Iodine-catalyzed efficient synthesis of azaarene substituted 3-hydroxy-2-oxindole derivatives through sp3 C-H functionalization

Article abstract of DOI:10.1016/j.tet.2012.07.051

Iodine-catalyzed benzylic sp³ C-H bond functionalization of lutidines or picolines to isatins is described. This synthetic method provides a rapid entry towards biologically interesting 3-azaarene substituted 3-hydroxy-2-oxindole derivatives.

Full text of DOI:10.1016/j.tet.2012.07.051

Tetrahedron 68 (2012) 8286e8292
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Iodine-catalyzed efficient synthesis of azaarene substituted 3-hydroxy-2-oxindole
3
derivatives through sp CeH functionalization
Srinivasu V.N. Vuppalapati, Yong Rok Lee *
School of Chemical Engineering, Yeungnam University, Gyeongsan 712-749, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Iodine-catalyzed benzylic sp3 CeH bond functionalization of lutidines or picolines to isatins is described.
This synthetic method provides a rapid entry towards biologically interesting 3-azaarene substituted 3-
hydroxy-2-oxindole derivatives.
Article history:
Received 30 June 2012
Received in revised form 13 July 2012
Accepted 14 July 2012
Available online 22 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
3
-Hydroxy-2-oxindoles
3
sp CeH functionalization
Iodine
1. Introduction
Recently, a methodology for azaarene-substituted 3-hydroxy-2-
oxindole derivatives has been reported by trifluoromethanesulfonic
3
8
The development of a new methodology for the direct func-
acid-catalyzed sp CeH functionalization. Although one synthetic
method has been described, there is still a demand for general and
facile synthetic methods that can efficiently provide various
azaarene substituents on the 3-position of the 2-oxindole ring using
tionalization of relatively unreactive CeH bonds has become
1
a major topic of research. The recent rapid growth of this area is
not surprising, since such methodology facilitates the direct for-
mation of CeC and CeZ bonds (Z¼O, N, B, Si, etc.) without utilizing
prefunctionalized CeX bonds (X¼halogen, OTf, etc.). Among them,
9
mild catalysts. Among these, we think molecular iodine is a viable
alternative, and may be a promising catalyst for the synthesis of
azaarene-substituted 3-hydroxy-2-oxindole derivatives due to its
high tolerance to air and moisture, low-cost, easy availability,
sustainability, non-toxicity, and high catalytic activity. In the related
work, the synthesis of new class of alkyl azaarene pyridinium
3
2
sp CeH bond activation adjacent to nitrogen followed by CeC
3
,4
bond forming reactions of azaarenes provide
straightforward
access to useful building blocks for the design and synthesis of
biologically active compounds.
3
Molecules bearing 3-substituted 3-hydroxy-2-oxindoles are
zwitterions by iodine-mediated sp CeH functionalization has
been recently described. We report herein on the iodine-catalyzed
5
10
found widely in nature and pharmaceutical materials (Fig. 1).
These compounds have a variety of potent biological and phar-
maceutical activities, such as anticancer, anti-HIV, antioxidant and
neuroprotective properties. Interestingly, the biological effects of
reaction of isatins with lutidines or picolines to afford a varie-
ty of azaarene-substituted 3-hydroxy-2-oxindole derivatives
(Scheme 1).
6
these compounds are known to vary with the substituent at the C3
position of oxindoles.6 Their wide range of biological activities has
promoted research into the development of convenient and effi-
cient syntheses of 3-substituted 3-hydroxy-2-oxindoles. The syn-
thetic routes for the preparation of 3-aryl or 3-alkyl substituted
e
2
. Results and discussion
Reaction of 1-methylisatin (1a, 1.0 mmol) with 2,6-lutidine (2a,
.5 mmol) was first examined in the presence of 10 or 20 mol % of I
2
2
3
-hydroxy-2-oxindoles have already been developed by several
7
as a catalyst in several solvents (Table 1). Across the range of sol-
vents tested, the best yield (80%) was obtained in the presence of
groups. However, few synthetic approaches for 3-azaarene-
3
,4
substituted 3-hydroxy-2-oxindole derivatives are known.
20 mol % of iodine and in refluxing dioxane for 8 h. The product 3a
was determined by analysis of spectral data and compared directly
8
with the reported data.
