Article

Cite This: J. Org. Chem. 2019, 84, 8194−8201 pubs.acs.org/joc

Organocatalytic Domino Reaction of Spiroaziridine Oxindoles and

Malononitrile for the Enantiopure Synthesis of
Spiro[dihydropyrrole-3,3′-oxindoles]
Saumen Hajra,*,† SK Abu Saleh,†,‡ Atanu Hazra,†,‡ and Maya Shankar Singh‡
†
Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow
226014, India
‡
Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India
*
S Supporting Information
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ABSTRACT: The first organocatalytic regio- and stereo-

selective domino reactions of spiroaziridine oxindoles and
malononitrile have been developed using DBU as a catalyst
without any metal/Lewis acid activation for the enantiopure
synthesis of spiro[dihydropyrrole-3,3′-oxindoles] (ee up to
>99%). The protocol is also equally effective for the phenyl
aziridine with excellent regio- and stereoselectivity.

■ INTRODUCTION
The spiro[pyrrolidine-3,3′-oxindole] is a prevalence hetero-
cyclic motif that constitutes the core of various family of
alkaloids natural products and unnatural compounds with
strong bioactivity profiles (Figure 1).1,2 The presence of an
Figure 1. Representative spiro[dihydropyrrole-3,3′-oxindoles] con-
taining natural/unnatural products.
additional double bond in a spiro-pyrrolidinyl unit, that is,
spiro[dihydropyrrole-3,3′-oxindole], is a unique feature of
some of the important natural products such as spirotrypsos-
tatin B, cyanogramide, and so forth.3
Considering the important bioactivities, huge efforts have
been devoted to synthesize the spiro[pyrrolidine-3,3′-oxin-
dole], where 1,3-dipolar cycloaddition of azomethine ylides
and its equivalent with the 3-alkylidene oxindoles was the
major successful strategies.4 Our continued research experi-
ences in the aziridine chemistry5,6 led us to presume that
spiroaziridines could be the suitable choice of substrate for the
synthesis of various nitrogen-containing spirooxindole-based
heterocycles. We realized that tricyclic spiro[pyrrolidine-3,3′-
oxindoles] can be synthesized via ring opening followed by
cyclization of spiroaziridine oxindoles with carbon pronucleo-
philes in a domino fashion.
Over the years, domino reaction has become a powerful tool
for the synthesis of structurally complex bioactive molecules in
a conducive manner.7 It has substantial advantages over
conventional linear synthesis because of its flexible, convergent,
and atom-economic nature. Again, organocatalytic domino
reaction represents the state of art in organic chemistry. There
are some elegant reports on domino ring opening and
cyclization of aziridine using Lewis acid and/or strong base
(Scheme 1, eq 1),8 but the organocatalytic ring opening
reaction of aziridine with carbon pronucleophiles is sparse in
the literature.9 Moreover, the chemistry of the spiroaziridine
oxindoles toward synthesis of higher spiro-N-heterocycle
oxindoles is still unexplored. The Dixon group first reported
the organic phosphorine base-catalyzed ring opening reaction
of unsubstituted simple N-sulfonyl aziridine with active
methylene carbon for the racemic synthesis of compounds
with an all-carbon quaternary center and later the same group
developed the catalytic asymmetric ring opening reaction using
a phase transfer catalyst (PTC) where the ring opening occurs
from the less hindered site (Scheme 1, eq 2).9b Similar reaction
using PTC was also reported by the Jørgensen group varying
only the protecting group of unsubstituted aziridines.9c To the
best of our knowledge, base/organo-catalytic domino ring
opening reaction of aziridine, in particular, at the more
substituted site has not been reported. In this context, we
report the first organocatalytic regio- and stereocontrolled
Received: May 7, 2019
Published: May 29, 2019

© 2019 American Chemical Society 8194 DOI: 10.1021/acs.joc.9b01226

J. Org. Chem. 2019, 84, 8194−8201
The Journal of Organic Chemistry Article

Scheme 1. Previous Reports and the Present Study
deprotonate another molecule of malononitrile and thus
continue the catalytic cycle.
To validate our concept, we began our studies of domino
reaction initially with racemic spiroaziridine (±)-1a altering
solvents, temperature, and base (Table 1). To our delight, the

Table 1. Optimization of Reaction Conditionsa

entry 1 base solvent temp (°C) time (h) yieldb (%)

1 (±)-1a t-BuOK THF 25 10 35
2 (±)-1a t-BuOK DMF 25 10 40
3 (±)-1a t-BuOK DMF 0 12 42
4 (±)-1a NaH DMF 25 8 37
5 (±)-1a Cs2CO3 DMF 25 5 80
6 (±)-1a Cs2CO3 DMF 0 6 81
7 (±)-1a DBU DMF 25 4.5 95
8 (±)-1a DBUc DMF 25 5 95
domino ring opening and cyclization reaction of spiroaziridine 9 (±)-1b DBUc DMF 25 9 85
oxindoles with malononitrile at the spirocenter that provides 10 (±)-1c DBUc DMF 25 11 84
easy access of enantiopure spiro[dihydropyrrole-3,3′-oxin- a
A solution of spiroaziridine (±)-1a (0.05 g, 0.16 mmol),
doles] (ee up to >99%). This organocatalytic protocol is also malononitrile (1.5 equiv) and base (1.5 equiv) in 1 mL solvent was
effective for the regio- and stereoselective domino reaction of stirred at specified temperature. bIsolated yield. c35 mol % base was
phenyl aziridine at the benzylic center.

■
used.

RESULTS AND DISCUSSION domino reaction of spiroaziridine (±)-1a gave exclusively

The unprecedented reactivity of spiroaziridine oxindoles
toward the regio- and stereoselective ring-opening reaction at
the spirocenter with retention of configuration without any
Lewis acid activation led us to envision that spiroaziridines 1
could undergo nucleophilic addition followed by cyclization
with malononitrile in the presence of a base to produce
enantiopure spiro[pyrroline-3,3′ oxindoles 3 with retention of
configuration (Scheme 2). We further wondered whether an
organic base could catalyze this domino reaction. After the ring
opening of spiroaziridine at the spirocenter with the anion of
malonitrile followed by cyclization, the adduct 4 should be
sufficiently basic either to abstract the proton from the
conjugate acid BH+ to regenerate the free base or to
Scheme 2. Presumption of Base-Catalyzed Domino
Reaction of Spiroaziridine
8195
spiro[pyrroline-3,3′ oxindoles] product (±)-3a in good yield
with Cs2CO3 as a base in dimethylformamide (DMF) at rt
(Table 1; entry 5). Using a catalytic amount of 1,8-
biazabicyclo[5.4.0]undec-7-ene (DBU; 35 mol %) also gave
full consumption of starting material with excellent yield
(Table 1; entry 8). Lowering the catalyst loading to 20 mol %
or lower led to incomplete conversion even after 24 h. Among
the inorganic base, none of the other bases can improve the
yield of the reaction even by using a stoichiometric amount.
Changing the protecting group from N-Me to N-Bn, N-allyl
does not improve the yield of this reaction (Table 1; entry 9,
10). Interestingly, no regio-isomer of the domino product was
detected by the 1H NMR analysis of the crude reaction
mixture.
After successful domino reaction of spiroaziridine (±)-1a,
the conditions were implemented to the enantiopure
spiroaziridine 1d (Table 2). It was found that not only DBU
but also other organic base like DIPEA, TMEDA, and DABCO
gave the desired domino product with excellent ee (Table 2,
entries 3−5). However, the best yield (95%) and enantiose-
lectivity (>99%) were achieved when DBU (35 mol %) was
used as a base (Table 2, entry 2). To our delight, reactions
with Cs2CO3 in DMF also afforded the desired domino
product 3d with 97% ee, but in little lower yield (Table 2,
entry 1).
On the basis of optimal reaction conditions, we explored the
substrate generality of this domino reaction with various spiro-
aziridine oxindoles 1d−1s (Figure 2). Irrespective of the N-
protection of spiroaziridines, N-methyl, N-benzyl, and N-allyl
gave excellent yields and enantioselectivities. Unlike earlier
works on tertiary nucleophilic fluorination,6e domino reaction
of N-unprotected spiroaziridine ent-1h produced the desired
DOI: 10.1021/acs.joc.9b01226
J. Org. Chem. 2019, 84, 8194−8201
The Journal of Organic Chemistry Article

