Enantioselective decarboxylative aldol addition of β-ketoacids to isatins catalyzed by binaphthyl-modified organocatalyst

Article abstract of DOI:10.1016/j.tetlet.2013.04.132

The catalytic enantioselective decarboxylative aldol addition reaction of isatins with β-ketoacids promoted by chiral bifunctional organocatalysts have been developed, allowing facile synthesis of the corresponding chiral 3-hydroxy-3-phenacyloxindole deri

Full text of DOI:10.1016/j.tetlet.2013.04.132

Tetrahedron Letters 54 (2013) 3651–3654
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Enantioselective decarboxylative aldol addition of b-ketoacids to isatins
catalyzed by binaphthyl-modified organocatalyst
⇑
Chang Won Suh, Chul Woo Chang, Keon Woong Choi, Young Jo Lim, Dae Young Kim
Department of Chemistry, Soonchunhyang University, Asan, Chungnam 336-745, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
The catalytic enantioselective decarboxylative aldol addition reaction of isatins with b-ketoacids pro-
moted by chiral bifunctional organocatalysts have been developed, allowing facile synthesis of the corre-
sponding chiral 3-hydroxy-3-phenacyloxindole derivatives with excellent enantioselectivity (up to 97%
ee).
Received 15 March 2013
Revised 23 April 2013
Accepted 30 April 2013
Available online 9 May 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric catalysis
Organocatalysis
Aldol addition
3-Hydroxy oxindole
Isatins
b-Ketoacids
The 3-substituted-2-oxindoles, one class of compounds bearing
the indole skeletal structure, exist in a number of biologically ac-
tive alkaloids and pharmacological agents.1 Intensive efforts have
been devoted to the development of asymmetric transformations
using isatin as an electrophile.2 They provide powerful tools for
the rapid and efficient construction of 3-hydroxy-2-oxindole con-
taining chiral quaternary carbon center at its 3-position.3 Among
them, the aldol addition of appropriate ketones to isatins should
be one of the most concise and straightforward approaches to this
kind of compounds.4 However, such direct aldol reactions of aro-
matic ketones were very slow, requiring four to seven days to com-
plete.5 In recent years, the enantioselective decarboxylative
additions of malonic acid half thioesters as ester enolate equiva-
lents have received much attention.6 Although a number of reac-
tions of malonic acid half-thioesters as carbon nucleophiles to
various electrophiles have been reported,7 the corresponding b-
ketoacids have received relatively little attention as carbon nucle-
ophiles. There have been a few reported examples of decarboxyla-
tive aldol, alkylation, Mannich, and Michael reactions of b-
ketoacids as surrogates of ketones.8 Very recently, Lu groups de-
scribed organocatalytic enantioselective decarboxylative aldol-
type reactions of b-ketoacids with isatins.9 There are still some
drawbacks to the previously reported procedure, such as the high
catalyst loading and long reaction time required for good
enantioselectivity.
As part of research program related to the development of syn-
thetic methods for the enantioselective construction of stereogenic
carbon centers,10 we recently reported enantioselective C–C bond
formations of active methylenes and methines using chiral cata-
lysts.11 Herein, we wish to describe the direct enantioelective
decarboxylative Michael addition of b-ketoacids to isatins cata-
lyzed by bifunctional organocatalysts bearing both central and ax-
ial chirality.
To determine suitable reaction conditions for the catalytic
enantioselective decarboxylative Michael addition reaction of b-
ketoacids, we initially investigated the reaction system with isatins
1 and benzoylacetic acid (2a) in the presence of 10 mol % of cata-
lysts (Fig. 1) in chloroform at room temperature. We first examined
the influences of the structure of isatin derivatives 1a–1a00 on the
reactivity and selectivity (Table 1, entries 1–3). N-Boc isatin (1a)
was selected as optimum substrate. We also examined the impact
of the structure of catalysts I–VI (Fig. 1) on the enantioselectivities
(79–92% ee, Table 1, entries 1 and 4–8). The best results were ob-
tained with catalyst IV which is binaphthyl-modified squaramide
bifunctional organocatalyst bearing central and axial chiral ele-
ments. In order to improve the selectivity, different solvents were
then tested in the presence of 10 mol % of catalyst IV together with
benzoylacetic acid (2a) and N-Boc isatin (1a). Aprotic solvents,
such as dichloromethane, carbon tetrachloride, 1,2-dichloroe-
thanes, 1,1,2-trichloroethane, diethyl ether, THF, toluene, and
accetonitrile were tolerated well in this conjugate addition with
slightly significant decrease in the enantioselectivities (31–89%
ee, Table 1, entries 6 and 9–16). Protic polar solvent such as MeOH
⇑
Corresponding author. Tel.: +82 41 530 1244; fax: +82 41 530 1247.
E-mail address: dyoung@sch.ac.kr (D.Y. Kim).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.132

