N-Heterocyclic carbene-catalyzed hydroacylation of isatins with aldehydes: Access to 3-acyloxy-1,3-dihydro-2H-indol-2-ones

Article abstract of DOI:10.1016/j.tet.2011.07.075

The N-heterocyclic carbene-catalyzed hydroacylation of isatins with aldehydes has been described. This process offers a highly efficient and atom-ecomonical access to 3-acyloxy-1,3-dihydro-2H-indol-2-ones in good to excellent yields.

Full text of DOI:10.1016/j.tet.2011.07.075

Tetrahedron 67 (2011) 7557e7562
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N-Heterocyclic carbene-catalyzed hydroacylation of isatins with aldehydes: access
to 3-acyloxy-1,3-dihydro-2H-indol-2-ones
,
a
a
a
a,b,
Ding Du a , Yingyan Lu , Jianlin Jin , Weifang Tang , Tao Lu
*
*
a Department of Organic Chemistry, China Pharmaceutical University, Nanjing 210009, China
b State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 May 2011
Received in revised form 10 July 2011
Accepted 25 July 2011
Available online 30 July 2011
The N-heterocyclic carbene-catalyzed hydroacylation of isatins with aldehydes has been described. This
process offers a highly efficient and atom-ecomonical access to 3-acyloxy-1,3-dihydro-2H-indol-2-ones
in good to excellent yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
N-Heterocyclic carbenes
Organocatalysis
Hydroacylation
Isatins
Aldehydes
1. Introduction
and versatile methods for the hydroacylation of carbonyl systems are
highly desirable in the pursuit of efficient, environmental benign and
The transition-metal-catalyzed hydroacylation of alkenes and al-
kynes using aldehydes as acyl donors have attracted considerable
attention due to their atom-economy and broad applications in the
preparation of various carbonyl compounds (Eq. 1, Scheme 1).1 In
recent years, N-heterocyclic carbenes (NHCs) have also been suc-
cessfully applied as efficient organocatalysts in the hydroacylation of
activated and even unactivated alkenes and alkynes, which serve as
acceptors for carbonyl anions generated from aldehydes via an NHC-
mediated umpolung process (Eq. 1, Scheme 1).2 Notwithstanding,
analogous hydroacylation processes involving aldehydes and car-
bonyl groups are much less explored, with some limited reactions
developed in the presence of transition-metal catalysts (Eq. 2,
Scheme 1).3 The NHC-catalyzed direct hydroacylation of carbonyl
compounds with aldehydes was only reported by Scheidt4 and fur-
ther improved by Pal5 using activated ketones as substrates (Eq. 3,
Scheme 1).6 In this process, differing from the mechanism of NHC-
catalyzed hydroacylation of CeC double or triple bonds, the carbene
facilitatedselective catalytic oxidationofanaldehydicCeH bondwith
concomitant reduction of a ketone, affording a hydroacylation prod-
uct or a carbonyl reduction product depending on the nature of sol-
vent used.4,5 Thus, continual efforts focused on the discovery of novel
atom-economical chemical transformations.
Scheme 1. Hydroacylation of alkenes, alkynes and carbonyl compounds.
Functionalized indoles and indol-2-ones are widely present in
a large number of natural products and synthetic compounds with
diverse bioactivities.7 As one of the subtypes, despite possessing
interesting biological activities,8 only a few 3-acyloxy-1,3-dihydro-
2H-indol-2-ones 3 are known, and few approaches toward 3 have
* Corresponding authors. Tel./fax: þ86 25 86185170; e-mail addresses:
ddmn9999@cpu.edu.cn (D. Du), lut163@163.com (T. Lu).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.075

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D. Du et al. / Tetrahedron 67 (2011) 7557e7562
been documented (Eq. 4, Scheme 1). Some commonly synthetic
methods are the acylation of isatins with carboxylic acid anhydrides
or acyl chlorides,8,9 as well as certain reactions utilizing several non-
isatins as starting materials under various conditions.10 Neverthe-
less, the above-mentioned strategies always suffered from one or
more drawbacks, such as drastic reaction conditions, unsatisfactory
yields, narrow scope of substrates and excessive use of toxic mate-
rials and reagents. As part of our ongoing program to explore effi-
cient and environmentally benign methodologies for chemical
transformations using NHCs as organocatalysts,11 we envision that
3-acyloxy-1,3-dihydro-2H-indol-2-ones 3 may be directly synthe-
sized by NHC-catalyzed hydroacylation of isatins 112 with aldehydes
2. Herein we report this new type of hydroacylation of isatins me-
diated by NHC (Eq. 4, Scheme 1). This method is superior to con-
ventional strategies with its advantages of atom-economy, short
reaction time, broad range of substrates and high yields.
83% yield of 3a for 15 min at 65 ꢀC (entry 6). Remarkably, the reaction
carried out in EtOH gave no carbonyl reduction product, which was
observed employing a-keto esters rather than isatins as the sub-
strates (entry 5).4,5 Further screening of a series of bases, reaction
temperature and time (entries 7e12) established the optimal re-
action conditions: 10 mol% of catalyst E and 20 mol% of t-BuOK in
toluene at 100 ꢀC for 15 min with 93% yield of 3a (entry 12).