To explore the generality and scope of this transformation, ad-
ditional reactions of several isatins with lutidines or picolines were
*
Corresponding author. Tel.: þ82 53 810 2529; fax: þ82 53 810 4631; e-mail
address: yrlee@yu.ac.kr (Y.R. Lee).
0
040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.051

S.V.N. Vuppalapati, Y.R. Lee / Tetrahedron 68 (2012) 8286e8292
8287
Fig. 1. Selected naturally occurring and pharmaceutical molecules with 3-subsituted 3-hydroxyeoxindoles.
Table 1
Reaction of 1-methylisatin (1a) with 2,6-lutidine (2a) in the presence of iodine in solvents
O
HO
N
catalyst
solvent
O +
N
O
N
2a
N
1a
3a
Entry
Catalyst
Solvent
Condition
Yield (%)
1
5
3
4
5
I
I
I
I
I
2
2
2
2
2
(20 mol %)
(20 mol %)
(20 mol %)
(20 mol %)
(10 mol %)
THF
Reflux, 12 h
Reflux, 12 h
Reflux, 10 h
Reflux, 8 h
Reflux, 8 h
45
10
52
80
67
Acetonitrile
Toluene
Dioxane
Dioxane
performed under the optimized reaction conditions. The results are
summarized in Table 2. Treatment of 1-methylisatin (1a) with 2,3-
lutidine (2b), 2-picoline (2c) or 4-picoline (2d) in the presence of
Table 2). Similarly, reactions of 1-phenylisatin (1b) with 2,6-lutidine
(2a) or 2-picoline (2c) gave products 3e and 3f in 71 and 62% yield
(entries 4e5). Other reactions of isatins without methyl or phenyl
substituents on the nitrogen atomwere also successful. Forexample,
treatment of isatin (1c) with 2,3-lutidine (2b) gave the desired
2
0 mol % iodine in refluxing dioxane for 8 h afforded desired
products 3be3d in 80, 70, and 64% yield, respectively (entries 1e3,
Table 2
Additional reactions of isatins with lutidines or picolines in the presence of 20 mol % of iodine
Entry
Isatins
Lutidines/Picolines
Time (h)
Product
Yield (%)
HO
1
8
N
80
N
3b
O
2
b
N
O
HO
N
2
8
70
O
N
3c
O
2
c
N
1a
N
(
continued on next page)

8288
S.V.N. Vuppalapati, Y.R. Lee / Tetrahedron 68 (2012) 8286e8292
Table 2 (continued )
Entry
Isatins
Lutidines/Picolines
Time (h)
Product
Yield (%)
N
HO
HO
3
8
64
3
d
N
O
2
d
N
O
N
O
O
4
8
3e
71
N
N
N
1b
N
2
a
HO
N
O
3f
5
8
62
N
2
c
O
3g
HO
N
6
8
50
O
N
N
N
O
1
c
2
b
H
N
H
O
HO
N
7
8
48
O
3h
2
2
a
c
O
N
1
d
H
N
H
HO
N
8
8
44
N
N
3i
O
N
H
HO
HO
N
Br
9
8
81
3
j
2
a
O
N
H
O
Br
10
8
Br
N
65
O
3k
N
N
O
1
e H
2b
N
H

S.V.N. Vuppalapati, Y.R. Lee / Tetrahedron 68 (2012) 8286e8292
8289
Table 2 (continued )
Entry
Isatins
Lutidines/Picolines
Time (h)
Product
Yield (%)
HO
N
Br
11
8
3l
50
N
O
2
c
N
H
N
HO
Br
12
8
3m
48
N
O
2
d
N
H
O
HO
N
1
3
O
8
80
N
O
3n
N
2
2
a
a
H
N
H
Br 1f
Br
O
Cl
HO
N
14
O
8
Cl
69
N
N
O
3o
H
N
1
g
H
O
HO
N
1
5
O
8
71
N
N
N
O
3p
N
2
2
2
a
a
c
H
N
Cl 1h
H
Cl
O
O N
2
HO
HO
N
16
O
8
O
O
2
N
71
N
O
3q
H
N
H
1
i
N
17
8
2
N
70
O
3r
N
H
product 3g in 50% yield (entry 6). Reactions of 5-methylisatin (1d)
and 2,6-ludine (2a) or 2-picoline (2c) with electron-donating group
on the benzene ring in refluxing dioxane for 8 h produced products
by coordination of an iodine catalyst to give N-iodopyridinium
cation 4. Importantly, the formation of this type of pyridinium
cation by the reaction of pyridine and iodine has been already
11
3
1
he3i in 48 and 44% yield, respectively (entries 7e8). With isatins
ee1i with electron-withdrawing groups on the benzene ring, the
reported in the literature. Cleavage of the CeH bond of 4 next
generates another intermediate 5, which subsequently undergoes
a nucleophilic addition to 1-methylisatin (1a) to give product 3a.