3652
C. W. Suh et al. / Tetrahedron Letters 54 (2013) 3651–3654
Table 1
a
Optimization of reaction conditions
OMe
N
O
O
HO
O
O
N
N
cat. (10 mol%)
solvent, rt
Ph
O
+
Ph
OH
O
HN
NH
N
R
N
S
R
HN
S
NH
1a : R = Boc
1a' : R = H
1a'' : R = Ts
2a
3
CF3
F3C
Yieldb (%)
eec (%)
F3C
CF3
Entry
Cat.
Solvent
Time (h)
1
I
I
I
II
III
IV
V
VI
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
CCl4
ClCH2CH2Cl
Cl2CHCH2Cl
Et2O
THF
toluene
MeCN
4
4
4
3
3
3
2
2
2
1
1
1
1
1
1
1
2
3
3
3
3
3
87
82
71
90
91
92
85
86
85
70
80
76
80
77
78
80
82
91
90
91
61
90
85
17
5
I
II
2d
3e
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18f
19g
20h
21i
22h,j
85
79
92
91
86
85
79
87
89
47
31
81
61
83
90
92
88
74
97
N
N
HN
HN
HN
O
S
HN
O
OMe
F3C
CF3
III
IV
MeOH
CHCl3
CHCl3
CHCl3
CHCl3
Ph
N
N
CHCl3
Ph
HN
HN
a
Reaction conditions: isatin (1a, 0.30 mmol), benzoylacetic acid (2a, 0.45 mmol),
catalyst (0.03 mmol), CHCl3 (3 mL) at room temperature.
O
O
b
Isolated yield.
HN
HN
c
O
Enantiopurity was determined by HPLC analysis using a Chiralpak ID column.
O
d
F3C
Isatin (1a0) was used as substrate.
e
N-Tosyl isatin (1a00) was used as substrate.
f
5 mol % of catalyst loading.
2.5 mol % of catalyst loading.
1 mol % of catalyst loading.
0.1 mol % of catalyst loading.
F3C
CF3
g
CF3
h
i
V
VI
j
This reaction was conducted at 0 °C.
Figure 1. Structures of chiral organocatalysts.
also afforded product with high yield and high selectivity (Table 1,
entry 17). Among the solvents probed, the best results (92% yield
and 92% ee) were achieved when the reaction was conducted in
chloroform (Table 1, entry 6). The present catalytic system toler-
ates catalyst loading down to 5.0, 2.5, or 1.0 mol % without com-
promising the yield or the enantioselectivity (Table 1, entries 18–
21). Finally, we conducted the aldol addition at low temperature
in order to improve the enantioselectivity. The enantioselectivity
was elevated up to 97% ee at 0 °C in the presence of 1.0 mol % of
catalyst IV (entry 22).
dol product in moderate yield with high enantioeselectivity (Ta-
ble 2, entries 9–16). We then explored the possibility of using a
wide range of isatins 1 with benzoylacetic acid (2a) in the presence
of 1.0 mol % of catalyst IV in chloform at 0 °C (Table 2). A range of
electron-donating and electron-withdrawing substitutions on the
aromatic ring of isatins 1 provided the reaction products in high
yields (83–98%) and with excellent enantioselectivities (93–95%
ee, Table 2, entries 17–19) The absolute configuration of the ad-
ducts 3 was determined for some derivatives by comparison of
their optical and HPLC properties with literature values.9
To examine the generality of the catalytic enantioselective
decarboxylative aldol addition reaction of the b-ketoacid deriva-
tives 2 by using chiral bifunctional organocatalyst IV, we studied
the aldol addition of various b-ketoacids 2 with N-Boc isatin deriv-
atives 1 in the presence of 1.0 mol % of catalyst IV in chloroform at
0 °C (Table 2).12 A range of electron-donating and electron-with-
drawing substitutions on the b-aryl ring of the b-ketoacids 2 pro-
vided the reaction products in high yields (76–90%) and with
excellent enantioselectivities (87–97%, Table 2, entries 1–6). The
naphthyl- and heteroaryl-substituted b-ketoacids 2 provided the
products with high selectivity (Table 2, entries 7–8). However,
the b-alkyl-substituted b-ketoacid, 3-oxobutanoic acid, was also
an acceptable starting material and provided the corresponding al-
The present method is operationally simple and efficient and,
thus, may be valuable for practical chemical synthesis. As shown
in Scheme 1, when 3-oxo-p-tolylpropanoic acid (2b) was treated
with N-Boc isatin (1a) under the optimal reaction conditions, the
reaction proceeded smoothly to afford the desired product 3b at
the gram scale with 92% yield and 95% ee (Scheme 1).
In conclusion, we have developed a highly efficient catalytic
enantioselective decarboxylative aldol addition reaction of b-keto-
acids to isatins using 1.0 mol % of a binaphthyl-derived bifunc-
tional organocatalyst. The desired aldol products were obtained
in good to high yields, and excellent enantioselectivities (up to
97% ee) were observed for all the substrates examined in this work.
We believe that this method provides a practical entry for the

