Enantioselective synthesis of 4,5-dihydropyrroles via domino ring-opening cyclization (DROC) of N-activated aziridines with malononitrile

Article abstract of DOI:10.1021/jo302815m

An efficient and practical strategy for the synthesis of highly functionalized racemic and non-racemic 4,5-dihydropyrroles via domino ring-opening cyclization (DROC) of activated aziridines with malononitrile in excellent yield and stereoselectivity is described. The reaction serves as a tool for the synthesis of a large variety of substituted 4,5-dihydropyrroles in enantiomerically pure forms.

Full text of DOI:10.1021/jo302815m

Article
pubs.acs.org/joc
Enantioselective Synthesis of 4,5-Dihydropyrroles via Domino Ring-
Opening Cyclization (DROC) of N‑Activated Aziridines with
Malononitrile
Manas K. Ghorai* and Deo Prakash Tiwari
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
S
* Supporting Information
ABSTRACT: An efficient and practical strategy for the
synthesis of highly functionalized racemic and non-racemic
4,5-dihydropyrroles via domino ring-opening cyclization
(DROC) of activated aziridines with malononitrile in excellent
yield and stereoselectivity is described. The reaction serves as a
tool for the synthesis of a large variety of substituted 4,5-
dihydropyrroles in enantiomerically pure forms.
Scheme 1. Stereoselective Synthesis of 4,5-Dihydropyrroles
via DROC of Aziridines with Malononitrile
INTRODUCTION
■
Dihydropyrroles are an important class of heterocyclic
compounds found as a functional core of various natural
products and pharmaceutical agents.1 Moreover, some of them
serve as excellent precursors for various nitrogen-containing
heterocyclic compounds of synthetic and biological interest.2 A
number of attractive routes have been designed for the synthesis
of these heterocycles.3 Although many efforts have been devoted
for the synthesis of 2,5- and 2,3-dihydropyrroles,3 comparatively
less attention has been paid to 4,5-dihydropyrroles4 despite their
numerous applications in natural product chemistry1a,c,2a and
spin trapping experiments.5
Table 1. Optimization Study
Aziridines6−8 have been utilized as one of the most suitable
building blocks for the synthesis of various nitrogen containing
heterocyclic compounds.7 Surprisingly, they have been less
explored for the synthesis of substituted dihydropyrroles.9,10 To
the best of our knowledge there is no report for the synthesis of
enantiomerically pure 4,5-dihydropyrroles from aziridines. Over
the years, we have been involved in SN2-type ring-opening
followed by alkylative cyclization of chiral aziridines8 for the
synthesis of enantioenriched targets of contemporary interes-
t.8a,c−h We realized that chiral substituted 4,5-dihydropyrroles
could easily be synthesized via ring-opening followed by
cyclization of chiral aziridines with malononitrile in a domino
fashion.
We have developed a simple and highly efficient strategy for
the stereoselective synthesis of 4,5-dihydropyrroles with a
synthetically important enaminonitrile moiety11 via a Lewis
acid (LA) catalyzed domino ring-opening cyclization (DROC)
of substituted aziridines with malononitrile for the first time
(Scheme 1). Herein, we present our results in detail.
a
yield
entry
conditions
NaH, THF
NaH, THF
temp
RT
time (h)
(%)
1
2
4.5
2.5
39
42
58
94
86
86
77
97
97
45
RT−60 °C
RT−60 °C
RT−60 °C
RT−60 °C
RT−60 °C
RT−60 °C
RT−60 °C
RT
b
3
NaH, Cu(OTf)2, THF
1.0
b
4
NaH, Sc(OTf)3, THF
0.5
b
5
NaH, Yb(OTf)3, THF
1.0
b
6
NaH, Zn(OTf)2, THF
1.75
1.25
0.5
b
7
NaH, Ti(OiPr)4, THF
b
8
t-BuOK, Sc(OTf)3, THF
b
9
t-BuOK, Sc(OTf)3, THF
1.5
10
t-BuOK, THF
RT−60 °C
2.0
a
b
Yields after column chromatographic purification. 20 mol % of LA
catalyst was used.
reaction (4.5 h), the corresponding 4,5-dihydropyrrole 3a was
obtained in 39% yield. In another set of experiments, when the
reaction mixture was heated at 60 °C, the starting material was
RESULTS AND DISCUSSION
■
Initially, we carried out a reaction of 2-phenyl-N-tosylaziridine 1a
with 1.5 equiv of malononitrile 2 using NaH as the base in THF
at room temperature (Table 1), and after completion of the
Received: December 28, 2012
© XXXX American Chemical Society
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fully consumed in 2.5 h without any appreciable improvement in
the yield of 3a.
dihydropyrroles in excellent yields (entry 2−5). It is needless
to mention that a fluoro substituent on the aromatic ring had
found numerous applications in the pharmaceutical industry.14
Interestingly, when 1n was reacted with malononitrile under
optimized reaction condition, the corresponding deacetylated
product 3n was obtained probably due to LA catalyzed hydrolysis
of the acetyl group under the reaction condition.
To broaden the scope of our protocol, it was extended further
for the synthesis of chiral 4,5-dihydropyrroles. For this purpose
enantiomerically pure alkyl (isopropyl, benzyl, methyl, etc.)
substituted aziridines (S)-1d,o,p and 2-phenyl-N-nosylaziridine
(R)-1g were employed as the substrates (Table 4). The DROC
of chiral aziridines (S)-1d,o,p with malononitrile produced the
corresponding dihydropyroles in enantiomerically pure forms as
a single regioisomer (Table 4). Similarly, when chiral 2-phenyl-
N-nosylaziridine (R)-1g was used as the substrate, the
corresponding dihydropyrrole (R)-3g was obtained in enantio-
merically pure form (entry 5).
To find out the optimum reaction conditions (shorter reaction
time and maximum yield), various Lewis acid catalysts and bases
were screened for the DROC of 1a with 2, and the results are
shown in Table 1. The best result was obtained using Sc(OTf)3
as the LA and t-BuOK as the base; 3a was produced in 97% yield
(Table 1, entry 8). Having the optimized reaction condition in
hand, we intended to apply our protocol for the synthesis of
various substituted 4,5-dihydropyrroles (Table 2). The product
Table 2. Scope of the Reaction with various Monosubstituted
N-Sulfonyl Aziridines
The strategy was further extended to 2,3-disubstituted chiral
aziridines7b to obtain highly substituted chiral 4,5-dihydropyr-
roles (Table 5). When trans-2-phenyl-3-n-propyl-N-tosylazir-
idine (2S,3S)-1q was reacted with malononitrile, the correspond-
ing cis-dihydropyrrole (4S,5S)-3q was obtained in quantitative
yield as a single diastereomer. A similar result was obtained with
(2S,3S)-1r as the substrate, and the corresponding product
(4S,5S)-3r was produced in diastereomerically pure form with
quantitative yield. The cis-stereochemistry of the products 3r−s
were determined by NOE experiments.15
a
yield
entry
aziridine
product(s)
(%)
bc
,
1
2
3
4
5
6
1a: R1 = C6H5, R2 = H, R3 = 4-MeC6H4
3a + 3a′
97
bd
,
1b: R1 = 3-ClC6H4, R2 = H, R3 = 4-MeC6H4 3b + 3b′
90
be
,
1c: R1 = C6H5, R2 = H, R3 = 4-t-BuC6H4
1d: R1 = iPr, R2 = H, R3 = 4-MeC6H4
1e: R1 = n-Oct, R2 = H, R3 = 4-MeC6H4
1f: R1 = R2 = -(CH2)4, R3 = 4-MeC6H4
3c + 3c′
>99
92
3d
3e
3f
99
75
a
Yields of isolated products after column chromatographic purifica-
b
c
d
tion. Combined yields of both the regioisomers. 3a:3a′ 8:1. 3b:3b′
In the compound 3r the allylic protons Ha and Hb showed
NOE enahancement with the aromatic ortho proton (Hortho),
whereas there was no such NOE relation of Hd (benzylic proton)
with Ha and/or Hb, confirming the cis relationship of the phenyl
and allyl groups (Figure 1).
