Organocatalytic asymmetric michael addition of 1-acetylindolin-3-ones to α,β-unsaturated aldehydes: Synthesis of 2-substituted indolin-3-ones

Article abstract of DOI:10.1021/jo201123p

A highly efficient asymmetric Michael addition of 1-acetylindolin-3-ones to α,β-unsaturated aldehydes is developed to afford 2-substituted indolin-3-one derivatives in high yields (up to 94%) with good stereoselectivities (up to 11:1 dr and 96% ee). The Michael adducts can be transformed into substituted cyclopentyl[b]indoline compounds conveniently without racemization.

Full text of DOI:10.1021/jo201123p

NOTE
pubs.acs.org/joc
Organocatalytic Asymmetric Michael Addition of
1-Acetylindolin-3-ones to r,β-Unsaturated Aldehydes:
Synthesis of 2-Substituted Indolin-3-ones
Yao-Zong Liu, Jie Zhang, Peng-Fei Xu,* and Yong-Chun Luo
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou 730000, People’s Republic of China
S Supporting Information
b
ABSTRACT: A highly efficient asymmetric Michael addition of
1-acetylindolin-3-ones to R,β-unsaturated aldehydes is devel-
oped to afford 2-substituted indolin-3-one derivatives in high
yields (up to 94%) with good stereoselectivities (up to 11:1 dr
and 96% ee). The Michael adducts can be transformed into
substituted cyclopentyl[b]indoline compounds conveniently
without racemization.
he Michael addition reaction is one of the most important
reactions for the formation of carbonÀcarbon bonds in organic
from rt to 0 °C. A higher ee value of 89% was obtained; again the
reaction proceeded very slowly (Table 1, entry 11). Other
chemicals were also added to the reaction and tested to improve
the stereoselectivity. However, either PhCOOH or NEt3 gave
disappointing results (Table 1, entries 12 and 13). To our
surprise, when 2.0 equiv of H2O was added, the reaction
proceeded very quickly with little effect on the stereoselectivity.
When the reaction temperature was dropped to À10 °C, the best
result was obtained in 84% yield with 6:1 dr and 94% ee (Table 1,
entry 15).
Under the optimized reaction conditions, the asymmetric
Michael addition reactions between a wide range of R,β-unsatu-
rated aldehydes 3 and 1-acetylindolin-3-ones 2 were investigated.
The results are summarized in Table 2. In most cases, the
Michael adducts were obtained in high yields with moderate dr
and high ee values.8 Structural variation of R,β-unsaturated
aldehydes is well tolerated (Table 2). Satisfactory results were
also obtained with electron-withdrawing (Table 2, entries 2À6),
electron-donating (Table 2, entries 7À9), and neutral (Table 2,
entry 1) systems of R2. The ee values decreased slightly when the
R,β-unsaturated aldehydes contain electron-donating groups at
the para-position of the phenyl ring (Table 2, entries 8 and 9).
2-Furyl-substituted R,β-unsaturated aldehyde 3j was also tested
under the optimized reaction conditions. Unfortunately, a rela-
tively low ee value was observed for the reaction (76% ee, Table 2,
entry 10). The reaction with crotonaldehyde 3k (Table 2, entry 11)
proceeded well under the optimized reaction conditions but gave
no diastereoselectivity. Substituted 1-acetylindolin-3-ones were
also well tolerated (Table 2, entries 12 and 13). With this
protocol, highly enantioenriched 2-substituted 1-acetylindolin-
3-ones can be easily produced.
T
synthesis. The organocatalyzed Michael addition has attracted con-
siderable interest from chemists all over the world, and remarkable
progress has been made in this field in recent years.1,2 Many different
types of this reaction have been developed and applied to the
synthesis of many biologically active natural products.3 At the same
time, new reactions and catalyst systems are also being explored.
Substituted 3-oxindole and cyclopenta[b]indole structures
exist widely in biologically active natural products and pharma-
ceutical compounds (Figure 1).4 However, the enantioselective
synthesis of these structures is much less explored, and new
approaches should be developed for the asymmetric synthesis of
enantiopure products. Indolin-3-ones, a class of important
building blocks, are frequently used in the total synthesis of
pharmaceutical compounds.5 As part of our continuing interest
in exploring the synthesis of 2-substituted indolin-3-ones,6 we
recently discovered that the silyl-protected diarylprolinols are
efficient catalysts for the asymmetric Michael addition of indolin-
3-ones with R,β-unsaturated aldehydes, which produces optically
pure 2-substituted indolin-3-ones. Here we report our prelimin-
ary results from this discovery.
