Glycerine and CeClH: An efficient and recyclable reaction medium for ring opening of epoxides with thioamides and amines

Article abstract of DOI:10.1055/s-0030-1258366

Oxiranes undergo rapid ring-opening reaction with a range of thioamides and amines to afford the corresponding -amino alcohol derivatives. The reactions were carried out using glycerine and cerium(III) chloride as a recyclable reaction medium. All the reactions were carried out at room temperature and the products were obtained in excellent yields. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258366

PAPER
485
Glycerine and CeCl3·7H2O: An Efficient and Recyclable Reaction Medium for
Ring Opening of Epoxides with Thioamides and Amines
G
.
H
O
Venkat Narsaiah,* Sachin B. Wadavrao, A. Ramesh Reddy, J. S. Yadav
3
Organic Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160387; E-mail: vnakkirala2001@yahoo.com
Received 22 October 2010; revised 4 November 2010
The use of solvents such as water, supercritical fluids, ion-
Abstract: Oxiranes undergo rapid ring-opening reaction with a
range of thioamides and amines to afford the corresponding b-ami-
no alcohol derivatives. The reactions were carried out using glycer-
ine and cerium(III) chloride as a recyclable reaction medium. All
ic liquids, and solvent-free conditions under microwave
irradiation has received much attention in recent years in
the area of green synthesis. In this respect, glycerine has
the reactions were carried out at room temperature and the products emerged as a green solvent with unique properties, such as
were obtained in excellent yields.
high polarity, thermal stability, immiscibility with a num-
ber of organic solvents, negligible vapor pressure, low-
toxicity, and recyclability.7 Accordingly, glycerine repre-
sents a novel substitute for volatile organic solvents in or-
ganic transformations. Moreover, glycerine is
inexpensive, readily available, and recyclable. Recently,
Silvera et al. reported glycerine–cerium(III) chloride hy-
drate as a new and efficient recyclable reaction medium
for the synthesis of bis(indole)methanes, and we also re-
ported the successful synthesis of Hantzsch pyridines and
quinoxalines in a similar manner.8 In this communication,
we wish to demonstrate the use of glycerine–CeCl3·7H2O
as a recyclable reaction medium for the ring opening of
Key words: epoxides, amines, thioamides, amino alcohols, glycer-
ine, cerium chloride.
Oxiranes are widely utilized as versatile synthetic inter-
mediates and are considered to be ‘spring-loaded’ rings
for nucleophilic ring opening. Their reactions are domi-
nated by the electrophilic nature of these heterocycles,
which generally involve cleavage of the three-membered
rings with a variety of nucleophiles to give b-substituted
alcohols and amines.1 The resultant b-amino alcohols rep-
resent a wide range of b-adrenergic blockers, such as
naptofidil (1), betaxolol (2), atenolol (3), and dopamine
(4), which are used in the management of cardiovascular
disorders, including hypertension, angina pectoris, cardi-
ac arrhythmias and for disorders related to the sympathet-
ic nervous system (Figure 1).2
N
O
O
OH
N
OH
MeO
One of the most straightforward synthetic approaches to
the preparation of b-amino alcohols involves treating an
epoxide with an excess of amine at elevated temperature.
Since some functional groups are sensitive to high tem-
perature, a variety of activators, such as alkali metal ha-
lides,3 metal perchlorates,4 metal triflates,5 Bu3P, ionic
liquids, and hexafluoro-2-propanol6 have been intro-
duced. However, many of these methods involve the use
of expensive catalysts, stoichiometric amounts of reagents
and also require extended reaction times. Therefore, the
development of an efficient and environmentally friendly,
green protocol is still in demand.