e
1
3:1. 3c:3c′ 5:1 (determined from H NMR of the crude reaction
mixture).
3a was obtained as a mixture of regioisomers (3a and 3a′) with
high regioisomeric ratio (8:1) (entry 1). Similar DROC of
aziridines 1b and 1c with 2 produced the corresponding
dihydropyrroles 3b (along with 3b′) and 3c (along with 3c′),
respectively, in excellent yields (entry 2, Table 2). Formation of
the minor regioisomer is probably due to the partial attack of the
malononitrile at the less substituted position of aziridines 1a−c.
When alkyl aziridines 1d,e were used as the substrates, the
corresponding 4,5-dihydropyroles 3d,e were obtained in
excellent yields as a single regioisomer via the attack of the
nucleophile at the less sterically hindered position of the
aziridines (entry 4 and 5). Compounds of the type 3e possessing
a hydrophilic head (-NH2 group) and a hydrophobic tail are of
both industrial (surfactants) and biological (lipid bilayer of cell
membranes) importance. The DROC of cyclohexene aziridine 1f
with malononitrile was found to be extremely efficient, and the
corresponding fused 4,5-dihydropyrrole 3f was obtained as a
single diastereomer. To the best of our knowledge, this is the first
report for the synthesis of fused dihydropyrrole with syntheti-
cally explorable enamino-nitrile functionality.
Since N-nosylaziridines are more reactive than N-tosylazir-
idines and also the nosyl group is easily removable,12 we explored
DROC of 2-aryl-N-nosylaziridines with malononitrile 2. When 2-
phenyl-N-nosylaziridine 1g was reacted with malononitrile, the
corresponding dihydropyrole 3g was obtained in excellent yield
as a single regioisomer after column chromatographic
purification.13 Encouraged by this result, a number of substituted
2-aryl-N-nosylaziridines were studied for DROC with malononi-
trile, and in all the cases the corresponding 4,5-dihydropyrroles
were obtained in excellent yields (Table 3). Various haloaryl,
especially fluoroaryl, substituted N-nosylaziridines were reacted
efficiently with malononitrile to afford the corresponding
With a view to synthesizing highly functionalized dihydro-
pyrroles suitable for further synthetic manipulations into various
other motifs, we studied the DROC of trans aziridine 1s with
malononitrile. As expected, the product 3s was obtained in
excellent yield as a single diastereomer with 4,5-cis appendages.
Compound 3s can be transformed into various other functional
groups via functional group interconversion of the TBS ether
group (Scheme 2).
We believe that the reaction follows an SN2-type pathway as
proposed by us earlier.8 The LA activated aziridine intermediate
(A) undergoes nucleophilic attack by malononitrile anion to
generate another intermediate B, which upon intramolecular
cyclization and quenching by aqueous NH4Cl followed by
tautomerization provides the dihydropyrrole products 3
(Scheme 3).
For wider applicability of the developed strategy as a general
methodology, the dihydropyrrole 3g was denosylated6l,8a to the
corresponding N-unsubstituted product 415 following literature
reports (Scheme 4).
CONCLUSION
■
In conclusion, we have developed a very simple, efficient, and
practical strategy for the synthesis of highly functionalized 4,5-
dihydropyrroles both in racemic as well as enantiopure forms via
a LA catalyzed DROC of activated aziridines with malononitrile.
EXPERIMENTAL SECTION
General Experimental. The progress of the reaction was monitored
via thin layer chromatography (TLC) performed using silica gel 60 F254
precoated plates, and the spots were visualized using a UV lamp or I2
■
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Table 3. Scope of the Reaction with Various Substituted N-Nosyl Aziridines
a
Yields of isolated products after column chromatographic purification.
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Table 4. Synthesis of Chiral 4,5-Dihydropyrroles
b
b
Yields of isolated products after column chromatographic purification. ee determined by chiral HPLC (see Supporting Information for details).
c
d
Combined yield of both the regioisomers. ee could not be determined as the compound was obtained as an inseparable mixture of regioisomers
(8:1).
Table 5. Synthesis of Highly Substituted Chiral 4,5-Dihydropyrroles from 2,3-Disubstituted Chiral Aziridines
a
Yields of isolated products after column chromatographic purification.
Scheme 2. Synthesis of Highly Functionalized 4,5-
Dihydropyrroles
Figure 1. NOE experiment for the determination of stereochemistry of
3r.
oven-dried glassware under nitrogen atmosphere using anhydrous
stain. Silica gel 230−400 mesh size was used for flash column
chromatography with a combination of ethyl acetate and petroleum
ether as eluent. Unless otherwise noted, all reactions were carried out in
solvents. Wherever appropriate, all reagents were purified prior to use
following Perrin and Armarego guidelines.16 Monosubstituted N-Ns
aziridines were synthesized according to a known literature report.17
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Scheme 3. Proposed Mechanism
found 340.1124. For (R)-3a: [α]25 = −35.1 (c 0.256, CHCl3);
Scheme 4. Denosylation of 4,5-Dihydropyrrole
D
enantioselectivity of (R)-3a could not be determined as it is an
inseparable mixture of regioisomers.
2-Amino-4-(3-chlorophenyl)-1-tosyl-4,5-dihydro-1H-pyr-
role-3-carbonitrile (3b). The general method described above was
followed when 1b (100 mg, 0.325 mmol) was reacted with malononitrile
(31 μL, 0.487 mmol) in the presence of t-BuOK (55 mg, 0.487 mmol)
using 20 mol % of Sc(OTf)3 (36 mg, 0.073 mmol) at 60 °C for 30 min to
afford 3b (110 mg, 0.292 mmol) as a white frothy solid in 90% yield as a
mixture of regioisomers (ratio 3:1): Rf 0.38 (25% ethyl acetate in
petroleum ether); IR νmax (KBr, cm−1) 3458, 3357, 2923, 2854, 2189,
1637, 1594, 1471, 1431, 1359, 1273, 1241, 1163, 1091, 1047, 809, 785,
743; 1H NMR of the major regioisomer (500 MHz, CDCl3) δ 2.49 (s,
3H), 3.49 (dd, J = 11.0, 4.9 Hz, 1H), 3.94 (dd, J = 10.4, 4.9 Hz, 1H), 4.14
(t, J = 10.4 Hz, 3H), 5.59 (s, 2H), 6.76−6.79 (m, 2H),7.09−7.26 (m,
3H), 7.36 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.3 Hz, 2H); 13C NMR of the
major regioisomer (125 MHz, CDCl3) δ 21.8, 42.5, 56.7, 63.5, 117.7,
126.8, 127.4, 127.7, 127.8, 130.3, 130.4, 132.6, 134.9, 144.0, 145.9,
155.3; HRMS (ESI) calcd for C18H16ClN3O2S (M − H)− 372.0574,
found 372.0577.
