Enantioselective squaramide-catalysed domino mannich-cyclization reaction of isatin imines

Article abstract of DOI:10.1002/ejoc.201301350

An enantioselective domino reaction of 4-bromo-3-oxobutanoates with isatin-derived ketimines was developed to construct 3-amino-2-oxindoles with a quaternary stereocentre. In the presence of 1 mol-% of a bifunctional squaramide or-ganocatalyst, the desired products were achieved in high yields (90-97%) and with excellent enantioselectivities (92-99% ee).

Full text of DOI:10.1002/ejoc.201301350

FULL PAPER
DOI: 10.1002/ejoc.201301350
Enantioselective Squaramide-Catalysed Domino Mannich–Cyclization Reaction
of Isatin Imines
Xi-Bo Wang,[a] Tian-Ze Li,[a] Feng Sha,*[a] and Xin-Yan Wu*[a]
Keywords: Organocatalysis / Asymmetric catalysis / Domino reactions / Nucleophilic addition / Oxygen heterocycles /
Cyclization
An enantioselective domino reaction of 4-bromo-3-oxobut-
anoates with isatin-derived ketimines was developed to con-
struct 3-amino-2-oxindoles with a quaternary stereocentre.
In the presence of 1 mol-% of a bifunctional squaramide or-
ganocatalyst, the desired products were achieved in high
yields (90–97%) and with excellent enantioselectivities (92–
99% ee).
rived ketimines with 4-bromo-3-oxobutanoates[9] catalysed
by tertiary-amine-based chiral bifunctional organocata-
lysts.[10]
Introduction
The enantioselective addition of carbon nucleophiles to
the C=N double bond of imines is one of the most direct
methods to prepare optically active nitrogen-containing
compounds. Due to the strategic importance of chiral
amines and their derivatives in organic synthesis, tremen-
dous efforts have been put into the development of catalytic
asymmetric addition reactions of imines over the past dec-
ades.[1] Although great progress has been made in the ad-
dition reactions of aldimines (imines derived from alde-
hydes), the use of ketimines (imines derived from ketones)
as electrophiles, which would lead to the enantioselective
construction of quaternary stereocentres, remains challeng-
ing.[2,3] The reaction of isatin-derived ketimines has recently
been the subject of great interest in the field of asymmetric
catalysis.[4,5]
The reaction of isatin-derived ketimines as electrophiles
gives a very straightforward approach to 3-substituted 3-
amino-2-oxindoles,[6] which are privileged structural motifs
that are found in many biologically active compounds and
drug candidates.[7] Several catalytic asymmetric addition re-
actions of isatin-derived ketimines, including Mannich reac-
tions,[5a–5c] Strecker reactions,[5d–5f] and several other reac-
tions,[5g–5k] have been reported. However, to the best of our
knowledge, the asymmetric domino reaction of isatin-de-
rived ketimines has only rarely been reported in the litera-
ture.[5i–5k] As part of our ongoing interest in the asymmetric
synthesis of 3,3-disubstituted 2-oxindoles by the addition of
carbon nucleophiles to isatin derivatives,[8] in this paper, we
report the enantioselective domino reaction of isatin-de-
Results and Discussion
We initially evaluated cinchona alkaloids catalysts for the
domino reaction between isatin-derived N-Boc ketamine 1a
(Boc = tert-butyloxycarbonyl) and ethyl 4-bromoacetoacet-
ate (2a). The reactions were carried out in toluene with
NaHCO3 as a scavenger of HBr at 25 °C for 3 d, and the
results are summarized in Table 1. Cinchonine and quin-
idine gave the desired product (i.e., 3a) with enantio-
selectivities higher than those seen with cinchonidine and
quinine (Table 1, entries 1–4). However, cinchonine and cin-
chonidine had better catalytic activities than quinine and
quinidine. The use of O-benzyl cinchonine derivative C1 re-
sulted in a poor conversion rate and negligible enantio-
selectivity (Figure 1; Table 1, entry 5), indicating that the
presence of hydrogen-bond donors might be essential for
this domino reaction. To improve the enantioselectivity of
the reaction, we used tertiary-amine–thiourea and squar-
amide catalysts with a cinchona alkaloid scaffold.[11,12]
Quinine-derived thiourea C2 gave similar results to quinine
(Table 1, cf. entries 6 and 3). Although excellent enantio-
selectivity was achieved with bifunctional squaramides C3
and C4 as catalysts, the yields of the reactions were unsatis-
factory. Takemoto catalyst C5 hardly catalysed the domino
reaction (Table 1, entry 9).
In most of the cases described above (Table 1, entries 3–
8), the low yields might have resulted from the low conver-
sion rate of the substrates and/or the Mannich adducts.