H
O
N
1
2
N
O
H
OH
OH
H
OMe
OMe
N
HO
O
HO
NH2
4
O
3
Figure 1
NH2
N
H
O
O
O
OH
glycerine
CeCl3⋅7H2O
r.t., 1 h
+
MeO
OMe
OMe
OMe
1
2
3
Scheme 1
SYNTHESIS 2011, No. 3, pp 0485–0489
x
x
.
x
x
.2
0
1
1
Advanced online publication: 14.12.2010
DOI: 10.1055/s-0030-1258366; Art ID: Z25910SS
© Georg Thieme Verlag Stuttgart · New York

486
A. V. Narsaiah et al.
PAPER
various epoxides with a variety of amines under mild con- afford the required product, which was purified by col-
ditions.
umn chromatography. Encouraged by the result obtained
with the above reaction, we applied this methodology to
the reaction of a variety of epoxides with amines and
amides. In another experiment, 2-[(naphthalene-1-
yloxy)methyl]oxirane and benzothioamide were reacted
under similar reaction conditions. This reaction was com-
plete within one hour to afford the corresponding product
N-[2-hydroxy-3-(naphthalen-1-yloxy)propyl]benzothio-
amide (3h) in very good yield. In a similar manner, 2-
[(naphthalen-1-yloxy)methyl]oxirane successfully react-
ed with N-Boc-piperazine, isopropyl amine, pyrrole, mor-
pholine, aniline, ethane thioamide and 1-phenylthiourea
(Table 1, entries 2–8) to afford the corresponding deriva-
tives with high yields.
In a typical experiment, 2-[(naphthalen-1-yloxy)meth-
yl]oxirane (1) and 2-(3,4-dimethoxyphenyl)ethanamine
(2) were stirred in glycerine at room temperature in the
presence of CeCl3·7H2O (10 mol%) for one hour, to afford
the corresponding product, 1-(3,4-dimethoxyphenylami-
no)-3-(naphthalen-1-yloxy)propan-2-ol (3a) in excellent
yield (Scheme 1). Upon completion of the reaction, ethyl
acetate (10 mL) was added to reaction mixture, which was
then stirred for 15 minutes and the glycerine was separat-
ed from the ethyl acetate layer by decantation. This pro-
cess was repeated three times and the residue was used for
further reactions. The separated ethyl acetate layers were
combined, washed with water, brine, dried over anhy-
drous Na2SO4 and concentrated under reduced pressure to
Table 1 Ring Opening of Epoxides Mediated by Glycerine–CeCl3·7H2O
Entry
1
Epoxide
Amine
Product
Time (min) Yield (%)
NH2
OMe
NH
O
O
O
3a
60
90
OH
OMe
OMe
OMe
HN
N
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
2
3
4
5
6
3b
3c
3d
3e
3f
45
30
45
49
30
89
90
88
92
95
N
OH
OH
OH
OH
OH
N Boc
Boc
NH
N
NH2
N
H
H
N
N
O
O
NH2
NH
S
O
O
S
O
O
O
O
N
H
7
8
3g
3h
60
60
84
86
OH
OH
NH2
S
S
N
H
NH2
Synthesis 2011, No. 3, 485–489 © Thieme Stuttgart · New York

PAPER
Glycerine-CeCl3·7H2O
487
Table 1 Ring Opening of Epoxides Mediated by Glycerine–CeCl3·7H2O (continued)
Entry
Epoxide
Amine
Product
Time (min) Yield (%)
NH2
OH
OH
O
O
H
N
OMe
OMe
9
3i
3j
45
60
92
87
OMe
OMe
H
N
H
N
H
NH2
N
10
S
S
NH2
OH
O
O
11
12
3k
3l
60
45
88
90
O
O
O
H
N
OH
O
N
N
O
O
H
N
Boc
O
O
OH
OH
13
14
3m
3n
60
60
87
89
O
O
N
N
O
O
N
Boc
NH2
OMe
OMe
OMe
OMe
NH2
OH
OH
O
O
H
N
O
O
O
O
15
16
3o
3p
60
45
86
90
NH2
H
N
NH2
OH
O
H
N
O
O
OMe
OMe
17
3q
60
87
OMe
OMe
In a continuation of the series of reactions, 2-(benzyl- (3,4-dimethoxyphenyl)ethanamine (entry 9) and 1-phe-
oxymethyl)oxirane was reacted with N-Boc-piperazine nylthiourea (entry 10) to afford the corresponding deriva-
using the reaction conditions established above. The ep- tives in very good yields. In another series of experiments,
oxide ring opening took place very efficiently within one 2-(phenoxymethyl)oxirane was reacted with isopropyl
hour to afford the corresponding product tert-butyl-4-[3- amine (entry 15) and aniline (entry 16) to afford the cor-
(benzyloxy)-2-hydroxypropyl]piperazine-1-carboxylate
(3m) in very good yields as shown in Scheme 2.
