Masked amino acid: A new C-nucleophile for I2-catalyzed stereoselective ring opening of epoxides in ionic liquid

Article abstract of DOI:10.1016/j.tetlet.2012.12.026

The first one-pot molecular iodine catalyzed direct aminoacetylation of terminal epoxides in ionic liquid [bmim]OH is reported. Herein, 2-phenyl-1,3-oxazolon-5-one and a variety of terminal epoxides afford 3-(N-substituted)aminofuran-2-ones in high yield (84-95%) and excellent cis diastereoselectivity (>94%) via ring-opening of terminal epoxides and aminoacetylative cyclization cascade. Operation simplicity, absence of by-product formation, and ambient temperature are the salient features of the present synthetic protocol. After isolation of the product, the ionic liquid [bmim]OH could be easily recycled for further use without any loss of efficiency.

Full text of DOI:10.1016/j.tetlet.2012.12.026

Tetrahedron Letters 54 (2013) 1071–1075
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Masked amino acid: a new C-nucleophile for I2-catalyzed stereoselective
ring opening of epoxides in ionic liquid
Vijai K. Rai a,b, , Roopali Sharma b, Anil Kumar b
⇑
a Department of Applied Chemistry, Institute of Technology, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chattisgarh 495 009, India
b School of Biology & Chemistry, Shri Mata Vaishno Devi University, Katra, J&K 182 332, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The first one-pot molecular iodine catalyzed direct aminoacetylation of terminal epoxides in ionic liquid
[bmim]OH is reported. Herein, 2-phenyl-1,3-oxazolon-5-one and a variety of terminal epoxides afford 3-
(N-substituted)aminofuran-2-ones in high yield (84–95%) and excellent cis diastereoselectivity (>94%)
via ring-opening of terminal epoxides and aminoacetylative cyclization cascade. Operation simplicity,
absence of by-product formation, and ambient temperature are the salient features of the present syn-
thetic protocol. After isolation of the product, the ionic liquid [bmim]OH could be easily recycled for fur-
ther use without any loss of efficiency.
Received 2 October 2012
Revised 6 December 2012
Accepted 8 December 2012
Available online 19 December 2012
Keywords:
Epoxide
Ionic liquid
Nucleophile
Stereoselectivity
Iodine
Ó 2012 Elsevier Ltd. All rights reserved.
Epoxides are well-known carbon electrophiles and their ability
to undergo regioselective ring opening with a variety of nucleo-
philes viz., carbon, nitrogen, selenium, sulfur, oxygen etc. makes
them an elite class of precursor in organic synthesis.1 Among, the
regio- and stereoselective ring opening of epoxides with carbon
based nucleophiles has been a matter of great interest to synthetic
chemists due to generation of a new carbon–carbon bond in a very
simple and stereo defined manner.2 Consequently numerous
catalytic methods for ring-opening of epoxides using various C-
nucleophiles viz., cyanides,3 Grignard reagents,4 organocuprates,5
organolithiums,6 organoaluminium,7 and organoselenium,1c have
been reported.8,9 Moreover, Lewis acid catalyzed Friedel Crafts
type alkylation of epoxides,10 ring-opening of epoxides with in-
doles11 as well as that with boron esters of electron-rich phenols
as carbon nucleophiles12 are also reported as C–C bond forming
reactions.13 The epoxide opening reaction with nucleophiles is
generally performed with acidic or basic catalysis, and in the ab-
sence of such catalysts, the reaction is moderately slow.14 Further-
more, ionic liquids (IL) have attracted considerable interest as
environmentally benign reaction media,15–18 catalysts,18–20 and re-
agents,21 and are also easy to recycle.21
Ph
H
N
I2
O
N
O
O
[Bmim]OH
rt
Ph
O
R
O
R
O
Scheme 1. Aminoacetylation of epoxides.