Fortunately, when Na2CO3 was used as the base, the dom-
ino Mannich/cyclization reaction gave excellent yields with
both catalysts C3 and C4 (Table 1, entries 10 and 11). The
catalyst loading of C4 could be reduced to 5 mol-%, and
[a] Key Laboratory for Advanced Materials and Institute of Fine
Chemicals, East China University of Science and Technology,
Shanghai 200237, P. R. China
E-mail: xinyanwu@ecust.edu.cn
http://hyxy.ecust.edu.cn/new/en/prof.php?id = 39
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301350.
Eur. J. Org. Chem. 2014, 739–744
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
739

X.-B. Wang, T.-Z. Li, F. Sha, X.-Y. Wu
FULL PAPER
Table 1. Screening of the chiral organocatalysts.[a]
Next, the solvent effect was investigated using C4 (5 mol-
%) as catalyst and Na2CO3 (0.5 equiv.) as base (Table 2).
The domino reaction did not take place in n-hexane due to
Table 2. Optimization of the reaction conditions.[a]
Entry Catalyst
Base
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
cinconine
cinchonidine
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
Na2CO3
Na2CO3
Na2CO3
Et3N
72
70
42
37
23
37
32
29
trace
87
76
–55
–59
75
4
78
–95
98
n.d.
–91
96
97
4
quinine
quinidine
C1
C4
[mol-%]
Na2CO3 Time
Yield
[%][b]
ee
Entry Solvent
[equiv.]
[d]
[%][c]
C2
C3
1
2
3
4
5
6
7
8
n-hexane
CH2Cl2
CH3Cl
CCl4
ClCH2CH2Cl
THF
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
5
5
5
5
5
5
5
5
3
2
1
0.5
1
1
1
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
3
3
3
3
3
3
3
2
2
2
2
2
2
1
2
2
trace
80
68
75
65
79
93
98
96
95
92
81
70
97
82
93
–
C4
98
98
96
98
47
63
98
98
98
98
95
98
97
98
97
9
C5
10[d]
11[d]
12[d,e]
13
C3
C4
96
82
98
C4
C4
[a] Unless stated otherwise, the domino reactions were carried out
with 1a (0.15 mmol), 2a (1.5 equiv.), base (1.0 equiv.), and catalyst
(0.015 mmol) in toluene (1.0 mL) at 25 °C for 3 d. [b] Isolated yield.
[c] The ee values were determined by chiral HPLC analysis.
[d] Using 0.5 equiv. of base. [e] Using 5 mol-% of catalyst.
9
10
11
12
13[d] CH2Cl2
14[e]
15[f]
CH2Cl2
CH2Cl2
16[g] CH2Cl2
1
under these conditions, the desired product was formed in
82% yield with 97% ee (Table 1, entry 12). Although the
addition of Et3N as the base promoted the domino reaction
to give the product in excellent yield, the enantioselectivity
of this reaction was poor, probably due to a background
reaction (Table 1, entry 13).
[a] Unless stated otherwise, the domino reactions were carried out
with 1a (0.15 mmol), 2a (1.5 equiv.) and catalyst C4 (0.015 mmol),
in solvent (1.0 mL) at 25 °C. [b] Isolated yield. [c] The ee values
were determined by chiral HPLC analysis. [d] The reactions were
carried out at 0 °C. [e] The reactions were carried out at 40 °C.
[f] The amount of solvent was 1.5 mL. [g] The amount of solvent
was 0.75 mL.
Figure 1. Structures of the organocatalysts screened.
740
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 739–744

Domino Mannich–Cyclization Reaction of Isatin Imines
the poor solubility of 1a (Table 2, entry 1). Alkyl halides Table 3. Substrate scope of the domino reaction.[a]
such as CH2Cl2, CH3Cl, CCl4, and ClCH2CH2Cl led to ex-
cellent enantioselectivities but moderate yields (96–98% ee,
65–80% yield; Table 2, entries 2–5). The reaction in THF
gave a moderate yield and a low enantioselectivity (Table 2,
entry 6). In the cases described above, the Mannich adduct
could be detected by TLC analysis. Although the use of
CH3CN as solvent resulted in an excellent yield, the
enantioselectivity was low (Table 2, entry 7).
To accelerate the intramolecular cyclization step, the
amount of Na2CO3 was tentatively increased to 1.0 equiv.,
and this did indeed result in a shorter reaction time with a
comparably excellent yield and selectivity (Table 2, cf. en-
Entry R1
R2
R3
Product Yield [%][b] ee [%][c]
tries 8 and 2). When the catalyst loading was decreased to
1 mol-% (Table 2, entries 8–12), the domino reaction still
proceeded with excellent results (92% yield and 98% ee;
Table 2, entry 11). The reaction temperature (Table 2, en-
tries 13 and 14) and the substrate concentration (Table 2,
entries 15 and 16) both influenced the yield but not the
enantioselectivity of the model reaction.
