The first I2-promoted efficient aminoacetylation of activated aziridines in ionic liquid

Article abstract of DOI:10.1055/s-0032-1317675

A novel and efficient aminoacetylation of aziridines is reported. Herein, 2-phenyl-1,3-oxazolan-5-one with tosylaziridines affords 3-(N-substituted)aminopyrrolidin-2-ones via regioselective terminal aziridine opening-aminoacetylative cyclization cascades. The reaction is performed using [bmim]OH/molecular iodine as a new catalyst system where ionic liquid [bmim]OH also works as reaction media and proceeds via an isolable intermediate. After isolation of the product, the ionic liquid, [bmim]OH can be easily recycled for further use without any loss of efficiency. No byproduct formation, operational simplicity, ambient temperature, high yield, and excellent diastereoselectivity are salient features of the present synthetic protocol.

Full text of DOI:10.1055/s-0032-1317675

LETTER
▌97
letter
The First I2-Promoted Efficient Aminoacetylation of Activated Aziridines in
Ionic Liquid
Efficient Aminoacetylation of Activated Aziridines
Vijai K. Rai,*a,b Nihar Sharma,b Anil Kumarb
a
Department of Applied Chemistry, Institute of Technology, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh 495 009, India
b
School of Biology and Chemistry, Shri Mata Vaishno Devi University, Katra, Jammu & Kashmir 182 320, India
Fax +91(7752)260148; E-mail: vijaikrai@hotmail.com
Received: 27.10.2012; Accepted after revision: 29.10.2012
tuted)aminopyrroildin-2-ones.22b,c Very recently, we have
Abstract: A novel and efficient aminoacetylation of aziridines is
reported the synthesis of 3-mercapto-pyrrolidin-2-one
reported. Herein, 2-phenyl-1,3-oxazolan-5-one with tosylaziridines
starting via ring opening of aziridines with masked mer-
affords 3-(N-substituted)aminopyrrolidin-2-ones via regioselective
terminal aziridine opening–aminoacetylative cyclization cascades.
captoacid.22d To date, there is no report on the direct syn-
The reaction is performed using [bmim]OH/molecular iodine as a thesis of 3-aminopyrrolidin-2-ones.
new catalyst system where ionic liquid [bmim]OH also works as re-
action media and proceeds via an isolable intermediate. After isola-
H
O
tion of the product, the ionic liquid, [bmim]OH can be easily
recycled for further use without any loss of efficiency. No byprod-
uct formation, operational simplicity, ambient temperature, high
yield, and excellent diastereoselectivity are salient features of the
present synthetic protocol.
N
O
N
N
O
HO
doxapram
ipalbidine
Key words: pyrrolidine-2-ones, ionic liquid, aziridines, diastereo-
selectivity, molecular iodine
O
OH
O
N
H
Me
HO
Ph
N
N
Me
Ph
Ph
Aziridines are an elite class of compounds present in var-
ious natural products and have been useful intermediates
as well as building blocks in organic synthesis.1 In terms
of synthetic transformations, the utility of aziridines de-
rives from their selective ring-opening reactions with var-
ious nucleophiles, which often form the basis for more
complex target syntheses, especially N-containing com-
pounds.2,3 γ-Butyrolactams (pyrrolidin-2-ones) are a class
of versatile core structures present in various natural prod-
ucts such as isocynamatrine4a,b and clausenamide4c–f and
are also important intermediates in the synthesis of a vari-
ety of nitrogenated heterocycles with interesting biologi-
cal activities (Figure 1).4–8
H
N
Me
( )-isocynometrine
(–)-clausenamide
Figure 1 Pyrrolidin-2-one ring-containing natural products and
pharmaceutical molecules
Ionic liquids (IL) have attracted much attention as envi-
ronmentally friendly reaction media,23–25 catalysts,26–28
and reagents29,30 and are also easy to recycle.29,30 More-
over, the synthesis of amides is important in many areas
of chemistry, including peptide, polymer, and complex
molecule synthesis.31 Inspired by these valid points and
keeping the synthetic and pharmacological importance of
the amide group in mind we turned our attention to utilize
masked amino acids as substrates viz. 2-phenyl-1,3-oxa-
zolan-5-one, which can introduce an amide group at the
α position into γ-lactam, which is the target molecule in
the present investigation.
