Organocatalytic stereoselective synthesis of 3-alkyl-3-hydroxy-2-oxindoles catalyzed by novel water-compatible axially unfixed biaryl-based bifunctional organocatalysts

Article abstract of DOI:10.1002/cjoc.201400166

In this work, six novel axially unfixed biaryl-based water-compatible bifunctional organocatalysts were designed and synthesized for the organocatalytic access to a variety of 3-alkyl-3-hydroxy-2-oxindole derivatives via aldol reactions in water. Organoca

Full text of DOI:10.1002/cjoc.201400166

FULL PAPER
DOI: 10.1002/cjoc.201400166
Organocatalytic Stereoselective Synthesis of 3-Alkyl-3-
hydroxy-2-oxindoles Catalyzed by Novel Water-compatible
Axially Unfixed Biaryl-based Bifunctional Organocatalysts
Hongwu Zhao,* Wei Meng, Zhao Yang, Ting Tian, Zhihui Sheng,
Hailong Li, Xiuqing Song, Yutong Zhang, Sen Yang, and Bo Li
College of Life Science and Bio-engineering, Beijing University of Technology, Beijing 100124, China
In this work, six novel axially unfixed biaryl-based water-compatible bifunctional organocatalysts were de-
signed and synthesized for the organocatalytic access to a variety of 3-alkyl-3-hydroxy-2-oxindole derivatives via
aldol reactions in water. Organocatalyzed by 5a, the direct aldol reactions of isatins with enolisable ketones under-
went readily in water, furnishing the structurally diverse 3-alkyl-3-hydroxy-2-oxindoles in various stereoselectivi-
ties (up to＞99% dr and ＞99% ee). Moreover, a plausible transition state of the conducted aldol reactions was hy-
pothesized to shed light on the observed stereoselectivities of the obtained 3-alkyl-3-hydroxy-2-oxindoles.
Keywords organocatalysis, 3-alkyl-3-hydroxy-2-oxindole, water-compatibility, bifunctionality
Introduction
acceptor activators. To the best of our knowledge, in the
literatures the organocatalytic aldol reactions of isatins
with the enolisable ketones and aldehydes usually un-
derwent smoothly in organic solvents to generate the
desired chiral 3-alkyl-3-hydroxy-2-oxindole in high
stereocontrols. In contrast, there have been relatively
few examples on the organocatalytic aldol reactions of
isatins with the enolisable ketones and aldehydes by
utilizing water as reaction medium.[24,26]
The development of organocatalytic aldol reactions
in water has attracted much attention from many organic
chemists since water is cheap, safe and benign to envi-
ronment as a reaction medium.[27] It has been com-
mented that the organocatalytic aldol reactions possess-
ing a high stereocontrol are mainly attributed to the fact
that the organocatalysts used in the aldol reactions can
assembly with the aldol donors and acceptors efficiently
via the hydrophobic interactions, and strongly inhibit
water to interfere with the transition states of the or-
ganocatalytic aldol reactions in water.[28,29] The hydro-
phobic properties of the organocatalysts can be finely
tuned by introducing the different bulky and hydropho-
bic groups into the skeletons of the organocatalysts.[30]
Very recently, the bulky and hydrophobic biphenyl mo-
tif was chosen as a skeleton to construct the different
classes of the water-compatible bifunctional organo-
catalysts, which exhibited excellent stereoselectivities in
the organocatalytic reactions in water.[31-34]
Chiral 3-alkyl-3-hydroxy-2-oxindoles, bearing a
quaternary stereogenic center, constitute the core skele-
tons of many natural products and medicinal molecules
which exhibited a wide range of biological and phar-
maceutical activities.[1] It has been evidenced that the
biological activities of the chiral 3-alkyl-3-hydroxy-2-
oxindoles are closely associated with the stereochemical
configuration of the quaternary C-3 center and the
chemical nature of the C-3 substituent of the chiral
3-alkyl-3-hydroxy-2-oxindoles.[2] The chiral 3-alkyl-3-
hydroxy-2-oxindoles were accessed by the organocata-
lytic aldol reactions of isatins with enolisable ketones or
aldehydes concisely and efficiently.[3] By now, the dif-
ferent stereoselective versions of the aldol reactions of
isatins with enolisable ketones or aldehydes have been
established to produce the chiral 3-alkyl-3-hydroxy-2-
oxindoles stereoselectively with the use of organocata-
lysis.[4-26] As presented in literature works, the bifunc-
tional organocatalysis is demonstrated to be the power-
ful and efficient method for the stereoselective con-
struction of chiral 3-alkyl-3-hydroxy-2-oxindoles via
the aldol reactions of isatins with enolisable ketones or
aldehydes. It was disclosed that the bifunctional or-
ganocatalysts used in the aldol reactions of isatins with
enolisable ketones or aldehydes necessarily incorporate
both the basic or nucleophilic amine functional groups
as aldol donor activators and the H-bond donors as aldol
*
E-mail: hwzhao@bjut.edu.cn; Tel.: 0086-010-67396211; Fax: 0086-010-6739-2001
Received March 20, 2014; accepted April 21, 2014; published online May 22, 2014.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201400166 or from the author.
Chin. J. Chem. 2014, 32, 417—428
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417

Zhao et al.
FULL PAPER
Results and discussion
tions, thus yielding the high reactivities and stereocon-
trols in the direct aldol reactions in water.
Herein, in this work we present the design and syn-
thesis of novel axially unfixed biphenyl-based bifunc-
tional organocatalysts, and their organocatalysis in the
direct aldol reaction of isatins with enolisable ketones in
water. In the case of the designed organocatalysts, the
urea or thiourea and amine moieties were constructed as
two organocatalytic sites: urea or thiourea functions as a
double H-bond donor to activate isatins; amine serves as
a nucleophile to activate enolisable ketones via the
enamine mechanism. Moreover, the axially unfixed
biaryl of the organocatalysts can freely adjust the spatial
orientation of the organocatalytic sites present in the
organocatalysts. In addition, it was envisioned that the
introduction of the hydrophobic biphenyl into the or-
ganocatalysts can endow the organocatalysts with the
appropriate and sufficient hydrophobicities. As a result,
the organocatalysts are able to aggregate with the hy-
drophobic reactants strongly and exclude water effi-
ciently from the transition states of the direct aldol reac-
As outlined in Scheme 1, the designed organocata-
lysts 5a, 5b were prepared easily by carrying out a se-
ries of chemical transformations. The catalytic hydro-
genation of biphenyl 1 gave the desired product 2 in
98% yield. The condensation of 2 with N-Boc-(S)-Ala
furnished product 3 in 70% yield. The subsequent
treatment of 3 with 3,5-bis(trifluoromethyl)phenyl iso-
thiocyanate or 3,5-bis(trifluoromethyl)phenyl isocyanate
afforded the desired products 4a (74% yield) and 4b
(74% yield), respectively. The deprotection of 4a and
4b with TFA generated organocatalysts 5a (70% yield)
and 5b (92% yield). Similarly, organocatalysts 8a and
8b were obtained respectively in 79% yield and 89%
yield according to Scheme 2 using N-Boc-(S)-Pro as a
chiral source. Simultaneously, for the purpose of inves-
tigating the structure-activity relationship, organocata-
lysts 11 and 13 with a C2-symmetry were also synthe-
sized on the basis of Scheme 3.
Scheme 1 Synthesis of novel organocatalysts 5a, 5b
CF3
NHBoc
10% Pd-C,
X
C
N
H2 (101 kPa),
EtOH, r.t.
NH2
NH2
CF3
CH2Cl2, 0 oC to r.t.
N-Boc-(S)-Ala
NO2
NO2
N
O
H
NH2
EDCI, CH2Cl2, r.t.
98%
2
1
3
70%
NHBoc
NH2
O
N
H
H
N
O
N
TFA, CH2Cl2, 0 oC to r.t.
H
H
N
CF3
H
H
N
N
CF3
X
X
CF3
4
CF3
5
4a: X = S, 74%
4b: X = O, 74%
5a: X = S, 70%
5b: X = O, 92%
Scheme 2 Synthesis of novel organocatalysts 8a, 8b
CF3
CF3
NH
O
NBoc
O
X
C N
TFA, CH2Cl2
0 oC to r.t.
NBoc
O
N
H
N-Boc-(S)-Pro
N
H
H
N
NH2
NH2
N
H
NH2
H
H
N
H
N
N
CF3
EDCI, CH2Cl2, r.t.
CH2Cl2, 0 oC to r.t.
CF3
X
X
8
CF3
2
7
CF3
6
52%
8a: X = S, 79%
8b
7a: X = S, 76%
7b
: X = O, 89%
: X = O, 94%
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© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 417—428