Under the optimal reaction conditions [C4 (1 mol-%)
and Na2CO3 (1.0 equiv.) in CH2Cl2 at 25 °C], we examined 10
the substrate scope of the reaction with various 4-bromo-
acetoacetates and isatin-derived ketimines (Table 3). The re-
1
2
3
4
5
6
7
8
9
H
H
H
H
5-Me
5-MeO
5-Cl
5-Br
6-Cl
6-Br
7-Me
7-F
Me
Me
Me
Ph
Et
Me
Bn
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
92
91
90
93
93
97
96
97
96
96
95
97
97
97
97
98
99
98
98
97
95
92
95
94
95
98
95
95
98
95
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
11
12
13
14
7-Cl
7-Br
7-CF3
sults indicated that methyl, ethyl, and n-butyl 4-bromo-
acetoacetates gave similarly good yields and enantio-
selectivities (Table 3, entries 1–3). The 1-phenyl ketimine de-
rived from isatin also gave excellent yields and enantio-
selectivities (Table 3, entry 4). Irrespective of the electronic
andstericproperties,thesubstituentsonthephenylgroupofthe
isatin-derived ketimines had a minimal effect on the reac-
tion (Table 3, entries 5–15). Ketimines containing either
electron-withdrawing or electron-donating groups at the
5-, 6-, or 7-position gave high yields (93–97%) and excellent
enantioselectivities (92–98% ee). The absolute configura-
tion of product 3j was determined to be R by X-ray analysis
(Figure 2, Table S1), and the configurations of the other
products were tentatively assigned by comparing with 3j.
15
[a] The reactions were carried out with
1 (0.15 mmol), 2
(1.5 equiv.), Na2CO3 (1.0 equiv.), and catalyst C4 (0.0015 mmol) in
CH2Cl2 (1 mL) at 25 °C. [b] Isolated yield. [c] The ee values were
determined by chiral HPLC analysis.
Conclusions
In conclusion, we have developed a highly efficient dom-
ino reaction of 4-bromo-3-oxobutanoates with isatin-de-
rived N-Boc ketimines. With only 1 mol-% of a bifunctional
squaramide catalyst, 3-substituted-3-amino-2-oxindoles
were formed in excellent yields and with excellent enantio-
selectivities. A wide range of substituted ketimines and 4-
bromo-3-oxobutanoates were tolerated.
Experimental Section
General Methods: Optical rotations were measured with a WZZ-
2A digital polarimeter at the wavelength of the sodium D line
1
(589 nm). H and 13C NMR spectra were recorded with a Bruker
400 spectrometer using CDCl3 as solvent. Chemical shifts were ref-
erenced to tetramethylsilane (δ = 0.00 ppm). IR spectra were re-
corded with a Nicolet Magna-I 550 spectrometer. High Resolution
Mass spectra (HRMS) were recorded with a Micromass GCT in-
strument using the Electrospray Ionization (ESI) technique. HPLC
analysis was carried out with a Waters instrument using a Chi-
ralpak AD-H or Chiralcel OD-H column.
THF was freshly distilled from sodium–benzophenone. CH2Cl2,
CH3Cl, CCl4, ClCH2CH2Cl, and CH3CN were freshly distilled
from CaH2. Thin-layer chromatography (TLC) was carried out on
10–40 μm silica gel plates. Column chromatography was carried out
using silica gel (300–400 mesh), eluting with ethyl acetate and
CH2Cl2. The isatin-derived N-Boc ketimines were synthesized ac-
Figure 2. X-ray crystal structure of product 3j.
Eur. J. Org. Chem. 2014, 739–744
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
741

X.-B. Wang, T.-Z. Li, F. Sha, X.-Y. Wu
FULL PAPER
cording to literature procedures.[5b] 4-Bromoacetoacetates were
synthesized from the corresponding acetoacetates.[13] Catalysts C1–
C5 were prepared according to literature procedures.[14]
7.34 (m, 2 H), 7.18 (t, J = 7.2 Hz, 1 H), 7.04 (t, J = 7.2 Hz, 1 H),
6.80 (s, 1 H), 4.63 (d, J = 16.0 Hz, 1 H), 4.58 (d, J = 16.0 Hz, 1
H), 4.34–4.26 (m, 2 H), 1.35 (s, 9 H), 1.16 (t, J = 6.4 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 194.54, 179.45, 173.76, 153.96,
135.02, 129.37, 128.59, 127.73, 126.53, 123.16, 123.08, 108.96,
91.17, 79.72, 77.20, 74.86, 67.32, 59.54, 28.22, 14.41 ppm. IR
Typical Procedure for the Enantioselective Domino Reaction:
The 4-bromoacetoacetate (0.225 mmol) was added to a solution of
catalyst C4 (0.0015 mmol, 0.9 mg), isatin-derived N-Boc ketimine
(0.15 mmol), and Na2CO3 (0.15 mmol, 16.0 mg) in CH2Cl2
(1.0 mL) at 25 °C. The resulting mixture was stirred at this tem-
perature (monitored by TLC), and then it was concentrated under
reduced pressure. The residue was purified by flash column
chromatography on silica gel to give the desired product (i.e., 3).
