Tandem michael addition-ring transformation reactions of 3-hydroxyoxindoles/3-aminooxindoles with olefinic azlactones: Direct access to structurally diverse spirocyclic oxindoles

Article abstract of DOI:10.1021/jo500432c

An efficient method for the direct construction of two classes of spirocyclic oxindoles by the reactions of 3-hydroxyoxindoles/3-aminooxindoles and (Z)-olefinic azlactones through a tandem Michael addition-ring transformation process has been developed. With DBU as the catalyst, a range of spiro-butyrolactoneoxindoles and spiro-butyrolactamoxindoles, containing an oxygen or a nitrogen heteroatom, respectively, in the spiro stereocenter, were smoothly obtained with good to excellent diastereoselectivities in high yields.

Full text of DOI:10.1021/jo500432c

Note
pubs.acs.org/joc
Tandem Michael Addition−Ring Transformation Reactions of
3‑Hydroxyoxindoles/3-Aminooxindoles with Olefinic Azlactones:
Direct Access to Structurally Diverse Spirocyclic Oxindoles
Bao-Dong Cui,†,§ Jian Zuo,†,§ Jian-Qiang Zhao,†,§ Ming-Qiang Zhou,†,§ Zhi-Jun Wu,‡ Xiao-Mei Zhang,†
and Wei-Cheng Yuan*,†
†National Engineering Research Center of Chiral Drugs, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences,
Chengdu 610041, China
‡Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
§University of the Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
ABSTRACT: An efficient method for the direct construction
of two classes of spirocyclic oxindoles by the reactions of 3-
hydroxyoxindoles/3-aminooxindoles and (Z)-olefinic azlac-
tones through a tandem Michael addition−ring transformation
process has been developed. With DBU as the catalyst, a range
of spiro-butyrolactoneoxindoles and spiro-butyrolactamoxin-
doles, containing an oxygen or a nitrogen heteroatom,
respectively, in the spiro stereocenter, were smoothly obtained with good to excellent diastereoselectivities in high yields.
he spirocyclic oxindole core is represented in some natural
3-hydroxyoxindoles/3-aminooxindoles and olefinic azlactones
Tand unnatural compounds possessing important biological (Scheme 1).11 Herein we report our progress in this area for
activities.1 It has been shown that a defined spatial arrangement
preparing spiro-butyrolactoneoxindoles and spiro-butyrolacta-
moxindoles with acceptable results.
of the structural element greatly influences the properties of
those compounds.2 Accordingly, there has been a powerful
inner impetus in organic chemists to develop creative
approaches to access spirocyclic oxindoles, and a lot of
methods for their generation have been designed.3 Potentially
promising skeletons are those containing a heteroatom
(especially N or O) in the spiro stereocenter at the C3
position of the oxindole because of their importance for the
synthesis of medicinally important compounds.4,5 However,
most of the studies have mainly focused on the synthesis of
spirocyclic oxindoles bearing an all-carbon quaternary stereo-
center at the C3 position of the oxindole. In contrast, the
construction of spirocyclic oxindoles bearing a heteroatom at
the C3 position is in need of further development.6 Because of
the correlation between molecular structure and biological
activity,7 it is strongly desired to develop an efficient method
for the construction of spirocyclic oxindoles bearing a
heteroatom at the spiro stereocenter.
We recently demonstrated that 3-aminooxindoles can serve
as nucleophiles for the enantioselective synthesis of quaternary
3-aminooxindoles.8 Some reports have shown that 3-hydrox-
yoxindoles can be used to prepare 3,3-disubstituted oxindole-
s6e−k and that olefinic azlactones can be applied as Michael
acceptors.9 Encouraged by these achievements and on the basis
of our recent successes in preparing diverse spirocyclic
oxindoles,10 we reasoned that two classes of spirocyclic
oxindoles could be constructed through a tandem Michael
addition−ring transformation process involving the reactions of
To optimize the reaction conditions, 3-hydroxyoxindole 1a
was reacted with (Z)-olefinic azlactone 2a (Table 1). When the
reaction was performed in CH2Cl2 at room temperature with
1,4-diazabicyclo[2.2.2]octane (DABCO) or 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) as the catalyst, spiro-
butyrolactoneoxindole 3a was obtained in a trace amount
(entries 1−2). When the temperature was increased to 40 °C,
3a was obtained in 60% yield with a 67:33:0:0 diastereomeric
ratio (dr) (entry 3). Using 20 mol % DBU at 40 °C for 5 h
afforded 3a in 92% yield with 75:25:0:0 dr (entry 4). The
reactions with other bases showed inferior results in terms of
the yield and dr value compared with DBU as the catalyst
(entries 4−6). Finally, with 20 mol % DBU as the catalyst,
solvent screening revealed CH2Cl2 to be the most selective for
the reaction (entry 4 vs entries 7−10).
With the optimized conditions in hand, we explored the
substrate scope of the reaction of 3-hydroxyoxindoles and (Z)-
olefinic azlactones (Table 2). The steric bulk of the substituent
at N1 in 1a−c had a slight influence on the diastereoselectivity
but almost no effect on the reactivity (entries 1−3). Substrate
1d incorporating a methyl group at the 5-position of the
oxindole ring was tolerated and provided product 3d with good
results (entry 4). Afterward, we investigated the reactions of 1a
with (Z)-olefinic azlactones 2b−k. It was observed that
Received: February 22, 2014
Published: May 2, 2014
© 2014 American Chemical Society
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Note
Scheme 1. Synthetic Strategy for Spiro-Butyrolactoneoxindoles and Spiro-Butyrolactamoxindoles
a
moxindoles 5i−p in good yields with excellent diastereose-
lectivities (entries 9−16). Two heteroaromatic azlactones, 2j
and 2r, were also successfully employed in the tandem reaction
(entries 17−19). A bulkier substituent such as naphthyl could
be used to obtaining spiro-butyrolactamoxindole 5t with
excellent results (entry 20). Introduction of a substituent on
the Ar2 group of the olefinic azlactone had no effect on the
stereoselectivity and reactivity (entry 21).
Table 1. Selected Optimiazation Studies
b
c
no.
catalyst
sol.
T (°C) t (h)
dr
yield (%)
The formyl group incorporated on the butyrolactam ring
could be readily deprotected by hydrolysis with 10% NaOH
solution, leading to compound 6 in 56% yield with >99:1:0:0 dr
(eq 1 in Scheme 2). Nevertheless, we performed an
intermolecular competition experiment between 3-hydroxyox-
indole 1a and 3-aminooxindole 4a by reacting them with 2g
under the standard conditions. The results revealed 3-
hydroxyoxindole to be more reactive and to be preferentially
converted (eq 2 in Scheme 2).
1
2
DABCO
DBU
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
25
25
40
40
40
40
40
40
40
40
12
12
12
5
nd
nd
trace
trace
60
3
DABCO
DBU
67:33:0:0
75:25:0:0
71:29:0:0
50:50:0:0
50:50:0:0
nd
4
92
5
Et3N
8
75
6
DMAP
DBU
8
71
7
5
87
d
8
DBU
DCE
5
trace
75
9
DBU
THF
5
67:33:0:0
50:50:0:0
We also tried to develop an enantioselective version of the
tandem Michael addition−ring transformation reaction. We
selected the reaction of 4c and 2a with 10 mol % 6′-OH
cinchona alkaloid A as the catalyst (Scheme 3). The product 5c
was obtained in 47% yield with >99:1:0:0 dr and 61% ee using
xylene as the solvent at room temperature. The absolute
configuration of 5c was not determined at the moment.
In conclusion, we have developed an efficient method for the
direct construction of two classes of spirocyclic oxindoles with
the reaction of 3-hydroxyoxindoles/3-aminooxindoles and (Z)-
olefinic azlactones. The chemistry is based on Michael addition
of the 3-hydroxyoxindole/3-aminooxindole to the (Z)-olefinic
azlactone and sequential ring transformation. With DBU as the
catalyst, the tandem reactions proceeded smoothly and
delivered a wide range of spiro-butyrolactoneoxindoles and
spiro-butyrolactamoxindoles, containing an oxygen heteroatom
or a nitrogen heteroatom, respectively, in the spiro stereo-
center, with very good to excellent diastereoselectivities in high
yields. Additionally, a preliminary trial of an asymmetric version
of the tandem Michael addition−ring transformation process
was conducted, and it afforded the product in moderate yield
with excellent diastereoselectivity and moderate enantioselec-
tivity.
10
DBU
toluene
8
51
a
Conditions: 1a (0.2 mmol), 2a (0.24 mmol), and 20 mol % catalyst
b
in 10 mL of solvent. Determined by 1H NMR spectroscopy. nd = not
c
d
determined. Isolated yields. DCE = 1,2-dichloroethane.
regardless of whether an electron-withdrawing group (2b−e) or
an electron-donating group (2f−h) was used as Ar1 of the
olefinic azlactone, the reactions proceeded well, giving spiro-
butyrolactoneoxindoles 3e−k in up to 93% yield and 83:17:0:0
dr (entries 5−11). 1-Naphthyl-based reactant 2i also gave rise
to the product 3l in 85% yield with 67:33:0:0 dr (entry 12).
Heteroaromatic subject 2j was also successfully employed to
react with 1a, furnishing 3m in excellent yield with 75:25:0:0 dr
(entry 13). The structure and relative configuration of the
product 3m were determined by X-ray analysis.12 A substituent
on the Ar2 group of the olefinic azlactone was well-tolerated
(entry 14). Subsequently, we examined the reaction of olefinic
azlactones 2l−p with 3-hydroxyoxindole 1b (entries 15−19). In
a similar fashion, introduction of an electron-withdrawing or
electron-donating group on Ar2 of the olefinic azlactone did not
affect the reactivity and stereoselectivity (entries 16−19).
The remarkable reactivity between 3-hydroxyoxindoles and
(Z)-olefinic azlactones prompted us to explore another tandem
reaction using 3-aminooxindoles 4 as nucleophiles for the
construction of spiro-butyrolactamoxindoles (Table 3). Differ-
ent substitutions at the N1 position of the 3-aminooxindole
were well-tolerated (entries 1−4, 7, and 8), as were different
groups at the N3 position (entries 5 and 6). A series of (Z)-
olefinic azlactones bearing various β-aryl groups were able to
undergo the Michael addition−ring transformation reaction
under the standard conditions, generating spiro-butyrolacta-
EXPERIMENTAL SECTION
■
General Methods. Reagents were purchased from commercial
sources and were used as received, unless mentioned otherwise.
Reactions were monitored by TLC. 1H NMR and 13C NMR (300 and
75 MHz, respectively) spectra were recorded in CDCl3 and DMSO-d6.
1H NMR chemical shifts are reported in parts per million relative to
tetramethylsilane (TMS) with the solvent resonance employed as the
internal standard (CDCl3 at 7.26 ppm, DMSO-d6 at 2.50 ppm). Data
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Note
Table 2. Scope of 3-Hydroxyoxindoles with Olefinic
Azlactones
Table 3. Scope of 3-Aminooxindoles with Olefinic
Azlactones
a
a
a
b
See the Experimental Section for experimental details. Determined
c
d
by 1H NMR spectroscopy. Isolated yields. The structure and relative
a
b
configuration of the product 5b were determined by X-ray analysis.12
See the Experimental Section for experimental details. Determined
c
d
e
by 1H NMR spectroscopy. Isolated yields. Run for 8 h. The
structure and relative configuration of 3m were determined by single-
crystal X-ray analysis.12
Synthesis of Substrates 4a−d. N-(1-Methyl-2-oxoindolin-3-
yl)formamide (4a). A solution of 3-amino-1-methylindolin-2-one
hydrochloride (2.5 g, 12.6 mmol) in ethyl formate (100 mL) was
heated to reflux under an Ar atmosphere, and Et3N (2.1 mL, 15.1
mmol) was added to the resulting mixture. The mixture was refluxed
for 15 h and then concentrated, and the residue was purified by flash
chromatography (petroleum ether/ethyl acetate = 1:1) to give 4a (1.7
g, 71% yield) as a white solid. Mp 175.8−177.3 °C; H NMR (300
MHz, DMSO-d6) δ 3.11 (s, 3H), 5.24 (d, J = 8.1 Hz, 1H), 6.97−7.04
(m, 2H), 7.17 (d, J = 7.2 Hz, 1H), 7.27−7.32 (m, 1H), 8.18 (s, 1H),
are reported as follows: chemical shift (multiplicity, coupling
constant(s) in Hz, integration). Multiplicities are abbreviated as
follows: s = singlet, br s = broad singlet, d = doublet, t = triplet, q =
quartet, m = multiplet. 13C NMR chemical shifts are reported in parts
per million from tetramethylsilane (TMS) with the solvent resonance
as the internal standard (CDCl3 at 77.20 ppm, DMSO-d6 at 39.51
ppm). Melting points were recorded on a melting point apparatus.