2-phenyl-1,3-oxazolon-5-one as a new carbon based nucleophile
for regio- and diastereoselective ring opening of epoxides using
molecular iodine as catalyst in IL [bmim]OH which is hitherto
unreported to the best of our knowledge (Scheme 1). The envis-
aged synthetic protocol is an outcome of our continuous interest
in new methodology development.22
Initially, we used glycine in the present synthetic protocol for
aminoacetylation of epoxide, but the reaction did not take place
probably due to the presence of free –NH2 and –COOH groups. In-
stead, we turned our attention to block the free –NH2 and –COOH
groups of glycine and thus activate its methylene group by con-
verting it into 2-phenyl-1,3-oxazolon-5-one,23 which is the corner-
stone in the present synthetic protocol. The present masked amino
acid is not only a novel addition in carbon nucleophiles for regio-
and diastereoselective epoxide ring opening reactions but also it
provides a conceptually new and direct one-pot procedure for syn-
Thus, to design a novel substrate and catalyst system with high
activity and selectivity, for regio- and stereoselective ring opening
of epoxides is still an interesting and growing area for synthetic
chemists. In this Letter, we report a novel substrate, that is,
thesis of
a-benzamido–c-lactones (Scheme 2). c-Lactones consti-
tute a core structure of many natural and synthetic products and
possess a wide range of biological activities,24 especially some aryl
substituted
c-lactones have shown cancer preventive and anti-
⇑
Corresponding author. Tel.: +91 758 717 8627.
E-mail address: vijaikrai@hotmail.com (V.K. Rai).
inflammatory activities.25 Moreover, the synthesis of amide is an
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.026

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V. K. Rai et al. / Tetrahedron Letters 54 (2013) 1071–1075
noteworthy that imidazolium salts undergo deprotonation in the
PhOCHN
O
presence of strong bases such as KH, NaH, LDA, KHMDS, or DABCO
and afford N-heterocyclic carbenes.28 However, the ionic liquid
[bmim]OH is highly stable during the reaction process29 under
ambient conditions and can be used in reactions without any diffi-
culty.27 The stability and catalytic efficiency of [bmim]OH is fur-
thermore evidenced by a variety of reactions viz., Henry,30a
Knoevenagel,30b Michael,27 and Mannich reaction30c etc. reported
in the literature.
R
O
PhOCHN
O
R
O
N
O
O
Ph
O
R
Scheme 2. Disconnection approach to the present protocol.
In order to elucidate the role of other solvents in lieu of IL as
reaction medium, various solvents were used in the present reac-
tion conditions. The results validate our premise that the reaction
would not only be faster but also result in higher yield using IL as
compared to other conventional solvents (Table 1, entries 2, 7–11).
Among several aprotic polar solvents used in the present reaction
condition (Table 1), yield of the target compound 3a was found
to be poor using DMSO and DMF (Table 1, entries 7 and 8), while
it was good in the case of 1,4-dioxane, acetonitrile, and DCM (Ta-
ble 1, entries 9–11). Also we tried water as solvent in the present
synthetic protocol, but product formation did not take place at
room temperature even after 24 h, rather unprotected amino acid
was obtained in the refluxing condition under present synthetic
protocol. Thus, [bmim]OH stands out as the choice, with its fast
conversion and quantitative yield in conjunction with molecular
iodine, as an inexpensive and versatile catalyst in the present
envisaged synthetic protocol. The optimum catalyst loading for
molecular iodine was found to be 10 mol %. When amount of the
catalyst was decreased to 5 mol % from 10 mol % relative to the
substrates, the yield and diastereoselectivity of product 3a were
reduced (Table 2, entries 2 and 12). However, the use of 15 mol %
of the catalyst showed the same yield and diastereoselectivity (Ta-
ble 1, entries 2 and 13). It was noted that a higher reaction temper-
ature, for example, in a refluxing solvent instead of at rt, led to
decreased diastereoselectivity (92:8) without any appreciable ef-
fect on the yield. Next, in order to investigate the substrate scope
for the general validity of the present investigation, a variety of ter-
minal epoxides 2 were used employing the present optimized reac-
tion conditions and different 3-(N-substituted)aminofuran-2-ones
3 were synthesized. The yields were consistently good (Table 2)
and the highest yield was 95% (Table 2, entry 4). In case of epichlo-
rohydrin 2j, excellent chemoselectivity was achieved and forma-
tion of possible new oxirane was not observed by extrusion of
the chlorine atom (Path B, Scheme 4)31 rather we obtained the cor-
responding lactone 3j (Path A, Scheme 4).