Table 2. Optimization of Reaction Conditions for product ent-3h with excellent enantioselectivity by using an
Stereocontrolled Domino Reactiona additional equivalent of the base. The substrate 1g with the
electron-withdrawing N-protecting group such as N-Boc also
underwent smooth reaction under the optimized reaction
condition and afforded 3g by taking a little more time. It seems
that less availability of the electron pair on nitrogen might
restrict the neighboring participation to the aziridine moiety.
Again, these results support our presumption of the anchimeric
base temp time yieldb eec assistance of the oxindole unit. To check the versatility, a wide
entry (x mol %) solvent (°C) (h) (%) (%) range of spiroaziridines with electron-withdrawing and
1 Cs2CO3 (150) DMF 25 5 80 97 electron-donating substitutions at C5, C7, and C4 positions
2 DBU (35) DMF 25 5 95 >99 were also tested. All underwent smooth reactions and afforded
3 DIPEA (35) DMF 25 5 75 95 the corresponding spiro[pyrroline-3,3′ oxindoles] 3i−s with
4 TMEDA (35) DMF 25 5 70 ND excellent yields and enantioselectivities (ee 93 to >99%).
5 DABCO (35) DMF 25 5 80 97 Interestingly, the electron-donating groups at the C5 and C7
a
A solution of spiroaziridine 1d (0.05 g, 0.17 mmol), malononitrile positions showed the higher reactivity by taking less time than
(1.5 equiv), and base (x mol %) in 1 mL solvent was stirred at a the substrates having the electron-withdrawing groups. It
specified temperature. bIsolated yield. cee determined by HPLC seems that the electron-donating group, in particular, at the C5
analysis on a chiral stationary phase. ND = not determined. and C7 position increases the electron density to the ring and
in turn might enhance the donating propensity of oxindole
nitrogen/oxygen toward anchimeric assistance leading to the
faster reaction.
In line with our previous report,6 organic base-catalyzed
domino ring opening and cyclization of spiroaziridines 1 and
malononitrile are also assumed to be a retention in
configuration at the C3-stereocenter. It is further confirmed
from the single-crystal X-ray analysis of ent-3m which was
recrystallized from ethyl acetate/hexanes (9:1). The crystal
structure unambiguously confirms the stereochemistry of the
C3-center of ent-3m as (S)-configuration derived from (S)-
spiroaziridine oxindole ent-1m (Figure 2).
To manifest the scalability and to check the withstanding
ability of the method, the domino reaction was extended up to
gram-scale under the optimized conditions (Scheme 3). The

Scheme 3. Gram-Scale Domino Reaction

spiroaziridine 1d (1 g, 3.14 mmol) underwent smooth reaction

with a DBU catalyst in DMF at 25 °C and produced
spiro[pyrroline-3,3′ oxindoles] 3d maintaining excellent
enantioselectivity and yield (ee >99 and 94%).
Further, an organocatalytic domino protocol was executed
with phenyl aziridine 5 to compare the reactivity pattern with
spiroaziridine 1 (Scheme 4). In contrast to the earlier report
where Lewis acid and strong base were found to be mandatory

Scheme 4. DBU-Catalyzed Domino Reaction of Phenyl

Aziridine 5

Figure 2. Enantiopure synthesis of spiro[pyrroline-3,3′ oxindoles]

oxindoles 2; ent-3e, ent-3h, ent-3j, ent-3l, and ent-3m were obtained
from (S)-spiroaziridines ent-1e, ent-1h, ent-1j, ent-1l, and ent-1m,
respectively.