The ee value was determined by HPLC analysis with a chiralpak
AD-H or chiralcel OD-H column.
(KBr): ν = 3414, 2979, 1740, 1716, 1596, 1499, 1172, 1017, 914,
˜
756, 625 cm–1. HRMS (ESI): calcd. for C25H26N2NaO6 [M +
Na]+ 473.1689; found 473.1709. HPLC analysis (OD-H column; λ
= 254 nm; n-hexane/i-PrOH, 90:10; flow rate = 0.9 mL/min): tR
=
36.37 min (minor), 39.45 min (major).
tert-Butyl
(R)-[3-(2-Ethoxy-4-oxo-4,5-dihydrofuran-3-yl)-1,5-di-
methyl-2-oxoindolin-3-yl]carbamate (3e): White solid, 93% yield,
1
97% ee, m.p. 183.1–183.9 °C. [α]2D0 = –120.3 (c = 0.16, CHCl3). H
tert-Butyl (R)-[3-(2-Ethoxy-4-oxo-4,5-dihydrofuran-3-yl)-1-methyl-
2-oxoindolin-3-yl]carbamate (3a): White solid, 92% yield, 98% ee,
m.p. 169.8–170.0 °C. [α]2D0 = –136.2 (c = 0.21, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 8.19 (br. s, 1 H), 7.28–7.24 (m, 2 H), 7.01
(t, J = 7.2 Hz, 1 H), 6.79 (d, J = 8.0 Hz, 1 H), 4.60 (d, J = 16.0 Hz,
1 H), 4.54 (d, J = 16.0 Hz, 1 H), 4.30–4.18 (m, 2 H), 3.26 (s, 3 H),
1.33 (s, 9 H), 1.18 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 194.38, 179.52, 174.90, 153.76, 143.19, 128.73, 122.72,
122.54, 107.18, 91.22, 79.55, 77.20, 74.78, 66.92, 59.33, 28.15,
NMR (400 MHz, CDCl3): δ = 8.12 (br. s, 1 H), 7.10 (s, 1 H), 7.05
(d, J = 7.6 Hz, 1 H), 6.67 (d, J = 7.6 Hz, 1 H), 4.59 (d, J = 16.0 Hz,
1 H), 4.54 (d, J = 16.0 Hz, 1 H), 4.32–4.16 (m, 2 H), 3.23 (s, 3 H),
2.29 (s, 3 H), 1.34 (s, 9 H), 1.20 (t, J = 7.2 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 194.53, 179.49, 174.10, 153.79,
140.85, 128.62, 123.26, 107.15, 91.48, 79.66, 77.20, 74.78, 66.90,
30.93, 28.19, 26.43, 21.00, 13.54 ppm. IR (KBr): ν = 3417, 3240,
˜
2974, 1721, 1606, 1502, 1391, 1360, 1169, 1014, 790, 550 cm–1.
HRMS (ESI): calcd. for C21H26N2NaO6 [M + Na]+ 425.1689;
found 425.1677. HPLC analysis (AD-H column; λ = 254 nm; n-
hexane/EtOH, 90:10; flow rate = 0.9 mL/min): tR = 20.57 min
(minor), 28.38 min (major).
26.18, 14.14 ppm. IR (KBr): ν = 3350, 3165, 1723, 1614, 1587,
˜
1471, 1367, 1252, 1101, 706, 599 cm–1. HRMS (ESI): calcd. for
C20H25N2O6 [M + H]+ 389.1713; found 389.1705. HPLC analysis
(AD-H column; λ = 254 nm; n-hexane/EtOH, 90:10; flow rate =
0.9 mL/min): tR = 24.26 min (minor), 32.68 min (major).