We initially investigated the reaction of 1-acetylindolin-3-one
2a with cinnamaldehyde 3a in the presence of readily available
diarylprolinol trimethylsilyl ether 1a (20% mol) in DCM.7 The
Michael addition reaction proceeded quickly to afford desired
product 4a in 87% yield, 4:1 dr, and 66% ee (Table 1, entry 1).
Then we screened organocatalysts 1aÀ1d for catalysis of the
reaction under the same reaction conditions (Table 1, entries
1À4). The result showed that catalyst 1c gave the highest
stereoselectivity, but the reaction proceeded too slowly. There-
fore, we chose the catalyst 1a to further optimize the reaction.
First, different organic solvents with 20% catalyst 1a were
screened, and the highest ee value was obtained in THF (Table 1,
entry 6). Then in THF the reaction, temperature was decreased
Received: June 1, 2011
Published: August 03, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo201123p J. Org. Chem. 2011, 76, 7551–7555
|

The Journal of Organic Chemistry
NOTE
Figure 1. Examples of 3-oxindole and cyclopenta[b]indole compounds.
Table 1. Catalyst Screening and Reaction Optimization
Table 2. Catalytic Asymmetric Michael Addition of 1-Acet-
ylindolin-3-ones to r,β-Unsaturated Aldehydes
entrya
R1
R2
t (h) yield (%)
drb
ee c (%)
1
2
H
Ph
48
24
72
48
36
48
36
48
48
48
24
24
60
84 (4a)
91 (4b)
89 (4c)
91 (4d)
81 (4e)
88 (4f)
85 (4g)
92 (4h)
94 (4i)
92 (4j)
90 (4k)
92 (4l)
91 (4m)
6:1 94
4:1 94
6:1 92
6:1 90
4:1 94
4:1 95
4:1 96
5:1 86
6:1 86
6:1 76
1:1 82 (95 d)
11:1 82
5:1 95
H
2-ClC6H4
2-NO2C6H4
3-ClC6H4
4-BrC6H4
4-ClC6H4
2-MeOC6H4
4-MeOC6H4
4-MeC6H4
2-furyl
3
H
4
H
T
t
yield
eec
5
H
entrya
1
solvent
additive
(°C) (h) (%) drb (%)
6
H
1
2
1a CH2Cl2 none
1b CH2Cl2 none
1c CH2Cl2 none
1d CH2Cl2 none
1a toluene none
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
3
3
87
92
82
81
93
92
82
87
93
92
87
85
66
85
84
4:1 66
4:1 63
5:1 90
7
H
8
H
3
72
24
8
9
H
4
1:2
7
10
11
12
13
H
5
5:1 59
6:1 76
5:1 64
4:1 67
6:1 55
4:1 85
6:1 89
4:1 39
5:1 31
5:1 86
6:1 94
H
Me
6
1a THF
none
8
4-Br
Ph
7
1a CH3CN none
1a CHCl3 none
4
5-Me Ph
a Unless otherwise noted, the reactions were carried out with 2 (0.2
mmol), 3 (0.4 mmol), H2O (0.4 mmol) and catalyst 1a (20%) in 0.4 mL
of THF at À10 °C. b Determined by 1H NMR spectroscopic analysis of
the crude product mixture. c Determined by chiral HPLC analysis. d The
ee of the other diastereomer.
8
5
9
1a Et2O
none
24
24
120
8
10
11
12
13
14
15
1a DMSO none
1a THF
1a THF
1a THF
1a THF
1a THF
none
PhCOOH (20%)
NEt3 (20%)
0
0
3
Scheme 1. N-Carbene-Catalyzed Benzoin Reaction
H2O (2.0 equiv)
0
12
48
H2O (2.0 equiv) À10
a Unless otherwise noted, reactions were carried out with 2a (0.2 mmol),
3a (0.4 mmol), and catalyst 1 (20%) in 0.4 mL of solvent. b Determined
by 1H NMR spectroscopic analysis of the crude product mixture.
c Determined by chiral HPLC analysis.
To determine the absolute configuration of asymmetric Michael
adduct, a single crystal of compound 5d bearing a chlorine atom
was obtained for X-ray crystallographic analysis.9 The newly
formed stereogenic centers in 5d were confirmed as (1R,9S).