2-Amino-1-(4-tert-butylphenylsulfonyl)-4-phenyl-4,5-dihy-
dro-1H-pyrrole-3-carbonitrile (3c). The general method described
above was followed when 1c (100 mg, 0.317 mmol) was reacted with
malononitrile (30 μL, 0.476 mmol) in the presence of t-BuOK (53 mg,
0.476 mmol) using 20 mol % of Sc(OTf)3 (31 mg, 0.063 mmol) at 60 °C
for 30 min to afford 3c (120 mg, 0.315 mmol) as a thick liquid in >99%
yield as a mixture of regioisomers (ratio ∼4:1): Rf 0.38 (25% ethyl
acetate in petroleum ether); IR νmax (KBr, cm−1) 3447, 3365, 2964,
2870, 2190, 1647, 1592, 1470, 1427, 1358, 1264, 1199, 1167, 1113,
1085, 1045, 878, 799, 735, 700, 630; 1H NMR of the major regioisomer
(400 MHz, CDCl3) δ 1.39 (s, 9H), 3.53 (dd, J = 10.8, 5.4 Hz, 1H), 3.99
(dd, J = 10.3, 5.4 Hz, 1H), 4.14 (t, J = 10.8 Hz, 3H), 5.66 (s, 2H), 6.83−
6.85 (m, 2H),7.14−7.28 (m, 3H), 7.58 (d, J = 8.8 Hz, 2H), 7.77 (d, J =
8.8 Hz, 2H); 13C NMR of the major regioisomer (125 MHz, CDCl3) δ
31.1, 35.5, 42.7, 56.9, 65.7, 118.1, 126.8, 126.9, 127.6, 127.8, 128.9,
132.6, 141.8, 155.1, 158.5; HRMS (ESI) calcd for C21H23N3O2S (M +
H)+ 382.1589, found 382.1583.
2-Amino-4-isopropyl-1-tosyl-4,5-dihydro-1H-pyrrole-3-car-
bonitrile (3d). The general method described above was followed
when 1d (100 mg, 0.418 mmol) was reacted with malononitrile (40 μL,
0.627 mmol) in the presence of t-BuOK (70 mg, 0.627 mmol) using 20
mol % of Sc(OTf)3 (41 mg, 0.084 mmol) at 60 °C for 30 min to afford
3d (118 mg, 0.386 mmol) as a white solid in 92% yield; mp 142−144 °C;
Rf 0.41 (20% ethyl acetate in petroleum ether); IR νmax (KBr, cm−1)
3459, 3364, 2961, 2925, 2854, 2190, 1729, 1650, 1596, 1463, 1421,
1359, 1294, 1264, 1188, 1166, 1089, 1022, 873, 814, 735, 706, 666; 1H
NMR (400 MHz, CDCl3) δ 0.90−0.92 (m, 6H), 2.15−2.31 (m, 3H),
2.47 (s, 3H), 3.81−3.86 (m, 1H), 5.38 (s, 2H), 7.36 (d, J = 7.8 Hz, 2H),
7.71 (d, J = 8.3 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 15.3, 18.2, 21.8,
26.8, 32.9, 61.5, 66.5, 118.4, 127.4, 130.3, 134.0, 145.3, 154.8; HRMS
(ESI) calcd for C15H19N3O2S (M + H)+ 306.1276, found 306.1275.
For (R)-3d [α]25D = +159.3 (c 0.203, CHCl3); er >99:1, enantiomeric
ratio was determined by chiral HPLC analysis (Chiralpak AS-H
column), hexane−isoproanol 95:5, flow rate = 1.0 mL/min; tR = 51.50
min.
Monosubstituted N-Ts aziridines18 and disubstituted aziridines8b were
prepared from the corresponding amino alcohols following earlier
reports. All commercial reagents were used as received without further
purification unless mentioned. 1H NMR spectra were recorded on 400
or 500 MHz instruments, and the chemical shifts were recorded in parts
per million (ppm, δ) taking tetramethyl silane (δ 0.00) as the internal
1
standard. Splitting patterns of H NMR are designated as singlet (s),
doublet (d), doublet of doublet (dd), triplet (t), quartet (q), multiplet
(m), etc. 13C NMR spectra were recorded on 100 or 125 MHz
instruments. HRMS were obtained using (ESI) mass spectrometer
(TOF). IR spectra of liquid compounds were recorded as neat, whereas
KBr plates were used for solid compounds. Melting points were
measured using hot stage apparatus and are uncorrected. Enantiomeric
excess (ee) was determined by HPLC using Chiralpak AS-H and
Chiralcel OD-H columns (detection at 254 nm). Optical rotations were
measured using a 6.0 mL cell with a 1.0 dm path length and are reported
as [α]25D (c in g per 100 mL solvent) at 25 °C.
Experimental Procedure. To a suspension of t-BuOK (1.5 equiv)
in THF (2.0 mL) was added malononitrile (1.5 equiv) was added at
room temperature under nitrogen atmosphere. Subsequently solutions
of N-sulfonyl aziridine (100 mg, 1.0 equiv) and Sc(OTf)3 (20 mol %) in
THF were added to the reaction mixture. Then the reaction mixture was
stirred at 60 °C for the appropriate time. After complete consumption of
the starting material (monitored by TLC), the reaction was quenched
with saturated aqueous NH4Cl solution (1.0 mL). After separating the
organic phase, the aqueous phase was extracted with ethyl acetate (3 ×
1.0 mL), and the combined organic extracts were washed with brine and
dried over anhydrous Na2SO4. After removal of the solvent under
reduced pressure, the crude reaction mixture was purified by flash
column chromatography on silica gel (230−400 mesh) using ethyl
acetate in petroleum ether as the eluent to give pure 4,5-
dihydropyrroles.