C. W. Suh et al. / Tetrahedron Letters 54 (2013) 3651–3654
3653
Table 2
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Robitzer, M.; Quignard, F. Chem. Commun. 2010, 46, 6288; (c) Kumar, A.;
Chimni, S. S. RSC Adv. 2012, 2, 9748.
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Pluhackova, K.; Kocovsky, P. Org. Lett. 2007, 26, 5473; (b) Itoh, T.; Ishikawa, H.;
Hayashi, Y. Org. Lett. 2009, 11, 3854; (c) Hara, N.; Nakamura, S.; Shibita, N.;
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Xiong, H. Y.; Hua, M.-Q.; Nie, J.; Zheng, Y.; Ma, J. A. Tetrahedron Lett. 2012, 53,
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7. (a) Lalic, G.; Aloise, A. D.; Shair, M. D. J. Am. Chem. Soc. 2003, 125, 2852; (b)
Magdziak, D.; Lalic, G.; Lee, H. M.; Fortner, K. C.; Aloise, A. D.; Shair, M. D. J. Am.
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Substrate Scopea
O
O
HO
O
O
R1
R1
R2
cat. IV (1 mol%)
R2
OH
O
+
O
CHCl3, 0oC
N
N
Boc
Boc
1
2
3
Entry
R1, R2
H, Ph
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
3
2
2
2
3
3
1
3
2
23
23
25
16
26
18
16
5
3a, 90
3b, 84
3c, 85
3d, 86
3e, 76
3f, 81
3g, 86
3h, 85
3i, 68
3j, 95
3k, 75
3l, 92
3m, 76
3n, 88
3o, 75
3p, 94
3q, 98
3r, 94
3s, 83
97
94
87
94
97
91
91
93
89
93
96
93
91
96
91
94
95
93
95
H, 4-MeC6H4
H, 4-MeOC6H4
H, 4-FC6H4
H, 4-ClC6H4
H, 3-ClC6H4
H, 2-Naphthyl
H, 2-Thienyl
H, Me
H, Et
H, n-Pr
H, i-Pr
H, t-Bu
H, Cyclohexyl
H, Bn
H, PhCH2CH2
Me, Ph
Cl, Ph
Br, Ph
3
2
a
Reaction conditions: isatin (1, 0.30 mmol), b-ketoacid (2, 0.45 mmol), catalyst
mol), CHCl3 (3 mL) at 0 °C.
Isolated yield.
(3.0
l
b
c
Enantiopurity was determined by HPLC analysis using Chiralpak ID (for 3a–3j
O
O
8. (a) Rohr, K.; Mahrwald, R. Org. Lett. 2011, 13, 1878; (b) Yang, C. F.; Wang, J. Y.;
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S.-K. Org. Lett. 2012, 14, 3092; (d) Zheng, Y.; Xiong, H.-Y.; Nie, J.; Hua, M.-Q.; Ma,
J.-A. Chem. Commun. 2012, 4308; (e) Zuo, J.; Liao, Y.-H.; Zhang, X.-M.; Yuan, W.-
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2012, 53, 6569; (g) Kang, Y. K.; Lee, H. J.; Moon, H. W.; Kim, D. Y. RSC Adv. 2013,
3, 1332.
N
Boc
HO
1a (1.00 g)
cat. IV (1 mol%)
O
O
CHCl3, 0 oC, 6 h
+
O
9. Zhong, F.; Yao, W.; Dou, X.; Lu, Y. Org. Lett. 2012, 14, 4018.
N
O
10. (a) Kim, D. Y.; Park, E. J. Org. Lett. 2002, 4, 545; (b) Park, E. J.; Kim, M. H.; Kim, D.
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Bang, H. T.; Kim, D. Y. Synlett 2008, 1821; (f) Lee, J. H.; Kim, D. Y. Adv. Synth.