OH
O
O
O
Encouraged by the result obtained with 2-(benzyloxy-
methyl)oxirane and N-Boc-piperazine, we extended this
procedure to successfully react the same oxirane with
aniline (Table 1, entry 11), morpholine (entry 12) and 2-
(3,4-dimethoxyphenyl)ethanamine (entry 14) to afford
the corresponding products in very good yields. In a sim-
ilar manner, styrene oxide was reacted smoothly with 2-
H
N
glycerine
CeCl3⋅7H2O
N
+
r.t., 1 h
N
N
boc
boc
Scheme 2
Synthesis 2011, No. 3, 485–489 © Thieme Stuttgart · New York

488
A. V. Narsaiah et al.
PAPER
IR (neat): 3363, 3055, 3008, 2927, 2879, 2844, 1691, 1579, 1509,
1458, 1418, 1363, 1336, 1270, 1246, 1174, 1143, 1105, 1012, 984,
867, 769, 740 cm–1.
1H NMR (CDCl3): d = 1.49 (s, 9 H), 2.40–2.50 (m, 2 H), 2.60–2.75
(m, 4 H), 3.40–3.55 (m, 4 H), 4.05–4.12 (m, 1 H), 4.19–4.20 (m,
2 H), 6.80 (d, J = 6.5 Hz, 1 H), 7.25–7.49 (m, 4 H), 7.75 (d,
J = 6.5 Hz, 1 H), 8.18 (d, J = 6.5 Hz, 1 H).
responding products in very good yields. In a similar man-
ner, the 2-(p-tolyloxymethyl)oxirane reacted well with 2-
(3,4-dimethoxyphenyl)ethanamine to afford the corre-
sponding product 1-(3,4-dimethoxyphenethylamino)3-(p-
tolyloxy)propan-2-ol (3q) in very good yields; the reac-
tion was also complete within one hour.
In general, all the reactions were carried out at room tem-
perature, using the catalyst cerium(III) chloride (10%
mol) in glycerine as solvent. All the reactions were com-
pleted within one hour and the products were obtained in
84–95% yield. In all cases, the epoxide ring opening took
place in a regioselective manner that favored terminal
ring-opening. All the products were confirmed by analysis
MS (EI, 70 eV): m/z (%) = 388 (40) [M + 2], 331 (50), 287 (10), 243
(10), 187 (10).
1-(Isopropylamino)-3-(naphthalen-1-yloxy)propan-2-ol (3c)
IR (neat): 3298, 3056, 3013, 2927, 2855, 1630, 1582, 1514, 1460,
1398, 1268, 1240, 1152, 1103, 1070, 1025, 869, 764, 666 cm–1.
1H NMR (CDCl3): d = 1.21 (s, 6 H), 3.15 (t, J = 6.0 Hz, 1 H), 3.31
(d, J = 6.0 Hz, 1 H), 3.35–3.42 (m, 1 H), 3.90–4.05 (m, 2 H), 4.50
(br s, 1 H), 6.48 (d, J = 7.0 Hz, 1 H), 7.15 (t, J = 7.0 Hz, 1 H), 7.30
(d, J = 7.0 Hz, 1 H), 7.40 (d, J = 7.0 Hz, 2 H), 7.70 (d, J = 7.0 Hz,
1 H), 8.18 (d, J = 7.0 Hz, 1 H).
1
of their respective IR, H NMR and mass spectroscopic
data.
In conclusion, the present methodology provides a simple
and efficient green protocol for ring opening of various
epoxides with amides and amines. The reaction medium,
glycerine–CeCl3·7H2O, was recycled and reused up to
five times without loss of activity. The notable features of
this procedure are mild reaction conditions, cleaner reac-
MS (EI, 70 eV): m/z (%) = 258 (10) [M – 1], 243 (10), 214 (10), 143
(20), 114 (25), 72 (100), 57 (20), 43 (25).