8196 DOI: 10.1021/acs.joc.9b01226

J. Org. Chem. 2019, 84, 8194−8201
The Journal of Organic Chemistry
for the regio- and stereoselective reaction at the more hindered
site, it interestingly gave the same reaction pattern. N-nosyl
aziridine 5a afforded exclusively the domino product 6a with
excellent yield, and no terminal product 6a′ was detected in
the crude reaction mixture, whereas N-tosyl substrate 5b gave
the product 6b as a major one along with a minor amount of
terminal product 6b′ (6b/6b′ = 4:1). Gratifyingly, both the
reactions showed excellent stereoselectivity (ee >99%).
Finally, this strategy was extended toward organocatalytic
asymmetric domino reaction of racemic spiroaziridine using
different organo-catalysts (for details, see the Supporting
Information). On preliminary investigation, the quinine (10
mol %) catalyzed the reaction of (±)-1a and malononitrile at
25 °C furnished the product 3a with the promising
enantioselectivity along with a kinetic resolution of spiroazir-
idine 1a (Scheme 5).
Scheme 5. Organocatalytic Asymmetric Domino Reaction
and Kinetic Resolution of Spiroaziridine
■ CONCLUSION
In conclusion, we have developed the first organocatalytic
regio- and stereoselective domino reaction of spiroaziridine
and malononitrile as a carbon pronucleophile at the spiro-
center using only DBU as a catalyst. The protocol provides
easy access of spiro[dihydropyrrole-3,3′-oxindole] with ex-
cellent enantiopurity (ee up to >99%) and yields. The
organocatalytic protocol is equally effective for the N-sulfonyl
phenyl aziridine, which usually needs Lewis acid and strong
base. Further preliminary investigation of organocatalytic
asymmetric domino reaction of racemic spiroaziridine showed
a promising result with concomitant kinetic resolution of
spiroaziridine. We intend to continue our research efforts
toward this asymmetric reaction and other ring opening
reaction of spiroaziridine in our laboratory.
■
EXPERIMENTAL SECTION
General Information. All the reactions were carried out under an
atmosphere of argon using oven-dried glass wares. Commercially
available reagents were purchased and used without further
purification. Solvents were dried and distilled following the standard
literature procedure. In all the cases, flash column chromatography
was performed using silica gel (230−400 mesh). Analytical TLC was
performed on aluminium-backed plates coated with silica gel 60 with
an F254 indicator, and compounds were visualized by irradiation of UV
light. The 1H NMR and 13C NMR spectra were recorded with Bruker
400 MHz and 100 MHz using CDCl3 and DMSO-d6. FT-IR
experiments were performed on PerkinElmer Spectrum Version
10.03.08. HRMS and electron spray ionization (ESI) mass
spectrometry (MS) experiments were performed on Agilent
Technologies 6530 Accurate-Mass Q-TOF LC/MS. Enantiomeric
excess (ee) was measured by HPLC analysis with chiral stationary
phase. The melting points (Mps) were determined using a STUART
SMP30 melting point apparatus and are uncorrected.
8197
Article
General Procedure for the Synthesis of (R)-Spiroaziridine
Oxindoles. The starting materials were prepared according to the
literature procedure.6a−c,e
General Procedure for the Synthesis of Spiro-
[dihydropyrrole-3,3′ oxindoles] 3. To a stirring suspended
solution of malononitrile 2 (0.013 mL, 0.25 mmol) and 4 Å MS in
anhydrous DMF (1 mL) under Ar atmosphere at 25 °C, DBU (9 μL,
35 mol %) was added. After 30 min, 1d (0.05 g, 0.17 mmol) was
added to the reaction mixture at the same temperature. The resulting
mixture was stirred at the same temperature and monitored by TLC.
After completion (5 h), the reaction mixture was quenched with brine
and extracted with ethyl acetate (3 × 25 mL) and washed with brine.
The combined organic layers were dried over Na2SO4 and solvent was
removed under reduced pressure. The residue was purified by silica
gel flash column chromatography with hexanes/ethyl acetate (2:1) to
afford spiro[dihydropyrrole-3,3′ oxindoles] 3d (0.058 g, 95% yield).
Organocatalytic Asymmetric Domino Reaction of Spiroa-
ziridine (±)-1a and Its Kinetic Resolution. In a screw-cap vial, a
solution of (±)-1a (0.05 g, 0.16 mmol), 2 (0.013 mL, 0.25 mmol),
and quinine (0.005 g, 0.016 mmol, 10 mol %) in anhydrous CH2Cl2
(0.5 mL) was stirred at 25 °C. After about 50% consumption of
starting spiroaziridine 1a monitored by TLC (9 h), the reaction
mixture was directly loaded on silica gel for flash column
chromatography and eluted with hexanes/ethyl acetate (2:1) to
afford spiro[dihydropyrrole-3,3′ oxindoles] 3a (0.021 g, 35% yield)
and recovered spiroaziridine 1a (0.023 g, 45% yield).
Characterization Data for Compounds. 1′-Methyl-1-
(phenylsulfonyl)spiro[aziridine-2,3′-indolin]-2′-one ((±)-1a). The
product was prepared by following the literature procedure and was
obtained as a gray solid (0.388 g; 92% yield): mp 126−128 °C; 1H
NMR (400 MHz, CDCl3): δ 7.97−7.95 (m, 2H), 7.74 (dd, J = 7.7,
1.3 Hz, 1H), 7.64−7.62 (m, 1H), 7.54−7.50 (m, 2H), 7.41−7.36 (m,
1H), 7.15−7.11 (m, 1H), 6.92 (dd, J = 7.9, 1.2 Hz, 1H), 3.46 (d, J =
1.0 Hz, 1H), 3.27 (d, J = 2.3 Hz, 3H), 3.14 (d, J = 0.9 Hz, 1H);
13
C{1H} NMR (100 MHz, CDCl3): δ 169.8, 145.1, 139.4, 133.7,
130.3, 129.1, 127.8, 125.3, 123.0, 120.3, 108.9, 48.3, 40.4, 26.9:
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H14N2NaO3S,
337.0623; found, 337.0622. HPLC analysis of recovered 1a: ee = 13
and 18% (in toluene); CHIRALCEL IB-3 column, 250 mm, n-
hexane/isopropyl alcohol = 90:10; flow rate 1.0 mL/min; 254 nm: tR
= 37.30 min (major), tR = 45.53 min (minor).
1′-Benzyl-1-(phenylsulfonyl)spiro[aziridine-2,3′-indolin]-2′-one
((±)-1b). The product was prepared by following the literature
procedure and was obtained as a gray solid (0.375 g; 90% yield): mp
140−142 °C; 1H NMR (400 MHz, CDCl3): δ 7.98−7.95 (m, 2H),
7.71 (dd, J = 7.7, 1.2 Hz, 1H), 7.64−7.60 (m, 1H), 7.53−7.49 (m,
2H), 7.35−7.24 (m, 6H), 7.09 (td, J = 7.6, 1.0 Hz, 1H), 6.78 (d, J =
7.9 Hz, 1H), 4.97 (s, 2H), 3.50 (d, J = 0.9 Hz, 1H), 3.27 (d, J = 0.9
Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 170.0, 144.3, 139.4,
135.1, 133.6, 130.2, 129.1, 128.9, 128.7, 127.8, 127.3, 125.3, 123.0,
120.4, 109.9, 48.3, 44.4, 40.4. HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C22H18N2NaO3S, 413.0936; found, 413.0924.
1′-Allyl-1-(phenylsulfonyl)spiro[aziridine-2,3′-indolin]-2′-one
((±)-1c). The product was prepared by following the literature
procedure and was obtained as a gray solid (0.378 g; 90% yield): mp
118−120 °C; 1H NMR (400 MHz, CDCl3): δ 7.96−7.94 (m, 2H),
7.73 (dd, J = 7.7, 1.2 Hz, 1H), 7.64−7.60 (m, 1H), 7.52 (dd, J = 8.5,
7.1 Hz, 2H), 7.35 (td, J = 7.8, 1.3 Hz, 1H), 7.12 (td, J = 7.6, 1.0 Hz,
1H), 6.91 (d, J = 7.8 Hz, 1H), 5.88−5.79 (m, 1H), 5.26−5.20 (m,