1
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Note
7.08−7.13 (m, 1H), 7.21−7.23 (m, 1H), 7.41−7.44 (m, 4H), 7.50−
7.55 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 14.4, 54.1, 61.6, 109.5,
123.3, 124.6, 126.2, 126.5, 128.2, 129.1, 129.6, 134.3, 143.8, 156.4,
173.8; HRMS (ESI-TOF) calcd for C17H16N2NaO3 [M + Na]+
319.1053, found 319.1053.
Scheme 2. Transformation of 5m and the Competition
Experiment with 1a and 4a
Ethyl N-(1-Benzyl-2-oxoindolin-3-yl)carbamate (4f). The method
for the synthesis of 4f was similar to that for 4e. Product 4f (1.0 g, 63%
yield) was obtained from 3-amino-1-benzylindolin-2-one hydro-
chloride (1.4 g, 5.1 mmol) as a white solid. Mp 125.9−127.4 °C;
1H NMR (300 MHz, CDCl3) δ 1.26 (s, 3H), 4.11−4.19 (m, 2H), 4.86
(d, J = 15.6 Hz, 1H), 4.97 (d, J = 15.6 Hz, 1H), 5.17 (d, J = 6.9 Hz,
1H), 5.37 (d, J = 6.9 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 7.01−7.06 (m,
1H), 7.17−7.22 (m, 1H), 7.27−7.39 (m, 6H); 13C NMR (75 MHz,
CDCl3) δ 14.4, 44.1, 53.9, 61.6, 109.3, 122.9, 124.3, 126.4, 127.3,
127.6, 128.7, 129.1, 135.4, 142.8, 156.4, 174.4; HRMS (ESI-TOF)
calcd for C18H18N2NaO3 [M + Na]+ 333.1210, found 333.1197.
General Procedure for the Synthesis of Compounds 3. In an
ordinary vial equipped with a magnetic stirring bar, compound 1 (0.2
mmol, 1.0 equiv), compound 2 (0.24 mmol, 1.2 equiv), and catalyst
(DBU, 20 mol %) were dissolved in 10 mL of CH2Cl2, and then the
mixture was refluxed for the indicated time under an Ar atmosphere.
After completion of the reaction as indicated by TLC, the solvent was
removed in vacuo, and the diastereomeric ratio (dr) was determined
by 1H NMR analysis of the crude mixture. The product 3 was isolated
by flash chromatography on silica gel (petroleum ether/ethyl acetate =
10/1−3/1).
Scheme 3. Catalytic Enantioselective Variant
8.78 (d, J = 8.1 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 26.2, 50.6,
108.4, 122.2, 123.4, 126.8, 128.7, 144.0, 161.3, 173.4; HRMS (ESI-
TOF) calcd for C10H10N2NaO2 [M + Na]+ 213.0634, found 213.0629.
N-(1-Ethyl-2-oxoindolin-3-yl)formamide (4b). The method for the
synthesis of 4b was similar to that for 4a. Product 4b (0.87 g, 91%
yield) was obtained from 3-amino-1-ethylindolin-2-one hydrochloride
N-(1′-Methyl-2′,5-dioxo-3-phenyl-4,5-dihydro-3H-spiro[furan-
2,3′-indolin]-4-yl)benzamide (3a). White solid (75.9 mg, 92% yield),
1
75:25:0:0 dr (as determined by H NMR spectroscopy of the crude
1
product); mp 215.8−216.9 °C; H NMR (300 MHz, DMSO-d6) δ
1
(1.0 g, 4.7 mmol) as a white solid. Mp 140.3−141.7 °C; H NMR
3.17 (s, 3H), 4.68 (d, J = 13.2 Hz, 1H), 6.10 (dd, J = 8.4 Hz, 13.2 Hz,
1H), 6.91 (d, J = 7.8 Hz, 1H), 7.01−7.14 (m, 6H), 7.23−7.28 (m,
1H), 7.46−7.59 (m, 3H), 7.73 (d, J = 7.5 Hz, 1H), 7.89 (d, J = 7.2 Hz,
2H), 9.32 (d, J = 8.4 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 27.0,
50.6, 52.4, 83.5, 109.8, 123.4, 123.9, 125.9, 127.7, 127.8, 128.3, 128.9,
131.4, 132.4, 132.5, 133.3, 143.7, 166.6, 172.2, 172.8; IR (KBr) v 3390,
3064, 2928, 2853, 1786, 1732, 1667, 1617, 1545, 1471, 1377, 1316,
1205, 1096, 1003, 706, 694 cm−1; HRMS (ESI-TOF) calcd for
C25H20N2NaO4 [M + Na]+ 435.1315, found 435.1303.
(300 MHz, DMSO-d6) δ 1.15 (t, J = 7.2 Hz, 3H), 3.70 (q, J = 7.2 Hz,
2H), 5.24 (d, J = 8.1 Hz, 1H), 7.00−7.10 (m, 2H), 7.20 (d, J = 7.2 Hz,
1H), 7.28−7.35 (m, 1H), 8.19 (s, 1H), 8.82 (d, J = 8.1 Hz, 1H); 13C
NMR (75 MHz, DMSO-d6) δ 12.4, 34.2, 50.6, 108.5, 122.0, 123.6,
126.9, 128.7, 143.0, 161.2, 173.0; HRMS (ESI-TOF) calcd for
C11H12N2NaO2 [M + Na]+ 227.0791, found 227.0789.
N-(2-Oxo-1-phenylindolin-3-yl)formamide (4c). The method for
the synthesis of 4c was similar to that for 4a. Product 4c (0.8 g, 82%
yield) was obtained from 3-amino-1-phenylindolin-2-one hydro-
chloride (1.0 g, 3.8 mmol) as a white solid. Mp 174.3−175.7 °C;
1H NMR (300 MHz, DMSO-d6) δ 5.43 (d, J = 8.1 Hz, 1H), 6.72 (d, J
= 7.8 Hz, 1H), 7.06−7.11 (m, 1H), 7.23−7.30 (m, 2H), 7.41−7.49 (m,
3H), 7.56−7.61 (m, 2H), 8.25 (s, 1H), 8.98 (d, J = 8.1 Hz, 1H); 13C
NMR (75 MHz, DMSO-d6) δ 50.9, 108.8, 122.8, 123.9, 126.6, 126.7,
128.0, 128.7, 129.6, 134.5, 143.8, 161.4, 173.0; HRMS (ESI-TOF)
calcd for C15H12N2NaO2 [M + Na]+ 275.0791, found 275.0786.
N-(1-Benzyl-2-oxoindolin-3-yl)formamide (4d). The method for
the synthesis of 4d was similar to that for 4a. Product 4d (0.65 g, 67%
yield) was obtained from 3-amino-1-benzylindolin-2-one hydro-
chloride (1.0 g, 3.6 mmol) as a white solid. Mp 139.8−141.2 °C;
1H NMR (300 MHz, DMSO-d6) δ 4.85 (d, J = 15.9 Hz, 1H), 4.96 (d, J
= 15.9 Hz, 1H), 5.37 (d, J = 8.1 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H),
7.00−7.03 (m, 1H), 7.17−7.42 (m, 7H), 8.23 (s, 1H), 8.98 (d, J = 8.1
Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 42.8, 50.9, 109.0, 122.3,
123.5, 126.8, 127.2, 127.3, 128.5, 129.1, 136.1, 142.9, 161.3, 173.6;
HRMS (ESI-TOF) calcd for C16H14N2NaO2 [M + Na]+ 289.0947,
found 289.0953.
Synthesis of Substrates 4e and 4f. Ethyl N-(2-Oxo-1-phenyl-
indolin-3-yl)carbamate (4e). To a solution of 3-amino-1-phenyl-
indolin-2-one hydrochloride (1.4 g, 5.4 mmol) in CHCl3 (30 mL) was
added Et3N (1.2 mL, 8.1 mmol) at 0 °C under an Ar atmosphere. The
resulting mixture was vigorously stirred for 15 min, and then ethyl
carbonochloridate (0.6 mL, 5.95 mmol) was slowly added to the
mixture via syringe. The resultant mixture was allowed to stir for 1 h
and then concentrated, and the residue was purified by flash
chromatography (petroleum ether/ethyl acetate = 2:1) to give 4e
N-(1′-Ethyl-2′,5-dioxo-3-phenyl-4,5-dihydro-3H-spiro[furan-2,3′-
indolin]-4-yl)benzamide (3b). White solid (79.3 mg, 93% yield),
1
50:50:0:0 dr (as determined by H NMR spectroscopy of the crude
1
product); mp 158.1−159.6 °C; H NMR (300 MHz, DMSO-d6) δ
(one diastereomer) 0.55 (t, J = 7.2 Hz, 3H), 3.27−3.34 (m, 1H),
3.47−3.54 (m, 1H), 4.57 (d, J = 12.6 Hz, 1H), 5.96 (dd, J = 8.4 Hz,
12.6 Hz, 1H), 6.89−6.91 (m, 2H), 7.03 (d, J = 7.8 Hz, 1H), 7.15−7.20
(m, 3H), 7.29−7.34 (m, 1H), 7.47−7.60 (m, 4H), 7.68 (d, J = 7.2 Hz,
1H), 7.84 (d, J = 7.2 Hz, 2H), 9.17 (d, J = 8.4 Hz, 1H); δ (the other
diastereomer) 1.11 (t, J = 6.9 Hz, 3H), 3.62−3.74 (m, 1H), 3.77−3.84
(m, 1H), 4.67 (d, J = 13.2 Hz, 1H), 6.11 (dd, J = 8.4 Hz, 13.2 Hz, 1H),
6.94 (d, J = 7.8 Hz, 1H), 6.98−7.03 (m, 1H), 7.05−7.15 (m, 4H),
7.22−7.27 (m, 2H), 7.46−7.56 (m, 3H), 7.73 (d, J = 7.2 Hz, 1H), 7.89
(d, J = 7.2 Hz, 2H), 9.33 (d, J = 8.4 Hz, 1H); 13C NMR (75 MHz,
DMSO-d6) δ (one diastereomer) 111.6, 34.0, 50.3, 53.3, 83.6, 109.6,
123.7, 124.0, 124.5, 127.2, 127.7, 128.3, 128.5, 128.7, 130.9, 131.9,
132.1, 132.8, 143.1, 166.3, 171.6, 172.9; δ (the other diastereomer)
12.2, 34.7, 50.1, 52.1, 83.0, 109.3, 122.8, 123.7, 125.7, 127.3, 127.5,
127.9, 128.2, 128.3, 128.5, 129.9, 131.0, 131.9, 132.0, 132.8, 142.1,
166.1, 171.4, 172.4; IR (KBr) v 3359, 3062, 2934, 1801, 1728, 1650,
1616, 1531, 1489, 1469, 1375, 1162, 1027, 753, 698 cm−1; HRMS
(ESI-TOF) calcd for C26H22N2NaO4 [M + Na]+ 449.1472, found
449.1472.
N-(1′-Benzyl-2′,5-dioxo-3-phenyl-4,5-dihydro-3H-spiro[furan-
2,3′-indolin]-4-yl)benzamide (3c). White solid (87.9 mg, 90% yield),
1
67:33:0:0 dr (as determined by H NMR spectroscopy of the crude
1
product); mp 145.8−147.2 °C; H NMR (300 MHz, DMSO-d6) δ
(one diastereomer) 4.48 (d, J = 16.2 Hz, 1H), 4.72 (d, J = 12.6 Hz,
1H), 4.90 (d, J = 16.2 Hz, 1H), 6.06 (dd, J = 8.4 Hz, 12.6 Hz, 1H),
6.48 (d, J = 7.2 Hz, 2H), 6.71 (d, J = 7.5 Hz, 1H), 7.01 (d, J = 7.5 Hz,
2H), 7.07−7.16 (m, 3H), 7.21−7.41 (m, 5H), 7.48−7.60 (m, 3H),
1
(0.8 g, 50% yield) as a white solid. Mp 181.9−183.2 °C; H NMR
(300 MHz, CDCl3) δ 1.25 (s, 3H), 4.17 (q, J = 7.2 Hz, 2H), 5.20 (d, J
= 6.9 Hz, 1H), 5.52 (d, J = 7.5 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H),
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Note
7.73 (d, J = 7.2 Hz, 1H), 7.84−7.87 (m, 2H), 9.21 (d, J = 8.4 Hz, 1H);
δ (the other diastereomer) 4.73 (d, J = 13.2 Hz, 1H), 4.85 (d, J = 15.9
Hz, 1H), 5.04 (d, J = 15.9 Hz, 1H), 6.11 (dd, J = 8.4 Hz, 13.2 Hz, 1H),
6.85 (d, J = 7.8 Hz, 1H), 6.96−7.10 (m, 5H), 7.20−7.22 (m, 3H),
7.30−7.36 (m, 3H), 7.38−7.41 (m, 1H), 7.48−7.51 (m, 2H), 7.54−
7.56 (m, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.87−7.90 (m, 2H), 9.34 (d, J
= 8.4 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ (one diastereomer)
43.2, 50.9, 53.2, 84.0, 110.7, 124.2, 124.4, 125.1, 126.7, 127.6, 128.5,
128.9, 129.0, 129.2, 131.2, 132.3, 132.5, 133.2, 135.1, 143.8, 166.7,
172.6, 173.2; δ (the other diastereomer) 43.3, 50.5, 52.0, 83.0, 110.0,
123.0, 123.6, 125.9, 127.3, 127.4, 127.6, 127.8, 128.4, 128.5, 128.6,
130.0, 131.0, 131.8, 131.9, 132.8, 135.3, 142.4, 166.1, 171.9, 172.3; IR
(KBr) v 3401, 3061, 2927, 1799, 1707, 1653, 1617, 1512, 1488, 1469,
1382, 1368, 1170, 1023, 753, 702 cm−1; HRMS (ESI-TOF) calcd for
C31H24N2NaO4 [M + Na]+ 511.1628, found 511.1627.