Spectral Data. 2-Amino-4-phenyl-1-tosyl-4,5-dihydro-1H-
pyrrole-3-carbonitrile (3a). The general method described above
was followed when 1a (100 mg, 0.366 mmol) was reacted with
malononitrile (35 μL, 0.549 mmol) in the presence of t-BuOK (62 mg,
0.549 mmol) using 20 mol % of Sc(OTf)3 (36 mg, 0.073 mmol) at 60 °C
for 30 min to afford 3a (120 mg, 0.354 mmol) as a white frothy solid in
97% yield as a mixture of regioisomers (ratio 8:1): Rf 0.44 (25% ethyl
acetate in petroleum ether); IR νmax (KBr, cm−1) 3448, 3362, 2963,
2190, 1646, 1594, 1469, 1454, 1425, 1355, 1276, 1164, 1088, 1043, 814,
770, 733; 1H NMR (500 MHz, CDCl3) δ 2.48 (s, 3H), 3.52 (dd, J = 10.7,
5.2 Hz, 1H), 3.97 (dd, J = 10.1, 5.2 Hz, 1H), 4.11 (t, J = 10.4 Hz, 3H),
5.67 (s, 2H), 6.83−6.86 (m, 2H), 7.14−7.18 (m, 3H), 7.35 (d, J = 8.3
Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 21.8,
42.8, 56.9, 65.7, 118.0, 126.9, 127.5, 127.8, 128.9, 130.4, 132.7, 141.7,
145.6, 155.1; HRMS (ESI) calcd for C18H17N3O2S (M + H)+ 340.1120,
E
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2-Amino-5-octyl-1-tosyl-4,5-dihydro-1H-pyrrole-3-carboni-
trile (3e). The general method described above was followed when 1e
(100 mg, 0.323 mmol) was reacted with malononitrile (31 μL, 0.485
mmol) in the presence of t-BuOK (54 mg, 0.485 mmol) using 20 mol %
of Sc(OTf)3 (32 mg, 0.065 mmol) at 60 °C for 1.0 h to afford 3e (120
mg, 0.320 mmol) as a white solid in 99% yield; mp 80−82 °C; Rf 0.43
(20% ethyl acetate in petroleum ether); IR νmax (KBr, cm−1) 3443, 3347,
2925, 2854, 2188, 1649, 1604, 1465, 1411, 1347, 1305, 1162, 1088,
1020, 990, 813, 707, 663, 592; 1H NMR (400 MHz, CDCl3) δ 0.89 (t, J =
6.8 Hz, 3H), 1.28−1.81 (m, 14H), 2.13 (dd, J = 13.2, 2.9 Hz, 1H), 2.42−
2.48 (m, 1H), 2.47 (s, 3H), 3.89−3.95 (m, 1H), 5.38 (s, 2H), 7.36 (d, J =
8.3 Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ
14.2, 21.8, 22.8, 24.4, 29.3, 29.5, 29.6, 31.2, 31.9, 36.6, 60.5, 62.0, 118.6,
127.3, 130.3, 134.2, 145.2, 154.4; HRMS (ESI) calcd for C20H29N3O2S
(M + H)+ 376.2059, found 376.2057.
described above was followed when 1i (100 mg, 0.295 mmol) was
reacted with malononitrile (28 μL, 0.443 mmol) in the presence of t-
BuOK (50 mg, 0.443 mmol) using 20 mol % of Sc(OTf)3 (29 mg, 0.059
mmol) at 60 °C for 5 min to afford 3i (106 mg, 0.262 mmol) as a yellow
solid in 89% yield; color changes to brown at 192 °C; Rf 0.31 (25% ethyl
acetate in petroleum ether); IR νmax (KBr, cm−1) 3423, 3329, 3271,
3221, 2190, 1662, 1603, 1530, 1474, 1434, 1403, 1368, 1349, 1316,
1278, 1168, 1088, 1052, 1003, 854, 786, 755, 742, 681, 655, 622, 599,
573; 1H NMR (400 MHz, CDCl3) δ 3.59 (dd, J = 11.2, 3.9 Hz, 1H), 3.97
(m, 1H), 4.25 (dd, J = 11.0, 10.2 Hz, 1H), 5.64 (s, 2H), 6.59 (s, 1H), 6.83
(d, J = 7.3 Hz, 1H), 7.11−7.18 (m, 2H), 7.99 (d, J = 8.8 Hz, 2H), 8.38 (d,
J = 9.0 Hz, 2H); 13C NMR (125 MHz, CDCl3+DMSO-d6) δ 42.1, 56.7,
63.4, 117.6, 124.6, 125.2, 126.1, 127.4, 128.8, 130.1, 134.2, 141.1, 144.3,
150.6, 154.5; HRMS (ESI) calcd for C17H13ClN4O4S (M + H)+
405.0424, found 405.0423.
2-Amino-1-tosyl-3a,4,5,6,7,7a-hexahydro-1H-indole-3-car-
bonitrile (3f). The general method described above was followed when
1f (100 mg, 0.398 mmol) was reacted with malononitrile (38 μL, 0.597
mmol) in the presence of t-BuOK (67 mg, 0.597 mmol) using 20 mol %
of Sc(OTf)3 (39 mg, 0.079 mmol) at 60 °C for 30 min to afford 3f (95
mg, 0.299 mmol) as a white solid in 75% yield; mp 152−154 °C; Rf 0.40
(25% ethyl acetate in petroleum ether); IR νmax (KBr, cm−1) 3444, 3359,
3243, 3194, 2937, 2861, 2186, 1636, 1581, 1494, 1447, 1415, 1368,
1307, 1274, 1230, 1213, 1188, 1166, 1140, 1122, 1089, 1042, 1019, 967,
2-Amino-4-(4-bromophenyl)-1-(4-nitrophenylsulfonyl)-4,5-
dihydro-1H-pyrrole-3-carbonitrile (3j). The general method
described above was followed when 1j (100 mg, 0.261 mmol) was
reacted with malononitrile (25 μL, 0.391 mmol) in the presence of t-
BuOK (44 mg, 0.391 mmol) using 20 mol % of Sc(OTf)3 (26 mg, 0.052
mmol) at 60 °C for 5 min to afford 3j (100 mg, 0.222 mmol) as a yellow
solid in 85% yield; starts blackening at 150 °C; Rf 0.31 (25% ethyl acetate
in petroleum ether); IR νmax (KBr, cm−1) 3424, 3327, 3267, 3216, 3097,
2924, 2854, 2192, 1663, 1606, 1532, 1487, 1467, 1429, 1402, 1365,
1345, 1313, 1291, 12276, 1176, 1163, 1109, 1085, 1051, 1008, 972, 853,
816, 777, 752, 739, 680, 654, 621, 610, 579, 557; 1H NMR (400 MHz,
CDCl3) δ 3.57 (dd, J = 10.7, 4.9 Hz, 1H), 3.98 (dd, J = 9.8, 4.9 Hz, 1H),
4.17 (dd, J = 10.8, 10.0 Hz, 1H), 5.64 (s, 2H), 6.80 (d, J = 8.3 Hz, 2H),
7.33 (d, J = 8.3 Hz, 2H), 8.01 (d, J = 8.8 Hz, 2H), 8.39 (d, J = 8.8 Hz,
2H); 13C NMR (125 MHz, CDCl3) δ 42.2, 57.1, 66.1, 117.0, 121.9,
124.9, 128.4, 129.0, 132.2, 140.2, 141.4, 151.0, 154.4; HRMS (ESI) calcd
for C17H13BrN4O4S, (M − H)− 446.9763, found 446.9769.