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Chem. Soc. 2011, 32, 785; (m) Moon, H. W.; Kim, D. Y. Bull. Korean Chem. Soc.
2011, 32, 291; (n) Kang, Y. K.; Kim, H. H.; Koh, K. O.; Kim, D. Y. Tetrahedron Lett.
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Boc
3b (1.75g)
(92% yield, 95 % ee)
OH
2b (1.30 g)
Scheme 1. Gram scale aldol addition of 3-oxo-p-tolylpropanoic acid (2b) with N-
Boc isatin (1a).
preparation of biologically important chiral 3-hydroxy-3-phenacy-
loxindole derivatives. Further study of this catalytic enantioselec-
tive decarboxylative addition reaction of b-ketoacids with various
carbon electrophiles is in progress.
Acknowledgment
This research was supported in part by the Soonchunhyang Uni-
versity Research Fund.
References and notes
12. Typical procedure for the aldol addition reaction of benzoylacetic acid (2a) with N-
Boc isatin (1a): To a stirred solution of N-Boc isatin (1a, 65.2 mg, 0.30 mmol)
1. (a) Jimenez, J.; Huber, U.; Moore, R.; Patterson, G. J. Nat. Prod. 1999, 62, 569; (b)
Lin, S.; Yang, Z. Q.; Kwok, B. H. B.; Koldobskiy, M.; Crews, C. M.; Danishefsky, S.
J. J. Am. Chem. Soc. 2004, 126, 6347; (c) Tokunaga, T.; Hume, W. E.; Nagamine, J.;
Kawamura, T.; Taiji, M.; Nagata, R. Bioorg. Med. Chem. Lett. 2005, 15, 1789; (d)
Xue, F.; Zhang, S.; Liu, L.; Duan, W.; Wang, W. Chem. Asian J. 2009, 4, 1664; (e)
Chen, W.-B.; Du, X.-L.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Tetrahedron 2010,
66, 1441.
and catalyst IV (2.1 mg, 3.0 lmol) in chloroform (3 mL) was added
benzoylacetic acid (2a, 73.9 g, 0.45 mmol) at 0 °C. The reaction mixture was
stirred for 3 h at 0 °C. After completion of the reaction, the resulting solution
was concentrated in vacuo and the obtained residue was purified by flash
chromatography (EtOAc/hexane, 1:2) to afford the 99.2 mg (90%) of the aldol
adduct 3a.
(R)-tert-Butyl
3-hydroxy-2-oxo-3-(2-oxo-2-phenylethyl)indoline-1-carboxylate

3654
C. W. Suh et al. / Tetrahedron Letters 54 (2013) 3651–3654
(3a): ½a 2D6
ꢀ
+80.0 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.90 (d, J = 8.0 Hz,
1H), 7.84 (m, 2H), 7.55 (t, J = 8.5 Hz, 1H), 7.33–7.43 (m, 4H), 7.12 (m, 1H), 4.30
(br s, 1H), 3.88 (d, J = 17.2 Hz, 1H), 3.68 (dd, J = 1.4 Hz, 17.2 Hz, 1H), 1.64 (s,
9H); 13C NMR (100 MHz, CDCl3) d 197.2, 175.1, 149.1, 140.0, 135.9, 133.7,
130.1, 128.7, 128.6, 128.1, 124.7, 123.5, 115.4, 84.5, 74.0, 45.6, 28.0; HRMS
(ESI) m/z calcd for C21H21NNaO5 [M+Na]+ 390.1317, found 390.1313; HPLC
(80:20, n-hexane/i-PrOH, 254 nm, 1.0 mL/min) Chiralpak ID, tR = 10.3 min
(minor), tR = 11.7 min (major), 97% ee.