Secondary-amine-catalyzed asymmetric Michael addition of N-tert-butoxycarbonyl-protected oxindoles to maleimides

Article abstract of DOI:10.1055/s-0032-1316577

A secondary-amine-catalyzed asymmetric Michael addition of 3-substituted N-(tert-butoxycarbonyl)oxindoles to maleimides with activation by a Bronsted base gives the corresponding products in high yields (86-98%), excellent diastereomeric ratios (dr > 99:1), and high enantiomeric excesses (86-91% ee). Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1316577

PAPER
▌2601
paper
Secondary-Amine-Catalyzed Asymmetric Michael Addition of
N-tert-Butoxycarbonyl-Protected Oxindoles to Maleimides
Secondary-Amine-Catalyzed Michael Addition
Xuena Yang, Chuan Wang, Qijian Ni, Dieter Enders*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
Received: 24.05.2012; Accepted: 31.05.2012
formations with high efficiencies and excellent levels of
asymmetric induction by activating various aldehydes or
ketones in a covalently bound fashion through enamine7
or iminium8 intermediates and through singly occupied
molecular orbital (SOMO) activation.9 Moreover, some
attention has recently been paid to investigations of chiral
secondary amines as Brønsted base catalysts through non-
covalently bound activation, and some good results have
Abstract: A secondary-amine-catalyzed asymmetric Michael addi-
tion of 3-substituted N-(tert-butoxycarbonyl)oxindoles to ma-
leimides with activation by a Brønsted base gives the corresponding
products in high yields (86–98%), excellent diastereomeric ratios
(dr > 99:1), and high enantiomeric excesses (86–91% ee).
Key words: Brønsted base, Michael addition, heterocycles,
organocatalysis, oxindole
been
achieved
in
asymmetric
epoxidations10,
sulfenylations11 and Michael additions.12 Recently, we
developed a secondary-amine-catalyzed asymmetric
Michael addition of N-Boc-protected oxindoles to ni-
troolefins through a Brønsted base activation mode, fur-
nishing the products in high-to-excellent enantio-
selectivities.4q As a continuation of our investigations in
this field, we envisaged a secondary-amine-catalyzed
Michael addition of N-Boc-protected oxindoles to ma-
leimides (Scheme 1).
The oxindole (2,3-dihydro-2H-indole-2-one) subunit is a
vital structural feature in a large number of natural prod-
ucts with various biological and pharmacological activi-
ties.1 Moreover, 3,3-disubstituted oxindoles have been
employed as chiral building blocks for the synthesis of
hexahydropyrrolo[2,3-b]indoles, which are present in var-
ious biologically active alkaloids.2 For these reasons,
many efforts have been made to construct the oxindole
structural motif in an asymmetric manner, and diverse
methods have been developed that use metal catalysts or
organocatalysts.3 The asymmetric Michael addition of 3-
substituted oxindoles to various acceptors provides a
straightforward entry to a variety of chiral 3,3-disubstitut-
ed oxindoles.4 In 2010, Yuan and co-workers4g reported a
highly stereoselective Michael addition of N-(tert-butoxy-
carbonyl)oxindoles to maleimides in the presence of chi-
ral bifunctional thiourea catalysts.5 However, excellent
results were obtained only in the cases of 3-aryl- or 3-al-
kyloxindoles as nucleophiles, whereas the use of 3-benzyl-
oxindole as a precursor resulted in the formation of the
corresponding product in a low diastereoselectivity
(dr = 63:37). Recently, Tan, Jiang and co-workers used a
chiral bicyclic guanidine as a catalyst for the Michael
addition of N-benzyl-protected 3-benzyl oxindoles to
maleimides, affording the products in excellent stereo-
selectivities.4s However, to remove the protecting benzyl
group, it is necessary to treat the product with sodium/
ammonia in tetrahydrofuran at –78 °C. We therefore be-
came interested in developing a highly stereoselective
Michael addition of N-Boc-protected 3-substituted oxin-
doles to maleimides, which would permit deprotection of
the products under simple and mild conditions.
Initially, we performed the reaction with the 3-substituted
N-(tert-butoxycarbonyl)oxindole (1a) and N-phenyl ma-
leimide (2a) in chloroform at room temperature with dido-
decylprolinol silyl ether 4 as catalyst.