In summary, we have developed a novel iodine-catalyzed cou-
pling reaction of isatins to lutidines or picolines through benzylic
products 3je3r were also produced in 48e81 % yield (entries 9e17).
These reactions provided a rapid route to the synthesis of a variety of
azaarene-substituted 3-hydroxy-2-oxindoles derivatives in mod-
erate to good yields.
3
sp CeH bond activation of methylpyridines followed by CeC bond
The formation of 3a can be explained by the proposed mecha-
nism as shown in Scheme 2. The 2,6-lutidine (2a) is first activated
formation. This transformation provides a facile and efficient
method for the synthesis of 3-azaarenylmethyl-3-hydroxy-2-

8290
S.V.N. Vuppalapati, Y.R. Lee / Tetrahedron 68 (2012) 8286e8292
H
I-
I2
-I2
HO
-HI
N
N
N
+
N
I
I
O
2a
4
H
I
5
N
3
a
O
O
N
a
1
Scheme 2.
oxindoles derivatives that are very important in organic and me-
dicinal chemistry. Further studies to expand reactions of iodine-
catalyzed benzylic sp CeH functionalization are ongoing in our
18.6; IR (KBr): 3463, 1713, 1619, 1467, 1374, 1241, 1118, 994,
ꢂ1
758 cm
.
3
laboratory.
3.2.3. 3-Hydroxy-1-methyl-3-(pyridin-2-ylmethyl)indolin-2-one
8
ꢁ
1
(3c). Yield 70%; a yellow solid; mp 136e138 C; H NMR
(
300 MHz, CDCl ):
3
d
8.53 (1H, d, J¼4.8, 0.6 Hz), 7.63 (1H, td, J¼7.8,
3
3
. Experimental section
1.2 Hz), 7.24e7.17 (2H, m), 7.02 (1H, d, J¼7.8 Hz), 6.89 (1H, t,
J¼7.5 Hz), 6.78e6.72 (2H, m), 3.29 (1H, d, J¼15.0 Hz), 3.11 (3H, d,
1
3
.1. General
J¼0.9 Hz), 3.08 (1H, d, J¼14.7 Hz); C NMR (75 MHz, CDCl
3
):
d
176.6, 157.5, 148.0, 142.8, 137.1, 130.9, 129.2, 124.5, 123.7, 122.6,
All the experiments were carried out in a nitrogen atmosphere.
Merck precoated silica gel plates (Art.5554) with a fluorescent in-
122.2, 108.1, 76.1, 42.5, 26.0; IR (KBr): 3317, 2935, 1695, 1608, 1470,
ꢂ1
1372, 1237, 1095, 994, 745 cm
.
dicator were used for analytical TLC. Flash column chromatography
1
13
was performed using silica gel 9385 (Merck). The H NMR and
NMR spectra were recorded on a Bruker Model ARX (300 and
5 MHz, respectively) spectrometer in CDCl and DMSO-d as the
C
3.2.4. 3-Hydroxy-1-methyl-3-(pyridin-4-ylmethyl)indolin-2-one
8
ꢁ
1
(3d). Yield 64%; a white solid; mp 199e200 C; H NMR
(300 MHz, CDCl ):
7
3
6
3
d
8.38 (2H, d, J¼2.4 Hz), 7.38 (1H, t, J¼7.8 Hz),
solvents. The IR spectra were recorded on a Jasco FTIR 5300 spec-
trophotometer. The HRMS were carried out at the Korea Basic
Science Institute.