important reaction in many areas of chemistry, including peptide,
polymer, and complex molecule system.26
In our preliminary experimentation, a controlled reaction was
carried out using 2-phenyl-1,3-oxazolan-5-one 1 and epoxide 2a
(R = Ph) in [bmim]OH but could not succeed (Table 1, entry 1) even
after 48 h. Then, we turned our attention to use molecular iodine as
catalyst in conjunction with different ILs. For this purpose, 2-phe-
nyl-1,3-oxazolan-5-one 1 and epoxide 2a (R = Ph) were chosen as
model substrates for the synthesis of representative compound 3a
(Table 1) wherein, molecular iodine evidenced its catalytic efficacy
in conjunction with [bmim]OH, affording 3a in excellent yield
(Table 1, entry 2). Several imidazolium-based ILs were tested by
varying their alkyl substituents as well as the counter anion and
[bmim]OH was found to be the most effective catalyst (Table 1, en-
tries 2–6) for the conversion of the epoxide 2a into corresponding
c-lactone 3a in the present synthetic protocol. On increasing the
cation size in the [bmim]OH no appreciable effect on yield and
diastereoselectivity was observed (Table 1, entries 2 and 6).
[Bmim]OH was prepared employing the known method.27 It is
Table 1
Optimization of reaction conditions for the formation of representative compound 3aa
Ph
H
N
N
solvent
O
O
O
Ph
O
I2, 4h, rt
Ph
O
Ph
O
1
2a
3a
Entry
Solvent
Catalyst (mol %)
Yieldb (%)
cis:transc
—
N
N
N
N
N
1
2
3
—
—
OH
Thus, the present optimized synthesis is accomplished by stir-
ring a mixture of 2-phenyl-1,3-oxazolan-5-one 1, epoxide 2, and
molecular iodine in [bmim]OH at rt for 4.5–5.0 h.32 Isolation and
purification by recrystallization afforded the target compound 3
in 84–95% yield with 95–98% diastereoselectivity (Table 2) in favor
of cis isomer. The product 3 was extracted with EtOAc leaving the
[bmim]OH behind 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 purification. The
crude isolates of 3 were found to be a diastereomeric mixture con-
taining 95–98% of the cis isomer. The intramolecular heterocycliza-
N
N
N
10
10
94
75
95:05
80:20
OH
Br
4
5
6
10
10
10
72
69
94
61:39
58:42
95:05
PF6
N
N
N
N
Cl
OH
7
8
9
10
11
DMSO
DMF
1,4-Dioxane
Acetonitrile
DCM
10
10
10
10
10
48
53
83
85
91
55:45
71:29
62:38
81:19
59:41
tion of adduct 4 to
c-lactone 3 was highly diastereoselective in
favor of cis isomer. The cis stereochemistry of the lactam 3 was as-
signed on the basis of J values of 5-H and on comparison with the
literature report,33 (J5H,4Ha = 7.3–7.8 Hz, J5H,4Hb = 6.1–6.5 Hz).
The formation of 3-(N-substituted)aminofuran-2-ones 3 can be
rationalized by nucleophilic attack of the methylene carbon (C-4)
of masked amino acid 1 to the less substituted carbon of epoxide
2 regioselectively, followed by protonation of epoxide oxygen lead-
ing to the intermediate 4 (Scheme 3). The adduct 4 undergoes
intramolecular nucleophilic attack of the oxygen atom of the OH
N
N
12
13
5
83
83
95:05
95:05
OH
OH
N
N
15
a
b
c
For the experimental procedure, see Ref. 32.
Yield of isolated and purified products.
As determined by 1H NMR spectroscopy of the crude products.