Organocatalytic Stereoselective Synthesis of 3-Alkyl-3-hydroxy-2-oxindoles
Scheme 3 Synthesis of novel organocatalysts 11 and 13
Bn
NH2
10% Pd-C,
H2 (101 kPa)
(1) N-Cbz-(S)-Phe
N
N
N
N
N
N
EDCI, DCM, r.t.
NO2
NO2
NH2
NH2
N
H
O
O
H
(2) 10% Pd-C,
H2 (101 kPa)
EtOH, r.t.
EtOH, r.t.
N
9
95%
10
Bn
NH2
NH2
11
70%
NHBoc
N
H
O
NH2 N-Boc-(S)-Ala
N
H
O
O
TFA, THF, r.t.
NH2
H
EDCI, CH2Cl2, r.t.
H
N
O
N
2
NHBoc
NH2
12 95%
90%
13
With the prepared organocatalyts 5a, 5b and 8a, 8b
in hand, we started to examine their reactivities and
stereoselectivities in the direct aldol reaction of isatin
with cyclohexanone in water in the presence of TFA as
acidic additive as outlined in Table 1. Noticeably, or-
ganocatalysts 5a and 5b showed the excellent reactivi-
ties and stereoselectivities in the aldol reaction, thus
furnishing the desired aldol adduct in＞99% yield with
3∶97－2∶98 dr and 89%－90% ee (Table 1, Entries 1,
2). In contrast, organocatalysts 8a and 8b resulted in
much lower reactivities and stereoselectivities in the
aldol reaction, and the aldol reaction underwent slug-
gishly (Table 1, Entries 3, 4). Therefore, it was reasoned
that the superior organocatalytic reactivities and stereo-
selectivities of 5a, 5b to those of 8a, 8b probably
stemmed from the existence of the primary amine moi-
ety in their scaffolds. In addition, with a goal to clarify
the effects of structural variations of organocatalysts on
the reactivity and stereoselectivity of the aldol reaction,
organocatalysts 11 and 13 as shown in Scheme 3 and 14
－17 as shown in Figure 1 have been further investi-
gated in the aldol reaction as shown in Table 1 (Entries
5－10). As compared with organocatalyst 5a, the reac-
tivity and stereoselectivity of organocatalyst 15 in the
aldol reaction were decreased significantly, and the al-
dol reaction gave rise to an inverse enantioselectivity
(Table 1, Entry 1 vs. Entry 8). Moreover, the organo-
catalysts 11 and 14 bearing a bipyridinyl moiety yielded
much lower reactivities and enantioselectivities than
those of organocatalyst 13 with a biphenyl subunit in
the aldol reaction, and it was assumed that the presence
of the bulky and hydrophobic biphenyl moiety in or-
ganocatalyst 13 ensured it to generate high reactivity
and stereoselectivity in the aldol reaction (Table 1, En-
try 6 vs. Entryies 5 & 7). In addition, another two or-
ganocatalysts 16 and 17 containing a biphenyl motif
were also attempted in the aldol reaction, and both of
them exhibited rather low activities, but significantly
they differed in their diastereoselectivities and enantio-
selectivities in the aldol reaction (Table 1, Entry 9 vs.
Entry 10). In comparison with 5a, organocatalyst 13
gave the similar ee and dr values in the aldol reaction,
but it showed a quite low reactivity (Table 1, Entry 1 vs.
Entry 6). Accordingly, among all the organocatalysts
examined, in the presence of TFA as an acidic additive,
organocatalyst 5a demonstrated to possess the excellent
reactivity and stereoselectivity in the aldol reaction in
water.
Table 1 Screening of biaryl organocatalystsa
15 mol% Cat.,
10 mol% TFA,
O
O
HO
O
H2O, r.t.
O +
O
N
N
H
H
Entry Catalyst Time/h Yieldb/% drc(syn/anti) eed/% (anti)
1
2
5a
5b
8a
8b
11
13
14
15
16
17
1.5
1.5
72
60
12
8
＞99
＞99
73
2∶98
3∶97
90
89
52
48
74
93
44
−53
89
18
3
30∶70
33∶67
4∶96
4
71
5
91
6
99
4∶96
7
24
60
72
72
91
0∶100
26∶74
41∶59
9∶91
8
61
9
74
10
40
a Reactions were carried out with 0.1 mmol of isatin (14.7 mg)
and 1.0 mmol of cyclohexanone (104.0 μL) in the presence of 15
mol% of catalyst and 10 mol% of TFA (0.8 μL) in 0.5 mL of
water at room temperature. b Isolated yield after column chroma-
tography. c Determined by chiral HPLC analysis. d Determined by
chiral HPLC analysis.
Next, as shown in Table 2, with the use of organo-
catalyst 5a we turned to investigating the acid effects on
the reactivity and stereoselectivity of the aldol reaction
of isatin with cyclohexanone in water. It can be seen
that in the case of most acidic additives examined, the
aldol reaction proceeded readily, and produced the
Chin. J. Chem. 2014, 32, 417—428
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419

Zhao et al.
FULL PAPER
aldol reactions provided the desired aldol adducts in the
comparable ee values in the range of 73% to 80% when
a wide range of other acidic additives were attempted in
the aldol reaction (Table 2, Entry 1 & Entries 6－10). It
is conclusive to say the best ee and dr values were ob-
tained in the aldol reaction when organocatalyst 5a was
used along with p-TsOH as additive.
NH2
OMe
N
N
N
N
H
O
O
CF3
H
NH
N
N
S
CF3
N
H
NH2
15
Also, as shown in Table 3, a wide range of organic
solvents were examined in the aldol reaction of isatin
with cyclohexanone, catalysed by organocatalyst 5a in
combination with p-TsOH as acidic additive, to clarify
their effects on the reactivities and stereoselectivities of
the aldol reaction. Noticeably, in the aldol reactions, the
reactivities and stereoselectivities of organocatalyst 5a
were significantly influenced by the used organic sol-
vents. When Et2O was employed as solvent, the reaction
proceeded rather sluggishly, and only a trace amount of
the aldol adduct was formed after a reaction time of 60
h. The use of THF as solvent delivered the aldol adduct
in 42% yield with 22∶78 dr and 35% ee. The similar
chemical yields and diastereoselectivities and enanti-
oselectivities were achieved in the aldol reactions by the
choice of CHCl3 and DMF as solvents (Table 3, Entry 1
vs. Entry 9). The almost same diastereoselectivities
were generated in the aldol reactions, but the enantiose-
lectivities ranged from 53% ee to 70% ee with the use
of CH3CN, benzene and toluene as solvents, respec-
tively (Table 3, Entries 6－8). Although the reaction
afforded the desired aldol adduct in high ee and dr val-
ues in n-hexane, the reaction rate seemed to be quite
slow and furnished the aldol adduct in 36% yield in 100
h (Table 3, Entry 10). By comparison with n-hexane as
the reaction solvent, the use of CH2Cl2 and MeOH as
the reaction solvents improved the chemical yields and
diastereoselectivities noticeably, however, the enanti-
oselectivities of the aldol reactions varied slightly (Ta-
ble 10, Entries 2 & 5 vs. Entry 10). Therefore, it is rea-
sonable to say that it is in water that organocatalyst 5a
produced the excellent reactivity (99% yield) and
stereoselectivity (1∶99 dr and 94% ee) in the aldol re-
action.
After having examined the effects of organic sol-
vents and acidic additives on the aldol reaction of isatin
with cyclohexanone in the presence of 5a as organo-
catalyst, we began to investigate the loading effects of
organocatalyst 5a and p-TsOH on the aldol reaction of
isatin with cyclohexanone as summarized in Table 4. It
was noted that in the absence of p-TsOH as additive,
organocatalyst 5a in 15 mol% loading can catalyse the
aldol reaction to complete in 2 h, yielding the desired
aldol adduct in 74% yield with 2∶98 dr and 67% ee.
Together with p-TsOH in 15 mol% or 5 mol%, organo-
catalyst 5a brought about the dramatic increases in the
chemical yields and enantioselectivities of the aldol re-
action by comparison with the case where no p-TsOH
was utilized as additive (Table 4, Entry 1 vs. Entries 4
& 9). Moreover, to our surprise, it was found that the
use of 5 mol% p-TsOH along with organocatalyst 5a
14
H
N
O
S
H
N
N
H
N
O
H
OH
H
OH
N
O
O
S
N
H
O
O
17
16
Figure
1
The known organocatalysts examined in this
work.[32,33,35,36]
Table 2 Screening of acidic additivesa
15 mol% 5a,
O
10 mol% additive,
H2O, r.t.
O
HO
O
O
O
+
N
H
N
H
Entry
Additive
HOAc
TFA
Time/h Yieldb/% drc (syn/anti) eed/% (anti)
1
2
3
1
74
99
99
1∶99
2∶98
1∶99
74
90
94
1.5
3.5
p-TsOH
2-HOC6H4
CO2H
4
5
6
0.5
4
82
94
98
2∶98
2∶98
3∶97
87
88
75
(＋)-CSA
4-CH3C6H4
CO2H
C6H5C2H4
CO2H
0.5
7
8
0.8
1
96
97
99
90
3∶97
3∶97
3∶97
1∶99
73
80
74
77
C6H5CO2H
2,2'-Dihydroxy-
biphenyl
9
0.8
10
Stearic acid
1.2
a Reactions were carried out with 0.1 mmol of isatin (14.7 mg)
and 1.0 mmol of cyclohexanone (104.0 μL) in the presence of 15
mol% of catalyst 5a (7.9 mg) and 10 mol% of additive in 0.5 mL
of water at room temperature. b Isolated yield after column chro-
matography. c Determined by chiral HPLC analysis. d Determined
by chiral HPLC analysis.
desired product in excellent yield with excellent di-
astereoselectivity in favour of anti diastereoisomer;
however, the enantioselectivity of the aldol reaction was
changed significantly with the used acidic additives
(Table 2, Entries 2－10). Remarkably, the excellent ee
values were achieved with using TFA and p-TsOH as
additives (Table 2, Entries 2, 3). The use of
2-HOC6H4CO2H and (＋)-CSA as additives promoted
the reaction to give the very similar enantioselectivities
of the anti diastereoisomers (Table 2, Entries 4, 5). The
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Chin. J. Chem. 2014, 32, 417—428

