Facile creation of 3-Substituted-3-Hydroxy-2-Oxindoles by arginine-catalyzed aldol reactions of α,β-unsaturated ketones with isatins

Article abstract of DOI:10.3390/molecules181214505

An efficient approach for the synthesis of 3-substituted-3-hydroxy-2- oxindoles has been achieved via an aldol reaction of α,β-unsaturated ketones and isatins using arginine as an organocatalyst. A range of 3-substituted-3-hydroxy-2-oxindoles were obtained in moderate to high (up to 99%) yields. These 3-substituted-3-hydroxy-2-oxindoles with an additional enone moiety provide an opportunity for further elaboration of the products and for potentially interesting biological activities. In addition, the formation of 3-substituted- 3-hydroxy-2-oxindole 3a was confirmed by X-ray crystallography. The possible reaction mechanism reveals that the reaction proceeds via a double action process.

Full text of DOI:10.3390/molecules181214505

Molecules 2013, 18, 14505-14518; doi:10.3390/molecules181214505
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Facile Creation of 3-Substituted-3-Hydroxy-2-Oxindoles by
Arginine-Catalyzed Aldol Reactions of α,β-Unsaturated Ketones
with Isatins
Tingting Yan 1,†, Xiaoyan Wang 2,†, Hongbao Sun 1, Jie Liu 1,* and Yongmei Xie 1,*
1
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School,
Sichuan University, Chengdu 610041, China; E-Mails: yttscu@163.com (T.Y.);
hongbaosun@163.com (H.S.)
2
Analytical & Testing Center, Sichuan University, Chengdu 610064, China;
E-Mail: wangxiaoyan@scu.edu.cn
†
These authors contributed equally to this work.
* Authors to whom correspondence should be addressed; E-Mails: liujie2011@scu.edu.cn (J.L.);
xieym@scu.edu.cn (Y.X.); Tel./Fax: +86-28-8550-3817 (J.L.).
Received: 14 October 2013; in revised form: 15 November 2013 / Accepted: 19 November 2013 /
Published: 25 November 2013
Abstract: An efficient approach for the synthesis of 3-substituted-3-hydroxy-2-oxindoles
has been achieved via an aldol reaction of α,β-unsaturated ketones and isatins using arginine
as an organocatalyst. A range of 3-substituted-3-hydroxy-2-oxindoles were obtained in
moderate to high (up to 99%) yields. These 3-substituted-3-hydroxy-2-oxindoles with an
additional enone moiety provide an opportunity for further elaboration of the products and
for potentially interesting biological activities. In addition, the formation of 3-substituted-
3-hydroxy-2-oxindole 3a was confirmed by X-ray crystallography. The possible reaction
mechanism reveals that the reaction proceeds via a double action process.
Keywords: 3-substituted-3-hydroxy-2-oxindoles; arginine; aldol reaction; isatins;
α,β-unsaturated ketones

Molecules 2013, 18
14506
1. Introduction
3-Substituted-3-hydroxy-2-oxindoles are heterocyclic organic compounds that possess a carbonyl
group at the 2-position of the 5-membered ring and a quaternary carbon centre at the 3-position of
this ring. This kind of compounds have become important synthetic targets as these structural
frameworks form the core units of many natural products and pharmaceutically active compounds [1].
Convolutamydines [2], arundaphine [3], donaxaridine [4], dioxibrassinine [5], maremycins [6],
paratunamide [7], celogentin K [8], TMC-95A-D [9], flustraminol [10], 3-hydroxy welwitindolinones [11]
and CPC-1 [12] are some examples of a growing list of bioactive 3-substituted-3-hydroxy-2-oxindole
natural products (Figure 1).
Figure 1. Biologically important molecules containing 3-substituted-3-hydroxy-2-oxindoles.
They display diverse biological and pharmacological activities such as potent antioxidant,
anticancer, anti-HIV, and neuroprotective properties. Owing to the significance of this structural motif,
numerous elegant synthetic methodologies have been developed [13–21] and aim to facilitate the
synthesis of sufficient quantities of the desired natural products and related analogues for biological
evaluation and structure-activity relationship studies, and thus finally contribute to the development of
new therapeutic agents or important biological tools. The most direct approach to 3-substituted-3-
hydroxy oxindoles is a nucleophilic addition of appropriate nucleophiles to isatins, such as the aldol
reaction or an alkylation of isatins. Recently, several elegant approaches to 3-aryl or alkyl-3-
hydroxyindolin-2-ones via the cross-aldol reaction between isatins and ketones have been extensively
studied [22–31]. However, few examples of the corresponding aldol reactions of various α,β-unsaturated
ketones with isatins were found in the literature. The aldol addition of an α,β-unsaturated ketone to

Molecules 2013, 18
14507
isatin could produce 3-substituted-3-hydroxy-2-oxindoles with an additional enone moiety and thus
provide a chance for further elaboration of the products (Scheme 1) and perhaps different or improved
biological activities [30,31]. The formation of quaternary carbon centers and the chemoselectivity
(α,β-unsaturated ketone as a nucleophile is arising from the inherent multiple reactivity that involve
ketone, β-carbon and methylene unit) via addition of α,β-unsaturated ketones to isatins represents a
major challenge and has stimulated many a synthetic chemist.
Scheme 1. Further elaboration of 3-hydroxy-3-(2-oxo-4-arylbut-3-enyl) indolin-2-one products.
R5
O
R2
O
[ Ref.30 ]
R1
R3
O
N
R4
O
O
R5
R2
HO
R2
[ Ref.31 ]
R1
R3
R1
R3
R5
O
O
N
N
R4
R4
R2
R1
OMe
[ Ref.31 ]
R3
N
R5
R4
α-Amino acids are readily available organic molecules, which have so far been utilized as chiral
auxiliaries, chiral ligands and chiral synthons for natural products and drugs. Using amino acids as a
catalyst over other organic molecules could provide considerable green technology benefits because
amino acids are a component of natural proteins and completely biodegradable in nature [32–35].
Since List, Lerner, and Barbas first reported the proline-catalyzed direct aldol reaction [36],
other amino-acid based organocatalysts have been developed as mimics of enzymes for various
reactions. The mechanism in the proline-mediated reactions is based on the initial formation of an
imine between the nitrogen atom of proline and the carbonyl group of the substrate and then conversion to
an enamine [37]. Such an imine can be formed by other amino acids and thus the other amino acids
could catalyze similar reactions. In view of this mechanism, we wish to further extend the use of amino
acids as organocatalysts. Herein, we describe the use of amino acids for the facile synthesis of 3-
substituted-3-hydroxy-2-oxindole frameworks in high yields (up to 99%) via the aldol reactions of
α,β-unsaturated ketones and isatins (Scheme 2).
Scheme 2. Synthesis of 3-substituted-3-hydroxy-2-oxindoles.

