THF, dioxane, and CH3CN were
used, respectively (Table 1, entries 8À12). It seems that the
yield cannot be further increased even if the reaction was
performed in refluxing toluene for 12 h (Table 1, entry 13).
With the optimal reaction conditions in hand, we then
first explored the scope and limitations of this reaction
using oxindole 2a and various aryl chlorides 3 as the
substrates under identical conditions (Table 2). As can be
seen from Table 2, all reactions performed well to give the
desired products 4 in moderate to high yields at 100 °C
or reflux, respectively. Substituents on the aryl chlorides
have some effect on the reactions. For example, sterically
hindered substrates such as 2-methylphenyl chloride 3d
and 2,6-dimethylphenyl chloride 3e can give the cor-
responding products 4d and 4e in very high yields, res-
pectively (Table 2, entries 3 and 4); however, when
2-methoxyphenyl chloride 3i was used as the substrate,
only a moderate yield of product 4i was obtained (Table 2,
entry 8). Heteroaryl chlorides such as 3-pyridinyl chloride
1
KOtBu
NaOtBu
Cs2CO3
NaOH
KOH
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMSO
DMF
78
2
NR
NR
NR
NR
NR
NR
NR
NR
<5
3
4
5
6
K2CO3
Na2CO3
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
7
8
9
10
11
12
13c
THF
dioxane
CH3CN
toluene
<5
NR
79
a Unless otherwise specified, all reactions were carried out using 2a
(1.3 mmol), 3a (1.0 mmol), 1 (1.0 mol %), base (4.0 equiv), and solvent
(2.0 mL) at 100 °C for 12 h. b Isolated yields. c The reaction was
performed in refluxing toluene for 12 h.
Table 2. NHC-Pd(II)-Im 1 Catalyzed Reactions of Oxindole 2a
with Aryl Chlorides 3
(5) For reviews on the NHC-Pd complexes catalyzed coupling reac-
tions, please see: (a) Hillier, A. C.; Grasa, G. A.; Viciu, M. S.; Lee, H. M.;
Yang, C.-L.; Nolan, S. P. J. Organomet. Chem. 2002, 653, 69–82.
(b) Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G. Angew. Chem.,
Int. Ed. 2007, 46, 2768–2813. (c) Marion, N.; Nolan, S. P. Acc. Chem.
€
Res. 2008, 41, 1440–1449. (d) Wurtz, S.; Glorius, F. Acc. Chem. Res.
2008, 41, 1523–1533. (e) Fortman, G. C.; Nolan, S. P. Chem. Soc. Rev.
2011, 40, 5151–5169. (f) Valente, C.; C-alimsiz, S.; Hoi, K. H.; Mallik, D.;
Sayah, M.; Organ, M. G. Angew. Chem., Int. Ed. 2012, 51, 3314–3332.
(6) For some selected examples, please see: (a) Xiao, Z.-K.; Shao,
L.-X. Synthesis 2012, 711–716. (b) Wang, Z.-Y.; Chen, G.-Q.; Shao,
L.-X. J. Org. Chem. 2012, 77, 6608–6614. (c) Chen, W.-X.; Shao, L.-X.
J. Org. Chem. 2012, 77, 9236–9236. (d) Lin, X.-F.; Li, Y.; Li, S.-Y.; Xiao,
Z.-K.; Lu, J.-M. Tetrahedron 2012, 68, 5806–5809.
a All reactions were carried out using 2a (0.65 mmol), 3 (0.5 mmol),
1 (1.0 mol %), KOtBu (4.0 equiv), and toluene (1.0 mL) at 100 °C or
refluxing for 12 h. b Isolated yields.
Org. Lett., Vol. 15, No. 6, 2013
1255

Table 3. NHC-Pd(II)-Im 1 Catalyzed Reactions of Oxindoles 2
with Aryl Chlorides 3
Table 4. NHC-Pd(II)-Im 1 Catalyzed Reactions of Oxindoles 2
with Aryl Chlorides 3 To Form Products 5
a Unless specified otherwise, all reactions were carried out using 2
(0.65 mmol), 3 (0.5 mmol), 1 (1.0 mol %), KOtBu (4.0 equiv), and
toluene (1.0 mL) at 100 °C or reflux for 12 h. b Isolated yields. c 2b/3j =
0.75/0.5 mmol.
a All reactions were carried out using 2 (0.65 mmol), 3 (0.5 mmol), 1
(1.0 mol %), KOtBu (4.0 equiv), and toluene (1.0 mL) at 100 °C or reflux
under N2 for 12 h, and then the mixture was stirred under air for another
3 h. b Isolated yields.
reaction mixture was further exposed toair for another 3 h,
3-aryl-3-hydroxy oxindoles 5 can be formed in accepatable
to good yields (Table 4). Substituents on the aryl chlorides
have some effect on these reactions. For example, when
2-methylphenyl chloride 3d and 2-methoxyphenyl chloride
3i were used as the substrates, somewhat lower yields of
products 5d (49%) and 5h (56%) were obtained, probably
due to the steric hindrance of the substrates (Table 4,
entries 4 and 8). Moreover, when 2,6-dimethylphenyl
chloride 3e was utilized, only the normal R-arylated pro-
duct 4o was obtained in 87% yield, and none its oxidized
product was detected.
In conclusion, to the best of our knowledge, we report in
this paper the first example of a phosphine-free, easily
prepared and highly active NHC-Pd(II) complex catalyzed
R-arylation of oxindoles with aryl chlorides. Furthermore,
the normal R-arylatedproducts can be furthertransformed
to the oxidized products, the 3-aryl-3-hydroxy-oxindoles,
under ambient conditions at room temperature in a one-
pot procedure. Both reactions can tolerate a variety of
substrates such as both oxindoles and aryl chlorides, which
thus will enrich the chemistry of NHC-Pd(II) complexes
3j was also a suitable partner to give product 4j in 87%
yield (Table 2, entry 9).
Furthermore, a variety of oxindoles 2 and aryl chlorides
3 were subjected to the optimal reaction conditions to test
the generality. As can be seen from Table 3, all reactions
also took place smoothly to give the desired products 4 in
moderate to high yields. It seems that substituents on both
of the substrates tested have no obvious effect in these
cases. For instance, whether electron-rich or -poor groups
were attached on the oxindoles 2 or aryl chlorides 3, all
reactions worked well. Sterically hindered substituents
such as 2-Me and 2,6-Me2 on the aryl chlorides 3 did not
significantly affect the reactions (Table 3, entries 4 and 5).
However, such substituents on the oxindoles 2 affected the
reactions to some extent. For instance, for the reactions
involving 5,7-dimethyloxindole 2d, the corresponding pro-
ducts 4abÀ4ad were formed only in 44À55% yields,
respectively, maybe due to the steric hindrance (Table 3,
entries 17À19).
To our pleasure, when the reactions between oxindoles 2
and aryl chlorides 3 were first carried out under identical
conditions shown in Tables 1À3 for 12 h and then the
1256
Org. Lett., Vol. 15, No. 6, 2013

in organic synthesis and make the R-arylation reaction of
oxindoles more practical.
Supporting Information Available. General procedure
for the formation of compounds 4 and 5 and their 1H and
13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. Financial support from the Natural
Science Foundation of Zhejiang Province (No. LY12B02012)
is greatly appreciated.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 6, 2013
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