An environmentally benign approach for the synthesis of 3,3′-pyrrolidonyl spirooxindole derivatives via a cascade Knoevenagel-Michael-cyclization multicomponent reaction

Article abstract of DOI:10.1039/c3ra44119a

A series of 3,3′-pyrrolidonyl spirooxindole derivatives have been synthesized in good yields from the cascade Knoevenagel-Michael-cyclization multicomponent reaction of isatin, malononitrile and α-isothiocyanato imide in the presence of a catalytic amount

Full text of DOI:10.1039/c3ra44119a

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An environmentally benign approach for the synthesis
of 3,39-pyrrolidonyl spirooxindole derivatives via a
cascade Knoevenagel–Michael–cyclization
multicomponent reaction3
Cite this: RSC Advances, 2013, 3,
18857
Chengbin Yu,a Hairong Lyu,a Yan Cai,a Xinyu Miaob and Zhiwei Miao*a
A series of 3,39-pyrrolidonyl spirooxindole derivatives have been synthesized in good yields from the
cascade Knoevenagel–Michael–cyclization multicomponent reaction of isatin, malononitrile and a-iso-
thiocyanato imide in the presence of a catalytic amount of triethylamine ‘‘on water’’ assisted with
ultrasonic irradiation. The advantages of this method include high efficiency, mild reaction conditions and
environmentally benign reagents. The current process provides a simple and green method for creating
diversity-oriented syntheses of this intriguing class of compounds with potential biological activities.
Received 8th June 2013,
Accepted 9th August 2013
DOI: 10.1039/c3ra44119a
www.rsc.org/advances
intermediates are subsequently trapped by the appropriate
electron-deficient olefins to provide cyclic products. In con-
Introduction
3,39-Pyrrolidonyl spirooxindoles are structural motifs fre-
quently formed in numerous natural products and significant
biologically active compounds.1 Many 3,39-pyrrolidonyl spir-
ooxindoles, such as coerulescine,2 horsfiline,3 elacomine,4 and
rychnophylline1b show interesting biological activities (Fig. 1).
Consequently, approaches towards the efficient synthesis of
these molecules have received considerable attention.5 Many
of the known strategies have resulted in a different class of
spirocycle oxindole fused pyrrolidines that are showing
promise as biologically active compounds.6 In this context,
searching for creative procedures that could achieve high
reactivity for the construction of structurally diverse spirocycle
oxindoles is still challenging.
tinuation of our work on the multi-component synthesis of
heterocyclic compounds,9 we designed a unique synthetic
route to privileged heterocyclic scaffolds of medicinal rele-
vance that combine the synthetic efficiency of multi-compo-
nent protocols with the environmental benefit of using water
as a reaction medium. This reaction was achieved by reacting
isatin 1, malononitrile 2 and a-isothiocyanato imide 3 as
starting materials ‘‘on water’’ assisted with ultrasonic irradia-
tion.
Results and discussion
The growing importance of green chemistry has high-
lighted the search for transformations that are capable of
promoting two or more distinct transformations sequentially
in one pot with eco-friendly conditions or under aqueous
conditions.7 In this respect, one of the most promising
approaches is to perform organic reactions in aqueous media
under mild conditions.
a-Isothiocyanato derivatives are highly attractive nucleo-
philic reagents for a number of cascade reactions and multi-
component reactions.8 Their a-protons are readily removed by
bases to generate nucleophilic anions. The resulting reaction
We initiated our studies by evaluating the reaction between
N-methyl substituted isatin 1a, malononitrile 2, and a-iso-
thiocyanato imide 3 using Et3N as the catalyst in toluene at
room temperature (Table 1). We found that the reaction
proceeded smoothly and afforded the desired product in high
yield (Table 1, entry 1). Further seeking insight into the origin
of the rate of acceleration in this reaction, the results show
that polar protic solvents accelerate the reaction. The observed
reaction rates are in the following order: isopropyl alcohol #
THF . CH2Cl2 . diethyl ether . toluene (Table 1, entries 2–5).
aState Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai
University, Tianjin 300071, P. R. China. E-mail: miaozhiwei@nankai.edu.cn;
Fax: +86 2350 2351; Tel: +86 2350 4783
bTianjin Yaohua High School, Tianjin, 300040, P. R. China
Electronic supplementary information (ESI) available. CCDC 939641. For ESI
3
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c3ra44119a
Fig. 1 Representative examples of bioactive 3,39-pyrrolidinyl-spirooxindoles.