With the optimized conditions in hand, we turned our attention
to explore the scope of the reaction (Table 2). We found that the
reaction can accommodate a variety of substituted benzaldehdyes
2bem (entries 2e13). The electronic property and the position of
the substituents on the phenyl ring of the aldehydes have certain
influence on the yields and reaction time. Except 4-
nitrobenzaldehyde 2g, which led to low conversion of the re-
action (entry 7), substituted benzaldehydes with both electron-
withdrawing groups (F, Cl, Br, I, and CN) and electron-donating
groups (Me and OMe) at 3- or 4-positions worked very well to af-
ford desired 3-acyloxy-1,3-dihydro-2H-indol-2-ones 3bej in good
to excellent yields after 15 min (entries 2e6 and 8e11). However,
the reaction between isatin 1a and benzaldehydes substituted with
2. Results and discussion
Our investigations commenced with the model reaction of isatin
1a (1.0 equiv) and benzaldehyde 2a (1.5 equiv) in the presence of
10 mol% of a carbene precursor using 20 mol% of a base (Table 1).
Initially, the efficiency of several carbene precursors was examined
(entries 1 and 2). Fortunately, in contrast to other NHCs which
resulted in low conversion of the substrates (entry 1), NHC gener-
ated in situ from precursor E proved suitable for this transformation,
affording 66% yield of desired product 3a after 15 min at 65 ꢀC
(entry 2). It was noteworthy that the undesirable benzoin conden-
sation of 2awas notobserved in this process. A survey of the solvents
(entries 3e6) convinced us that toluene was the optimal one with
Table 2
Scope of the reactiona
Entry
R1, R2, 1
R3, 2
3
Yieldb (%)
1
2
3
4
5
6
7
8
H, Bn, a
H, Bn, a
H, Bn, a
H, Bn, a
H, Bn, a
H, Bn, a
H, Bn, a
H, Bn, a
H, Bn, a
H, Bn, a
H, Bn, a
H, Bn, a
H, Bn, a
Ph, a
a
b
c
d
e
f
d
g
h
i
93
91
86
83
Table 1
(4-F)Ph, b
(4-Cl)Ph, c
(4-Br)Ph, d
(4-I)Ph, e
(4-CN)Ph, f
(4-NO2)Ph, g
(4-Me)Ph, h
(4-OMe)Ph, i
(3-Cl)Ph, j
(3-OMe)Ph, k
(2-F)Ph, l
Optimization of the reaction conditions
81
75
dc,d
92
90
95
9
10
11
12
13
j
k
l
91
79e
26d
(2-Cl)Ph, m
14
H, Bn, a
m
92
, n
15
16
17
H, Bn, a
H, Bn, a
H, Bn, a
n
o
p
81
99
69
, o
, p
, q
Entry
Catalyst, base, solvent
Temp (ꢀC)
Time (min)
Yielda (%)
1
2
3
4
5
6
7
8
AeD, FeH, DBU, THF
E, DBU, THF
E, DBU, DCM
E, DBU, CH3CN
E, DBU, EtOH
E, DBU, PhMe
E, Et3N, PhMe
E, DIPEA, PhMe
E, K2CO3, PhMe
E, C2CO3, PhMe
E, t-BuOK, PhMe
E, t-BuOK, PhMe
65
65
40
65
65
65
65
65
65
65
65
100
120
15
15
60
60
db
66
69
18
19
20
21
22
23
24
25
26
H, Bn, a
n-Pr, r
Ph, a
Ph, a
Ph, a
Ph, a
Ph, a
Ph, a
Ph, a
Ph, a
q
r
s
t
u
v
d
d
w
57
85
90
77
91
85
5-Me, Bn, b
5-F, Bn, c
5-Cl, Bn, d
7-Me, Bn, e
7-Cl, Bn, f
4,6-Me2, Bn, g
H, Bz, h
Traceb
db
83
15
120
120
120
120
15
35
30
39
40
87
93
dc,d
dd,f
80
9
10
11
12
H, H, i
a
Isatins 1 (0.3 mmol), aldehydes 2 (0.45 mmol), catalyst E (0.03 mmol), and
t-BuOK (0.06 mmol) were employed.
15
b
The bold values provided in entry 12 is to emphasize that this reaction condition is
the optimal one.
Isolated yield based on 1.
Low conversion of 1 and 2.
The reaction time was 120 min.
The reaction time was 30 min.
c
a
d
Isolated yield based on 1a.
Low conversion of both 1a and 2a. DBU¼1,8-diazabicyclo[5.4.0]-undec-7-ene.
b
e
f
DIPEA¼N,N-diisopropylethyiamine.
The reaction was complex.

D. Du et al. / Tetrahedron 67 (2011) 7557e7562
7559
sterically hindered groups (2-F and 2-Cl) needed relatively longer
reaction time (entry 12) or went sluggishly with significantly de-
creased yield (entry 13). The reaction proceeded equally well for 1-
naphthaldehyde 2n and heteroaromatic aldehydes 2o and 2p with
short reaction time and high yields (entries 14e16). To our great
delight, aliphatic aldehydes 2q and 2r also demonstrated good
tolerance with this process (entry 17 and 18). Next, isatins with
different substituents were tested for the generality of this reaction
(entries 19e26). Isatins 1bef with substituents at 5- or 7-positions
reacted with 2a smoothly to give the corresponding products in
high yields after 15 min (entries 19e23), while the conversion of
the reaction between 4,6-dimethyl isatin 1g and 2a was low (entry
24). Isatins with different N-substituents (Bz, H) were also studied.
N-Benzoyl isatin 1h failed to produce the desired product due to the
complexity of the reaction (entry 25), whereas N-unsubstituted
isatin 1i worked well to give 3w in 80% yield (entry 26).
chromatography (TLC), which was visualized by ultraviolet light
(254 nm). All solvents were obtained from commercial sources and
were purified according to standard procedures. All aldehydes 2
were obtained from commercial sources without further purifica-
tion. Substituted isatins 113 and NHC precursors were prepared
according to literature method.14 Purification of the products
was accomplished by flash chromatography using silica gel
(200e300 mesh).