O
O
O
Ph
N
Ph
2a
O
O
N
O
O
O
cat. (20 mol%)
solvent
O
O
N
N
Boc
Boc
1a
3a
Me
O
11 Me
N
N
11
N
H
N
H
OMe
H
OTMS
4
5
6
Ph
Ph
N
H
OTMS
Since the renaissance of organocatalysis6 at the beginning
of this century, chiral secondary amines have played sig-
nificant roles in this field, as they can catalyze many trans-
7
Scheme 1 Secondary-amine-catalyzed Michael addition of N-Boc-
protected oxindole 1a to maleimide 2a in the presence of pyrrolidine-
type catalysts
SYNTHESIS 2012, 44, 2601–2606
Advanced online publication: 06.07.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316577; Art ID: SS-2012-Z0463-OP
© Georg Thieme Verlag Stuttgart · New York

2602
X. Yang et al.
PAPER
In this case, the reaction was complete within 24 hours, loading of 4 to 15 mol%, the reaction still proceeded
giving the product in an excellent yield (95%) and a high smoothly, affording the product in excellent yield (98%),
diastereomeric ratio (dr >99:1), albeit with a low enantio- high diastereoselectivity (dr >99:1), and high enantiose-
meric excess of 33% ee (Table 1, entry 1). We then per- lectivity (89% ee) (entry 12).
formed a brief screening study for a suitable solvent.
When the reaction was performed in methanol or acetoni-
trile, only traces of the desired product were obtained (en-
tries 2 and 3, respectively). Similar results were obtained
with ethyl acetate, diethyl ether, and tetrahydrofuran (en-
tries 4–6, respectively); the best outcome with respect to
Next, we evaluated the scope of the reaction by studying
the reactions of 3-substituted oxindoles 1 with maleimides
2 under the optimized conditions. Generally, the reactions
were complete within 24 hours at –60 °C in diethyl ether
with catalyst 4 and they gave high yields (86–98%) of
products 3 with excellent diastereomeric ratios (dr > 99:1)
enantioselectivity (41% ee) was achieved with diethyl
and high enantioselectivities (86–91% ee) (Table 2).
ether as the solvent (entry 5). Subsequently, we evaluated
two enantiomerically pure secondary amines 5 and 6 as
catalysts for the reaction, but little or no enantioselectivity
was observed (entries 7 and 8, respectively). In an attempt
to increase the degree of asymmetric induction, we carried
out the reaction at –30 °C in diethyl ether with the dido-
decylprolinol silyl ether 4 as the catalyst; this gave the ex-
pected product with a good enantioselectivity (76% ee)
(entry 9). We also examined the diphenylprolinol silyl
ether 7 as a catalyst for the Michael addition, but this gave
a lower enantioselectivity (57% ee) (entry 10). Next, we
reduced the reaction temperature to –60 °C with didodec-
ylprolinol silyl ether 4 as the catalyst. To our delight the
reaction was complete within 24 hours and gave the prod-
uct with a high stereoselectivity and no decrease in the
yield (entry 11). Finally, when we reduced the catalyst
Table 2 Yields and Stereoselectivities of the Asymmetric Michael
Addition of N-Boc-Protected Oxindoles 1 to Maleimides 2 to Afford
3a
R2
O
N
R1
O
O
R1
4 (15 mol%)
R2
O
N
+
O
N
Et2O, –60 °C
24 h
Boc
N
O
Boc
1
2
3
Product R1
R2
Yield drc
(%)b
ee
(%)d
3a
3b
3c
3d
3e
3f
1,3-benzodioxol-5-ylmethyl Ph
98 >99:1 89
93 >99:1 88
86 >99:1 89
90 >99:1 89
92 >99:1 86
87 >99:1 91
Bn
Ph
Ph
Ph
Ph
Ph
Table 1 Optimization of the Reaction Conditions for the Asymmet-
ric Michael Addition
4-MeC6H4CH2
Entrya Catalyst Solvent Temp Time Yield drc
ee
4-MeOC6H4CH2
(°C) (h)
(%)b
(%)d
3-FC6H4CH2
1
2
4
4
4
4
4
4
5
6
4
7
4
4
CHCl3
MeOH r.t.
MeCN r.t.
EtOAc r.t.
r.t.
24
24
24
16
12
48
12
12
95
>99:1
n.d.e
33
n.d.
n.d.
34
41
35
0
Me
Bn
Me
trace
trace
98
3g
3h
4-BrC6H4 89 >99:1 87
4-BrC6H4 88 >99:1 90
3
n.d.
a Reactions were performed on a 0.5-mmol scale for the N-Boc-pro-
tected oxindoles 1 by using 1.2 equiv of maleimides 2, and 15 mol%
catalyst 4 at –60 °C in Et2O (10 mL).
4
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
5
Et2O
THF
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
r.t.
r.t.
r.t.
r.t.
98
b Yields of the isolated products after flash column chromatography.
c Determined by HPLC.
6
90
d Determined by HPLC on a chiral stationary phase.
7
91
8
90
8
The Boc protecting group can be readily removed under
mild conditions (Scheme 2). Thus, the N-(tert-butoxycar-
bonyl)oxindole 3b was successfully deprotected by treat-
ment with trifluoroacetic acid at room temperature in
dichloromethane to give the deprotected product 8 in an
excellent yield (97%). Notably, the enantiomeric excess
remained at a high level (86%).