Organocatalytic Stereoselective Synthesis of 3-Alkyl-3-hydroxy-2-oxindoles
Table 3 Screening of solventsa
to go to completion. Interestingly, it has been indicated
that under catalysis of organocatalyst 5a in 10 mol%,
the reaction rate of the aldol reaction decreased as the
amount of p-TsOH was increased in the range of 5 to 30
mol% (Table 4, Entries 2, 3, 5, 8). When both organo-
catalyst 5a and p-TsOH were loaded in the same
amount of 5 mol% in the aldol reaction, the reaction
processed in excellent chemical yield (99% yield) with
excellent stereoselectivity (2∶98 dr, 92% ee). To our
delight, the aldol reaction remained to undergo with
excellent chemical yield and stereoselectivity even
when both organocatalyst 5a and p-TsOH were loaded
in an amount of 1 mol% in the aldol reaction, respec-
tively. Conclusively, in the aldol reaction both the best
chemical yield (99%) and stereoselectivity (1∶99 dr,
94% ee) were achieved with the use of the optimal reac-
tion conditions of 15 mol% 5a/10 mol% p-TsOH/wa-
ter/room temperature.
With the optimal reaction conditions in hand, the re-
action scope of the aldol reaction was broadened ini-
tially by reacting cyclohexanone with a variety of isatins
as presented in Table 5. In the case of most isatins ex-
amined, the aldol reactions underwent smoothly and
provided excellent dr values and high to excellent ee
values (Table 5, Entries 1－4 & 6－12). It has been in-
dicated that the enantioselectivity of the aldol reactions
highly depended on the chemical structure of isatins
used. For instances, 5-methyl-isatin afforded the lowest
ee value; in contrast, the excellent ee values were ob-
tained with isatin, N-Boc-isatin, N-Bn-5-nitro-isatin,
N-Bn-5-bromo-isatin (Table 5, Entries 8, 9 & 11, 12).
Moreover, it was important to note that N-Bn group of
isatins played a crucial role in enhancing the enantiose-
lectivity of the aldol reactions. When 5-NO2-, 5-Br-, and
5-Me-isatins were chosen as aldol acceptors, the ee val-
ues of the obtained aldol adducts changed from 67% to
87% ee (Table 5, Entries 1, 3 & 5). By comparison, the
introduction of Bn group onto N-position of isatins al-
lowed for a significant increase in the enantioselectivity
of the aldol adducts (Table 5, Entries 1 vs. 8, 3 vs. 9, 5
vs. 10). In contrast with isatin, the ee value of the aldol
adduct increased slightly when N-Boc-isatin was util-
ized as an aldol acceptor. Meanwhile, as summarized in
Table 6, the reaction scope of the aldol reaction was
also extended by reacting different isatins with a variety
of ketones. In the most cases, the aldol reactions exhib-
ited rather low enantioselectivities (Table 6, Entries 1－
5). However, it was delighted to find that the aldol reac-
tion of N-Bn-5-bromo-isatin or N-Bn-5-NO2-isatin with
tetrahydrothiopyran-4-one gave excellent ee values (Ta-
ble 6, Entries 6 & 7). Therefore, on the basis of the ex-
perimental results as mentioned above, it was in conclu-
sion that the organocatalytic efficiency of organocata-
lyst 5a was closely associated with the structural nature
of isatins and ketones involved in the aldol reactions
under the optimized reaction conditions.
15 mol% 5a
10 mol% -TsOH,
Solvent, r.t.
,
O
O
HO
p
O
O
O
+
N
H
N
H
Entry Solvent Time/h Yieldb/% drc (syn/anti) eed/% (anti)
1
2
3
4
5
6
7
8
9
CHCl3
CH2Cl2
THF
87
60
87
60
79
79
60
60
100
28
74
25∶75
1∶99
22∶78
－
62
92
35
－
89
53
70
67
64
94
94
42
Et2O
Trace
74
MeOH
CH3CN
Benzene
Toluene
DMF
2∶98
2∶98
4∶96
1∶99
18∶82
11∶89
1∶99
58
58
70
30
10 n-Hexane 100
36
11 H2O 3.5
99
a Reactions were carried out with 0.1 mmol of isatin (14.7 mg)
and 1.0 mmol of cyclohexanone (104.0 μL) in the presence of 15
mol% of catalyst 5a (7.9 mg) and 10 mol% of p-TsOH (1.9 mg)
in 0.5 mL of water at room temperature. b Isolated yield after
column chromatography. c Determined by chiral HPLC analysis.
d Determined by chiral HPLC analysis.
Table 4 Screening of catalytic loadings of 5a and p-TsOHa
O
O
5a
cat. , p-TsOH
H2O, r.t.
HO
O
O +
O
N
H
N
H
5a/ p-TsOH/
mol% mol%
Entry
Time/h Yieldb/% drc (syn/anti) eed/% (anti)
1
2
3
4
5
6
7
8
9
15
10
10
15
10
5
0
30
20
15
10
5
2
74
86
94
99
99
99
99
99
99
2∶98
10∶90
4∶96
4∶96
4∶96
2∶98
2∶98
1∶99
1∶99
67
86
92
84
88
92
92
89
88
39
20
6
8.7
9.4
15
6.2
0.7
1
1
10
5
15
5
a Reactions were carried out with 0.1 mmol of isatin (14.7 mg)
and 1.0 mmol of cyclohexanone (104.0 μL) in the presence of
indicated amounts of catalyst and indicated amounts of p-TsOH
in 0.5 mL of water at room temperature. b Isolated yield after
column chromatography. c Determined by chiral HPLC analysis.
d Determined by chiral HPLC analysis.
enable the aldol reaction to finish in 0.7 h; in contrast, a
longer reaction of 6 h was needed for the aldol reaction
Chin. J. Chem. 2014, 32, 417—428
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421

Zhao et al.
FULL PAPER
Table 5 Aldol reactions of isatins with cyclohexanonea
O
O
cat. 5a, p-TsOH,
H2O, r.t.
HO
R1
O
O
+
N
R1
O
N
R2
R2
Entry
1e
2f
3f
4f
5f
6f
7f
8f
R1
5-NO2
5-Cl
5-Br
4-Br
5-Me
H
R2
H
Time/h
Yieldb/%
drc (syn/anti)
＞1∶99
2∶98
eed/% (anti)
6
3
96
68
87
80
86
87
67
82
86
98
99
83
−98
94
H
H
6
94
3∶97
H
6
98
＞1∶99
5∶95
H
7.5
4.5
5
49
Me
Bn
Bn
Bn
Bn
Boc
H
97
1∶99
H
96
3∶97
5-NO2
5-Br
5-Me
H
7
＞99
70
＞1∶99
3∶97
9f
10
5
10f
11f
12f
86
＞1∶99
2∶98
4.5
91
H
3.5
99
1∶99
a Reactions were carried out with 0.1 mmol of isatins and 1.0 mmol of cyclohexanone (104 μL) in the presence of 15 mol% of catalyst 5a
(7.9 mg) and 10 mol% of p-TsOH (1.9 mg) in 0.5 mL of water at room temperature. b Isolated yield after column chromatography.
e
c Determined by chiral HPLC analysis. d Determined by chiral HPLC analysis. Absolute configuration determined by comparison with
the reported specific optical rotation in ref. 37. f Absolute configuration determined by comparison with the reported specific optical rota-
tion in ref. [23].
Table 6 Aldol reactions of isatins with ketonesa
R4
O
O
5a
(15 mol%)
R3
HO
.
p-TsOH H2O (10 mol%)
R1
O
+
O
R3 R4
H2O, r.t.
N
R1
O
R2
N
R2
Entry
1d
R1
H
R2
H
R3, R4
H, H
Time/h
Yieldb/%
80
drc (syn/anti)
eec/% (anti)
54
－
5
2e
3e
4e
5e
6e
7e
H
H
H
H
13
98
72
97
94
40
32
30∶70
20∶80
10∶90
12∶88
38∶62
13∶87
26
21
68
37
30
24
23
O
S
H
H
57
H
H
25
N
Boc
5-Br
Bn
96
S
5-NO2
Bn
＞99
S
a Reactions were carried out with 0.1 mmol of isatins and 1.0 mmol of ketones in the presence of 15 mol% of catalyst 5a (7.9 mg) and
10 mol% of p-TsOH (1.9 mg) in 0.5 mL of water at room temperature. b Isolated yield after column chromatography. c Determined by
d
chiral HPLC analysis. Absolute configuration determined by comparison with the reported specific optical rotation in ref. [11].
e Absolute configuration was not assigned.
422
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© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 417—428