2-Amino-4-(4-fluorophenyl)-1-(4-nitrophenylsulfonyl)-4,5-
dihydro-1H-pyrrole-3-carbonitrile (3k). The general method
described above was followed when 1k (100 mg, 0.310 mmol) was
reacted with malononitrile (29 μL, 0.465 mmol) in the presence of t-
BuOK (52 mg, 0.465 mmol) using 20 mol % of Sc(OTf)3 (31 mg, 0.062
mmol) at 60 °C for 5 min to afford 3k (105 mg, 0.271 mmol) as a yellow
solid in 87% yield; melts to black liquid at 200 °C; Rf 0.30 (25% ethyl
acetate in petroleum ether); IR νmax (KBr, cm−1) 3442, 3321, 3264,
3209, 2195, 1660, 1606, 1532, 1508, 1468, 1433, 1403, 1361, 1349,
1317, 1277, 1226, 1164, 1086, 1052, 1012, 857, 837, 761, 737, 681, 618,
580; 1H NMR (400 MHz, CDCl3) δ 3.56 (dd, J = 10.5, 4.9 Hz, 1H), 4.01
(dd, J = 9.8, 5.1 Hz, 1H), 4.16 (dd, J = 10.5, 10.2 Hz, 1H), 5.61 (s, 2H),
6.89 (d, J = 6.6 Hz, 4H), 8.03 (d, J = 8.8 Hz, 2H), 8.40 (d, J = 9.0 Hz,
2H); 13C NMR (125 MHz, CDCl3) δ 42.1, 57.3, 66.7, 116.0, 116.1,
124.9, 128.3, 128.4, 129.1, 136.8(2C), 141.4, 151.0, 154.2, 161.3, 163.3, ;
HRMS (ESI) calcd for C17H13FN4O4S, (M + H)+ 389.0720, found
389.0726.
1
887, 835, 814, 779, 765, 736, 706, 662, 584; H NMR (400 MHz,
CDCl3) δ 0.98−1.09 (m, 1H), 1.17−1.30 (m, 2H), 1.63−1.73 (m, 2H),
1.86−1.89 (m, 2H), 2.00−2.05 (m, 1H), 2.37−2.60 (m, 2H), 2.48 (s,
3H), 5.70 (s, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 8.3 Hz, 2H); 13C
NMR (125 MHz, CDCl3) δ 21.8, 24.9, 25.0, 29.1, 30.7, 45.2, 65.5, 70.7,
118.1, 127.9, 130.3, 134.3, 145.5, 157.0; HRMS (ESI) calcd for
C16H19N3O2S (M + H)+ 318.1276, found 318.1277.
2-Amino-1-(4-nitrophenylsulfonyl)-4-phenyl-4,5-dihydro-
1H-pyrrole-3-carbonitrile (3g). The general method described above
was followed when 1g (100 mg, 0.329 mmol) was reacted with
malononitrile (31 μL, 0.493 mmol) in the presence of t-BuOK (55 mg,
0.493 mmol) using 20 mol % of Sc(OTf)3 (32 mg, 0.066 mmol) at 60 °C
for 5 min to afford 3g (107 mg, 0.289 mmol) as a yellow solid in 88%
yield; color changes to brown at 150 °C; Rf 0.41 (25% ethyl acetate in
petroleum ether); IR νmax (KBr, cm−1) 3450, 3321, 3266, 3219, 3108,
2924, 2193, 1651, 1595, 1532, 1496, 1457, 1423, 1404, 1349, 1308,
1226, 1174, 1088, 964, 887, 856, 775, 762, 738, 702, 682, 645, 616, 597;
1H NMR (400 MHz, CDCl3) δ 3.61 (dd, J = 10.7, 4.4 Hz, 1H), 4.00 (dd,
J = 9.8, 4.4 Hz, 1H), 4.22 (dd, J = 11.2, 9.8 Hz, 1H), 5.64 (s, 2H), 6.85 (d,
J = 6.4 Hz, 2H), 7.13−7.22 (m, 3H), 7.98 (d, J = 9.3 Hz, 2H), 8.33 (d, J =
8.8 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 42.7, 57.5, 66.6, 117.2,
124.8, 126.6, 127.8, 128.9, 129.0, 141.3, 141.5, 151.0, 154.2; HRMS
(ESI) calcd for C17H14N4O4S (M + H)+ 371.0814, found 371.0815.
For (R)-3g [α]25D = +10.8 (c 0.425, CHCl3); er >99:1, enantiomeric
ratio was determined by chiral HPLC analysis (Chiralcel OD-H
column), hexane−isoproanol 90:10, flow rate = 1.0 mL/min; tR = 66.75
min.
2-Amino-4-(4-chlorophenyl)-1-(4-nitrophenylsulfonyl)-4,5-
dihydro-1H-pyrrole-3-carbonitrile (3h). The general method
described above was followed when 1h (100 mg, 0.295 mmol) was
reacted with malononitrile (28 μL, 0.443 mmol) in the presence of t-
BuOK (50 mg, 0.443 mmol) using 20 mol % of Sc(OTf)3 (29 mg, 0.059
mmol) at 60 °C for 5 min to afford 3h (102 mg, 0.252 mmol) as a yellow
solid in 85% yield; color changes to brown at 152 °C; Rf 0.37 (25% ethyl
acetate in petroleum ether); IR νmax (KBr, cm−1) 3424, 3327, 3216,
2922, 2192, 1662, 1606, 1534, 1490, 1468, 1429, 1402, 1365, 1346,
1313, 1277, 1163, 1086, 1052, 1012, 853, 819, 783, 753, 739, 680, 654,
615, 580; 1H NMR (400 MHz, CDCl3) δ 3.57 (dd, J = 10.8, 4.9 Hz, 1H),
3.99 (dd, J = 9.8, 4.9 Hz, 1H), 4.17 (dd, J = 10.3, 10.5 Hz, 1H), 5.65 (s,
2H), 6.86 (d, J = 8.5 Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H), 8.01 (d, J = 8.8
Hz, 2H), 8.39 (d, J = 8.8 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 42.2,
57.2, 66.2, 117.0, 124.9, 128.1, 129.1, 129.3, 133.9, 139.6, 141.4, 151.0,
154.3; HRMS (ESI) calcd for C17H13ClN4O4S, (M + H)+ 405.0424,
found 405.0421.