All NMR spectra were recorded with a spectrometer at 300 MHz
or 500 MHz (1H NMR) in CDCl3: chemical shifts (
d) are given in
parts per million, coupling constants (J) in Hz, the solvent signals
were used as references (residual CHCl3 in CDCl3: dH¼7.26 ppm,
dc¼77.0 ppm). High-resolution mass spectra were recorded on
a Waters/Micromass QTOF MS spectrometer. IR spectra were
recorded on an FTIR-8400s spectrometer. Melting points were
obtained on a Yanaco-241 apparatus and are uncorrected.
Based on the mechanism proposed by Scheidt4 and Pal,5
a plausible mechanism for the hydroacylation of isatins 1 with al-
dehydes 2 in the presence of carbene precursor E is illustrated in
Scheme 2. The hydroacylation process initiates with the addition of
NHC I generated upon deprotonation of carbene precursor E with t-
BuOK to aldehydes 2, affording the tetrahedral intermediate II. A
rapid hydride transfer from II to isatins 1 (like Cannizzaro-type
reaction) leads to the formation of acyl triazolium activated spe-
cies IV and intermediate III. After subsequent O-acylation of III with
IV, products 3 are produced accompanied with the release of NHC I
for the next catalytic cycle (Scheme 2).
4.2. General procedure for NHC-catalyzed hydroacylation of
isatins with aldehydes
To an oven-dried 25 mL three-necked glassware was charged
with catalyst E (8 mg, 0.03 mmol), t-BuOK (7 mg, 0.06 mmol), isa-
tins 1 (0.3 mmol), and aldehydes 2 (0.45 mmol) under nitrogen
atmosphere. Then toluene (2 mL) was added and the mixture was
stirred at 100 ꢀC for a certain period. After completion of the re-
action as monitored by TLC, the mixture was cooled to room tem-
perature. The solvent was evaporated under reduced pressure and
the residue was purified by chromatography on silica gel (typically
petroleum ether/ethyl acetate¼20:1 to 10:1) to afford the desired
products 3.
4.2.1. 1-Benzyl-2-oxo-1,3-dihydro-2H-indol-3-yl benzoate (3a).
White solid, mp: 121e123 ꢀC (lit.10f mp: 124e125 ꢀC). 1H NMR
(500 M, CDCl3):
d
4.93 and 5.00 (2ꢁd, J¼15.7 Hz, 2H), 6.27 (s, 1H),
6.75 (d, J¼7.9 Hz, 1H), 7.02 (t, J¼7.6 Hz, 1H), 7.23 (d, J¼7.8 Hz, 1H),
7.27e7.47 (m, 8H), 7.59 (t, J¼7.4 Hz, 1H), 8.12 (d, J¼7.3 Hz, 2H). 13C
NMR (125 M, CDCl3):
d 44.0, 70.4, 109.6, 123.1, 124.4, 125.6, 127.3,
127.7, 128.4, 128.8, 129.0, 130.1, 130.2, 133.5, 135.3, 143.7, 165.8,
172.3.
4.2.2. 1-Benzyl-2-oxo-1,3-dihydro-2H-indol-3-yl 4-fluorobenzoate
(3b). White solid, mp: 91e93 ꢀC. 1H NMR (500 M, CDCl3):
d 4.92
and 4.99 (2ꢁd, J¼15.7 Hz, 2H), 6.26 (s, 1H), 6.75 (d, J¼7.9 Hz, 1H),
7.03 (t, J¼7.6 Hz, 1H), 7.13 (t, J¼8.6 Hz, 2H), 7.24 (d, J¼7.8 Hz, 1H),
7.27e7.42 (m, 6H), 8.13e8.16 (m, 2H). 13C NMR (125 M, CDCl3):
d
44.1, 70.5, 109.6, 115.6 (d, JCeF¼22.0 Hz, 1C), 123.1, 124.3, 125.3 (d,
JCeF¼2.8 Hz, 1C), 125.6, 127.3, 127.8, 128.8, 130.3, 132.8 (d,
JCeF¼9.4 Hz, 1C), 135.3, 143.7, 164.9, 166.1 (d, JCeF¼255.0 Hz, 1C),
172.2. HRMS (EI) calcd for C22H16NO3F (MþH)þ: 362.1192, found
Scheme 2. Proposed mechanism for NHC-catalyzed hydroacylation of isatins.
362.1196. IR (KBr):
n 758, 849, 1121, 1152, 1177, 1269, 1373, 1462,
3. Conclusion
1495, 1604, 1722, 3040, 3063 cmꢂ1
.
In conclusion, we have developed a transition-metal-free NHC-
organocatalyzed intermolecular hydroacylation of isatins with al-
dehydes, which offers a powerful strategy for the synthesis of useful
3-acyloxy-1,3-dihydro-2H-indol-2-ones. In this atom-economical
process, functionalized isatins are effective substrates in combina-
tion with a broad range of aromatic and aliphatic aldehydes, fur-
nishing the desired products in high yields with short reaction time.
4.2.3. 1-Benzyl-2-oxo-1,3-dihydro-2H-indol-3-yl 4-chlorobenzoate
(3c). White solid, mp: 120e121 ꢀC. 1H NMR (500 M, CDCl3):
d
4.93 and 4.99 (2ꢁd, J¼15.7 Hz, 2H), 6.25 (s, 1H), 6.75 (d, J¼7.9 Hz,
1H), 7.03 (t, J¼7.5 Hz, 1H), 7.24 (d, J¼7.8 Hz, 1H), 7.28e7.44 (m, 8H),
8.05 (d, J¼8.6 Hz, 2H). 13C NMR (125 M, CDCl3):
d 44.1, 70.5, 109.6,
123.1, 124.2, 125.6, 127.3, 127.5, 127.8, 128.80, 128.84, 130.3, 131.5,
135.2, 140.1, 143.7, 165.0, 172.1. HRMS (EI) calcd for C22H16NO3Cl
(MþH)þ: 378.0897, found 378.0901. IR (KBr):
n 748, 843, 993, 1013,
4. Experimental
4.1. General
1090, 1117, 1177, 1271, 1350, 1375, 1462, 1489, 1593, 1611, 1730, 2867,
2922, 2945, 3032, 3063 cmꢂ1
.