N-(3-(4-Cyanophenyl)-1′-methyl-2′,5-dioxo-4,5-dihydro-3H-
spiro[furan-2,3′-indolin]-4-yl)benzamide (3h). White solid (79.6 mg,
1
91% yield), 50:50:0:0 dr (as determined by H NMR spectroscopy of
the crude product); mp 256.8−258.2 °C; 1H NMR (300 MHz,
DMSO-d6) δ (one diastereomer) 3.16 (s, 3H), 4.73 (d, J = 12.9 Hz,
1H), 6.14 (dd, J = 8.1 Hz, 12.9 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H),
6.97−7.03 (m, 1H), 7.24−7.29 (m, 3H), 7.44−7.55 (m, 3H), 7.63 (d, J
= 8.1 Hz, 2H), 7.77 (d, J = 7.5 Hz, 1H), 7.86 (d, J = 7.5 Hz, 2H), 9.34
(d, J = 8.1 Hz, 1H); δ (the other diastereomer) 2.86 (s, 3H), 4.71 (d, J
= 12.3 Hz, 1H), 5.93 (dd, J = 8.1 Hz, 12.3 Hz, 1H), 7.04 (d, J = 7.8
Hz, 1H), 7.13 (d, J = 8.4 Hz, 2H), 7.31−7.36 (m, 1H), 7.46−7.56 (m,
4H), 7.69−7.75 (m, 3H), 7.80−7.85 (m, 2H), 9.22 (d, J = 8.1 Hz,
1H); 13C NMR (75 MHz, DMSO-d6) δ (one diastereomer) 27.0, 50.6,
52.4, 83.1, 109.9, 111.2, 118.6, 123.4, 123.5, 126.0, 127.8, 128.9, 129.0,
131.7, 132.5, 132.8, 133.1, 138.4, 143.6, 166.6, 171.9, 172.3; δ (the
other diastereomer) 26.0, 50.6, 52.6, 83.2, 109.8, 111.3, 118.2, 123.3,
124.0, 124.4, 127.1, 127.3, 128.6, 128.7, 132.1, 132.4, 132.7, 136.9,
144.1, 166.3, 171.6, 172.2; IR (KBr) v 3369, 3062, 2935, 1801, 1725,
1658, 1616, 1531, 1491, 1471, 1377, 1311, 1243, 1161, 1007, 754, 694
cm−1; HRMS (ESI-TOF) calcd for C26H19N3NaO4 [M + Na]+
460.1268, found 460.1252.
N-(1′,5′-Dimethyl-2′,5-dioxo-3-phenyl-4,5-dihydro-3H-spiro-
[furan-2,3′-indolin]-4-yl)benzamide (3d). White solid (77.6 mg, 91%
1
yield), 75:25:0:0 dr (as determined by H NMR spectroscopy of the
crude product); mp 259.2−260.5 °C; 1H NMR (300 MHz, DMSO-d6)
δ 2.41 (s, 3H), 2.81 (s, 3H), 4.63 (d, J = 12.6 Hz, 1H), 5.90 (dd, J =
8.4 Hz, 12.3 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.95−6.97 (m, 2H),
7.19−7.21 (m, 3H), 7.29 (d, J = 8.1 Hz, 1H), 7.47−7.57 (m, 4H),
7.84−7.86 (m, 2H), 9.19 (d, J = 8.4 Hz, 1H); 13C NMR (75 MHz,
DMSO-d6) δ 21.1, 26.3, 51.2, 53.1, 84.1, 109.8, 124.3, 125.2, 127.6,
128.0, 128.1, 128.7, 128.9, 129.0, 130.5, 131.7, 132.4, 132.5, 133.2,
133.4, 142.3, 166.7, 172.3, 173.2; IR (KBr) v 3273, 3061, 2926, 1784,
1739, 1644, 1603, 1552, 1499, 1332, 1201, 1111, 999, 697 cm−1;
HRMS (ESI-TOF) calcd for C26H22N2NaO4 [M + Na]+ 449.1472,
found 449.1478.
N-(1′-Methyl-2′,5-dioxo-3-(p-tolyl)-4,5-dihydro-3H-spiro[furan-
2,3′-indolin]-4-yl)benzamide (3i). White solid (77.6 mg, 91% yield),
1
80:20:0:0 dr (as determined by H NMR spectroscopy of the crude
1
product); mp 105.8−107.3 °C; H NMR (300 MHz, DMSO-d6) δ
2.15 (s, 3H), 2.86 (s, 3H), 4.56 (d, J = 12.6 Hz, 1H), 5.94 (dd, J = 8.4
Hz, 12.6 Hz, 1H), 6.84 (d, J = 8.1 Hz, 2H), 6.98−7.01 (m, 3H), 7.29−
7.34 (m, 1H), 7.47−7.57 (m, 4H), 7.66 (d, J = 7.2 Hz, 1H), 7.82−7.85
(m, 2H), 9.15 (d, J = 8.4 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ
20.9, 26.4, 51.3, 53.1, 84.0, 110.1, 124.2, 124.3, 124.7, 127.6, 128.0,
128.4, 129.0, 129.5, 132.2, 132.5, 133.2, 138.0, 144.7, 166.7, 172.5,
173.3; IR (KBr) v 3377, 3056, 2931, 1806, 1732, 1650, 1616, 1516,
1494, 1470, 1343, 1256, 1164, 978, 754, 696 cm−1; HRMS (ESI-TOF)
calcd for C26H22N2NaO4 [M + Na]+ 449.1472, found 449.1472.
N-(3-(4-Methoxyphenyl)-1′-methyl-2′,5-dioxo-4,5-dihydro-3H-
spiro[furan-2,3′-indolin]-4-yl)benzamide (3j). White solid (77.9 mg,
N-(3-(2-Fluorophenyl)-1′-methyl-2′,5-dioxo-4,5-dihydro-3H-
spiro[furan-2,3′-indolin]-4-yl)benzamide (3e). White solid (80.1 mg,
93% yield), 75:25:0:0 dr (as determined by 1H NMR spectroscopy of
the crude product); mp 120.2−121.5 °C; 1H NMR (300 MHz,
DMSO-d6) δ 2.89 (s, 3H), 5.01 (d, J = 12.6 Hz, 1H), 5.93 (dd, J = 8.4
Hz, 12.6 Hz, 1H), 6.97 (d, J = 7.8 Hz, 2H), 7.21−7.29 (m, 3H), 7.45−
7.65 (m, 6H), 7.81−7.84 (m, 2H), 9.19 (d, J = 8.4 Hz, 1H); 13C NMR
(75 MHz, DMSO-d6) δ 26.1, 45.2, 51.1, 83.3, 109.6, 115.5 (d, J = 22.2
Hz, 1C), 118.0 (d, J = 13.7 Hz, 1C), 123.4, 123.7, 124.6 (d, J = 3.5 Hz,
1C), 124.7, 127.2, 128.7, 128.9, 130.6 (d, J = 8.6 Hz, 1C), 132.0 (d, J =
28.1 Hz, 1C), 132.7, 143.9, 161.0 (d, J = 245.8 Hz, 1C), 166.4, 172.1,
172.5; IR (KBr) v 3376, 3063, 2934, 1801, 1728, 1657, 1616, 1530,
1494, 1472, 1380, 1239, 1165, 753, 693 cm−1; HRMS (ESI-TOF)
calcd for C25H19FN2NaO4 [M + Na]+ 453.1221, found 453.1214.
N-(3-(2-Bromophenyl)-1′-methyl-2′,5-dioxo-4,5-dihydro-3H-
spiro[furan-2,3′-indolin]-4-yl)benzamide (3f). White solid (85.5 mg,
87% yield), 80:20:0:0 dr (as determined by 1H NMR spectroscopy of
the crude product); mp 117.9−119.3 °C; 1H NMR (300 MHz,
DMSO-d6) δ 2.94 (s, 3H), 5.39 (d, J = 12.3 Hz, 1H), 5.65 (dd, J = 7.8
Hz, 12.3 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H), 7.14−7.26 (m, 2H), 7.39−
7.57 (m, 6H), 7.71 (d, J = 7.2 Hz, 2H), 7.81 (d, J = 7.2 Hz, 2H), 9.24
(d, J = 7.8 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 26.1, 50.4, 53.6,
83.8, 109.6, 122.9, 123.3, 126.0, 127.2, 128.0, 128.6, 129.4, 130.5,
130.8, 131.8, 132.1, 132.7, 133.2, 143.8, 166.4, 172.1, 172.5; IR (KBr)
v 3339, 3061, 2925, 1802, 1727, 1654, 1616, 1530, 1491, 1472, 1377,
1241, 1160, 752, 693 cm−1; HRMS (ESI-TOF) calcd for
C25H19BrN2NaO4 [M + Na]+ 513.0420, found 513.0413.
1
88% yield), 83:17:0:0 dr (as determined by H NMR spectroscopy of
the crude product); mp 285.6−287.1 °C; 1H NMR (300 MHz,
DMSO-d6) δ 3.16 (s, 3H), 3.57 (s, 3H), 4.59 (d, J = 13.2 Hz, 1H),
6.04 (dd, J = 8.4 Hz, 13.2 Hz, 1H), 6.69 (d, J = 8.7 Hz, 2H), 6.91−7.01
(m, 3H), 7.05 (d, J = 7.5 Hz, 1H), 7.25−7.30 (m, 1H), 7.45−7.58 (m,
3H), 7.74 (d, J = 7.2 Hz, 1H), 7.87−7.89 (m, 2H), 9.28 (d, J = 8.4 Hz,
1H); 13C NMR (75 MHz, DMSO-d6) δ 26.5, 50.5, 51.5, 54.9, 83.2,
109.4, 113.9, 123.0, 123.6, 123.7, 125.5, 127.3, 128.5, 128.7, 131.0,
132.0, 132.9, 143.3, 158.6, 166.1, 171.8, 172.5; IR (KBr) v 3383, 3068,
2936, 1806, 1725, 1635, 1616, 1533, 1517, 1492, 1472, 1380, 1259,
1150, 1026, 830, 719 cm−1; HRMS (ESI-TOF) calcd for
C26H22N2NaO5 [M + Na]+ 465.1421, found 465.1402.
N-(3-(Benzo[d][1,3]dioxol-5-yl)-1′-methyl-2′,5-dioxo-4,5-dihydro-
3H-spiro[furan-2,3′-indolin]-4-yl)benzamide (3k). White solid (83.1
mg, 91% yield), 75:25:0:0 dr (as determined by 1H NMR spectroscopy
1
of the crude product); mp 242.8−244.2 °C; H NMR (300 MHz,
DMSO-d6) δ 3.16 (s, 3H), 4.58 (d, J = 13.2 Hz, 1H), 5.86 (s, 2H),
5.99 (dd, J = 8.4 Hz, 13.2 Hz, 1H), 6.48 (d, J = 8.1 Hz, 1H), 6.68 (d, J
= 6.6 Hz, 2H), 6.95 (d, J = 7.8 Hz, 1H), 7.03−7.08 (m, 1H), 7.28−
7.33 (m, 1H), 7.46−7.59 (m, 3H), 7.78 (d, J = 7.5 Hz, 1H), 7.89 (d, J
= 7.2 Hz, 2H), 9.29 (d, J = 8.4 Hz, 1H); 13C NMR (75 MHz, DMSO-
d6) δ 26.6, 50.7, 51.7, 83.1, 101.1, 107.5, 108.3, 109.5, 121.4, 123.0,
123.6, 125.7, 127.4, 128.5, 131.1, 132.0, 132.8, 143.3, 146.7, 147.3,
166.2, 171.8, 172.3; IR (KBr) v 3290, 3065, 2895, 1798, 1724, 1664,
1615, 1541, 1493, 1471, 1376, 1245, 1160, 936, 758 cm−1; HRMS
(ESI-TOF) calcd for C26H20N2NaO6 [M + Na]+ 479.1214, found
479.1201.