tert-Butyl
(R)-[3-(2-Ethoxy-4-oxo-4,5-dihydrofuran-3-yl)-5-meth-
oxy-1-methyl-2-oxoindolin-3-yl] carbamate (3f): White solid, 97%
yield, 95% ee, m.p. 158.7–159.4 °C. [α]2D0 = –76.4 (c = 0.20, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 8.21 (br. s, 1 H), 6.90 (s, 1 H),
6.81 (d, J = 8.4 Hz, 1 H), 6.70 (d, J = 8.4 Hz, 1 H), 4.61 (d, J =
16.0 Hz, 1 H), 4.55 (d, J = 16.0 Hz, 1 H), 4.32–4.18 (m, 2 H), 3.77
(s, 3 H), 3.23 (s, 3 H), 1.34 (s, 9 H), 1.19 (t, J = 7.2 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 194.34, 179.28, 173.91, 156.25,
153.96, 136.77, 113.37, 109.61, 108.23, 90.84, 79.51, 77.20, 74.75,
tert-Butyl (R)-[3-(2-Methoxy-4-oxo-4,5-dihydrofuran-3-yl)-1-meth-
yl-2-oxoindolin-3-yl]carbamate (3b): White solid, 91% yield, 99%
ee, m.p. 159.7–160.6 °C. [α]2D0 = –133.0 (c = 0.24, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 8.03 (br. s, 1 H), 7.30–7.24 (m, 2 H), 7.01
(t, J = 7.6 Hz, 1 H), 6.81 (d, J = 8.0 Hz, 1 H), 4.61 (d, J = 16.0 Hz,
1 H), 4.55 (d, J = 16.0 Hz, 1 H), 3.89 (s, 3 H), 3.27 (s, 3 H), 1.32
(s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 194.59, 179.52,
174.40, 154.17, 143.73, 128.80, 122.79, 122.58, 107.92, 91.42, 79.57,
66.91, 59.83, 55.72, 28.16, 26.17, 14.12 ppm. IR (KBr): ν = 3397,
˜
74.80, 57.36, 29.91, 27.97, 26.37 ppm. IR (KBr): ν = 3417, 2981,
˜
3284, 2997, 2949, 1706, 1654, 1596, 1510, 1391, 1289, 1166, 1025,
914, 756, 558 cm–1. HRMS (ESI): calcd. for C21H26N2NaO7 [M +
Na]+ 441.1638; found 441.1637. HPLC analysis (AD-H column; λ
1738, 1718, 1585, 1491, 1353, 1252, 1169, 1009, 937, 760 cm–1.
HRMS (ESI): calcd. for C19H23N2O6 [M + H]+ 375.1556; found
375.1529. HPLC analysis (AD-H column; λ = 254 nm; n-hexane/
EtOH, 90:10; flow rate = 0.9 mL/min): tR = 57.38 min (minor),
62.67 min (major).
= 254 nm; n-hexane/EtOH, 90:10; flow rate = 0.9 mL/min): tR
=
18.01 min (minor), 43.96 min (major).
tert-Butyl (R)-[5-chloro-3-(2-ethoxy-4-oxo-4,5-dihydrofuran-3-yl)-1-
methyl-2-oxoindolin-3-yl]carbamate (3g): White solid, 96% yield,
tert-Butyl
(R)-{3-[2-(benzyloxy)-4-oxo-4,5-dihydrofuran-3-yl]-1-
1
92% ee, m.p. 163.3–164.2 °C. [α]2D0 = –65.7 (c = 0.21, CHCl3). H
methyl-2-oxoindolin-3-yl}carbamate (3c): White solid, 90% yield,
98% ee, m.p. 145.4–146.9 °C. [α]2D0 = –137.7 (c = 0.29, CHCl3). H
1
NMR (400 MHz, CDCl3): δ = 8.20 (br. s, 1 H), 7.25–7.22 (m, 2
H), 6.73 (d, J = 8.0 Hz, 1 H), 4.62 (d, J = 16.4 Hz, 1 H), 4.58 (d,
J = 16.4 Hz, 1 H), 4.32–4.19 (m, 2 H), 3.24 (s, 3 H), 1.35 (s, 9 H),
1.19 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
194.38, 178.77, 173.86, 153.77, 142.27, 128.60, 127.73, 123.10,
108.42, 90.34, 79.69, 77.20, 74.88, 67.09, 59.67, 28.15, 26.40,
NMR (400 MHz, CDCl3): δ = 8.20 (br. s, 1 H), 7.38–7.32 (m, 3
H), 7.27–7.21 (m, 2 H), 7.06 (d, J = 6.4 Hz, 2 H), 7.03–6.98 (t, J
= 7.6 Hz, 1 H), 6.61 (d, J = 7.6 Hz, 1 H), 5.16 (d, J = 11.6 Hz, 1
H), 5.12 (d, J = 11.6 Hz, 1 H), 4.64 (d, J = 16.0 Hz, 1 H), 4.58 (d,
J = 16.0 Hz, 1 H), 2.86 (s, 3 H), 1.32 (s, 9 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 194.47, 179.14, 174.10, 153.91, 143.06,
132.79, 129.25, 128.64, 128.38, 122.68, 122.49, 107.72, 91.22, 79.63,
14.15 ppm. IR (KBr): ν = 3407, 3217, 2982, 1717, 1600, 1490, 1389,
˜
1346, 1169, 1013, 923, 828, 545 cm–1. HRMS (ESI): calcd. for
C20H23ClN2NaO6 [M + Na]+ 445.1142; found 455.1144. HPLC
analysis (AD-H column; λ = 254 nm; n-hexane/EtOH, 90:10; flow
rate = 0.9 mL/min): tR = 24.28 min (minor), 33.47 min (major).