Organocatalytic Stereoselective Synthesis of 3-Alkyl-3-hydroxy-2-oxindoles
To elucidate the catalytic mechanism and stereose-
lectivity of organocatalyst 5a in the aldol reaction of
isatin with cyclohexanone, a transition state was pro-
posed as illustrated in Figure 2. Obviously, organocata-
lyst 5a has shown a bifunctional organocatalysis in the
aldol reaction. As an aldol acceptor, isatin was activated
by 5a with triple H-bonds; and the activation of cyclo-
hexanone was conducted via the enamine mechanism.
Subsequent attack of Re of the enamine formed in situ
on the Si face of 3-carbonyl of isatin delivered the
stereoconfigurations which are consistent with those
observed in the aldol reactions.
zation (ESI) conditions. Enantiomeric excesses were
determined by HPLC analyses on a Waters system
equipped with a photodiode array detector (monitored at
200－400 nm), using Chiracel AD, OD, AD-H, OD-H,
OJ-H, and IC columns (25 cm×0.46 cm) from Daicel
Chemical Ind., Ltd.
Synthesis of (S)-tert-butyl(1-((2'-amino-[1,1'-biphe-
nyl]-2-yl)amino)-1-oxopropan-2-yl)carbamate (3)
Compound 2 was prepared according to the reported
1
procedure and the H NMR data were consistent with
1
the reported values.[32] Compound 2: H NMR (400
MHz, CDCl3) δ: 7.20 (d, J＝14 Hz, 2H), 7.13 (dd, J＝
19.2, 7.6 Hz, 2H), 6.82 (t, J＝7.6 Hz, 2H), 6.75 (d, J＝
7.6 Hz, 2H), 3.68 (br s, 4H). To a well stirred solution
of 2 (700 mg, 3.8 mmol) in anhydrous dichloromethane
(15 mL) was added EDCI (441 mg, 2.3 mmol), and
added N-Boc-S-Ala-OH (287 mg, 1.52 mmol) dropwise
at 0 ℃. The resulting mixture was stirred for 0.5 h at 0
℃. Then the reaction mixture was stirred for 3 h at
room temperature. The reaction was quenched by addi-
tion of saturated NaHCO3, and extracted with CH2Cl2
(10 mL×3). The combined organic layers were dried
over anhydrous Na2SO4 and concentrated in vacuo. The
residue was purified by flash chromatography on silica
gel (petroleum ether/ethyl acetate, V∶V＝5∶1) to
yield a white solid 3 (377 mg, 70% yield). [α]1D7 −25.4
(c 0.20, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 8.21 (d,
J＝8.0 Hz, 1H), 7.38－7.41 (t, J＝8.0 Hz, 1H), 7.19－
7.28 (m, 4H), 7.07 (d, J＝7.6 Hz, 1H), 6.80－6.89 (m,
2H), 5.15 (br s, 0.5H), 4.98 (br s, 0.5H), 4.19 (d, J＝6.4
Hz, 1H), 3.65 (br s, 2H), 1.42 (d, J＝8.4 Hz, 9H), 1.25
－1.33 (m, 3H); 13C NMR (100 MHz, CDCl3) δ: 170.9,
155.2, 143.4, 135.3, 135.2, 131.1, 130.8, 129.8, 129.5,
128.7, 125.0, 123.5, 122.0, 119.5, 119.3, 116.0, 115.8,
79.9, 50.9, 28.3, 28.2, 18.7; HRMS (ESI) calcd for
C20H25N3O3 (M＋H＋) 356.1969, found 356.1960.
F3C
S
CF3
N
N
O
H
H
H
H
N
O
HN
HN
O
CH3
Figure 2 Proposed transition state for the aldol reaction cata-
lyzed by 5a.
Conclusions
In conclusion, several water-compatible organocata-
lysts bearing an axially unfixed biphenyl as scaffold
have been designed and synthesized for the aldol reac-
tion of a wide range of isatins and ketones in water.
Under the optimal reaction conditions, organocatalyst
5a was identified with the best organocatalytic effi-
ciency among all the organocatalysts examined in this
work, and delivered the desired aldol adducts differing
in chemical yields and stereoselectivities in water. The
further studies on the organocatalytic mechanisms and
the utility of the water-compatible bifunctional organo-
catalyst in other asymmetric transformations in water
are in progress in our laboratory, and will be reported in
due course.
Synthesis of (S)-tert-butyl(1-((2'-(3-(3,5-bis(trifluoro-
methyl)phenyl)thioureido)-[1,1'-biphenyl]-2-yl)-
amino)-1-oxopropan-2-yl)carbamate (4a)
To a well stirred solution of 3 (355 mg, 1.0 mmol) in
dry CH2Cl2 (10 mL) was added 1-thiocyanato-3,5-
bis(trifluoromethyl)benzene (200 μL, 1.1 mmol) drop-
wise at 0 ℃. The reaction mixture was stirred at room
temperature for 16 h. The reaction mixture was concen-
trated under reduced pressure. The crude product was
purified by flash chromatography on silica gel (petro-
leum ether/ethyl acetate, V∶V＝4∶1) to yield 4a as
white solid (463 mg, 74% yield). [α]1D7 −45.3 (c 0.20,
Experimental
General
All reagents were commercially available and used
without further purification. All solvents were distilled
from the appropriate drying agents immediately before
use. All reactions were carried out directly under open
air and monitored by TLC carried out on 0.25 mm SDS
silica gel coated glass plates (60F254) visualized with
UV light and/or with iodide. Purification of the crude
products was performed using flash column chromatog-
raphy on silica gel (0.035－0.070 mm). Optical rota-
tions were measured with a Perkin-Elmer 241 po-
larimeter. NMR spectra were recorded on a Bruker
DRX 400 instrument and calibrated using tetramethyl-
silane (TMS) as internal reference. High resolution mass
spectra (HRMS) were recorded under electrospray ioni-
1
CHCl3); H NMR (400 MHz, CDCl3) δ: 9.45 (br s,
0.5H), 8.97 (br s, 0.5H), 8.38 (br s, 1H), 8.02 (br s, 1H),
7.73 (s, 1H), 7.57－7.63 (m, 3H), 7.41－7.51 (m, 3H),
7.31－7.37 (m, 4H), 4.92 (br s, 0.5H), 4.78 (d, J＝6.4
Hz, 0.5H), 4.05 (t, J＝7.2 Hz, 1H), 1.37－1.44 (m, 9H),
1.22 (s, 1H＋0.5H), 1.13 (d, J＝7.2 Hz, 1H＋0.5H); 13
C
NMR (100 MHz, CDCl3) δ: 179.9, 179.4, 171.4, 171.2,
155.9, 140.3, 134.7, 134.4, 133.9, 133.7, 131.7, 131.4,
130.5, 129.1, 129.0, 128.9, 127.9, 127.4, 126.9, 125.1,
Chin. J. Chem. 2014, 32, 417—428
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
423

Zhao et al.
FULL PAPER
124.7, 124.4, 121.7, 121.6, 118.9, 80.1, 53.4, 50.2, 28.2,
17.5; HRMS (ESI) calcd for C29H28F6N4O3S (M＋H＋)
627.1859, found 627.1821.
0.20, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ: 9.73－
9.76 (m, 0.6H), 8.31 (d, J＝8.0 Hz, 0.5H), 8.17 (d, J＝
8.0 Hz, 0.4H), 7.93－8.00 (m, 3H), 7.60 (s, 2H), 7.42 (d,
J＝6.0 Hz, 2H), 7.19－7.24 (m, 4H), 3.18－3.24 (m,
1H), 0.99－1.05 (m, 3H); 13C NMR (100 Hz, DMSO-d6)
δ: 174.5, 153.0, 142.2, 136.5, 136.3, 131.4, 131.2, 129.6,
129.2, 129.1, 129.0, 128.9, 125.1, 124.7, 124.5, 124.4,
122.4, 121.8, 120.9, 118.0, 114.7, 51.1, 51.0, 21.1;
Synthesis of (S)-tert-butyl(1-((2'-(3-(3,5-bis(trifluoro-
methyl)phenyl)ureido)-[1,1'-biphenyl]-2-yl)amino)-1-
oxopropan-2-yl)carbamate (4b)
By following the same procedure as that of 4a,
starting from 3 (355 mg, 1.0 mmol), 4b was prepared as
a white solid (451 mg, 74% yield). [α]1D7 −24.7 (c 0.20,
CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.60－8.20 (m,
8H), 7.35－7.50 (m, 3H＋0.4H), 7.10－7.25 (m, 2H),
6.95 (br s, 0.4H), 6.73 (br s, 0.2H), 5.01 (br s, 0.6H),
4.86 (d, J＝7.2 Hz, 0.4H), 4.16－4.20 (m, 0.6H), 4.05 (t,
J＝6.8 Hz, 0.4H), 1.37 (d, J＝4.4 Hz, 9H), 1.19 (d, J＝
7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 172.4,
155.5, 153.1, 153.0, 142.5, 142.4, 142.3, 136.2, 136.1,
131.3, 131.1, 131.0, 130.9, 130.6, 129.0, 128.9, 128.7,
128.3, 128.0, 126.0, 125.1, 124.2, 124.0, 122.4, 119.7,
117.9, 114.5, 79.7, 78.7, 78.4, 50.8, 50.4, 28.5, 17.9,
17.6; HRMS (ESI) calcd for C29H28F6N4O4 (M＋ H＋)
611.2088, found 6112069.
HRMS (ESI) calcd for C24H20F6N4O2 (M ＋H ＋
)
511.1563, found 511.1576.
Synthesis of (S)-tert-butyl-2-((2'-(3-(3,5-bis(trifluoro-
methyl)phenyl)thioureido)-[1,1'-biphenyl]-2-yl)-
carbamoyl)pyrrolidine-1-carboxylate (7a)
Compound 6 was prepared according to the reported
1
procedure and the H NMR data were consistent with
the reported values.[31] Compound 6: [α]1D7 ＋10.3 (c
1
0.18, CHCl3); H NMR (400 MHz, CDCl3) δ: 8.39－
8.96 (m, 1H), 8.06－8.15 (m, 1H), 7.41－7.43 (m, 1H),
7.22－7.33 (m, 3H), 7.03－7.08 (m, 1H), 6.81－6.90
(m, 2H), 4.23－4.26 (m, 1H), 3.59－3.70 (m, 2H), 3.19
－3.29 (m, 2H), 2.07－2.12 (m, 2H), 1.61－1.88 (m,
2H), 1.30－1.43 (m, 9H). To a well stirred solution of 6
(380 mg, 1.0 mmol) in dry CH2Cl2 (10 mL) was added
1-thiocyanato-3,5-bis(trifluoromethyl)benzene (200 μL,
1.1 mmol) dropwise at 0 ℃. The reaction mixture was
stirred at room temperature for 20 h. The reaction mix-
ture was concentrated under reduced pressure. The
crude product was purified by flash chromatography on
silica gel (eluent: petroleum ether/EtOAc, V∶V＝5∶1)
to yield 7a as white solid (494 mg, 76% yield). [α]1D7
Synthesis of (S)-2-amino-N-(2'-(3-(3,5-bis(trifluoro-
methyl)phenyl)thioureido)-[1,1'-biphenyl]-2-yl)-
propanamide (5a)
To a well stirred solution of compound 4a (463 mg,
0.74 mmol) in CH2Cl2 (6 mL) was added TFA (2 mL)
dropwise at 0 ℃. The resulting mixture was stirred for
5 h at room temperature and the mixture was concen-
trated under reduced pressure. The obtained residue was
dissolved in CH2Cl2 (15 mL), and treated with saturated
Na2CO3 to reach pH 8. The mixture was extracted with
CH2Cl2 (20 mL×3). The combined organic layers were
dried with anhydrous Na2SO4, and concentrated under
reduced pressure. The crude product was purified by
flash chromatography on neutral Al2O3 (eluent:
CH2Cl2/MeOH, V∶V＝100∶1) to yield 5a as white
solid (272 mg, 70% yield). [α]1D7 −32.0 (c 0.20, CHCl3);
1H NMR (400 MHz, CDCl3) δ: 9.58－9.73 (m, 1H),
9.42 (d, J＝10.4 Hz, 1H), 8.25－8.35 (m, 1H), 7.28－
7.75 (m, 11H), 3.32 (dd, J＝10.4, 7.2 Hz, 1H), 1.50－
1.90 (br s, 2H), 1.22 (d, J＝7.2 Hz, 1H＋0.5H), 1.02 (d,
J＝6.8 Hz, 1H＋0.5H); 13C NMR (100 MHz, CDCl3) δ:
179.4, 179.3, 174.8, 174.5, 140.2, 140.0, 135.0, 134.9,
134.6, 134.2, 133.9, 133.3, 132.1, 131.6, 131.3, 130.1,
130.3, 130.1, 129.0, 128.8, 128.7, 127.9, 127.4, 127.1,
126.9, 126.5, 125.2, 124.7, 124.4, 121.7, 118.8, 50.7,
50.5, 29.7, 21.0, 20.8; HRMS (ESI) calcd for
C24H20F6N4OS (M＋H＋) 527.1335, found 527.1345.
1
−66.3 (c 0.18, CHCl3); H NMR (400 MHz, CDCl3) δ:
9.67 (s, 0.3H), 9.00－9.06 (m, 0.7H), 8.48－8.63 (m,
0.7H), 7.73－7.90 (m, 1H＋0.3H), 7.33－7.64 (m, 11H),
4.16 (d, J＝7.6 Hz, 1H), 3.30 (br s, 2H), 2.06－2.11 (m,
2H), 1.45－1.81 (m, 11H); 13C NMR (100 MHz, CDCl3)
δ: 180.2, 179.5, 174.8, 170.4, 156.8, 140.7, 140.4, 135.4,
131.5, 131.2, 130.7, 129.2, 128.9, 128.2, 127.2, 126.0,
125.8, 127.5, 124.9, 124.5, 123.9, 121.7, 119.0, 118.5,
81.2, 60.2, 59.8, 47.1, 28.3, 24.3, 21.3, 20.7, 19.7;
HRMS (ESI) calcd for C31H30F6N4O3S (M ＋H ＋
)
653.2016, found 653.1973.
Synthesis of (S)-tert-butyl-2-((2'-(3-(3,5-bis(trifluoro-
methyl)phenyl)ureido)-[1,1'-biphenyl]-2-yl)carbamo-
yl)pyrrolidine-1-carboxylate (7b)
By following the same procedure as that of 7a,
starting from 6 (300 mg, 0.79 mmol), 7b was prepared
as white solid (470 mg, 94% yield). [α]1D7 −99.3 (c 0.20,
CHCl3); 1H NMR (400 MHz, CDCl3) δ: 8.30－8.55 (m,
2H), 8.00－8.10 (m, 1H), 7.65－7.80 (m, 3H), 7.12－
7.43 (m, 8H), 4.24－4.11 (m, 1H), 3.14－3.23 (m, 2H),
1.70－1.99 (m, 4H), 1.35－1.43 (m, 9H); 13C NMR
(100 MHz, CDCl3) δ: 175.2, 172.0, 155.7, 152.8, 140.8,
136.1, 134.9, 132.6, 132.1, 132.0, 131.8, 131.7, 130.5,
130.1, 129.3, 128.9, 128.8, 127.3, 126.8, 126.2, 125.1,
124.6, 124.1, 122.3, 121.9, 118.5, 118.3, 115.5, 115.4,
81.04, 60.6, 47.2, 47.1, 29.1, 24.2, 20.8; HRMS (ESI)
calcd for C31H30F6N4O4 (M＋H＋) 637.2244, found
Synthesis of (S)-2-amino-N-(2'-(3-(3,5-bis(trifluoro-
methyl)phenyl)thioureido)-[1,1'-biphenyl]-2-yl)-
propanamide (5b)
By following the same procedure as that of 5a,
starting from 4b (451 mg, 0.74 mmol), the crude prod-
uct was purified by flash chromatography on silica gel
(eluent: CH2Cl2/MeOH, V∶V＝100∶1) to yield a
white solid 5b (347 mg, 92% yield). [α]1D7 −19.6 (c
424
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© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 417—428