7.27 (1H, d, J¼7.2 Hz), 7.16 (1H, t, J¼7.5 Hz), 7.03 (2H, d, J¼3.0 Hz),
6.77 (1H, d, J¼7.2 Hz), 3.42 (1H, d, J¼12.0 Hz), 3.24 (1H, d,
1
3
J¼12.6 Hz), 3.10 (3H, s); C NMR (75 MHz, CDCl
3
): d 176.8, 148.0,
1
43.6, 142.4, 129.1, 128.9, 125.0, 123.6, 122.0, 107.5, 75.8, 43.1,
2
5.2; IR (KBr): 3087, 1716, 1606, 1474, 1359, 1222, 1074, 1006,
ꢂ1
3
.2. General procedure for the preparation of azaarene
755 cm
.
substituted 3-hydroxy-2-oxindole derivatives (3ae3r)
3
.2.5. 3-Hydroxy-3-{(6-methylpyridin-2-yl)methyl}-1-phenylindolin-
1
To
a
stirred solution of substituted indoline-2,3-diones
2-one (3e). Yield 71%; a thick syrup; H NMR (300 MHz, CDCl
7.88 (1H, br s), 7.44e7.23 (6H, m), 7.09 (1H, td, J¼7.2, 0.6 Hz), 7.01
(1H, d, J¼7.8 Hz), 6.88e6.76 (3H, m), 6.71 (1H, d, J¼7.8 Hz), 3.31 (1H,
3
):
(
(
1.0 mmol) in dioxane (1 mL) was added lutidines/picolines
2.5 mmol) and Iodine (20 mol %). The resulting mixture was heated
d
13
at reflux for 8 h. After completion of the reaction, poured EtOAc and
then washed with an ice cold saturated aqueous Na solution
d, J¼14.7 Hz), 3.10 (1H, d, J¼14.7 Hz), 2.47 (3H, s); C NMR (75 MHz,
CDCl ): 176.0, 157.0, 156.4, 142.6, 137.2, 134.0, 130.7, 129.3, 129.0,
2
S
2
O
3
3
d
(
10 mLꢀ2). Organic layer washed sequentially with brine, ice water
127.7, 126.1, 124.0, 122.9, 121.7, 121.4, 109.3, 76.1, 42.7, 24.1; IR (neat):
3397, 2343, 1728, 1602, 1468, 1373, 1201, 1100, 755 cm ; HRMS (EI)
ꢂ1
and dried over anhydrous MgSO
4
. Evaporation of the organic sol-
vent afforded the crude products, which was purified by silica gel
column chromatography using n-hexane/ethyl acetate (4:1e1:1) as
eluent to give desired products.
calculated for C21
18 2 2
H N O : 330.1368, found: 330.1367.
3.2.6. 3-Hydroxy-1-phenyl-3-(pyridin-2-ylmethyl)indolin-2-one
ꢁ
1
(3f). Yield 62%; a yellow solid; mp 138e140 C; H NMR (300 MHz,
3
.2.1. 3-Hydroxy-1-methyl-3-((6-methylpyridin-2-yl)methyl)in-
CDCl ):
3
d
8.48 (1H, d, J¼4.2 Hz), 7.57 (1H, t, J¼7.8 Hz), 7.43e7.38 (2H,
8
ꢁ
1
dolin-2-one (3a). Yield 80%; a yellow solid; mp 124e127 C;
NMR (300 MHz, CDCl ):
8.01 (1H, br s), 7.52 (1H, t, J¼7.5 Hz),
.27e7.21 (1H, m), 7.12 (1H, d, J¼7.5 Hz), 6.93e6.74 (4H, m), 3.29
1H, d, J¼15.0 Hz), 3.17 (3H, s), 3.00 (1H, d, J¼14.7 Hz), 2.59 (3H, s);
H
m), 7.32e7.26 (3H, m), 7.18e7.07 (2H, m), 7.01 (1H, d, J¼7.8 Hz),
6.92e6.88 (2H, m), 6.71 (1H, d, J¼7.8 Hz), 3.37 (1H, d, J¼14.7 Hz),
3
d
13
7
3.22 (1H, d, J¼14.7 Hz); C NMR (75 MHz, CDCl
3
): d 176.1, 157.2,
(
148.1, 142.8, 137.0, 134.1, 130.5, 129.4, 129.1, 127.8, 126.2, 124.6, 124.1,
1
3
C NMR (75 MHz, CDCl
3
):
d
176.5, 156.9, 156.7, 142.7, 137.1, 131.0,
123.1, 122.2, 109.4, 76.2, 43.2; IR (KBr): 3432, 2340, 1727, 1606, 1490,
1374, 1201, 1102, 755 cm ; HRMS (EI) calculated for C20
316.1212, found: 316.1209.