4.2.4. 1-Benzyl-2-oxo-1,3-dihydro-2H-indol-3-yl 4-bromobenzoate
All reactions were carried out under an atmosphere of nitrogen
in dry glassware, and were monitored by analytical thin-layer
(3d). White solid, mp: 142e144 ꢀC. 1H NMR (500 M, CDCl3):
d
4.92 and 4.98 (2ꢁd, J¼15.7 Hz, 2H), 6.24 (s, 1H), 6.74 (d, J¼7.9 Hz,

7560
D. Du et al. / Tetrahedron 67 (2011) 7557e7562
1H), 7.02 (t, J¼7.5 Hz, 1H), 7.23 (d, J¼7.8 Hz, 1H), 7.27e7.41 (m, 6H),
7.59 (d, J¼8.5 Hz, 2H), 7.97 (d, J¼8.5 Hz, 2H). 13C NMR (125 M,
(d, J¼7.9 Hz, 1H), 7.01 (t, J¼7.5 Hz, 1H), 7.12 (dd, J¼2.1, 8.2 Hz, 1H),
7.22 (t, J¼8.1 Hz, 1H), 7.26e7.41 (m, 7H), 7.62 (s, 1H),7.71 (d,
CDCl3):
d
44.0, 70.5, 109.6, 123.1, 124.1, 125.6, 127.3, 127.7, 127.9,
J¼7.6 Hz, 1H). 13C NMR (125 M, CDCl3):
d 44.0, 55.4, 70.5, 109.5,
128.7, 128.8, 130.3, 131.5, 131.8, 135.2, 143.6, 165.0, 172.0. HRMS (EI)
114.4, 120.2, 122.6, 123.0, 124.4, 125.5, 127.3, 127.7, 128.8, 129.4,
130.2, 130.3, 135.3, 143.7, 159.6, 165.7, 172.2. HRMS (EI) calcd for
calcd for C22H16NO3Br (MþH)þ: 422.0392, found 422.0374. IR
(KBr):
n
750, 843, 918, 997, 1011, 1069, 1084, 1103, 1123, 1170, 1263,
C23H19NO4 (MþH)þ: 374.1392, found 374.1381. IR (KBr):
n 748, 804,
1323, 1361, 1464, 1491, 1591, 1616, 1719, 1732, 2926, 2951, 3038,
849, 872, 905, 997, 1030, 1121, 1179, 1227, 1283, 1323, 1348, 1377,
3065 cmꢂ1
.
1429, 1462, 1489, 1609, 1726, 2870, 2922, 2955, 3030, 3067 cmꢂ1
.
4.2.5. 1-Benzyl-2-oxo-1,3-dihydro-2H-indol-3-yl 4-iodobenzoate
(3e). White solid, mp: 158e160 ꢀC. 1H NMR (500 M, CDCl3):
4.93
4.2.11. 1-Benzyl-2-oxo-1,3-dihydro-2H-indol-3-yl 2-fluorobenzoate
(3k). White solid, mp: 118e120 ꢀC. 1H NMR (500 M, CDCl3):
d
and 4.99 (2ꢁd, J¼15.7 Hz, 2H), 6.25 (s, 1H), 6.75 (d, J¼7.9 Hz, 1H),
d
4.90 and 4.97 (2ꢁd, J¼15.7 Hz, 2H), 6.24 (s, 1H), 6.73 (d, J¼7.9 Hz,
7.03 (t, J¼7.3 Hz,1H), 7.24 (d, J¼7.8 Hz,1H), 7.28e7.41 (m, 6H), 7.82 (s,
1H), 7.01 (t, J¼7.5 Hz, 1H), 7.11e7.36 (m, 8H), 7.43 (d, J¼7.4 Hz, 1H),
4H). 13C NMR (125 M, CDCl3):
d 44.1, 70.5, 101.6, 109.6, 123.1, 124.1,
7.52 (m, 1H), 8.0 (td, J¼1.5, 7.7 Hz, 1H). 13C NMR (125 M, CDCl3):
125.6,127.3,127.7,128.5,128.8,130.3,131.5,135.2,137.8,143.7,165.4,
d
43.9, 70.4, 109.4, 116.9 (d, JCeF¼22.0 Hz, 1C), 117.4 (d, JCeF¼9.3 Hz,
172.1. HRMS (EI) calcd for C22H16NO3I (MþH)þ: 470.0253, found
1C), 123.0, 123.9 (d, JCeF¼3.8 Hz, 1C), 124.1, 125.4, 127.2, 127.6, 128.7,
130.1, 132.3, 135.0 (d, JCeF¼9.1 Hz, 1C), 135.1, 143.6, 162.1 (d,
JCeF¼261.7 Hz, 1C), 163.2 (d, JCeF¼3.8 Hz, 1C), 171.9. HRMS (EI) calcd
470.0239. IR (KBr):
n 748, 843, 1007, 1084, 1101, 1121, 1170, 1263,
1464, 1491, 1586, 1614, 1721, 1728, 2924, 2950, 3064, 3082 cmꢂ1
.