2H), 4.40 (dt, J = 5.4, 1.7 Hz, 2H), 3.48 (d, J = 0.9 Hz, 1H), 3.19 (d, J
= 0.8 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 169.6, 144.4,
139.4, 133.6, 130.9, 130.2, 129.1, 127.8, 125.4, 122.9, 120.3, 118.1,
109.8, 48.2, 43.0, 40.4; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C18H16N2NaO3S, 363.0779; found, 363.0774.
5′-Amino-1-methyl-2-oxo-1′-(phenylsulfonyl)-1′,2′-
dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile ((±)-3a). The
product was prepared by following the general procedure and was
obtained as a white solid (0.057 g; 95% yield): mp 200−202 °C; 1H
NMR (400 MHz, CDCl3): δ 7.99−7.89 (m, 2H), 7.80 (t, J = 7.6 Hz,
1H), 7.68 (t, J = 7.7 Hz, 2H), 7.31−7.22 (m, 1H), 6.93 (t, J = 7.5 Hz,
DOI: 10.1021/acs.joc.9b01226
J. Org. Chem. 2019, 84, 8194−8201
The Journal of Organic Chemistry
1H), 6.79 (d, J = 7.8 Hz, 1H), 6.45 (d, J = 7.4 Hz, 1H), 5.91 (s, 2H),
4.11 (d, J = 10.9 Hz, 1H), 3.82 (d, J = 10.9 Hz, 1H), 3.17 (s,
3H);13C{1H} NMR (100 MHz, CDCl3): δ 176.3, 156.1, 143.0, 135.6,
134.6, 130.1, 129.9, 129.6, 127.8, 123.5, 123.3, 115.8, 108.6, 65.0,
57.6, 52.4, 26.8; FT-IR (ν cm−1): 3368, 2925, 2191, 1715, 1613, 1468,
1361, 1090, 755, 604, 584; HRMS (ESI-TOF) m/z: [M + Na]+ calcd
for C19H16N4NaO3S, 403.0841; found, 403.0828. HPLC analysis of
3a: ee = 12%; CHIRALCEL IA-3 column, 250 mm, n-hexane/
isopropyl alcohol = 80:20; flow rate: 1.0 mL/min; 254 nm; tR = 35.13
min (major), tR = 20.83 min (minor).
5′-Amino-1-benzyl-2-oxo-1′-(phenylsulfonyl)-1′,2′-dihydrospiro-
[indoline-3,3′-pyrrole]-4′-carbonitrile ((±)-3b). The product was
prepared by following the general procedure and was obtained as a
white solid (0.05 g; 85% yield): mp 204−206 °C; 1H NMR (400
MHz, CDCl3): δ 7.90 (d, J = 7.9 Hz, 2H), 7.73 (d, J = 7.5 Hz, 1H),
7.62 (t, J = 7.6 Hz, 2H), 7.31−7.23 (m, 2H), 7.19 (d, J = 7.6 Hz, 3H),
7.08 (t, J = 7.8 Hz, 1H), 6.84 (t, J = 7.6 Hz, 1H), 6.59 (d, J = 7.9 Hz,
1H), 6.39 (d, J = 7.5 Hz, 1H), 5.96 (s, 2H), 4.92 (d, J = 15.8 Hz, 1H),
4.72 (d, J = 15.8 Hz, 1H), 4.15 (d, J = 10.9 Hz, 1H), 3.82 (d, J = 10.9
Hz, 1H);13C{1H} NMR (100 MHz, CDCl3): δ 176.6, 156.2, 142.0,
135.5, 135.0, 134.6, 130.1, 129.9, 129.6, 128.9, 127.9, 127.8, 127.1,
123.5, 123.4, 116.0, 109.7, 65.0, 57.6, 52.5, 44.2; FT-IR (ν cm−1)
3355, 2924, 2853, 2191, 1715, 1644, 1612, 1467, 1363, 1170, 1089,
753, 687, 581; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C25H20N4NaO3S, 479.1154; found, 479.1138.
1-Allyl-5′-amino-2-oxo-1′-(phenylsulfonyl)-1′,2′-dihydrospiro-
[indoline-3,3′-pyrrole]-4′-carbonitrile ((±)-3c). The product was
prepared by following the general procedure and was obtained as a
white solid (0.05 g; 84% yield): mp 132−134 °C; 1H NMR (400
MHz, CDCl3): δ 7.94−7.91 (m, 2H), 7.80−7.76 (m, 1H), 7.66 (t, J =
7.8 Hz, 2H), 7.21 (td, J = 7.8, 1.2 Hz, 1H), 6.90 (td, J = 7.6, 0.8 Hz,
1H), 6.76 (d, J = 7.8 Hz, 1H), 6.44 (d, J = 7.0 Hz, 1H), 6.00 (s, 2H),
5.82−5.72 (m, 1H), 5.20−5.15 (m, 2H), 4.35 (dd, J = 16.5, 4.9 Hz,
1H), 4.20 (dd, J = 16.5, 5.2 Hz, 1H), 4.12 (d, J = 10.9 Hz, 1H), 3.83
(d, J = 10.9 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 176.2,
156.1, 142.1, 135.6, 134.6, 130.6, 130.1, 129.9, 129.5, 127.8, 123.4,
123.4, 117.7, 115.9, 109.5, 64.9, 57.5, 52.4, 42.7; FT-IR (ν cm−1)
3445, 2925, 2191, 1716, 1645, 1590, 1487, 1363, 1218, 1171, 1089,
944, 856, 755, 687, 583; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C21H18N4NaO3S, 429.0997; found, 429.0979.
(R)-5′-Amino-1′-(tert-butylsulfonyl)-1-methyl-2-oxo-1′,2′-
dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (3d). The prod-
uct was prepared by following the general procedure and was obtained
as a white solid (small scale: 0.058 g; 95% yield. Gram-scale: 1.15 g,
94% yield): mp 178−181 °C; 1H NMR (400 MHz, CDCl3): δ 7.35−
7.31 (m, 2H), 7.14 (t, J = 7.5 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 5.76
(s, 2H), 4.19 (d, J = 10.8 Hz, 1H), 4.12 (d, J = 10.7 Hz, 1H), 3.21 (s,
3H), 1.58 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 177.2,
158.3, 143.7, 129.8, 128.5, 124.0, 123.7, 116.4, 108.7, 65.2, 63.1, 59.2,
51.7, 26.6, 24.4. FT-IR (ν cm−1) 3436, 2920, 2188, 1714, 1643, 1585,
1470, 1373, 1262, 1128, 1056, 754, 662, 568; HRMS (ESI-TOF) m/
z: [M + Na]+ calcd for C17H20N4NaO3S, 383.1154; found, 383.1149;
HPLC analysis: ee >99%; CHIRALCEL IA-3 column, 250 mm, n-
hexane/isopropyl alcohol = 85:15; flow rate: 1.0 mL/min; 254 nm, tR
= 28.91 min (major), tR = 25.63 min (minor).
(S)-5′-Amino-1-benzyl-1′-(tert-butylsulfonyl)-2-oxo-1′,2′-
dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (ent-3e). The
product was prepared by following the general procedure and was
obtained as a white solid (0.052 g; 88% yield): mp 115−116 °C; 1H
NMR (400 MHz, CDCl3): δ 7.35−7.31 (m, 3H), 7.27 (d, J = 6.5 Hz,
3H), 7.21 (t, J = 7.8 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 6.70 (d, J = 7.8
Hz, 1H), 5.73 (s, 2H), 5.02 (d, J = 15.8 Hz, 1H), 4.81 (d, J = 15.8 Hz,
1H), 4.25 (d, J = 10.7 Hz, 1H), 4.18 (d, J = 10.6 Hz, 1H), 1.60 (s,
9H); 13C{1H} NMR (100 MHz, CDCl3): δ 177.5, 158.2, 146.1,
142.7, 135.0, 129.7, 128.9, 127.8, 127.0, 124.1, 123.8, 116.3, 109.8,
65.3, 63.4, 59.3, 51.9, 44.1, 24.4; FT-IR (ν cm−1) 3350, 2920, 2187,
1713, 1639, 1467, 1129, 756, 665, 568; HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C23H24N4NaO3S, 459.1467; found, 459.1450. HPLC
analysis: ee = 98%; CHIRALCEL IB-3 column, 250 mm, n-hexane/
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isopropyl alcohol = 85:15; flow rate: 1.0 mL/min; 254 nm; tR = 15.48
min (major), tR = 14.57 min (minor).
(R)-1-Allyl-5′-amino-1′-(tert-butylsulfonyl)-2-oxo-1′,2′-
dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (3f). The product
was prepared by following the general procedure and was obtained as
a white solid (0.054 g; 90% yield): mp 156−158 °C; 1H NMR (400
MHz, CDCl3): δ 7.30−7.25 (m, 1H), 7.23 (dd, J = 7.7, 1.3 Hz, 1H),
7.07 (t, J = 7.5 Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H), 5.85 (s, 2H), 5.77
(ddd, J = 15.9, 10.5, 5.1 Hz, 1H), 5.22−5.12 (m, 2H), 4.33 (dd, J =
4.9, 1.9 Hz, 1H), 4.24−4.05 (m, 3H), 1.52 (s, 9H); 13C{1H} NMR
(100 MHz, CDCl3): δ 177.1, 158.4, 142.8, 130.6, 129.7, 128.6, 124.1,
123.7, 117.7, 116.5, 109.5, 65.2, 62.9, 59.2, 51.8, 42.5, 24.4; FT-IR (ν
cm−1) 3437, 2920, 2188, 1715, 1643, 1585, 1487, 1364, 1130, 1045,
757, 662, 568; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C19H22N4NaO3S, 409.1310; found, 409.1304. HPLC analysis: ee
>99%; CHIRALCEL IA-3 column, 250 mm, n-hexane/isopropyl
alcohol = 90:10; flow rate: 1.0 mL/min; 254 nm; tR = 42.01 min
(major), tR = 30.14 min (minor).
tert-Butyl-(R)-5′-amino-1′-(tert-butylsulfonyl)-4′-cyano-2-oxo-
1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-1-carboxylate (3g). The
product was prepared by following the general procedure and was