Molecules 2013, 18
14508
2. Results and Discussion
In our initial studies, the direct aldol reaction between isatin (1a) as an acceptor and
(E)-4-phenylbut-3-en-2-one (2a) as a donor with a catalyst loading of 20 mol% in MeOH at room
temperature was selected as a benchmark for catalyst evaluation. Some screening results are listed in
Table 1. The simple amino acids bearing only an amino group and a carboxyl group could not catalyze
this reaction. No expected aldol adducts were observed after direct determination by TLC (Table 1,
entries 1–5). This indicated that it is impossible for the aldol reaction in which these primary amine
and secondary amine catalysts unilaterally activate the (E)-4-phenylbut-3-en-2-one (2a) to form an
enamine intermediate. Then, we turned our attention to other complex amino acids such as arginine,
tryptophan and histidine as catalysts (Table 1, entries 6–8). Pleasingly, arginine, an amino acid
skeleton with a guanidine group, was effective for the reaction, affording the desired product 3a in 88%
yield (Table 1, entry 7). The formation of 3a was confirmed by X-ray crystallography (Figure 2) [38].
Although L-arginine was used as a catalyst, the product was obtained as a racemic mixture. The
decrease of the reaction temperature down to 0 °C did not alter the enantioselectivity (data not shown).
Table 1. Catalyst screening and reaction conditions optimization a.
Entry
1
Catalyst
Solvent
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
Time/h
24
Yield (%) b
N.D c
N.D
N.D
N.D
N.D
N.D
88
Proline
2
Phenylalanine
Leucine
24
3
24
4
Tyrosine
24
5
Tyrosine methyl ester
Histidine
24
6
24
7
Arginine
24
8
Tryptophan
Boc-Arginine
Arginine
24
N.D
N.D
79
9
24
10 d
11 e
12 f
13 g
14 e,h
15 e,h
16 e
17 e
24
Arginine
24
91
Arginine
24
76
Arginine
24
44
Arginine
12
49
Arginine
24
52
Arginine
12
55
Arginine
48
98
a Unless indicated otherwise, the reaction was carried out in 0.1 mmol scale in solvent (1.0 mL) at 25 °C for
b
c
24 h, and the ratio of 1a/2a/catalyst is 1:1:0.2; Isolated yield based on isatin; N.D. refers to no reaction;
d Catalyst loading is 5 mol%; e Catalyst loading is 10 mol%; f Catalyst loading is 30 mol%; g Catalyst loading
is 50 mol%; h Temperature is 60 °C.

Molecules 2013, 18
14509
Figure 2. X-ray crystal structure of 3a.
To further improve the yields, efforts were made to optimize other reaction parameters including
solvents, catalyst loading and reaction temperatures. Thus, the reaction was studied in different
solvents that included CH2Cl2, THF, dioxane, CH3CN, toluene, EtOH, i-BuOH, n-BuOH and H2O, but
no better result was obtained. In general, reactions carried out in protic solvents gave better yields than
those in aprotic solvents. This may be caused by poor solubility of arginine in aprotic solvents and H2O.
Catalyst loading influenced the rate of the reaction. As the catalyst loading increased to 10 mol %, the
yield increased steadily (Table 1, entries 7, 10, 11). Further improvement, however, was not achieved
by further increasing the catalyst loading (Table 1, entries 12, 13). Temperature also influenced the rate
of the reaction. Elevating the reaction temperature resulted in a low yield, while conducting the reaction at
60 °C gave a certain amount of byproducts (Table 1, entries 14, 15). The relatively higher yield of
reaction could be compensated by prolonging reaction time to 48 h, and up to 98% yield was obtained
(Table 1, entry 17). Through extensive screening, the optimized catalytic system was found to be
1a/2a/arginine = 1/1/0.1, 1.0 mL MeOH as solvent at 25 °C for 48 h.
Having the optimized conditions in hand, the aldol reaction of α,β-unsaturated ketones with
different structures was investigated. As shown in Table 2, a variety of α,β-unsaturated ketones proved
to be excellent nucleophiles for this reaction, and provided the corresponding 3-substituted-3-hydroxy-
2-oxindoles in good yields (up to 98%) (Table 2, entries 1–15). The electronic properties and steric
hindrance of the substituents at the aromatic ring influenced the yields slightly. Generally, α,β-unsaturated
ketones with electron-donating groups gave higher yields than those with electron-withdrawing groups
(Table 2, entries 2, 10 vs. 3–8). Ortho- and meta-substituted α,β-unsaturated ketones gave higher yields
than para-substituted α,β-unsaturated ketones (Table 2, entries 2‒5 vs. 8‒11). α,β-Unsaturated ketones
bearing naphthyl and heterocyclic substituents participated in smooth aldol reactions in 81% and 88%
yield, respectively (Table 2, entries 13, 14). Moreover, it is worthwhile to note that an α,β-unsaturated
ketones derived from an aliphatic aldehyde was investigated and it was transformed with moderate
yield (Table 2, entry 15). To further extend the application of arginine, substituted isatins with several
representative α,β-unsaturated ketones were also examined (Table 2, entries 16–18). Incorporating
protecting groups on the N1 of oxindole had no effect on reactivity, and gave the desired product in
almost quantitative yield (99%) (Table 2, entry 16). However, the electronic properties of the
substituents at the isatin affected the yields strongly (Table 2, entries 17–20). Isatin with an electron-
donating group only gave 60% yield.