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Table 1 Screening of reaction conditionsa
Table 2 Substrate scope of the cascade Knoevenagel–Michael–cyclization
multicomponent reactionsa
R1 R2
Time (h) Yield (%)b Threo : erythro ratioc
Volume
(mL)
TEA
(mol%)
Time
(h)
Yield
(%)b
Entry
1
Entry
Solvent
1
2
3
4
5
6
7
8
1a CH3
1b CH3 5-CH3
1c CH3 5-NO2 24
1d CH3 5-Br
1e CH3 5-Cl
1f CH3 7-CH3
H
1.1
1.5
98
98
91
98
98
98
95
98
93
83
85
81
98
91
68
,10
51 : 49
55 : 45
64 : 36
51 : 49
56 : 44
51 : 49
51 : 49
55 : 45
52 : 48
51 : 49
51 : 49
63 : 37
61 : 39
62 : 38
67 : 33
—
1
2
3
4
5
6
7
8
PhCH3
Et2O
CH2Cl2
THF
3
3
3
3
3
3c
3d
5
5
5
5
5
5
5
15
15
15
15
15
15
15
15
15
30
50
100
10
5
9.0
8.5
5.5
0.8
0.8
0.8
0.8
24
1.0
1.0
0.6
0.3
1.1
1.5
95
98
98
98
98
98
98
98
98
98
98
98
98
98
7
8
5
8
(CH3)2CHOH
(CH3)2CHOH–H2O
(CH3)2CHOH–H2O
H2O
1g
1h
1i
1j
1k
1l
1m
1n
H
H
H
H
H
H
H
H
H
5-CH3 10
5-OCH3
5-NO2 30
5-Br
5-Cl
6-OCH3 10
7-CH3
H
9
3
9
H2Oe
10
11
12
13
14
15d
16
10
11
12
13
14
H2Oe
25
25
H2Oe
H2Oe
H2Oe
7
72
72
H2Oe
1o Bn
1p Ac
H
a
Reaction conditions: A solution of 1a (0.3 mmol), TEA, and
a
malononitrile 2 (0.3 mmol) in the right amount of solvent was
stirred at room temperature. After the reaction was completed
(monitored by TLC), a-isothiocyanato imide 3 (0.33 mmol) was
added and the mixture was further stirred at room temperature.
All reactions were carried out with isatin 1 (0.3 mmol),
malononitrile 2 (0.3 mmol) and Et3N (0.03 mmol) in H2O (5.0 mL) at
room temperature. After the reaction was completed (monitored by
TLC), a-isothiocyanato imide 3 (0.33 mmol) was added and the
mixture was sonicated at room temperature for 1 min in an
b
c
After purification by column chromatography. V(CH ) CHOH/VH O
=
3
2
2
d
e
b
1 : 1. V(CH ) CHOH/VH O = 1 : 2. Sonication irradiation 1 min.
ultrasound bath. After purification by column chromatography.
3
2
2
c
Threo/erythro ratio was determined by 1H NMR spectra of crude
d
product. 30 mol% Et3N has been employed.
This trend suggests that hydrogen bonding and dipolar effects
may be important for rate acceleration.10
Remarkably, with the use of aqueous isopropyl alcohol
solutions, the reaction proceeded efficiently and afforded
excellent yields (Table 1, entries 6,7). This observation
encouraged us to exclude organic solvents from the reaction
mixture. Interestingly, by using pure water as a solvent the
reaction proceeded very well and obtained the desired product
4a with an excellent yield (Table 1, entry 8). Sonication enables
the rapid dispersion of solids on the water surface allowing for
better contact between water and the reactants. The use of
Having established the optimal reaction parameters, we
then examined the generality of this reaction (Table 2). It is
shown that structurally varied isatin derivatives
1 can
efficiently engage in the reaction (Table 2, entries 1–14).
High yields (81–98%) were obtained, irrespective of the
differences in electronic and steric properties of the sub-
stituents appending to the aromatic rings of the oxindole
framework. Notably, the reaction proceeded slowly when
electron-withdrawing substituents were at the 5-position on
the aromatic ring (Table 2, entry 3 and entries 10–12). It
appears that the N-protecting group in the oxindole is critical
for achieving a high yield. Masking of the ‘‘N’’ (e.g., Bn, entry
15) led to a dramatic decrease of the yield (68%). When
N-acetyl protected isatin 1p was employed as the substrate the
reaction proceeded exclusively in lower yields (,10%) despite
a long reaction time (Table 2, entry 16). The diastereomeric
ultrasound as
a means of accelerating reactions is an
important technique and one which is rapidly developing for
green processes.11 In order to accelerate the rate of this
reaction, we proceeded with the reaction assisted with
ultrasonic irradiation. A large rate acceleration was observed
in the reaction (Table 1, entry 9).