obtained as a white solid (0.038 g; 65% yield): mp 169−171 °C; 1H
NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8.8 Hz, 1H), 7.36 (ddd, J =
7.3, 4.4, 2.8 Hz, 2H), 7.25 (d, J = 5.8 Hz, 1H), 5.80 (s, 2H), 4.24 (d, J
= 10.9 Hz, 1H), 4.12 (d, J = 10.7 Hz, 1H), 1.65 (s, 9H), 1.57 (s, 9H);
13
C{1H} NMR (100 MHz, CDCl3): δ 176.4, 158.5, 148.6, 139.7,
130.0, 127.1, 125.5, 124.0, 116.3, 115.4, 85.2, 65.3, 63.6, 60.1, 52.3,
28.1, 24.4; FT-IR (ν cm−1) 3350, 2918, 2189, 1734, 1642, 1466,
1338, 1129, 759, 566; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C21H26N4NaO5S, 469.1522; found, 469.1509. HPLC analysis: ee =
98%; CHIRALCEL IA-3 column, 250 mm, n-hexane/isopropyl
alcohol = 90:10; flow rate: 1.0 mL/min; 254 nm tR = 14.66 min
(major), tR = 17.62 min (minor).
(S)-5′-Amino-1′-(tert-butylsulfonyl)-2-oxo-1′,2′-dihydrospiro-
[indoline-3,3′-pyrrole]-4′-carbonitrile (ent-3h). The product was
prepared by following the general procedure and was obtained as a
white solid (0.056 g; 90% yield); mp 214−216 °C; 1H NMR (400
MHz, DMSO-d6): δ 10.49 (s, 1H), 7.35 (d, J = 7.4 Hz, 1H), 7.23 (t, J
= 7.7 Hz, 1H), 7.07−6.94 (m, 3H), 6.85 (d, J = 7.7 Hz, 1H), 4.16 (d,
J = 10.8 Hz, 1H), 3.98 (d, J = 10.8 Hz, 1H), 1.46 (s, 9H); 13C{1H}
NMR (100 MHz, DMSO-d6): δ 179.3, 158.2, 142.5, 130.7, 129.6,
124.7, 122.9, 117.7, 110.3, 64.8, 61.3, 58.8, 52.4, 24.1; FT-IR (ν
cm−1): 3317, 2924, 2188, 1716, 1641, 1583, 1471, 1329, 1129, 1044,
757, 660, 596; HRMS (ESI-TOF) m/z: [M + Na]+ calcd
C16H18N4NaO3S, 369.0997; found, 369.0992. HPLC analysis: ee
>99%; CHIRALCEL OJ-H column, 250 mm, n-hexane/isopropyl
alcohol = 85:15; flow rate: 1.0 mL/min; 254 nm, tR = 15.12 min
(major), tR = 18.80 min (minor).
(R)-5′-Amino-1′-(tert-butylsulfonyl)-5-methoxy-1-methyl-2-oxo-
1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (3i). The
product was prepared by following the general procedure and was
obtained as a white solid (0.055 g; 92% yield); mp 214−216 °C; 1H
NMR (400 MHz, CDCl3): δ 6.92 (s, 1H), 6.83 (dd, J = 8.5, 2.5 Hz,
1H), 6.73 (d, J = 8.4 Hz, 1H), 5.85 (s, 2H), 4.18 (d, J = 10.6 Hz, 1H),
4.09 (d, J = 10.5 Hz, 1H), 3.79 (s, 3H), 3.17 (s, 3H), 1.57 (s, 9H);
13
C{1H} NMR (100 MHz, CDCl3): δ 177.0, 158.4, 156.8, 137.0,
129.8, 116.5, 114.4, 111.0, 109.2, 65.2, 62.9, 59.2, 55.9, 52.1, 26.7,
24.4; FT-IR (ν cm−1) 3437, 2925, 2187, 1709, 1643, 1584, 1499,
1435, 1365, 1289, 1129, 1036, 853, 806, 755, 660, 597, 509; HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C18H22N4NaO4S, 413.1259;
found, 413.1253. HPLC analysis: ee >99%; CHIRALCEL IA-3
column, 250 mm, n-hexane/isopropyl alcohol = 75:25; flow rate: 1.0
mL/min; 254 nm, tR = 21.25 min (major), tR = 31.97 min (minor).
(S)-5′-Amino-1′-(tert-butylsulfonyl)-1,5-dimethyl-2-oxo-1′,2′-
dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (ent-3j). The
product was prepared by following the general procedure and was
obtained as a white solid (0.053 g; 88% yield): mp 225−227 °C; 1H
NMR (400 MHz, CDCl3): δ 7.16−7.08 (m, 2H), 6.71 (d, J = 7.9 Hz,
1H), 5.81 (s, 2H), 4.16 (d, J = 10.7 Hz, 1H), 4.10 (d, J = 10.8 Hz,
1H), 3.18 (s, 3H), 2.34 (s, 3H), 1.57 (s, 9H); 13C{1H} NMR (100
DOI: 10.1021/acs.joc.9b01226
J. Org. Chem. 2019, 84, 8194−8201
The Journal of Organic Chemistry
MHz, CDCl3): δ 177.2, 158.3, 141.3, 133.4, 130.0, 128.5, 124.8,
116.6, 108.4, 65.2, 63.0, 59.3, 51.8, 26.6, 24.4, 21.2; FT-IR (ν cm−1)
3436, 2921, 2188, 1712, 1639, 1585, 1501, 1432, 1327, 1265, 1129,
1055, 808, 751, 661, 597, 552; HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C18H22N4NaO3S, 397.1310; found, 397.1305. HPLC
analysis: ee = 99% CHIRALCEL IA-3 column, 250 mm, n-hexane/
isopropyl alcohol = 90:10; flow rate: 1.0 mL/min; 254 nm, tR = 30.92
min (major), tR = 38.13 min (minor).
(R)-5′-Amino-1′-(tert-butylsulfonyl)-1,5,7-trimethyl-2-oxo-1′,2′-
dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (3k). The prod-
uct was prepared by following the general procedure and was obtained
as a white solid (0.054 g; 90% yield): mp 228−230 °C; 1H NMR
(400 MHz, CDCl3): δ 6.96 (s, 1H), 6.84 (s, 1H), 5.79 (s, 2H), 4.14
(d, J = 10.6 Hz, 1H), 4.06 (d, J = 10.7 Hz, 1H), 3.44 (s, 3H), 2.50 (s,
3H), 2.28 (s, 3H), 1.57 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3):
δ 177.9, 158.2, 138.9, 133.9, 133.1, 129.4, 122.7, 120.0, 116.6, 65.2,
63.5, 59.7, 51.3, 29.9, 24.4, 20.8, 18.7; FT-IR (ν cm−1) 3436, 2920,
2189, 1708, 1644, 1585, 1483, 1338, 1266, 1048, 762, 571; HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C19H24N4NaO3S, 411.1467;
found, 411.1463. HPLC analysis: ee >99%; CHIRALCEL IA-3
column, 250 mm, n-hexane/isopropyl alcohol = 85:15; flow rate: 1.0
mL/min; 254 nm, tR = 26.65 min (major), tR = 15.39 min (minor).
(S)-5′-Amino-1′-(tert-butylsulfonyl)-5-fluoro-1-methyl-2-oxo-
1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (ent-3l).
The product was prepared by following the general procedure and
was obtained as a white solid (0.052 g; 86% yield): mp 189−191 °C;
1
H NMR (400 MHz, CDCl3): δ 7.10−7.01 (m, 2H), 6.77 (dd, J = 8.5,
4.0 Hz, 1H), 5.85 (s, 2H), 4.19 (d, J = 10.6 Hz, 1H), 4.09 (d, J = 10.6
Hz, 1H), 3.20 (s, 3H), 1.57 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3): δ 177.0, 159.8 (d, JC−F = 243.0 Hz, 2C), 139.6, 139.6, 130.2,
116.3, 116.1, 112.2 (d, JC−F = 25.0 Hz, 2C), 109.4 (d, JC−F = 7.0 Hz,
2C), 65.3, 62.4, 59.1, 52.1 (d, JC−F = 2.0 Hz, 2C), 26.8, 24.3; . 19F
NMR (376 MHz, CDCl3): δ −118.546; FT-IR (ν cm−1) 3344, 2919,
2186, 1756, 1584, 1463, 1311, 1128, 667, 597; HRMS (ESI-TOF) m/
z: [M + Na]+ calcd for C17H19FN4NaO3S, 401.1060; found, 401.1054.
HPLC analysis: ee = 98%; CHIRALCEL IA-3 column, 250 mm, n-
hexane/isopropyl alcohol = 90:10; flow rate: 1.0 mL/min; 254 nm, tR
= 52.91 min (major), tR = 46.97 min (minor); .
(S)-5′-Amino-1′-(tert-butylsulfonyl)-5-chloro-1-methyl-2-oxo-
1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (ent-3m).
The product was prepared by following the general procedure and
was obtained as a white solid (0.051 g; 85% yield); mp 239−241 °C;
1
H NMR (400 MHz, CDCl3): δ 7.65 (dd, J = 8.2, 1.7 Hz, 1H), 7.62
(d, J = 1.7 Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H), 5.76 (s, 2H), 4.18 (d, J =
10.8 Hz, 1H), 4.10 (d, J = 10.8 Hz, 1H), 3.19 (s, 3H), 1.58 (s, 9H);
13
C{1H} NMR (100 MHz, CDCl3): δ 176.5, 158.4, 143.4, 138.7,
132.9, 130.9, 116.1, 110.7, 86.0, 65.3, 62.7, 59.1, 51.7, 26.7, 24.4; FT-
IR (ν cm−1) 3435, 2922, 2187, 1716, 1640, 1464, 1341, 1129, 1053,
810, 750, 665, 597; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C17H19ClN4NaO3S/C17H1937ClN4NaO3S, 417.0764 and 419.0764;
found, 417.0757 and 419.0756, respectively. HPLC analysis: ee >99%;
CHIRALCEL IB-3 column, 250 mm, n-hexane/isopropyl alcohol =
85:15; flow rate 1.0 mL/min; 254 nm, tR = 23.61 min (major), tR =
27.97 min (minor).