ꢂ1
129.0, 123.5, 122.4, 121.6, 121.3, 108.0, 75.9, 42.1, 25.9, 24.0; IR (KBr):
16 2 2
H N O :
ꢂ1
.
3
290, 1696, 1613, 1461, 1085, 1009, 755, 664, 600 cm
3
.2.2. 3-Hydroxy-1-methyl-3-((3-methylpyridin-2-yl)methyl)in-
3.2.7. 3-Hydroxy-3-((3-methylpyridin-2-yl)methyl)indolin-2-one
8
ꢁ
1
ꢁ
1
dolin-2-one (3b). Yield 80%; a red solid; mp 118e120 C; H NMR
300 MHz, CDCl ):
8.33 (1H, d, J¼4.8 Hz), 7.41 (1H, d, J¼7.8 Hz),
.19 (1H, td, J¼7.8, 1.5 Hz), 7.14 (1H, dd, J¼7.5, 4.8 Hz), 6.84e6.71
3H, m), 3.26 (1H, d, J¼15.6 Hz), 3.10 (3H, s), 2.97 (1H, d, J¼15.6 Hz),
.98 (3H, s); 13C NMR (75 MHz, CDCl
): 176.6, 156.3, 145.1, 142.7,
38.3, 132.3, 131.4, 129.1, 123.6, 122.5, 122.0, 108.1, 75.9, 38.2, 26.0,
(3g). Yield 50%; a yellow solid; mp 163e165 C; H NMR
(300 MHz, CDCl ):
(
7
(
1
3
d
3
d
8.82 (1H, br s), 8.42 (1H, d, J¼4.8 Hz), 7.48
(1H, d, J¼7.8 Hz), 7.18e7.13 (2H, m), 6.86e6.82 (2H, m), 6.78 (1H,
d, J¼7.5 Hz), 3.34 (1H, d, J¼15.3 Hz), 3.09 (1H, d, J¼15.3 Hz), 2.05
13
3
d
(3H, s); C NMR (75 MHz, CDCl
3
):
d
179.4, 156.2, 145.2, 140.0,
1
138.5, 132.6, 131.9, 129.1, 124.0, 122.6, 122.2, 110.3, 38.4, 18.7; IR

S.V.N. Vuppalapati, Y.R. Lee / Tetrahedron 68 (2012) 8286e8292
8291
(
7
2
KBr): 3378, 3206, 1724, 1620, 1460, 1191, 1116, 1032, 957,
140.7, 132.9, 131.7, 127.4, 127.3, 125.4, 113.1, 111.4, 76.0, 42.2; IR
ꢂ1
55 cm ; HRMS (EI) calculated for C15
54.1054.
H
14
N
2
O
2
: 254.1055, found:
(KBr): 3352, 2978, 2813, 2708, 1709, 1609, 1465, 1209, 1004, 812,
ꢂ1
624 cm ; HRMS (EI) calculated for C14
found: 318.0002.