Subsequently, with Et3N as the catalyst, different catalyst
loadings were studied (Table 1, entries 10–14). Finally, it was
observed that the reaction was able to proceed to completion
in 66 min with 10 mol% Et3N affording product 4a as a
mixture of two diastereoisomers in a 98% yield (Table 1, entry
13). Thus, the optimal reaction conditions for this transforma-
tion were determined to be 0.3 mmol isatin 1, 0.3 mmol
malononitrile 2, 0.33 mmol a-isothiocyanato imide 3, 10 mol%
Et3N in 5 mL H2O as solvent at room temperature with
ultrasonic irradiation.
1
ratio of product was determined by H NMR spectroscopy of
the crude product. In order to determine the structure of the
products, a single crystal X-ray diffraction study of 4b was
performed.12 The molecular structure of 4b is shown in Fig. 2,
and the structure showed that the relative configuration of the
main product was assigned as threo.
The mechanism of this multicomponent cascade reaction
is proposed as shown in Scheme 1. The first step involves the
Knoevenagel reaction of isatin 1 with malononitrile 2 to form a
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spirooxindoles ‘‘on water’’ assisted with ultrasonic irradiation.
The reaction has been shown to display relatively good
functional group tolerance, high yields, and product isolation
is very straightforward. The power of this straightforward
process is highlighted by its extremely high efficiency in
synthesizing the spirooxindole skeleton in one single opera-
tion. Further studies into expanding the application of this
strategy to synthesize more promising candidates for drug
discovery as well as the biological evaluation of these
compounds are currently underway.
Fig. 2 X-ray crystal structure of 4b.
Experimental section
Solvents were dried and distilled prior to use according to
standard methods. Unless otherwise indicated, all materials
were obtained from commercial sources, and used as
purchased without dehydration. Flash column chromatogra-
phy was performed on silica gel (particle size 10–40 mm, Ocean
dicyanoalkene intermediate A. The next step is the Michael
addition of the Knoevenagel adduct with a-isothiocyanato
imide 3 which is initiated by Et3N to form the enolate
intermediate B, resulting in intermediate C. The intermediate
C undergoes an intramolecular cyclization reaction to afford
the product 4 through the intermediate D. Overall, this three-
component cascade transformation leads to the generation of
three C–C bonds.
1
Chemical Factory of Qingdao, China). H NMR and 13C NMR
spectra were recorded in DMSO on Bruker AV 400 MHz
spectrometers, TMS served as the internal standard (d = 0
ppm). Data are presented as follows: chemical shift, integra-
tion, multiplicity (br = broad, s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, cm = complex multiplet) and
coupling constant in Hertz (Hz). The crystal structure was
determined on a Bruker SMART 1000 CCD diffractometer.
Mass spectra were recorded on a LCQ advantage spectrometer
Conclusions
We have developed a versatile new method for the room-
temperature synthesis of functionalized 3,39-pyrrolidonyl
as shown in the ESI. HR-MS was recorded on APEXII and ZAB-
3
HS spectrometers. Melting points were determined on a T-4
melting point apparatus (uncorrected).
Typical reaction procedure for the synthesis of
3,39-pyrrolidinyl-spirooxindole
A solution of isatin 1 (0.3 mmol), TEA (0.03 mmol) and
malononitrile 2 (0.3 mmol) in 5 ml H2O was stirred at room
temperature. After the reaction was completed (monitored by
TLC), a-isothiocyanato imide 3 (0.33 mmol) was added and the
mixture was sonicated for 1 min in an ultrasound bath, then
further stirred at room temperature. After the complete
consumption of the dicyanoalkene, as indicated by TLC (ethyl
acetate–hexane = 3 : 1), the solvent was evaporated. The
residue was purified by column chromatography over silica
gel (ethyl acetate–hexane = 3 : 1) to afford the product as a
colorless powder.
1-Methyl-2-oxo-29-(2-oxooxazolidine-3-carbonyl)-
59-thioxospiro[indoline-3,39-pyrrolidine]-49,49-dicarbonitrile
Major diastereoisomer 4a: white solid. mp 151–153 uC; 1H
NMR (300 MHz, DMSO): d 12.33 (br, 1H), 7.26–7.62 (m, 4H),
5.77 (s, 1H), 4.15–4.66 (dt, J = 7.8 Hz, J = 4.2 Hz, 4H), 3.25 (s,
3H). 13C NMR (101 MHz, DMSO): d 187.31, 173.07, 166.94,
154.19, 145.87, 133.13, 125.61, 124.25, 119.59, 112.05, 111.47,
66.76, 64.73, 57.87, 43.22, 31.86, 28.10. HRMS calculated [M +
Na]+ for C18H13N5O4SNa: 418.0580, found: 418.0583.