(R)-5′-Amino-1′-(tert-butylsulfonyl)-5-bromo-1-methyl-2-oxo-
1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (3n). The
product was prepared by following the general procedure and was
obtained as a white solid (0.05 g; 85% yield): mp 225−227 °C; 1H
NMR (400 MHz, CDCl3): δ 7.45 (dd, J = 4.4, 2.4 Hz, 2H), 6.72 (d, J
= 8.8 Hz, 1H), 5.84 (s, 2H), 4.18 (d, J = 10.9 Hz, 1H), 4.10 (d, J =
10.7 Hz, 1H), 3.19 (s, 3H), 1.57 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3): δ 176.7, 158.5, 142.7, 132.7, 130.7, 127.3, 116.3, 110.1,
108.7, 65.3, 62.3, 59.0, 51.8, 26.7, 24.4; FT-IR (ν cm−1) 3436, 2922,
2187, 1716, 1642, 1609, 1583, 1488, 1341, 1268, 1106, 1054, 813,
751, 655, 570; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C17H19BrN4NaO3S/C17H1981BrN4NaO3S, 461.0259 and 463.0259;
found, 461.0243 and 463.0234, respectively. HPLC analysis: ee >99%;
CHIRALCEL IA-3 column, 250 mm, n-hexane/isopropyl alcohol =
90:10; flow rate 1.0 mL/min, 254 nm; tR = 44.57 min (major), tR =
50.10 min (minor).
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(R)-5′-Amino-1′-(tert-butylsulfonyl)-5-iodo-1-methyl-2-oxo-
1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (3o). The
product was prepared by following the general procedure and was
obtained as a white solid (0.052 g; 90% yield): mp 226−228 °C; 1H
NMR (400 MHz, CDCl3): δ 7.32−7.30 (m, 2H), 6.78−6.76 (m, 1H),
5.77 (s, 2H), 4.19 (d, J = 10.8 Hz, 1H), 4.10 (d, J = 10.8 Hz, 1H),
3.20 (s, 3H), 1.57 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ
176.8, 158.4, 142.2, 130.3, 129.8, 129.1, 124.6, 116.1, 109.7, 65.3,
62.6, 59.1, 51.9, 26.7, 24.4; FT-IR (ν cm−1) 3436, 2923, 2188, 1717,
1640, 1583, 1465, 1342, 1129, 1053, 812, 751, 654, 597; HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C17H19IN4NaO3S, 509.0120; found,
509.0104. HPLC analysis: ee >99%; CHIRALCEL IA-3 column, 250
mm, n-hexane/isopropyl alcohol = 90:10; flow rate 1.0 mL/min; 254
nm; tR = 50.00 min (major), tR = 46.12 min (minor).
(R)-5′-Amino-1′-(tert-butylsulfonyl)-7-fluoro-1-methyl-2-oxo-
1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (3p). The
product was prepared by following the general procedure and was
obtained as a white solid (0.048 g; 80% yield): mp 210−212 °C; 1H
NMR (400 MHz, CDCl3): δ 7.11−7.10 (m, 1H), 7.06−7.03 (m, 2H),
5.90 (s, 2H), 4.18 (d, J = 10.8 Hz, 1H), 4.08 (d, J = 10.9 Hz, 1H),
3.41 (d, J = 2.7 Hz, 3H), 1.56 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3): δ 177.0, 158.4, 147.7 (d, JC−F = 244.0 Hz, 2C), 131.4, 130.3
(d, JC−F = 8.6 Hz, 2C), 124.3 (d, JC−F = 6.4 Hz, 2C), 119.9 (d, JC−F =
1.2 Hz, 2C), 117.8 (d, JC−F = 19.2 Hz, 2C), 116.2, 65.3, 62.9, 59.3,
52.0 (d, JC−F = 2.5 Hz, 2C), 29.1 (d, JC−F = 5.7 Hz, 2C), 24.3; 19F
NMR (376 MHz, CDCl3): δ −135.981; FT-IR (ν cm−1) 3435, 2921,
2189, 1717, 1632, 1585, 1482, 1329, 1128, 1048, 665, 571; HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C17H19FN4NaO3S, 401.1060;
found, 401.1046. HPLC analysis: ee = 93%; CHIRALCEL IA-3
column, 250 mm, n-hexane/isopropyl alcohol = 90:10; flow rate: 1.0
mL/min; 254 nm; tR = 38.79 min (major), tR = 29.90 min (minor).
(R)-5′-Amino-1′-(tert-butylsulfonyl)-7-chloro-1-methyl-2-oxo-
1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (3q). The
product was prepared by following the general procedure and was
obtained as a white solid (0.051 g; 85% yield): mp 201−203 °C; 1H
NMR (400 MHz, CDCl3): δ 7.24−7.21 (m, 2H), 7.04 (dd, J = 8.2,
7.5 Hz, 1H), 5.82 (s, 2H), 4.17 (d, J = 10.8 Hz, 1H), 4.07 (d, J = 10.7
Hz, 1H), 3.58 (s, 3H), 1.57 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3): δ 177.5, 158.4, 139.6, 133.8, 132.1, 124.4, 122.7, 116.3,
116.1, 65.3, 62.9, 59.5, 51.5, 30.0, 24.3; FT-IR (ν cm−1) 3438, 2924,
2189, 1721, 1643, 1585, 1464, 1365, 1259, 1130, 1061, 814, 757, 688,
569; HRMS (ESI-TOF) m/z: [M + Na] + calcd for
C17H19ClN4NaO3S/C17H1937ClN4NaO3S, 417.0764 and 419.0764;
found, 417.0758 and 419.0756, respectively. HPLC analysis: ee =
95%; CHIRALCEL IA-3 column, 250 mm, n-hexane/isopropyl
alcohol = 85:15; flow rate: 1.0 mL/min; 254 nm; tR = 29.99 min
(major), tR = 22.01 min (minor).
(R)-5′-Amino-7-bromo-1′-(tert-butylsulfonyl)-1-methyl-2-oxo-
1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (3r). The
product was prepared by following the general procedure and was
obtained as a white solid (0.05 g; 85% yield): mp 211−213 °C; 1H
NMR (400 MHz, CDCl3): δ 7.42 (d, J = 8.1 Hz, 1H), 7.25 (dd, J =
7.4, 1.3 Hz, 1H), 6.97 (t, J = 7.8 Hz, 1H), 5.88 (s, 2H), 4.16 (d, J =
10.8 Hz, 1H), 4.05 (d, J = 10.7 Hz, 1H), 3.58 (s, 3H), 1.56 (s, 9H);
13
C{1H} NMR (100 MHz, CDCl3): δ 177.7, 158.5, 141.0, 135.4,
131.8, 124.8, 123.2, 116.4, 102.9, 65.3, 62.7, 59.6, 51.5, 30.3, 24.3; FT-
IR (ν cm−1) 3435, 2921, 2188, 1719, 1643, 1581, 1459, 1329, 1129,
1057, 767, 633, 569; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C17H19BrN4NaO3S/C17H1981BrN4NaO3S, 461.0259 and 463.0259;
found, 461.0249 and 463.0230, respectively. HPLC analysis: ee =
96%; CHIRALCEL IA-3, 250 mm, eluent: n-hexane/isopropyl alcohol
= 85:15; flow rate: 1.0 mL/min; 254 nm): tR = 31.96 min (major), tR
= 23.60 min (minor).
(R)-5′-Amino-1′-(tert-butylsulfonyl)-4,7-dichloro-1-methyl-2-
oxo-1′,2′-dihydrospiro[indoline-3,3′-pyrrole]-4′-carbonitrile (3s).
The product was prepared by following the general procedure and
was obtained as a white solid (0.041 g; 70% yield): mp 180−182 °C;
1
H NMR (400 MHz, CDCl3): δ 7.21 (d, J = 8.7 Hz, 1H), 6.99 (d, J =
8.7 Hz, 1H), 5.80 (s, 2H), 4.40 (d, J = 9.9 Hz, 1H), 4.14 (d, J = 10.1
Hz, 1H), 3.58 (s, 3H), 1.57 (s, 9H); 13C{1H} NMR (100 MHz,
DOI: 10.1021/acs.joc.9b01226
J. Org. Chem. 2019, 84, 8194−8201
The Journal of Organic Chemistry
CDCl3): δ 177.1, 159.0, 140.9, 133.0, 130.2, 127.2, 125.1, 116.2,
114.8, 65.4, 60.6, 56.3, 52.5, 30.2, 24.5; FT-IR (ν cm−1) 3436, 2919,
2187, 1725, 1642, 1596, 1453, 1329, 1128, 1044, 752, 658, 599;
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C17H18Cl2N4NaO3S/
C 17 H 18 37 Cl 35 ClN 4 NaO 3 S/C 17 H 18 37 Cl 37 ClN 4 NaO 3 S, 451.0374,
453.0374 and 455.0374; found, 451.0361, 453.0353 and 455.0344,
respectively. HPLC analysis: ee = 96%; CHIRALCEL IA-3 column,
250 mm, n-hexane/isopropyl alcohol = 90:10; flow rate: 1.0 mL/min;
254 nm; tR = 27.25 min (major), tR = 39.36 min (minor).
(S)-2-Amino-1-((4-nitrophenyl)sulfonyl)-4-phenyl-4,5-dihydro-
1H-pyrrole-3-carbonitrile (6a). The product was prepared by
following the general procedure and was obtained as a yellow solid
(0.053 g; 90% yield): mp 171−173 °C; 1H NMR (400 MHz, CDCl3):
δ 8.31 (d, J = 8.3 Hz, 2H), 7.97 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.1
Hz, 3H), 6.85 (d, J = 7.1 Hz, 2H), 5.74 (s, 2H), 4.20 (t, J = 10.4 Hz,
1H), 4.00 (dd, J = 10.0, 4.6 Hz, 1H), 3.60 (dd, J = 10.9, 4.6 Hz, 1H);
13