In order to apply this reaction to the synthesis of indole
derivatives, the Michael adduct 4a was transformed into sub-
stituted cyclopentyl[b]indoline compound 6a via an intramole-
cular cross benzoin reaction catalyzed by N-heterocyclic carbene
(Scheme 1). It should be noted that the reaction proceeds with
excellent diastereoselectivity with the generation of a quaternary
stereocenter. The absolute configuration of 6 was determined by
X-ray crystallographic analysis of 6e.9 To our surprise, the
stereogenic center at C1 was converted from R to S. This may
be due to the enolization of product 6 in the presence of NEt3
and the favored cyclization to form the compound of S config-
uration. This can be ascertained by the fact that the other isomer
of 4a yields the same product. The compound 6a which contains
a bicyclic tertiary alcohol might be applied to the total synthesis
of some indole-related natural products.
In conclusion, we have developed an organocatalyzed asym-
metric Michael addition of 1-acetylindolin-3-ones to R,β-unsa-
turated aldehydes in high yields, moderate diastereoselectivities,
and excellent enantioselectivities, which produces chiral 2-sub-
stituted indolin-3-ones. The corresponding products can be
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The Journal of Organic Chemistry
NOTE
subsequently converted to substituted cyclopentyl[b]indoline
compounds without loss of enantioselectivities. Further investi-
gation into and application of this methodology are still ongoing.
corresponding alcohol 5d with NaCNBH3, and enantiomeric excess was
determined by HPLC with an AS-H column (hexane/i-PrOH = 80:20),
1.0 mL/min; major enantiomer tR = 14.1 min, minor enantiomer tR =
19.4 min.
(S)-3-((R)-1-Acetyl-3-oxoindolin-2-yl)-3-(4-bromophenyl)propanal
’ EXPERIMENTAL SECTION
(4e): colorless oil (64 mg, 81% yield, 4:1 dr, 94% ee), [R]20 = +64
D
(c 1.0, CH2Cl2); IR (KBr) 3410, 2933, 2732, 1714, 1675, 1607, 1466,
1381, 1288, 1009, 761, 539 cmÀ1; 1H NMR (400 MHz, CDCl3) δ 9.90
(s, 1H), 8.21 (s, 1H), 7.45 (t, J = 7.2 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H),
7.02 (t, J = 7.6 Hz, 1H), 4.84 (d, J = 8.4 Hz, 2H), 4.60 (s, 1H), 4.06
(s, 2H), 3.00 (s, 1H), 2.64 (s, 3H) ; 13C NMR (100 MHz, CDCl3) δ
200.1, 198.1, 168.6, 137.1, 134.7, 131.1, 129.8, 125.0, 124.0, 122.9, 121.6,
118.2, 66.3, 43.0, 40.3, 24.1; HRMS (ESI) m/z calcd for C19H17BrNO3
[M + H]+ 386.0386; found 386.0383. The product was converted to
corresponding alcohol 5e with NaCNBH3, and enantiomeric excess was
determined by HPLC with an AS-H column (hexane/i-PrOH = 90:10),
1.0 mL/min; major enantiomer tR = 38.9 min, minor enantiomer tR =
46.1 min.
(S)-3-((R)-1-Acetyl-3-oxoindolin-2-yl)-3-(4-chlorophenyl)propanal
(4f): colorless oil (60 mg, 88% yield, 4:1 dr, 95% ee), [R]20D = +186 (c
1.0, CH2Cl2); IR (KBr) 3412, 2931, 2732, 1715, 1676, 1607, 1466, 1381,
1287, 1094, 1011, 761 cmÀ1; 1H NMR (400 MHz, CDCl3) δ 9.93 (s,
1H), 8.23 (s, 1H), 7.45 (t, J = 6.8 Hz, 2H), 7.02À6.89 (m, 5H), 4.60 (s,
1H), 4.07 (s, 2H), 2.98 (s, 1H), 2.66 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 200.1, 198.1, 168.6, 153.3, 137.1, 134.2, 133.5, 129.5, 128.2,
126.2, 125.1, 124.0, 122.9, 118.3, 66.4, 43.1, 40.3, 24.0; HRMS (ESI)
m/z calcd for C19H17ClNO3 [M + H]+ 342.0891; found 342.0888. The
product was converted to corresponding alcohol 5f with NaCNBH3, and
enantiomeric excess was determined by HPLC with an AS-H column
(hexane/i-PrOH = 90:10), 1.0 mL/min; major enantiomer tR = 36.6
min, minor enantiomer tR = 43.6 min.