Molecules 2013, 18
Table 2. Substrate scope for the aldol reaction of isatins and α,β-unsaturated ketones a.
14510
Entry
1
1
2
3
Yield (%) b
3a 98
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R1 = R2 = R3 = R4 = H
R5 = Ph
2
R5 = 4-MeO-C6H4 3b 95
3
R5 = 4-F-C6H4
R5 = 4-Cl-C6H4
R5 = 4-Br-C6H4
R5 = 4-NO2-C6H4
R5 = 3-CF3-C6H4
R5 = 3-Br-C6H4
R5 = 3-Cl-C6H4
3c 87
3d 80
3e 82
3f 75
3g 86
3h 85
4
5
6
7
8
9
3i
82
10
11
12
13
14
15
16
17
18
19
20
R5 = 3-MeO-C6H4 3j 96
R5 = 2-F-C6H4
3k 92
R5 = 3,4-diCl-C6H4 3l 73
R5 = 2-Naphthyl
R5 = 2-Furyl
R5 = Propyl
3m 81
3n 88
3o 67
3p 99
3q 60
3r 99
3s 93
3t 92
R1 = R2 = R3 = H, R4 = CH2Ph R5 = Ph
R1 = Me, R2 = R3 = R4 = H
R1 = Br, R2 = R3 = R4 = H
R3 = Cl, R1 = R2 = R4 = H
R2 = Cl, R1 = R3 = R4 = H
R5 = Ph
R5 = Ph
R5 = Ph
R5 = Ph
a
The reaction was carried out in 0.1 mmol scale in MeOH (1.0 mL) at 25 °C for 48 h, and the ratio of
1/2/arginine is 1:1:0.1; b Isolated yield based on isatins.
Based on the results (Table 1, entries 1–9) and previous reports, [39–41] a possible reaction mechanism
for the formation of 3-substituted-3-hydroxy-2-oxindoles could be proposed. As depicted in Scheme 3,
in solid form or in polar solutions, amino acids can exist as zwitterions, which contain a protonated
amino group and deprotonated carboxylate group. It is obvious that simple amino acids (only bearing
an amine group and a carboxyl group) in zwitterionic form could not be considered as a base and
therefore did not participate in this reaction (Table 1, entries 1–5). However, arginine, as a basic amino
acid which possesses side chain basicity (pKa = 12.48) due to its guanidine group, can take a proton
from the protonated amino group thereby resulting in the formation of the naked amino group.
Then, the naked amino group can also form an enamine with the carbonyl group of the substrate
(Table 1, entries 7, 9) and the guanidine group presumably activates the carbonyl group of isatin
(Table 1, entries 6–8). This double action of the amino acid may play a key role in this reaction and
hence facilitate the aldol reaction.

Molecules 2013, 18
14511
Scheme 3. The double action catalysis mechanism.
O
R
O
R
O
OH
O
NH
NH3
R3
R3
simple amino acids
in zwitterions form
2
NH2
N
O
H
N
O
O
NH2
O
R1
NH
O
-H2O
H
H
O
H2N
N
H
O
R3
N
R3
O
NH2
O
R2
Arginine
2
1
N
R1
R2
NH
N
O
O
R3
H
N
O
HO
N
R1
H
H
HN
O
R3
OH
O
R2
N
3
R1
R2
3. Experimental
3.1. General
All chemicals were obtained from commercial sources and used without further purification.
Column chromatography was carried out on silica gel (300–400 mesh, Qingdao Marine Chemical Ltd.,
Qingdao, China). Thin layer chromatography (TLC) was performed on TLC silica gel 60 F254 plates.
1H-NMR spectra were recorded on a Bruker AVII-400 MHz NMR spectrometer. The chemical shifts
were recorded in ppm relative to tetramethylsilane and with the solvent resonance as the internal
standard. Data were reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet,
q = quartlet, m = multiplet), coupling constants (Hz), integration. 13C-NMR data were collected at
100 MHz with complete proton decoupling. Chemical shifts were reported in ppm from the
tetramethylsilane with the solvent resonance as internal standard. MS spectra were obtained on a
Waters Quattro Premier XETM triple quadrupole mass spectrometer and methanol was used to
dissolve the sample. Melting points were recorded at SGW X-4 Melting point instrument (Shanghai
Precision & Scientific Instrument Co., Ltd, Shanghai, China).
3.2. Experimental Procedures
A mixture of isatin 1a (0.1 mmol), (E)-4-phenylbut-3-en-2-one (2a, 0.1 mmol), arginine (0.01 mmol)
in MeOH (1.0 mL) was stirred for 48 h at 25 °C. After completion of the reaction (TLC), the solvent
was removed under vacuum. The crude product was subjected to column chromatography on silica gel
using petroleum ether/ethyl acetate = 1:1 as the eluent to give 3a.
Compounds 3b–t were synthesized by a similar procedure as described for compound 3a. For the
separation of these compounds, the eluent of silica gel column chromatography consisted of
appropriate mixtures of petroleum ether and ethyl acetate.

