Efficient copper-catalyzed intramolecular N-arylation for the synthesis of oxindoles

Article abstract of DOI:10.1016/j.tetlet.2012.12.082

An efficient copper-catalyzed intramolecular N-arylation was performed by using substituted 2-(2-bromoaryl)acetamide with a small amount of Cu ₂O and benzene-1,2-diamine as catalytic system under aerobic conditions, which provided good to excellent yields of oxindoles with tolerance of a wide variety of substrates.

Full text of DOI:10.1016/j.tetlet.2012.12.082

Tetrahedron Letters 54 (2013) 1155–1159
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Tetrahedron Letters
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Efficient copper-catalyzed intramolecular N-arylation for the synthesis of
oxindoles
⇑
Yu-Huei Jhan, Ting-Wei Kang, Jen-Chieh Hsieh
Department of Chemistry, Tamkang University, New Taipei City, 25137 Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient copper-catalyzed intramolecular N-arylation was performed by using substituted
2-(2-bromoaryl)acetamide with small amount of Cu2O and benzene-1,2-diamine as catalytic system
under aerobic conditions, which provided good to excellent yields of oxindoles with tolerance of a wide
variety of substrates.
Received 29 October 2012
Revised 15 December 2012
Accepted 18 December 2012
Available online 27 December 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Cu2O
Ullmann coupling
Benzene-1,2-diamine
Oxindole
N-arylation
Oxindoles are very important compounds for organic synthesis
because of their wide application in natural alkaloids,1 bioactive
compounds2 and pharmaceuticals.3 Numerous well-established
methods were applied to access this structure motif, and the palla-
dium catalysis4–8 have been often chosen as a main strategy for the
synthetic approach. Although the palladium-catalyzed cyclization
is the most powerful method to establish elaborated structures,
the high cost and air-sensitive nature make other methods worth
developing.
A copper-catalyzed coupling reaction is an alternative pathway
to synthesize oxindoles, which possesses the advantages of large
scale synthesis and could be conducted under aerobic conditions.9
However, only few literatures are related to the copper-mediated
construction of oxindoles. In 2006, Ma reported copper-catalyzed
intramolecular arylation of b-keto amides for the synthesis of
3-acyloxindoles.10 Later, Kündig built oxindole subunits by the
copper-mediated C–H functionalization.11 More recently, Taylor
first realized the copper-catalyzed C–H activation to synthesize
oxindoles.12 The intramolecular N-arylation was utilized for the
formation of some specific oxindoles as well.13 In those former re-
ports; however, the installation of protecting groups on the nitro-
gen atom is always necessary to facilitate the construction of
oxindoles. To address this limitation, we recently disclosed the
synthesis of oxindoles via copper-catalyzed domino coupling reac-
tion, which was successfully applied as a key step to the total syn-
thesis of ( )-coerulescine and ( )-horsfiline (Scheme 1).14 This
method provides a shortest synthetic route and highest overall
yields for the synthesis of these two alkaloids.
Based on the preliminary result and our previous experience in
the catalytic coupling reactions,15 we then tried to explore the
possibility for the synthesis of oxindoles via the copper-catalyzed
N-arylation without pre-installing N-protecting groups.
Our previous condition was used for the initial test; thus,
2-(2-bromophenyl)-2-methylpropanamide (1a) was treated with
5 mol % CuI, 10 mol % N-acetylglycine (L1) and 3.0 equiv NaOH in
t-BuOH at 100 °C for 24 h, affording 3,3-dimethyloxindole (2a) in
75% NMR yield (Table 1, entry 1). To optimize this reaction, we first
explored the influence of different ligands. Therefore, some other
amino acids were selected as ligands to study the effect for this
intramolecular N-arylation (entries 2–4). When the 1H-imidaz-
ole-4-carboxylic acid (L2) and 2-(methylamino)acetic acid (L3)
were employed as ligands, the desired product 2a was obtained
in 67% and 74% yields, respectively (entries 2 and 3), which shows
no further improvement comparing to entry 1. Similar result was
found when L-proline (L4) was used as ligand (entry 4). Because
no improvement was exhibited, we then turned to test the aniline
and phenanthroline type ligands.
Accordingly, 1,10-phenanthroline (L5), 8-aminoquinoline (L6),
2-aminophenol (L7) and benzene-1,2-diamine (L8) were employed
for screening (entries 5–8). It was found that 1,10-phenanthroline
(L5) is almost functionless, but aniline type ligands performed very
well. Among the various aniline ligands, L8 exhibited the best per-
formance and gave good yield of 2a.
With the best ligand in hand, we further optimized the reaction
conditions and the results are summarized in Table 2. Both polar
⇑
Corresponding author. Tel.: +886 2 26215656x2545; fax: +886 2 26209924.
E-mail address: jchsieh@mail.tku.edu.tw (J.-C. Hsieh).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.082