(S)-3-((R)-1-Acetyl-3-oxoindolin-2-yl)-3-(2-methoxyphenyl)propa-
nal (4g): colorless oil (57 mg, 85% yield, 4:1 dr, 96% ee), [R]20D = +440
(c 1.0, CH2Cl2); IR (KBr) 3408, 2938, 2731, 1714, 1676, 1605, 1465,
1383, 1287, 1245, 1027, 758 cmÀ1; 1H NMR (400 MHz, CDCl3) δ 9.94
(s, 1H), 8.20 (d, J = 6.4 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.36 (t, J = 8.0
Hz, 1H), 6.96À6.92 (m, 2H), 6.87 (d, J = 8.0 Hz, 1H), 6.61À6.56 (m,
2H), 4.83À4.78 (m, 1H), 4.61 (s, 1H), 4.15À4.05 (m, 1H), 3.72 (s, 3H),
2.87 (d, J = 19.2 Hz, 1H), 2.65 (s, 3H) ; 13C NMR (100 MHz,CDCl3) δ
200.9, 198.9, 169.4, 157.0, 153.5, 136.6, 128.5, 128.1, 125.1, 124.4, 123.3,
122.6, 120.1, 117.8, 109.9, 66.5, 55.1, 42.9, 32.2, 23.7; HRMS (ESI) m/z
calcd for C20H19NNaO4[M + Na]+ 360.1206; found 360.1202. The
product was converted to corresponding alcohol 5g with NaCNBH3,
and enantiomeric excess was determined by HPLC with an AS-H
column (hexane/i-PrOH = 85:15), 1.0 mL/min; major enantiomer
tR = 16.6 min, minor enantiomer tR = 21.0 min.
Representative Procedure for the Synthesis of 2-Substi-
tuted Indolin-3-ones. To a solution of R,β-unsaturated aldehyde 3
(0.4 mmol, 2.0 equiv), catalyst 1a (13 mg, 0.04 mmol, 0.2 equiv), and
H2O (7.2 μL, 0.4 mmol, 2.0 equiv) in THF (0.4 mL) cooled at À10 °C
was added 1-acetylindolin-3-one 2 (0.2 mmol, 1.0 equiv). The resulting
solution was stirred at À10 °C until 2 was consumed as monitored by
TLC. The reaction mixture was concentrated in vacuo and purified by
flash column chromatography (PE/EA = 2:1).
(S)-3-((R)-1-Acetyl-3-oxoindolin-2-yl)-3-phenylpropanal (4a):
colorless oil (51 mg, 84% yield, 6:1 dr, 94% ee), [R]20D = +86 (c 1.0,
CH2Cl2); IR (KBr) 3410, 2925, 2731, 1715, 1675, 1464, 1381, 1288,
762, 702 cmÀ1; 1H NMR (400 MHz, CDCl3) δ 9.91 (s, 1H), 8.17 (s,
1H), 7.41À7.35 (m, 2H), 6.98À6.92 (m, 6H), 4.59 (s, 1H), 4.07 (s, 2H),
3.02 (s, 1H), 2.62 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 200.5, 198.2,
168.6, 153.2, 136.6, 135.6, 128.2, 127.9, 127.5, 125.2, 123.7, 122.7, 118.1,
66.5, 43.0, 40.8, 24.0; HRMS (ESI) m/z calcd for C19H18NO3 [M + H]+
308.1281, found 308.1275. The product was converted to correspond-
ing alcohol 5a with NaCNBH3, and enantiomeric excess was determined
by HPLC with an AS-H column (hexane/i-PrOH = 80:20), 1.0 mL/min;
major enantiomer tR = 12.9 min, minor enantiomer tR = 18.3 min.
(S)-3-((R)-1-Acetyl-3-oxoindolin-2-yl)-3-(2-chlorophenyl)propanal
(4b): colorless oil (62 mg, 91% yield, 4:1 dr, 94% ee), [R]20D = +329
(c 1.0, CH2Cl2); IR (KBr) 3379, 2840, 2732, 1707, 1668, 1601, 1462,
1
1373, 1317, 1004, 757 cmÀ1; H NMR (400 MHz, CDCl3) δ 9.90
(s, 1H), 8.22 (s, 1H), 7.47À7.39 (m, 2H), 7.13 (dd, J = 2.0, 7.2 Hz, 1H),
7.01À6.89 (m, 4H), 4.82 (s, 1H), 4.66 (s, 1H), 4.06 (s, 1H), 2.93
(s, 1H), 2.64 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 199.9, 198.7,
169.2, 153.4, 136.9, 134.7, 134.0, 129.5, 128.8, 128.6, 126.5, 125.2, 123.8,
122.7, 118.4, 66.6, 43.5, 36.2, 23.9; HRMS (ESI) m/z calcd for
C19H17ClNO3 [M + H]+ 342.0891; found 342.0898. The product
was converted to corresponding alcohol 5b with NaCNBH3, and
enantiomeric excess was determined by HPLC with an AS-H column
(hexane/i-PrOH = 70:30), 1.0 mL/min; major enantiomer tR = 8.8 min,
minor enantiomer tR = 16.2 min.