for C22H16NO3F (MþH)þ: 362.1192, found 362.1190. IR (KBr):
n 756,
4.2.6. 1-Benzyl-2-oxo-1,3-dihydro-2H-indol-3-yl 4-cyanobenzoate
829, 851, 997, 1034, 1059, 1130, 1179, 1225, 1261, 1341, 1371, 1464,
(3f). White solid, mp: 128e130 ꢀC. 1H NMR (500 M, CDCl3):
1491, 1613, 1730, 2922, 2945, 3040, 3074 cmꢂ1
.
d
4.93 and 4.97 (2ꢁd, J¼15.7 Hz, 2H), 6.26 (s, 1H), 6.76 (d, J¼7.9 Hz,
1H), 7.02 (t, J¼7.3 Hz, 1H), 7.23e7.40 (m, 7H), 7.73 (d, J¼8.5 Hz, 2H),
4.2.12. 1-Benzyl-2-oxo-1,3-dihydro-2H-indol-3-yl 2-chlorobenzoate
(3l). White solid, mp: 94e96 ꢀC. 1H NMR (500 M, CDCl3):
4.92
8.19 (d, J¼8.5 Hz, 2H). 13C NMR (125 M, CDCl3):
d
44.0, 70.9, 109.7,
d
116.9, 117.7, 123.1, 123.7, 125.5, 127.3, 127.8, 128.8, 130.45, 130.48,
132.2, 132.7, 135.1, 143.7, 164.2, 171.6. HRMS (EI) calcd for
and 4.97 (2ꢁd, J¼15.7 Hz, 2H), 6.29 (s, 1H), 6.74 (d, J¼7.9 Hz, 1H),
7.03 (t, J¼7.5 Hz,1H), 7.22e7.36 (m, 7H), 7.42e7.48 (m, 3H), 7.95 (dd,
C23H16N2O3 (MþH)þ: 369.1239, found 369.1248. IR (KBr):
n
756,
J¼1.3, 7.8 Hz, 1H). 13C NMR (125 M, CDCl3):
d 44.1, 70.6, 109.6, 123.2,
124.1, 125.8, 126.6, 127.3, 127.8, 128.77, 128.84, 130.3, 131.2, 132.0,
133.1, 134.3, 135.2, 143.7, 164.7, 172.0. HRMS (EI) calcd for
804, 847, 862, 991, 1016, 1116, 1179, 1273, 1352, 1377, 1464, 1491,
1613, 1726, 2232, 2928, 3071 cmꢂ1
.
C22H16NO3Cl (MþH)þ: 378.0897, found 378.0883. IR (KBr):
n 750,
4.2.7. 1-Benzyl-2-oxo-1,3-dihydro-2H-indol-3-yl 4-methylbenzoate
849, 993, 1032, 1125, 1177, 1250, 1288, 1339, 1362, 1464, 1489, 1611,
(3g). White solid, mp: 106e107 ꢀC. 1H NMR (500 M, CDCl3):
1726, 2922, 3024, 3063 cmꢂ1
.
d
2.42 (s, 3H), 4.93 and 5.00 (2ꢁd, J¼15.7 Hz, 2H), 6.26 (s, 1H), 6.74
(d, J¼7.9 Hz, 1H), 7.02 (td, J¼0.7, 7.6 Hz, 1H), 7.22e7.39 (m, 8H), 7.42
4.2.13. 1-Benzyl-2-oxo-1,3-dihydro-2H-indol-3-yl 1-naphthoate
(d, J¼7.4 Hz, 1H), 8.01 (d, J¼8.2 Hz, 2H). 13C NMR (125 M, CDCl3):
(3m). White solid, mp: 142e144 ꢀC. 1H NMR (500 M, CDCl3):
d
21.7, 44.0, 70.3, 109.5, 123.0, 124.6, 125.6, 126.3, 127.3, 127.7, 128.8,
d
4.92 and 4.98 (2ꢁd, J¼15.7 Hz, 2H), 6.37 (s, 1H), 6.73 (d, J¼7.9 Hz,
129.1, 130.1, 130.2, 135.3, 143.7, 144.3, 165.9, 172.4. HRMS (EI) calcd
1H), 7.02 (t, J¼7.5 Hz,1H), 7.21 (t, J¼7.8 Hz,1H), 7.26 (t, J¼7.1 Hz,1H),
7.32 (t, J¼7.5 Hz, 2H), 7.37 (d, J¼7.5 Hz, 2H), 7.45e7.53 (m, 3H), 7.61
(t, J¼7.7 Hz, 1H), 7.85 (d, J¼8.1 Hz, 1H), 8.01 (d, J¼8.2 Hz, 1H), 8.31
(d, J¼7.3 Hz, 1H), 8.99 (d, J¼8.7 Hz, 1H). 13C NMR (125 M, CDCl3):
for C23H19NO3 (MþH)þ: 358.1443, found 358.1440. IR (KBr):
n 746,
999, 1063, 1080, 1119, 1179, 1273, 1356, 1370, 1466, 1491, 1613, 1730,
2918, 2949, 3036, 3055 cmꢂ1
.
d
44.0, 70.4,109.5, 123.1, 124.4, 124.5,125.6, 125.7, 126.3, 127.3, 127.7,
4.2.8. 1-Benzyl-2-oxo-1,3-dihydro-2H-indol-3-yl 4-methoxybenzoate
(3h). White solid, mp: 104e106 ꢀC. 1H NMR (500 M, CDCl3):
3.87
128.0, 128.5, 128.8,130.2, 131.1,131.4,133.8, 134.1,135.3, 143.7,166.5,
d
172.4. HRMS (EI) calcd for C26H19NO3 (MþH)þ: 394.1443, found
(s, 3H), 4.93 and 5.00 (2ꢁd, J¼15.7 Hz, 2H), 6.24 (s, 1H), 6.74 (d,
J¼7.9 Hz, 1H), 6.93 (d, J¼8.9 Hz, 2H), 7.02 (t, J¼7.5 Hz, 1H), 7.23 (t,
J¼7.8 Hz, 1H), 7.27e7.43 (m, 6H), 8.07 (d, J¼8.9 Hz, 2H). 13C NMR
394.1427. IR (KBr): n 746, 997, 1020, 1117, 1179, 1213, 1273, 1371,
1464, 1491, 1610, 1728, 2920, 2949, 3036, 3055 cmꢂ1
.