Molecules 2013, 18
14512
3.3. Spectral Data
(E)-3-Hydroxy-3-(2-oxo-4-phenylbut-3-en-1-yl)indolin-2-one (3a). Yield 98%; White solid; m.p.
1
159–160 °C; H-NMR (400 MHz, TMS, DMSO): δ 3.23 (d, J = 16.0 Hz, 1H), 3.65 (d, J = 16.0 Hz,
1H), 6.05 (s, 1H), 6.74–6.80 (m, 2H), 6.88 (t, J = 8.0 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 7.28 (d,
J = 8.0 Hz, 1H), 7.42–7.43 (m, 3H), 7.55 (d, J = 16.4 Hz, 1H), 7.67 (m, 2H), 10.24 (s, 1H); 13C-NMR
(100 MHz, DMSO): δ 47.6, 73.1, 109.4, 121.1, 123.7, 126.4, 128.4, 128.9, 130.5, 131.5, 134.3, 142.5,
142.7, 178.2, 196.2; MS: m/z = 316 [M+Na]+.
(E)-3-Hydroxy-3-(4-(4-methoxyphenyl)-2-oxobut-3-en-1-yl)indolin-2-one (3b). Yield 95%; White solid;
m.p. 167–168 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.20 (d, J = 16.4 Hz, 1H), 3.63 (d, J = 16.4 Hz,
1H), 3.80 (s, 3H), 6.04 (s, 1H), 6.62 (d, J = 16.4 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.88 (t, J = 7.6 Hz,
1H), 6.98 (t, J = 8.4 Hz, 2H), 7.16 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 7.51 (d, J = 16.4 Hz,
1H), 7.62 (d, J = 8.4 Hz, 2H), 10.23 (s, 1H); 13C-NMR (100 MHz, DMSO): δ 47.4, 55.3, 73.1, 109.3,
114.4, 121.1, 123.7, 124.1, 126.8, 128.9, 130.3, 131.5, 142.5, 142.7, 161.2, 178.3, 196.0; MS:
m/z = 346 [M+Na]+.
(E)-3-(4-(4-Fluorophenyl)-2-oxobut-3-en-1-yl)-3-hydroxyindolin-2-one (3c). Yield 87%; White solid;
m.p. 177–178 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.23 (d, J = 16.4 Hz, 1H), 3.66 (d, J = 16.4 Hz,
1H), 6.07 (s, 1H), 6.72 (d, J = 16.4 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.88 (t, J = 7.6 Hz, 1H), 7.16
(t, J = 7.6 Hz, 1H), 7.24–7.29 (m, 3H), 7.56 (d, J = 16.4 Hz, 1H), 7.74 (m, 2H), 10.26 (s, 1H);
13C-NMR (100 MHz, DMSO): δ = 47.6, 73.1, 109.4, 115.9 (d, J = 22 Hz), 121.1, 123.7, 126.3, 128.9,
130.8 (d, J = 8 Hz), 130.9 (d, J = 3 Hz), 131.5, 141.4, 142.7, 163.3 (d, J = 248 Hz), 178.2, 196.2; MS:
m/z = 334 [M+Na]＋.
(E)-3-(4-(4-Chlorophenyl)-2-oxobut-3-en-1-yl)-3-hydroxyindolin-2-one (3d). Yield 80%; White solid;
m.p. 196–197 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.23 (d, J = 16.4 Hz, 1H), 3.65 (d, J = 16.4 Hz,
1H), 6.07 (s, 1H), 6.77 (m, 2H), 6.88 (t, J = 7.6 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 7.2 Hz,
1H), 7.51 (m, 3H), 7.70 (d, J =8.4 Hz, 2H), 10.25 (s, 1H);13C-NMR (100 MHz, DMSO): δ 47.7,
73.1, 109.4, 121.1, 123.7, 127.0, 129.0, 130.1, 131.4, 133.3, 135.0, 141.1, 142.6, 178.2, 196.2;
MS: m/z = 350 [M+Na]＋.
(E)-3-(4-(4-Bromophenyl)-2-oxobut-3-en-1-yl)-3-hydroxyindolin-2-one (3e). Yield 82%; White solid;
m.p. 205–206 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.22 (d, J = 16.4 Hz, 1H), 3.64 (d, J = 16.4 Hz,
1H), 6.05 (s, 1H), 6.79 (m, 2H), 6.88 (t, J = 7.6 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 7.2 Hz,
13
1H), 7.52 (d, J = 16.0 Hz, 1H), 7.62 (s, 4H), 10.23 (s, 1H); C-NMR (100 MHz, DMSO): δ = 47.7,
73.1, 109.4, 121.1, 123.7, 123.8, 127.1, 128.9, 130.3, 131.4, 131.9, 133.6, 141.1, 142.6, 178.2, 196.2;
MS: m/z = 394 [M+Na]＋.
(E)-3-Hydroxy-3-(4-(4-nitrophenyl)-2-oxobut-3-en-1-yl)indolin-2-one (3f). Yield 75%; White solid;
m.p. 195–196 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.25 (d, J = 16.4 Hz, 1H), 3.68 (d, J = 16.4 Hz,
1H), 6.09 (s, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.89 (t, J = 7.6 Hz, 1H), 6.95 (d, J = 16.4 Hz, 1H), 7.16 (t,
J = 7.6 Hz, 1H), 7.28 (d, J =7.2 Hz, 1H), 7.63 (d, J =16.4 Hz, 1H), 7.94 (d, J =8.8 Hz, 2H), 8.25 (d,