V. K. Rai et al. / Tetrahedron Letters 54 (2013) 1071–1075
1073
Table 2
One-step synthesis of 3-(N-substituted)aminofuran-2-ones 3a
H
O
N
R
N
I2
O
O
O
Ph
Ph
O
1
N
R
N
O
2
OH
3
rt
c,d
Entry
1
Epoxide 2
Reaction timeb (h)
4.5
3-(N-substituted)aminofuran-2-one 3
Yield
94
(%)
cis/transe
O
H
C6H5
O
N
95:5
98:2
O
O
Ph
O
2a
3a
3b
O
H
N
4-ClC6H4
O
2
3
4
5.0
5.0
4.5
91
89
95
Ph
O
Cl
2b
O
H
4-MeOC6H4
4-NO2C6H4
O
O
N
97:3
98:2
O
O
Ph
O
3c
3d
3e
OMe
NO2
2c
O
H
N
Ph
O
2d
O
H
4-BrC6H4
2-BrC6H4
O
N
5
6
4.5
5.0
94
88
98:2
97:3
O
O
Ph
O
Br
2e
O
H
O
N
Ph
O
3f
Br
2f
O
OMe
OMe
OMe
OMe
H
O
O
N
7
8
4.5
5.0
90
91
95:5
98:2
O
Ph
2g
O
3g
O
H
N
O
O
O
O
Ph
2h
O
O
3h
H
O
N
9
5.0
4.5
84
89
95:5
96:4
2i
Ph
Ph
Ph
O
3i
3j
O
H
O
N
Cl
Cl
10
2j
O
O
H
O
N
Ph
O
O
11
5.0
92
96:4
O
3k
2k
O
H
O
N
4-ClC6H4
O
O
12
13
4.5
4.5
87
84
97:3
95:5
O
Ph
O
3l
Cl
2l
NO2
H
O
O
N
2-NO2C6H4
O
O
O
Ph
O
3m
2m
(continued on next page)

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V. K. Rai et al. / Tetrahedron Letters 54 (2013) 1071–1075
Table 2 (continued)
c,d
Entry
Epoxide 2
Reaction timeb (h)
3-(N-substituted)aminofuran-2-one 3
Yield
93
(%)
cis/transe
O
OMe
H
O
O
O
N
O
14
5.0
97:3
O
O
OMe
Ph
2n
O
3n
a
b
c
For the experimental procedure, see Ref. 32.
Time required for completion of the reaction at rt as monitored by TLC.
Yield of isolated and purified products.
d
e
All compounds gave C, H, and N analyses within 0.37%, and satisfactory spectral (IR, 1H NMR, 13C NMR, and EIMS) data.
As determined by 1H NMR spectroscopy of the crude products.
O
R
O
N
N
N
N
N
R
OH
2
Ph
Ph
Ph
O
O
N
O
O
O
O
-H2O
1
1'
R
O
O
R
R
H
N
Ph
N
H2O
OH
O
Ph
Ph
H
O
O
O
-I2
O
O
I I
4
3
Scheme 3. Tentative mechanism for the formation of 3-(N-substituted)aminofuran-2-ones 3.
group at the carbonyl carbon (C-5) of the 1,3-oxazolan-5-one moi-
ety to yield the target compounds 3 as in Scheme 2. This conclusion
is based on the observation that the representative intermediate
compounds 4a (R = Ph), 4e (R = 4-BrC6H4) and 4i (R = Me) could
be isolated in 42–51% yield, these could be converted into the
corresponding lactones 3a, 3e, and 3i in quantitative yields.34 Pre-
sumably, 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 OH of epoxide 2.
Furthermore, the imidazolium hydroxide perhaps helps in increas-
ing the nucleophilicity of 1 via formation of 10 (Scheme 3) while, in
case of ionic liquids with halide ion and other solvents, the mech-
anism seems to be operated via enol form of the masked amino
acid 1, stabilized by imidazolium moiety. However, epoxide ring
opens regioselectively where nucleophile attack took place at ter-
minal carbon rather benzylic carbon presumably following steric
effect due to bulky nature of attacking nucleophile.