Due to their versatile applications in organic and medici-
nal chemistry, the development of new synthetic routes
for the preparation of pyrrolidin-2-ones is an important
endeavor and has been well documented in the litera-
ture.10–21 However, most of the reactions suffer from one
or more disadvantages, such as expensive reagents, long
reaction times, low yields, tedious workup, and, most im-
portantly, none of these methods cater a direct process for
the synthesis of 3-(N-substituted)aminopyrrolidin-2-ones
and tend to be lengthy and cumbersome if the lactam con-
tains any sort of substitution. Recently, Ghorai et al. have
reported the synthesis of pyrrolidin-2-one via a nucleo-
philic ring opening with a methylene group22a in addition
to other literature reports on the synthesis of 4-(N-substi-
In this Letter, we report a new molecular-iodine-catalyzed
one-pot atom efficient method for the preparation of 3-(N-
substituted)aminopyrrolidin-2-ones 3 in a single step us-
ing [bmim]OH as a green reaction promoter. This one-pot
synthetic protocol is highly atom efficient as there is no
byproduct formation and involves novel utilization of the
masked amino acid 2-phenyl-1,3-oxazolan-5-one (1) with
terminal aziridines 2 affording 3-(N-substituted)amino-
pyrrolidin-2-ones 3 in high yield and excellent diastereo-
selectivity, in favor of the cis isomer (Scheme 1).
Furthermore, the present synthesis of 3-(N-substitut-
ed)amino functionalized γ-lactam 3 is an outcome of our
SYNLETT 2013, 24, 0097–0101
Advanced online publication: 04.12.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317675; Art ID: ST-2012-B0924-L
© Georg Thieme Verlag Stuttgart · New York

98
V. K. Rai et al.
LETTER
quest for developing new synthetic routes employing is accomplished by stirring a mixture of 2-phenyl-1,3-
green chemistry protocols.32
oxazolan-5-one (1), aziridine 2, and molecular iodine in
[bmim]OH at room temperature for 5–6 hours.33
H
Ts
N
O
N
[bmim]OH
I2, r.t., 5–6 h
Ar
Ph
NHTs
N
Ts
+
O
Ph
N
[bmim]OH
N
O
Ph
N
N
Ar
+
O
Ts
O
r.t.
Ph
O
1
2
3
O
Ph
Ph
O
1
2a
4a
Scheme 1 One-pot aminoacetylation of aziridines 2 in ionic liquid
[bmim]OH
Scheme 2 Reaction of masked amino acid 1 and aziridines 2 in
[bmim]OH
In a preliminary experimentation, a controlled reaction
was carried out using 2-phenyl-1,3-oxazolan-5-one (1)
and aziridine 2a (Ar = Ph) in [bmim]OH but the reaction
did not afford the desired γ-lactam 3a (Table 1, entry 1)
even after 48 hours, rather conversion of tosylaziridines
2a into the corresponding amine 4a was observed
(Scheme 2). Then, we turned our attention to use molecu-
lar iodine as catalyst in conjunction with different room-
temperature ionic liquid (RTIL). For this purpose, 2-phe-
nyl-1,3-oxazolan-5-one (1) and aziridine 2a (R = Ph) were
chosen as model substrates for the synthesis of represen-
tative compound 3a (Table 1) wherein molecular iodine
evidenced its catalytic efficacy in conjunction with RTIL,
affording 3a in excellent yield (Table 1, entry 1). A vari-
ety of RTIL were screened for the present reaction and
amongst [bmim]BF4, [bmim]OH, [bmim]PF6, and
[bmim]Br, [bmim]OH was found to be the most effective
RTIL for the conversion of the tosyl aziridine 2a to the
corresponding γ-lactam 3a (Table 1, entries 2–4).