(125 M, CDCl3):
d
44.0, 55.4, 70.2, 109.5, 113.7, 121.4, 123.0, 124.7,
4.2.14. 1-Benzyl-2-oxo-1,3-dihydro-2H-indol-3-yl furan-2-
carboxylate (3n). Yellowish oil. 1H NMR (500 M, CDCl3):
4.88
125.6,127.3,127.7,128.8,130.1,132.3,135.4,143.6,163.9,165.5,172.5.
d
HRMS (EI) calcd for C23H19NO4 (MþH)þ: 374.1392, found 374.1399.
and 4.95 (2ꢁd, J¼15.7 Hz, 2H), 6.22 (s, 1H), 6.50 (dd, J¼1.7, 3.5 Hz,
1H), 6.72 (d, J¼7.9 Hz, 1H), 6.99 (td, J¼0.8, 7.6 Hz, 1H), 7.19e7.36 (m,
7H), 7.39 (d, J¼7.4 Hz, 1H), 7.58 (dd, J¼0.8, 1.7 Hz, 1H). 13C NMR
IR (KBr): n 745, 766, 847,1022,1119,1169,1258,1316,1341,1371,1466,
1491, 1510, 1603, 1726, 2843, 2936, 3001, 3022, 3055 cmꢂ1
.
(125 M, CDCl3):
d 43.9, 70.0, 109.5, 112.0, 119.4, 123.0, 123.9, 125.5,
4.2.9. 1-Benzyl-2-oxo-1,3-dihydro-2H-indol-3-yl 3-chlorobenzoate
(3i). White solid, mp: 51e53 ꢀC. 1H NMR (500 M, CDCl3):
4.93
127.2, 127.6, 128.7,130.2, 135.1,143.4,143.6, 147.0, 157.6,171.8. HRMS
d
(EI) calcd for C20H15NO4 (MþH)þ: 334.1079, found 334.1082. IR
and 4.99 (2ꢁd, J¼15.7 Hz, 2H), 6.26 (s, 1H), 6.75 (d, J¼7.9 Hz, 1H),
7.03 (t, J¼7.5 Hz,1H), 7.23e7.41 (m, 8H), 7.56 (ddd, J¼0.9, 2.0, 8.0 Hz,
1H), 8.0 (d, J¼7.8 Hz, 1H), 8.09 (t, J¼1.7 Hz, 1H). 13C NMR (125 M,
(film): n 731, 754, 885, 910, 993, 1014, 1080, 1117, 1175, 1368, 1470,
1491, 1573, 1616, 1730, 2252, 2926, 3032, 3063, 3140 cmꢂ1
.
CDCl3):
d
44.1, 70.7, 109.7, 123.2, 124.1, 125.6, 127.4, 127.8, 128.3,
4.2.15. 1-Benzyl-2-oxo-1,3-dihydro-2H-indol-3-yl thiophene-2-
128.9, 129.8, 130.2, 130.4, 130.8, 133.6, 134.7, 135.2, 143.7, 164.7,
carboxylate (3o). White solid, mp: 88e92 ꢀC. 1H NMR (500 M,
172.0. HRMS (EI) calcd for C22H16NO3Cl (MþH)þ: 378.0897, found
CDCl3):
d
4.91 and 4.98 (2ꢁd, J¼15.7 Hz, 2H), 6.21 (s, 1H), 6.74 (d,
378.0892. IR (KBr):
n
748, 810, 995, 1078, 1125, 1175, 1252, 1281,
J¼7.9 Hz, 1H),7.02 (td, J¼0.8, 7.6 Hz, 1H), 7.10 (dd, J¼3.8, 4.9 Hz, 1H),
7.23 (t, J¼7.8 Hz, 1H), 7.26e7.29 (m, 1H), 733e7.38 (m, 4H), 7.42 (d,
J¼7.4 Hz, 1H), 7.60 (dd, J¼1.2, 5.0 Hz, 1H), 7.89 (dd, J¼1.2, 3.8 Hz,
1364, 1427, 1468, 1491, 1576, 1614, 1728, 2924, 3032, 3064 cmꢂ1
.
4.2.10. 1-Benzyl-2-oxo-1,3-dihydro-2H-indol-3-yl 3-methoxyben-
1H). 13C NMR (125 M, CDCl3):
d 44.0, 70.4, 109.5, 123.0, 124.1, 125.5,
zoate (3j). White solid, mp: 112e114 ꢀC. 1H NMR (500 M, CDCl3):
127.3, 127.7, 127.8,128.8, 130.2, 132.1, 133.4, 134.6, 135.2, 143.6, 161.3,
d
3.83 (s, 3H), 4.91 and 4.99 (2ꢁd, J¼15.7 Hz, 2H), 6.24 (s, 1H), 6.74
172.0. HRMS (EI) calcd for C20H15NO3S (MþH)þ: 350.0851, found

D. Du et al. / Tetrahedron 67 (2011) 7557e7562
7561
350.0860. IR (KBr):
1263, 1281, 1354, 1370, 1416, 1466, 1491, 1520, 1613, 1711, 1730,
2922, 3024, 3059, 3090 cmꢂ1
n
737, 752, 854, 972, 1008, 1030, 1078, 1117, 1175,
(m, 2H), 7.57e7.60 (m, 1H), 8.13e8.15 (m, 2H). 13C NMR (125 M,
CDCl3): 18.6, 45.3, 70.0, 120.3, 123.1, 123.3, 125.1, 125.7, 127.2,
d
.