Minor diastereoisomer 4a9: 1H NMR (300 MHz, DMSO): d
12.33 (br, 1H), 7.13–7.25 (m, 4H), 5.63 (s, 1H), 3.85–4.11 (dt, J =
7.8 Hz, J = 4.2 Hz, 4H), 3.20 (s, 3H). 13C NMR (101 MHz,
Scheme 1 Plausible reaction mechanism.
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DMSO): d 187.31, 169.38, 165.79, 155.41, 144.20, 132.67,
126.88, 124.88, 123.68, 112.05, 111.32, 68.75, 65.08, 59.15,
43.69, 31.86, 28.10.
3H). 13C NMR (101 MHz, DMSO): d 186.18, 167.95, 164.21,
154.21, 142.11, 131.50, 127.35, 126.82, 122.94, 111.81, 110.18,
66.87, 63.99, 57.77, 55.96, 42.48, 27.10. HRMS calculated [M +
Na]+ for C18H12ClN5O4S: 452.0191, found: 452.0195.
Minor diastereoisomer 4e9: 1H NMR (400 MHz, DMSO): d
12.40 (br, 1H), 7.11–7.31 (m, 3H), 5.79 (s, 1H), 3.75–4.07 (dt, J =
8.2 Hz, J = 4.2 Hz, 4H), 3.26 (s, 3H). 13C NMR (101 MHz,
DMSO): d 186.06, 171.38, 165.60, 153.09, 143.80, 131.93,
126.84, 124.08, 112.08, 110.45, 108.93, 65.33, 63.79, 56.18,
55.57, 42.23, 27.14.
1,5-Dimethyl-2-oxo-29-(2-oxooxazolidine-3-carbonyl)-
59-thioxospiro[indoline-3,39-pyrrolidine]-49,49-dicarbonitrile
Major diastereoisomer 4b: white solid. mp 165–168 uC; 1H
NMR (400 MHz, DMSO): d 12.30 (br, 1H), 7.16–7.45 (m, 3H),
5.79 (s, 1H), 4.13–4.59 (dt, J = 8.0 Hz, J = 4.0 Hz, 4H), 3.23 (s,
3H), 2.36 (s, 3H). 13C NMR (101 MHz, DMSO): d 186.50, 171.71,
165.69, 152.94, 142.40, 132.33, 132.20, 124.63, 122.89, 110.67,
110.35, 110.06, 65.17, 63.53, 56.53, 55.81, 42.08, 26.90, 20.59.
HRMS calculated [M + Na]+ for C19H15N5O4SNa: 432.0737,
found: 432.0740.
1,7-Dimethyl-2-oxo-29-(2-oxooxazolidine-3-carbonyl)-
59-thioxospiro[indoline-3,39-pyrrolidine]-49,49-dicarbonitrile
Major diastereoisomer 4f: white solid; mp 166–168 uC; 1H
NMR (400 MHz, DMSO): d 12.33 (br, 1H), 7.13–7.36 (m, 3H),
5.75 (s, 1H), 4.13–4.61 (dt, J = 7.8 Hz, J = 4.0 Hz, 4H), 3.50 (s,
3H), 2.58 (s, 3H). 13C NMR (101 MHz, DMSO): d 186.92, 168.70,
164.60, 154.21, 140.71, 135.01, 123.62, 122.81, 121.41, 120.18,
110.30, 109.24, 67.41, 63.91, 57.44, 42.48, 30.64, 29.89, 18.32.
HRMS calculated [M + Na]+ for C19H15N5O4SNa: 432.0737,
found: 432.0741.
Minor diastereoisomer 4b9: 1H NMR (400 MHz, DMSO): d
12.30 (br, 1H), 7.00–7.15 (m, 3H), 5.64 (s, 1H), 3.83–4.08 (dt, J =
8.0 Hz, J = 4.0 Hz, 4H), 3.17 (s, 3H), 2.33 (s, 3H). 13C NMR (101
MHz, DMSO): d 186.84, 168.02, 164.51, 154.16, 140.76, 132.82,
131.79, 125.53, 118.35, 110.77, 109.94, 109.22, 67.14, 63.88,
57.89, 56.11, 42.48, 30.63, 20.70.