Table 1 Optimization of Reaction Conditions for the Formation of
3aa
Ts
H
N
O
N
Ph
[bmim]OH
I2, r.t.
N
+
O
Ph
O
N
Ph
Ph
O
Ts
1
2a
3a
Entry
RTIL/solvent
I2 (mol%) Time (h)b Yield (%)c
1
2
[bmim]OH
[bmim]OH
[bmim]PF6
[bmim]Br
1,4-dioxane
MeCN
–
48
5
–
10
10
10
10
10
10
10
10
5
94
86
88
74
78
75
41
46
88
94
3
10
10
17
15
18
16
16
5
4
5
6
7
CH2Cl2
In order to elucidate the role of other solvents in lieu of
RTIL as reaction medium, various solvents were used un-
der the present reaction conditions. The results validate
our premise that the reaction would not only be faster but
also result in higher yield using RTIL as compared to oth-
er conventional solvents (Table 1, entries 2, 5–9). Interest-
ingly, yield of the target compound 3a is poor using polar
aprotic solvents (Table 1, entries 8 and 9). Thus, RTIL
[bmim]OH stands out as the choice, with its fast conver-
sion and quantitative yield in conjunction with molecular
iodine, as an inexpensive and versatile catalyst in the pres-
ent envisaged synthetic protocol. The optimum catalyst
loading for molecular iodine was found to be 10 mol%.
When the amount of catalyst decreased from 10 mol% to
5 mol% relative to the substrates, the yield of product 3a
was reduced (Table 2, entries 2 and 10). However, the use
of 15 mol% of the catalyst showed the same yield, and the
same time was required (Table 1, entries 2 and 11). It was
noted that a higher reaction temperature (up to 60 °C)
instead of room temperature had no appreciable effect on
the yield.
8
DMF
9
DMSO
10
11
[bmim]OH
[bmim]OH
15
5
a Reaction conditions: 1 (2 mmol), 2a (2 mmol), I2 (0.2 mmol),
[bmim]OH (5 mL).
b Stirring time at r.t.
c Yield of isolated and purified product 3a.
Isolation and purification by recrystallization afforded the
target compound 3 in 85–96% yield with 96–98% diaste-
reoselectivity (Table 2) in favor of the cis isomer. Product
3 was extracted with EtOAc leaving the [bmim]OH be-
hind, which can be recycled easily for further use without
loss of efficiency (Table 3). The diastereomeric ratios in
the crude isolates were checked by 1H NMR spectroscopy
to note any alteration of these ratios during subsequent pu-
rification. The crude isolates of 3 were found to be a dia-
stereomeric mixture containing 96–98% of the cis isomer.
Next, in order to investigate the substrate scope for the
general validity of the present investigation, a variety of
tosyl aziridines 2 were used under the optimized reaction
conditions, and different 3-(N-substituted)aminopyrro-
lidin-2-ones 3 were synthesized. The yields were consis-
tently good (Table 2), and the highest yield was 96%
(Table 2, entry 3). Thus, the present optimized synthesis
1
On the basis of H NMR spectroscopy and the literature
precedent,34 the cis stereochemistry was conclusively as-
signed to 3, as their coupling constants (J5H,4Ha = 7.0–7.6
Hz, J5H,4Hb = 6.3–6.7 Hz) was lower than that for the minor
trans isomer (J5H,4Ha = 10.5–10.8 Hz, J5H,4Hb = 11.5–11.9
Hz). Furthermore, the assigned cis stereochemistry of lac-
Synlett 2013, 24, 97–101
© Georg Thieme Verlag Stuttgart · New York

LETTER
Efficient Aminoacetylation of Activated Aziridines
99
less substituted carbon of tosyl aziridine 2 regioselective-
ly, followed by protonation of aziridine nitrogen leading
to the intermediate 4 (Scheme 3). The adduct 4 undergoes
intramolecular nucleophilic attack of the nitrogen atom of
the NHTs group at the carbonyl carbon (C-5) of the 1,3-
oxazolan-5-one moiety to yield the target compounds 3
(Scheme 3). This conclusion is based on the observation
that the representative intermediate compounds 4a (Ar =
Ph), 4e (Ar = 4-ClC6H4), and 4i (Ar = 4-FC6H4) could be
isolated in 41–49% yield, these could be converted into
the corresponding lactams 3a, 3e, and 3i in quantitative
yields.35
Table 2 One-Pot Synthesis of 3-(N-Substituted)aminopyrrolidin-2-
ones 3
H
Ts
N
O
N
Ar
N
[bmim]OH
I2, r.t.