9
–30 24
–30 24
–60 24
–60 24
98
76
57
89
89
10
11
12f
98
98
98
a Unless otherwise specified, reactions were performed on a 0.50-
mmol scale with N-Boc-protected oxindole 1a by using 1.2 equiv of
N-phenylmaleimide (2a) and 20 mol% of the catalyst in the specified
solvent (10 mL).
By comparing the NMR spectra and the optical rotation of
8 with the corresponding data recently reported in the lit-
erature,13 the relative and absolute configuration of 8 were
assigned as S for both the quaternary stereocenter and the
tertiary stereocenter. We have assumed that the N-Boc-
protected products 3 have the same configuration as 8.
b Yield of the isolated product after flash column chromatography.
c Determined by HPLC.
d Determined by HPLC on a chiral stationary phase.
e Not determined.
f The reaction was performed with 15 mol% catalyst.
Synthesis 2012, 44, 2601–2606
© Georg Thieme Verlag Stuttgart · New York

PAPER
Secondary-Amine-Catalyzed Michael Addition
2603
13C NMR (75 MHz, CDCl3): δ = 176.1, 175.8, 174.0, 148.3, 147.0,
146.4, 140.5, 131.6, 129.7, 129.3, 129.0 (2 C), 128.0, 126.5, 125.6
(2 C), 124.9, 123.6, 123.3, 115.4, 110.1, 107.6, 100.7, 84.7, 56.5,
44.7, 42.4, 31.9, 28.0 (3 C).
MS (EI, 70 eV): m/z (%) = 540 [M+] (2), 440 (3), 135 (100), 77 (8),
58 (13).
Ph
Ph
O
N
O
N
O
O
Bn
TFA, CH2Cl2, r.t., 24 h
97%
Bn
O
O
N
N
Boc
H
HRMS (ESI): m/z calcd for C31H28N2NaO7: 563.1789; found:
563.1788.
3b
8
dr > 99:1, 86% ee
tert-Butyl (3S)-3-Benzyl-3-[(3S)-2,5-dioxo-1-phenylpyrrolidin-
3-yl]-2-oxoindoline-1-carboxylate (3b)
Scheme 2 Deprotection of the N-(tert-butoxycarbonyl)oxindole 3b
Yield: 231 mg (93%); colorless solid; mp 89 °C; [α]D20 +169
(c = 0.69, CHCl3).
HPLC: tR = 14.88 and 21.04 min [Chiralcel IA, heptane–i-PrOH
(7:3), 0.5 mL/min]; tR = 21.04 min; ee = 88%.
In summary, we have developed a secondary-amine-cata-
lyzed Michael addition of 3-substituted N-Boc-protected
oxindoles to maleimides. This process proceeds through a
Brønsted base activation mode, affording the products
containing a quaternary stereocenter in high yields (86–
98%), excellent diastereomeric ratios (dr >99:1), and high
enantiomeric excesses (86–91% ee).
IR (ATR): 2981, 1790, 1761, 1710, 1602, 1465, 1383, 1340, 1289,
1248, 1147, 1072, 1003, 940, 901, 841, 749, 695 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.53–7.30 (m, 4 H), 7.28–7.08 (m,
5 H), 7.00–6.90 (m, 3 H), 6.73–6.70 (m, 2 H), 3.90 (d, J = 13.2 Hz,
1 H, CHH), 3.68 (dd, J = 9.3, 5.1 Hz, 1 H, CHC=O), 3.38 (d,
J = 13.2 Hz, 1 H, CHH), 2.88 (dd, J = 18.3, 9.3 Hz, 1 H, CHHC=O),
2.04 (dd, J = 18.3, 5.1 Hz, 1 H, CHHC=O), 1.48 [s, 9 H, OC(CH3)3].
13C NMR (75 MHz, CDCl3): δ = 176.1, 175.8, 174.0, 148.1, 140.5,
134.4, 131.5, 129.8 (2 C), 129.1, 129.3, 128.9 (2 C), 127.7 (2 C),
126.9, 126.5 (2 C), 125.8, 124.8, 123.7, 115.4, 84.6, 56.4, 44.8,
42.8, 32.0, 28.0 (3 C).
Unless otherwise noted, all commercially available compounds
were used without further purification. Racemic samples of the 3,3-
disubstituted oxindoles 3a–h were prepared by using Et3N (40
mol%) as a catalyst in Et2O at r.t. Preparative flash column chroma-
tography was performed on Merck silica gel 60 (particle size 0.040–
0.063 mm; 230–240 mesh). Analytical TLC was performed on sili-
ca gel 60 F254 plates (Merck, Darmstadt). Visualization of the devel-
oped TLC plates was performed with UV radiation (254 nm).