Molecules 2013, 18
14513
13
J = 8.8 Hz, 2H), 10.27 (s, 1H); C-NMR (100 MHz, DMSO): δ = 47.9, 73.1, 109.4, 121.2, 123.8,
124.0, 129.0, 129.4, 129.9, 131.3 139.7, 140.9, 142.6, 148.0, 178.1, 196.3; MS: m/z = 361 [M+Na]＋.
(E)-3-Hydroxy-3-(2-oxo-4-(3-(trifluoromethyl)phenyl)but-3-en-1-yl)indolin-2-one (3g). Yield 86%;
White solid; m.p. 114–115 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.23 (d, J = 16.4 Hz, 1H), 3.65
(d, J = 16.4 Hz, 1H), 6.06 (s, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.88 (m, 2H), 7.16 (td, J = 7.6 Hz,
J = 1.2 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 7.65 (m, 2H), 7.76 (d, J =7.6 Hz, 1H), 7.97 (d, J =8.0 Hz,
13
1H), 8.05 (s, 1H), 10.24 (s, 1H); C-NMR (100 MHz, DMSO): δ 47.9, 73.1, 109.4, 121.1, 123.8, 123.9
(q, J = 271 Hz), 124.9 (q, J = 14 Hz), 126.6 (q, J = 4 Hz), 128.2, 129.0, 129.6, 130.0, 131.4, 132.0,
135.6, 140.5, 142.6, 178.1, 196.2; MS: m/z = 384 [M+Na]＋.
(E)-3-(4-(3-Bromophenyl)-2-oxobut-3-en-1-yl)-3-hydroxyindolin-2-one (3h). Yield 85%; White solid;
m.p. 173–174 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.23 (d, J = 16.4 Hz, 1H), 3.65 (d, J = 16.4 Hz,
1H), 6.08 (s, 1H), 6.78–6.90 (m, 3H), 7.17 (t, J = 7.2 Hz, 1H), 7.27 (d, J = 6.8 Hz, 1H), 7.37 (t, J = 7.6 Hz,
1H), 7.50 (d, J =16.4 Hz, 1H), 7.61 (d, J = 7.2 Hz, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.91 (s, 1H), 10.26
13
(s, 1H); C-NMR (100 MHz, DMSO): δ 47.8, 73.1, 109.4, 121.1, 122.3, 123.7, 127.4, 127.7, 129.0,
130.8, 131.0, 131.4, 132.9, 136.9, 140.7, 142.6, 178.2, 196.2; MS: m/z = 394 [M+Na]＋.
(E)-3-(4-(3-Chlorophenyl)-2-oxobut-3-en-1-yl)-3-hydroxyindolin-2-one (3i). Yield 82%; White solid;
m.p. 150–151 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.22 (d, J = 16.4 Hz, 1H), 3.65 (d, J = 16.4 Hz,
1H), 6.06 (s, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.84 (d, J = 16.4 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 7.16
(td, J = 7.6 Hz, J = 0.8 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 7.42–7.53 (m, 3H), 7.63 (d, J = 7.2 Hz, 1H),
7.77 (s, 1H), 10.24 (s, 1H); 13C-NMR (100 MHz, DMSO): δ 47.8, 73.1, 109.4, 121.1, 123.7, 127.0, 127.8,
127.9, 129.0, 130.0, 130.7, 131.4, 133.7, 136.6, 140.7, 142.6, 178.1, 196.2; MS: m/z = 350 [M+Na]＋.
(E)-3-Hydroxy-3-(4-(3-methoxyphenyl)-2-oxobut-3-en-1-yl)indolin-2-one (3j). Yield 96%; White solid;
m.p. 158–159 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.21 (d, J = 16.0 Hz, 1H), 3.64 (d, J = 16.4 Hz,
1H), 3.78 (s, 3H), 6.05 (s, 1H), 6.75–6.79 (m, 2H), 6.88 (t, J = 7.6 Hz, 1H), 6.99 (d, J = 6.8 Hz, 1H),
7.16 (t, J = 7.6 Hz, 1H), 7.23–7.28 (m, 3H), 7.33 (t, J = 8.0 Hz, 1H), 7.51 (d, J = 16.0 Hz, 1H), 10.23
(s, 1H); 13C-NMR (100 MHz, DMSO): δ47.6, 55.2, 73.1, 109.4, 113.1, 116.6, 121.0, 121.1, 123.7,
126.7, 128.9, 129.9, 131.5, 135.7, 142.5, 142.7, 159.6, 178.2, 196.3; MS: m/z = 346 [M+Na]＋.
(E)-3-(4-(2-Fluorophenyl)-2-oxobut-3-en-1-yl)-3-hydroxyindolin-2-one (3k). Yield 92%; White solid;
m.p. 155–156 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.24 (d, J = 16.4 Hz, 1H), 3.63 (d, J = 16.4 Hz,
1H), 6.09 (s, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.84–6.90 (m, 2H), 7.14–7.18 (m, 1H), 7.23–7.30 (m, 3H),
7.45–7.48 (m, 1H), 7.53 (d, J = 16.4 Hz, 1H), 7.78 (t, J = 7.2 Hz, 1H), 10.27 (s, 1H); 13C-NMR
(100 MHz, DMSO): δ = 48.1, 73.1, 109.4, 116.1(d, J = 22 Hz), 121.2, 121.8, 121.9, 123.8, 125.0 (d,
J = 3 Hz), 128.4 (d, J = 5 Hz), 129.0, 129.2, 131.4, 132.5 (d, J = 9 Hz), 133.9 (d, J = 3 Hz), 142.6,
160.8 (d, J = 250 Hz), 178.2; MS: m/z = 334 [M+Na]＋.
(E)-3-(4-(3,4-Dichlorophenyl)-2-oxobut-3-en-1-yl)-3-hydroxyindolin-2-one (3l). Yield 73%; White solid;
m.p. 166–167 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.22 (d, J = 16.4 Hz, 1H), 3.63 (d, J = 16.4 Hz,
1H), 6.07 (s, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.88 (m, 2H), 7.16 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 7.6 Hz,