+
O
N
Ph
Ph
O
O
Ar
Ts
1
2
3
Entry Aziridine Ar
Time Product Yield
cis/
2
(h)a,b
3
(%)c,d transe
1
2
2a
2b
2c
2d
2e
2f
Ph
5
5
5
5
5
5
6
6
5
6
5
5
3a
3b
3c
3d
3e
3f
94
89
96
93
92
95
88
91
85
91
94
89
96:4
96:4
98:2
96:4
98:2
98:2
97:3
97:3
96:4
97:3
98:2
98:2
4-MeOC6H4
4-O2NC6H4
4-BrC6H4
4-ClC6H4
3-ClC6H4
4-MeC6H4
4-AcC6H4
4-FC6H4
Presumably, in the ring-transformation step, iodine plays
a key role in the reaction by polarizing the carbonyl group
of the substrate 1, thereby enhancing the electrophilicity
of the carbonyl carbon, which facilitates the nucleophilic
attack of the NHTs of aziridine 2. Usually, the electronic
factor favors the aziridine ring opening by a nucleophilic
attack at the benzylic carbon. However, when the steric
factor predominates over the electronic factor, the nucleo-
phile prefers to attack at the terminal carbon rather than
the benzylic carbon.36 Here, presumably due to bulky na-
ture of the attacking nucleophile, the steric factor predom-
inates over the electronic effect to afford products 3.
3
4
5
6
7
2g
2h
2i
3g
3h
3i
8
9
10
11
12
2j
3-MeC6H4
3-BrC6H4
1-naphthyl
3j
2k
2l
3k
3l
Table 3 Recyclability of [bmim]OH in the Synthesis of 3a
Run
1
2
3
4
5
a Reaction conditions: 1 (2 mmol), 2a (2 mmol), I2 (0.2 mmol),
[bmim]OH (5 mL).
Yield (%)
96
96
95
95
92
b Stirring time at r.t.
c Yield of isolated and purified product.
d All compounds gave C, H, and N analyses ± 0.39% and satisfactory
spectral (IR, 1H NMR, 13C NMR] and MS (EI) data.
NOE 7.8
NOE 8.1
e As determined by 1H NMR spectroscopy of the crude products.
Ha
O
H
4
H
5
Hb
3
Ph
N
Ar
Ts
N
H
2
1
tams 3 was also established by NOE observations (Figure
2). For example, 7.8% NOE was observed by between 5-
H and 4-Ha; 8.1% between 3-H and 4-Ha of product 3a.
This indicates that 3-H, 4-Ha, and 5-H are located on the
same face of the molecule, that is, cis to one another.
O
Figure 2 NOE observations of pyrrolidin-2-ones 3
In conclusion, we have documented an original and prac-
tical regio- and diastereoselective route to synthetically
and pharmaceutically important 3-(N-substituted)amino-
pyrrolidin-2-ones via nucleophilic aziridine ring opening
with a novel substrate viz. 2-phenyl-1,3-oxazolan-5-one.