Optical rotations were measured on a Perkin-Elmer 241 polarime-
ter. Microanalyses were performed with a Vario EL element analyz-
er. Mass spectra were acquired on a Finnigan SSQ 7000 (EI, 70 eV)
spectrometer and high-resolution mass spectra were recorded on a
Thermo Fisher Scientific Orbitrap XL. IR spectra were recorded on
a Perkin-Elmer FT-IR Spectrum 100 using an attenuated total re-
flection (ATR) unit. 1H and 13C NMR spectra were recorded at r.t.
on Mercury 300 or Vnmrs 400 instruments with TMS as the internal
standard. Analytical HPLC was performed on a Hewlett-Packard
1100 Series instrument using a chiral stationary phase (Chiralpak
AD, Chiralcel IA, or Chiralcel OD).
MS (EI, 70 eV): m/z (%) = 496 (4) [M+], 396 (39), 222 (49), 91 (87).
HRMS (ESI): m/z calcd for C30H28N2NaO5: 519.1890; found:
519.1892.
tert-Butyl (3S)-3-[(3S)-2,5-Dioxo-1-phenylpyrrolidin-3-yl]-3-(4-
methylbenzyl)-2-oxoindoline-1-carboxylate (3c)
Yield: 219 mg (86%); colorless solid; mp 93 °C; [α]D20 +176
(c = 1.5, CHCl3).
HPLC: tR = 10.53 and 15.77 min [Chiralcel IA, heptane–i-PrOH
(7:3), 0.7 mL/min]; tR = 15.77 min; ee = 89%.
IR (ATR): 3477, 3022, 2980, 2930, 2716, 1603, 1477, 1386, 1346,
1291, 1251, 1152, 1110, 1076, 1039, 1005, 941, 905, 842, 756, 695,
667, 621, 578, 541, 471 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 8.0 Hz, 1 H), 7.51–
7.47 (m, 2 H), 7.44–7.41 (m, 1 H), 7.32–7.14 (m, 5 H), 6.80 (d,
J = 7.6 Hz, 2 H), 6.65 (d, J = 8.0 Hz, 2 H), 3.89 (d, J = 13.6 Hz, 1
H, CHH), 3.72 (dd, J = 9.2, 5.2 Hz, 1 H, CHC=O), 3.40 (d, J = 13.2
Hz, 1 H, CHH), 2.93 (dd, J = 18.4, 9.2 Hz, 1 H, CHHC=O), 2.16 (s,
3 H, CH3), 2.11 (dd, J = 18.4, 5.2 Hz, 1 H, CHHC=O), 1.54 [s, 9 H,
OC(CH3)3].
13C NMR (101 MHz, CDCl3): δ = 176.1, 175.8, 174.0, 148.1, 140.5,
136.3, 131.6, 131.2, 129.7 (2 C), 129.6, 129.3 (2 C), 128.9, 128.4 (2
C), 126.5 (2 C), 125.8, 124.7, 123.6, 115.3, 84.5, 56.4, 44.7, 42.4,
32.0, 27.9 (3 C), 20.9.
tert-Butyl 3-(2,5-Dioxopyrrolidin-3-yl)-2-oxoindoline-1-carbox-
ylates 3: General Procedure
The N-aryl maleimide 2 (0.60 mmol) was added to a soln of the 3-
substituted N-Boc-protected oxindole 1 (0.50 mmol) and the dido-
decylprolinol trimethylsilyl ether 4 (15 mol%) in Et2O (10 mL) at
–60 °C, and the mixture was stirred for 24 h. The solvent was then
removed in vacuum and the residue was purified by flash column
chromatography [silica gel, pentane–Et2O (2:1)].
tert-Butyl (3S)-3-(1,3-Benzodioxol-5-ylmethyl)-3-[(3S)-2,5-di-
oxo-1-phenylpyrrolidin-3-yl]-2-oxoindoline-1-carboxylate (3a)
Yield: 264 mg (98%); colorless syrup; [α]D20 +152 (c = 0.36,
CHCl3).
MS (EI, 70 eV): m/z (%) = 510 (1) [M+], 410 (19), 236 (16), 105
(100), 58 (26).
HPLC: tR = 9.56 and 12.18 min [Chiralpak AD, heptane–i-PrOH
(8:2), 1.3 mL/min]; tR = 12.18 min; ee = 89%.
HRMS (ESI): m/z calcd for C31H30N2O5Na: 533.2047; found:
533.2047.