2 2
H11BrN O : 318.0004,
3
.2.8. 3-Hydroxy-5-methyl-3-{(6-methylpyridin-2-yl)methyl}in-
ꢁ
1
dolin-2-one (3h). Yield 48%; a yellow solid; mp 200e203 C;
NMR (300 MHz, DMSO-d ):
H
3.2.14. 7-Bromo-3-hydroxy-3-{(6-methylpyridin-2-yl)methyl}in-
ꢁ
1
6
d
10.03 (1H, s), 7.50 (1H, t, J¼7.5 Hz),
dolin-2-one (3n). Yield 80%; a white solid; mp 158e160 C; H NMR
(300 MHz, CDCl ): 8.08 (1H, br s), 7.80 (1H, s), 7.51 (1H, t,
7
3
.01e6.89 (3H, m), 6.66 (1H, s), 6.57 (1H, d, J¼7.8 Hz), 6.29 (1H, s),
3
d
.23 (1H, d, J¼13.2 Hz), 3.09 (1H, d, J¼13.2 Hz), 2.29 (3H, s), 2.14 (3H,
J¼7.8 Hz), 7.26 (1H, dd, J¼8.1, 0.9 Hz), 7.08 (1H, d, J¼8.1 Hz), 6.81
13
s); C NMR (75 MHz, DMSO-d
6
): d 178.6, 156.3, 155.5, 139.1, 136.1,
(1H, d, J¼7.5 Hz), 6.75 (1H, t, J¼7.5 Hz), 6.65e6.63 (1H, m), 3.25 (1H,
13
1
31.1, 129.5, 128.8, 125.4, 121.1, 120.7, 108.8, 75.6, 44.6, 23.7, 20.6; IR
d, J¼15.0 Hz), 3.00 (1H, d, J¼14.7 Hz), 2.53 (3H, s); C NMR
(
KBr): 3342, 2966, 2803, 1708, 1595, 1475, 1297, 1147, 1090, 813,
3
(75 MHz, CDCl ): d 177.4, 157.2, 156.3, 139.3, 137.6, 133.0, 131.8,
ꢂ1
6
2
47 cm ; HRMS (EI) calculated for C16
68.1213.
H
16
N
2
O
2
: 268.1212, found:
123.9, 123.0, 122.1, 121.6, 103.1, 77.6, 42.2, 24.1; IR (KBr): 3445, 3154,
ꢂ1
1731, 1613, 1464, 1323, 1220, 1119, 784, 729 cm ; HRMS (EI) cal-
culated for C15
2 2
H13BrN O : 332.0160, found: 332.0159.
3
.2.9. 3-Hydroxy-5-methyl-3-(pyridin-2-ylmethyl)indolin-2-one
ꢁ
1
(3i). Yield 44%;
a
white solid; mp 212e213 C;
H NMR
3.2.15. 5-Chloro-3-hydroxy-3-{(6-methylpyridin-2-yl)methyl}in-
ꢁ
1
(
7
0
300 MHz, DMSO-d
6
):
d
10.01 (1H, s), 8.31 (1H, dd, J¼5.4, 1.8 Hz),
dolin-2-one (3o). Yield 69%; a white solid; mp 191e193 C; H NMR
(300 MHz, DMSO-d ):
.60 (1H, td, J¼7.8, 1.2 Hz), 7.14e7.12 (2H, m), 6.90 (1H, dd, J¼7.8,
6
d
10.24 (1H, s), 7.51 (1H, t, J¼7.5 Hz), 7.15 (1H,
.9 Hz), 6.71 (1H, s), 6.55 (1H, d, J¼7.8 Hz), 6.25 (1H, s), 3.29 (1H,
dd, J¼8.4, 2.4 Hz), 7.00 (2H, t, J¼8.1 Hz), 6.90 (1H, d, J¼2.1 Hz), 6.68
13
d, J¼13.2 Hz), 3.17 (1H, d, J¼13.2 Hz), 2.15 (3H, s); C NMR
75 MHz, DMSO-d ): 178.5, 156.1, 148.3, 139.1, 135.8, 131.0, 129.7,
28.9, 125.2, 124.3, 121.6, 108.9, 75.7, 45.1, 20.6; IR (KBr): 3320,
(1H, d, J¼8.4 Hz), 6.38 (1H, s), 3.29 (1H, d, J¼13.5 Hz), 3.14 (1H, d,
13
(
1
3
6
d
J¼13.5 Hz), 2.26 (3H, s); C NMR (75 MHz, DMSO-d
6
): d 178.2,
156.3, 155.0, 140.6, 136.2, 133.1, 128.3, 124.8, 121.1, 120.7, 110.4, 75.6,
44.4, 23.6; IR (KBr): 3295, 2965, 2804, 2686, 1711, 1481, 1291, 1166,
ꢂ1
016, 2814, 1709, 1488, 1205, 1114, 808, 752, 645 cm ; FAB-
þ
ꢂ1
HRMS m/z (MþH) calculated for C15
H
15
N
2
O
2
: 255.1134, found:
1012, 839, 647 cm ; HRMS (EI) calculated for C15
2 2
H13ClN O :
2
55.1134.
288.0666, found: 288.0667.
