The quinine thiourea-catalyzed asymmetric Strecker reaction: An approach for the synthesis of 3-aminooxindoles

Article abstract of DOI:10.1002/adsc.201200630

An organocatalytic enantioselective Strecker reaction for the synthesis of 3-amino-3-cyanooxindoles has been developed. Employing a quinine-derived thiourea catalyst, the nucleophilic addition of trimethylsilyl cyanide to N-Boc-ketimines affords 3-amino-3-canooxindoles in good to excellent yields (78-98%) and very good enantioselectivities (up to 94%). Furthermore, to the best of our knowledge, this method also represents the first enantioselective organocatalyzed Strecker reaction with N-Boc-ketimines as electrophiles.

Full text of DOI:10.1002/adsc.201200630

FULL PAPERS
DOI: 10.1002/adsc.201200630
The Quinine Thiourea-Catalyzed Asymmetric Strecker Reaction:
An Approach for the Synthesis of 3-Aminooxindoles
Dong Wang,a,c Jinyan Liang,a,c Jingchao Feng,a Kairong Wang,a Quantao Sun,a
Long Zhao,a Dan Li,a Wenjin Yan,a,* and Rui Wanga,b,*
a
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Life Sciences, School of Basic Medical
Sciences, School of Pharmacy, State Key Laboratory of Applied Organic Chemistry and Institute of Biochemistry and
Molecular Biology, Lanzhou University, Lanzhou 730000, Peopleꢀs Republic of China
Fax : (+86)-931-891-1255; e-mail: yanwj@lzu.edu.cn or wangrui@lzu.edu.cn
b
State Key Laboratory of Chiroscience and Department of Applied Biology & Chemical Technology, The Hong Kong
Polytechnic University, Kowloon, Hong Kong
E-mail: bcrwang@polyu.edu.hk
These authors contributed equally to this work.
c
Received: July 18, 2012; Revised: October 1, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200630.
Abstract: An organocatalytic enantioselective edge, this method also represents the first enantiose-
Strecker reaction for the synthesis of 3-amino-3-cya- lective organocatalyzed Strecker reaction with N-
nooxindoles has been developed. Employing a qui- Boc-ketimines as electrophiles.
nine-derived thiourea catalyst, the nucleophilic addi-
tion of trimethylsilyl cyanide to N-Boc-ketimines af-
fords 3-amino-3-canooxindoles in good to excellent Keywords: 3-amino-3-cyanooxindoles; N-Boc-keti-
yields (78–98%) and very good enantioselectivities mines; organocatalysis; quaternary stereocenters;
(up to 94%). Furthermore, to the best of our knowl- Strecker reaction
Introduction
Substituted 3-amino-2-oxindoles have been recog-
nized as a core structure in a variety of bioactive mol-
Optically active a-amino nitriles are synthetically ver- ecules.[3] Among them, one classical example is the
satile intermediates for a wide range of natural prod- spirohydantoin (A) (Scheme 1) which was developed
ucts and pharmaceuticals.[1] As well-known a-amino by AstraZeneca for potential use in the treatment of
acid precursors, these useful compounds also provide pain.[4] Experimentally, this useful compound could be
access to valuable a-amino aldehydes, ketones, b- achieved by the conversion of optically active 3-
amino alcohols and 1,2-diamines. Spurred on by the amino-3-cyanooxindoles (Figure 1). Considering the
ever-increasing demand for these enantioenriched synthetic utility of this intermediate, Zhouꢀs[5] and
compounds, the asymmetric Strecker reaction has Sacchettiꢀs[6] groups described the asymmetric addi-
become one of the hottest topics in recent years.[2]
tion of TMSCN to isatin ketimines, respectively, how-
ever, both with moderate yields and stereoselectivi-
ties.
Although there are several highly efficient catalytic
enantioseletive systems for Strecker reaction with ke-
timines as the substrate,[7,8] to the best of our knowl-
edge no related Strecker reactions of N-Boc-keti-
mines have been reported.[9] As part of our ongoing
interest in the stereoselective synthesis of 3-aminoox-
indoles through the addition of carbon nucleophiles
to isatin-derived ketimines,[10] we herein report
a facile method for the construction of optically
active 3-amino-3-cyanooxindoles.
Scheme 1. Synthesis of spirohydantoin (A) from 3-amino-3-
cyanooxindole.
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on the influence of solvents. As presented in Table 2,
although toluene, diethyl ether and 1,2-dichloro-
ethane gave similar results (entries 1,4 and 6,
Table 2), a relatively shorter reaction time was ob-
served with 1,2-dichloroethane as solvent. When the
reaction was carried out at 08C, the enantioselectivity
improved slightly compared to that at room tempera-
ture (entry 10, Table 2). The Strecker product could
be obtained in 98% yield and 93% ee when the reac-
tion temperature was decreased to À258C (entry 11,
Table 2). Meanwhile, we also found that further low-
ering the temperature could not improve the enantio-
selectivity (entry 12, Table 2). Then, the effects of
molar ratio and concentration were investigated (en-
tries 13–16, Table 2). The results indicated that satis-
factory results could be obtained with 1.5 equiv. of
TMSCN and in 1 mL of solvent. Aimed to test the re-
activity, another efficient source CNÀ, NCCOOC2H5,
Figure 1. Catalysts for screening.
Results and Discussion
Our investigation began with the addition of TMSCN was also examined, but no adduct was found even
to ketimine 1a using natural Cinchona alkaloids as after four days.
catalysts. As expected, the reactions gave products in
excellent yields respectively, however, both with
lower ee. Furthermore, long reaction times, even
Table 2. Optimization of the reaction conditions.[a]
more than 3 days, were needed (entries 1 and 2,
Table 1). The catalysts quinine-thiourea L3 and quini-
dine-thiourea L4 were involved in the next investiga-
tion. To our delight, catalyst L3 gave satisfactory re-
sults of 98% yield and 88% ee, and the enantiomer
2a’ could be achieved in a similar manner to 2a with
quinidine-thiourea L4 as catalyst. As shown in
Table 1, good yields and faster reaction rates were ob-
served when catalyst L5 was used, however, with
moderate stereoselectivities.
Using L3 as the selected catalyst, a reaction optimi-
zation was carried out with the addition of TMSCN
to 1a as the model reaction. The initial study focused
Entry
Solvent
Time [h]
Yield [%]
ee [%][b]
1
2
3
4
5
6
7
8
toluene
DCM
CHCl3
DCE
THF
Et2O
t-BuOMe
EtOAc
CH3CN
DCE
DCE
DCE
24
16
16
12
40
24
17
17
17
16
24
48
48
18
36
42
–
96
83
98
98
65
91
89
94
98
98
96
72
94
96
91
98
–
88
86
84
88
80
88
87
68
83
91
93
93
93
92
92
93
–
Table 1. Catalyst screening for the enantioselective Strecker
9
reaction.[a]
10[c]
11[d]
12[e]
13[c,f]
14[c,g]
15[c,h]
16[c,i]
17[j]
DCE
DCE
DCE
DCE
DCE
Catalyst[b]
Time [h]
Yield [%]
ee [%][c]
[a]
Entry
Reaction
conditions:
1a
(0.1 mmol),
TMSCN
(0.15 mmol), in 1 mL solvent and at room temperature.
Determined by HPLC analysis.
At 08C.
1
2
3
4
5
L1
L2
L3
L4
L5
108
96
24
24
17
95
83
96
96
94
34
18
88
[b]
[c]
[d]
[e]
[f]
At À258C.