128.4, 128.9, 129.1, 130.1, 133.5, 134.1,137.2, 141.6, 165.7,173.3. HRMS
(EI) calcd for C23H19NO3 (MþH)þ: 358.1443, found 358.1459. IR
4.2.16. 1-Benzyl-2-oxo-1,3-dihydro-2H-indol-3-yl cyclohexanecarbo-
xylate (3p). Colorless oil. 1H NMR (300 M, CDCl3):
1.21e1.37 (m,
(KBr): n 710, 735, 766, 787, 824, 995, 1022, 1069, 1113, 1180, 1256,
d
1321, 1360, 1450, 1472, 1493, 1651, 1717, 2926, 3042, 3064,
3H), 1.47e1.67 (m, 3H), 1.74e1.84 (m, 2H), 1.95e2.03 (m, 2H),
2.45e2.54 (m, 1H), 4.87 and 4.94 (2ꢁd, J¼15.7 Hz, 2H), 6.03 (s, 1H),
6.71 (d, J¼7.8 Hz, 1H), 7.01 (t, J¼7.5 Hz, 1H), 7.21 (t, J¼7.8 Hz, 1H),
3088 cmꢂ1
.
4.2.22. 1-Benzyl-7-chloro-2-oxo-1,3-dihydro-2H-indol-3-yl benzoate
(3v). White solid, mp: 131e132 ꢀC. 1H NMR (500 M, CDCl3):
5.34
7.26e7.34 (m, 6H). 13C NMR (75 M, CDCl3):
d
25.18, 25.21, 25.6,
d
28.78, 28.88, 42.7, 43.9, 69.5, 109.4, 122.9, 124.6, 125.1, 127.2, 127.6,
128.7, 129.9, 135.2, 143.5, 172.4, 175.1. HRMS (EI) calcd for
and 5.41 (2ꢁd, J¼16.1 Hz, 2H), 6.22 (s, 1H), 6.94 (dd, J¼7.4, 8.2 Hz,
1H), 7.18e7.20 (m, 1H), 7.22e7.27 (m, 1H), 7.30e7.32 (m, 5H),
7.42e7.45 (m, 2H), 7.55e7.59 (m, 1H), 8.09e8.11 (m, 2H). 13C NMR
C22H23NO3 (MþH)þ: 350.1756, found 350.1750. IR (film):
n 700, 731,
752, 847, 812, 912, 1003, 1028, 1076, 1103, 1128, 1159, 1244, 1364,
(125 M, CDCl3): d 45.1, 69.7, 115.8, 123.97, 124.00, 126.5, 127.2, 128.4,
1450, 1466, 1489, 1614, 1730, 2855, 2930, 3030, 3059 cmꢂ1
.
128.6, 128.8, 130.1, 132.7, 133.7, 137.0, 139.7, 165.6, 172.7. HRMS (EI)
calcd for C22H16NO3Cl (MþH)þ: 378.0897, found 378.0890. IR (KBr):
4.2.17. 1-Benzyl-2-oxo-1,3-dihydro-2H-indol-3-yl butyrate (3q).
Colorless oil. 1H NMR (300 M, CDCl3):
n 706, 762, 785, 849, 901, 934, 968,1022,1078,1128,1163,1200,1273,
d
0.99 (t, J¼7.4 Hz, 3H),
1314, 1344, 1356, 1456, 1584, 1609, 1726, 2928, 3032, 3059 cmꢂ1
.
1.67e1.79 (m, 2H), 2.38e2.54 (m, 2H), 4.90 (s, 2H), 6.04 (s, 1H), 6.71
(d, J¼7.8 Hz, 1H), 7.01 (t, J¼7.5 Hz, 1H), 7.21 (t, J¼7.8 Hz, 1H),
4.2.23. 2-Oxo-1,3-dihydro-2H-indol-3-yl benzoate (3w). White
solid, mp: 130e132 ꢀC. 1H NMR (500 M, CDCl3):
6.21 (s, 1H), 6.92
7.26e7.35 (m, 6H). 13C NMR (75 M, CDCl3):
d
13.5, 18.3, 35.7, 43.8,
d
69.7, 109.4, 122.9, 124.5, 125.3, 127.2, 127.6, 128.7, 130.0, 135.2, 143.5,
(d, J¼7.8 Hz, 1H), 7.01 (t, J¼7.5 Hz, 1H), 7.24 (d, J¼7.7 Hz, 1H), 7.37 (d,
172.3, 172.8. HRMS (EI) calcd for C19H19NO3 (MþH)þ: 310.1443,
J¼7.4 Hz, 1H), 7.43 (t, J¼7.7 Hz, 2H), 7.57 (t, J¼7.4 Hz, 1H), 8.10 (d,
found 310.1456. IR (film):
n
700, 752, 1001, 1078, 1103, 1366, 1466,
J¼7.5 Hz, 2H), 9.31 (br, 1H). 13C NMR (125 M, CDCl3):
d 70.7, 110.6,
1489, 1614, 1728, 2874, 2928, 2963, 3038, 3061 cmꢂ1
.