IR (ATR): 2981, 1790, 1760, 1711, 1603, 1490, 1441, 1383, 1342,
1290, 1248, 1149, 1102, 1076, 1038, 1003, 933, 901, 843, 811, 753,
694 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.68–7.65 (m, 1 H), 7.53–7.40 (m,
3 H), 7.34–7.17 (m, 5 H), 6.46 (d, J = 8.1 Hz, 1 H), 6.30 (d, J = 1.8
Hz, 1 H), 6.26 (dd, J = 7.8, 1.5 Hz, 1 H), 5.79 (dd, J = 8.7, 1.5 Hz,
2 H), 3.88 (d, J = 13.2 Hz, 1 H, CHH), 3.71 (dd, J = 9.0, 5.1 Hz, 1
H, CHC=O), 3.39 (d, J = 13.2 Hz, 1 H, CHH), 2.94 (dd, J = 18.3,
9.0 Hz, 1 H, CHHC=O), 2.10 (dd, J = 18.3, 5.1 Hz, 1 H, CHHC=O),
1.59 [s, 9 H, OC(CH3)3].
tert-Butyl (3S)-3-[(3S)-2,5-Dioxo-1-phenylpyrrolidin-3-yl]-3-(4-
methoxybenzyl)-2-oxoindoline-1-carboxylate (3d)
Yield: 237 mg (90%); colorless syrup; [α]D20 +159 (c = 0.47,
CHCl3).
HPLC: tR = 13.26 and 19.73 min [Chiralcel IA, heptane–i-PrOH
(7:3), 0.7 mL/min]; tR = 19.73 min; ee = 89%.
IR (ATR): 2979, 2932, 1786, 1759, 1712, 1608, 1509, 1466, 1380,
1349, 1289, 1248, 1149, 1110, 1078, 1034, 1005, 939, 904, 838,
755, 695 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2601–2606

2604
X. Yang et al.
PAPER
1H NMR (300 MHz, CDCl3): δ = 7.60 (d, J = 8.1 Hz, 1 H), 7.53–
7.43 (m, 3 H), 7.33–7.17 (m, 5 H), 6.71 (d, J = 8.4 Hz, 2 H), 6.54
(d, J = 8.4 Hz, 2 H), 3.90 (d, J = 13.5 Hz, 1 H, CHH), 3.73 (dd,
J = 9.3, 5.1 Hz, 1 H, CHC=O), 3.66 (s, 3 H, OCH3), 3.40 (d,
J = 13.5 Hz, 1 H, CHH), 2.95 (dd, J = 18.6, 9.3 Hz, 1 H, CHHC=O),
2.11 (dd, J = 18.6, 5.1 Hz, 1 H, CHH=CO), 1.56 [s, 9 H, OC(CH3)3].
tert-Butyl (3S)-3-Benzyl-3-[(3S)-1-(4-bromophenyl)-2,5-dioxo-
pyrrolidin-3-yl]-2-oxoindoline-1-carboxylate (3g)
Yield: 255 mg (89%); colorless solid; mp 72 °C; [α]D20 +173
(c = 2.1, CHCl3).
HPLC: tR = 18.12 and 24.94 min [Chiralcel OD, heptane–EtOH
(9:1), 0.7 mL/min]; tR = 18.12 min; ee = 87%.
13C NMR (75 MHz, CDCl3): δ = 176.4, 176.2, 174.3, 158.6, 148.4,
140.7, 131.8, 131.1 (2 C), 129.9, 129.6 (2 C), 129.2, 126.7 (2 C),
126.6, 126.0, 125.0, 123.9, 115.6, 113.4 (2 C), 84.9, 56.8, 55.3,
44.9, 42.2, 32.2, 28.2 (3 C).
MS (EI, 70 eV): m/z (%) = 426 (2) [M – HBoc]+, 318 (1), 121 (100),
58 (8).
IR (ATR): 3481, 3026, 2987, 2930, 1717, 1606, 1487, 1384, 1291,
1251, 1151, 1110, 1072, 1038, 1010, 938, 899, 842, 756, 704, 669,
622, 584, 532, 499 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.61 (d, J = 8.8 Hz, 2 H), 7.57 (d,
J = 8.0 Hz, 1 H), 7.28–7.24 (m, 2 H), 7.18–7.13 (m, 3 H), 7.04–6.97
(m, 3 H), 6.76 (d, J = 7.2 Hz, 2 H), 3.92 (d, J = 13.2 Hz, 1 H, CHH),
3.73 (dd, J = 9.2, 5.2 Hz, 1 H, CHC=O), 3.42 (d, J = 13.2 Hz, 1 H,
CHH), 2.94 (dd, J = 18.4, 9.2 Hz, 1 H, CHHC=O), 2.12 (dd,
J = 18.4, 5.2 Hz, 1 H, CHHC=O), 1.54 [s, 9 H, OC(CH3)3].