1-Methyl-5-nitro-2-oxo-29-(2-oxooxazolidine-3-carbonyl)-
59-thioxospiro[indoline-3,39-pyrrolidine]-49,49-dicarbonitrile
Minor diastereoisomer 4f9: 1H NMR (400 MHz, DMSO): d
12.33 (br, 1H), 6.85–7.11 (m, 3H), 5.60 (s, 1H), 3.76–4.08 (dt, J =
7.8 Hz, J = 4.0 Hz, 4H), 3.44 (s, 3H), 2.60 (s, 3H). 13C NMR (101
MHz, DMSO): d 186.50, 172.57, 165.71, 152.96, 142.43, 135.48,
126.25, 122.25, 121.47, 118.75, 110.85, 110.67, 65.38, 63.51,
56.10, 42.02, 30.64, 30.03, 18.40.
Major diastereoisomer 4c: white solid; mp 161–163 uC; 1H
NMR (400 MHz, DMSO): d 12.53 (br, 1H), 8.03–8.57 (m, 3H),
5.89 (s, 1H), 4.26–4.62 (dt, J = 7.8 Hz, J = 4.0 Hz, 4H), 3.36 (s,
3H). 13C NMR (101 MHz, DMSO): d 185.94, 168.85, 163.95,
154.24, 148.91, 142.96, 128.50, 119.58, 118.79, 110.67, 108.74,
66.88, 64.10, 57.43, 42.49, 30.63, 27.48. HRMS calculated [M +
Na]+ for C18H12N6O6SNa: 463.0431, found: 463.0435.
2-Oxo-29-(2-oxooxazolidine-3-carbonyl)-59-thioxospiro[indoline-
3,39-pyrrolidine]-49,49-dicarbonitrile
Minor diastereoisomer 4c9: 1H NMR (400 MHz, DMSO): d
12.53 (br, 1H), 7.42–7.88 (m, 3H), 5.83 (s, 1H), 3.91–4.23 (dt, J =
7.8 Hz, J = 4.0 Hz, 4H), 3.36 (s, 3H). 13C NMR (101 MHz,
DMSO): d 185.94, 172.22, 165.54, 153.33, 150.36, 142.83,
128.78, 125.39, 119.44, 110.86, 110.05, 65.37, 63.97, 55.72,
42.23, 30.63, 27.48.
Major diastereoisomer 4g: white solid; mp 171–173 uC; 1H
NMR (400 MHz, DMSO): d 12.30 (br, 1H), 11.51 (s, 1H), 7.17–
7.55 (m, 4H), 5.81 (s, 1H), 4.26–4.60 (dt, J = 7.9 Hz, J = 4.1 Hz,
4H). 13C NMR (101 MHz, DMSO): d 186.81, 173.51, 165.76,
152.96, 141.70, 131.88, 124.67, 123.00, 122.73, 122.32, 118.94,
110.99, 64.94, 63.87, 56.80, 42.04, 30.65. HRMS calculated [M +
Na]+ for C17H11N5O4SNa: 404.0424, found: 404.0428.
5-Bromo-1-methyl-2-oxo-29-(2-oxooxazolidine-3-carbonyl)-
59-thioxospiro[indoline-3,39-pyrrolidine]-49,49-dicarbonitrile
Minor diastereoisomer 4g9: 1H NMR (400 MHz, DMSO): d
12.30 (br, 1H), 11.32 (s, 1H), 6.93–7.17 (m, 4H), 5.67 (s, 1H),
3.74–4.60 (dt, J = 7.9 Hz, J = 4.1 Hz, 4H). 13C NMR (101 MHz,
DMSO): d 186.58, 169.64, 164.51, 154.19, 143.44, 131.44,
126.29, 123.00, 122.73, 122.32, 118.94, 111.09, 66.88, 63.87,
58.36, 42.44, 30.65.
Major diastereoisomer 4d: white solid; mp 173–175 uC; 1H
NMR (400 MHz, DMSO): d 12.40 (br, 1H), 7.35–7.87 (m, 3H),
5.77 (s, 1H), 4.25–4.63 (dt, J = 7.7 Hz, J = 4.0 Hz, 4H), 3.20 (s,
3H). 13C NMR (101 MHz, DMSO): d 186.17, 167.87, 164.19,
154.20, 142.52, 134.35, 126.86, 125.57, 114.92, 112.54, 110.53,
108.92, 66.88, 63.98, 57.72, 42.48, 30.66, 27.08. HRMS
calculated [M + Na]+ for C18H12BrN5O4SNa: 495.9686, found:
495.9689.