N-(3-(2,4-Dichlorophenyl)-1′-methyl-2′,5-dioxo-4,5-dihydro-3H-
spiro[furan-2,3′-indolin]-4-yl)benzamide (3g). White solid (79.9 mg,
1
83% yield), 80:20:0:0 dr (as determined by H NMR spectroscopy of
the crude product); mp 180.4−181.7 °C; 1H NMR (300 MHz,
DMSO-d6) δ 2.96 (s, 3H), 5.30 (d, J = 12.3 Hz, 1H), 5.72 (dd, J = 8.1
Hz, 12.3 Hz, 1H), 7.00 (d, J = 7.8 Hz, 1H), 7.23−7.28 (m, 1H), 7.43−
7.61 (m, 6H), 7.64−7.70 (m, 2H), 7.80 (d, J = 7.8 Hz, 2H), 9.20 (d, J
= 8.4 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 26.6, 48.1, 53.3,
83.8, 110.2, 123.4, 123.9, 125.9, 127.6, 128.1, 128.5, 129.1, 129.6,
131.1, 132.3, 132.6, 133.0, 134.4, 136.2, 144.2, 166.8, 172.3, 172.6; IR
(KBr) v 3381, 3065, 2930, 1801, 1725, 1650, 1616, 1531, 1473, 1378,
1329, 1166, 1009, 752, 694 cm−1; HRMS (ESI-TOF) calcd for
C25H18Cl2N2NaO4 [M + Na]+ 503.0536, found 503.0531.
N-(1′-Methyl-3-(naphthalen-1-yl)-2′,5-dioxo-4,5-dihydro-3H-
spiro[furan-2,3′-indolin]-4-yl) benzamide (3l). White solid (78.6 mg,
1
85% yield), 67:33:0:0 dr (as determined by H NMR spectroscopy of
the crude product); mp 255.6−257.1 °C; 1H NMR (300 MHz,
DMSO-d6) δ (one diastereomer) 2.76 (s, 3H), 5.65 (d, J = 12.6 Hz,
1H), 6.06 (dd, J = 8.4 Hz, 12.3 Hz, 1H), 6.71 (d, J = 6.9 Hz, 1H),
7.18−7.35 (m, 4H), 7.41−7.62 (m, 5H), 7.75−7.87 (m, 6H), 9.13 (d, J
5309
dx.doi.org/10.1021/jo500432c | J. Org. Chem. 2014, 79, 5305−5314

The Journal of Organic Chemistry
Note
= 8.1 Hz, 1H); δ (the other diastereomer) 2.85 (s, 3H), 5.51 (d, J =
12.9 Hz, 1H), 6.37 (dd, J = 8.1 Hz, 12.9 Hz, 1H), 6.65 (d, J = 7.8 Hz,
1H), 6.95−7.00 (m, 1H), 7.10−7.15 (m, 1H), 7.28−7.37 (m, 2H),
7.41−7.46 (m, 2H), 7.49−7.54 (m, 1H), 7.64−7.74 (m, 3H), 7.77−
7.93 (m, 5H), 9.33 (d, J = 8.1 Hz, 1H); 13C NMR (75 MHz, DMSO-
d6) δ (one diastereomer) 25.9, 46.9, 52.7, 84.2, 109.6, 122.3, 123.5,
123.7, 124.7, 125.2, 125.4, 125.6, 125.9, 126.9, 127.1, 128.6, 129.0,
131.7, 132.0, 132.1, 132.7, 133.2, 143.9, 166.4, 172.5, 172.8; δ (the
other diastereomer) 26.3, 47.2, 51.1, 83.1, 109.1, 122.4, 122.7, 123.6,
124.8, 125.7, 125.9, 126.1, 126.6, 127.3, 128.0, 128.1, 128.4, 128.7,
130.7, 131.8, 131.9, 132.8, 133.0, 142.8, 166.2, 172.4, 172.6; IR (KBr)
v 3367, 3058, 2929, 1801, 1716, 1671, 1616, 1526, 1492, 1471, 1379,
1325, 1163, 1011, 778, 693 cm−1; HRMS (ESI-TOF) calcd for
C29H22N2NaO4 [M + Na]+ 485.1472, found 485.1471.
HRMS (ESI-TOF) calcd for C26H21BrN2NaO4 [M + Na]+ 527.0577,
found 527.0577.
N-(1′-Ethyl-2′,5-dioxo-3-phenyl-4,5-dihydro-3H-spiro[furan-2,3′-
indolin]-4-yl)-2-methylbenzamide (3q). White solid (81.1 mg, 92%
1
yield), 67:33:0:0 dr (as determined by H NMR spectroscopy of the
crude product); mp 115.6−117.1 °C; 1H NMR (300 MHz, DMSO-d6)
δ 0.57 (t, J = 6.9 Hz, 3H), 2.24 (s, 3H), 3.26−3.33 (m, 1H), 3.46−3.55
(m, 1H), 4.50 (d, J = 12.6 Hz, 1H), 5.93 (dd, J = 8.7 Hz, 12.6 Hz, 1H),
6.90−6.92 (m, 2H), 7.03 (d, J = 7.8 Hz, 1H), 7.19−7.34 (m, 8H),
7.46−7.51 (m, 1H), 7.64 (d, J = 7.2 Hz, 1H), 8.86 (d, J = 8.4 Hz, 1H);
13C NMR (75 MHz, DMSO-d6) δ 12.0, 19.6, 34.4, 50.4, 53.7, 83.9,
110.0, 124.1, 124.4, 124.9, 126.1, 127.2, 128.0, 128.8, 128.9, 130.4,
131.2, 131.3, 132.3, 135.8, 135.9, 143.5, 169.7, 171.9, 173.2; IR (KBr)
v 3347, 3063, 2924, 1766, 1712, 1670, 1614, 1532, 1489, 1468, 1383,
1316, 1190, 730, 698 cm−1; HRMS (ESI-TOF) calcd for
C27H24N2NaO4 [M + Na]+ 463.1628, found 463.1617.
N-(1′-Methyl-2′,5-dioxo-3-(thiophen-2-yl)-4,5-dihydro-3H-spiro-
[furan-2,3′-indolin]-4-yl)benzamide (3m). White solid (79.5 mg, 95%
1
yield), 75:25:0:0 dr (as determined by H NMR spectroscopy of the
N-(1′-Ethyl-2′,5-dioxo-3-phenyl-4,5-dihydro-3H-spiro[furan-2,3′-
crude product); mp 134.3−135.8 °C; 1H NMR (300 MHz, DMSO-d6)
δ 2.96 (s, 3H), 4.80 (d, J = 12.3 Hz, 1H), 5.78 (dd, J = 8.4 Hz, 12.3
Hz, 1H), 6.88−6.92 (m, 2H), 7.10 (d, J = 7.8 Hz, 1H), 7.31−7.36 (m,
2H), 7.52−7.61 (m, 5H), 7.85−7.88 (m, 2H), 9.25 (d, J = 8.4 Hz,
1H); 13C NMR (75 MHz, DMSO-d6) δ 26.1, 48.7, 52.6, 83.0, 109.9,
123.3, 123.9, 124.4, 126.4, 126.6, 127.0, 127.2, 128.7, 132.2, 132.8,
133.8, 144.7, 166.4, 171.8, 172.2; IR (KBr) v 3360, 3062, 2928, 1802,
1727, 1651, 1616, 1530, 1491, 1471, 1383, 1244, 1162, 1004, 753, 709
cm−1; HRMS (ESI-TOF) calcd for C23H18N2NaO4S [M + Na]+
441.0879, found 441.0877.
indolin]-4-yl)-4-methylbenzamide (3r). White solid (79.3 mg, 90%
1
yield), 75:25:0:0 dr (as determined by H NMR spectroscopy of the
crude product); mp 117.2−118.6 °C; 1H NMR (300 MHz, DMSO-d6)
δ 0.55 (t, J = 6.9 Hz, 3H), 2.34 (s, 3H), 3.28−3.33 (m, 1H), 3.47−3.54
(m, 1H), 4.57 (d, J = 12.6 Hz, 1H), 5.96 (dd, J = 8.4 Hz, 12.6 Hz, 1H),
6.89−6.91 (m, 2H), 7.02 (d, J = 7.8 Hz, 1H), 7.18−7.20 (m, 3H),
7.28−7.34 (m, 3H), 7.47−7.49 (m, 1H), 7.67 (d, J = 6.6 Hz, 1H), 7.75
(d, J = 8.1 Hz, 2H), 9.08 (d, J = 8.4 Hz, 1H); 13C NMR (75 MHz,
DMSO-d6) δ 12.0, 21.4, 34.3, 50.6, 53.7, 84.0, 110.0, 124.1, 124.5,
124.9, 127.6, 128.1, 128.7, 128.8, 129.5, 130.5, 131.3, 132.2, 142.5,
143.5, 166.6, 172.0, 173.4; IR (KBr) v 3371, 3061, 2931, 1801, 1724,
1648, 1614, 1535, 1490, 1469, 1375, 1211, 1161, 1018, 751, 699 cm−1;
HRMS (ESI-TOF) calcd for C27H24N2NaO4 [M + Na]+ 463.1628,
found 463.1625.
N-(3-(3-Fluorophenyl)-1′-methyl-2′,5-dioxo-4,5-dihydro-3H-
spiro[furan-2,3′-indolin]-4-yl) benzamide (3n). White solid (80.1 mg,
93% yield), 75:25:0:0 dr (as determined by 1H NMR spectroscopy of
the crude product); mp 138.4−139.8 °C; 1H NMR (300 MHz,
DMSO-d6) δ 3.15 (s, 3H), 4.64 (d, J = 13.2 Hz, 1H), 6.08 (dd, J = 8.1
Hz, 13.2 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 6.97−7.15 (m, 6H), 7.22−
7.27 (m, 1H), 7.38−7.44 (m, 1H), 7.48−7.57 (m, 1H), 7.67 (d, J = 9.6
Hz, 1H), 7.74 (d, J = 7.5 Hz, 2H), 9.41 (d, J = 8.1 Hz, 1H); 13C NMR
(75 MHz, DMSO-d6) δ 26.6, 50.4, 51.9, 83.2, 109.4, 114.2 (d, J = 22.9
Hz, 1C), 119.0 (d, J = 20.9 Hz, 1C), 123.0, 123.5, 123.6 (d, J = 2.6 Hz,
1C), 125.7, 127.4, 127.9, 128.5, 130.8 (d, J = 8.0 Hz, 1C), 131.0, 132.0,
135.1 (d, J = 6.8 Hz, 1C), 143.3, 162.0 (d, J = 243.2 Hz, 1C), 164.9,
171.8, 172.3; IR (KBr) v 3282, 3069, 2928, 1797, 1727, 1663, 1615,
1536, 1486, 1471, 1376, 1331, 1152, 1003, 802, 749 cm−1; HRMS
(ESI-TOF) calcd for C25H19FN2NaO4 [M + Na]+ 453.1221, found
453.1218.
N-(1′-Ethyl-2′,5-dioxo-3-phenyl-4,5-dihydro-3H-spiro[furan-2,3′-
indolin]-4-yl)-4-methoxybenzamide (3s). White solid (85.8 mg, 94%
1
yield), 67:33:0:0 dr (as determined by H NMR spectroscopy of the
crude product); mp 108.4−109.8 °C; 1H NMR (300 MHz, DMSO-d6)
δ 1.09 (t, J = 6.9 Hz, 3H), 3.61−3.68 (m, 1H), 3.76−3.83 (m, 4H),
4.64 (d, J = 13.2 Hz, 1H), 6.06 (dd, J = 8.4 Hz, 13.2 Hz, 1H), 6.91−
7.11 (m, 9H), 7.20−7.25 (m, 1H), 7.69 (d, J = 7.5 Hz, 1H), 7.85 (d, J
= 8.7 Hz, 2H), 9.14 (d, J = 8.4 Hz, 1H); 13C NMR (75 MHz, DMSO-
d6) δ 12.2, 34.7, 50.0, 52.2, 55.5, 83.0, 109.4, 113.7, 122.8, 123.8, 125.1,
125.7, 127.5, 127.9, 128.4, 129.3, 131.0, 132.1, 142.2, 162.1, 165.7,
171.4, 172.6; IR (KBr) v 3354, 3066, 2919, 1797, 1718, 1660, 1605,
1528, 1508, 1471, 1330, 1257, 1175, 1025, 850, 798, 699 cm−1; HRMS
(ESI-TOF) calcd for C27H24N2NaO5 [M + Na]+ 479.1577, found
479.1576.