À86
At À408C.
63
2 mL DCM were used.
[a]
[g]
[h]
[i]
Reaction
conditions:
1a
(0.1 mmol),
TMSCN
0.5 mL DCM was used.
(0.15 mmol), CH3C6H5 (1 mL) and at room temperature.
Catalyst loading: 10 mol%.
Determined by HPLC analysis.
TMSCN (0.13 mmol) was used.
TMSCN (0.17 mmol) was used.
CNCOOC2H5 was used and no adduct was found.
[b]
[c]
[j]
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The Quinine Thiourea-Catalyzed Asymmetric Strecker Reaction
Table 3. Effect of sdditives in the reaction.[a]
Table 4. Effect of substituent groups at ketimine 1-posi-
tion.[a]
Entry
Additive
Time [h]
Yield [%]
ee [%][b]
Entry R1
Time [h] Product Yield [%] ee [%][b]
1
2
MeOH
EtOH
i-PrOH
i-PrOH
i-PrOH
18
18
18
60
18
83
90
96
–
93
93
93
–
À93
TMSCN
1
2
Me
Bn
18
24
2a
3a
4a
5a
–
96
98
88
95
–
93
93
91
90
–
3
4[c]
5[d]
3
MOM 18
H
Ac
Boc
4[c]
5
12
–
94
[a]
Reaction
conditions:
1a
(0.1 mmol),
6
–
–
–
–
(0.15 mmol), in 1 mL DCE, at À258C and with
[a]
Reaction
conditions:
1a
(0.1 mmol),
TMSCN
0.15 mmol protic additive.
[b]
[c]
[d]
(0.15 mmol), at À258C, with 0.15 mmol i-PrOH and with
Determined by HPLC analysis.
With 1 mL i-PrOH as solvent.
With L4 as catalyst.
10 mol% catalyst loading.
Determined by HPLC analysis.
[b]
[c]
The ee was determined by HPLC after a simple chemical
conversion and see also ref.[13]
To further improve this addition reaction, a series
of alcoholic additives was tested.[11] In general, the re- evaluated different N-Boc-ketimines to define the
action rate was improved greatly with 0.15 mmol of scope of this Strecker reaction. As summarized in
a protic additive. And the reactions gave the products Scheme 2, the reactions of a variety of structurally di-
in similar enantioselectivity (entries 1–3, Table 3). In verse N-Boc-ketimines bearing electron-withdrawing,
view of the best yield, i-PrOH was selected as the electron-neutral or electron-donating substituents in
suitable additive for further investigation of the sub- the aromatic ring, with TMSCN were tested. We were
strate scope. Partly because of the poor solubility of delighted to obtain the corresponding adducts for all
ketimine 1a in i-PrOH, no adduct was observed even ketimines with good to excellent yields (78–98%)
after 60 h with i-PrOH as solvent. In addition, the op- under the optimized conditions. The general conclu-
posite enantiomer 2a’ of compound 2a could be ob- sion drawn from the results was that the steric effect
tained in 94% yield and 93% ee under the optimal on reactivity and stereoselectivity was more pro-
conditions with L4 as catalyst.[12]
nounced than the electronic effect. For example, the
After the establishment of the optimal reaction reactions of ketimines containing Cl or Br at the 4-po-
protocol, the effect of the substituent groups at the 1- sition gave poorer enatioselectivities (see 2b and 2c),
position of ketimines was investigated. As listed in while the same substituents at the 6-position gave the
Table 4, with CH3, CH2C6H5 and CH2OCH3 as the products in higher yields and enantioselectivities (see
substituent group, the addition reactions were carried 2i and 2j). With halogen substituents at the 7-position,
out smoothly and gave the products in high yields and the regular response was obtained (see 2k, 2l and
excellent enantioselectivities, respectively (entries 1– 2m).
3, Table 4). Although similar results were seen, a sig-
As the increase of the substitutentꢀs atomic radius,
nificantly slower reaction rate was observed with N- a downward trend of reactivity was shown (see 2k, 2l
benzyl-Boc-ketimine as the substrate. It was notewor- and 2m). The effect of the electronic nature in the ar-
thy that the ketimine without the substituent group at omatic ring was also observed. With the change from
the 1-position showed good reactivity in this addition electron-withdrawing to electron-donating group in
reaction and gave the product 5a in 95% yield and the 5-position the corresponding reaction time in-
90% ee (entry 4, Table 4).[13] At the same time, lost re- creased, while the similar yields and enantioselectivi-
activity was observed with the bulky substituent Boc ties were afforded (see 2d, 2e, 2f, 2g and 2h).
or an acetyl group at the 1-position of ketimine. The
In addition, it turned out that this asymmetric addi-
above-mentioned results indicated that a negative tion of TMSCN to disubstituted ketimine also fol-
impact on the reactivity of ketimines was made by the lowed the same reaction pattern. When 7-methyl-5-
increase of the size or electron-withdrawing ability of bromoketimine was used as the substrate, the corre-
the substituent.
sponding product was obtained in 96% yield and 86%
After the end of the reactivity assessment of sub- ee. As to 5,7-dibromoketimine, 96% yield and 86% ee
stituent groups at the ketimine 1-position, we then were observed.
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Table 5. Cyanation reaction of N-allylketimines.[a]
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Entry Substrate Time [h] Product Yield [%] ee [%][b]
1
2
3
1p
1q
1r
16
16
16
2p
2q
2r
96
96
98
91
92
91
[a]
Reaction conditions: ketimine (0.1 mmol), TMSCN
(0.15 mmol), 0.15 mmol i-PrOH, in 1 mL DCE, at À258C
and with 10 mol% catalyst loading.
[b]
Determined by HPLC analysis.
the differences between the L1- and L3-catalyzed cy-
anation reactions. As demonstrated in Table 1, with
quinine L1 as catalyst, although the cyanation of keti-
mine 1a was carried out smoothly, the lower reaction
rate was shown. By contrast, with quinine-thiourea L3
as catalyst, the reaction need only 24 h. The different
reaction rate was caused by the difference of the
group at the quinine 9-position. In view of this point,
the extra H bond donation ability played an impor-
tant role in the activation of thiourea to ketimines.
Scheme 2. Scope of the enantioselective addition reaction.
In order to obtain the precursor of spirohydantoin
(A), several ketimines with allyl group at the 1-posi-
tion of isatin were synthesized. The result turned out
that N-allylketimines could also be efficiently applied
under the present reaction conditions. As shown in
À
À
Table 5, with CH2CH=CH2, and CH2CH=CH2C6H5
as the substituent groups the addition reaction was
carried out smoothly and gave the products in high
yields and excellent enantioselectivities, respectively
(entries 1 and 2, Table 5). To our delight, with keti-
mine 1r as the substrate, the reaction gave the precur-
sor of spirohydantoin (A) in 98% yield and 91% ee.
To explore the role of the thiourea and tertiary
amine in this cyanation reaction, we first compared Figure 2. Conditions for exploration of the mechanism,
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The Quinine Thiourea-Catalyzed Asymmetric Strecker Reaction
In the next step, we designed several reactions to was obtained in 60% yield. The above experiments
discover the role of tertiary amine. As presented in shown that the tertiary amine played a critical role in
Figure 2, taking cyanation of ketimine 1a with the activation of TMSCN.