(S)-3-((R)-1-Acetyl-3-oxoindolin-2-yl)-3-(2-nitrophenyl)propanal
(4c): colorless oil (63 mg, 89% yield, 6:1 dr, 92% ee, [R]20 = +322
D
(c 1.0, CH2Cl2); IR (KBr) 3412, 2841, 2735, 1715, 1681, 1607, 1526,
1466, 1379, 1285, 1009, 763, 599 cmÀ1; 1H NMR (400 MHz, CDCl3) δ
9.92 (s, 1H), 8.19 (s, 1H), 7.49À7.39 (m, 3H), 7.26À7.18 (m, 2H), 7.13
(t, J = 7.2 Hz, 1H), 6.98 (t, J = 7.2 Hz, 1H), 5.12 (s, 1H), 4.65 (s, 1H),
4.13 (s, 1H), 3.10 (s, 1H), 2.54 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
199.3, 198.3, 168.8, 150.7, 137.0, 132.0, 130.0, 129.1, 128.3, 124.3, 124.2,
124.0, 123.7, 118.6, 66.4, 42.8, 34.0, 23.4; HRMS (ESI) m/z calcd for
C19H17N2O5 [M + H]+ 353.1132; found 353.1137. The product was
converted to corresponding alcohol 5c with NaCNBH3, and enantio-
meric excess was determined by HPLC with an AD-H column (hexane/
i-PrOH = 70:30), 1.0 mL/min; minor enantiomer tR = 16.7 min, major
enantiomer tR = 17.9 min.
(S)-3-((R)-1-Acetyl-3-oxoindolin-2-yl)-3-(3-chlorophenyl)propanal
(4d): colorless oil (62 mg, 91% yield, 6:1 dr, 90% ee), [R]20D = +109
(c 1.0, CH2Cl2); IR (KBr) 3408, 2932, 2732, 1713, 1676, 1606, 1467,
1383, 1290, 1093, 763, 694, 603 cmÀ1; 1H NMR (400 MHz, CDCl3)
δ 9.92 (s, 1H), 8.21 (s, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.02À6.92
(m, 4H), 6.48 (d, J = 6.8 Hz, 2H), 4.60 (s, 1H), 4.06 (s, 2H), 3.01 (s,
1H), 2.65 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 200.0, 198.0, 168.5,
153.2, 137.7, 137.0, 133.9, 129.2, 128.3, 127.8, 126.5, 124.0, 122.9, 118.2,
66.3, 42.9, 40.7, 24.0; HRMS (ESI) m/z calcd for C19H17ClNO3
[M + H]+ 342.0891; found 342.0894. The product was converted to
(S)-3-((R)-1-Acetyl-3-oxoindolin-2-yl)-3-(4-methoxyphenyl)propa-
nal (4h): colorless oil (62 mg, 92% yield, 5:1 dr, 86% ee), [R]20D = +135
(c 1.0, CH2Cl2); IR (KBr) 3406, 2937, 2617, 1713, 1676, 1608, 1514,
1
1466, 1384, 1290, 1251, 1184, 1034, 763, 538 cmÀ1; H NMR (400
MHz, CDCl3) δ 9.90 (s, 1H), 8.20 (s, 1H), 7.41À7.37 (m, 2H), 6.96 (t,
J = 7.2 Hz, 1H), 6.86 (d, J = 7.2 Hz, 2H), 6.51 (d, J = 8.8 Hz, 2H), 4.55 (s,
1H), 4.01 (s, 2H), 3.59 (s, 3H), 2.98 (s, 1H), 2.62 (s, 3H) ; 13C NMR
(100 MHz,CDCl3) δ 200.7, 198.5, 168.8, 158.8, 136.8, 129.2, 127.6,
125.2, 123.8, 122.8, 118.6, 118.2, 113.4, 66.7, 55.0, 43.3, 40.2, 24.0;
HRMS (ESI) m/z calcd for C20H20NO4 [M + H]+ 338.1387; found
338.1391. The product was converted to corresponding alcohol 5h with
NaCNBH3, and enantiomeric excess was determined by HPLC with an
AS-H column (hexane/i-PrOH = 80:20), 1.0 mL/min; major enantio-
mer tR = 20.8 min, minor enantiomer tR = 30.1 min.