Organocatalytic Stereoselective Synthesis of 3-Alkyl-3-hydroxy-2-oxindoles
637.2218.
combined organic layers were dried over anhydrous
Na2SO4 and concentrated in vacuo. The residue was
purified by flash chromatography on silica gel (petro-
leum ether/ethyl acetate, V∶V＝2∶1) to yield a white
solid (126 mg, 80% yield). A suspension of this white
solid (126 mg, 0.17 mmol) and 10% Pd-C (21 mg, 0.02
mmol) in absolute EtOH (5 mL) was hydrogenated un-
der 1.0 atm for 10 min. The reaction mixture was di-
luted with EtOH (10 mL), and filtered through a Celite
pad under reduced pressure. The filtrate was concen-
trated under reduced pressure, and the resulted residue
was purified by flash chromatography on silica gel
(eluent: petroleum ether/ethyl acetate/TFA, V∶V∶V＝
1∶1∶0.01) to afford white semi-solid 11 (57 mg, 70%
Synthesis of (S)-N-(2'-(3-(3,5-bis(trifluoromethyl)-
phenyl)thioureido)-[1,1'-biphenyl]-2-yl)pyrrolidine-2-
carboxamide (8a)
To a well stirred solution of compound 7a (494 mg,
0.75 mmol) in CH2Cl2 (8 mL) was added TFA (4 mL)
dropwise at 0 ℃. The resulting mixture was stirred for
8 h at room temperature, and the mixture was concen-
trated under reduced pressure, dissolved in CH2Cl2 (15
mL), and treated with saturated Na2CO3 to reach pH 8.
The mixture was extracted with CH2Cl2 (20 mL×3).
The combined organic layers were dried with anhydrous
Na2SO4, and concentrated under reduced pressure. The
crude product was purified by flash chromatography on
neutral Al2O3 (eluent: CH2Cl2/MeOH, V∶V＝100∶1)
to yield 8a as a white solid (330 mg, 79% yield). [α]1D7
1
yield). [α]1D7 −43.3 (c 0.14, CHCl3); H NMR (400
MHz, CDCl3) δ: 13.25 (s, 2H), 9.08 (d, J＝8.4 Hz, 2H),
8.33 (d, J＝3.6 Hz, 2H), 7.23－7.31 (m, 10H), 3.67 (br
s, 2H), 3.35 (dd, J＝13.6, 3.6 Hz, 2H), 2.77 (dd, J＝
13.6, 9.6 Hz, 2H), 1.45 (br s, 4H); 13C NMR (100 MHz,
CDCl3) δ: 174.4, 143.3, 141.5, 137.8, 135.4, 130.0,
129.2, 128.7, 126.9, 123.8, 58.0, 41.3; HRMS (ESI)
calcd for C28H28N6O2 (M ＋H ＋ ) 481.2347, found
481.2355.
1
−64.0 (c 0.24, CHCl3); H NMR (400 MHz, CDCl3) δ:
9.69－9.72 (m, 1H), 8.34－8.43 (m, 1H), 7.15－7.62
(m, 12H), 3.53－3.58 (m, 1H), 2.77－3.01 (m, 2H),
2.28－2.34 (m, 1H), 1.62－2.10 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ: 179.4, 174.5, 174.4, 140.5, 135.0,
134.3, 133.7, 131.7, 131.4, 130.6, 130.3, 130.0, 128.9,
128.8, 128.7, 128.6, 128.2, 127.5, 127.0, 126.8, 126.2,
125.2, 124.5, 124.1, 121.8, 118.6, 60.4, 60.1, 47.4, 47.0,
30.3, 30.2, 26.2, 26.1; HRMS (ESI) calcd for
C26H20F6N4OS (M＋H＋) 553.1491, found 553.1502.
Synthesis of di-tert-butyl((2R,2'R)-([1,1'-biphenyl]-
2,2'-diylbis(azandiyl))bis(1-oxopropane-2,1-diyl))-
dicarbamate (12)
To a well stirred solution of 2 (92 mg, 0.5 mmol) in
anhydrous dichloromethane (5 mL) was added EDCI
(288 mg, 1.5 mmol), and added N-Boc-(S)-Ala-OH (284
mg, 1.5 mmol) dropwise at room temperature. The re-
sulting mixture was stirred for 8 h at room temperature,
then was quenched by addition of saturated NaHCO3,
and extracted with CH2Cl2 (10 mL×3). The combined
organic layers were dried over anhydrous Na2SO4 and
concentrated in vacuo. The residue was purified by flash
chromatography on silica gel (petroleum ether/ethyl
acetate, V∶V＝2∶1) to yield a white solid 12 (250 mg,
Synthesis of (S)-N-(2'-(3-(3,5-bis(trifluoromethyl)-
phenyl)ureido)-[1,1'-biphenyl]-2-yl)pyrrolidine-2-
carboxamide (8b)
By following the same procedure as that of 8a,
starting from 7b (470 mg, 0.74 mmol), 8b was prepared
as white solid (352 mg, 89% yield). [α]1D7 −47.3 (c 0.20,
1
CHCl3); H NMR (400 MHz, DMSO-d6) δ: 9.78－9.88
(m, 1H), 8.31－8.41 (m, 1H), 8.15 (d, J＝32.4 Hz, 8.4
Hz, 1H), 8.00 (d, J＝6.0 Hz, 2H), 7.15－7.64 (m, 7H),
3.51－3.54 (m, 1H), 2.65 (d, J＝6.8 Hz, 1H), 2.31－
2.05 (m, 1H), 1.38－1.86 (m, 4H); 13C NMR (100 MHz,
DMSO-d6) δ: 173.9, 173.7, 152.7, 142.2, 142.1, 136.8,
136.7, 136.5, 131.1, 130.9, 129.4, 129.2, 129.1, 129.0,
128.4, 125.1, 124.3, 123.9, 122.4, 121.5, 120.8, 120.2,
118.0, 114.7, 79.4, 79.1, 60.9, 60.8, 55.3, 46.7, 46.5,
30.8, 30.7, 26.0; HRMS (ESI) calcd for C26H22F6N4O2
(M＋H＋) 537.1720, found 537.1730.
1
95% yield). [α]1D7 −24.4 (c 0.15, CHCl3); H NMR
(400 MHz, CDCl3) δ: 8.01 (s, 2H), 7.68－7.73 (m, 2H),
7.42－7.48 (m, 2H), 7.18－7.30 (m, 4H), 4.90－5.17
(m, 2H), 4.00－4.25 (m, 2H), 1.18－1.45 (m, 24H); 13C
NMR (100 MHz, CDCl3) δ: 171.6, 155.5, 134.9, 130.4,
130.1, 129.5, 129.2, 125.6, 123.3, 50.5, 28.3, 28.2, 18.2,
17.2; HRMS (ESI) calcd for C28H38N4O6 (M＋H＋)
527.2864, found 527.2867.
Synthesis of (2S,2'S)-N,N'-([2,2'-bipyridine]-3,3'-
diyl)bis(2-amino-3-phenylpropanamide) (11)
Synthesis of (2S,2'S)-N,N'-([1,1'-biphenyl]-2,2'-diyl)-
bis(2-aminopropanamide) (13)
Compound 10 was prepared according to the re-
1
ported procedure and the H NMR data were consistent
To a well stirred solution of compound 12 (263 mg,
0.50 mmol) in THF (2 mL) was added TFA (1 mL)
dropwise at 0 ℃. The resulting mixture was stirred for
8 h at room temperature, and then the mixture was dis-
solved in THF (10 mL), and treated with 2 mol•L−1
NaOH(aq.) to reach pH 8, a large amount of white solid
was precipitated from the biphase solvent. The solid
was filtered and dried under vacuo to yield 13 as white
solid (147 mg, 90% yield). [α]1D7 −24.7 (c 0.10, CHCl3);
1H NMR (400 MHz, DMSO-d6) δ: 8.24 (d, J＝8.0 Hz,
1
with the reported values.[35] Compound 10: H NMR
(400 MHz, CDCl3) δ: 7.98 (d, J＝1.6 Hz, 2H), 7.01－
7.06 (m, 4H), 6.28 (br s, 4H). To a well stirred solution
of 10 (40 mg, 0.22 mmol) in anhydrous dichloro-
methane (2 mL) was added EDCI (83 mg, 0.66 mmol)
and N-Cbz-(S)-Phe-OH (193 mg, 0.66 mmol) at room
temperature. The resulting mixture was stirred for 1 h,
then the mixture was quenched by addition of saturated
NaHCO3, and extracted with CH2Cl2 (10 mL×3). The
Chin. J. Chem. 2014, 32, 417—428
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
425