TMSCN as the model reaction, quinine-thiourea L3
The absolute configuration of product 2m was as-
combined with 0.15 mmol benzoic acid was employed certained as (R) on the basis of an X-ray crystal struc-
as catalyst (conditions 1, Figure 2). Surprisingly, no ture analysis (Figure 3).[14] These data allowed us to
adduct was observed after 72 h even at room temper- propose a possible mechanism for the addition of
ature. This showed that the bonding of tertiary amine TMSCN to Boc-ketimines derived from N-methylisa-
with H+ made the catalyst L3 lose catalytic activity. tins. As shown in Figure 4, similar to the model sug-
To verify this result, L6, which has no alkali atoms in gested by Feng,[7e] the catalyst serves the dual function
the molecule was used as catalyst (conditions 2, of activating both reaction partners. The tertiary
Figure 2). However, the substrate ketimine was quan- amine of the catalyst promotes the formation of
titatively recovered after 72 h. For further verification HCN, and then, through coordination, holds it in
of the role of the tertiary amine, the combination of close proximity, while the thiourea moiety binds and
10 mol% L6 and 10 mol% DABCO was used as cata- activates the ketimine through hydrogen bonds. Fol-
lyst (conditions 3, Figure 2). The expected adduct 2a lowing an enantioselective addition of CN to ketimine
from the Re-face, the (R) configurated product was
obtained.
To further demonstrate the synthetic utility of the
present system, a gram-scale reaction was carried out.
As shown in Scheme 3, with 2 mmol 1a as the sub-
strate, similar to the 0.1 mmol scale, the addition reac-
tion gave the product 2a in 97% yield and 93% ee
under optimized conditions. The conversion of the
cyano group into amide and ester groups, respectively,
was explored next. As expected, the corresponding
Boc-amino amide 2ab and amino ester 2ac were read-
ily achieved without the loss of stereochemical purity.
Figure 3. Absolute configuration of 2m.
Figure 4. Proposed catalytic cycle for the Strecker reaction of ketimines.
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Scheme 3. Demonstration of the synthetic utility.
135.3, 130.5, 124.4, 123.5, 119.3, 118.5, 110.2, 83.5, 42.5, 28.0;
IR (KBr): u=3434, 2980, 2933, 1740, 1722, 1681, 1613, 1469,
1371, 1350, 1249, 1164, 1146, 1097, 938, 763 cmÀ1; HR-MS:
m/z=309.1209, calcd. for C16H18N2NaO3 [M+Na]+:
309.1210.
Conclusions
In conclusion, we have developed a highly practical
method for the asymmetric synthesis of 3-amino-3-ca-
nooxindoles through the addition of TMSCN to
isatin-derived N-Boc-ketimines with the catalysis of
quinine-thiourea. In addition, a variety of ketimines
bearing electron-withdrawing and electron-donating
substituents at different positions on the aromatic
ring were tested. The reactions provided the expected
products with good yields and enantioselectivities.
(E)-tert-Butyl (1-cinnamyl-2-oxoindolin-3-ylidene)carba-
mate (1q): Ketimine 1q was obtained as a yellow solid;
yield: 91%; mp 130–1328C.1H NMR (300 MHz, CDCl3): d=
7.67 (d, J=7.0 Hz, 1H), 7.45 (t, J=7.4 Hz, 1H), 7.36–7.25
(m, 5H), 7.09 (t, J=7.3 Hz, 1H), 6.90 (d, J=7.8 Hz, 1H),
6.64 (d, J=15.9 Hz, 1H), 6.16 (dt, J=15.9, 6.0 Hz, 1H), 4.50
(d, J=5.2 Hz, 2H), 1.64 (s, 9H); 13C NMR (75 MHz,
CDCl3): d=160.5, 157.0, 153.1, 147.4, 135.8, 135.4, 133.8,
128.7, 128.2, 126.5, 124.4, 123.5, 121.7, 119.4, 110.2, 83.6,
42.1, 28.1; IR (KBr): u=3432, 2985, 2935, 2361, 1740, 1719,
1680, 1618, 1470, 1348, 1251, 1154, 1098, 970, 750 cmÀ1; HR-
MS: m/z=385.1523, calcd. for C22H22N2NaO3 [M+Na]+:
385.1523.
Experimental Section
General
(E)-tert-Butyl {1-[(E)-3-(3,4-dichlorophenyl)allyl]-2-oxo-
indolin-3-ylidene}carbamate (1r): Ketimine 1r was obtained
as a yellow solid; yield: 94%; mp 80–828C. 1H NMR
(300 MHz, CDCl3); d=7.69 (d, J=7.1 Hz, 1H), 7.47 (td, J=
7.8, 1.1 Hz, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.37 (d, J=8.3 Hz,
1H), 7.18–7.09 (m, 2H), 6.87 (d, J=7.9 Hz, 1H), 6.53 (d, J=
16.0 Hz, 1H), 6.18 (dt, J=16.0, 5.8 Hz, 1H), 4.49 (d, J=
4.9 Hz, 2H), 1.64 (s, 9H); 13C NMR (75 MHz, CDCl3): d=
160.4, 157.0, 152.9, 147.1, 135.9, 135.4, 132.8, 131.8, 131.2
130.6, 128.2, 125.6, 124.6, 123.9 123.7 119.4, 109.9, 83.7 41.8,
28.0; IR (KBr): u=3436, 2980, 1738, 1350, 1253, 1151, 1100,
All commercially available reagents were used without fur-
ther purification unless otherwise stated. Reactions were
monitored by thin layer chromatography (TLC), column
chromatography purifications were carried out using silica
gel. Proton nuclear magnetic resonance (1H NMR) spectra
were recorded on a 300 MHz spectrometer in CDCl3 and
carbon nuclear magnetic resonance (13C NMR) spectra were
recorded on a 75 MHz spectrometer in CDCl3 using tetra-
methylsilane (TMS) as internal standard. Data are present-
ed as follows: chemical shift, integration, multiplicity (s=
singlet, d=doublet, dd=doublet of doublets, t=triplet, m=
multiplet) and coupling constant in Hertz (Hz). Dichlorome-
thane and 1,2-dichloroethane was freshly distilled from
CaH2 before use; other solvents (THF, Et2O, 1,4-dioxane, t-
BuOMe and toluene) were freshly distilled from sodium.
The thiourea catalysts were prepared according to the litera-
ture procedures.[10b][15]
965, 752 cmÀ1
;
HR-MS: m/z=453.0739, calcd. for
C22H20Cl2N2NaO3 [M+Na]+: 453.0743.
General Procedure for the Strecker Reaction of
TMSCN with N-Boc-ketimines
In a 5-mL vial, N-Boc-ketimine (0.1 mmol) and quinine-de-
rived thiourea catalyst L3 5.9 mg (0.01 mmol, 10 mol%)
were placed. After an injection of 1,2-dichloroethane
(1 mL), the reaction mixture was cooled to À258C, then,
20 mL (0.15 mmol) TMSCN were added, followed by the ad-
dition of 11.5 mL i-PrOH. After that the mixture was stirred
until complete disappearance of the ketimine. The mixture
was purified by flash chromatography (silica gel, hexane/
ethyl acetate) and afforded the resulting products as de-
scribed below.
General Procedure for the Synthesis of N-Boc-
ketimines
The synthesis of N-Boc-ktimines was performed according
to the literature procedure.[10b] Characterization data of
three new substrates are presented as below.