3
.2.10. 5-Bromo-3-hydroxy-3-{(6-methylpyridin-2-yl)methyl}in-
3.2.16. 7-Chloro-3-hydroxy-3-{(6-methylpyridin-2-yl)methyl}in-
ꢁ
1
ꢁ
1
dolin-2-one (3j). Yield 81%; a white solid; mp 194e196 C;
NMR (300 MHz, DMSO-d ):
10.28 (1H, s), 7.52 (1H, t, J¼7.5 Hz),
.28 (1H, dd, J¼8.1, 1.5 Hz), 7.01e6.96 (3H, m), 6.65 (1H, d,
J¼8.4 Hz), 6.39 (1H, s), 3.29 (1H, d, J¼13.2 Hz), 3.13 (1H, d,
H
dolin-2-one (3p). Yield 71%; a white solid; mp 167e169 C;
H
6
d
NMR (300 MHz, CDCl ): 8.31 (1H, br s), 8.10 (1H, br s), 7.55 (1H, t,
3
d
7
J¼7.8 Hz), 7.16e7.09 (2H, m), 6.85e6.79 (2H, m), 6.64 (1H, d,
J¼7.2 Hz), 3.31 (1H, d, J¼14.7 Hz), 3.03 (1H, d, J¼14.7 Hz), 2.56 (3H,
13
13
J¼13.2 Hz), 2.27 (3H, s); C NMR (75 MHz, DMSO-d
56.3, 155.0, 141.0, 136.2, 133.5, 131.2, 127.7, 121.2, 120.8, 112.8,
11.0, 75.6, 44.4, 23.6; IR (KBr): 3428, 3174, 2353, 1737, 1628, 1125,
6
):
d
178.2,
s); C NMR (75 MHz, CDCl
3
):
d
177.9, 177.8, 157.2, 156.3, 137.7,
1
1
8
137.5, 133.0, 129.0, 123.4, 122.4, 122.0, 121.5, 115.2, 42.1, 24.1; IR
(KBr): 3294, 2966, 2804, 2687, 1714, 1468, 1292, 1167, 1104, 846,
ꢂ1
ꢂ1
15 cm ; HRMS (EI) calculated for C15
H
13BrN
2
O
2
: 332.0160,
647 cm ; HRMS (EI) calculated for C15
found: 288.0668.
2 2
H13ClN O : 288.0666,
found: 332.0159.
3
.2.11. 5-Bromo-3-hydroxy-3-{(3-methylpyridin-2-yl)methyl}in-
3.2.17. 3-Hydroxy-3-{(6-methylpyridin-2-yl)methyl}-5-nitroindolin-
ꢁ
1
ꢁ
1
dolin-2-one (3k). Yield 65%; a yellow solid; mp 208e210 C;
NMR (300 MHz, DMSO-d ): 10.29 (1H, s), 8.04 (1H, s), 7.46 (1H, d,
H
2-one (3q). Yield 71%; a yellow solid; mp 206e208 C; H NMR
(300 MHz, DMSO-d ):
6
d
6
d
10.88 (1H, s), 8.11 (1H, dd, J¼8.7, 2.4 Hz),
J¼6.9 Hz), 7.28 (1H, d, J¼8.1 Hz), 7.15 (1H, s), 7.03 (1H, s), 6.70 (1H, d,
J¼7.5 Hz), 6.35 (1H, s), 3.47 (1H, d, J¼16.5 Hz), 3.25 (1H, d,
7.82 (1H, d, J¼2.4 Hz), 7.51 (1H, t, J¼7.8 Hz), 7.00 (2H, t, J¼6.0 Hz),
6.89 (1H, d, J¼8.7 Hz), 6.53 (1H, s), 3.42 (1H, d, J¼13.8 Hz), 3.24 (1H,
13
13
J¼15.0 Hz), 2.24 (3H, s); C NMR (75 MHz, DMSO-d
6
):
d
178.2,
d, J¼13.8 Hz), 2.20 (3H, s); C NMR (75 MHz, DMSO-d
6
): d 179.0,
154.9, 145.3, 141.7, 137.2, 134.5, 131.6, 131.1, 126.7, 121.4, 112.4, 111.0,
156.4, 154.7, 148.6, 141.5, 136.4, 132.2, 126.0, 121.2, 120.9, 120.4,
7
5.2, 18.4; IR (KBr): 3380, 2937, 2349, 1732, 1616, 1464, 1290, 1204,
109.3, 75.1, 44.1, 23.5; IR (KBr): 3298, 2976, 1722, 1616, 1527, 1466,
ꢂ1
ꢂ1
1100, 954, 756 cm ; HRMS (EI) calculated for C15
H13BrN
2
O
2
:
1335, 1168, 1104, 637 cm ; HRMS (EI) calculated for C15
299.0906, found: 299.0906.