2-Amino-1-(4-nitrophenylsulfonyl)-4-p-tolyl-4,5-dihydro-
1H-pyrrole-3-carbonitrile (3l). The general method described above
was followed when 1l (100 mg, 0.314 mmol) was reacted with
malononitrile (30 μL, 0.471 mmol) in the presence of t-BuOK (53 mg,
0.471 mmol) using 20 mol % of Sc(OTf)3 (31 mg, 0.063 mmol) at 60 °C
for 5 min to afford 3l (107 mg, 0.278 mmol) as a yellow solid in 89%
yield; starts blackening at 154 °C; Rf 0.37 (25% ethyl acetate in
petroleum ether); IR νmax (KBr, cm−1) 3426, 3329, 3271, 3220, 2924,
2191, 1665, 1606, 1529, 1470, 1429, 1367, 1347, 1314, 1281, 1177,
1
1088, 1054, 1007, 851, 809, 757, 740, 681, 619, 555 ; H NMR (400
MHz, CDCl3) δ 2.27 (s, 3H), 3.59 (dd, J = 10.8, 4.4 Hz, 1H), 3.96 (dd, J
= 9.8, 4.4 Hz, 1H), 4.20 (dd, J = 10.5, 10.3 Hz, 1H), 5.59 (s, 2H), 6.72 (d,
J = 7.8 Hz, 2H), 6.95 (d, J = 8.1 Hz, 2H), 7.97 (d, J = 8.8 Hz, 2H), 8.32
(d, J = 8.8 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 21.0, 42.3, 57.7,
66.8, 117.3, 124.8, 126.4, 129.0, 129.7, 137.7, 138.3, 141.5, 150.9, 154.1;
HRMS (ESI) calcd for C18H16N4O4S, (M + H)+ 385.0971, found
385.0974.
2-Amino-4-(4-tert-butylphenyl)-1-(4-nitrophenylsulfonyl)-
4,5-dihydro-1H-pyrrole-3-carbonitrile (3m). The general method
described above was followed when 1m (100 mg, 0.277 mmol) was
reacted with malononitrile (26 μL, 0.416 mmol) in the presence of t-
2-Amino-4-(3-chlorophenyl)-1-(4-nitrophenylsulfonyl)-4,5-
dihydro-1H-pyrrole-3-carbonitrile (3i). The general method
F
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BuOK (47 mg, 0.416 mmol) using 20 mol % of Sc(OTf)3 (27 mg, 0.055
mmol) at 60 °C for 5 min to afford 3m (99 mg, 0.232 mmol) as a yellow
solid in 84% yield; color changes to black at 124 °C; Rf 0.40 (25% ethyl
acetate in petroleum ether); IR νmax (KBr, cm−1) 3436, 3325, 3265,
3211, 2962, 2926, 2869, 2193, 1664, 1605, 1531, 1464, 1430, 1402,
1366, 1348, 1315, 1271, 1166, 1087, 1050, 1013, 855, 833, 784, 754, 740,
681, 617, 587; 1H NMR (400 MHz, CDCl3) δ 1.25 (s, 9H), 3.59 (dd, J =
10.8, 4.6 Hz, 1H), 3.99 (dd, J = 9.8, 4.6 Hz, 1H), 4.19 (dd, J = 10.7, 10.0
Hz, 1H), 5.58 (s, 2H), 6.76 (d, J = 8.3 Hz, 2H), 7.16 (d, J = 8.3 Hz, 2H),
8.00 (d, J = 9.0 Hz, 2H), 8.36 (d, J = 8.8 Hz, 2H); 13C NMR (125 MHz,
CDCl3) δ 31.3, 34.5, 42.2, 57.5, 66.9, 117.3, 124.8, 125.9, 126.2, 129.1,
138.0, 141.5, 150.9(2C), 154.1; HRMS (ESI) calcd for C21H22N4O4S,
(M + H)+ 427.1440, found 427.1455.
3320, 3211, 2963, 2938, 2877, 2200, 1642, 1597, 1493, 1454, 1420,
1357, 1273, 1189, 1165, 1087, 1026, 993, 943, 884, 848, 809, 754, 728,
705, 662, 582; 1H NMR (500 MHz, CDCl3) δ 0.68 (t, J = 7.3 Hz, 3H),
0.99−1.05 (m, 2H), 1.24−1.27 (m, 1H), 1.45−1.55 (m, 1H), 2.49 (s,
3H), 3.89 (d, J = 8.6 Hz, 1H), 4.04−4.12 (m, 1H), 5.53 (s, 2H), 7.10 (d, J
= 6.9 Hz, 2H), 7.23−7.30 (m, 3H), 7.41 (d, J = 8.3 Hz, 2H), 7.78 (d, J =
8.3 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 13.9, 18.9, 21.9, 33.5, 48.5,
66.4, 66.8, 118.1, 127.4, 127.9, 128.6, 128.9, 130.5, 134.4, 136.0, 145.5,
155.7; HRMS (ESI) calcd for C21H23N3O2S (M + H)+ 382.1589, found
382.1591.
(4S,5S)-5-Allyl-2-amino-4-phenyl-1-tosyl-4,5-dihydro-1H-
pyrrole-3-carbonitrile (3r). The general method described above was
followed when 1r (100 mg, 0.319 mmol) was reacted with malononitrile
(30 μL, 0.479 mmol) in the presence of t-BuOK (54 mg, 0.479 mmol)
using 20 mol % of Sc(OTf)3 (31 mg, 0.064 mmol) at 60 °C for 2.0 h to
afford 3r (121 mg, 0.318 mmol) as a white solid in >99% yield as a single
diastereomer; mp 160−162 °C; Rf 0.45 (25% ethyl acetate in petroleum
2-Amino-4-(4-hydroxyphenyl)-1-(4-nitrophenylsulfonyl)-
4,5-dihydro-1H-pyrrole-3-carbonitrile (3n). The general method
described above was followed when 1n (100 mg, 0.276 mmol) was
reacted with malononitrile (26 μL, 0.414 mmol) in the presence of t-
BuOK (47 mg, 0.414 mmol) using 20 mol % of Sc(OTf)3 (27 mg, 0.055
mmol) at 60 °C for 5 min to afford 3n (94 mg, 0.243 mmol) as a yellow
solid in 88% yield; blackens at 208 °C; Rf 0.31 (55% ethyl acetate in
petroleum ether); IR νmax (KBr, cm−1) 3462, 3424, 3361, 3222, 3109,
2190, 1651, 1609, 1529, 1468, 1426, 1364, 1315, 1268, 1169, 1140,
ether); [α]25 = +113.1 (c 0.175, CHCl3); IR νmax (KBr, cm−1) 3445,
D
3316, 2924, 2854, 2191, 1729, 1640, 1596, 1453, 1421, 1356, 1274,
1165, 1087, 1032, 995, 914, 889, 809, 749, 706, 667, 569; 1H NMR (500
MHz, CDCl3) δ 1.94−1.98 (m, 1H), 2.28−2.34 (m, 1H), 2.49 (s, 3H),
3.98 (d, J = 8.9 Hz, 1H), 4.13 (q, J = 6.7 Hz, 1H), 4.81 (d, J = 17.1 Hz,
1H), 4.90 (d, J = 10.1 Hz, 1H), 5.36−5.42 (m, 1H), 5.59 (s, 2H), 7.12 (d,
J = 6.7 Hz, 2H), 7.25−7.30 (m, 3H), 7.41 (d, J = 8.3 Hz, 2H), 7.78 (d, J =
8.3 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 21.9, 36.1, 48.1, 66.0, 66.1,
117.9, 118.0, 127.4, 128.0, 128.6, 129.1, 130.5, 133.3, 134.4, 135.8, 145.6,
155.6; HRMS (ESI) calcd for C21H21N3O2S, (M + H)+ 380.1433, found
380.1430.