(E)-tert-Butyl (1-allyl-2-oxoindolin-3-ylidene)carbamate
(1p): Ketimine 1p was obtained as a yellow solid; yield:
1
92%; mp 80–828C. H NMR (300 MHz, CDCl3): d=7.66 (d,
J=6.9 Hz, 1H), 7.46 (td, J=7.8, 1.0 Hz, 1H), 7.09 (t, J=
7.5 Hz, 1H), 6.84 (d, J=7.9 Hz, 1H), 5.89–5.76 (m, 1H),
5.33–5.26 (m, 2H), 4.33 (d, J=4.0 Hz, 2H), 1.63 (s, 9H);
13C NMR (75 MHz, CDCl3): d=160.5, 156.9, 153.1, 147.4,
(R)-tert-Butyl (3-cyano-1-methyl-2-oxoindolin-3-yl)carba-
mate (2a): According to the general procedure, compound
2a was obtained as a pale yellow solid; yield: 27.6 mg
(96%); mp 176–1778C. 93%. The ee was determined by
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The Quinine Thiourea-Catalyzed Asymmetric Strecker Reaction
HPLC analysis (Daicel Chiralcel AD-H column, hexane/2-
propanol 60: 40, 1.0 mLminÀ1); retention times: tmajor =10.4
and tminor =14.2 min. [a]2D6: +68 (c 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): d=7.84 (d, J=7.5 Hz, 1H), 7.44 (td, J=
7.8, 1.2 Hz, 1H), 7.19 (td, J=7.5, 0.9 Hz, 1H), 6.91 (d, J=
7.8 Hz, 1H), 5.62 (s, 1H), 3.29 (s, 3H), 1.41 (s, 9H);
13C NMR (75 MHz, CDCl3) d=167.9, 153.6, 143.0, 131.4,
126.2, 124.7, 124.3, 114.6, 109.3, 82.3, 54.6, 28.1, 27.3; IR
(KBr): u=3315, 2978, 2927, 2247, 1742, 1719, 1612, 1492,
1473, 1369, 1255, 1160, 755 cmÀ1; HR-MS (ESI): m/z=
310.1164, calcd. for C15H17N3NaO3 [M+Na]+: 310.1168.
(S)-tert-Butyl (3-cyano-1-methyl-2-oxoindolin-3-yl)carba-
mate (2a’): According to the general procedure, except for
using L4 as the catalyst, compound 2a’ was obtained as
a pale yellow solid; yield: 27.0 mg (94%); mp 157–1588C.
93% ee was determined by HPLC analysis (Daicel Chiralcel
AD-H column, hexane/2-propanol 60: 40, 1.0 mLminÀ1): re-
tention times: tmajor =10.5 and tminor =14.4 min. [a]2D6: À66 (c
1.0, CHCl3). 1H NMR (300 MHz, CDCl3): d=7.83 (d, J=
7.4 Hz, 1H), 7.44 (td, J=7.8, 1.3 Hz, 1H), 7.18 (td, J=7.7,
1.0 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 5.62 (s, 1H), 3.29 (s,
3H), 1.41 (s, 9H); 13C NMR (75 MHz, CDCl3): d=167.9,
153.6, 143.0, 131.4, 126.2, 124.7, 124.3, 114.6, 109.3, 82.3,
54.6, 28.1, 27.3; IR (KBr): u=3310, 2977, 2928, 2247, 1741,
1719, 1612, 1492, 1473, 1369, 1254, 1159, 755 cmÀ1; HR-MS
(ESI): m/z=310.1163, calcd. for C15H17N3NaO3 [M+Na]+:
310.1162.
8.73 (s, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.35 (td, J=7.8,
1.2 Hz, 1H), 7.15 (td, J=7.7, 0.9 Hz, 1H), 6.91 (d, J=
7.8 Hz, 1H), 5.91 (s, 1H), 1.42 (s, 9H); 13C NMR (75 MHz,
CDCl3): d=169.6, 153.6, 140.3, 131.4, 125.9, 125.0, 124.2,
114.3, 111.2, 82.7, 55.0, 28.1; IR (KBr): u=3289, 2979, 2928,
2249, 1746, 1620, 1474, 1369, 1254, 1158, 753 cmÀ1; HR-MS
(ESI): m/z=296.1006, calcd. for C14H15N3NaO3 [M+Na]+:
296.1006.
(R)-tert-Butyl (4-chloro-3-cyano-1-methyl-2-oxoindolin-3-
yl)carbamate (2b): According to the general procedure com-
pound 2b was obtained as a white solid; yield: 31.2 mg
(97%); mp 194–1958C. 62% ee was determined by HPLC
analysis (Daicel Chiralcel AD-H column, hexane/2-propanol
80: 20, 1.0 mLminÀ1): retention times: tmajor =22.0 and tminor
=
19.6 min. [a]26: +38 (c 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): d=7D.38 (t, J=8.1 Hz, 1H), 7.10 (dd, J=8.3, 0.5 Hz,
1H), 6.82 (dd, J=7.9, 0.5 Hz, 1H), 5.89 (s, 1H), 3.30 (s,
3H), 1.32 (s, 9H); 13C NMR (75 MHz, CDCl3) d=167.1,
152.4, 145.2, 132.4, 131.2, 124.4, 120.3, 112.8, 107.7, 82.3,
54.9, 28.0, 27.6; IR (KBr): u=3307, 2979, 2927, 2249, 1751,
1707, 1607, 1459, 1290, 1122, 1033, 764 cmÀ1. HR-MS (ESI):
m/z=344.0778, calcd. for C15H16ClN3NaO3 [M+Na]+:
344.0778.
(R)-tert-Butyl (4-bromo-3-cyano-1-methyl-2-oxoindolin-3-
yl)carbamate (2c): According to the general procedure com-
pound 2c was obtained as a yellow solid; yield: 28.6 mg
(78%); mp 211–2128C. 60% ee was determined by HPLC
analysis (Daicel Chiralcel AD-H column, hexane/2-propanol
(R)-tert-Butyl (1-benzyl-3-cyano-2-oxoindolin-3-yl)carba-
mate (3a): According to the general procedure, compound
3a was obtained as a yellow solid; yield: 35.6 mg (98%); mp
190–1928C. 93% ee was determined by HPLC analysis
(Daicel Chiralcel OD-H column, hexane/2-propanol 96: 4,
80: 20, 1.0 mLminÀ1): retention time: tmajor =27.0 and tminor
=
23.2 min. [a]2D6: +29 (c 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): d=7.34–7.25 (m, 2H), 6.86 (dd, J=7.2, 1.4 Hz,
1H), 5.92 (s, 1H), 3.30 (s, 3H), 1.32 (s, 9H); 13C NMR
(75 MHz, CDCl3): d=167.0, 152.3, 145.4, 132.6, 127.4, 122.0,
119.2, 112.7, 108.3, 82.3, 56.0, 28.0, 27.6; IR (KBr): u=3306,
2979, 2926, 2247, 1747, 1708, 1603, 1457, 1363, 1287, 1157,
1113, 1025, 781, 756 cmÀ1; HR-MS (ESI): m/z=388.0271,
calcd. for C15H16BrN3NaO3 [M+Na]+: 388.0273.
1.0 mLminÀ1); retention times:
tmajor =19.9 and tminor =
18.5 min. [a]26: +46 (c 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): d=7D.83 (d, J=7.5 Hz, 1H), 7.37–7.27 (m, 6H), 7.13
(td, J=7.7, 0.9 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 5.72 (s,
1H), 4.96 (s, 2H), 1.43 (s, 9H); 13C NMR (75 MHz, CDCl3)
d=168.3, 153.6, 142.2, 134.2, 131.2, 129.0, 128.1, 127.2, 126.3,
124.7, 124.3, 114.6, 110.3, 82.4, 54.8, 44.9, 28.1; IR (KBr): u=
3218, 2979, 2928, 2247, 1720, 1611, 1487, 1370, 1278, 1255,
1160, 754, 700 cmÀ1; HR-MS (ESI): m/z=386.1481, calcd.
for C21H21N3NaO3 [M+Na]+: 386.1481.