1-(Naphthalen-1-yloxy)-3-(phenylamino)propan-2-ol (3f)
Yellow syrup.
tions, improved yields, enhanced reaction rates, and sim- IR (neat): 3404, 3053, 2126, 1601, 1506, 1459, 1398, 1318, 1268,
1240, 1101, 1069, 1021, 993, 956, 876, 767, 693 cm–1.
plicity of operation, which makes it a useful and attractive
1H NMR (CDCl3): d = 3.39 (q, J = 6.5 Hz, 1 H), 3.55 (dd, J = 5.0,
12 Hz, 1 H), 4.25 (d, J = 6.5 Hz, 2 H), 4.38–4.45 (m, 1 H), 6.69 (q,
J = 7.5 Hz, 2 H), 6.80 (d, J = 7.5 Hz, 1 H), 7.15 (t, J = 7.5 Hz, 2 H),
7.32 (t, J = 7.5 Hz, 1 H), 7.40–7.50 (m, 3 H), 7.72–7.80 (m, 1 H),
8.18–8.25 (m, 1 H).
process for the synthesis of b-amino alcohols.
IR spectra were recorded with a Perkin–Elmer FT-IR 240-c spectro-
1
photometer. H NMR spectra were recorded with a Gemini-300
spectrometer in CDCl3 using TMS as internal standard. Mass spec-
tra were recorded with a Finnigan MAT 1020 mass spectrometer
operating at 70 eV.
MS (EI, 70 eV): m/z (%) = 294 (100) [M + 1], 183 (10), 150 (15),
131 (10), 139 (15), 103 (10), 99 (10).
1-(2-Hydroxy-2-phenylethyl)-3-phenylthiourea (3j)
IR (neat): 3445, 3057, 2923, 2854, 1652, 1588, 1485, 1452, 1395,
1268, 1236, 1160, 1100, 1069, 1021, 944, 766, 694 cm–1.
1H NMR (CDCl3): d = 3.55–3.72 (m, 2 H), 5.05–5.15 (m, 1 H), 6.95
(d, J = 6.5 Hz, 2 H), 7.09 (q, J = 6.5 Hz, 1 H), 7.29–7.52 (m, 8 H).
MS (EI, 70 eV): m/z (%) = 272 (10) [M]+, 244 (100), 132 (10), 121
(10), 101 (15).
General Procedure
To a stirred mixture of epoxide (1 mmol) in glycerine (2 mL) was
added amine (1 mmol) and the catalyst CeCl3·7H2O (0.1 mmol) at
r.t. The resulting reaction mixture was stirred for the specified time
(Table 1). The progress of the reaction was monitored by thin-layer
chromatography (TLC). After complete conversion of the starting
material, as indicated by TLC, the reaction mixture was extracted
with EtOAc (3 × 10 mL). The combined organic layers were
washed with H2O (2 × 5 mL) and brine (5 mL), dried over Na2SO4
and concentrated under reduced pressure to obtain the crude prod-
ucts, which was purified by column chromatography (silica gel 60–
120 mesh; EtOAc–petroleum ether, 3:7). The identities of the prod-
1-(Benzyloxy)-3-morpholinopropan-2-ol (3l)
Yellow liquid.
IR (neat): 3421, 2925, 2857, 1454, 1366, 1271, 1116, 1010, 947,
864, 745, 699 cm–1.
1
ucts were confirmed by analysis of their H NMR, IR and mass
spectroscopic data.
1H NMR (CDCl3): d = 2.40–2.50 (m, 4 H), 2.60–2.69 (m, 2 H), 3.45
(d, J = 5.0 Hz, 2 H), 3.66–3.71 (m, 4 H), 3.85–3.92 (m, 1 H), 4.54
(s, 2 H), 5.00 (br s, 1 H, OH), 7.25–7.35 (m, 5 H).
1-(3,4-Dimethoxyphenethylamino)-3-(naphthalen-1-yloxy)pro-
pan-2-ol (3a)
Yellow syrup.
MS (EI, 70 eV): m/z (%) = 252 (100) [M + 1].
IR (neat): 3298, 3056, 3013, 2927, 2855, 1630, 1582, 1514, 1460,
1398, 1268, 1240, 1152, 1103, 1070, 1025, 869, 764, 666 cm–1.