N-(3-(4-Chlorophenyl)-1′-ethyl-2′,5-dioxo-4,5-dihydro-3H-spiro-
[furan-2,3′-indolin]-4-yl)benzamide (3o). White solid (82.0 mg, 89%
1
yield), 80:20:0:0 dr (as determined by H NMR spectroscopy of the
General Procedure for the Synthesis of Compounds 5. In an
ordinary vial equipped with a magnetic stirring bar, compound 4 (0.15
mmol, 1.0 equiv), compound 2 (0.18 mmol, 1.2 equiv), and catalyst
(DBU, 20 mol %) were dissolved in 10 mL of CH2Cl2, and then the
mixture was refluxed for the indicated time. After completion of the
reaction as indicated by TLC, the reaction mixture was directly
purified by flash chromatography (petroleum ether/ethyl acetate = 10/
1−2/1) on silica gel to yield the product 5.
N-(1′-Formyl-1-methyl-2,5′-dioxo-3′-phenylspiro[indoline-3,2′-
pyrrolidin]-4′-yl)benzamide (5a). White solid (61.3 mg, 93% yield),
>99:1:0:0 dr; mp 278.5−279.8 °C; 1H NMR (300 MHz, DMSO-d6) δ
3.13 (s, 3H), 4.37 (d, J = 13.2 Hz, 1H), 6.02 (dd, J = 8.4 Hz, 12.9 Hz,
1H), 6.79 (d, J = 7.8 Hz, 1H), 6.95−6.99 (m, 3H), 7.04−7.14 (m,
4H), 7.44−7.55 (m, 3H), 7.66 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 7.2 Hz,
2H), 9.08 (s, 1H), 9.24 (d, J = 8.4 Hz, 1H); 13C NMR (75 MHz,
DMSO-d6) δ 26.5, 51.9, 52.2, 65.7, 108.5, 122.4, 124.0, 124.5, 127.3,
127.9, 128.1, 128.5, 129.7, 131.7, 132.0, 132.9, 143.2, 159.1, 166.2,
172.6, 172.7; IR (KBr) v 3362, 3061, 2925, 1765, 1713, 1665, 1615,
1536, 1492, 1472, 1382, 1341, 1253, 1096, 752, 697 cm−1; HRMS
(ESI-TOF) calcd for C26H21N3NaO4 [M + Na]+ 462.1424, found
462.1432.
crude product); mp 252.2−253.7 °C; 1H NMR (300 MHz, DMSO-d6)
δ 1.11 (t, J = 6.9 Hz, 3H), 3.66−3.82 (m, 2H), 4.64 (d, J = 13.2 Hz,
1H), 6.09 (dd, J = 8.1 Hz, 13.2 Hz, 1H), 6.97−7.11 (m, 4H), 7.21−
7.28 (m, 3H), 7.46−7.57 (m, 3H), 7.78 (d, J = 7.5 Hz, 1H), 7.88 (d, J
= 7.2 Hz, 2H), 9.33 (d, J = 8.1 Hz, 1H); 13C NMR (75 MHz, DMSO-
d6) δ 12.6, 35.2, 50.6, 52.1, 83.2, 109.9, 123.3, 123.9, 126.2, 127.8,
128.8, 128.9, 129.9, 131.5, 131.6, 132.4, 133.0, 133.2, 142.5, 166.6,
171.7, 172.6; IR (KBr) v 3357, 3057, 2927, 1797, 1717, 1667, 1618,
1520, 1489, 1469, 1384, 1334, 1162, 1021, 752, 725 cm−1; HRMS
(ESI-TOF) calcd for C26H21ClN2NaO4 [M + Na]+ 483.1082, found
483.1067.
4-Bromo-N-(1′-ethyl-2′,5-dioxo-3-phenyl-4,5-dihydro-3H-spiro-
[furan-2,3′-indolin]-4-yl)benzamide (3p). White solid (92.0 mg, 91%
1
yield), 80:20:0:0 dr (as determined by H NMR spectroscopy of the
crude product); mp 117.9−119.4 °C; 1H NMR (300 MHz, DMSO-d6)
δ 0.55 (t, J = 7.2 Hz, 3H), 3.29−3.33 (m, 1H), 3.47−3.54 (m, 1H),
4.55 (d, J = 12.6 Hz, 1H), 5.95 (dd, J = 8.4 Hz, 12.6 Hz, 1H), 6.88−
6.91 (m, 2H), 7.02 (d, J = 7.8 Hz, 1H), 7.16−7.20 (m, 3H), 7.29−7.34
(m, 1H), 7.47−7.52 (m, 1H), 7.67 (d, J = 6.9 Hz, 1H), 7.72 (d, J = 8.7
Hz, 2H), 7.79 (d, J = 8.7 Hz, 2H), 9.27 (d, J = 8.4 Hz, 1H); 13C NMR
(75 MHz, DMSO-d6) δ 12.0, 34.3, 50.7, 53.7, 84.0, 110.0, 124.1, 124.3,
124.9, 126.3, 128.1, 128.7, 128.9, 129.7, 131.2, 132.1, 132.3, 143.5,
165.8, 171.9, 173.2; IR (KBr) v 3350, 3062, 2935, 1801, 1725, 1664,
1616, 1533, 1484, 1469, 1375, 1211, 1162, 1012, 752, 699 cm−1;
N-(1-Ethyl-1′-formyl-2,5′-dioxo-3′-phenylspiro[indoline-3,2′-pyr-
rolidin]-4′-yl)benzamide (5b). White solid (62.6 mg, 92% yield),
1
92:8:0:0 dr; mp 268.5−269.7 °C; H NMR (300 MHz, DMSO-d6) δ
1.08 (t, J = 6.9 Hz, 3H), 3.64−3.78 (m, 2H), 4.38 (d, J = 13.2 Hz, 1H),
5310
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The Journal of Organic Chemistry
Note
6.03 (dd, J = 8.4 Hz, 13.2 Hz, 1H), 6.82 (d, J = 7.8 Hz, 1H), 6.94−7.14
(m, 7H), 7.46−7.55 (m, 3H), 7.67 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 7.2
Hz, 2H), 9.08 (s, 1H), 9.25 (d, J = 8.4 Hz, 1H); 13C NMR (75 MHz,
DMSO-d6) δ 12.0, 34.6, 52.0, 52.2, 65.6, 108.6, 122.2, 124.2, 124.8,
127.4, 127.9, 128.0, 128.1, 128.5, 129.7, 131.6, 132.0, 132.9, 142.2,
159.1, 166.2, 172.3, 172.7; IR (KBr) v 3377, 3062, 2931, 1763, 1705,
1666, 1615, 1530, 1490, 1469, 1379, 1338, 1316, 1286, 1097, 713, 698
cm−1; HRMS (ESI-TOF) calcd for C27H23N3NaO4 [M + Na]+
476.1581, found 476.1588.
47.4, 53.5, 64.9, 108.5, 122.0, 123.9, 125.2, 126.5, 127.4, 128.5, 128.7,
129.5, 129.9, 132.0, 132.2, 132.8, 133.1, 135.3, 143.3, 159.2, 166.2,
172.1, 172.6; IR (KBr) v 3333, 3061, 2933, 1764, 1717, 1662, 1615,
1532, 1492, 1472, 1381, 1337, 1297, 1254, 755, 695 cm−1; HRMS
(ESI-TOF) calcd for C26H19Cl2N3NaO4 [M + Na]+ 530.0645, found
530.0670.
N-(3′-(2,4-Dichlorophenyl)-1′-formyl-2,5′-dioxo-1-phenylspiro-
[indoline-3,2′-pyrrolidin]-4′-yl)benzamide (5h). White solid (73.6
1
mg, 86% yield), 96:4:0:0 dr; mp 278.2−279.7 °C; H NMR (300
MHz, DMSO-d6) δ 4.95 (d, J = 12.6 Hz, 1H), 6.19 (dd, J = 8.1 Hz,
12.3 Hz, 1H), 6.49 (d, J = 7.8 Hz, 1H), 6.99−7.04 (m, 1H), 7.10−7.15
(m, 1H), 7.24−7.29 (m, 3H), 7.45−7.63 (m, 8H), 7.85 (d, J = 7.2 Hz,
2H), 7.96 (d, J = 7.2 Hz, 1H), 9.18 (s, 1H), 9.37 (d, J = 8.1 Hz, 1H);
13C NMR (75 MHz, DMSO-d6) δ 47.5, 53.7, 65.2, 108.9, 122.7, 123.7,
N-(1′-Formyl-2,5′-dioxo-1,3′-diphenylspiro[indoline-3,2′-pyrroli-
din]-4′-yl)benzamide (5c). White solid (67.7 mg, 90% yield),
1
>99:1:0:0 dr; mp 296.2−297.6 °C; H NMR (300 MHz, DMSO-d6)
δ 4.47 (d, J = 12.9 Hz, 1H), 6.11 (dd, J = 8.4 Hz, 12.9 Hz, 1H), 6.40
(d, J = 7.8 Hz, 1H), 6.99−7.15 (m, 7H), 7.24 (d, J = 7.8 Hz, 2H),
7.43−7.54 (m, 4H), 7.57−7.63 (m, 2H), 7.76 (d, J = 7.2 Hz, 1H), 7.86
(d, J = 7.8 Hz, 2H), 9.16 (s, 1H), 9.29 (d, J = 8.4 Hz, 1H); 13C NMR
(75 MHz, DMSO-d6) δ 52.2, 52.3, 65.9, 108.9, 123.1, 123.8, 125.2,
126.4, 127.4, 128.0, 128.1, 128.2, 128.5, 128.6, 128.7, 129.9, 130.0,
131.7, 132.1, 132.9, 133.8, 143.1, 159.4, 166.3, 172.4, 172.5; IR (KBr)
v 3351, 3062, 2924, 1769, 1708, 1667, 1614, 1533, 1500, 1467, 1378,
1317, 1259, 1026, 755, 700 cm−1; HRMS (ESI-TOF) calcd for
C31H23N3NaO4 [M + Na]+ 524.1581, found 524.1583.
125.9, 126.3, 126.7, 127.4, 128.6, 128.8, 129.4, 129.9, 130.0, 132.1,
132.3, 132.8, 133.4, 134.0, 135.4, 143.2, 159.5, 166.2, 172.0, 172.2; IR
(KBr) v 3351, 3061, 2923, 1771, 1727, 1705, 1668, 1615, 1516, 1483,
1466, 1331, 1303, 1223, 756, 702 cm−1; HRMS (ESI-TOF) calcd for
C31H21Cl2N3NaO4 [M + Na]+ 592.0801, found 592.0817.
N-(1-Benzyl-3′-(2-fluorophenyl)-1′-formyl-2,5′-dioxospiro-
[indoline-3,2′-pyrrolidin]-4′-yl)benzamide (5i). White solid (72.8 mg,
1
91% yield), >99:1:0:0 dr; mp 218.3−219.5 °C; H NMR (300 MHz,
DMSO-d6) δ 4.76 (d, J = 12.9 Hz, 1H), 4.83 (d, J = 16.2 Hz, 1H), 4.94
(d, J = 16.2 Hz, 1H), 6.11 (dd, J = 8.4 Hz, 12.9 Hz, 1H), 6.56 (d, J =
7.8 Hz, 1H), 6.90−6.97 (m, 3H), 7.01−7.13 (m, 2H), 7.22−7.33 (m,
6H), 7.45−7.58 (m, 3H), 7.78 (d, J = 7.5 Hz, 1H), 7.86−7.88 (m,
2H), 9.15 (s, 1H), 9.31 (d, J = 8.1 Hz, 1H); 13C NMR (75 MHz,
DMSO-d6) δ 43.3, 45.0, 52.4, 65.3, 109.2, 115.1 (d, J = 21.9 Hz, 1C),
119.0 (d, J = 14.3 Hz, 1C), 122.3, 123.9, 125.1, 127.0, 127.4, 128.4,
128.6, 129.8, 130.0, 130.1, 132.1, 132.8, 135.6, 142.6, 159.3, 161.1 (d, J
= 244.6 Hz, 1C), 166.2, 172.3, 172.7; IR (KBr) v 3387, 3067, 2921,
1765, 1719, 1661, 1614, 1519, 1489, 1468, 1338, 1309, 1257, 754, 697
cm−1; HRMS (ESI-TOF) calcd for C32H24FN3NaO4 [M + Na]+
556.1643, found 556.1653.
N-(1-Benzyl-1′-formyl-2,5′-dioxo-3′-phenylspiro[indoline-3,2′-
pyrrolidin]-4′-yl)benzamide (5d). White solid (72.7 mg, 94% yield),
>99:1:0:0 dr; mp 231.2−232.7 °C; 1H NMR (300 MHz, DMSO-d6) δ
4.45 (d, J = 13.2 Hz, 1H), 4.86 (d, J = 15.9 Hz, 1H), 4.97 (d, J = 15.9
Hz, 1H), 6.04 (dd, J = 8.4 Hz, 13.2 Hz, 1H), 6.62 (d, J = 7.8 Hz, 1H),
6.92−7.06 (m, 7H), 7.24−7.29 (m, 5H), 7.44−7.55 (m, 3H), 7.73 (d, J
= 7.2 Hz, 1H), 7.87 (d, J = 7.2 Hz, 2H), 9.14 (s, 1H), 9.27 (d, J = 8.4
Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 43.4, 52.2, 52.6, 65.8,
109.3, 122.5, 124.1, 124.9, 127.4, 127.5, 128.0, 128.1, 128.4, 128.5,
128.6, 129.7, 131.5, 132.0, 132.9, 135.6, 142.5, 159.3, 166.3, 172.6,
172.9; IR (KBr) v 3369, 3062, 2926, 1801, 1728, 1649, 1615, 1532,
1489, 1469, 1383, 1330, 1181, 1163, 998, 752, 698 cm−1; HRMS (ESI-
TOF) calcd for C32H25N3NaO4 [M + Na]+ 538.1737, found 538.1756.