(R)-tert-Butyl (3-cyano-1-methyl-5-nitro-2-oxoindolin-3-
yl)carbamate (2d): According to the general procedure com-
pound 2d was obtained as a yellow solid; yield: 31.2 mg
(94%); mp 94–958C. 89% ee was determined by HPLC
analysis (Daicel Chiralcel AD-H column, hexane/2-propanol
(R)-tert-Butyl [3-cyano-1-(methoxymethyl)-2-oxoindolin-
3-yl]carbamate (4a): According to the general procedure
compound 4a was obtained as a pale yellow solid; yield:
27.9 mg (88%); mp 149–1518C. 91% ee was determined by
HPLC analysis (Daicel Chiralcel OD-H column, hexane/2-
propanol 95: 5, 1.0 mLminÀ1): retention times: tmajor =11.3
and tminor =14.6 min. [a]2D6: +62 (c 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): d=7.75 (d, J=7.5 Hz, 1H), 7.43 (td, J=
7.8, 1.2 Hz, 1H), 7.21 (td, J=7.7, 0.9 Hz, 1H), 7.11 (d, J=
7.9 Hz, 1H), 5.79 (s, 1H), 5.19 (s, 2H), 3.40 (s, 3H), 1.40 (s,
9H); 13C NMR (75 MHz, CDCl3): d=168.7, 153.3, 141.4,
131.5, 125.6, 124.7, 124.1, 114.5, 110.8, 82.4, 72.4, 56.8, 55.1,
28.1. IR (KBr): u=3220, 2979, 2932, 2248, 1752, 1719, 1612,
1487, 1368, 1343, 1282, 1252, 1160, 1097, 756 cmÀ1; HR-MS
(ESI): m/z=340.1272, calcd. for C16H19N3NaO4 [M+Na]+:
340.1273.
80: 20, 1.0 mLminÀ1); retention times:
t
t
major =12.4 and
minor =20.3 min. [a]2D6: +50 (c 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): d=8.62 (d, J=2.2 Hz, 1H), 8.42 (dd, J=
8.7, 2.3 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 5.85 (d, J=7.9 Hz,
1H), 3.39 (s, 3H), 1.42 (s, 9H); 13C NMR (75 MHz, CDCl3):
d=168.1, 153.2, 148.5, 144.4, 128.1, 125.2, 121.5, 113.3, 109.2,
83.2, 54.2, 28.1, 27.9; IR (KBr): u=3320, 2979, 2927, 2374,
1756, 1719, 1528, 1493, 1340, 1159, 756 cmÀ1; HR-MS (ESI):
m/z=355.1019, calcd. for C15H16N4NaO5 [M+Na]+:
355.1018.
(R)-tert-Butyl (5-bromo-3-cyano-1-methyl-2-oxoindolin-3-
yl)carbamate (2e): According to the general procedure com-
pound 2e was obtained as a pale yellow solid; yield: 35.9 mg
(98%); mp 175–1778C. 92% ee was determined by HPLC
analysis (Daicel Chiralcel AD-H column, hexane/2-propanol
80: 20, 1.0 mLminÀ1): retention times: tmajor =8.4 and tminor
=
(R)-tert-Butyl (3-cyano-2-oxoindolin-3-yl)carbamate (5a):
According to the general procedure compound 5a was ob-
tained as a yellow solid; yield: 26.0 mg (95%); mp 88–908C.
13.4 min. [a]26: +54 (c 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): d=7D.96 (s, 1H), 7.57 (dd, J=8.4, 2.0 Hz, 1H), 6.80
(d, J=8.4 Hz, 1H), 5.65 (s, 1H), 3.28 (s, 3H), 1.43 (s, 9H).
13C NMR (75 MHz, CDCl3): d=167.4, 153.5, 142.1, 134.3,
1
[a]2D6: +55 (c 1.0, CHCl3). H NMR (300 MHz, CDCl3): d=
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Dong Wang et al.
FULL PAPERS
129.4, 126.2, 116.8, 114.0, 110.8, 82.7, 54.4, 28.1, 27.5. IR
(KBr): u=3315, 2977, 2927, 2249, 1747, 1609, 1487, 1358,
1255, 1160, 759 cmÀ1; HR-MS (ESI): m/z=388.0271, calcd.
for C15H16BrN3NaO3 [M+Na]+: 388.0273.
(R)-tert-Butyl (6-bromo-3-cyano-1-methyl-2-oxoindolin-3-
yl)carbamate (2j): According to the general procedure com-
pound 2j was obtained as a yellow solid; yield: 35.9 mg
(98%); mp 90–918C. 93% ee was determined by HPLC
analysis (Daicel Chiralcel AD-H column, hexane/2-propanol
(R)-tert-Butyl (3-cyano-1,5-dimethyl-2-oxoindolin-3-yl)-
carbamate (2f): According to the general procedure com-
pound 2f was obtained as a yellow solid; yield: 29.5 mg
(98%); mp 204–2058C. 90% ee was determined by HPLC
analysis (Daicel Chiralcel OD-H column, hexane/2-propanol
80: 20, 1.0 mLminÀ1): retention times: tmajor =8.4 and tminor
=
11.7 min. [a]26: +59 (c 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): d=7D.69 (d, J=8.0 Hz, 1H), 7.32 (dd, J=8.1, 1.7 Hz,
1H), 7.07 (d, J=1.7 Hz, 1H), 5.65 (s, 1H), 3.28 (s, 3H), 1.42
(s, 9H); 13C NMR (75 MHz, CDCl3): d=167.8, 153.5, 144.3,
127.5, 127.2, 125.3, 123.4, 114.0, 112.9, 82.6, 54.3, 28.1, 27.5;
IR (KBr): u=3316, 2978, 2928, 2249, 1748, 1605, 1491, 1367,
1253, 1159, 759 cmÀ1; HR-MS (ESI): m/z=388.0272, calcd.
for C15H16BrN3NaO3 [M+Na]+: 388.0273.
80: 20, 1.0 mLminÀ1): retention times: tmajor =6.8 and tminor
=
6.2 min. [a]2D6: +75 (c 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): d=7.66 (s, 1H), 7.26–7.19 (m, 1H), 6.79 (d, J=
8.0 Hz, 1H), 5.57 (s, 1H), 3.26 (s, 3H), 2.37 (s, 3H), 1.44 (d,
J=9.6 Hz, 9H); 13C NMR (75 MHz, CDCl3): d=167.8,
153.6, 140.6, 134.2, 131.6, 126.8, 124.7, 114.7, 109.0, 82.2,
54.7, 28.1, 27.3, 21.1; IR (KBr): u=3313, 2955, 2925, 2246,
1741, 1720, 1610, 1501, 1364, 1253, 1162 cmÀ1; HR-MS
(ESI): m/z=324.1324, calcd. for C16H19N3NaO3 [M+Na]+:
324.1324.