77.20, 75.04, 72.29, 28.17, 25.99, 18.34 ppm. IR (KBr): ν = 3421,
˜
3292, 1719, 1670, 1597, 1456, 1365, 1252, 1008, 914, 756, 536 cm–1.
HRMS (ESI): calcd. for C25H26N2NaO6 [M + Na]+ 473.1689;
found 473.1701. HPLC analysis (AD-H column; λ = 254 nm; n-
hexane/EtOH, 90:10; flow rate = 0.9 mL/min): tR = 31.67 min
(minor), 42.82 min (major).
tert-Butyl (R)-[5-Bromo-3-(2-ethoxy-4-oxo-4,5-dihydrofuran-3-yl)-1-
methyl-2-oxoindolin-3-yl]carbamate (3h): White solid, 97% yield,
95% ee, m.p. 169.3–170.4 °C. [α]2D0 = –83.6 (c = 0.21, CHCl3). H
1
tert-Butyl (R)-[3-(2-Ethoxy-4-oxo-4,5-dihydrofuran-3-yl)-2-oxo-1- NMR (400 MHz, CDCl3): δ = 8.18 (br. s, 1 H), 7.38 (d, J = 5.2 Hz,
phenylindolin-3-yl]carbamate (3d): White solid, 93% yield, 98% ee,
m.p. 137.8–139.3 °C. [α]2D0 = –111.6 (c = 0.21, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 8.22 (br. s, 1 H), 7.53–7.52 (m, 4 H), 7.40–
2 H), 6.68 (d, J = 8.8 Hz, 1 H), 4.61 (d, J = 16.0 Hz, 1 H), 4.57 (d,
J = 16.0 Hz, 1 H), 4.32–4.21 (m, 2 H), 3.23 (s, 3 H), 1.34 (s, 9 H),
1.19 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
742
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 739–744

Domino Mannich–Cyclization Reaction of Isatin Imines
194.06, 179.18, 173.75, 153.69, 142.80, 131.51, 125.84, 115.23,
254 nm; n-hexane/EtOH, 90:10; flow rate = 0.9 mL/min): tR
=
115.23, 109.11, 89.98, 79.89, 77.20, 67.10, 59.14, 28.14, 26.36, 20.72 min (minor), 24.10 min (major).
14.16 ppm. IR (KBr): ν = 3397, 3208, 2990, 1737, 1715, 1596, 1490,
˜
tert-Butyl (R)-[7-Chloro-3-(2-ethoxy-4-oxo-4,5-dihydrofuran-3-yl)-1-
methyl-2-oxoindolin-3-yl]carbamate (3m): White solid, 97% yield,
1389, 1167, 1010, 923, 828, 532 cm–1. HRMS (ESI): calcd. for
C20H24BrN2O6 [M + H]+ 467.0818; found 467.0795. HPLC analy-
sis (AD-H column; λ = 254 nm; n-hexane/EtOH, 90:10; flow rate
= 0.9 mL/min): tR = 21.56 min (minor), 32.57 min (major).
1
95% ee, m.p. 159.9–161.3 °C. [α]2D0 = –89.2 (c = 0.21, CHCl3). H
NMR (400 MHz, CDCl3): δ = 8.24 (br. s, 1 H), 7.17 (d, J = 7.6 Hz,
2 H), 6.92 (t, J = 7.6 Hz, 1 H), 4.61 (d, J = 16.0 Hz, 1 H), 4.55 (d,
J = 16.0 Hz, 1 H), 4.33–4.21 (m, 2 H), 3.62 (s, 3 H), 1.34 (s, 9 H),
1.24 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
194.09, 179.13, 174.66, 153.78, 139.42, 130.86, 123.49, 121.10,
114.96, 90.34, 79.84, 77.20, 74.83, 67.12, 59.13, 29.70, 28.12,
tert-Butyl (R)-[6-Chloro-3-(2-ethoxy-4-oxo-4,5-dihydrofuran-3-yl)-1-
methyl-2-oxoindolin-3-yl]carbamate (3i): White solid, 96% yield,
94% ee, m.p. 167.4–168.3 °C. [α]2D0 = –67.2 (c = 0.20, CHCl3). H
1
NMR (400 MHz, CDCl3): δ = 8.16 (br. s, 1 H), 7.19 (d, J = 8.0 Hz,
1 H), 6.98 (d, J = 7.2 Hz, 1 H), 6.79 (s, 1 H), 4.61 (d, J = 16.0 Hz,
1 H), 4.56 (d, J = 16.0 Hz, 1 H), 4.30–4.20 (m, 2 H), 3.24 (s, 3 H),
1.33 (s, 9 H), 1.21 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 194.07, 179.01, 174.27, 154.01, 144.95, 134.38, 123.54,
122.53, 108.44, 90.02, 80.27, 77.20, 74.88, 67.12, 59.52, 28.16,
14.10 ppm. IR (KBr): ν = 3416, 2984, 1721, 1608, 1506, 1462, 1391,
˜
1172, 1109, 1014, 742, 562 cm–1. HRMS (ESI): calcd. for
C20H23ClN2NaO6 [M + Na]+ 445.1142; found 445.1136. HPLC
analysis (AD-H column; λ = 254 nm; n-hexane/EtOH, 90:10; flow
rate = 0.9 mL/min): tR = 23.13 min (minor), 26.94 min (major).