(S)-3-((R)-1-Acetyl-3-oxoindolin-2-yl)-3-(p-tolyl)propanal (4i):
colorless oil (60 mg, 94% yield, 6:1 dr, 86% ee), [R]20D = +116 (c 1.0,
CH2Cl2); IR (KBr) 3378, 2974, 2738, 1714, 1674, 1607, 1465, 1382,
1
1291, 1092, 762 cmÀ1; H NMR (400 MHz, CDCl3) δ 9.91 (s, 1H),
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NOTE
8.21 (s, 1H), 7.42À7.38 (m, 2H), 6.97 (t, J = 7.6 Hz, 1H), 6.85À6.79 (m,
4H), 4.59 (s, 1H), 4.04 (s, 2H), 3.00 (s, 1H), 2.63 (s, 3H), 2.10 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 200.7, 198.4, 168.8, 153.4, 137.3, 136.7,
132.6, 128.7, 128.1, 125.3, 123.8, 122.8, 118.3, 66.7, 43.3, 40.6, 24.1,
20.8; HRMS (ESI) m/z calcd for C20H20NO3 [M + H]+ 322.1438;
found 322.1443. The product was converted to corresponding alcohol 5i
with NaCNBH3, and enantiomeric excess was determined by HPLC
with an AS-H column (hexane/i-PrOH = 80:20), 1.0 mL/min; major
enantiomer tR = 12.5 min, minor enantiomer tR = 16.7 min.
(R)-3-((R)-1-Acetyl-3-oxoindolin-2-yl)-3-(furan-2-yl)propanal (4j):
colorless oil (54 mg, 92% yield, 6:1 dr, 76% ee), [R]20D = +153 (c 1.0,
CH2Cl2); IR (KBr) 3410, 3925, 2734, 1718, 1674, 1466, 1382, 1291,
1010, 759, 599 cmÀ1; 1H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 8.34
(s, 1H), 7.56À7.520 (m, 2H), 7.08 (t, J = 7.2 Hz, 1H), 6.97 (s, 2H), 5.94
(m, 1H), 4.58 (s, 1H), 4.21 (s, 1H), 3.86 (s, 1H), 3.03 (s, 1H), 2.56
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 199.8, 197.6, 168.5, 150.2,
141.9, 137.3, 136.8, 124.1, 123.8, 123.6, 123.1, 109.9, 108.1, 65.6, 41.6,
35.1, 23.9; HRMS (ESI) m/z calcd for C17H16NO4 [M + H]+ 298.1074;
found 298.1078. The product was converted to corresponding alcohol 5j
with NaCNBH3, and enantiomeric excess was determined by HPLC
with an AS-H column (hexane/i-PrOH = 80:20), 1.0 mL/min; major
enantiomer tR = 14.2 min, minor enantiomer tR = 21.5 min.
reaction mixture was warmed to rt overnight. Three milliliters of brine
was added, and the pH was adjusted to 7 with saturated NaHCO3
solution. The aqueous layer was extracted three times with 10 mL of EA,
and the combined organic layers were dried over Na2SO4. After
evaporation of the solvents under vacuum, the residue was purified by
flash column chromatography (PE/EA = 1:2).
(R)-1-Acetyl-2-((S)-3-hydroxy-1-phenylpropyl)indolin-3-one (5a):
colorless oil (21 mg, 68% yield), [R]20D = +121; IR (KBr) 3413, 2928,
1
1713, 1673, 1607, 1466, 1385, 1303, 761, 703 cmÀ1; H NMR (400
MHz, CDCl3) δ 8.16 (s, 1H), 7.38À7.34 (m, 2H), 6.95 (s, 5H), 4.65 (s,
1H), 3.87 (s, 1H), 3.76 (s, 1H), 3.71À3.66 (m, 1H), 3.12 (s, 1H),
2.54À2.49 (m, 1H), 2.46 (s, 3H), 2.35À2.27 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 198.4, 168.5, 152.9, 136.4, 128.2, 127.7, 127.1, 125.2,
123.6, 122.5, 118.1, 68.0, 60.0, 44.7, 31.2, 23.6; HRMS (ESI) m/z calcd
for C19H20NO3 [M + H]+ 310.1438; found 310.1445.
(R)-1-Acetyl-2-((S)-1-(3-chlorophenyl)-3-hydroxypropyl)indolin-3-
one (5d): colorless oil (21 mg, 61% yield), [R]20 = +128; IR (KBr)
D
1
3409, 2926, 1713, 1676, 1606, 1468, 1384, 762, 704 cmÀ1; H NMR
(400 MHz, CDCl3) δ 8.19 (s, 1H), 7.50À7.42 (m, 2H), 7.03À6.86 (m,
5H), 4.72 (s, 1H), 3.90À3.80 (m, 2H), 3.73À3.67 (m, 1H), 2.56À2.49
(m, 4H), 2.32À2.23 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 198.2,
168.3, 136.8, 133.7, 129.1, 128.6, 127.4, 126.6, 124.0, 120.1, 67.7, 60.3,
44.7, 31.5, 24.0; HRMS (ESI) m/z calcd for C19H19ClNO3 [M + H]+
344.1048; found 344.1051.