Molecules 2013, 18
14514
13
1H), 7.51 (d, J = 16.0 Hz, 1H), 7.67–7.69 (m, 2H), 7.99 (s, 1H), 10.25 (s, 1H); C-NMR (100 MHz,
DMSO): δ47.8, 73.0, 109.4, 121.1, 123.7, 128.2, 128.3, 129.0, 130.1, 131.0, 131.4, 131.7, 132.6,
135.3, 139.7, 142.6, 178.1, 196.2; MS: m/z = 384 [M+Na]＋.
(E)-3-Hydroxy-3-(4-(naphthalen-2-yl)-2-oxobut-3-en-1-yl)indolin-2-one (3m). Yield 81%; White solid;
m.p. 172–173 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.28 (d, J = 16.0 Hz, 1H), 3.71 (d, J = 16.4 Hz,
1H), 6.09 (s, 1H), 6.81 (d, J = 7.6 Hz, 1H), 6.88–6.93 (m, 2H), 7.17 (t, J = 7.6 Hz, 1H), 7.31 (d,
J = 7.2 Hz, 1H), 7.57 (m, 2H), 7.70 (d, J = 16.4 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.94 (m, 3H), 8.19
13
(s, 1H), 10.27 (s, 1H); C-NMR (100 MHz, DMSO): δ 47.8, 73.2, 109.4, 121.1, 123.8, 123.9, 126.6,
126.8, 127.4, 127.7, 128.4, 128.5, 128.9, 130.2, 131.5, 131.9, 132.9, 133.8, 142.4, 142.7, 178.2, 196.2;
MS: m/z = 344 [M+H]＋.
(E)-3-(4-(Furan-2-yl)-2-oxobut-3-en-1-yl)-3-hydroxyindolin-2-one (3n). Yield 88%; White solid; m.p.
1
151–152 °C; H-NMR (400 MHz, TMS, DMSO): δ 3.15 (d, J = 16.0 Hz, 1H), 3.55 (d, J = 16.0 Hz,
1H), 6.04 (s, 1H), 6.47 (d, J = 15.6 Hz, 1H), 6.64 (s, 1H), 6.77 (d, J = 7.2 Hz, 1H), 6.88 (m, 1H),
6.95 (m, 1H), 7.16 (m, 1H), 7.25 (m, 1H), 7.33 (d, J = 16.0 Hz, 1H), 7.85 (s, 1H), 10.23 (s, 1H);
13C-NMR (100 MHz, DMSO): δ 47.7, 73.1, 109.4, 113.0, 116.8, 121.1, 123.1, 123.8, 128.9, 129.0,
131.4, 142.6, 146.1, 150.4, 178.2, 195.6; MS: m/z = 306 [M+Na]＋.
1
(E)-3-Hydroxy-3-(2-oxohept-3-en-1-yl)indolin-2-one (3o). Yield 67%; oil; H-NMR (400 MHz, TMS,
DMSO): δ 0.91 (t, J = 4.0 Hz, 3H), 1.40 (m, 2H), 2.16 (m, 2H), 3.12 (d, J = 16.0 Hz, 1H), 3.52 (d,
J = 16.0 Hz, 1H), 5.96–6.04 (m, 2H), 6.77 (d, J = 7.6 Hz, 1H), 6.87 (t, J = 7.6 Hz, 1H), 7.04 (d,
J = 16.0 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 10.19 (s, 1H); 13C-NMR
(100 MHz, DMSO): δ 13.7, 21.9, 30.1, 47.7, 73.1, 109.3, 121.1, 123.6, 128.8, 131.5, 139.1, 142.6,
146.2, 178.2, 196.2; MS: m/z = 282 [M+Na]＋.
(E)-1-Benzyl-3-hydroxy-3-(2-oxo-4-phenylbut-3-en-1-yl)indolin-2-one (3p). Yield 99%; White solid;
m.p. 57–58 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.40 (d, J = 16.8 Hz, 1H), 3.83 (d, J = 16.8 Hz,
1H), 4.85 (d, J = 8.0 Hz, 1H), 4.93 (d, J = 8.0 Hz, 1H), 6.30 (s, 1H), 6.73–6.81 (m, 2H), 6.95 (t,
J = 7.2 Hz, 1H), 7.16 (t, J = 7.2 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 7.33–7.47 (m, 8H), 7.60 (d,
J = 16.0 Hz, 1H), 7.67 (m, 2H); 13C-NMR (100 MHz, DMSO): δ 42.7, 47.7, 72.8, 108.9, 122.0, 123.5,
126.2, 127.2, 128.4, 128.5, 128.9, 129.0, 130.6, 130.9, 134.2, 136.4, 142.9, 143.2, 176.8, 196.3;
MS: m/z = 384 [M+H]＋.
(E)-3-Hydroxy-5-methyl-3-(2-oxo-4-phenylbut-3-en-1-yl)indolin-2-one (3q). Yield 60%; White solid;
m.p. 136–137 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 2.19 (s, 3H), 3.23 (d, J = 16.4 Hz, 1H), 3.62
(d, J = 16.4 Hz, 1H), 6.02 (s, 1H), 6.68 (d, J =8.0 Hz, 1H), 6.76 (d, J = 16.0 Hz, 1H), 6.96 (d, J = 7.6 Hz,
13
1H), 7.10 (s, 1H), 7.43 (m, 3H), 7.53 (d, J = 16.0 Hz, 1H), 7.66 (m, 2H), 10.15 (s, 1H); C-NMR
(100 MHz, DMSO): δ = 20.6, 47.7, 73.2, 109.1, 124.4, 126.4, 128.4, 128.9, 129.1, 129.8, 130.5, 131.5,
134.3, 140.2, 142.5, 178.2, 196.2; MS: m/z = 330 [M+Na]＋.
(E)-5-Bromo-3-hydroxy-3-(2-oxo-4-phenylbut-3-en-1-yl)indolin-2-one (3r). Yield 99%; White solid;
m.p. 201–202 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.30 (d, J = 16.8 Hz, 1H), 3.75 (d, J = 16.8 Hz,

Molecules 2013, 18
14515
1H), 6.20 (s, 1H), 6.74–6.79 (m, 2H), 7.34–7.59 (m, 6H), 7.67 (m, 2H), 10.40 (s, 1H); 13C-NMR
(100 MHz, DMSO): δ = 47.4, 73.1, 111.4, 112.9, 126.2, 126.7, 128.5, 128.9, 130.6, 131.5, 134.1,
134.2, 142.1, 142.8, 177.8, 196.3; MS: m/z = 394 [M+Na]＋.
(E)-6-Chloro-3-hydroxy-3-(2-oxo-4-phenylbut-3-en-1-yl)indolin-2-one (3s). Yield 93%; Yellow solid;
m.p. 188–189 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.27 (d, J = 16.8 Hz, 1H), 3.70 (d, J = 16.8 Hz,
1H), 6.15 (s, 1H), 6.75 (d, J = 16.0 Hz, 1H), 6.79 (m, 1H), 6.93 (m, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.43
(m, 3H), 7.55 (d, J = 16.0 Hz, 1H), 7.67 (m, 2H), 10.41 (s, 1H); 13C-NMR (100 MHz, DMSO): δ = 47.4,
72.6, 109.4, 120.8, 125.1, 126.2, 128.5, 128.9, 130.5, 130.6, 133.1, 134.2, 142.8, 144.3, 178.2, 196.3;
MS: m/z = 350 [M+Na]＋.
(E)-4-Chloro-3-hydroxy-3-(2-oxo-4-phenylbut-3-en-1-yl)indolin-2-one (3t). Yield 92%; Yellow solid;
m.p. 193–195 °C; 1H-NMR (400 MHz, TMS, DMSO): δ 3.25 (d, J = 16.8 Hz, 1H), 4.03 (d, J = 16.8 Hz,
1H), 6.22 (s, 1H), 6.76 (m, 2H), 6.86 (d, J = 8.4 Hz, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.43 (m, 3H), 7.58
(d, J = 16.4 Hz, 1H), 7.68 (m, 2H), 10.50 (s, 1H); 13C-NMR (100 MHz, DMSO): δ = 45.8, 73.8, 108.5,
122.0, 125.8, 127.5, 128.5, 128.9, 129.8, 130.6, 134.1, 143.0, 145.0, 177.4, 196.2; MS: m/z = 350
[M+Na]＋.
4. Conclusions
In conclusion, we have developed an efficient approach for the direct preparation of 3-substituted-3-
hydroxy-2-oxindoles via an aldol reaction of α,β-unsaturated ketones and isatins using arginine as an
organocatalyst. A range of 3-substituted-3-hydroxy-2-oxindoles were obtained in moderate to high
yields (up to 99%). The formation of 3-substituted-3-hydroxy-2-oxindole (3a) was confirmed by X-ray
crystallography. The reaction is simple, the catalyst easily availability, and the procedure convenient
with mild reaction conditions, which make it useful. The possible reaction mechanism reveals that the
reaction proceeds via a double action process. The 3-substituted-3-hydroxy-2-oxindoles with an
additional enone moiety and provide a chance for finding new or improved biological activities and
further elaboration of the products. Further study on the antibacterial and antitumor activities of these
compounds is underway.
Acknowledgments
We appreciate the financial support of National Natural Science Foundation of China (No.
81202403) and Youth Foundation of Sichuan University (Nos. 2012SCU11090 and 2011SCU11005).
We also thank Sichuan University Analytical & Testing Center for the NMR analysis.
Conflicts of Interest
The authors declare no conflict of interest.
References and Notes
1. Peddibhotla, S. 3-Substituted-3-hydroxy-2-oxindole, an emerging new scaffold for drug discovery
with potential anti-cancer and other biological activities. Curr. Bioact. Compd. 2009, 5, 20–38.