1H NMR (CDCl3): d = 2.75–2.81 (m, 1 H), 2.90–3.08 (m, 3 H), 3.75
(s, 3 H), 3.79 (s, 3 H), 3.95–4.12 (m, 5 H), 4.20–4.30 (m, 1 H),
6.58–6.71 (m, 3 H), 7.28 (t, J = 7.0 Hz, 1 H), 7.35–7.45 (m, 3 H),
7.71 (d, J = 7.0 Hz, 1 H), 8.18 (d, J = 7.0 Hz, 1 H).
tert-Butyl 4-[3-(Benzyloxy)-2-hydroxypropyl]piperazine-1-car-
boxylate (3m)
1H NMR (CDCl3): d = 1.98 (s, 9 H), 2.40–2.50 (m, 4 H), 2.05–2.15
(m, 2 H), 3.39–3.48 (m, 6 H), 3.88–3.95 (m, 1 H), 4.52 (s, 2 H),
7.20–7.35 (m, 5 H).
1-(Benzyloxy)-3-(3,4-dimethoxyphenethylamino)propan-2-ol
(3n)
Liquid.
MS (EI, 70 eV): m/z (%) = 382 (10) [M + 2], 349 (20), 318 (10), 215
(20), 186 (35), 168 (30), 143 (50), 127 (100), 103 (25), 96 (10).
IR (neat): 3425, 2924, 2856, 1613, 1512, 1460, 1239, 1146, 1031,
811, 760 cm–1.
tert-Butyl 4-[2-Hydroxy-3-(naphthalen-1-yloxy)propyl]pipera-
zine-1-carboxylate (3b)
Yellow syrup.
Synthesis 2011, No. 3, 485–489 © Thieme Stuttgart · New York

PAPER
Glycerine-CeCl3·7H2O
489
1H NMR (CDCl3): d = 2.65–2.75 (m, 4 H), 2.85–2.95 (m, 1 H),
3.02–3.18 (m, 1 H), 3.35–3.45 (m, 2 H), 3.80 (s, 6 H), 3.83–3.90
(m, 1 H), 4.50 (s, 2 H), 6.65–6.73 (m, 2 H), 7.22–7.38 (m, 6 H).
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MS (EI, 70 eV): m/z (%) = 346 (100) [M + 1], 258 (15), 181 (10),
167 (25), 91 (10).
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1-(Isopropylamino)-3-phenoxypropan-2-ol (3o)
1H NMR (CDCl3): d = 1.29 (s, 3 H), 1.95 (s, 3 H), 2.65–2.92 (m,
2 H), 3.85–3.99 (m, 2 H), 4.05–4.18 (m, 1 H), 3.7 (m, 1 H,), 6.80–
6.95 (m, 3 H), 7.18–7.28 (m, 2 H).
1-Phenoxy-3-(phenylamino)propan-2-ol (3p)
1H NMR (CDCl3): d = 3.14–3.40 (m, 2 H), 3.90–4.05 (m, 2 H),
4.15–4.25 (m, 1 H), 6.55–6.70 (m, 3 H), 6.80–6.90 (m, 3 H), 7.10–
7.30 (m, 4 H).
1-(3,4-Dimethoxyphenethylamino)-3-(p-tolyloxy)propan-2-ol
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(3q)
IR (neat): 3425, 2924, 2856, 1613, 1512, 1460, 1239, 1146, 1031,
811, 760 cm–1.
1H NMR (CDCl3): d = 2.30 (s, 3 H), 2.70–2.80 (m, 3 H), 2.85–2.95
(m, 1 H), 3.79–3.88 (m, 5 H), 3.98–4.06 (m, 1 H), 6.65–6.75 (m,
5 H), 7.05 (d, J = 7.5 Hz, 2 H).
MS (EI, 70 eV): m/z (%) = 347 (30) [M + 2], 346 (100) [M + 1], 259
(10), 181 (10), 165 (35), 150 (10).
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Acknowledgment
S.B.W. and A.R.R. are thankful to CSIR New Delhi for providing
fellowships.
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Synthesis 2011, No. 3, 485–489 © Thieme Stuttgart · New York