Zhao et al.
FULL PAPER
(dd, J＝12.8, 4.0 Hz, 0.6H), 3.20－3.40 (m, 0.4H),
1.59 －2.36 (m, 8H). HPLC separation conditions:
Chiralcel OJ-H, solvent: Hexane/i-PrOH, V∶V＝85∶
15, flow rate＝1.0 mL/min, λ＝254 nm. Retention time:
tR(anti,major)＝61.46 min and tR(anti,minor)＝48.03
min.
(R)-3-Hydroxy-5-methyl-3-((S)-2-oxocyclohexyl)-
indolin-2-one (Table 5, Entry 5):[23] [α]1D7 −26.7 (c 0.10,
CHCl3, 67% ee); NMR (400 MHz, DMSO-d6) δ: 10.07
(d, J＝18.4 Hz, 1H), 6.93－7.09 (m, 2H), 6.62－6.68
(m, 1H), 5.67－5.77 (m, 1H), 3.04－3.23 (m, 1H),
2.21－2.50 (m, 4H), 1.44－2.07 (m, 4H). HPLC separa-
tion conditions: Chiralcel AD, hexane/i-PrOH＝90∶10,
flow rate＝1.0 mL/min, λ＝254 nm). Retention time:
tR(anti,major)＝49.26 min and tR(anti,minor)＝42.53
min.
(R)-3-Hydroxy-1-methyl-3-((S)-2-oxocyclohexyl)-
indolin-2-one (Table 5, Entry 6):[23] [α]1D7 −9.3 (c 0.15,
CHCl 3, 82% ee); 1H NMR (400 MHz, CDCl3) δ: 7.36－
7.40 (m, 2H), 7.08 (t, J＝7.6 Hz,1H), 6.84 (d, J＝8.0 Hz,
1H), 4.85 (br s, 1H), 3.20 (s, 3H), 2.96－3.21 (m, 1H),
2.47 (d, J＝14.8 Hz, 1H), 2.28－2.36 (m, 1H), 2.04 (d,
J＝13.6 Hz, 1H), 1.88 (s, 1H), 1.54－1.69 (m, 4H).
HPLC separation conditions: Chiralcel AD, solvent:
Hexane/i-PrOH, V∶V＝90∶10, flow rate＝1.0 mL/
min, λ＝254 nm. Retention time: tR(anti,major)＝34.81
min and tR(anti,minor)＝31.12 min.
(R)-1-Benzyl-3-hydroxy-3-((S)-2-oxocyclohexyl)-
indolin-2-one (Table 5, Entry 7):[23] [α]1D7 −3.3 (c 0.20,
CHCl3, 86% ee); 1H NMR (400 MHz, CDCl3) δ: 7.27－
7.47 (m, 7H), 7.04 (t, J＝7.2 Hz, 1H), 6.70 (d, J＝8.0
Hz, 1H), 4.97 (d, J＝16.0 Hz, 1H), 4.83 (d, J＝16.0 Hz,
1H), 3.05 (d, J＝6.8 Hz, 1H), 2.52 (d, J＝15.2 Hz, 1H),
2.31－2.39 (m, 1H), 2.04 (br s, 2H), 1.90 (br s, 1H),
1.57 －1.71 (m, 3H). HPLC separation conditions:
Chiralcel AD-H, solvent: Hexane/i-PrOH, V∶V＝80/20,
flow rate＝1.0 mL/min, λ＝254 nm. Retention time:
tR(anti,major)＝57.55 min and tR(anti,minor)＝50.87
min.
1H), 8.13 (d, J＝8.0 Hz, 1H), 7.39－7.43 (m, 2H), 7.18
－7.23 (m, 4H), 3.23 (dd, J＝6.8, 3.6 Hz, 2H), 1.05－
1.06 (m, 6H); 13C NMR (100 MHz, DMSO-d6) δ: 174.8,
174.5, 136.3, 136.1, 131.0, 130.8, 129.2, 129.1, 128.7,
124.7, 124.5, 121.8, 121.0, 51.1, 21.3, 21.3; HRMS
(ESI) calcd for C18H22N4O2 (M＋H＋) 327.1816, found
327.1814.
Typical procedure for the organocatalytic synthesis
of 3-alkyl-3-hydroxy-2-oxindoles in water
A mixture of catalyst 5a (7.9 mg, 0.015 mmol),
p-TsOH (1.9 mg, 0.01 mmol) and cyclohexanone (104
μL, 1.0 mmol) in 0.5 mL of water was stirred for 10 min
at room temperature. Isatin (14.7 mg, 0.1 mmol) was
added, and then the resulted reaction mixture was stirred
for 3.5 h at room temperature. After rermoval of water
under the reduced pressure, the resulted residue was
purified with flash column chromatography on silica gel
(petroleum/ethyl acetate, V∶V＝1∶1) to afford the
desired (R)-3-hydroxy-3-((S)-2-oxocyclohexyl)indolin-
2-one (24.3 mg, 99%).
(R)-3-Hydroxy-5-nitro-3-((S)-2-oxocyclohexyl)indo-
lin-2-one (Table 5, Entry 1):[37] [α]1D7 −67.3 (c 0.05,
1
CHCl3, 86% ee); H NMR (400 MHz, DMSO-d6) δ:
11.03 (s, 1H), 8.19 (d, J＝8.4 Hz, 1H), 7.98 (s, 1H),
7.02 (d, J＝8.8 Hz, 1H), 6.03 (s, 1H), 3.19 (dd, J＝12.8,
4.4 Hz, 1H), 2.66 (d, J＝10.0 Hz, 1H), 2.34－2.37 (m,
1H), 1.49－2.05 (m, 6H). HPLC separation conditions:
Chiralcel AD-H, solvent: Hexane/i-PrOH, V∶V＝80∶
20, flow rate＝1.0 mL/min, λ＝254 nm. Retention time:
tR(anti,major)＝68.50 min and tR(anti,minor)＝53.10
min.
(R)-5-Chloro-3-hydroxy-3-((S)-2-oxocyclohexyl)-
indolin-2-one (Table 5, Entry 2):[23] [α]1D7 −36.0 (c 0.10,
1
CHCl3, 80% ee). H NMR (400 MHz, DMSO-d6) δ:
10.38 (s, 1H), 7.23 (d, J＝8.0 Hz, 1H), 7.19 (s, 1H),
6.80 (d, J＝8.0 Hz, 1H), 6.03 (s, 1H), 3.09 (dd, J＝12.8,
4.8 Hz, 1H), 2.58 (d, J＝10.8 Hz, 1H), 2.29－2.37 (m,
1H), 1.92－2.08 (m, 3H), 1.66－1.83 (m, 2H), 1.49－
1.55 (m, 1H). HPLC separation conditions: Chiralcel IC,
solvent: Hexane/i-PrOH, V∶V＝85∶15, flow rate＝
1.0 mL/min, λ＝254 nm. Retention time: tR(anti,major)＝
50.08 min and tR(anti,minor)＝64.25 min.
(R)-1-Benzyl-3-hydroxy-5-nitro-3-((S)-2-oxocyclo-
hexyl)indolin-2-one (Table 5, Entry 8): [α]1D7 −49.0 (c
1
0.14, CHCl3, 98% ee); H NMR (400 MHz, CDCl3) δ:
8.17－8.24 (m, 2H), 7.27－7.35 (m, 5H), 6.78 (d, J＝
8.8 Hz, 1H), 4.80－5.20 (m, 2H), 3.10－3.25 (m, 1H),
2.29－2.49 (m, 3H), 2.11 (br s, 1H), 2.02 (br s, 1H),
1.65－1.71 (m, 3H); 13C NMR (100 MHz, CDCl3) δ:
213.3, 210.8, 177.4, 175.4, 149.6, 148.8, 143.8, 143.4,
134.4, 134.3, 130.7, 129.7, 129.1, 129.0, 128.2, 128.1,
127.3, 126.8, 126.7, 121.2, 120.3, 109.3, 56.0, 44.3,
42.5, 42.0, 28.1, 27.3, 26.9, 26.4, 24.6, 24.3; HRMS
(ESI) calcd for C12H20N2O5 (M＋H＋) 283.0713, found
283.0708. HPLC separation conditions: Chiralcel OD-H,
solvent: Hexane/i-PrOH, V∶V＝80∶20, flow rate＝
1.0 mL/min, λ＝254 nm. Retention time: tR(anti,major)＝
47.15 min and tR(anti,minor)＝61.08 min.
(R)-5-Bromo-3-hydroxy-3-((S)-2-oxocyclohexyl)-
indolin-2-one (Table 5, Entry 3):[23] [α]1D7 −23.6 (c 0.07,
1
CHCl3, 86% ee); H NMR (400 MHz, DMSO-d6) δ:
10.38 (s, 1H), 7.36 (d, J＝8.4 Hz, 1H), 7.30 (s, 1H),
6.76 (d, J＝8.4 Hz, 1H), 6.03 (s, 1H), 3.09 (dd, J＝12.4,
4.4 Hz, 1H), 2.29－2.59 (m, 1H), 2.21 (s, 1H), 1.93－
2.05 (m, 3H), 1.46－1.79 (m, 3H). HPLC separation
conditions: Chiralcel IC, solvent: Hexane/i-PrOH, V∶
V＝85∶15, flow rate＝1.0 mL/min, λ＝254 nm. Reten-
tion time: tR(anti,major)＝50.42 min and tR(anti, minor)
＝61.87 min.
(R)-4-Bromo-3-hydroxy-3-((S)-2-oxocyclohexyl)-
indolin-2-one (Table 5, Entry 4):[23] [α]1D7 −52.0 (c 0.01,
1
(R)-1-Benzyl-5-bromo-3-hydroxy-3-((S)-2-oxocyclo-
CHCl3, 87% ee); H NMR (400 MHz, DMSO-d6) δ:
10.61 (s, 0.4H), 10.36 (s, 0.6H), 6.97－7.16 (m, 2H),
6.74－6.83 (m, 1H), 6.20 (s, 0.4H), 6.03 (s, 0.6H), 3.90
hexyl)indolin-2-one (Table 5, Entry 9): [α]1D7 −9.1 (c
1
0.18, CHCl3, 99% ee); H NMR (400 MHz, CDCl3) δ:
426
www.cjc.wiley-vch.de
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 417—428