The formation of 3-(N-substituted)aminopyrrolidin-2-
ones 3 can be rationalized by nucleophilic attack of the
methylene carbon (C-4) of the masked amino acid 1 to the
Ts
N
Ar
–
N
N
N
Ar
[bmim]OH
– H2O
2
NTs
–
Ph
Ph
Ph
O
O
N
O
O
O
O
1
1'
Ar
O
Ar
H
N
Ph
N
H2O
+N
H
Ts
NHTs
Ph
NTs
Ar
Ph
O
O
O
– I2
O
–O
I+ I–
4
3
Scheme 3 Plausible mechanism for the formation of 3-(N-substituted)aminopyrrolidin-2-ones 3
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 97–101

100
V. K. Rai et al.
LETTER
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(33) General Procedure for the Synthesis of γ-Lactams 3
A mixture of 2-phenyl-1,3-oxazol-5-one (1, 2.0 mmol),
tosylaziridine 2 (2.0 mmol), and a catalytic amount of I2 (0.2
mmol) in [bmim]OH (5 mL) was stirred at r.t. for 5–6 h.
After completion of the reaction as indicated by TLC, H2O
(10 mL) was added, and the mixture was extracted thrice
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(6) (a) Kralj, D.; Novak, A.; Dahmann, G.; Grošelj, U.; Meden,
A.; Svete, J. J. Comb. Chem. 2008, 10, 664. (b) Bagnoli, L.;
Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Scarponi, C.;
Tiecco, M. J. Org. Chem. 2010, 75, 2134.
Synlett 2013, 24, 97–101
© Georg Thieme Verlag Stuttgart · New York

LETTER
with EtOAc (10 mL). The combined organic layer was
Efficient Aminoacetylation of Activated Aziridines
101
H), 4.66 (ddd, J = 8.9, 7.5, 4.3 Hz, 1 H), 4.86 (dd, J = 7.1, 6.7
Hz, 1 H), 7.19–7.55 (m, 9 H), 7.79–7.92 (m, 4 H), 8.17 (br,
exch, 1 H). 13C NMR (100 MHz, CDCl3): d = 25.6, 33.1,
43.5, 53.5, 127.7, 128.4, 129.0, 129.6, 130.3, 131.1, 131.8,
132.5, 133.2, 134.0, 134.8, 140.1, 171.0, 178.8. MS (EI): m/z
= 452 [M+]. Anal. Calcd for C24H21FN2O4S: C, 63.70; H,
4.68; N, 6.19. Found: C, 63.89; H, 4.91; N, 5.87.
washed with brine (10 mL), dried over anhyd Na2SO4,
filtered, and evaporated under reduced pressure to afford an
analytically pure sample of a single diastereomers 3 (Table
2). After isolation of the products, the remaining aqueous
layer containing the ionic liquid was washed with hexane
and dried in vacuum resulting in recycled ionic liquid,
[bmim]OH (Table 3). The structure of the product 3 was
confirmed by their elemental and spectral analyses.
(34) Brace, N. O. J. Fluorine Chem. 2003, 123, 237.
(35) Isolation of 4a (Ar = Ph), 4e (Ar = 4-ClC6H4), and 4i (Ar =
4-FC6H4) and Their Conversion into the Corresponding
Pyrrolidin-2-ones 3a, 3e, and 3i
Characterization Data of Representative Compounds 3
Compound 3a: colorless solid, mp 103–104 °C. IR (KBr):
ν
max = 3348, 3031, 2938, 1746, 1701, 1605, 1583, 1451 cm–
The procedure followed was the same as described above for
the synthesis of 3, except that the reaction time in this case
was only 2 h instead of 5–6 h used for 3. To obtain
analytically pure samples of 3a, 3e, and 3i and to assign
stereochemistry the same procedure was adopted as
described for 3a, 3e, and 3i. Finally, these intermediates
were stirred at r.t. for the next 3–4 h to give the
corresponding cyclized products 3a, 3e, and 3i respectively.