In summary, we have documented an original regio- and diaste-
reoselective ring opening of terminal epoxides with masked amino
acid, viz., 2-phenyl-1,3-oxazolan-5-one, as new carbon nucleo-
phile. In the present synthetic protocol no by-product formation
is observed and also the ionic liquid [bmim]OH used could be eas-
ily recycled for further use without any loss of efficiency. Thus, the
envisaged methodology for the synthetically and pharmaceutically
important 3-(N-substituted)aminofuran-2-ones would be a practi-
cal alternative to the existing procedures for the production of this
kind of fine chemicals to cater to the need of academic institutions
as well as of industries.
O
Cl
Cl
N
O
N
2j
O
Ph
O
O
1'
Ph
O
Path A
PhOCHN
O
Cl
-PhCOMe
O
3j
O
Cl
O
2j
N
N
Ph
O
O
Path B
O
Ph
O
Acknowledgments
1'
We sincerely thank the CSIR, New Delhi (01(2441)/10) EMR-II)
and DST, New Delhi (SR/FT/CS-99/2010) for financial support. We
are also thankful to IIIM Jammu and SAIF, Punjab University, Chan-
digarh, for providing microanalyses and spectra.
Scheme 4. Chemoselectivity in the case of epichlorohydrin 2j.
Table 3
Recyclability of [bmim]OH
References and notes
Table 2
Entry 4
Run 1
Run 2
95
Run 3
94
Run 4
94
Run 5
93
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32. General procedure for one-pot synthesis of 3-(N-substituted) aminofuran-2-one
3a–n:
A mixture of 2-phenyl-1,3-oxazol-5-one 1 (2.0 mmol), epoxide 2
(2.0 mmol), and a catalytic amount of iodine (0.2 mmol) in [bmim]OH (6 mL)
was stirred at rt for 4.5–5 h. After completion of the reaction as indicated by
TLC, 10 mL of water was added and the mixture was extracted thrice with
10 mL of EtOAc. The combined organic extracts were treated with an aqueous
solution of Na2S2O3 (1 M) and then washed with brine (10 mL). The organic
layer was dried over anhydrous Na2SO4, filtered, and evaporated under
reduced pressure to afford an analytically pure sample of
a single
diastereomer (Table 2). After isolation of the products, the remaining
3
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. Physical
data of representative compounds. Compound 3a: colorless solid, mp 123–
125 °C. IR (KBr) t .
max 3341, 3048, 2942, 1761, 1735, 1601, 1585, 1450 cmꢀ1 1H
NMR (400 MHz; CDCl3) d = 2.62 (ddd, J = 11.1, 7.8, 4.1 Hz, 1H), 2.89 (ddd, J =
11.1, 9.3, 6.1 Hz, 1H), 4.52 (ddd, J = 9.3, 7.1, 4.1 Hz, 1H), 4.99 (dd, J = 7.8, 6.1 Hz,
1H), 7.26–7.48 (m, 10H), 8.03 (br, exchangable, 1H). 13C NMR (100 MHz, CDCl3)
d = 31.3, 54.1, 80.6, 126.2, 127.1, 127.9, 130.2, 130.8, 131.3, 131.9, 135.5, 171.2,
178.2. EIMS (m/z): 281 (M+). Anal. Calcd for C17H15NO3: C, 72.58; H, 5.37; N,
4.98%. Found: C, 72.89; H, 5.08; N, 4.79%. Compound 3e: Colorless solid, mp
111–112 °C. IR (KBr) tmax 3339, 3051, 2942, 1755,1741, 1595, 1582,
1455 cmꢀ1 1H NMR (400 MHz; CDCl3) d = 2.59 (ddd, J = 11.5, 7.7, 4.3 Hz,
.