Organocatalytic Stereoselective Synthesis of 3-Alkyl-3-hydroxy-2-oxindoles
1
7.28－7.47 (m, 7H), 6.57 (d, J＝8.4 Hz, 1H), 4.95 (d,
J＝16.0 Hz, 1H), 4.83 (d, J＝15.6 Hz, 1H), 3.02－3.07
(m, 1H), 2.51 (d, J＝15.2 Hz, 1H), 2.31－2.39 (m, 1H),
2.08 (d, J＝14.8 Hz, 2H), 1.94 (s, 1H), 1.62－1.72 (m,
3H); 13C NMR (100 MHz, CDCl3) δ: 214.0, 211.3,
176.6, 174.5, 142.7, 142.1, 135.1, 134.9, 132.5, 132.4,
131.7, 130.9, 128.9, 128.8, 128.7, 127.9, 127.8, 127.5,
127.3, 116.1, 115.6, 111.1, 55.8, 55.7, 44.0, 42.6, 42.0,
28.2, 27.2, 26.8, 26.2, 24.6, 24.3; HRMS (ESI) calcd for
C21H20BrNO3 (M＋H＋) 414.0699, found 414.0696.
HPLC separation conditions: Chiralcel AD-H, solvent:
Hexane/i-PrOH, V ∶V ＝80 ∶20, flow rate ＝1.0
mL/min, λ＝254 nm. Retention time: tR(anti,major)＝
56.36 min and tR(anti,minor)＝66.83 min.
Entry 1):[11] [α]1D7 ＋2.20 (c 0.10, CHCl3, 5% ee); H
NMR (400 MHz, DMSO-d6) δ: 10.19 (s, 1H), 7.24－
7.15 (m, 2H), 6.92－6.88 (m, 1H ), 6.77 (d, J＝7.6 Hz,
1H), 5.95 (s, 1H), 3.26 (d, J＝16.4 Hz, 1H), 2.99 (d, J＝
16.4 Hz, 1H), 2.00 (s, 3H). HPLC separation conditions:
Chiralcel OJ-H, solvent: Hexane/i-PrOH, V∶V＝80∶
20, flow rate＝1.0 mL/min, λ＝254 nm. Retention time:
tR(major)＝28.11 min and tR(minor)＝41.98 min.
3-Hydroxy-3-(2-oxocyclopentyl)indolin-2-one (Table
6, Entry 2):[23] [α]1D7 ＋31.33 (c 0.10, CHCl3, 26% ee);
1H NMR (400 MHz, DMSO-d6) δ: 10.30 (s, 1H), 7.36
(d, J＝7.2 Hz, 1H), 7.18 (t, J＝7.6 Hz, 1H), 6.89 (t, J＝
7.6 Hz, 1H), 5.99 (s, 1H), 2.88 (t, J＝10.0 Hz, 1H),
2.22 －1.72 (m, 6H). HPLC separation conditions:
Chiralcel AD-H, solvent: Hexane/i-PrOH, V∶V＝90∶
10, flow rate＝1.0 mL/min, λ＝254 nm. Retention time:
tR(major)＝40.32 min and tR(anti,minor)＝44.76 min.
3-Hydroxy-3-(4-oxotetrahydro-2H-pyran-3-yl)indo-
lin-2-one (Table 6, Etry 3):[37] [α]1D7 −26.0 (c 0.10,
(R)-1-Benzyl-3-hydroxy-5-methyl-3-((S)-2-oxocyclo-
hexyl)indolin-2-one (Table 5, Entry 10): [α]1D7 −14.7 (c
1
0.20, CHCl3, 86% ee); H NMR (400 MHz, CDCl3) δ:
7.28－7.34 (m, 5H), 7.18 (s, 1H), 7.01 (d, J＝8.0 Hz,
1H), 6.58 (d, J＝8.0 Hz, 1H), 5.01 (br s, 1H), 4.96 (d,
J＝16.0 Hz, 1H), 4.82 (d, J＝16.0 Hz, 1H), 3.00－3.05
(m, 1H), 2.52 (d, J＝15.2 Hz, 1H), 2.34－2.39 (m, 1H),
2.04 (br s, 1H), 1.90 (s, 1H), 1.57－1.73 (m, 4H); 13C
NMR (100 MHz, CDCl3) δ: 211.9, 211.8, 177.0, 176.9,
175.0, 141.2, 135.7, 132.5, 130.0, 128.9, 128.8, 128.7,
127.5, 124.9, 109.3, 55.7, 55.4, 53.5, 43.9, 42.7, 42.1,
28.3, 27.2, 26.8, 26.1, 24.5, 24.3, 21.2, 21.1; HRMS
(ESI) calcd for C22H24NO3 (M＋H＋) 350,1750, found
350.1743. HPLC separation conditions: Chiralcel AD,
solvent: Hexane/i-PrOH, V∶V＝80∶20, flow rate＝
1.0 mL/min, λ＝254 nm. Retention time: tR(anti,major)＝
29.08 min and tR(anti,minor)＝25.02 min.
1
CHCl3, 21% ee); H NMR (400 MHz, DMSO-d6) δ:
10.30 (s, 1H), 7.24 (d, J＝7.6 Hz, 1H), 7.18 (t, J＝7.6
Hz, 1H), 6.88 (t, J＝7.6 Hz, 1H), 6.79 (d, J＝7.6 Hz,
1H), 6.08 (s, 1H), 4.50 (dd, J＝13.2, 4.8 Hz, 1H),
4.01－4.07 (m, 2H), 3.56－3.62 (m, 2H), 3.18－3.22
(m, 1H), 2.02－2.08 (m, 1H). HPLC separation condi-
tions: Chiralcel AD-H, solvent: Hexane/i-PrOH, V∶V
＝85∶15, flow rate＝1.0 mL/min, λ＝254 nm. Reten-
tion time: tR(major)＝78.22 min and tR(minor)＝88.50
min.
3-Hydroxy-3-(4-oxotetrahydro-2H-thiopyran-3-yl)-
indolin-2-one (Table 6, Entry 4): [α]1D7 −14.7 (c 0.18,
1
(S)-tert-Butyl-3-hydroxy-2-oxo-3-((R)-2-oxocyclo-
CHCl3, 57% ee); H NMR (400 MHz, DMSO-d6) δ:
hexyl)indoline-1-carboxylate (Table 5, Entry 11): [α]1D7
10.28 (s, 1H), 7.25 (d, J＝7.2 Hz, 1H), 7.17 (t, J＝7.6
Hz, 1H), 6.86 (t, J＝7.6 Hz, 1H), 6.79 (d, J＝7.6 Hz,
1H), 6.08 (s, 1H), 3.47 (d, J＝11.6 Hz, 1H), 3.19－3.31
(m, 2H), 2.90 (d, J＝6.8 Hz, 2H), 2.42－2.65 (m, 2H);
13C NMR (100 MHz, DMSO-d6) δ: 208.1, 207.0, 178.5,
178.4, 143.7, 143.6, 130.7, 129.3, 129.2, 125.4, 123.5,
121.6, 121.5, 110.0, 109.6, 74.4, 73.5, 60.5, 45.2, 44.2,
30.9, 30.8, 29.4, 29.2; HRMS (ESI) calcd for
C13H13NO3S (M ＋H ＋ ) 264.0689, found 264.0683.
HPLC separation conditions: Chiralcel AD-H, solvent:
Hexane/i-PrOH, V ∶V ＝85 ∶15, flow rate ＝1.0
mL/min, λ＝254 nm. Retention time: tR(major)＝46.13
min and tR(minor)＝54.30 min.
1
＋29.4 (c 0.12, CHCl3, −98% ee); H NMR (400 MHz,
CDCl3) δ: 7.89 (d, J＝8.0 Hz, 1H), 7.35－7.39 (m, 2H),
7.17－7.28 (m, 1H), 4.98 (br s, 1H), 3.01 (dd, J＝12.8,
4.8 Hz, 1H), 2.47 (d, J＝15.2 Hz, 1H), 2.27－2.33 (m,
1H), 1.80－2.20 (m, 2H), 1.57－1.71 (m, 12H); 13C
NMR (100 MHz, CDCl3) δ: 213.5, 211.5, 175.4, 173.7,
149.1, 148.9, 140.6, 140.0, 130.2, 129.9, 127.7, 125.0,
124.7, 124.0, 115.3, 84.4, 56.4, 56.1, 42.6, 41.9, 28.1,
27.0, 26.8, 25.8, 24.4, 24.3; HRMS (ESI) calcd for
C19H23NO5Na (M＋Na＋) 368.1468, found 368.1460.
HPLC separation conditions: Chiralcel AD, solvent:
Hexane/i-PrOH, V ∶V ＝80 ∶20, flow rate ＝1.0
mL/min, λ＝254 nm. Retention time: tR(anti,major)＝
15.24 min and tR(anti,minor)＝14.39 min.
tert-Butyl-3-(3-hydroxy-2-oxoindolin-3-yl)-4-oxo-
piperidine-1-carboxylate (Table 6, Entry 5): [α]1D7
1
(R)-3-Hydroxy-3-((S)-2-oxocyclohexyl)indolin-2-
＋22.2 (c 0.11, CHCl3, 25% ee); H NMR (400 MHz,
one (Table 5, Entry 12):[23] [α]1D7 −25.3 (c 0.11, CHCl3,
DMSO-d6) δ: 10.30 (s, 1H), 7.25 (d, J＝7.2 Hz, 1H),
7.15 (t, J＝7.6 Hz, 1H), 6.87 (t, J＝7.6 Hz, 1H), 6.76 (d,
J＝8.0 Hz, 1H), 6.01 (s, 1H), 4.60 (br s, 1H), 4.11 (br s,
1H), 3.52 (br s, 1H), 3.04 (br s, 1H), 2.41－2.47 (m,
1H), 2.08－2.26 (m, 2H), 1.46 (s, 9H); 13C NMR (400
MHz, DMSO-d6) δ: 207.2, 206.6, 178.2, 154.3, 143.1,
129.4, 125.3, 123.8, 121.6, 110.1, 109.7, 79.8, 74.1,
73.2, 56.5, 55.4, 28.5, 28.4; HRMS (ESI) calcd for
C18H22N2O5 (M ＋H ＋ ) 347.1602, found 347.1595.
HPLC separation conditions: Chiralcel AD-H, solvent:
1
94% ee); H NMR (400 MHz, DMSO-d6) δ: 10.20 (s,
1H), 7.22－7.14 (m, 2H), 6.87－6.77 (m, 2H), 5.83 (s,
1H), 3.07 (dd, J＝13.2, 4.8 Hz, 1H), 2.59 (d, J＝11.2
Hz, 1H), 2.27－2.36 (m, 1H), 1.45－2.04 (m, 6H).
HPLC separation conditions: Chiralcel OJ-H, hexane/
i-PrOH, V∶V＝80∶20, flow rate＝1.0 mL/min, λ＝
254 nm; Retention time: tR(anti,major)＝15.75 min and
tR(anti,minor)＝19.56 min.
(R)-1-(3-Hydroxyindolin-3-yl)propan-2-one (Table 6,
Chin. J. Chem. 2014, 32, 417—428
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
427