C{1H} NMR (100 MHz, CDCl3): δ 154.3, 150.9, 141.4, 141.3,
129.0, 128.9, 127.7, 126.5, 124.8, 117.3, 66.1, 57.4, 42.6; FT-IR (ν
cm−1) 3369, 2929, 2190, 1650, 1531, 1349, 1169, 1088, 740, 614,
597; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C17H14N4NaO4S,
393.0633; found, 393.0614. HPLC analysis: ee >99%; CHIRALCEL
OD-H column, 250 mm, n-hexane/isopropyl alcohol = 90:10; flow
rate: 1.0 mL/min; 254 nm; tR = 41.22 min (major), tR = 54.44 min
(minor).
(S)-2-Amino-4-phenyl-1-tosyl-4,5-dihydro-1H-pyrrole-3-carboni-
trile (6b). The product was prepared by following the general
procedure and was obtained as a white solid (0.054 g; 88% yield
overall, inseparable Regio-isomers 6b:6b′ = 4:1): mp 93−95 °C; 1H
NMR (400 MHz, CDCl3): δ 7.67 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.3
Hz, 2H), 7.13 (d, J = 6.0 Hz, 3H), 6.82 (d, J = 4.6 Hz, 2H), 5.83 (s,
2H), 4.07 (t, J = 10.3 Hz, 1H), 3.92 (dd, J = 10.1, 5.2 Hz, 1H), 3.47
(dd, J = 10.6, 5.2 Hz, 1H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 155.4, 145.5, 141.8, 132.7, 130.3, 128.8, 127.7, 127.4,
126.8, 118.2, 65.0, 56.9, 42.7, 21.7. FT-IR (ν cm−1) 3447, 3367, 2922,
2189, 1646, 1594, 1426, 1365, 1164, 1089, 1045, 814, 757, 701, 662,
596, 562, 544; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C18H17N3NaO2S, 362.0939; found, 362.0929. HPLC analysis: ee
>99% of 6b and 6b′; CHIRALCEL IA-3 column, 250 mm, n-hexane/
isopropyl alcohol = 90:10; flow rate: 1.0 mL/min; 254 nm major
regio-isomer 6b tR = 28.79 min (major), tR = 24.42 min (minor).
Minor regio-isomer 6b′ tR = 23.26 min (major), tR = 22.84 min
(minor).
■
*
ASSOCIATED CONTENT
S Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.9b01226.
NMR spectra for all new compounds 1, 3, and 6 and
HPLC chromatogram of compounds 3 and 6 (PDF)
Crystal data of compound ent-3m (CIF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail: saumen.hajra@cbmr.res.in. Phone: (+91)-522-
2668861. Fax: (+91)-522-2668995.
ORCID
Saumen Hajra: 0000-0003-0303-4647
Maya Shankar Singh: 0000-0002-3199-0823
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
We thank MoES, New Delhi (MoES/09-DS/12/2015 PC-IV)
for providing financial support. S.A.S. and A.H. thank UGC
and CSIR, New Delhi, respectively, for their fellowships. We
8200
Article
are thankful to Prof. P. Banerjee and his research group, IIT
Ropar for X-ray crystal analysis.
■
REFERENCES
(1) For reviews, see: (a) Galliford, C. V.; Scheidt, K. A. Pyrrolidinyl-
spirooxindole natural products as inspirations for the development of
potential therapeutic agents. Angew. Chem., Int. Ed. 2007, 46, 8748−
8758. (b) Marti, C.; Carreira, E. M. Construction of Spiro-
[pyrrolidine-3,3′-oxindoles] − Recent Applications to the Synthesis
of Oxindole Alkaloids. Eur. J. Org. Chem. 2003, 2003, 2209−2219.
(c) Cui, C.-B.; Kakeya, H.; Osada, H. Novel Mammalian Cell Cycle
lnhibitors, Spirotryprostatins A and B, Produced by Aspergillusfumi-
gatus, Which Inhibit Mammalian Cell Cycle at G2/M Phase1.
Tetrahedron 1996, 52, 12651−12666. (d) Cui, C.-B.; Kakeya, H.;
Osada, H. Spirotryprostatin B, a novel mammalian cell cycle inhibitor
produced by Aspergillus fumigatus. J. Antibiot. 1996, 49, 832−835.
(e) Yu, B.; Yu, D.-Q.; Liu, H.-M.; Spirooxindoles. Promising scaffolds
for anticancer agents. Eur. J. Med. Chem. 2015, 97, 673−698. (f) Xu,
P.-W.; Yu, J.-S.; Chen, C.; Cao, Z.-Y.; Zhou, F.; Zhou, J. Catalytic
Enantioselective Construction of Spiro Quaternary Carbon Stereo-
centers. ACS Catal. 2019, 9, 1820−1882. (g) Cao, Z.-Y.; Wang, X.;
Tan, C.; Zhao, X.-L.; Zhou, J.; Ding, K. Highly Stereoselective Olefin
Cyclopropanation of Diazooxindoles Catalyzed by a C2-Symmetric
Spiroketal Bisphosphine/Au(I) Complex. J. Am. Chem. Soc. 2013,
135, 8197−8200. (h) Liu, Y.-L.; Wang, X.; Zhao, Y.-L.; Zhu, F.; Zeng,
X.-P.; Chen, L.; Wang, C.-H.; Zhao, X.-L.; Zhou, J. One-Pot Tandem
Approach to Spirocyclic Oxindoles Featuring Adjacent Spiro-Stereo-
centers. Angew. Chem., Int. Ed. 2013, 52, 13735−13739. (i) Yin, X.-P.;
Zeng, X.-P.; Liu, Y.-L.; Liao, F.-M.; Yu, J.-S.; Zhou, F.; Zhou, J.
Asymmetric Triple Relay Catalysis: Enantioselective Synthesis of
Spirocyclic Indolines through a One-Pot Process Featuring an
Asymmetric 6π Electrocyclization. Angew. Chem., Int. Ed. 2014, 53,
13740−13745. (j) Cao, Z.-Y.; Zhou, F.; Zhou, J. Development of
Synthetic Methodologies via Catalytic Enantioselective Synthesis of
3,3-Disubstituted Oxindoles. Acc. Chem. Res. 2018, 51, 1443−1454.
(2) (a) Girgis, A. S. Regioselective synthesis of dispiro[1H-indene-
2,3’-pyrrolidine-2’,3’’-[3H]indole]-1,2’’(1’’H)-diones of potential anti-
tumor properties. Eur. J. Med. Chem. 2009, 44, 91−100. (b) Kumar, R.
R.; Perumal, S.; Senthilkumar, P.; Yogeeswari, P.; Sriram, D. A facile
synthesis and antimycobacterial evaluation of novel spiro-pyrido-
pyrrolizines and pyrrolidines. Eur. J. Med. Chem. 2009, 44, 3821−
3829. (c) Kouznetsov, V. V.; Arenas, D. R. M.; Arvelo, F.; Forero, J. S.
B.; Sojo, F.; Muñoz, A. 4-Hydroxy-3-methoxyphenyl substituted 3-
methyl-tetrahydroquinoline derivatives obtained through imino diels-
alder reactions as potential antitumoral agents. Lett. Drug Des.
Discovery 2010, 7, 632−639. (d) Maheswari, S. U.; Balamurugan, K.;
Perumal, S.; Yogeeswari, P.; Sriram, D. A facile 1,3-dipolar
cycloaddition of azomethine ylides to 2-arylidene-1,3-indanediones:
synthesis of dispiro-oxindolylpyrrolothiazoles and their antimycobac-
terial evaluation. Bioorg. Med. Chem. Lett. 2010, 20, 7278−7282.
(e) Prasanna, P.; Balamurugan, K.; Perumal, S.; Yogeeswari, P.;
Sriram, D. A regio- and stereoselective 1,3-dipolar cycloaddition for
the synthesis of novel spiro-pyrrolothiazolyloxindoles and their
antitubercular evaluation. Eur. J. Med. Chem. 2010, 45, 5653−5661.
(f) Lo, M. M.-C.; Neumann, C. S.; Nagayama, S.; Perlstein, E. O.;
Schreiber, S. L. A Library of Spirooxindoles Based on a Stereoselective
Three-Component Coupling Reaction. J. Am. Chem. Soc. 2004, 126,
16077−16086. (g) Antonchick, A. P.; Gerding-Reimers, C.;
Catarinella, M.; Schürmann, M.; Preut, H.; Ziegler, S.; Rauh, D.;
Waldmann, H. Highly enantioselective synthesis and cellular
evaluation of spirooxindoles inspired by natural products. Nat.
Chem. 2010, 2, 735−740.
(3) (a) Edmondson, S.; Danishefsky, S. J.; Sepp-Lorenzino, L.;
Rosen, N. Total Synthesis of Spirotryprostatin A, Leading to the
Discovery of Some Biologically Promising Analogues. J. Am. Chem.
Soc. 1999, 121, 2147−2155. (b) Meyers, C.; Carreira, E. M. Total
synthesis of (-)-spirotryprostatin B. Angew. Chem., Int. Ed. 2003, 42,
694−696. (c) Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Wang, G.;
Qiu, S.; Shangary, S.; Gao, W.; Qin, D.; Stuckey, J.; Krajewski, K.;
DOI: 10.1021/acs.joc.9b01226
J. Org. Chem. 2019, 84, 8194−8201
The Journal of Organic Chemistry Article