Molecules 2013, 18
14516
2. Zhang, H.P.; Kamano, Y.; Ichihara, Y.; Kizu, H.; Komiyama, K.; ltokawa, H.; Pettit, G.R.
Isolation and structure of convolutamydines B–D from marine bryozoan Amathia convoluta.
Tetrahedron 1995, 51, 5523–5528.
3. Khuzhaev, V.U.; Zhalolov, I.; Turguniv, K.K.; Tashkhodzhaev, B.; Levkovich, M.G.; Arpova, S.F.;
Shashkov, A.S. Alkaloids from Arundo donax. XVII. structure of the dimeric indole alkaloid
arundaphine. Chem. Nat. Compd. 2004, 40, 269–272.
4. Rasmussen, H.B.; MacLeod, J.K. Total synthesis of donaxaridine. J. Nat. Prod. 1997, 60, 1152–1154.
5. Suchý, M.; Kutschy, P.; Monde, K.; Goto, H.; Harada, N.; Takasugi, M.; Dzurilla, M.; Balentová, E.
Synthesis, absolute configuration, and enantiomeric dnrichment of a ruciferous oxindole
phytoalexin, (S)-(−)-Spirobrassinin, and its oxazoline analog. J. Org. Chem. 2001, 66, 3940–3947.
6. Tang, Y.Q.; Sattler, I.; Thiericke, R.; Grabley, S.; Feng, X.Z. Maremycins C and D, new
diketopiperazines, and maremycins E and F, novel polycyclic spiro-Indole metabolites isolated
from Streptomyces sp. Eur. J. Org. Chem. 2001, 2001, 261–267.
7. Kagata, T.; Saito, S.; Shigemori, H.; Ohsaki, A.; Ishiyama, H.; Kubota, T.; Kobayashi, J.
Paratunamides A–D, oxindole alkaloids from Cinnamodendron axillare. J. Nat. Prod. 2006, 69,
1517–1521.
8. Suzuki, H.; Morita, H.; Shiro, M.; Kobayashi, J. Celogentin K, a new cyclic peptide from the
seeds of Celosia argentea and X-ray structure of moroidin. Tetrahedron 2004, 60, 2489–2495.
9. Koguchi, Y.; Kohno, J.; Nishio, M.; Takahashi, K.; Okuda, T.; Ohnuki, T.; Komatsubara, S.
TMC-95A, B, C, and D, novel proteasome inhibitors produced by Apiospora montagnei Sacc. TC
1093. Taxonomy, production, isolation, and biological activities. J. Antibiot. 2000, 53, 105–109.
10. Carle, J.S.; Christophersen, C. Marine alkaloids. 3. Bromo-substituted alkaloids from the marine
bryozoan Flustra foliacea, flustramine C and flustraminol A and B. J. Org. Chem. 1981, 46,
3440–3443.
11. Jimenez, J.I.; Huber, U.; Moore, R.E.; Patterson, G.M.L. Oxidized Welwitindolinones from
Terrestrial Fischerella spp. J. Nat. Prod. 1999, 62, 569–572.
12. Kitajima, M.; Mori, I.; Arai, K.; Kogure, N.; Takayama, H. Two new tryptamine-derived
alkaloids from Chimonanthus praecox f. concolor. Tetrahedron Lett. 2006, 47, 3199–3202.
13. Lee, S.; Hartwig, J.F. Improved catalysts for the palladium-catalyzed synthesis of oxindoles by
amide α-arylation. rate acceleration, use of aryl chloride substrates, and a new carbene ligand for
asymmetric transformations. J. Org. Chem. 2001, 66, 3402–3415.
14. Shibata, N.; Tarui, T.; Doi, Y.; Kirk, K.L. Synthesis of fluorogypsetin and fluorobrevianamide E
by a novel fluorination-cyclization of cyclo-L-Trp-L-AAs. Angew. Chem. Int. Ed. 2001, 40,
4461–4463.
15. Shibata, N.; Suzuki, E.; Asahi, T.; Shiro, M. Enantioselective fluorination mediated by cinchona
alkaloid derivatives/selectfluor combinations: Reaction scope and structural information for
N-fluorocinchona alkaloids. J. Am. Chem. Soc. 2001, 123, 7001–7009.
16. Funabashi, K.; Jachmann, M.; Kanai, M.; Shibasaki, M. Multicenter strategy for the development
of catalytic enantioselective nucleophilic alkylation of ketones: Me2Zn addition to α-ketoesters.
Angew. Chem. Int. Ed. 2003, 42, 5489–5492.
17. Hamashima, Y.; Suzuki, T.; Takano, H.; Shimura, Y.; Sodeoka, M. Catalytic enantioselective
fluorination of oxindoles. J. Am. Chem. Soc. 2005, 127, 10164–10165.