2-Amino-5-((tert-butyldimethylsilyloxy)methyl)-4-phenyl-1-
tosyl-4,5-dihydro-1H-pyrrole-3-carbonitrile (3s). The general
method described above was followed when 1s (100 mg, 0.239
mmol) was reacted with malononitrile (23 μL, 0.359 mmol) in the
presence of t-BuOK (40 mg, 0.359 mmol) using 20 mol % of Sc(OTf)3
(24 mg, 0.048 mmol) at 60 °C for 2.0 h to afford 3s (115 mg, 0.238
mmol) as a white solid in >99% yield as a single diastereomer; mp 166−
168 °C; Rf 0.41 (20% ethyl acetate in petroleum ether); IR νmax (KBr,
cm−1) 3450, 3304, 3259, 3208, 2951, 2928, 2855, 2194, 1653, 1595,
1495, 1458, 1423, 1354, 1307, 1255, 1188, 1162, 1143, 1090, 1064,
1031, 1006, 912, 890, 839, 813, 780, 756, 704, 666, 600, 567; 1H NMR
(500 MHz, CDCl3) δ −0.14 (s, 3H), −0.12 (s, 3H), 0.80 (s, 9H), 2.50 (s,
3H), 3.47−3.54 (m, 2H), 3.98−4.03 (m, 1H), 4.07 (d, J = 9.8 Hz, 1H),
5.56 (s, 2H), 7.19 (d, J = 6.6 Hz, 2H), 7.23−7.28 (m, 3H), 7.41 (d, J = 8.0
Hz, 2H), 7.78 (d, J = 8.3 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ −5.7,
−5.6, 18.2, 21.8, 25.9, 47.1, 62.3, 66.3, 66.4, 118.0, 127.4, 127.7, 128.2,
129.4, 130.5, 134.2, 135.7, 145.5, 155.8; HRMS (ESI) calcd for
C25H33N3O3SSi, (M + H)+ 484.2090, found 484.2094.
1
1085, 1049, 1008, 855, 826, 760, 738, 681, 653; H NMR (500 MHz,
CDCl3+DMSO-d6) δ 2.59−2.60 (m, 1H), 3.53 (dd, J = 11.0, 4.9 Hz,
1H), 3.90 (dd, J = 9.8, 4.6 Hz, 1H), 4.15 (dd, J = 10.7, 9.8 Hz, 1H), 6.42
(s, 2H), 6.60 (d, J = 8.6 Hz, 2H), 6.65 (d, J = 8.6 Hz, 2H), 8.02 (d, J = 8.9
Hz, 2H), 8.35 (d, J = 8.9 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 41.9,
57.6, 65.3, 115.6, 118.0, 124.6, 127.5, 129.0, 132.1, 141.5, 150.6, 154.1,
156.7; HRMS (ESI) calcd for C17H14N4O5S, (M + H)+ 387.0763, found
387.0760.
(S)-2-Amino-4-benzyl-1-tosyl-4,5-dihydro-1H-pyrrole-3-car-
bonitrile (3o). The general method described above was followed
when 1o (100 mg, 0.348 mmol) was reacted with malononitrile (33 μL,
0.522 mmol) in the presence of t-BuOK (59 mg, 0.522 mmol) using 20
mol % of Sc(OTf)3 (34 mg, 0.069 mmol) at 60 °C for 30 min to afford
3o (117 mg, 0.331 mmol) as a white solid in 95% yield; mp 141−143 °C;
Rf 0.46 (25% ethyl acetate in petroleum ether); [α]25D = +156.9 (c 0.385,
CHCl3); IR νmax (KBr, cm−1) 3454, 3364, 2924, 2854, 2190, 1730, 1648,
1595, 1495, 1454, 1425, 1359, 1294, 1266, 1165, 1089, 1034, 1004, 814,
738, 703, 664, 590, 548, 531; 1H NMR (500 MHz, CDCl3) δ 2.20−2.31
(m, 2H), 2.45 (s, 3H), 2.89 (dd, J = 13.5, 9.8 Hz, 1H), 3.24 (dd, J = 13.5,
3.7 Hz, 1H), 4.11−4.16 (m, 1H), 5.40 (s, 2H), 7.22−7.26 (m, 3H),
7.30−7.33 (m, 2H), 7.35 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 8.3 Hz, 2H);
13C NMR (125 MHz, CDCl3) δ 21.8, 30.1, 42.6, 59.9, 62.6, 118.4, 127.1,
127.3, 128.7, 129.7, 130.4, 134.3, 136.2, 145.4, 154.1; HRMS (ESI) calcd
for C19H19N3O2S (M + H)+ 354.1276, found 354.1275.
Procedure for Denosylation of Compound 3g. Compound 3g
(100 mg, 0.269 mmol) dissolved in CH3CN (4.0 mL) was added to a
suspension of K2CO3 (149 mg, 1.076 mmol, 4.0 equiv) in CH3CN (4.7
mL), followed by addition of PhSH (83.0 μL, 0.809 mmol, 3.0 equiv) at
room temperature under nitrogen atmosphere. Next DMSO (0.3 mL)
was added to the reaction mixture, and stirring was continued at room
temperature for 1 h. After complete consumption of the starting
compound (monitored by TLC using 20% ethyl acetate in petroleum
ether as the eluent), the reaction mixture was evaporated to give a pale
yellow residue. The crude compound (the pale yellow residue) was
purified by acid−base treatment as described below.
Acid−Base Treatment. To the pale yellow residue were added water
(5.0 mL) and diethyl ether (10.0 mL). After separating, the organic layer
was washed with dilute NaHCO3 solution (3 × 2.0 mL). The organic
layer was acidified with 5% HCl (5.0 mL). The aqueous layer was
separated, and the organic layer was extracted with 5% HCl (2 × 5.0
mL). The combined aqueous extract was covered with a layer of diethyl
ether (10.0 mL) and was made alkaline with aqueous 5 N NaOH
solution (pH approximately 10) at 0 °C. The organic layer was
separated, and the aqueous layer was extracted with diethyl ether (3 ×
10.0 mL). The combined organic extract was washed with brine, dried
over anhydrous Na2SO4, and evaporated to dryness to provide 4 in 80%
yield (40 mg, 0.216 mmol) as a white solid in pure form as indicated by
1H and 13C NMR and HRMS. Compound 4 was found to decompose
(S)-2-Amino-5-methyl-1-tosyl-4,5-dihydro-1H-pyrrole-3-car-
bonitrile (3p). The general method described above was followed
when 1p (100 mg, 0.473 mmol) was reacted with malononitrile (45 μL,
0.709 mmol) in the presence of t-BuOK (80 mg, 0.709 mmol) using 20
mol % of Sc(OTf)3 (47 mg, 0.095 mmol) at 60 °C for 30 min to afford
3p (121 mg, 0.436 mmol) as a white solid in 95% yield; mp 146−148 °C;
Rf 0.46 (25% ethyl acetate in petroleum ether); [α]25D = +73.4 (c 0.515,
CHCl3); IR νmax (KBr, cm−1) 3443, 3346, 2963, 2926, 2182, 1920, 1643,
1595, 1494, 1420, 1378, 1357, 1339, 1311, 1294, 1210, 1159, 1091,
1
1029, 890, 829, 813, 701, 680, 663, 626, 588; H NMR (400 MHz,
CDCl3) δ 1.43 (d, J = 6.8 Hz, 3H), 2.06 (dd, J = 13.2, 3.4 Hz, 1H), 2.46
(s, 3H), 2.58 (dd, J = 13.2, 9.8 Hz, 1H), 3.98−4.06 (m, 1H), 5.48 (s,
2H), 7.36 (d, J = 7.8 Hz, 2H), 7.72 (d, J = 8.3 Hz, 2H); 13C NMR (125
MHz, CDCl3) δ 21.8, 23.6, 33.4, 57.9, 59.3, 118.7, 127.3, 130.3, 134.2,
145.3, 154.0; HRMS (ESI) calcd for C13H15N3O2S, (M + H)+ 278.0963,
found 278.0967.