Zhao et al.
FULL PAPER
[3] (a) Suh, C. W.; Chang, C. W.; Choi, K. W.; Lim, Y. J.; Kim, D. Y.
Tetrahedron Lett. 2013, 54, 3651; (b) Liu, Y.; Zhu, F.; Wang, C.;
Zhou, J. Chin. J. Org. Chem. 2013, 33, 1595 (in Chinese).
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Tomasini, C. J. Org. Chem. 2005, 70, 7418.
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Kaptein, B.; Broxterman, Q. B.; Garden, S. J.; Tomasini, C.
Tetrahedron 2006, 62, 12017.
Hexane/i-PrOH, V ∶V ＝90 ∶10, flow rate ＝1.0
mL/min, λ＝254 nm. Retention time: tR(major)＝63.61
min and tR(minor)＝44.73 min.
1-Benzyl-5-bromo-3-hydroxy-3-(4-oxotetrahydro-2H-
thiopyran-3-yl)indolin-2-one (Table 6, Entry 6): [α]1D7
1
＋14.7 (c 0.10, CHCl3, 96% ee); H NMR (400 MHz,
CDCl3) δ: 7.51 (d, J＝1.6 Hz, 1H), 7.28－7.35 (m, 6H),
6.60 (d, J＝8.4 Hz, 1H), 4.96 (d, J＝15.6 Hz, 1H), 4.84
(d, J＝15.6 Hz, 1H), 4.10 (br s, 1H), 3.66 (dd, J＝12.0,
5.2 Hz, 1H), 2.78－2.97 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ: 208.7, 207.4, 176.7, 176.0, 143.6, 143.0,
136.5, 136.4, 134.6, 134.5, 132.5, 132.0, 131.8, 128.9,
128.1, 127.7, 127.6, 126.5, 114.4, 114.3, 111.5, 111.1,
74.2, 73.3, 73.2, 60.8, 60.2, 45.1, 44.3, 43.4, 43.1, 30.7,
30.6, 29.4, 29.2; HRMS (ESI) calcd for C20H19BrNO3S
(M＋H＋) 432.0263, found 432.0261. HPLC separation
conditions: Chiralcel AD, solvent: Hexane/i-PrOH, V∶
V＝80∶20, flow rate＝1.0 mL/min, λ＝254 nm. Reten-
tion time: tR(major)＝34.48 min and tR(minor)＝39.83
min.
[6] Malkov, A. V.; Kabeshov, M. A.; Bella, M.; Kysilka, O.; Malyshev,
D. A.; Pluhácǩ ová, K.; Kočovský, P. Org. Lett. 2007, 9, 5473.
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Xiao, W.-J. Tetrahedron 2007, 63, 10437.
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T. Chem.-Eur. J. 2008, 14, 8079.
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Lett. 2009, 50, 814.
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49, 9460.
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2010, 352, 1621.
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2157.
1-Benzyl-3-hydroxy-5-nitro-3-(4-oxotetrahydro-2H-
[14] Pearson, A. J.; Panda, S. Org. Lett. 2011, 13, 5548.
[15] Hu, S.; Zhang, L.; Li, J.; Luo, S.; Cheng, J.-P. Eur. J. Org. Chem.
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Asymmetry 2011, 22, 1423.
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2011, 52, 4080.
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Asymmetry 2011, 22, 708.
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J. Chem.-Eur. J. 2012, 18, 11899.
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68, 92.
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9921.
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Y. Adv. Synth. Catal. 2013, 355, 2029.
thiopyran-3-yl)indolin-2-one (Table 6, Entry 7): [α]1D7
1
−16.0 (c 0.10, CHCl3, 99% ee); H NMR (400 MHz,
CDCl3) δ: 8.17－8.24 (m, 2H), 7.28－7.38 (m, 5H),
6.80 (d, J＝8.8 Hz, 1H), 5.04 (d, J＝15.6 Hz, 1H), 4.92
(d, J＝16.0 Hz, 1H), 3.72－3.78 (m, 2H), 2.97－3.02
(m, 3H), 2.79－2.81 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ: 209.1, 207.6, 177.1, 175.7, 149.5, 149.0,
143.7, 143.5, 134.3, 134.2, 130.6, 129.1, 128.2, 127.3,
127.2, 126.9, 120.4, 119.9, 109.6, 109.4, 75.2, 75.0,
59.7, 59.6, 45.2, 44.5, 44.4, 44.2, 30.6, 30.5. 29.7, 29.6;
HRMS (ESI) calcd for C20H19N2O5S (M ＋ H ＋
)
399.1009, found 399.0999. HPLC separation conditions:
Chiralcel AD, solvent: Hexane/i-PrOH, V∶V＝70∶30,
flow rate＝1.0 mL/min, λ＝254 nm. Retention time:
tR(major)＝33.18 min and tR(minor)＝38.64 min.
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Acknowledgement
We thank the Beijing Municipal Commission of
Education (No. JC015001200902), the Beijing Municipal
Natural Science Foundation (Nos. 710201, 2122008), the
Basic Research Foundation of Beijing University of
Technology (No. X4015001201101), the Funding Project
for Academic Human Resources Development in
Institutions of Higher Learning under the Jurisdiction of
Beijing Municipality (No. PHR201008025) and the
Doctoral Scientific Research Start-up Foundation of
Beijing University of Technology (No. 52015001200701)
for financial supports.
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Yang, Z.; Meng, W.; Yang, Z. Synlett 2013, 24, 2160.
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X.-Q.; Yang, Z. Synlett 2013, 24, 2743.
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Z.-H.; Meng, W.; Guo, X-Y. Synlett 2014, 25, 293.
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(Zhao, C.)
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