5-Methyl-2-oxo-29-(2-oxooxazolidine-3-carbonyl)-
59-thioxospiro[indoline-3,39-pyrrolidine]-49,49-dicarbonitrile
Major diastereoisomer 4h: white solid; mp 175–178 uC; 1H
NMR (400 MHz, DMSO): d 12.26 (br, 1H), 11.41 (s, 1H), 6.98–
7.38 (m, 3H), 5.81 (s, 1H), 4.17–4.59 (dt, J = 8.0 Hz, J = 4.2 Hz,
4H), 2.32 (s, 3H). 13C NMR (101 MHz, DMSO): d 186.63, 173.45,
165.81, 152.91, 141.03, 132.16, 131.77, 124.81, 123.05, 110.83,
109.32, 64.92, 63.48, 56.77, 55.77, 42.10, 20.59. HRMS
calculated [M + Na]+ for C18H13N5O4SNa: 418.0580, found:
418.0582.
Minor diastereoisomer 4d9: 1H NMR (400 MHz, DMSO): d
12.40 (br, 1H), 7.15–7.33 (m, 3H), 5.79 (s, 1H), 3.73–4.05 (dt, J =
7.7 Hz, J = 4.0 Hz, 4H), 3.25 (s, 3H). 13C NMR (101 MHz,
DMSO): d 186.07, 171.28, 165.62, 153.06, 144.22, 134.78,
127.15, 120.54, 114.15, 112.25, 110.45, 110.17, 65.34, 63.80,
56.10, 42.22, 30.66, 27.12.
5-Chloro-1-methyl-2-oxo-29-(2-oxooxazolidine-3-carbonyl)-
59-thioxospiro[indoline-3,39-pyrrolidine]-49,49-dicarbonitrile
Major diastereoisomer 4e: white solid; mp 158–161 uC; 1H
NMR (400 MHz, DMSO): d 12.40 (br, 1H), 7.34–7.78 (m, 3H),
5.77 (s, 1H), 4.24–4.59 (dt, J = 8.2 Hz, J = 4.2 Hz, 4H), 3.20 (s,
Minor diastereoisomer 4h9: 1H NMR (400 MHz, DMSO): d
12.26 (s, 1H), 11.21 (s, 1H), 6.85–6.98 (m, 3H), 5.66 (s, 1H),
3.68–4.17 (dt, J = 8.0 Hz, J = 4.2 Hz, 4H), 2.29 (s, 3H). 13C NMR
(101 MHz, DMSO): d 186.79, 169.63, 164.53, 154.14, 139.32,
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131.97, 131.77, 126.29, 119.04, 110.83, 110.39, 66.88, 63.83,
58.44, 56.41, 42.43, 20.71.
65.06, 63.74, 59.73, 42.24, 14.05. HRMS calculated [M + Na]+
for C17H10ClN5O4SNa: 438.0034, found: 438.0039.
Minor diastereoisomer 4l9: 1H NMR (400 MHz, DMSO): d
12.35 (s, 1H), 11.50 (s, 1H), 7.01–7.24 (m, 3H), 5.81 (s, 1H),
3.81–4.15 (dt, J = 8.0 Hz, J = 4.0 Hz, 4H). 13C NMR (101 MHz,
DMSO): d 186.10, 169.54, 164.22, 154.19, 140.84, 131.46,
127.59, 126.03, 123.15, 112.60, 110.64, 110.21, 66.63, 63.95,
56.49, 42.44, 20.73.
5-Methoxy-2-oxo-29-(2-oxooxazolidine-3-carbonyl)-
59-thioxospiro[indoline-3,39-pyrrolidine]-49,49-dicarbonitrile
Major diastereoisomer 4i: white solid; mp 173–175 uC; 1H NMR
(400 MHz, DMSO): d 12.29 (s, 1H), 11.15 (s, 1H), 7.01–7.16 (m,
3H), 5.72 (s, 1H), 4.23–4.57 (dt, J = 7.8 Hz, J = 4.2 Hz, 4H), 3.73
(s, 3H). 13C NMR (101 MHz, DMSO): d 186.70, 169.49, 164.46,
155.25, 154.13, 134.92, 127.14, 115.48, 111.62, 110.90, 110.37,
110.05, 66.75, 63.84, 58.72, 55.56, 42.43, 30.62. HRMS
calculated [M + Na]+ for C18H13N5O5S: 434.0530, found:
434.0532.