(4S,5S)-2-Amino-4-phenyl-5-propyl-1-tosyl-4,5-dihydro-1H-
pyrrole-3-carbonitrile (3q). The general method described above was
followed when 1q (100 mg, 0.317 mmol) was reacted with malononitrile
(30 μL, 0.476 mmol) in the presence of t-BuOK (53 mg, 0.476 mmol)
using 20 mol % of Sc(OTf)3 (31 mg, 0.063 mmol) at 60 °C for 2.5 h to
afford 3q (121 mg, 0.315 mmol) as a white solid in >99% yield as a single
diastereomer; mp 140−142 °C; Rf 0.46 (25% ethyl acetate in petroleum
ether); [α]25 = +52.8 (c 0.378, CHCl3); IR νmax (KBr, cm−1) 3452,
D
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slowly at room temperature and upon exposure to light and/or air.
However, it can be stored under Ar at lower temperature (−20 °C).
2-Amino-4-phenyl-4,5-dihydro-1H-pyrrole-3-carbonitrile (4).
Rf 0.35 (10% methanol in chloroform); IR νmax (KBr, cm−1) 3418, 3342,
3373, 3258, 3222, 2922, 2887, 2156, 1654, 1639, 1591, 1509, 1468,
1450, 1343, 1312, 1204, 1155, 1071, 1028, 705, 767, 594, 551; 1H NMR
(500 MHz, CDCl3) δ 3.57−3.68 (m, 1H), 3.68−3.76 (m, 1H), 3.77−
3.87 (m, 1H), 4.02−4.13 (m, 1H), 4.42−5.10 (m, 2H) 7.19−7.30 (m,
5H); 1H NMR (500 MHz, CDCl3 + D2O) δ 3.72 (dd, J = 13.7, 8.3 Hz,
1H), 3.88 (t, J = 8.0 Hz, 1H), 4.15 (dd, J = 13.8, 8.1 Hz, 1H), 4.71 (s,
1H), 7.23−7.38 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 43.7, 50.9,
62.4, 116.4, 127.0, 128.0, 128.8, 129.2, 158.0; HRMS (ESI) calcd for
C11H11N3, (M + H)+ 186.1031, found 186.1031.
Kimpe, N. Chem. Rev. 2007, 107, 2080. (e) Schneider, C. Angew. Chem.,
Int. Ed. 2009, 48, 2082. (f) Stankovic, S.; D’hooghe, M.; Catak, S.; Eum,
́
H.; Waroquier, M.; Speybroeck, V. V.; De Kimpe, N.; Ha, H.-J. Chem.
Soc. Rev. 2012, 41, 643 and references therein. For some representative
examples on aziridine chemistry see: (g) Enders, D.; Janeck, C. F.;
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Carrillo, L. J. Org. Chem. 2001, 66, 5801. (i) Cossy, J.; Bellosta, V.;
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M. M. J. Am. Chem. Soc. 2007, 129, 14463. (l) Moss, T. A.;
Fenwick, D. R.; Dixon, D. J. J. Am. Chem. Soc. 2008, 130, 10076.
(m) Paixao, M. W.; Nielsen, M.; Jacobsen, C. B.; Jørgensen, K. A. Org.
̃
Biomol. Chem. 2008, 6, 3467. (n) Minakata, S.; Murakami, Y.; Satake,
M.; Hidaka, I.; Okada, Y.; Komatsu, M. Org. Biomol. Chem. 2009, 7, 641.
(o) Wu, B.; Gallucci, J. C.; Parquette, J. R.; RajanBabu, T. V. Angew.
Chem., Int. Ed. 2009, 48, 1126. (p) Wu, B.; Parquette, J. R.; RajanBabu,
ASSOCIATED CONTENT
* Supporting Information
NMR spectra for all the new compounds and HPLC chromato-
grams. This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
T. V. Science 2009, 326, 1662. (q) Joullie,
́
M. M.; Kelley, B. T. Org. Lett.
2010, 12, 4244. (r) Yadav, J. S.; Satheesh, G.; Murthy, C. V. S. R. Org.
̌
Lett. 2010, 12, 2544. (s) Zukauskaite, A.; Mangelinckx, S.; Buinauskaite,
̌
̌
V.; Sackus, A.; De Kimpe, N. Amino Acids 2011, 41, 541. (t) De Rycke,
AUTHOR INFORMATION
Corresponding Author
*E-mail: mkghorai@iitk.ac.in.
Notes
■
N.; David, O.; Couty, F. Org. Lett. 2011, 13, 1836. (u) D’hooghe, M.;
Kenis, S.; Vervisch, K.; Lategan, C.; Smith, P. J.; Chibale, K.; De Kimpe,
N. Eur. J. Med. Chem. 2011, 46, 579. (v) Bera, M.; Pratihar, S.; Roy, S. J.
Org. Chem. 2011, 76, 1475. (w) Hajra, S.; Sinha, D. J. Org. Chem. 2011,
76, 7334. (x) Xu, Y.; Lin, L.; Kanai, M.; Matsunaga, S.; Shibasaki, M. J.
Am. Chem. Soc. 2011, 133, 5791. (y) Cockrell, J.; Wilhelmsen, C.; Rubin,
H.; Martin, A.; Morgan, J. B. Angew. Chem., Int. Ed. 2012, 51, 9842.
(z) De Vreese, R.; D’hooghe, M. Beilstein J. Org. Chem. 2012, 8, 398.
(7) For synthesis of heterocyclic compounds from aziridines, see:
(a) Karikomi, M.; D’hooghe, M.; Verniest, G.; De Kimpe, N. Org.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
M.K.G. is grateful to IIT-Kanpur and DST, India. D.P.T. thanks
UGC and IIT Kanpur, India for a research fellowship.
■
́ ́
Biomol. Chem. 2008, 6, 1902. (b) Ochoa-Teran, A.; Concellon, J. M.;
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Article
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