Molecules 2013, 18
14517
18. Shintani, R.; Inoue, M.; Hayashi, T. Rhodium-catalyzed asymmetric addition of aryl- and
alkenylboronic acids to isatins. Angew. Chem. Int. Ed. 2006, 45, 3353–3356.
19. Nakamura, T.; Shirokawa, S.; Hosokawa, S.; Nakazaki, A.; Kobayashi, S. Enantioselective total
synthesis of convolutamydines B and E. Org. Lett. 2006, 8, 677–679.
20. Guo, X.; Huang, H.X.; Yang, L.P.; Hu, W.H. Trapping of oxonium ylide with isatins: Efficient
and stereoselective construction of adjacent quaternary carbon centers. Org. Lett. 2007, 9,
4721–4723.
21. Malkov, A.V.; Kabeshov, M.A.; Bella, M.; Kysilka, O.; Malyshev, D.A.; Pluháčková, K.;
Kočovský, P. Vicinal amino alcohols as organocatalysts in asymmetric cross-aldol reaction of
ketones: Application in the synthesis of convolutamydine A. Org. Lett. 2007, 9, 5473–5476.
22. Chen, J.R.; Liu, X.P.; Zhu, X.Y.; Li, L.; Qiao, Y.F.; Zhang, J.M.; Xiao, W.J. Organocatalytic
asymmetric aldol reaction of ketones with isatins: Straightforward stereoselective synthesis of
3-alkyl-3-hydroxyindolin-2-ones. Tetrahedron 2007, 63, 10437–10444.
23. Angelici, G.; Corrêa, R.J.; Garden, S.J.; Tomasini, C. Water influences the enantioselectivity in
the proline or prolinamide-catalyzed aldol addition of acetone to isatins. Tetrahedron Lett. 2009,
50, 814–817.
24. Hara, N.; Nakamura, S.; Shibata, N.; Toru, T. Enantioselective aldol reaction using recyclable
montmorillonite-entrapped N-(2-thiophenesulfonyl) prolinamide. Adv. Synth. Catal. 2010, 352,
1621–1624.
25. Guo, Q.S.; Bhanushali, M.; Zhao, C.G. Quinidine Thiourea-catalyzed aldol reaction of
unactivated ketones: Highly enantioselective synthesis of 3-alkyl-3-hydroxyindolin-2-ones.
Angew. Chem. Int. Ed. 2010, 49, 9460–9464.
26. Raj, M.; Veerasamy, N.; Singh, V.K. Highly enantioselective synthesis of 3-cycloalkanone-3-
hydroxy-2-oxindoles, potential anticonvulsants. Tetrahedron Lett. 2010, 51, 2157–2159.
27. Allu, S.; Molleti, N.; Panem, R.; Singh, V.K. Enantioselective organocatalytic aldol reaction of
unactivated ketones with isatins. Tetrahedron Lett. 2011, 52, 4080–4083.
28. Kinsella, M.; Duggan, P.G.; Lennon, C.M. Screening of simple N-aryl and N-heteroaryl
pyrrolidine amide organocatalysts for the enantioselective aldol reaction of acetone with isatin.
Tetrahedron Asymmetry 2011, 22, 1423–1433.
29. Liu, G.G.; Zhao, H.; Lan, Y.B.; Wu, B.; Huang, X.F.; Chen, J.; Tao, J.C.; Wang, X.W.
Asymmetric cross aldol addition of isatins with α,β-unsaturated ketones catalyzed by a
bifunctional Brønsted acid–Brønsted base organocatalyst. Tetrahedron 2012, 68, 3843–3850.
30. Cui, H.L.; Tanaka, F. Catalytic enantioselective formal hetero-Diels-Alder reactions of enones
with isatins to give spirooxindole tetrahydropyranones. Chem. Eur. J. 2013, 19, 6213–6216.
31. Beccalli, E.M.; Marchesini, A.; Pilati, T. Synthesis of the carbazole alkaloids hyellazole and
6-chlorohyellazole and related derivatives. J. Chem. Soc. Perkin Trans. 1994, 1, 579–587.
32. Peng, Y.Y.; Wang, Q.; He, J.Q.; Cheng, J.P. Arginine catalyzed direct aldol reactions in pure
water: An environmentally friendly reaction system. Chin. J. Chem. 2008, 26, 1454–1460.
33. Ma, J.A. Recent developments in the catalytic asymmetric synthesis of α- and β-amino acids.
Angew. Chem. Int. Ed. 2003, 42, 4290–4299.
34. Maruoka, K.; Ooi, T. Enantioselective amino acid synthesis by chiral phase-transfer catalysis.
Chem. Rev. 2003, 103, 3013–3028.

Molecules 2013, 18
14518
35. Plaquevent, J.C.; Levillain, J.; Guillen, F.; Malhiac, C.; Gaumont, A.C. Ionic liquids: New targets
and media for α-amino acid and peptide chemistry. Chem. Rev. 2008, 108, 5035–5060.
36. List, B.; Lerner, R.A.; Barbas, C.F., III; Proline-catalyzed direct asymmetric aldol reactions.
J. Am. Chem. Soc. 2000, 122, 2395–2396.
37. List, B. Proline-catalyzed asymmetric reactions. Tetrahedron 2002, 58, 5573–5590.
38. Crystallographic data of 3a reported in this manuscript have been deposited with Cambridge
Crystallographic Data Centre as supplementary publication No. CCDC-936278. Copies of the
data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from
the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge, CB21EZ, UK;
fax: +441223 336033; or deposit@ccdc.cam.ac.uk).
39. Kim, J.; Jung, S.; Park, S.; Park, S. Amino-acid-mediated epoxidation of α,β-unsaturated ketones
by hydrogen peroxide in aqueous media. Tetahedron Lett. 2011, 52, 2866–2868.
40. Rahmati, A.; Vakili K. L-Histidine and L-arginine promote Knoevenagel reaction in water.
Amino Acids 2010, 39, 911–916.
41. Yu, Z.P.; Liu, X.H.; Zhou, L.; Lin, L.L.; Feng, X.M. Bifunctional guanidine via an amino Amide
skeleton for asymmetric michael reactions of β-ketoesters with nitroolefins: A concise synthesis
of bicyclic β-amino acids. Angew. Chem. Int. Ed. 2009, 48, 5195–5198.
Sample Availability: Samples of all the compounds are available from the authors.
© 2013 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).