1156
Y.-H. Jhan et al. / Tetrahedron Letters 54 (2013) 1155–1159
N
N
CuI (5.0 mol %)
O
R
N-acetylglycine (10 mol %)
R
OH
Br
R
KI (1.0 mol %), NaOH (3.0 equiv)
CN
N
H
O
O
t-BuOH, 100 oC, air
Br
R = H, OMe
3 steps
N
H
Br
R = H, OMe
N-acetylglycine
R = H, 91%, coerulescine
R = OMe, 88%,
horsf iline
Scheme 1. Total synthesis of ( )-coerulescine and ( )-horsfiline.
Table 1
Comparison of various ligands in the coupling reactiona
Table 2
Optimization of reaction conditionsa
CuI (5.0 mol %), L (10.0 mol %)
NH2
NH2
L8
(2x mol %)
[Cu] (x mol %),
NaOH (3.0 equiv)
Base (3.0 equiv)
O
O
O
O
t-BuOH, 100 oC, 24 h, air
Br
N
H
2a
N
H
2a
Br
1a
Solvent, T oC, 24 h,air
1a
Entry
x
[Cu]
Solvent
Base
T (°C)
Yieldb (%)
HN
O
H
OH
OH
N
OH
OH
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17c
18
19
20
5
5
5
5
5
5
5
5
5
5
5
5
1
1
1
1
1
1
1
1
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
t-BuOH
Dioxane
DMF
DME
DMSO
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
82
64
42
51
69
37
76
23
91
99
11
8
87
64
78
81
99
18
0
N
H
N
N
H
N
H
L1
L4
L8
L2
L3
O
O
O
O
Benzene
Toluene
CH3CN
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
L5
L6
L7
NH2
HO
N
N
H2N
H2N
NH2
Entry
L
Yieldb (%)
NaOMe
NaOtBu
K2CO3
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
75
67
74
64
16
65
71
82
Cs2CO3
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
CuI
CuSCN
Cu(OAc)2
Cu(OTf)2
Cu2O
Cu2O
Cu2O
Cu2O
a
Reactions were carried out using 0.1 mmol 2-(2-bromophenyl)-2-methylpro-
60
rt
panamide (1a) with 5 mol % CuI, 10 mol % ligand and 3.0 equiv NaOH in 1.0 mL t-
BuOH at 100 °C for 24 h (under air).
0
a
1H NMR yield based on internal standard mesitylene.
b
Reactions were carried out using 0.1 mmol 2-(2-bromophenyl)-2-methylpro-
panamide (1a) with copper source, ligand and 3.0 equiv base in 1.0 mL solvent for
24 h (under air).
b
1H NMR yield based on internal standard mesitylene.
18 h.
c
and non-polar solvents afforded desired product 2a (Table 2, en-
tries 1–8); among them, t-BuOH provided better yields than others.
Therefore, t-BuOH was chosen for further examination of this
intramolecular N-arylation. The performance of this reaction also
strongly depends on the selection of base (entries 9–12); we found
that only the strong base could smoothly promote the reaction and
provide product 2a in excellent yield. Next, we reduced the load-
ings of catalyst and employed different copper sources (entries
13–17). Among the various copper sources employed as catalysts,
Cu2O was found to be the most effective one, providing excellent
yield of 2a (entry 17). In addition, lower temperature significantly
diminished the yield of desired product or shut down the reaction
(entries 18–20), and the desired product was not obtained in the
absence of Cu2O. The reaction proceeded well under either nitro-
gen atmosphere or air, and both provided excellent yields of 2a.
The Cu-catalyzed intramolecular N-arylation was successfully
extended to various substrates (1); the results are listed in Table 3.
The electronic density on the arene moiety slightly affected the
reaction (entries 1–3). Thus, substrates with electron-withdrawing
group in the para position of bromide (1b) provided better yield of
the desired product than those with electron-donating group in the
same position (1c, 1d). Naphthyl moiety is also tolerated to give
the corresponding product 2e in 91% yield (entry 4). A wide variety
of substituents and spiro rings on the 3,3-position of oxindole
could also be well tolerated (2f–2o). It was observed that the steric
effect of the substituents on the 3,3-position of the oxindole dom-
inated the yields of the reactions (entries 5 and 6). Thus, the yields
of the corresponding products decreased along with the larger
substituents.
Oxindoles with a spiro ring on the 3,3-position were also
obtained in good to excellent yields (entries 7–14). For the same
spiro ring on the 3,3-position of oxindoles, the yields depended
only on the electronic effect of the arene moiety (2h vs 2i vs 2j,
2k vs 2l). The larger size of the spiro ring provided lower yields
of the desired products (2h vs 2m vs 2n). Moreover, a natural alka-
loid ( )-coerulescine (2o) could be obtained by this method in good
yield (entry 14) as well. Not only the quaternary carbon on the
3-position, but also the products with secondary carbon of 3,3-
unsubstituted oxindoles (2p, 2q) can be successfully generated.
The N-protected substrates were well processed and gave desired
products in good to excellent yields (entries 17–20); however,
cyclization of the substrate with N-acetylamide (entry 20, 1u)
accompanied unexpected deprotection to furnish an unprotected
oxindole (2a) in excellent yield.
Various substrates with N-acetylamide were further examined
by using the same protocol, and the results indicate that all the
substrates provided the surprisingly deprotected oxindoles (Table
4). Reactions for those substrates bearing various substituents on
the arene moiety and with different groups alpha to the amide car-
bonyl all proceeded well and gave desired products in excellent
yields. Comparing with the substrates without N-substituents,