123.0, 124.8, 125.7, 128.4, 128.9, 130.1, 130.3, 133.5, 141.9, 165.9,
175.0. HRMS (EI) calcd for C15H11NO3 (MþH)þ: 254.0817, found
4.2.18. 1-Benzyl-5-methyl-2-oxo-1,3-dihydro-2H-indol-3-yl benzo-
254.0810. IR (KBr): n 706, 766, 822, 889, 947, 1020, 1067, 1111, 1179,
ate (3r). White solid, mp: 133e135 ꢀC. 1H NMR (500 M, CDCl3):
1258, 1344, 1393, 1470, 1601, 1620, 1695, 1724, 1742, 2936, 3032,
d
2.24 (s, 3H), 4.90 and 4.95 (2ꢁd, J¼15.7 Hz, 2H), 6.24 (s, 1H), 6.61
3121, 3179 cmꢂ1
.
(d, J¼8.0 Hz, 1H), 7.00 (d, J¼8.0 Hz, 1H), 7.22e7.36 (m, 6H), 7.43 (t,
J¼7.8 Hz, 2H), 7.54e7.58 (m, 1H), 8.11e8.13 (m, 2H). 13C NMR
Acknowledgements
(125 M, CDCl3):
d 20.8, 44.0, 70.5, 109.2, 124.4, 126.3, 127.2, 127.6,
128.3, 128.7,129.0, 130.1, 130.3, 132.7,133.4, 135.4, 141.2, 165.8, 172.1.
We thank the National Natural Science Foundation of China
(Nos. 21002124, 30973609), Specialized Research Fund for the
Doctoral Program of Higher Education of China (No.
20100096120009) and Fundamental Research Funds for the Central
Universities (No. JKQ2009012) for financial support.
HRMS (EI) calcd for C23H19NO3 (MþH)þ: 358.1443, found 358.1449.
IR (KBr):
n 702, 806, 901, 997, 1024, 1061, 1107, 1150, 1196, 1273,
1346, 1373, 1452, 1499, 1602, 1626, 1726, 2862, 2916, 2943, 3034,
3057 cmꢂ1
.
4.2.19. 1-Benzyl-5-fluoro-2-oxo-1,3-dihydro-2H-indol-3-yl benzoate
(3s). White solid, mp: 134e136 ꢀC. 1H NMR (300 M, CDCl3):
4.93
Supplementary data
d
(s, 2H), 6.18 (s, 1H), 6.63 (dd, J¼4.0, 8.6 Hz, 1H), 6.87e6.93 (m, 1H),
7.17 (dd, J¼1.7, 7.1 Hz, 1H), 7.27e7.35 (m, 5H), 7.43 (t, J¼7.7 Hz, 2H),
7.57 (t, J¼7.3 Hz, 1H), 8.11 (d, J¼7.5 Hz, 2H). 13C NMR (75 M, CDCl3):
Copies of NMR spectra for all products. Supplementary data
associated with this article can be found, in the online version, at
doi:10.1016/j.tet.2011.07.075.
d
44.1, 70.3, 110.1 (d, JCeF¼8.0 Hz, 1C), 113.7 (d, JCeF¼25.3 Hz, 1C),
116.4 (d, JCeF¼23.4, 1C), 125.8 (d, JCeF¼8.4 Hz, 1C), 127.2, 127.8,
128.4, 128.7, 128.8, 130.1, 133.6, 134.9, 139.4 (d, JCeF¼2.1 Hz, 1C),
159.1 (d, JCeF¼242.2 Hz, 1C), 165.6, 171.9. HRMS (EI) calcd for
References and notes
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C22H16NO3F (MþH)þ: 362.1192, found 362.1182. IR (KBr):
n 704,
770, 812, 880, 851, 999, 1024, 1063, 1119, 1153, 1179, 1209, 1271,
1344, 1371, 1454, 1489, 1611, 1726, 2868, 2920, 3036, 3069 cmꢂ1
.
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4.2.20. 1-Benzyl-5-chloro-2-oxo-1,3-dihydro-2H-indol-3-yl benzoate
(3t). White solid, mp: 166e168 ꢀC. 1H NMR (300 M, CDCl3):
4.95
d
(s, 2H), 6.19 (s, 1H), 6.65 (d 8.6 Hz, 1H), 7.19 (dd, J¼1.4, 8.3 Hz, 1H),
7.27e7.41 (m, 6H), 7.46 (t, J¼7.7 Hz, 2H), 7.60 (t, J¼7.3 Hz, 1H), 8.12
(d, J¼7.5 Hz, 2H). 13C NMR (75 M, CDCl3):
d 44.1, 70.1, 110.5, 125.9,
127.2, 127.9, 128.0, 128.5, 128.6, 128.8, 128.9, 130.0, 130.1, 133.7,
134.8, 142.1, 165.6, 171.8. HRMS (EI) calcd for C22H16NO3Cl (MþH)þ:
378.0897, found 378.0890. IR (KBr): n 704, 741, 804, 893, 1022, 1057,
1076, 1123, 1173, 1275, 1344, 1452, 1487, 1610, 1653, 1732, 2930,
€
2953, 3034, 3061 cmꢂ1
.
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4.2.21. 1-Benzyl-7-methyl-2-oxo-1,3-dihydro-2H-indol-3-yl benzo-
ate (3u). White solid, mp: 113e115 ꢀC. 1H NMR (500 M, CDCl3):
d
2.27 (s, 3H), 5.22 and 5.26 (2ꢁd, J¼16.9 Hz, 2H), 6.30 (s, 1H), 6.96
(t, J¼7.5 Hz, 1H), 7.02 (d, J¼7.7 Hz, 1H), 7.25e7.37 (m, 6H), 7.44e7.47

7562
D. Du et al. / Tetrahedron 67 (2011) 7557e7562
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