Ethyl 4′-Benzamido-2,5′-dioxo-1,3′-diphenylspiro[indoline-3,2′-
pyrrolidine]-1′-carboxylate (5e). White solid (71.2 mg, 87% yield),
N-(1-Benzyl-3′-(4-chlorophenyl)-1′-formyl-2,5′-dioxospiro-
[indoline-3,2′-pyrrolidin]-4′-yl)benzamide (5j). White solid (71.8 mg,
1
87% yield), 94:6:0:0 dr; mp 190.2−191.7 °C; H NMR (300 MHz,
1
95:5:0:0 dr; mp 196.8−198.3 °C; H NMR (300 MHz, DMSO-d6) δ
DMSO-d6) δ 4.40 (d, J = 12.9 Hz, 1H), 4.87 (d, J = 15.9 Hz, 1H), 4.97
(d, J = 15.9 Hz, 1H), 6.00 (dd, J = 8.4 Hz, 12.9 Hz, 1H), 6.68 (d, J =
7.8 Hz, 1H), 6.95−7.00 (m, 3H), 7.08−7.13 (m, 3H), 7.24−7.29 (m,
5H), 7.45−7.50 (m, 2H), 7.53−7.58 (m, 1H), 7.77 (d, J = 7.2 Hz,
1H), 7.86 (d, J = 7.2 Hz, 2H), 9.14 (s, 1H), 9.26 (d, J = 8.1 Hz, 1H);
13C NMR (75 MHz, DMSO-d6) δ 43.3, 51.7, 52.7, 65.6, 109.4, 122.6,
1.05 (t, J = 6.9 Hz, 3H), 4.13 (q, J = 6.9 Hz, 2H), 4.38 (d, J = 13.2 Hz,
1H), 5.99 (dd, J = 8.7 Hz, 13.2 Hz, 1H), 6.42 (d, J = 7.2 Hz, 1H),
7.02−7.14 (m, 7H), 7.22 (d, J = 7.8 Hz, 2H), 7.44−7.54 (m, 4H),
7.58−7.63 (m, 2H), 7.78 (d, J = 7.2 Hz, 1H), 7.85 (d, J = 7.8 Hz, 2H),
9.18 (d, J = 8.4 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 13.9, 52.1,
55.0, 63.2, 68.1, 108.8, 123.1, 124.5, 125.0, 126.2, 127.3, 128.0, 128.2,
128.5, 129.8, 130.0, 131.7, 131.9, 133.0, 133.8, 142.7, 149.8, 166.2,
169.7, 173.2; IR (KBr) v 3386, 3060, 2925, 1806, 1731, 1668, 1613,
1529, 1501, 1374, 1337, 1316, 1268, 1218, 1039, 751, 699 cm−1;
HRMS (ESI-TOF) calcd for C33H27N3NaO5 [M + Na]+ 568.1843,
found 568.1865.
Ethyl 4′-Benzamido-1-benzyl-2,5′-dioxo-3′-phenylspiro[indoline-
3,2′-pyrrolidine]-1′- carboxylate (5f). White solid (77.2 mg, 92%
yield), >99:1:0:0 dr; mp 85.8−87.4 °C; 1H NMR (300 MHz, DMSO-
d6) δ 0.96 (t, J = 6.9 Hz, 3H), 3.95−4.05 (m, 2H), 4.33 (d, J = 13.2
Hz, 1H), 4.78 (d, J = 15.9 Hz, 1H), 4.89 (d, J = 15.9 Hz, 1H), 5.88
(dd, J = 8.4 Hz, 13.2 Hz, 1H), 6.64 (d, J = 7.8 Hz, 1H), 6.91−7.08 (m,
7H), 7.17−7.28 (m, 5H), 7.44−7.50 (m, 3H), 7.70 (d, J = 7.2 Hz,
1H), 7.82 (d, J = 7.2 Hz, 2H), 9.13 (d, J = 8.4 Hz, 1H); 13C NMR (75
MHz, DMSO-d6) δ 13.7, 43.5, 51.8, 52.6, 63.0, 68.0, 109.2, 122.5,
124.2, 125.3, 127.3, 127.5, 128.0, 128.4, 128.5, 129.7, 131.6, 131.9,
133.0, 135.6, 142.4, 149.6, 166.2, 169.8, 173.8; IR (KBr) v 3332, 3062,
2927, 1764, 1730, 1708, 1676, 1616, 1544, 1488, 1469, 1369, 1298,
1260, 1183, 1032, 749, 700 cm−1; HRMS (ESI-TOF) calcd for
C34H29N3NaO5 [M + Na]+ 582.1999, found 582.2022.
123.8, 124.9, 127.3, 127.4, 127.5, 128.1, 128.5, 128.6, 129.9, 130.2,
130.6, 132.1, 132.7, 132.8, 135.6, 142.3, 159.3, 166.3, 172.3, 172.7; IR
(KBr) v 3367, 3067, 2931, 1765, 1719, 1665, 1618, 1535, 1489, 1471,
1378, 1339, 1298, 1253, 753, 697 cm−1; HRMS (ESI-TOF) calcd for
C32H24ClN3NaO4 [M + Na]+ 572.1348, found 572.1361.
N-(1-Benzyl-3′-(4-cyanophenyl)-1′-formyl-2,5′-dioxospiro-
[indoline-3,2′-pyrrolidin]-4′-yl)benzamide (5k). White solid (74.6
1
mg, 92% yield), 94:6:0:0 dr; mp 192.3−193.7 °C; H NMR (300
MHz, DMSO-d6) δ 4.49 (d, J = 12.9 Hz, 1H), 4.85 (d, J = 15.9 Hz,
1H), 5.00 (J = 15.9 Hz, 1H), 6.08 (dd, J = 8.1 Hz, 12.9 Hz, 1H), 6.69
(d, J = 7.8 Hz, 1H), 6.94−6.99 (m, 1H), 7.06−7.13 (m, 1H), 7.17 (d, J
= 8.4 Hz, 2H), 7.28−7.31 (m, 5H), 7.45−7.58 (m, 5H), 7.80 (d, J =
7.2 Hz, 1H), 7.84−7.87 (m, 2H), 9.15 (s, 1H), 9.30 (d, J = 8.1 Hz,
1H); 13C NMR (75 MHz, DMSO-d6) δ 43.4, 52.1, 52.5, 65.5, 109.4,
110.8, 118.2, 122.7, 123.5, 125.0, 127.4, 127.5, 127.6, 128.5, 128.6,
129.4, 130.0, 131.9, 132.1, 132.7, 135.6, 137.4, 142.2, 159.3, 166.3,
172.1, 172.5; IR (KBr) v 3262, 3063, 2925, 1769, 1722, 1698, 1652,
1614, 1540, 1489, 1468, 1334, 1309, 1252, 1029, 751, 700 cm−1;
HRMS (ESI-TOF) calcd for C33H24N4NaO4 [M + Na]+ 563.1690,
found 563.1689.
N-(3′-(2,4-Dichlorophenyl)-1′-formyl-1-methyl-2,5′-dioxospiro-
N-(1′-Formyl-3′-(3-methoxyphenyl)-2,5′-dioxo-1-phenylspiro-
[indoline-3,2′-pyrrolidin]-4′-yl)benzamide (5g). White solid (68.6
[indoline-3,2′-pyrrolidin]-4′-yl)benzamide (5l). White solid (70.2 mg,
1
1
mg, 90% yield), >99:1:0:0 dr; mp 333.8−335.2 °C; H NMR (300
88% yield), >99:1:0:0 dr; mp 171.2−172.7 °C; H NMR (300 MHz,
MHz, DMSO-d6) δ 3.08 (s, 3H), 4.81 (d, J = 12.6 Hz, 1H), 6.09 (dd, J
= 8.4 Hz, 12.3 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 6.92−6.97 (m, 1H),
7.15−7.20 (m, 2H), 7.39−7.58 (m, 5H), 7.83−7.85 (m, 3H), 9.10 (s,
1H), 9.32 (d, J = 8.1 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 26.6,
DMSO-d6) δ 3.59 (s, 3H), 4.46 (d, J = 12.9 Hz, 1H), 6.10 (dd, J = 8.4
Hz, 12.9 Hz, 1H), 6.46 (d, J = 7.8 Hz, 1H), 6.66−6.70 (m, 3H), 7.00−
7.04 (m, 1H), 7.06−7.13 (m, 2H), 7.26 (d, J = 7.5 Hz, 2H), 7.48−7.62
(m, 6H), 7.79 (d, J = 7.2 Hz, 1H), 7.89 (d, J = 7.2 Hz, 2H), 9.17 (s,
5311
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The Journal of Organic Chemistry
Note
1H), 9.31 (d, J = 8.1 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 52.2,
52.3, 55.0, 65.8, 108.9, 113.5, 113.6, 120.4, 123.0, 123.8, 125.2, 126.4,
127.4, 128.6, 128.7, 129.4, 129.9, 130.0, 132.1, 132.9, 133.3, 133.9,
143.1, 158.9, 159.4, 166.3, 172.4; IR (KBr) v 3375, 3061, 2922, 1765,
1715, 1702, 1664, 1613, 1528, 1499, 1466, 1377, 1330, 1294, 1261,
1028, 751, 699 cm−1; HRMS (ESI-TOF) calcd for C32H25N3NaO5 [M
+ Na]+ 554.1686, found 554.1667.
6.80 (s, 1H), 6.94−7.02 (m, 2H), 7.22−7.24 (m, 2H), 7.47−7.57 (m,
3H), 7.63 (d, J = 7.2 Hz, 1H), 7.88 (d, J = 6.9 Hz, 2H), 9.06 (s, 1H),
9.28 (d, J = 8.4 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 12.0, 34.7,
47.6, 54.5, 65.4, 108.8, 122.3, 124.0, 124.9, 126.3, 126.6, 126.8, 127.3,
128.4, 128.6, 130.1, 132.0, 132.9, 134.5, 142.8, 159.1, 166.3, 171.8,
171.9; IR (KBr) v 3326, 3063, 2926, 1771, 1718, 1703, 1675, 1616,
1540, 1492, 1469, 1297, 1263, 1026, 755, 697 cm−1; HRMS (ESI-
TOF) calcd for C25H21N3NaO4S [M + Na]+ 482.1145, found
482.1122.
N-(1′-Formyl-3′-(4-methoxyphenyl)-2,5′-dioxo-1-phenylspiro-
[indoline-3,2′-pyrrolidin]-4′-yl)benzamide (5m). White solid (68.6
1
mg, 86% yield), 96:4:0:0 dr; mp 264.3−265.8 °C; H NMR (300
N-(1-Benzyl-1′-formyl-2,5′-dioxo-3′-(thiophen-2-yl)spiro-
MHz, DMSO-d6) δ 3.60 (s, 3H), 4.39 (d, J = 13.2 Hz, 1H), 6.04 (dd, J
= 8.4 Hz, 13.2 Hz, 1H), 6.46 (d, J = 7.8 Hz, 1H), 6.72 (d, J = 8.7 Hz,
2H), 7.00−7.06 (m, 3H), 7.09−7.14 (m, 1H), 7.26 (d, J = 7.5 Hz,
2H), 7.45−7.56 (m, 4H), 7.59−7.64 (m, 2H), 7.77 (d, J = 7.2 Hz,
1H), 7.87 (d, J = 7.2 Hz, 2H), 9.15 (s, 1H), 9.25 (d, J = 8.4 Hz, 1H);
13C NMR (75 MHz, DMSO-d6) δ 51.8, 52.4, 55.0, 65.9, 108.9, 113.6,
[indoline-3,2′-pyrrolidin]-4′-yl)benzamide (5r). White solid (68.8 mg,
1
88% yield), >99:1:0:0 dr; mp 275.6−277.1 °C; H NMR (300 MHz,
DMSO-d6) δ 4.65 (d, J = 12.9 Hz, 1H), 4.85 (d, J = 16.2 Hz, 1H), 5.02
(d, J = 16.2 Hz, 1H), 5.73 (dd, J = 8.4 Hz, 12.6 Hz, 1H), 6.67−6.75
(m, 3H), 6.97−7.02 (m, 1H), 7.13−7.28 (m, 7H), 7.46−7.58 (m, 3H),
7.71 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 7.2 Hz, 2H), 9.12 (s, 1H), 9.30
(d, J = 8.1 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 43.4, 48.1, 55.1,
65.5, 109.5, 122.7, 123.9, 125.0, 126.6, 127.1, 127.4, 127.5, 128.5,
128.6, 130.1, 132.1, 132.9, 134.3, 135.5, 142.9, 159.3, 166.3, 171.7,
172.5; IR (KBr) v 3310, 3064, 2923, 1770, 1718, 1702, 1672, 1614,
1541, 1489, 1468, 1298, 1265, 1025, 719, 699 cm−1; HRMS (ESI-
TOF) calcd for C30H23N3NaO4S [M + Na]+ 544.1301, found
544.1319.