6-Methoxy-2-oxo-29-(2-oxooxazolidine-3-carbonyl)-
59-thioxospiro[indoline-3,39-pyrrolidine]-49,49-dicarbonitrile
Major diastereoisomer 4m: white solid; mp 143–145 uC; 1H
NMR (400 MHz, DMSO): d 12.22 (s, 1H), 11.46 (s, 1H), 6.70–
7.20 (m, 3H), 5.79 (s, 1H), 4.23–4.58 (dt, J = 7.8 Hz, J = 4.2 Hz,
4H), 3.80 (s, 3H). 13C NMR (101 MHz, DMSO): d 186.72, 174.09,
165.89, 161.97, 152.96, 144.94, 125.75, 111.09, 110.28, 107.61,
97.51, 67.13, 64.76, 64.11, 55.46, 42.06, 30.61. HRMS calculated
[M + Na]+ for C18H13N5O5SNa: 434.0530, found: 434.0532.
Minor diastereoisomer 4i9: 1H NMR (400 MHz, DMSO): d
12.29 (s, 1H), 11.36 (s, 1H), 6.65–7.01 (m, 3H), 5.83 (s, 1H),
3.86–4.23 (dt, J = 7.8 Hz, J = 4.2 Hz, 4H), 3.73 (s, 3H). 13C NMR
(101 MHz, DMSO): d 186.57, 173.33, 165.89, 154.78, 152.95,
136.57, 120.02, 116.02, 111.76, 111.22, 110.74, 109.28, 64.96,
63.54, 56.90, 55.78, 42.26, 30.62.
1
Minor diastereoisomer 4m9: H NMR (400 MHz, DMSO): d
12.22 (s, 1H), 11.46 (s, 1H), 6.35–6.68 (m, 3H), 5.63 (s, 1H),
3.86–4.21(dt, J = 7.8 Hz, J = 4.2 Hz, 4H), 3.96 (s, 3H). 13C NMR
(101 MHz, DMSO): d 186.85, 170.21, 164.50, 161.74, 154.14,
143.19, 123.85, 111.09, 110.46, 107.94, 97.51, 64.11, 63.82,
58.33, 56.79, 42.43, 29.53.
5-Nitro-2-oxo-29-(2-oxooxazolidine-3-carbonyl)-
59-thioxospiro[indoline-3,39-pyrrolidine]-49,49-dicarbonitrile
Major diastereoisomer 4j: white solid; mp 193–195 uC; 1H NMR
(400 MHz, DMSO): d 12.46 (br, 1H), 12.09 (s, 1H), 8.03–8.49 (m,
3H), 5.93 (s, 1H), 4.17–4.62 (dt, J = 7.6 Hz, J = 4.0 Hz, 4H). 13C
NMR (101 MHz, DMSO): d 185.71, 173.80, 163.92, 154.21,
148.12, 142.53, 128.47, 119.97, 119.22, 111.44, 110.48, 108.84,
66.65, 64.04, 58.11, 42.44, 30.61. HRMS calculated [M 2 H]2
for C17H10N6O6S: 425.0305, found: 425.0305.
7-Methyl-2-oxo-29-(2-oxooxazolidine-3-carbonyl)-
59-thioxospiro[indoline-3,39-pyrrolidine]-49,49-dicarbonitrile
Major diastereoisomer 4n: white solid; mp 148–151 uC; 1H
NMR (400 MHz, DMSO): d 12.25 (s, 1H), 11.53 (s, 1H), 7.07–
7.34 (m, 3H), 5.81 (s, 1H), 4.15–4.56 (dt, J = 7.6 Hz, J = 4.2 Hz,
4H), 2.24 (s, 3H). 13C NMR (101 MHz, DMSO): d 186.69, 174.04,
165.81, 152.92, 142.03, 133.07, 122.19, 121.93, 120.57, 118.63,
111.07, 110.68, 64.97, 63.45, 57.01, 42.04, 30.64, 16.44. HRMS
calculated [M + Na]+ for C18H13N5O4SNa: 418.0580, found:
418.0579.
Minor diastereoisomer 4j9: 1H NMR (400 MHz, DMSO): d
12.46 (br, 1H), 12.30 (s, 1H), 7.11–8.03 (m, 3H), 5.86 (s, 1H),
3.65–4.17 (dt, J = 7.6 Hz, J = 4.0 Hz, 4H). 13C NMR (101 MHz,
DMSO): d 186.04, 170.35, 165.64, 153.30, 149.64, 142.32,
128.74, 126.05, 120.10, 111.44, 110.39, 110.05, 65.11, 63.90,
56.06, 42.23, 30.61.
Minor diastereoisomer 4n9: 1H NMR (400 MHz, DMSO): d
12.25 (s, 1H), 11.36 (s, 1H), 6.98–7.05 (m, 3H), 5.66 (s, 1H),
3.88–4.11 (dt, J = 7.6 Hz, J = 4.2 Hz, 4H), 2.26 (s, 3H). 13C NMR
(101 MHz, DMSO): d 186.88, 170.12, 164.54, 154.17, 140.31,
132.66, 126.01, 122.97, 120.52, 119.92, 110.36, 109.31, 66.95,
63.85, 58.62, 42.43, 30.64, 16.38.