HRMS (ESI): m/z calcd for C26H23N2O4 [M – HBoc]+: 427.1652;
found: 426.1651.
tert-Butyl (3S)-3-[(3S)-2,5-Dioxo-1-phenylpyrrolidin-3-yl]-3-(3-
fluorobenzyl)-2-oxoindoline-1-carboxylate (3e)
Yield: 236 mg (92%); colorless syrup; [α]D20 +143 (c = 0.53,
CHCl3).
13C NMR (101 MHz, CDCl3): δ = 175.7 (2 C), 173.5, 148.0, 140.5,
134.2, 132.5 (2 C), 130.5, 129.8 (2 C), 129.7, 128.0 (2 C), 127.7 (2
C), 126.9, 125.5, 124.7, 123.5, 122.8, 115.3, 84.7, 56.3, 44.8, 42.8,
31.9, 27.9 (3 C).
MS (EI, 70 eV): m/z (%) = 574 (17) [M+], 474 (13), 222 (44), 158
(11), 91 (100), 58 (68).
HPLC: tR = 10.71 and 13.54 min [Chiralcel IA, heptane–i-PrOH
(7:3), 0.7 mL/min]; tR = 13.54 min; ee = 86%.
IR (ATR): 2981, 2933, 1758, 1711, 1590, 1480, 1380, 1349, 1289,
1250, 1147, 1077, 1005, 936, 902, 873, 841, 796, 753, 692 cm–1.
HRMS (ESI): m/z calcd for for C30H27BrN2NaO5: 597.0996; found:
597.0996.
1H NMR (300 MHz, CDCl3): δ = 7.56 (d, J = 8.1 Hz, 1 H), 7.47–
7.37 (m, 3 H), 7.27–7.11 (m, 5 H), 6.93–6.86 (m, 1 H), 6.72–6.66
(m, 1 H), 6.49–6.45 (m, 2 H), 3.92 (d, J = 13.2 Hz, 1 H, CHH), 3.67
(dd, J = 9.3, 5.1 Hz, 1 H, CHC=O), 3.37 (d, J = 13.2 Hz, 1 H, CHH),
2.88 (dd, J = 18.3, 9.3 Hz, 1 H, CHHC=O), 2.00 (dd, J = 18.3, 5.1
Hz, 1 H, CHHC=O), 1.50 [s, 9 H, OC(CH3)3].
13C NMR (75 MHz, CDCl3): δ = 176.3, 175.8, 174.1, 162.4 (d,
J = 244 Hz), 148.4, 140.7, 137.1 (d, J = 7.3 Hz), 131.7, 130.2, 129.6
(2 C), 129.4, 129.3 (2 C), 126.7 (2 C), 125.8 (d, J = 2.5 Hz), 125.4,
123.8, 117.5 (d, J = 21.4 Hz), 115.6, 114.1 (d, J = 20.8 Hz), 85.2,
56.5, 44.9, 42.6, 32.1, 28.1 (3 C).
tert-Butyl (3S)-3-[(3S)-1-(4-Bromophenyl)-2,5-dioxopyrrolidin-
3-yl]-3-methyl-2-oxoindoline-1-carboxylate (3h)
Yield: 219 mg (88%); pale-yellow solid; mp 168 °C; [α]D20 +168
(c = 0.8, CHCl3).
HPLC: tR = 31.44 and 34.89 min [Chiralcel OD, heptane–i-PrOH
(9.5:0.5), 0.7 mL/min]; tR = 34.89 min; ee = 90%.
IR (ATR): 2978, 2931, 1763, 1704, 1606, 1482, 1392, 1345, 1286,
1249, 1149, 1101, 1068, 1005, 937, 878, 848, 823, 796, 754, 718,
664 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.89 (d, J = 8.4 Hz, 1 H), 7.61 (d,
J = 8.7 Hz, 2 H), 7.41–7.35 (m, 2 H), 7.18–7.16 (m, 2 H), 7.11 (d,
J = 8.4 Hz, 1 H), 3.54 (dd, J = 9.3, 5.1 Hz, 1 H, CHC=O), 2.90 (dd,
J = 18.3, 9.3 Hz, 1 H, CHHC=O), 2.15 (dd, J = 18.3, 5.1 Hz, 1 H,
CHHC=O), 1.81 (s, 3 H, CH3), 1.67 [s, 9 H, OC(CH3)3].
MS (EI, 70 eV): m/z (%) = 514 (2) [M+], 414 (18), 319 (8), 240 (56),
186 (19), 158 (20), 109 (14), 57 (100).
HRMS (ESI): m/z calcd for C30H27FN2NaO5: 537.1796; found:
537.1796.