26.19, 14.20 ppm. IR (KBr): ν = 3417, 3291, 2980, 1735, 1607,
˜
tert-Butyl (R)-[7-Bromo-3-(2-ethoxy-4-oxo-4,5-dihydrofuran-3-yl)-1-
methyl-2-oxoindolin-3-yl]carbamate (3n): White solid, 97% yield,
1577, 1495, 1392, 1164, 1073, 714, 558 cm–1. HRMS (ESI): calcd.
for C20H23ClN2NaO6 [M + Na]+ 445.1142; found 445.1136. HPLC
analysis (AD-H column; λ = 254 nm; n-hexane/EtOH, 90:10; flow
rate = 0.9 mL/min): tR = 21.30 min (minor), 28.81 min (major).
98% ee, m.p. 162.1–162.8 °C. [α]2D0 = –130.1 (c = 0.20, CHCl3). H
1
NMR (400 MHz, CDCl3): δ = 8.25 (br. s, 1 H), 7.35 (d, J = 8.0 Hz,
1 H), 7.21 (t, J = 6.8 Hz, 1 H), 6.87–6.84 (m, 1 H), 4.61 (d, J =
16.0 Hz, 1 H), 4.55 (d, J = 16.0 Hz, 1 H), 4.32–4.19 (m, 2 H), 3.63
(s, 3 H), 1.34 (s, 9 H), 1.24 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 194.20, 179.13, 174.84, 153.79, 140.74,
134.19, 123.91, 121.64, 102.04, 90.48, 79.87, 77.20, 74.84, 67.13,
tert-Butyl (R)-[6-Bromo-3-(2-ethoxy-4-oxo-4,5-dihydrofuran-3-yl)-1-
methyl-2-oxoindolin-3-yl]carbamate (3j): White solid, 96% yield,
1
95% ee, m.p. 164.2–165.4 °C. [α]2D0 = –73.3 (c = 0.22, CHCl3). H
NMR (400 MHz, CDCl3): δ = 8.14 (br. s, 1 H), 7.14 (s, 2 H), 6.94
(s, 1 H), 4.61 (d, J = 16.0 Hz, 1 H), 4.55 (d, J = 16.0 Hz, 1 H),
4.30–4.20 (m, 2 H), 3.23 (s, 3 H), 1.33 (s, 9 H), 1.21 (t, J = 7.2 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 194.43, 179.01, 174.13,
153.80, 144.60, 125.47, 123.90, 122.09, 111.09, 90.55, 80.09, 77.20,
59.13, 29.90, 28.15, 14.13 ppm. IR (KBr): ν = 3437, 2983, 1719,
˜
1598, 1513, 1457, 1327, 1164, 1109, 1014, 742, 562 cm–1. HRMS
(ESI): calcd. for C20H24BrN2O6 [M + H]+ 467.0818; found
467.0813; HPLC analysis (AD-H column; λ = 254 nm; n-hexane/
EtOH, 90:10; flow rate = 0.9 mL/min): tR = 24.37 min (minor),
27.57 min (major).
74.87, 67.13, 59.33, 28.15, 26.20, 14.20 ppm. IR (KBr): ν = 3421,
˜
3294, 2981, 1720, 1597, 1516, 1458, 1365, 1165, 1007, 914, 756,
536 cm–1. HRMS (ESI): calcd. for C20H24BrN2O6 [M + H]+
467.0818; found 467.0810. HPLC analysis (AD-H column; λ =
tert-Butyl (R)-[3-(2-Ethoxy-4-oxo-4,5-dihydrofuran-3-yl)-1-methyl-
2-oxo-7-(trifluoromethyl)indolin-3-yl]carbamate (3o): White solid,
97% yield, 95% ee, m.p. 163.2–163.6 °C. [α]2D0 = –96.3 (c = 0.22,
254 nm; n-hexane/EtOH, 90:10; flow rate = 0.9 mL/min): tR
=
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 8.34 (br. s, 1 H), 7.56–
20.72 min (minor), 29.04 min (major).