5-Bromo-2-oxo-29-(2-oxooxazolidine-3-carbonyl)-
59-thioxospiro[indoline-3,39-pyrrolidine]-49,49-dicarbonitrile
Major diastereoisomer 4k: white solid; mp 158–160 uC; 1H
NMR (400 MHz, DMSO): d 12.34 (s, 1H), 11.49 (s, 1H), 7.31–
7.77 (m, 3H), 5.80 (s, 1H), 4.28–4.59 (dt, J = 7.8 Hz, J = 4.0 Hz,
4H). 13C NMR (101 MHz, DMSO): d 186.10, 172.98, 165.73,
154.18, 141.23, 134.29, 127.11, 125.81, 113.24, 113.02, 110.55,
110.21, 66.66, 64.11, 56.42, 42.23, 30.65. HRMS calculated [M +
Na]+ for C17H10BrN5O4S: 481.9529, found: 481.9535.
1-Benzyl-2-oxo-29-(2-oxooxazolidine-3-carbonyl)-
59-thioxospiro[indoline-3,39-pyrrolidine]-49,49-dicarbonitrile
Major diastereoisomer 4o: white solid; mp 218–221 uC; 1H
NMR (400 MHz, DMSO): d 12.36 (br, 1H), 7.03–7.55 (m, 9H),
5.89 (s, 1H), 5.16 (d, J = 16 Hz, 2H), 4.15–4.66 (dt, J = 7.8 Hz, J =
4.2 Hz, 4H). 13C NMR (101 MHz, DMSO): d 186.94, 172.48,
166.12, 153.44, 144.34, 135.36, 132.44, 129.03, 128.17, 127.86,
125.11, 123.71, 118.72, 111.35, 111.08, 65.60, 64.05, 57.06,
Minor diastereoisomer 4k9: 1H NMR (400 MHz, DMSO): d
12.34 (s, 1H), 11.73 (s, 1H), 6.95–7.27 (m, 3H), 5.82 (s, 1H),
3.75–4.09 (dt, J = 7.8 Hz, J = 4.0 Hz, 4H). 13C NMR (101 MHz,
DMSO): d 186.20, 169.44, 164.22, 153.03, 143.00, 134.70,
127.96, 121.28, 114.14, 113.31, 110.64, 109.03, 65.10, 63.74,
58.34, 42.44, 30.65.
56.26, 44.13, 42.56. HRMS calculated [M
24H17N5O4SNa: 494.0893, found: 494.0897.
Minor diastereoisomer 4o9: 1H NMR (400 MHz, DMSO): d
+
Na]+ for
5-Chloro-2-oxo-29-(2-oxooxazolidine-3-carbonyl)-
59-thioxospiro[indoline-3,39-pyrrolidine]-49,49-dicarbonitrile
C
Major diastereoisomer 4l: white solid; mp 163–165 uC; 1H NMR
(400 MHz, DMSO): d 12.35 (s, 1H), 11.74 (s, 1H), 7.20–7.63 (m,
3H), 5.83 (s, 1H), 4.19–4.59 (dt, J = 8.0 Hz, J = 4.0 Hz, 4H). 13C
NMR (101 MHz, DMSO): d 186.18, 173.10, 165.70, 153.06,
142.59, 131.89, 126.58, 124.30, 120.94, 112.80, 110.55, 109.03,
12.36 (br, 1H), 7.03–7.55 (m, 9H), 5.78 (s, 1H), 4.90 (d, J = 16
Hz, 2H), 3.81–4.08 (dt, J = 7.8 Hz, J = 4.2 Hz, 4H). 13C NMR (101
MHz, DMSO): d 186.94, 168.81, 164.84, 154.69, 142.67, 135.65,
132.01, 129.10, 127.65, 125.76, 124.35, 123.22, 118.72, 111.48,
111.20, 67.30, 64.45, 58.53, 57.00, 44.13, 42.95.
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RSC Advances
S. Neumann, M. M.-C. Lo and S. L. Schreiber, Angew.
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Acknowledgements
We thank the National Natural Science Foundation of China
(21072102), the Committee of Science and Technology of
Tianjin (11JCYBJC04200) and State Key Laboratory of
Elemento-Organic Chemistry in Nankai University for finan-
cial support.
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18862 | RSC Adv., 2013, 3, 18857–18862
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