Representative Procedure for the Benzoin Reaction of 4.
To a solution of 4 (0.1 mmol, 1.0 equiv) in 2.0 mL of CHCl3 were added
5 mg (0.02 mmol, 0.2 equiv) of 3-benzyl-5-(2-hydroxyethyl)-4-
methylthiazolium chloride and 7 μL (0.05 mmol, 0.5 equiv) of NEt3.
The reaction mixture was refluxed under Ar until the reaction com-
pleted. After concentrated in vacuo, the residue was purified by flash
column chromatography (PE/EA = 2:1).
(R)-3-((R)-1-Acetyl-3-oxoindolin-2-yl)butanal (4k): colorless oil (44
mg, 90% yield, 1:1 dr, 82% ee), [R]20D = +213 (c 1.0, CH2Cl2); IR (KBr)
3413, 2968, 2729, 1716, 1675, 1607, 1464, 1380, 1297, 1007, 762 cmÀ1
;
1H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 8.53 (s, 1H), 7.70À7.64
(m, 2H), 7.21 (t, J = 7.6 Hz, 1H), 4.45 (d, J = 3.6 Hz, 1H), 3.52 (s, 1H),
2.97 (s, 1H), 2.63 (dd, J = 3.6, 19.6 Hz, 1H), 2.55 (s, 3H), 0.71 (d, J = 6.8
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 201.1, 198.7, 169.1, 153.8,
137.3, 125.2, 124.3, 123.2, 118.6, 66.4, 45.3, 30.4, 23.9, 13.3; HRMS
(ESI) m/z calcd for C14H16NO3 [M + H]+ 246.1125; found 246.1131.
The product was converted to corresponding acetyl ester with
NaCNBH3 and Ac2O, and enantiomeric excess was determined by
HPLC with an AS-H column (hexane/i-PrOH = 70:30), 1.0 mL/min;
major enantiomer tR = 9.7 min, minor enantiomer tR = 14.0 min.
(S)-3-((R)-1-Acetyl-4-bromo-3-oxoindolin-2-yl)-3-phenylpropanal
(3S,3aS,8bR)-4-Acetyl-8b-hydroxy-3-phenyl-2,3,3a,4-tetrahydro-
cyclopenta[b]indol-1(8bH)-one (6a): colorless oil (22 mg, 70% yield,
93% ee), [R]20D = +214 (c 1.0, CH2Cl2); IR (KBr) 3317, 2924, 1711,
1
1673, 1464, 1379, 1295, 1084, 757, 702 cmÀ1; H NMR (400 MHz,
DMSO-d6) δ 8.10 (d, J = 8.0 Hz, 1H), 7.45À7.30 (m, 7H), 7.16 (t, J =
8.0 Hz, 1H), 6.53 (s, 1H), 4.72 (d, J = 8.0 Hz, 1H), 3.00 (dd, J = 8.0, 18.4
Hz, 1H), 2.86À2.73 (m, 2H), 1.48 (s, 3H); 13C NMR (100 MHz,
DMSO-d6) δ 211.1, 168.4, 142.2, 141.5, 130.4, 129.4, 128.9, 128.1,
128.0, 127.7, 127.5, 127.4, 124.9, 124.1, 117.9, 83.6, 76.4, 44.9, 43.8,
22.8; HRMS (ESI) m/z calcd for C19H18NO3 [M + H]+ 308.1281;
found 308.1287. The enantiomeric excess was determined by HPLC
with an AS-H column (hexane/i-PrOH = 80:20), 1.0 mL/min; minor
enantiomer tR = 20.4 min, major enantiomer tR = 23.0 min.
(4l): colorless oil (71 mg, 92% yield, 11:1 dr, 82% ee), [R]20 = +80
D
(c 1.0, CH2Cl2); IR (KBr) 3412, 2922, 2730, 1716, 1679, 1598, 1424, 1378,
1263, 933, 702 cmÀ1; 1H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 8.46 (s,
1H), 7.25 (s, 1H), 7.10À7.04 (m, 4H), 6.94 (s, 2H), 4.60 (s, 1H), 4.06 (s,
2H), 3.00 (d, J= 16.4 Hz, 1H), 2.67 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
200.4, 197.1, 168.9, 158.5, 135.2, 132.1, 128.5, 128.4, 128.2, 127.9, 127.8, 127.3,
123.5, 121.2, 66.8, 42.9, 40.9, 24.0; HRMS (ESI) m/z calcd for C19H17BrNO3
[M + H]+ 386.0386; found 386.0375. The product was converted to
corresponding alcohol 5l with NaCNBH3, and enantiomeric excess was
determined by HPLC with an AS-H column (hexane/i-PrOH = 80:20),
1.0 mL/min; major enantiomer tR = 12.4 min, minor enantiomer tR = 18.4 min.