Characterization Data of Representative Compound
Compound 4a: IR (KBr): νmax = 3345, 3030, 2930, 1708,
1605, 1581, 1455 cm–1. 1H NMR (400 MHz, 3): d = 2.23 (s,
3 H), 2.51–2.53 (m, 2 H), 3.81 (m, 1 H), 4.01 (dd, J = 7.9,
3.8 Hz, 1 H), 5.29 (br, exch, 1 H), 7.21–7.59 (m, 12 H), 7.85–
7.81 (m, 2 H). 13C NMR (100 MHz, 3): d = 25.1, 37.2, 45.5,
64.2, 126.7, 127.5, 128.2, 129.0, 129.7, 130.3, 132.0, 132.6,
133.3, 134.0, 135.2, 138.5, 169.8, 177.2. MS (EI): m/z = 434
[M+]. Anal. Calcd for C24H22N2O4S: C, 66.34; H, 5.10; N,
6.45. Found: C, 66.63; H, 4.88; N, 6.19.
1. 1H NMR (400 MHz, 3): d = 2.31 (s, 3 H), 2.81 (ddd, J =
10.8, 7.1, 4.3 Hz, 1 H), 2.90 (ddd, J = 10.8, 8.9, 6.5 Hz, 1 H),
4.61 (ddd, J = 8.9, 7.5, 4.3 Hz, 1 H), 4.89 (dd, J = 7.1, 6.5
Hz, 1 H), 7.21–7.49 (m, 10 H), 7.85–7.98 (m, 4 H), 8.12 (br,
exch, 1 H). 13C NMR (100 MHz 3): d = 25.1, 33.7, 43.3, 53.5,
127.1, 127.9, 128.6, 129.3, 130.0, 130.7, 132.5, 133.2,
133.8, 134.7, 139.2, 140.1, 171.0, 178.3. MS (EI): m/z = 434
[M+]. Anal. Calcd for C24H22N2O4S: C, 66.34; H, 5.10; N,
6.45. Found: C, 66.59; H, 5.31; N, 6.27
Compound 3e: colorless solid, mp 151–153 °C. IR (KBr):
νmax = 3355, 3032, 2925, 1741, 1701, 1596, 1577, 1451 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.28 (s, 3 H), 2.78 (ddd, J
= 10.7, 7.4, 4.8 Hz, 1 H), 2.90 (ddd, J = 10.7, 9.0, 6.6 Hz, 1
H), 4.63 (ddd, J = 9.0, 7.5, 4.8 Hz, 1 H), 4.85 (dd, J = 7.4, 6.6
Hz, 1 H), 7.26–7.53 (m, 9 H), 7.88–7.91 (m, 4 H), 8.15 (br,
exch, 1 H). 13C NMR (100 MHz, CDCl3): d = 25.5, 33.2,
43.8, 54.0, 127.2, 127.9, 128.7, 129.5, 130.1, 130.8, 131.4,
132.0, 132.7, 133.3, 134.0, 138.9, 171.2, 178.2. MS (EI): m/z
= 468, 470 [M+, M+ + 2]. Anal. Calcd for C24H21ClN2O4S: C,
61.47; H, 4.51; N, 5.97. Found: C, 61.69; H, 4.13; N, 6.19.
Compound 3i: colorless solid, mp 135–137 °C. IR (KBr):
(36) (a) Wang, Z.; Cui, Y.-T.; Xu, Z.-B.; Qu, J. J. Org. Chem.
2008, 73, 2270. (b) Minakata, S.; Hotta, T.; Oderaotoshi, Y.;
Komatsu, M. J. Org. Chem. 2006, 71, 7471. (c) Lu, P.
Tetrahedron 2010, 66, 2549. (d) Garima, V. P. S.; Yadav, L.
D. S. Green Chem. 2010, 12, 1460. (e) Minakata, S.; Kano,
D.; Oderaotoshi, Y.; Komatsu, M. Angew. Chem. Int. Ed.
2004, 43, 79.
ν
max = 3350, 3029, 2932, 1743, 1702, 1601, 1578, 1445 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.28 (s, 3 H), 2.82 (ddd, J
= 10.9, 7.1, 4.3 Hz, 1 H), 2.92 (ddd, J = 10.9, 8.9, 6.7 Hz, 1
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 97–101

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