(R)-tert-Butyl (3-cyano-7-fluoro-1-methyl-2-oxoindolin-3-
yl)carbamate (2k): According to the general procedure com-
pound 2k was obtained as a white solid; yield: 29.9 mg
(98%); mp 124–1258C. 91% ee was determined by HPLC
analysis (Daicel Chiralcel OD-H column, hexane/2-propanol
(R)-tert-Butyl (3-cyano-5-methoxy-1-methyl-2-oxoindolin-
3-yl)carbamate (2g): According to the general procedure
compound 2g was obtained as a white solid; yield: 29.5 mg
(93%); mp 158–1598C. 93% ee was determined by HPLC
analysis (Daicel Chiralcel AD-H column, hexane/2-propanol
90: 10, 1.0 mLminÀ1); retention times: tmajor =6.8 and tminor
=
7.7 min. [a]2D6: +63 (c 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): d=7.58 (d, J=7.0 Hz, 1H), 7.21–7.08 (m, 2H), 5.71
(s, 1H), 3.50 (d, J=2.8 Hz, 3H), 1.41 (s, 9H); 13C NMR
(75 MHz, CDCl3): d=167.6, 153.3, 149.4, 146.2, 130.0, 129.9,
127.0, 124.9, 124.8, 121.6, 119.5, 119.2, 114.1, 82.5, 54.6, 30.0,
29.9, 28.1; IR (KBr): u=3319, 2980, 2929, 2251, 1750, 1720,
1631, 1487, 1367, 1246, 1161, 758, 734 cmÀ1; HR-MS (ESI):
m/z=328.1074, calcd. for C15H16FN3NaO3 [M+Na]+:
328.1073.
80: 20, 1.0 mLminÀ1): retention times: tmajor =17.2 and tminor
=
14.1 min. [a]26: +67 (c 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): d=7D.49 (s, 1H), 6.96 (dd, J=8.6, 2.6 Hz, 1H), 6.82
(d, J=8.6 Hz, 1H), 5.64 (s, 1H), 3.82 (s, 3H), 3.26 (s, 3H),
1.43 (s, 9H); 13C NMR (75 MHz, CDCl3): d=167.6, 157.0,
153.7, 136.2, 125.8, 116.3, 114.6, 112.9, 109.9, 82.3, 56.0, 54.9,
28.1, 27.4; IR (KBr): u=3312, 2977, 2930, 2248, 1738, 1607,
1500, 1366, 1285, 1162, 756 cmÀ1. HR-MS (ESI): m/z=
340.1273, calcd. for C16H19N3NaO4 [M+Na]+: 340.1273.
(R)-tert-Butyl (7-chloro-3-cyano-1-methyl-2-oxoindolin-3-
yl)carbamate (2l): According to the general procedure com-
pound 2l was obtained as a yellow solid; yield: 31.5 mg
(98%); mp 153–1548C. 91% ee was determined by HPLC
analysis (Daicel Chiralcel OD-H column, hexane/2-propanol
(R)-tert-Butyl
[3-cyano-1-methyl-2-oxo-5-(trifluorome-
thoxy)indolin-3-yl]carbamate (2h): According to the general
procedure compound 2h was obtained as a pale yellow
solid; yield: 35.6 mg (96%); mp 133–1348C. 90% ee was de-
termined by HPLC analysis (Daicel Chiralcel AD-H
column, hexane/2-propanol 80: 20, 1.0 mLminÀ1): retention
times: tmajor =5.4 and tminor =8.3 min. [a]2D6: +55 (c 1.0,
90: 10, 1.0 mLminÀ1): retention times: tmajor =6.8 and tminor
=
7.9 min. [a]2D6: +85 (c 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): d=7.69 (d, J=7.3 Hz, 1H), 7.36 (dd, J=8.3, 1.2 Hz,
1H), 7.10 (dd, J=8.2, 7.6 Hz, 1H), 5.75 (s, 1H), 3.66 (s,
3H), 1.40 (s, 9H); 13C NMR (75 MHz, CDCl3): d=168.3,
153.3, 139.1, 133.6, 127.1, 124.9, 124.3, 116.6, 114.0, 82.6,
54.4, 31.0, 28.1; IR (KBr): u=3320, 2979, 2928, 2250, 1747,
1607, 1464, 1365, 1255, 1160, 1109, 759, 737 cmÀ1; HR-MS
(ESI): m/z=344.0777, calcd. for C15H16ClN3NaO3 [M+Na]+:
344.0778.
1
CHCl3). H NMR (300 MHz, CDCl3): d=7.78 (s, 1H), 7.33
(ddd, J=8.6, 2.4, 0.8 Hz, 1H), 6.93 (d, J=8.6 Hz, 1H), 5.71
(s, 1H), 3.31 (s, 3H), 1.43 (s, 9H); 13C NMR (75 MHz,
CDCl3): d=167.7, 145.6, 141.7, 125.9, 124.6, 122.1, 120.4,
118.7, 113.9, 110.0, 82.8, 54.5, 28.0, 27.5; IR (KBr): u=3314,
2980, 2928, 2250, 1748, 1721, 1621, 1498, 1368, 1258, 1218,
1165, 759 cmÀ1; HR-MS (ESI): m/z=394.0990, calcd. for
C16H16F3N3NaO4 [M+Na]+: 394.0991.
(R)-tert-Butyl (7-bromo-3-cyano-1-methyl-2-oxoindolin-3-
yl)carbamate (2m): According to the general procedure
compound 2m was obtained as a white solid; yield: 35.9 mg
(98%); mp 163–1648C. 91% ee was determined by HPLC
analysis (Daicel Chiralcel AD-H column, hexane/2-propanol
(R)-tert-Butyl (6-chloro-3-cyano-1-methyl-2-oxoindolin-3-
yl)carbamate (2i): According to the general procedure com-
pound 2i was obtained as a yellow solid; yield: 31.5 mg
(98%); mp 148–1508C. 94% ee was determined by HPLC
analysis (Daicel Chiralcel AD-H column, hexane/2-propanol
80: 20, 1.0 mLminÀ1): retention times: tmajor =7.6 and tminor
=
9.2 min. [a]2D6: +50 (c 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): d=7.73 (d, J=7.2 Hz, 1H), 7.54 (dd, J=8.2, 1.2 Hz,
1H), 7.03 (dd, J=8.1, 7.6 Hz, 1H), 5.77 (s, 1H), 3.67 (s,
3H), 1.39 (s, 9H); 13C NMR (75 MHz, CDCl3): d=168.5,
153.3, 140.5, 137.0, 127.4, 125.3, 124.8, 114.0, 103.3, 82.6,
54.3, 31.2, 28.1; IR (KBr): u=3320, 2956, 2927, 2250, 1747,
1606, 1459, 1365, 1255, 1160, 1105, 737 cmÀ1; HR-MS (ESI):
m/z=388.0273, calcd. for C15H16BrN3NaO3 [M+Na]+:
388.0273.
80: 20, 1.0 mLminÀ1): retention times: tmajor =9.5 and tminor
=
15.4 min. [a]26: +65 (c 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): d=7D.75 (d, J=8.1 Hz, 1H), 7.16 (dd, J=8.1, 1.9 Hz,
1H), 6.92 (d, J=1.8 Hz, 1H), 5.69 (s, 1H), 3.28 (s, 3H), 1.42
(s, 9H); 13C NMR (75 MHz, CDCl3): d=167.9, 153.5, 144.2,
137.4, 127.2, 124.2, 122.9, 114.1, 110.1, 82.6, 54.2, 28.1, 27.5;
IR (KBr): u=3318, 2979, 2928, 2249, 1747, 1720, 1610, 1493,
1368, 1253, 1160, 1073, 736 cmÀ1; HR-MS (ESI): m/z=
344.0777, calcd. for C15H16ClN3NaO3 [M+Na]+: 344.0778.