(S)-3-((R)-1-Acetyl-5-methyl-3-oxoindolin-2-yl)-3-phenylpropanal
(4m): colorless oil (59 mg, 91% yield, 5:1 dr, 95% ee), [R]20D = +170
(c 0.5, CH2Cl2); IR (KBr) 3408, 2924, 2732, 1714, 1672, 1489, 1380,
1287, 732, 703 cmÀ1; 1H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 8.09
(s, 1H), 7.11 (d, J = 7.6 Hz, 2H), 7.02À6.95 (m, 5H), 4.58 (s, 1H), 4.07
(s, 2H), 2.99 (d, J = 17.2 Hz, 1H), 2.64 (s, 3H), 2.23 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 200.6, 198.3, 168.6, 151.7, 137.9, 135.7, 133.6,
128.2, 128.0, 127.6, 125.2, 122.4, 118.0, 66.7, 43.1, 41.0, 23.8, 20.5;
HRMS (ESI) m/z calcd for C20H20NO3 [M + H]+ 322.1438; found
322.1435. The product was converted to corresponding alcohol 5m with
NaCNBH3, and enantiomeric excess was determined by HPLC with an
AS-H column (hexane/i-PrOH = 80:20), 1.0 mL/min; major enantio-
mer tR = 13.1 min, minor enantiomer tR = 21.6 min.
(3S,3aS,8bR)-4-Acetyl-3-(4-bromophenyl)-8b-hydroxy-2,3,3a,4-tetra-
hydrocyclopenta[b]indol-1(8bH)-one (6e): colorless oil (26 mg, 68%
yield, 94% ee), [R]20 = +32 (c 1.0, CH2Cl2); IR (KBr) 3363, 2923,
D
1
1750, 1648, 1470, 1396, 1244, 1073, 1025, 755 cmÀ1; H NMR (400
MHz, DMSO-d6) δ 8.09 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 2H),
7.44À7.38 (m, 4H), 7.16 (t, J = 8.0 Hz, 1H), 6.54 (s, 1H), 4.73 (d, J = 8.0
Hz, 1H), 3.04 (dd, J = 9.6, 17.6 Hz, 1H), 2.80À2.76 (m, 2H), 1.55 (s,
3H); 13C NMR (100 MHz, DMSO-d6) δ 211.0, 168.4, 142.2, 141.2,
131.8, 130.5, 130.1, 129.4, 124.9, 124.2, 120.4, 118.0, 83.6, 76.0, 44.3,
43.8, 23.0; HRMS (ESI) m/z calcd for C19H17BrNO3 [M + H]+
386.0386; found 386.0389. The enantiomeric excess was determined
by HPLC with an AS-H column (hexane/i-PrOH = 80:20), 1.0 mL/
min; minor enantiomer tR = 21.6 min, major enantiomer tR = 28.3 min.
’ ASSOCIATED CONTENT
S
Supporting Information. General information, spectro-
Representative Procedure for the Reduction of 2-Substi-
tuted Indolinones 4. A solution of 4 (0.1 mmol, 1.0 equiv) in 1.0 mL
of THF was cooled to 0 °C, and 0.125 mL of concentrated AcOH and 11
mg (0.2 mmol, 2.0 equiv) of NaCHBH3 were subsequently added. The
b
gram for new compounds, and X-ray crystallographic data (CIF file
of 5d, CCDC 825030; and 6e, CCDC 825029). This material is
available free of charge via the Internet at http://pubs.acs.org.
7554
dx.doi.org/10.1021/jo201123p |J. Org. Chem. 2011, 76, 7551–7555

The Journal of Organic Chemistry
NOTE
’ AUTHOR INFORMATION
(9) CCDC 825029 and 825030 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif.
Corresponding Author
*E-mail: xupf@lzu.edu.cn.
’ ACKNOWLEDGMENT
We are grateful for the National Basic Research Program of
China (Nos. 2009CB626604, 2010CB833203), the NSFC
(20972058, 21032005), the Fundamental Research Funds for
the Central Universities (Lzujbky-2010-112), and the “111”
program from MOE of P. R. China.
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7555
dx.doi.org/10.1021/jo201123p |J. Org. Chem. 2011, 76, 7551–7555