13C NMR (75 MHz, CDCl3): δ = 176.3, 175.4, 173.6, 148.7, 139.6,
132.4 (2 C), 130.4, 129.6, 128.0, 127.9 (2 C), 125.1, 123.1, 122.8,
115.7, 85.2, 49.9, 45.4, 31.5, 28.1 (3 C), 22.7.
tert-Butyl (3S)-3-[(3S)-2,5-Dioxo-1-phenylpyrrolidin-3-yl]-3-
methyl-2-oxoindoline-1-carboxylate (3f)
Yield: 183 mg (87%); pale-yellow solid; mp 123 °C; [α]D20 +202
(c = 1.04, CHCl3).
MS (EI, 70 eV): m/z (%) = 498 (2) [M+], 398 (28), 146 (47), 135
(21), 57 (100).
HPLC: tR = 12.50 and 13.43 min [Chiralcel IA, heptane–i-PrOH
(7:3), 0.5 mL/min]; tR = 13.43 min; ee = 91%.
Anal. Calcd for C24H23N2O5Br: C, 57.73; H, 4.64; N, 5.61. Found:
C, 57.89; H, 4.69; N, 5.42.
IR (ATR): 2980, 2393, 2253, 2220, 2139, 2108, 2039, 2008, 1987,
1958, 1929, 1770, 1707, 1598, 1478, 1386, 1347, 1286, 1250, 1145,
1101, 1074, 1045, 1003, 941, 875, 843, 755, 697, 665 cm–1.
(3S)-3-[(3S)-3-Benzyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-1-phe-
nylpyrrolidine-2,5-dione (8)
1H NMR (300 MHz, CDCl3): δ = 7.82 (d, J = 8.1 Hz, 1 H), 7.44–
7.28 (m, 4 H), 7.13–7.11 (m, 4 H), 3.48 (dd, J = 9.3, 5.1 Hz, 1 H,
CHC=O), 2.84 (dd, J = 18.3, 9.3 Hz, 1 H, CHHC=O), 2.06 (dd,
J = 18.3, 5.1 Hz, 1 H, CHHC=O), 1.75 (s, 3 H, CH3), 1.60 [s, 9 H,
OC(CH3)3].
13C NMR (75 MHz, CDCl3): δ = 177.1, 176.0, 174.2, 149.0, 139.8,
131.7, 129.8, 129.5 (2 C), 129.2, 128.2, 126.7 (2 C), 125.4, 123.5,
115.9, 85.4, 50.2, 45.6, 31.7, 28.3 (3 C), 22.9.
TFA (0.75 mmol, 5.0 equiv) was added to a soln of the N-Boc-pro-
tected product 3b (0.50 mmol) in CH2Cl2 (5 mL), and the mixture
was stirred for 24 h at r.t. The mixture was then treated with sat. aq
K2CO3 (5 mL) and extracted with CH2Cl2 (3 × 30 mL). The organic
layers were combined, washed with sat. aq NaCl, dried (MgSO4),
filtered, and concentrated under reduced pressure. The crude prod-
uct was purified by flash chromatography [silica gel, pentane–
Et2O–CH2Cl2 (2:8:1)] to give a colorless solid; yield: 192 mg
(97%); [α]D20 +260 (c = 0.9, CHCl3).
MS (EI, 70 eV): m/z (%) = 420 (3) [M+], 320 (86), 146 (100), 58
(95).
HPLC: tR = 13.38 and 20.76 min [Chiralcel IA, heptane–i-PrOH
(7:3), 0.7 mL/min]; tR = 20.76 min; ee = 86%.
Anal. Calcd for C24H24N2O5: C, 68.56; H, 5.75; N, 6.66. Found: C,
68.19; H, 5.71; N, 6.48.
IR (ATR): 3301, 1974, 1779, 1704, 1619, 1494, 1472, 1383, 1340,
1289, 1180, 1112, 1076, 1024, 909, 847, 731, 694 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.66 (br s, 1 H), 7.51–7.47 (m, 2
H), 7.42 (dt, J = 7.2, 1.2 Hz, 1 H), 7.31 (d, J = 7.6 Hz, 1 H), 7.24–
7.22 (m, 2 H), 7.18 (dd, J = 8.0, 1.2 Hz, 1 H), 7.09–6.98 (m, 4 H),
Synthesis 2012, 44, 2601–2606
© Georg Thieme Verlag Stuttgart · New York

PAPER
Secondary-Amine-Catalyzed Michael Addition
2605
6.85 (dd, J = 8.4, 1.2 Hz, 2 H), 6.67 (d, J = 8.0 Hz, 1 H), 4.03 (d,
J = 13.2 Hz, 1 H, CHHBn), 3.67 (dd, J = 9.2, 5.2 Hz, 1 H, CHC=O),
3.42 (d, J = 13.2 Hz, 1 H, CHHBn), 2.92 (dd, J = 18.4, 9.2 Hz, 1 H,
CHHC=O), 2.11 (dd, J = 18.4, 5.2 Hz, 1 H, CHHC=O).