13 3 4
H N O :
3
32.0160, found: 332.0158.
3
.2.12. 5-Bromo-3-hydroxy-3-(pyridin-2-ylmethyl)indolin-2-one
3.2.18. 3-Hydroxy-5-nitro-3-(pyridin-2-ylmethyl)indolin-2-one
ꢁ
1
ꢁ
1
(3l). Yield 50%;
a
yellow solid; mp 215e216 C;
H
NMR
(3r). Yield 70%; a yellow solid; mp 221e223 C; H NMR (300 MHz,
DMSO-d ):
(
300 MHz, DMSO-d
6
):
d
8.30 (1H, d, J¼3.9 Hz), 7.63 (1H, t,
6
d
10.87 (1H, s), 8,25 (1H, d, J¼3.9 Hz), 8.09 (1H, dd, J¼8.4,
J¼8.1 Hz), 7.27 (1H, d, J¼7.2 Hz), 7.17e7.11 (2H, m), 7.05 (1H, s),
2.1 Hz), 7.84 (1H, d, J¼2.4 Hz), 7.62 (1H, td, J¼7.5, 1.8 Hz), 7.19 (1H, d,
6
.62 (1H, d, J¼8.1 Hz), 6.39 (1H, s), 3.34 (1H, d, J¼10.5 Hz), 3.21
J¼7.8 Hz), 7.14e7.10 (1H, m), 6.86 (1H, d, J¼8.7 Hz), 6.57 (1H, s), 3.47
13
13
(
1
4
1H, d, J¼13.2 Hz); C NMR (75 MHz, DMSO-d
6
):
d
178.0, 155.7,
(1H, d, J¼13.5 Hz), 3.30 (1H, d, J¼13.2 Hz); C NMR (75 MHz,
48.3, 140.9, 135.9, 133.4, 131.3, 127.5, 124.3, 121.7, 112.7, 111.2, 75.7,
6
DMSO-d ): d 178.9, 155.3, 148.4, 141.6, 136.1, 132.0, 126.1, 124.4,
ꢂ1
4.8; IR (KBr): 3344, 2934, 1714, 1473, 1194, 1110, 898, 747 cm
;
121.8,120.3,120.2,109.4, 75.2, 44.6; IR (KBr): 3497, 3393,1743,1616,
ꢂ1
HRMS (EI) calculated for
C
14
H
11BrN 318.0004, found:
2
O
2
:
1482, 1335, 1264, 1199, 1005, 834, 751 cm ; HRMS (EI) calculated
318.0002.
11 3 4
for C14H N O : 285.0750, found: 285.0748.
3
.2.13. 5-Bromo-3-hydroxy-3-(pyridin-4-ylmethyl)indolin-2-one
ꢁ
1
(3m). Yield 48%; a yellow solid; mp 225e228 C; H NMR
Acknowledgements
(
300 MHz, DMSO-d ): 10.29 (1H, s), 8.33 (2H, s), 7.33 (1H, d,
6
d
J¼8.1 Hz), 7.25 (1H, s), 6.95 (2H, d, J¼4.8 Hz), 6.61 (1H, d,
This study was supported by grant No. RTI04-01-04 from the
Regional Technology Innovation Program of the Ministry of
Knowledge Economy (MKE).
J¼8.1 Hz), 6.39 (1H, s), 3.23 (1H, d, J¼12.3 Hz), 3.01 (1H, d,
1
3
J¼12.3 Hz); C NMR (75 MHz, DMSO-d
6
): d 177.8, 148.7, 143.7,

8
292
S.V.N. Vuppalapati, Y.R. Lee / Tetrahedron 68 (2012) 8286e8292
6. (a) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209; (b) Dounay, A. B.;
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