Y.-H. Jhan et al. / Tetrahedron Letters 54 (2013) 1155–1159
1157
Table 3
Copper-catalyzed intramolecular N-arylation to form oxindolesa
R3 R2
Cu2O (1.0 mol %), L8 (2.0 mol %)
R3
R2
NHR4
NaOtBu (3.0 equiv)
O
t-BuOH, 100 oC, air
O
N
R1
Br
R1
R4
NH2
2
1
L8 :
NH2
Entry
1
1
2
t (h)
Yieldb (%)
85 (84)c
Entry
1
2
t (h)
Yieldb (%)
Cl
NH2
Cl
MeO
O
MeO
NH2
O
18
11
24
74
46
N
H
Br
O
1b
2b
O
N
H
Br
1l
2l
O
O
MeO
NH2
MeO
O
O
NH2
2
3
24
24
76
69
12
13
24
36
N
H
Br
1c
O
2c
O
N
H
Br
1m
2m
NH2
O
O
O
O
O
O
N
H
Br
84 (68)c
1d
2d
NH2
O
O
O
N
H
Br
Br
1n
2n
NH2
N
N
O
O
NH2
N
H
4
24
91
14
24
87
Br
O
1e
2e
O
N
H
1o
2o
NH2
Cl
Cl
NH2
O
99 (99)c
15
16
24
24
81
70
O
5
6
18
24
O
N
H
Br
1p
2p
Br
1f
N
H
2f
NH2
MeO
MeO
O
O
O
O
N
Br
NH2
1q
80
H
2q
O
N
H
O
Br
2g
1g
H
N
NH2
O
7
8
9
18
18
24
95 (97)c
86 (84)c
55
17
18
19
48
36
18
92 (76)c
87 (74)c
89 (91)c
O
O
O
O
O
N
N
Br
Br
Br
Br
1r
O
2r
N
H
Br
1h
2h
H
N
Cl
Cl
Bn
NH2
O
O
1s
O
N
H
2s
Bn
Br
1i
2i
H
N
Ts
NH2
O
O
O
O
O
O
N
Ts
1t
O
N
H
2t
Br
1j
2j
H
N
O
NH2
10
24
88
20
18
99 (99)c
O
N
O
1u
H
2a
O
N
H
Br
1k
2k
a
Reactions were carried out using 0.5 mmol (1) with 1.0 mol % Cu2O, 2.0 mol % benzene-1,2-diamine and 3.0 equiv NaOtBu in 5.0 mL t-BuOH at 100 °C for the specific time
(t) of various substrates (under air).
b
Isolated yield after column chromatography.
Yield for 24 h.
c