13C NMR (101 MHz, CDCl3): δ = 178.2, 176.3, 174.3, 141.1, 135.1,
131.6, 130.0 (2 C), 129.5, 129.3 (2 C), 128.9, 127.7 (2 C), 127.0,
126.7, 126.6 (2 C), 124.6, 123.0, 110.1, 56.1, 44.4, 41.2, 31.7.
8758. (f) Guo, C.; Song, J.; Huang, J.-Z.; Chen, P.-H.; Luo,
S.-W.; Gong, L.-Z. Angew. Chem. Int. Ed. 2012, 51, 1046.
(3) For reviews on the asymmetric synthesis of 3-substituted
oxindoles, see: (a) Marti, C.; Carreira, E. M. Eur. J. Org.
Chem. 2003, 2209. (b) Galliford, C. V.; Scheidt, K. A.
Angew. Chem. Int. Ed. 2007, 46, 8748. (c) Trost, B. M.;
Brennan, M. K. Synthesis 2009, 3003. (d) Zhou, F.; Liu, J.-
L.; Zhou, J. Adv. Synth. Catal. 2010, 352, 1381.
(4) For selected examples of asymmetric Michael additions
using oxindoles as nucleophiles, see ref. 2e and: (a) Kato,
Y.; Furutachi, M.; Chen, Z.; Mitsunuma, H.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 9168. (b) He,
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131, 16620. (c) He, R.; Ding, C.; Maruoka, K. Angew.
Chem. Int. Ed. 2009, 48, 4559. (d) Galzerano, P.;
MS (EI, 70 eV): m/z (%) = 396 (24) [M+], 222 (42), 206 (40), 158
(25), 135 (22), 118 (51), 91 (100), 65 (15), 45 (29).
HRMS (ESI): m/z calcd for C25H20N2NaO3: 419.1366; found:
419.1364.
Acknowledgment
Bencivenni, G.; Pesciaioli, F.; Mazzanti, A.; Giannichi, B.;
Sambri, L.; Bartoli, G.; Melchiorre, P. Chem.–Eur. J. 2009,
15, 7846. (e) Bravo, N.; Mon, I.; Companyó, X.; Alba, A.-
N.; Moyano, A.; Rios, R. Tetrahedron Lett. 2009, 50, 6624.
(f) Zhu, Q.; Lu, Y. Angew. Chem. Int. Ed. 2010, 49, 7753.
(g) Liao, Y.-H.; Liu, X.-L.; Wu, Z.-J.; Cun, L.-F.; Zhang, X.-
M.; Yuan, W.-C. Org. Lett. 2010, 12, 2896. (h) Li, X.; Luo,
S.; Cheng, J.-P. Chem.–Eur. J. 2010, 16, 14290. (i) Sun, W.;
Hong, L.; Liu, C.; Wang, R. Tetrahedron: Asymmetry 2010,
21, 2493. (j) Ding, M.; Zhou, F.; Liu, Y.-L.; Wang, C.-H.;
Zhao, X.-L.; Zhou, J. Chem. Sci. 2011, 2, 2035. (k) Freund,
M. H.; Tsogoeva, S. B. Synlett 2011, 503. (l) Zheng, W.;
Zhang, Z.; Kaplan, M. J.; Antilla, J. C. J. Am. Chem. Soc.
2011, 133, 3339. (m) Duan, S.-W.; An, J.; Chen, J.-R.; Xiao,
W.-J. Org. Lett. 2011, 13, 2290. (n) Tan, B.; Candeias, N. R.;
Barbas, C. F. III Nat. Chem. 2011, 3, 473. (o) Zhang, T.;
Cheng, L.; Hameed, S.; Liu, L.; Wang, D.; Chen, Y.-J.
Chem. Commun. 2011, 47, 6644. (p) Bergonzini, G.;
Melchiorre, P. Angew. Chem. Int. Ed. 2012, 51, 971.
(q) Wang, C.; Yang, X.; Enders, D. Chem.–Eur. J. 2012, 18,
4832. (r) Retini, M.; Bergonzini, G.; Melchiorre, P. Chem.
Commun. 2012, 48, 3336. (s) Li, L.; Chen, W.; Yang, W.;
Pan, Y.; Liu, H.; Tan, C.-H.; Jiang, Z. Chem. Commun.
2012, 48, 5124.
We thank the former Degussa AG and BASF SE for the donation of
chemicals. Q.N. thanks the China Scholarship Council for a
scholarship.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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Synthesis 2012, 44, 2601–2606
© Georg Thieme Verlag Stuttgart · New York