7.47 (m, 2 H), 7.09 (s, 1 H), 4.63 (d, J = 16.0 Hz, 1 H), 4.57 (d, J
= 16.0 Hz, 1 H), 4.28–4.21 (m, 2 H), 3.45 (s, 3 H), 1.39 (s, 9 H),
1.17 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
194.74, 179.30, 175.28, 153.97, 141.46, 133.52, 126.50, 126.03,
124.95, 122.05, 90.35, 80.22, 77.20, 74.89, 67.22, 58.43, 29.03,
tert-Butyl
(R)-[3-(2-Ethoxy-4-oxo-4,5-dihydrofuran-3-yl)-1,7-di-
methyl-2-oxoindolin-3-yl]carbamate (3k): White solid, 95% yield,
98% ee, m.p. 175.3–175.4 °C. [α]2D0 = –125.6 (c = 0.18, CHCl3). H
1
NMR (400 MHz, CDCl3): δ = 8.16 (br. s, 1 H), 7.13 (d, J = 7.2 Hz,
1 H), 6.98 (d, J = 7.6 Hz, 1 H), 6.89 (t, J = 7.6 Hz, 1 H), 4.58 (d,
J = 16.0 Hz, 1 H), 4.52 (d, J = 16.0 Hz, 1 H), 4.33–4.18 (m, 2 H),
3.53 (s, 3 H), 2.56 (s, 3 H), 1.34 (s, 9 H), 1.23 (t, J = 7.2 Hz, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 194.75, 178.97, 174.72,
153.27, 141.38, 132.41, 122.65, 120.59, 118.92, 91.76, 79.70, 77.20,
28.15, 13.89 ppm. IR (KBr): ν = 3416, 2984, 1740, 1599, 1461,
˜
1461, 1346, 1169, 1042, 929, 742, 562 cm–1. HRMS (ESI): calcd.
for C21H23F3N2NaO6 [M + Na]+ 479.1406; found 479.1426. HPLC
analysis (AD-H column; λ = 254 nm; n-hexane/EtOH, 90:10; flow
rate = 0.9 mL/min): tR = 14.25 min (minor), 16.10 min (major).
74.70, 66.84, 58.96, 29.54, 28.15, 18.55, 14.16 ppm. IR (KBr): ν =
˜
CCDC-943424 (for 3j) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
3437, 3306, 2982, 1719, 1599, 1513, 1457, 1355, 1164, 1095, 1011,
775, 560 cm–1. HRMS (ESI): calcd. for C21H26N2NaO6 [M + Na]
+
425.1689; found 425.1697. HPLC analysis (AD-H column; λ =
254 nm; n-hexane/EtOH, 90:10; flow rate = 0.9 mL/min): tR
=
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra and HPLC chromato-
grams of the products; X-ray analysis for compound 3i.
24.96 min (minor), 31.12 min (major).
tert-Butyl (R)-[3-(2-Ethoxy-4-oxo-4,5-dihydrofuran-3-yl)-7-fluoro-1-
methyl-2-oxoindolin-3-yl]carbamate (3l): White solid, 97% yield,
1
95% ee, m.p. 134.1–135.3 °C. [α]2D0 = –80.3 (c = 0.22, CHCl3). H
Acknowledgments
NMR (400 MHz, CDCl3): δ = 8.22 (br. s, 1 H), 7.07–6.93 (m, 3
H), 4.61 (d, J = 16.0 Hz, 1 H), 4.56 (d, J = 16.0 Hz, 1 H), 4.31–
4.24 (m, 2 H), 3.47 (s, 3 H), 1.34 (s, 9 H), 1.24 (t, J = 7.2 Hz, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 194.05, 179.34, 174.20,
154.17, 148.85, 146.18, 123.34, 118.41, 116.58, 90.90, 80.25, 77.20,
The authors are grateful for the financial support from National
Natural Science Foundation of China (NSFC) (grant number
21242007) and the Fundamental Research Funds for the Central
Universities.
74.86, 67.13, 59.86, 29.21, 28.18, 14.17 ppm. IR (KBr): ν = 3311,
˜
2981, 1721, 1603, 1487, 1454, 1357, 1167, 1041, 930, 857, 741,
562 cm–1. HRMS (ESI): calcd. for C20H23FN2NaO6 [M + Na]+
429.1438; found 429.1421. HPLC analysis (AD-H column; λ =
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Received: September 6, 2013
Published Online: November 21, 2013
744
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Eur. J. Org. Chem. 2014, 739–744