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Y.-H. Jhan et al. / Tetrahedron Letters 54 (2013) 1155–1159
Table 4
Formation of oxindoles from protected N-acetylamidea
R2 R1
Cu2O (1.0 mol %),
NaOtBu (3.0 equiv)
(2.0 mol %)
R3
R2
L8
H
N
O
O
O
t-BuOH, 100 oC, 24 h, air
N
Br
R1
R4
H
NH2
1
2
L8 :
NH2
Entry
1
1
2
Yieldb (%)
88
H
N
MeO
MeO
O
O
O
N
H
Br
1v
2c
H
N
O
O
O
O
O
2
3
94
89
O
O
O
N
Br
1w
H
2d
H
N
O
N
H
O
2f
Br
1x
1y
H
N
4
5
97
93
O
O
O
N
H
Br
2h
H
N
O
O
O
N
H
Br
1z
2n
a
Reactions were carried out using 0.5 mmol (1) with 1.0 mol % Cu2O, 2.0 mol % benzene-1,2-diamine, and 3.0 equiv NaOtBu in 5.0 mL
t-BuOH at 100 °C for 24 h (under air).
b
Isolated yield after column chromatography.
Table 5
Time-controlled formation of 2a
Cu2O (1.0 mol %)
L8
O
O
+
H
N
(2.0 mol %)
NaOtBu (3.0 equiv)
N
N
H
2a
2a'
O
O
O
t
Br
1a'
t-BuOH, 100 oC, , air
NH2
O
Br
1a
a
a
Entry
t (h)
1a0
2aa
2a0
1aa
1
2
3
4
4
8
12
16
74
37
16
3
21
49
75
94
0
0
1
0
5
14
12
3
a
Ratios were determined by GC–MS.
substrates with N-acetylamide provided better isolated yields of
the corresponding oxindoles (entries 1, 2 and 5).
N-arylation. A small amount of 1a was found along with the
formation of 2a, which made us propose the reaction pathway
(Scheme 2).
The reaction is likely to proceed by the nucleophilic substitution
of tert-butoxide to 1a0, followed by the subsequent coordination to
the copper complex affording complex A. Cyclization of complex A
generates product 2a, and the protonation of complex A by tert-
butanol produces compound 1a.
To understand the reason why the substrates with N-acetyla-
mide caused higher yields of desired oxindoles, a control experi-
ment was carried out to probe the reaction pathway (Table 5).
We found that almost no 2a0 was detected in the reaction and
the formation of 1a was observed during the reaction period,
which means deprotection occurred before the intramolecular

Y.-H. Jhan et al. / Tetrahedron Letters 54 (2013) 1155–1159
1159
H
N
H
OtBu
NH2
N
t-BuOH
[Cu]
O
O
O
O
[Cu]
Br
1a'
O
Br
Br
[Cu]
OtBu
A
1a
O
N
H
2a
Scheme 2. Proposed reaction pathway.
K. Synthesis 2009, 3003; (d) Millemaggi, A.; Taylor, R. J. K. Eur. J. Org. Chem.
2010, 4527; (e) Pedras, M. S. C.; Yaya, E. E.; Glawischnig, E. Nat. Prod. Rep. 2011,
28, 1381.
In conclusion, we have developed an effective method for the
synthesis of oxindoles via Cu2O/benzene-1,2-diamine catalytic
condition for the intramolecular N-arylation. This method effi-
ciently provided poly-substituted oxindoles in moderate to excel-
lent yields with good tolerance of various substrates and only
required very small amount of catalyst under aerobic conditions;
thus, increased its potential for industrial applications. Further
studies to extend the application of this catalytic system are cur-
rently underway.
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Acknowledgment
We thank the National Science Council of the Republic of China
(NSC-101-2113-M-032-004-MY2) for the financial support of this
research.
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Supplementary data
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Supplementary data associated (experimental procedure, 1H
and 13C NMR spectra and spectral data for all the new compounds)
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2012.12.082.
ˇ
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