(R)-tert-Butyl (5-bromo-3-cyano-1,7-dimethyl-2-oxoindo-
lin-3-yl)carbamate (2n): According to the general procedure
compound 2n was obtained as a pale yellow solid; yield:
8
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
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The Quinine Thiourea-Catalyzed Asymmetric Strecker Reaction
36.5 mg (96%); mp 204–2058C. 86% ee was determined by
HPLC analysis (Daicel Chiralcel AD-H column, hexane/2-
propanol 80: 20, 1.0 mLminÀ1): retention times: tmajor =7.0
and tminor =10.0 min. [a]2D8: +52 (c=1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): d=7.75 (d, J=1.5 Hz, 1H), 7.32 (dd, J=
2.0, 0.6 Hz, 1H), 5.60 (s, 1H), 3.54 (s, 3H), 2.55 (s, 3H), 1.42
(s, 9H); 13C NMR (75 MHz, CDCl3): d=168.2, 153.3, 140.0,
137.5, 126.8, 126.7, 122.9, 116.5, 114.1, 82.6, 54.2, 30.9, 28.1,
18.8; IR (KBr): u=32316, 2957, 2926, 2250, 1740, 1720,
1602, 1463, 1342, 1257, 1161, 745 cmÀ1; HR-MS (ESI): m/z=
402.0432, calcd. for C16H18BrN3NaO3 [M+Na]+: 402.0424.
(R)-tert-Butyl (5,7-dibromo-3-cyano-1-methyl-2-oxoindo-
lin-3-yl)carbamate (2o): According to the general procedure
compound 2o was obtained as a white solid; yield: 43.2 mg
(97%); mp 205–2068C. 87% ee was determined by HPLC
analysis (Daicel Chiralcel OD-H column, hexane/2-propanol
by HPLC analysis (Daicel Chiralcel IA column, hexane/2-
propanol 60:40, 1.0 mLminÀ1): retention times: tmajor =6.8
and tminor =6.1 min. [a]2D3: +15 (c 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): d=7.79 (d, J=7.5 Hz, 1H), 7.43–7.34
(m, 3H), 7.19 (t, J=7.8 Hz, 2H), 6.91 (d, J=7.9 Hz, 1H),
6.60 (d, J=16.0 Hz, 1H), 6.20 (dt, J=16.0, 5.4 Hz, 1H), 5.78
(s, 1H), 4.55 (qd, J=16.6, 5.0 Hz, 2H), 1.43 (s, 9H);
13C NMR (75 MHz, CDCl3): d=167.9, 153.4, 142.1, 136.0,
132.7, 131.7, 131.4, 131.0, 130.5, 128.4, 125.9, 125.6, 124.6,
124.4, 123.1, 114.5, 109.9, 100.0, 82.4, 54.8, 42.7, 28.1; IR
(KBr): u=3318, 2957, 2926, 2853, 1741, 1718, 1612, 1471,
1369, 1279, 1255, 1160, 1026, 755 cmÀ1; HR-MS (ESI): m/z=
480.0860, calcd. for C23H21Cl2N3NaO3 [M+Na]+: 480.0852.
Synthesis of 2ab from 2a
95: 5, 1.0 mLminÀ1); retention times: tmajor =11.5 and tminor
=
In a 25-mL round-bottom flask, 143.5 mg 2a (0.5 mmol)
were placed. After an injection of 5 mL acetone, the mixture
was stirred for 10 min. Then, 1.5 mL aqueous solution of
Na2CO3 (1N, 3 equiv.) was added, followed by the addition
of 1.6 mL of H2O2 (30%, 27 equiv.). After that the mixture
was stirred for 2 h. After an evaporation of the volatile or-
ganic solvents, the resulting mixture was extracted with
CH2Cl2 (3ꢂ10 mL). The combined organic layers were dried
over Na2SO4. After filtration and evaporation of the solvent,
the crude residue was purified by flash chromatography
(silica gel, hexane/ethyl acetate), giving the product 2ab as
a white solid; yield: 128 mg (84%); mp 163–1648C. 93% ee,
as determined by HPLC analysis (Daicel Chiralcel AD-H
column, hexane/2-propanol 90:10, 1.0 mLminÀ1): retention
times: tmajor =28.5 and tminor =23.7 min. [a]2D6: À14 (c 1.0,
CHCl3). 1H NMR (300 MHz, CDCl3): d=7.38 (td, J=7.7,
1.2 Hz, 1H), 7.30 (d, J=7.4 Hz, 1H), 7.12 (t, J=7.5 Hz,
1H), 6.92 (d, J=7.8 Hz, 1H), 6.39 (s, 1H), 5.82 (s, 1H), 5.53
(s, 1H), 3.27 (s, 3H), 1.25 (s, 9H); 13C NMR (75 MHz,
CDCl3): d=172.6, 167.0, 153.5, 144.0, 130.2, 127.5, 123.7,
123.6, 109.0, 80.6, 66.1, 28.0, 27.0; IR (KBr): u=3385, 3326,
3195, 2958, 2926, 2291, 1718, 1695, 1617, 1471, 1367, 1250,
1164, 1125, 753 cmÀ1; HR-MS (ESI): m/z=328.1272, calcd.
for C15H19N3NaO4 [M+Na]+: 328.1268,.
13.5 min. [a]26: +59 (c 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): d=7D.83 (d, J=1.3 Hz, 1H), 7.71 (d, J=1.9 Hz, 1H),
5.77 (s, 1H), 3.65 (s, 3H), 1.42 (s, 9H); 13C NMR (75 MHz,
CDCl3): d 168.0, 153.2, 139.79, 138.9, 128.5, 127.9, 117.0,
113.5, 103.9, 83.0, 54.2, 31.2, 28.1; IR (KBr): u=3312, 2956,
2925, 2377, 1750, 1719, 1460, 1370, 1335, 1253, 1159, 1112,
759, 740 cmÀ1; HR-MS (ESI): m/z=465.9375, calcd. for
C15H15Br2N3NaO3 [M+Na]+: 465.9372.
(R)-tert-Butyl
(1-allyl-3-cyano-2-oxoindolin-3-yl)carba-
mate (2p): According to the general procedure compound
2p was obtained as a pale yellow solid; yield: 27.5 mg
(96%); mp 138–1408C. 91% ee was determined by HPLC
analysis (Daicel Chiralcel OJ-H column, hexane/2-propanol
90:10, 1.0 mLminÀ1): retention times: tmajor =10.1 and tminor
=
12.5 min. [a]23: +50 (c 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): d=7D.85 (d, J=7.5 Hz, 1H), 7.40 (td, J=7.8, 1.2 Hz,
1H), 7.17 (td, J=7.7, 0.8 Hz, 1H), 6.90 (d, J=7.9 Hz, 1H),
5.91–5.78 (m, 1H), 5.65 (s, 1H), 5.35–5.27 (m, 2H), 4.39 (d,
J=1.8 Hz, 2H), 1.43 (s, 10H); 13C NMR (75 MHz, CDCl3):
d 167.8, 153.6, 142.2, 131.2, 129.9, 126.3, 124.7, 124.2, 118.6,
114.6, 110.1, 82.3, 54.6, 43.4, 28.1; IR (KBr): u=3295, 2957,
2925, 1739, 1711, 1611, 1487, 1466, 1369, 1280, 1254, 1160,
1019, 755 cmÀ1; HR-MS (ESI): m/z=336.1321, calcd for
C17H19N3NaO3 [M+Na]+: 336.1319.