1H), 2.91 (ddd, J = 11.5, 9.1, 6.0 Hz, 1H), 4.49 (ddd, J = 9.1, 7.0, 4.3 Hz, 1H), 5.01
(dd, J = 7.7, 6.0 Hz, 1H), 7.11–7.56 (m, 7H), 7.81–7.92 (m, 2H), 8.01 (br,
exchangable, 1H). 13C NMR (100 MHz, CDCl3) d = 31.7, 54.0, 80.5, 125.9, 126.5,
127.4, 128.3, 129.1, 129.8, 131.2, 132.0, 171.1, 178.5. EIMS (m/z): 359, 361, (M+,
M++2). Anal. Calcd for C17H14BrNO3: C, 56.69; H, 3.92; N, 3.89%. Found: C,
56.32; H, 4.18; N, 3.61%. Compound 3i: Colorless solid, mp 136–138 °C. IR (KBr)
t
max 3340, 3049, 2948, 1756, 1742, 1605, 1580, 1449 cmꢀ1 1H NMR (400 MHz;
.
CDCl3) d = 1.89 (s, 3H), 2.66 (ddd, J = 11.0, 7.8, 4.2 Hz, 1H), 2.88 (ddd, J = 11.0,
8.9, 6.5 Hz, 1H), 4.55 (ddd, J = 8.9, 7.3, 4.2 Hz, 1H), 4.72 (m, 1H), 7.21–7.52 (m,
5H), 8.0 (br, exchangable, 1H). 13C NMR (100 MHz, CDCl3) d = 23.2, 31.0, 54.7,
78.3, 127.1, 128.5, 131.2, 132.5, 171.9, 178.5. EIMS (m/z): 219 (M+). Anal. Calcd
for C12H13NO3: C, 65.74; H, 5.98; N, 6.39%. Found: C, 65.93; H, 6.15; N, 6.02%.
33. Brace, N. O. Fluorine Chem. 2003, 123, 237.
34. Isolation of 4a, 4e, and 4i and their conversion into corresponding 3-(N-
substituted) aminofuran-2-one 3a, 3e, and 3i: 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 3.5–4 h used for 3. To obtain analytically pure
sample 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 rt for next 2 h to give the corresponding cyclized product 3a, 3e, and
3i respectively. Physical data of representative compound 4a. Compound 4a:
Colorless solid, mp 142–144 °C. IR (KBr) tmax 3381, 3050, 2939, 1758, 1604,
17. Zhao, D.; Wu, M.; Kou, Y.; Min, E. Catal. Today 2002, 74, 157–189.
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19. Qiao, K.; Yakoyama, C. Chem. Lett. 2004, 33, 472–473.
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21. (a) Kamal, A.; Chouhan, G. Tetrahedron Lett. 2005, 46, 1489–1491; (b) Earle, M.
J.; Ktdare, S. P.; Seddon, K. R. Org. Lett. 2004, 6, 707–710.
22. (a) Rai, V. K.; Tiku, P.; Kumar, A. Synth. Commun. 2012, 42, 1489; (b) Rai, V. K.;
Rai, P. K.; Bajaj, S.; Kumar, A. Green Chem. 2011, 13, 1217; (c) Rai, V. K.; Singh,
S.; Singh, P.; Yadav, L. D. S. Synthesis 2010, 4051; (d) Yadav, L. D. S.; Singh, S.;
Rai, V. K. Green Chem. 2009, 11, 878; (e) Yadav, L. D. S.; Rai, V. K. Tetrahedron
Lett. 2006, 47, 395.
1583, 1455 cmꢀ1 1H NMR (400 MHz; CDCl3) d = 2.43–2.58 (m, 2H), 3.58 (dd, J =
.
8.1, 3.7 Hz, 1H), 3.71 (J = 2.8 Hz, 1H), 3.92 (m, 1H), 7.29–7.69 (m, 10H). 13C NMR
(100 MHz, CDCl3) d = 43.2, 63.9, 68.9, 125.9, 126.6, 127.3, 128.0, 128.7, 129.4,
130.1, 130.9, 168.5, 177.5. EIMS (m/z): 281 (M+). Anal. Calcd for C17H15NO3: C,
72.58; H, 5.37; N, 4.98%. Found: C, 72.39; H, 5.15; N, 5.21%.