123.1, 123.3, 124.0, 125.1, 126.5, 127.4, 128.6, 128.7, 129.2, 129.9,
130.0, 132.0, 132.9, 133.9, 143.1, 158.8, 159.4, 166.2, 172.5; IR (KBr)
v 3371, 3063, 2928, 1769, 1712, 1660, 1614, 1517, 1501, 1467, 1315,
1256, 1231, 1028, 754, 700 cm−1; HRMS (ESI-TOF) calcd for
C32H25N3NaO5 [M + Na]+ 554.1686, found 554.1670.
N-(1-Benzyl-1′-formyl-2,5′-dioxo-3′-(p-tolyl)spiro[indoline-3,2′-
pyrrolidin]-4′-yl)benzamide (5n). White solid (71.5 mg, 90% yield),
>99:1:0:0 dr; mp 199.8−201.2 °C; 1H NMR (300 MHz, DMSO-d6) δ
2.07 (s, 3H), 4.36 (d, J = 13.2 Hz, 1H), 4.84 (d, J = 15.9 Hz, 1H), 4.94
(d, J = 15.9 Hz, 1H), 5.97 (dd, J = 8.4 Hz, 13.2 Hz, 1H), 6.61 (d, J =
7.8 Hz, 1H), 6.81−6.87 (m, 4H), 6.92−6.97 (m, 1H), 7.04−7.09 (m,
1H), 7.20−7.29 (m, 5H), 7.43−7.56 (m, 3H), 7.71 (d, J = 7.2 Hz,
1H), 7.84 (d, J = 7.2 Hz, 2H), 9.11 (s, 1H), 9.21 (d, J = 8.4 Hz, 1H);
13C NMR (75 MHz, DMSO-d6) δ 20.9, 43.6, 52.3, 53.1, 66.1, 109.7,
122.8, 124.5, 125.1, 127.6, 127.7, 127.8, 128.6, 128.8, 128.9, 129.0,
130.1, 132.3, 133.2, 135.9, 137.5, 142.8, 159.6, 166.5, 173.0, 173.2; IR
(KBr) v 3270, 3063, 2925, 1762, 1719, 1704, 1655, 1615, 1548, 1487,
1333, 1319, 1308, 1250, 1026, 752, 700 cm−1; HRMS (ESI-TOF)
calcd for C33H27N3NaO4 [M + Na]+ 552.1894, found 552.1899.
N-(1-Benzyl-1′-formyl-3′-(4-methoxyphenyl)-2,5′-dioxospiro-
[indoline-3,2′-pyrrolidin]-4′-yl)benzamide (5o). White solid (72.8
mg, 89% yield), >99:1:0:0 dr; mp 87.2−88.7 °C; 1H NMR (300 MHz,
DMSO-d6) δ 3.57 (s, 3H), 4.36 (d, J = 13.2 Hz, 1H), 4.87 (d, J = 16.2
Hz, 1H), 4.94 (d, J = 16.2 Hz, 1H), 5.96 (dd, J = 8.4 Hz, 12.9 Hz, 1H),
6.57 (d, J = 8.4 Hz, 2H), 6.66 (d, J = 7.8 Hz, 1H), 6.89 (d, J = 8.4 Hz,
2H), 6.95−7.00 (m, 1H), 7.07−7.13 (m, 1H), 7.28−7.32 (m, 5H),
7.45−7.58 (m, 3H), 7.73 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 7.5 Hz, 2H),
9.13 (s, 1H), 9.23 (d, J = 8.4 Hz, 1H); 13C NMR (75 MHz, DMSO-
d6) δ 43.3, 51.8, 52.9, 54.9, 65.8, 109.3, 113.4, 122.5, 123.1, 124.2,
124.8, 127.4, 127.5, 128.5, 128.6, 129.6, 129.7, 132.0, 132.9, 135.6,
142.5, 158.7, 159.3, 166.2, 172.6, 172.9; IR (KBr) v 3337, 3062, 2930,
1762, 1714, 1668, 1614, 1534, 1516, 1468, 1340, 1313, 1252, 1181,
1026, 700 cm−1; HRMS (ESI-TOF) calcd for C33H27N3NaO5 [M +
Na]+ 568.1843, found 568.1838.
N-(1′-Formyl-3′-(furan-2-yl)-2,5′-dioxo-1-phenylspiro[indoline-
3,2′-pyrrolidin]-4′-yl)benzamide (5s). White solid (60.5 mg, 82%
yield), 94:6:0:0 dr; mp 175.6−177.2 °C; 1H NMR (300 MHz, DMSO-
d6) δ 4.47 (d, J = 12.6 Hz, 1H), 5.86 (dd, J = 8.4 Hz, 12.6 Hz, 1H),
6.18 (s, 1H), 6.29 (d, J = 3.0 Hz, 1H), 6.59 (d, J = 7.8 Hz, 1H), 6.98−
7.03 (m, 1H), 7.15−7.20 (m, 1H), 7.38−7.41 (m, 3H), 7.49−7.59 (m,
4H), 7.62−7.67 (m, 3H), 7.91 (d, J = 7.2 Hz, 2H), 9.14 (s, 1H), 9.39
(d, J = 8.4 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 46.4, 52.3, 64.6,
108.5, 108.9, 110.4, 123.0, 123.6, 125.1, 126.6, 127.4, 128.7, 130.0,
132.1, 132.9, 134.1, 143.4, 143.6, 147.9, 159.5, 166.4, 171.8, 172.1; IR
(KBr) v 3356, 3063, 2928, 1773, 1716, 1668, 1616, 1545, 1491, 1465,
1292, 1268, 1026, 755, 697 cm−1; HRMS (ESI-TOF) calcd for
C29H21N3NaO5 [M + Na]+ 514.1373, found 514.1389.
N-(1-Benzyl-1′-formyl-3′-(naphthalen-1-yl)-2,5′-dioxospiro-
[indoline-3,2′-pyrrolidin]-4′-yl)benzamide (5t). White solid (78.9 mg,
1
93% yield), >99:1:0:0 dr; mp 305.6−307.2 °C; H NMR (300 MHz,
DMSO-d6) δ 4.39 (d, J = 16.2 Hz, 1H), 4.63 (d, J = 16.2 Hz, 1H), 5.45
(d, J = 12.9 Hz, 1H), 6.18−6.25 (m, 2H), 6.77 (d, J = 7.2 Hz, 2H),
6.92−7.01 (m, 4H), 7.06−7.11 (m, 1H), 7.18−7.23 (m, 1H), 7.38−
7.53 (m, 6H), 7.65 (d, J = 8.1 Hz, 1H), 7.77−7.90 (m, 4H), 8.06 (d, J
= 8.4 Hz, 1H), 9.18 (s, 1H), 9.25 (d, J = 8.1 Hz, 1H); 13C NMR (75
MHz, DMSO-d6) δ 43.1, 46.0, 54.2, 65.9, 109.3, 122.4, 122.6, 124.4,
124.5, 126.5, 126.6, 127.1, 127.3, 127.6, 128.3, 128.4, 128.5, 128.8,
132.4, 132.8, 133.1, 135.1, 142.1, 159.4, 166.3, 172.7, 173.4; IR (KBr)
v 3357, 3067, 2924, 1768, 1720, 1698, 1668, 1615, 1538, 1490, 1468,
1334, 1315, 1298, 780, 757, 715 cm−1; HRMS (ESI-TOF) calcd for
C36H27N3NaO4 [M + Na]+ 588.1894, found 588.1900.
N-(1-Benzyl-1′-formyl-2,5′-dioxo-3′-phenylspiro[indoline-3,2′-
N-(3′-(Benzo[d][1,3]dioxol-5-yl)-1-benzyl-1′-formyl-2,5′-
pyrrolidin]-4′-yl)-4-bromobenzamide (5u). White solid (73.1 mg,
dioxospiro[indoline-3,2′-pyrrolidin]-4′-yl)benzamide (5p). White
1
1
82% yield), >99:1:0:0 dr; mp 286.8−288.3 °C; H NMR (300 MHz,
solid (73.0 mg, 87% yield), >99:1:0:0 dr; mp 213.5−214.9 °C; H
DMSO-d6) δ 4.39 (d, J = 13.2 Hz, 1H), 4.85 (d, J = 15.9 Hz, 1H), 4.95
(d, J = 15.9 Hz, 1H), 6.00 (dd, J = 8.4 Hz, 12.9 Hz, 1H), 6.62 (d, J =
7.8 Hz, 1H), 6.92−7.09 (m, 7H), 7.26−7.32 (m, 5H), 7.69−7.81 (m,
5H), 9.12 (s, 1H), 9.34 (d, J = 8.1 Hz, 1H); 13C NMR (75 MHz,
DMSO-d6) δ 43.4, 52.1, 52.7, 65.8, 109.3, 122.5, 124.0, 124.9, 125.9,
127.4, 127.5, 128.0, 128.1, 128.3, 128.5, 129.5, 129.7, 131.5, 131.7,
132.0, 135.6, 142.4, 159.3, 165.4, 172.5, 172.9; IR (KBr) v 3367, 3056,
2924, 1769, 1718, 1706, 1658, 1615, 1528, 1485, 1467, 1335, 1315,
1301, 1012, 751, 727, 697 cm−1; HRMS (ESI-TOF) calcd for
C32H24BrN3NaO4 [M + Na]+ 616.0842, found 616.0860.
Procedure for the Catalytic Asymmetric Reaction of 3-
Aminooxindole 4c and (Z)-Olefinic Azlactone 2a. In an ordinary
vial equipped with a magnetic stirring bar, a solution of 4c (0.10
mmol), 2a (0.12 mmol), and catalyst A (5 mg, 10 mol %, 0.01 mmol)
in 3 mL of xylene was stirred at room temperature for 9 days. Then the
reaction mixture was directly purified by flash chromatography
(petroleum ether/ethyl acetate = 10/1−2/1) on silica gel to yield
NMR (300 MHz, DMSO-d6) δ 4.33 (d, J = 13.2 Hz, 1H), 4.87 (d, J =
16.2 Hz, 1H), 4.93 (d, J = 16.2 Hz, 1H), 5.84−5.94 (m, 3H), 6.41 (d, J
= 8.1 Hz, 1H), 6.55−6.58 (m, 2H), 6.65 (d, J = 7.8 Hz, 1H), 6.95−
7.00 (m, 1H), 7.09−7.14 (m, 1H), 7.27−7.30 (m, 5H), 7.44−7.56 (m,
3H), 7.75 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 7.2 Hz, 2H), 9.10 (s, 1H),
9.23 (d, J = 8.1 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 43.4, 52.0,
53.1, 65.8, 101.1, 107.9, 108.2, 109.4, 122.5, 124.1, 124.9, 125.2, 127.2,
127.4, 127.5, 128.5, 128.6, 129.8, 132.0, 132.9, 135.6, 142.5, 146.8,
146.9, 159.3, 166.2, 172.4, 172.9; IR (KBr) v 3330, 3064, 2925, 1761,
1719, 1702, 1658, 1615, 1504, 1490, 1335, 1307, 1243, 1040, 753, 700
cm−1; HRMS (ESI-TOF) calcd for C33H25N3NaO6 [M + Na]+
582.1636, found 582.1646.
N-(1-Ethyl-1′-formyl-2,5′-dioxo-3′-(thiophen-2-yl)spiro[indoline-
3,2′-pyrrolidine]-4′-yl)benzamide (5q). White solid (58.6 mg, 85%
yield), 92:8:0:0 dr; mp 223.5−234.9 °C; 1H NMR (300 MHz, DMSO-
d6) δ 1.14 (t, J = 6.9 Hz, 3H), 3.75 (q, J = 6.9 Hz, 2H), 4.59 (d, J =
12.9 Hz, 1H), 5.78 (dd, J = 8.4 Hz, 12.9 Hz, 1H), 6.75−6.77 (m, 1H),
5312
dx.doi.org/10.1021/jo500432c | J. Org. Chem. 2014, 79, 5305−5314

The Journal of Organic Chemistry
Note
chiral product 5c (23.6 mg, 47% yield) as a white solid with >99:1 dr
and 61% ee. [α]2D0 = +2.5 (c 0.50, CHCl3); the ee was determined by
HPLC (Chiralpak OD-H, i-PrOH/hexane = 20/80, flow rate = 1.0
mL/min, λ = 254 nm, tminor = 8.0 min, tmajor = 7.2 min); the 1H NMR
and 13C NMR data for chiral compound 5c were same as those of the
racemic compound 5c.