Synthesis of 2ac from 2a
ACHTUNGTRENNUNG(R,E)-tert-Butyl (1-cinnamyl-3-cyano-2-oxoindolin-3-yl)-
carbamate (2q): According to the general procedure com-
pound 2q was obtained as a colorless amorphous solid;
yield: 34.7 mg (96%); 92% ee was determined by HPLC
analysis (Daicel Chiralcel AD-H column, hexane/2-propanol
In a 25-mL round-bottom flask, 143.5 mg 2a (0.5 mmol)
were placed. After an injection of 5 mL absolute methanol,
the mixture was cooled to 08C. Then, dried HCl was bub-
bled slowly. This process lasted for 15 min. After that, the
resulting solution stirred at room temperature over ight.
After an evaporation of the volatile organic solvents, 5 mL
water were added followed by the addition of 2 mL saturat-
ed aqueous solution of NaHCO3. The resulting mixture was
extracted with CH2Cl2 (3ꢂ10 mL). The combined organic
layers were dried over Na2SO4. After filtration and evapora-
tion of the solvent, the crude residue was purified by flash
chromatography (silica gel, hexane/ethyl acetate), com-
pound 2ac was obtained as a yellow solid; yield: 103.5 mg
(94%); mp 109–1108C. 93% ee was determined by HPLC
analysis (Daicel Chiralcel AD-H column, hexane/2-propanol
90:10, 1.0 mLminÀ1): retention times: tmajor =23.0 and tminor
=
26.1 min. [a]23: +40 (c 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): d=7D.84 (d, J=7.5 Hz, 1H), 7.41–7.24 (m, 6H), 7.17
(t, J=7.6 Hz, 1H), 6.95 (d, J=7.9 Hz, 1H), 6.68 (d, J=
16.0 Hz, 1H), 6.18 (dt, J=15.9, 5.8 Hz, 1H), 5.69 (s, 1H),
4.54 (d, J=5.5 Hz, 2H), 1.43 (s, 9H); 13C NMR (75 MHz,
CDCl3): d 167.8, 153.6, 142.3, 135.8, 133.9, 131.3, 128.6,
128.2, 126.6, 126.3, 124.7, 124.3, 121.1, 114.6, 110.2, 82.4,
54.7, 43.1, 28.1; IR (KBr): u=3408, 3311, 2958, 2925, 1744,
1711, 1611, 1487, 1467, 1364, 1281, 1223, 1162, 1018,
755,531 cmÀ1
C23H23N3NaO3 [M+Na]+: 412.1632.
(R,E)-tert-Butyl {3-cyano-1-[3-(3,4-dichlorophenyl)allyl]-
; HR-MS (ESI): m/z=412.1637, calcd. for
60: 40, 1.0 mLminÀ1): retention times: tmajor =8.9 and tminor
=
10.5 min. [a]2D6: À122 (c 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): d=7.37 (td, J=7.8, 1.2 Hz, 1H), 7.30 (dd, J=7.4,
0.7 Hz, 1H), 7.09 (td, J=7.6, 0.9 Hz, 1H), 6.89 (d, J=
7.8 Hz, 1H), 3.68 (s, 3H), 3.25 (s, 3H), 2.28 (s, 2H);
ACHTUNGTRENNUNG
2-oxoindolin-3-yl}carbamate (2r): According to the general
procedure compound 2r was obtained as a colorless amor-
phous solid; yield: 42.1 mg (98%). 91% ee was determined
Adv. Synth. Catal. 0000, 000, 0 – 0
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Dong Wang et al.
FULL PAPERS
13C NMR (75 MHz, CDCl3): d=174.7, 170.7, 144.2, 130.1,
128.9, 123.29, 123.26, 108.8, 65.2, 53.3, 26.7; IR (KBr): u=
3372, 3304, 2955, 2926, 1749, 1720, 1612, 1494, 1470, 1374,
1242, 1126, 1083, 1001, 755 cmÀ1; HR-MS (ESI): m/z=
243.0746, calcd. for C11H12N2NaO3 [M+Na]+: 243.0746.
[3] For reviews, see: a) A. B. Dounay, L. E. Overman,
Chem. Rev. 2003, 103, 2945–2963; b) C. V. Galliford,
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5165–5181.
Synthesis of 5ab from 5a
In a 5-mL round-bottom flask, 10 mg NaH (0.25 mmol, 60%
in mineral oil, 2.5 equiv.) were placed, after an injection of
0.5 mL THF, the mixture was cooled to 08C, 26 mg com-
pound 5a in 1 mL THF were dropwise added. The resulting
solution was stirred 15 min, and 20 mL MOMCl were added.
After that, the resulting solution stirred at room tempera-
ture overnight. Then, the solution was neutralized by the ad-
dition of a saturated aqueous solution of NH4Cl and then
the volatile organic solvents were removed under vacuum.
The aqueous layer was extracted with CH2Cl2 (3ꢂ10 mL).
The organic layer obtained was dried over Na2SO4, filtered
and concentrated under reduced pressure. The crude residue
was purified by flash chromatography (silica gel, hexane/
ethyl acetate), compound 5ab was obtained as a colorless
oil; yield: 23 mg (64%). 90% ee was determined by HPLC
analysis (Daicel Chiralcel OD-H column, hexane/2-propanol
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Strecker reaction, see: a) R. P. Herrera, V. Sgarzani, L.
Bernardi, F. Fini, D. Pettersen, A. Ricci, J. Org. Chem.
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95: 5, 1.0 mLminÀ1): retention times: tmajor =7.3 and tminor
=
8.3 min. [a]2D6: À5 (c 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): d=7.53 (d, J=7.5 Hz, 1H), 7.42 (td, J=7.8, 1.2 Hz,
1H), 7.18 (t, J=7.3 Hz, 1H), 7.10 (d, J=7.9 Hz, 1H), 5.31
(d, J=11.1 Hz, 1H), 5.24 (d, J=11.0 Hz, 1H), 5.13 (s, 1H),
5.05 (d, J=11.1 Hz, 1H), 3.48 (s, 3H), 3.43 (s, 3H), 1.26 (s,
9H); 13C NMR (75 MHz, CDCl3): d=168.9, 152.2, 141.6,
135.8, 131.0, 124.4, 124.3, 113.7, 110.4, 83.4, 78.6, 72.5, 60.6,
56.8, 56.0, 27.8; IR (KBr): u=3288, 2955, 2925, 1752, 1711,
1610, 1465, 1369, 1298, 1154, 1095, 757 cmÀ1; HR-MS (ESI):
m/z=384.1530, calcd. for C18H23N3NaO5 [M+Na]+:
384.1530.
Acknowledgements
We are grateful for the grants from the National Natural Sci-
ence Foundation of China (nos. 20932003. 91213302,
21272102, 21272108, 31200584), the Key National S&T Pro-
gram “Major New Drug Development” of the Ministry of
Science and Technology of China (2012ZX09504001-003).
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12 The Quinine Thiourea-Catalyzed Asymmetric Strecker
Reaction: An Approach for the Synthesis of 3-
Aminooxindoles
Adv. Synth. Catal. 2013, 355, 1 – 12
Dong Wang, Jinyan Liang, Jingchao Feng, Kairong Wang,
Quantao Sun, Long Zhao, Dan Li, Wenjin Yan,* Rui Wang*
12
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