Roller, P. P.; Wang, S. Structure-based design of spiro-oxindoles as Lactams. J. Org. Chem. 2010, 75, 6173−6181. (f) Bhattacharyya, A.;
potent, specific small-molecule inhibitors of the MDM2-p53 Shahi, C. K.; Pradhan, S.; Ghorai, M. K. Stereospecific Synthesis of
interaction. J. Med. Chem. 2006, 49, 3432−3435. (d) Zhao, Y.; Liu, 1,4,5,6-Tetrahydropyrimidines via Domino Ring-Opening Cyclization
L.; Sun, W.; Lu, J.; McEachern, D.; Li, X.; Yu, S.; Bernard, D.; of Activated Aziridines with α-Acidic Isocyanides. Org. Lett. 2018, 20,
Ochsenbein, P.; Ferey, V.; Carry, J.-C.; Deschamps, J. R.; Sun, D.; 2925−2928. (g) Shiomi, N.; Kuroda, M.; Nakamura, S. Desymmet-
Wang, S. Diastereomeric Spirooxindoles as Highly Potent and rization of aziridine with malononitrile using cinchona alkaloid
Efficacious MDM2 Inhibitors. J. Am. Chem. Soc. 2013, 135, 7223− amide/zinc(II) catalysts. Chem. Commun. 2017, 53, 1817−1820.
7234. (e) Fu, P.; Kong, F.; Li, X.; Wang, Y.; Zhu, W. Cyanogramide (9) (a) Moss, T. A.; Alba, A.; Hepworth, D.; Dixon, D. J. Efficient
with a New Spiro[indolinone-pyrroloimidazole] Skeleton from base catalyzed alkylation reactions with aziridine electrophiles. Chem.
Actinoalloteichus cyanogriseus. Org. Lett. 2014, 16, 3708−3711. Commun. 2008, 2474−2476. (b) Moss, T. A.; Fenwick, D. R.; Dixon,
(f) Hong, S.; Jung, M.; Park, Y.; Ha, M. W.; Park, C.; Lee, M.; D. J. Enantio- and diastereoselective catalytic alkylation reactions with
Park, H.-g. Efficient enantioselective total synthesis of (-)-horsfiline. aziridines. J. Am. Chem. Soc. 2008, 130, 10076−10077. (c) Paixão, M.
Chem.Eur. J. 2013, 19, 9599−9605. W.; Nielsen, M.; Jacobsen, C. B.; Jørgensen, K. A. Organocatalytic
(4) For review, see: (a) Fang, X.; Wang, C.-J. Catalytic asymmetric asymmetric ring-opening of aziridines. Org. Biomol. Chem. 2008, 6,
construction of spiropyrrolidines via 1,3-dipolar cycloaddition of 3467−3470.
azomethine ylides. Org. Biomol. Chem. 2018, 16, 2591−2601. For
selected examples see: (b) Shanmugam, P.; Viswambharan, B.;
Madhavan, S. Synthesis of Novel Functionalized 3-Spiropyrrolizidine
and 3-Spiropyrrolidine Oxindoles from Baylis−Hillman Adducts of
Isatin and Heteroaldehydes with Azomethine Ylides via [3+2]-
Cycloaddition. Org. Lett. 2007, 9, 4095−4098. (c) Sebahar, P. R.;
Williams, R. M. The Asymmetric Total Synthesis of (+)- and
(−)-Spirotryprostatin B. J. Am. Chem. Soc. 2000, 122, 5666−5667.
(5) (a) Hajra, S.; Maji, B.; Mal, D. A Catalytic and Enantioselective
Synthesis of trans-2- Amino-1-aryltetralins. Adv. Synth. Catal. 2009,
351, 859−864. (b) Hajra, S.; Bar, S. Catalytic enantioselective
synthesis of A-86929, a dopamine D1 agonist. Chem. Commun. 2011,
47, 3981−3982. (c) Hajra, S.; Sinha, D. Catalytic Enantioselective
Aziridoarylation of Aryl Cinnamyl Ethers toward Synthesis of trans-3-
Amino-4-arylchromans. J. Org. Chem. 2011, 76, 7334−7340.
(d) Hajra, S.; Akhtar, S. M. S.; Aziz, S. M. Catalytic asymmetric
aminolactonization of 1,2-disubstituted alkenoic acid esters: Efficient
construction of aminolactones with an all-carbon quaternary stereo-
centre. Chem. Commun. 2014, 50, 6913−6916.
(6) (a) Hajra, S.; Aziz, S. M.; Jana, B.; Mahish, P.; Das, D. Synthesis
of Chiral Spiro-Aziridine Oxindoles via Aza-Corey−Chaykovsky
Reaction of Isatin Derived N-tert-Butanesulfinyl Ketimines. Org.
Lett. 2016, 18, 532−535. (b) Hajra, S.; Roy, S. S.; Aziz, S. M.; Das, D.
Catalyst-Free “On-Water” Regio- and Stereospecific Ring-Opening of
Spiroaziridine Oxindole: Enantiopure Synthesis of Unsymmetrical
3,3′-Bisindoles. Org. Lett. 2017, 19, 4082−4085. (c) Hajra, S.; Roy, S.
S.; Biswas, A.; Saleh, S. A. Catalyst-Free Ring Opening of
Spiroaziridine Oxindoles by Heteronucleophiles: An Approach to
the Synthesis of Enantiopure 3-Substituted Oxindoles. J. Org. Chem.
2018, 83, 3633−3644. (d) Hajra, S.; Roy, S.; Saleh, S. A. Domino
Corey−Chaykovsky Reaction for One-Pot Access to Spirocyclopropyl
Oxindoles. Org. Lett. 2018, 20, 4540−4544. (e) Hajra, S.; Hazra, A.;
Mandal, P. Stereocontrolled Nucleophilic Fluorination at the Tertiary
sp3-Carbon Center for Enantiopure Synthesis of 3-Fluorooxindoles.
Org. Lett. 2018, 20, 6471−6475.
(7) For reviews, see: (a) Tietze, L. F. Domino Reactions in Organic
Synthesis. Chem. Rev. 1996, 96, 115−136. (b) Pellissier, H.
Stereocontrolled Domino Reactions. Chem. Rev. 2013, 113, 442−
524. (c) Chanda, T.; Zhao, J. C.-G. Recent Progress in Organo-
catalytic Asymmetric Domino Transformations. Adv. Synth. Catal.
2018, 360, 2−79.
(8) For review see: (a) Hu, X. E. Nucleophilic ring opening of
aziridines. Tetrahedron 2004, 60, 2701−2743. (b) Singh, G. S.;
Sudheesh, S.; Keroletswe, N. Recent applications of aziridine ring
expansion reactions in heterocyclic synthesis. Arkivoc 2017, 2018,
50−113. (c) Talukdar, R.; Saha, A.; Ghorai, M. K. Domino-Ring
Opening-Cyclization (DROC) of DonorAcceptor (DA) Cyclo-
propanes. Isr. J. Chem. 2016, 56, 445−453. For selected examples
see: (d) Ghorai, M. K.; Tiwari, D. P. Enantioselective Synthesis of 4,5-
Dihydropyrroles via Domino RingOpening Cyclization (DROC) of
N-Activated Aziridines with Malononitrile. J. Org. Chem. 2013, 78,
2617−2625. (e) Ghorai, M. K.; Tiwari, D. P. Lewis Acid Catalyzed
Highly Stereoselective Domino-Ring-Opening Cyclization of Acti-
vated Aziridines with Enolates: Synthesis of Functionalized Chiral γ-

8201 DOI: 10.1021/acs.joc.9b01226

J. Org. Chem. 2019, 84, 8194−8201