(2) Peddibhotla, S. Curr. Bioact. Compd. 2009, 5, 20.
(3) For reviews of the construction of spirocyclic oxindoles, see:
(a) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209. (b) Trost,
B. M.; Brennan, M. K. Synthesis 2009, 3003. (c) Liu, Y.-L.; Zhou, J.
Adv. Synth. Catal. 2010, 352, 1381. (d) Alba, A.-N. R.; Rios, R.
Chem.Asian J. 2011, 6, 720. (e) Ball-Jones, N. R.; Badillo, J. J.; Franz,
A. K. Org. Biomol. Chem. 2012, 10, 5165. (f) Dalpozzo, R.; Bartoli, G.;
Bencivenni, G. Chem. Soc. Rev. 2012, 41, 7247. (g) Hong, L.; Wang, R.
Adv. Synth. Catal. 2013, 355, 1023.
(4) For selected examples containing a nitrogen atom at the C3
position of the oxindole unit, see: (a) Ochi, M.; Kawasaki, K.; Kataoka,
H.; Uchio, Y.; Nishi, H. Biochem. Biophys. Res. Commun. 2001, 283,
1118. (b) Bernard, K.; Bogliolo, S.; Ehrenfeld, J. Br. J. Pharmacol. 2005,
144, 1037. (c) Czarna, A.; Beck, B.; Srivastava, S.; Popowicz, G. M.;
Synthesis of N-(3′-(4-Methoxyphenyl)-2,5′-dioxo-1-
phenylspiro[indoline-3,2′-pyrrolidin]-4′-yl)benzamide (6). To
a solution of compound 5m (0.11 mmol, 59 mg) in CH2Cl2 (12 mL)
were successively added 10% NaOH(aq) (11 mL) and TBAB (3.5 mg,
0.011 mmol). The resulting mixture was stirred at the room
temperature for 5 h. After completion of the reaction as indicated
by TLC, the mixture was extracted with CH2Cl2, and the combined
organic layers were dried over anhydrous Na2SO4 and concentrated.
The residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 2/1) to yield product 6 as a white
Wolf, S.; Huang, Y.; Bista, M.; Holak, T. A.; Domling, A. Angew. Chem.,
̈
Int. Ed. 2010, 49, 5352. (d) Vintonyak, V. V.; Warburg, K.; Kruse, H.;
1
solid (31.0 mg, 56% yield, >99:1:0:0 dr). Mp 301.2−302.7 °C; H
Grimme, S.; Hubel, K.; Rauh, D.; Waldmann, H. Angew. Chem., Int. Ed.
̈
NMR (300 MHz, DMSO-d6) δ 3.59 (s, 3H), 4.31 (d, J = 12.6 Hz,
1H), 5.80 (dd, J = 9.0 Hz, 12.6 Hz, 1H), 6.48 (d, J = 7.5 Hz, 1H), 6.69
(d, J = 8.7 Hz, 2H), 7.00 (d, J = 8.7 Hz, 2H), 7.05−7.15 (m, 2H), 7.27
(d, J = 7.5 Hz, 2H), 7.42−7.55 (m, 5H), 7.59−7.64 (m, 2H), 7.88 (d, J
= 7.2 Hz, 2H), 8.76 (s, 1H), 9.02 (d, J = 9.0 Hz, 1H); 13C NMR (75
MHz, DMSO-d6) δ 51.1, 54.8, 55.0, 65.5, 109.1, 113.5, 123.3, 125.0,
125.3, 126.4, 127.4, 127.6, 128.4, 128.5, 129.0, 129.5, 130.0, 131.7,
133.4, 133.9, 142.3, 158.5, 166.3, 173.2, 174.8; IR (KBr) v 3359, 3061,
2928, 1731, 1705, 1659, 1614, 1543, 1515, 1500, 1466, 1254, 1033,
750, 700 cm−1; HRMS (ESI-TOF) calcd for C31H25N3NaO4 [M +
Na]+ 526.1737, found 526.1747.
2010, 49, 5902. (e) Crosignani, S.; Jorand-Lebrun, C.; Page, P.;
Campbell, G.; Colovray, V.; Missotten, M.; Humbert, Y.; Cleva, C.;
Arrighi, J.-F.; Gaudet, M.; Johnson, Z.; Ferro, P.; Chollet, A. ACS Med.
Chem. Lett. 2011, 2, 644.
(5) For selected examples containing an oxygen atom at the C3
position of the oxindole unit, see: (a) Heindel, N. D.; Minatelli, J. A. J.
Pharm. Sci. 1981, 70, 84. (b) Jimenez, J. I.; Huber, U.; Moore, R. E.;
Patterson, G. M. L. J. Nat. Prod. 1999, 62, 569. (c) Jiang, X.; Cao, Y.;
Wang, Y.; Liu, L.; Shen, F.; Wang, R. J. Am. Chem. Soc. 2010, 132,
15328. (d) Franz, A. K.; Dreyfuss, P. D.; Schreiber, S. L. J. Am. Chem.
Soc. 2007, 129, 1020. (e) Quasdorf, K. W.; Huters, A. D.; Lodewyk, M.
W.; Tantillo, D. J.; Garg, N. K. J. Am. Chem. Soc. 2012, 134, 1396.
(f) Rana, S.; Natarajan, A. Org. Biomol. Chem. 2013, 11, 244.
(6) For selected examples, see: (a) Yan, W.; Wang, D.; Feng, J.; Li,
P.; Zhao, D.; Wang, R. Org. Lett. 2009, 11, 3874. (b) Mouri, S.; Chen,
Z.; Mitsunuma, H.; Furutachi, M.; Matsunaga, S.; Shibasaki, M. J. Am.
Chem. Soc. 2010, 132, 1255. (c) Jung, H. H.; Buesking, A. W.; Ellman,
J. A. Org. Lett. 2011, 13, 3912. (d) Shen, K.; Liu, X.; Wang, G.; Lin, L.;
Feng, X. Angew. Chem., Int. Ed. 2011, 50, 4684. (e) Bergonzini, G.;
Melchiorre, P. Angew. Chem., Int. Ed. 2012, 51, 971. (f) Trost, B. M.;
Hirano, K. Org. Lett. 2012, 14, 2446. (g) Retini, M.; Bergonzini, G.;
Melchiorre, P. Chem. Commun. 2012, 48, 3336. (h) Chen, D.; Xu, M.-
H. Chem. Commun. 2013, 49, 1327. (i) Yamaguchi, E.; Mowat, J.;
Luong, T.; Krische, M. J. Angew. Chem., Int. Ed. 2013, 52, 8428.
(j) Wang, Q.-L.; Peng, L.; Wang, F.-Y.; Zhang, M.-L.; Jia, L.-N.; Tian,
F.; Xu, X.-Y.; Wang, L.-X. Chem. Commun. 2013, 49, 9422. (k) Silvi,
M.; Chatterjee, I.; Liu, Y.; Melchiorre, P. Angew. Chem., Int. Ed. 2013,
52, 10780.
Competition Experiment with 1a and 4a. In an ordinary vial
equipped with a magnetic stirring bar, 1a (0.1 mmol, 1.0 equiv), 4a
(0.1 mmol, 1.0 equiv), 2g (0.1 mmol, 1.0 equiv), and catalyst (DBU,
20 mol %) were dissolved in 10 mL of CH2Cl2, and then the mixture
was refluxed for 8 h under an Ar atmosphere. After completion of the
reaction as indicated by TLC, the solvent was removed in vacuo, and
1
the ratio of 3j and 5v was determined by H NMR analysis of the
crude mixture.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C NMR spectra for the products and single-
crystal X-ray crystallography data for 3m and 5b. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: yuanwc@cioc.ac.cn.
■
(7) For selected reviews, see: (a) Kitson, R. R. A.; Millemaggi, A.;
Taylor, R. J. K. Angew. Chem., Int. Ed. 2009, 48, 9426. (b) Elford, T.
G.; Hall, D. G. Synthesis 2010, 893.
Notes
The authors declare no competing financial interest.
(8) Cui, B.-D.; Han, W.-Y.; Wu, Z.-J.; Zhang, X.-M.; Yuan, W.-C. J.
Org. Chem. 2013, 78, 8833.
(9) For selected examples, see: (a) Shi, F.; Dai, A.-X.; Zhang, S.;
Zhang, X.-H.; Tu, S.-J. Eur. J. Med. Chem. 2003, 38, 597. (b) Yadav, L.
D. S.; Singh, A. Tetrahedron Lett. 2003, 44, 5637. (c) Tu, S.; Zhang, J.;
Jia, R.; Jiang, B.; Zhang, Y.; Jiang, H. Org. Biomol. Chem. 2007, 5, 1450.
(d) Yadav, L. D. S.; Rai, V. K. Tetrahedron 2007, 63, 6924. (e) Jiang,
H.; Gschwend, B.; Albrecht, Ł.; Hansen, S. G.; Jørgensen, K. A.
Chem.Eur. J. 2011, 17, 9032. (f) Alba, A.-N. R.; Calbet, T.; Font-
Bardía, M.; Moyano, A.; Rios, R. Eur. J. Org. Chem. 2011, 2053.
(g) Steurer, M.; Jensen, K. L.; Worgull, D.; Jørgensen, K. A. Chem.
Eur. J. 2012, 18, 76. (h) Halskov, K. S.; Johansen, T. K.; Davis, R. L.;
Steurer, M.; Jensen, F.; Jørgensen, K. A. J. Am. Chem. Soc. 2012, 134,
12943. (i) Uraguchi, D.; Ueki, Y.; Sugiyama, A.; Ooi, T. Chem. Sci.
2013, 4, 1308. (j) Dell’Amico, L.; Albrecht, Ł.; Naicker, T.; Poulsen, P.
H.; Jørgensen, K. A. J. Am. Chem. Soc. 2013, 135, 8063.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (21372217) and the Sichuan
Youth Science and Technology Foundation (2011JQ0046 and
2013JQ0021).
REFERENCES
■
(1) (a) Lin, H.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 36.
(b) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46,
8748. (c) Badillo, J. J.; Hanhan, N. V.; Franz, A. K. Curr. Opin. Drug
Discovery Dev. 2010, 13, 758. (d) Rottmann, M.; McNamara, C.;
Yeung, B. K. S.; Lee, M. C. S.; Zou, B.; Russell, B.; Seitz, P.; Plouffe, D.
M.; Dharia, N. V.; Tan, J.; Cohen, S. B.; Spencer, K. R.; Gonzalez-Paez,
G. E.; Lakshminarayana, S. B.; Goh, A.; Suwanarusk, R.; Jegla, T.;
Schmitt, E. K.; Beck, H. P.; Brun, R.; Nosten, F.; Renia, L.; Dartois, V.;
Keller, T. H.; Fidock, D. A.; Winzeler, E. A.; Diagana, T. T. Science
2010, 329, 1175. (e) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112,
6104.
(10) (a) Chen, W.-B.; Wu, Z.-J.; Pei, Q.-L.; Cun, L.-F.; Zhang, X.-M.;
Yuan, W.-C. Org. Lett. 2010, 12, 3132. (b) Chen, W.-B.; Wu, Z.-J.; Hu,
J.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2011, 13, 2472.
(c) Han, Y.-Y.; Chen, W.-B.; Han, W.-Y.; Wu, Z.-J.; Zhang, X.-M.;
Yuan, W.-C. Org. Lett. 2012, 14, 490. (d) Han, Y.-Y.; Han, W.-Y.; Hou,
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Note
X.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2012, 14, 4054. (e) Liu, X.-L.;
Han, W.-Y.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2013, 15, 1246.
(f) Chen, W.-B.; Han, W.-Y.; Han, Y.-Y.; Zhang, X.-M.; Yuan, W.-C.
Tetrahedron 2013, 69, 5281. (g) Han, W.-Y.; Li, S.-W.; Wu, Z.-J.;
Zhang, X.-M.; Yuan, W.-C. Chem.Eur. J. 2013, 19, 5551.
(11) For selected reviews of the application of tandem reactions in
organic synthesis, see: (a) Enders, D.; Grondal, C.; Huttl, M. R. M.
̈
Angew. Chem., Int. Ed. 2007, 46, 1570. (b) Grondal, C.; Jeanty, M.;
Enders, D. Nat. Chem. 2010, 2, 167. (c) Westermann, B.; Ayaz, M.;
van Berkel, S. S. Angew. Chem., Int. Ed. 2010, 49, 846. (d) Moyano, A.;
Rios, R. Chem. Rev. 2011, 111, 4703. (e) Pellissier, H. Chem. Rev. 2013,
113, 442.
(12) See the Supporting Information for details about the single-
crystal X-ray analyses of products 3m and 5b in this paper.
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