Y(NO3)3·6H2O catalyzed regioselective ring opening of epoxides with aliphatic, aromatic, and heteroaromatic amines

Article abstract of DOI:10.1016/j.tetlet.2008.03.152

Yttrium nitrate hexahydrate [Y(NO₃)₃·6H₂O] was found to be an efficient catalyst for selective ring opening of epoxides with aliphatic, aromatic, and heteroaromatic amines at room temperature under solvent-free conditions. The system tolerated a variety of hindered and functionalized epoxides/amines and afforded the desired β-amino alcohols at low catalyst concentration.

Full text of DOI:10.1016/j.tetlet.2008.03.152

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3672–3676
Y(NO3)3Á6H2O catalyzed regioselective ring opening of epoxides
with aliphatic, aromatic, and heteroaromatic amines
Mayur J. Bhanushali, Nitin S. Nandurkar, Malhari D. Bhor, Bhalchandra M. Bhanage *
Department of Chemistry, Institute of Chemical Technology (Autonomous), University of Mumbai, N. Parekh Marg, Matunga, Mumbai 400 019, India
Received 15 January 2008; revised 25 March 2008; accepted 28 March 2008
Available online 8 April 2008
Abstract
Yttrium nitrate hexahydrate [Y(NO3)3Á6H2O] was found to be an efficient catalyst for selective ring opening of epoxides with
aliphatic, aromatic, and heteroaromatic amines at room temperature under solvent-free conditions. The system tolerated a variety of
hindered and functionalized epoxides/amines and afforded the desired b-amino alcohols at low catalyst concentration.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Epoxides; Amines; 2-Amino alcohols; Yttrium nitrate hexahydrate; Regioselectivity
Amino alcohols constitute an important class of com-
pounds having both chemical and biological applications.
They are important pharmacophores present in various
inhibitors and are used as building blocks for the synthesis
of biologically active natural products, insecticidal agents
and chiral auxillaries for asymmetric reactions.1a–f They
act as starting materials for the synthesis of oxazolines
which are useful in the polymer industry.1g Owing to their
widespread applications, the synthesis of amino alcohols
has received much attention in recent years.
Traditionally, 2-amino alcohols are prepared by heating
an epoxide with an excess of amine at elevated tempera-
ture. The use of a high temperature leads to undesired side
reactions and also limits the applicability towards temper-
ature sensitive substrates. To overcome these drawbacks
various promoters such as ZnCl2,2 ScOTf,3 MgBr2ÁOEt2,4
bismuth salts,5 CoCl2,6 CuBF4,7 DIPAT,8 Ti(OiPr)4,9
TaCl5,10 ZrCl4,11 Sm(OTf)3,12 potassium dodecatungstoco-
baltate,13 and aluminosilicate14 have been employed for the
above transformation. The use of non-conventional tech-
niques such as microwave irradiation at elevated tempera-
ture has also been reported.15 Recently, the use of Al(OTf)3
(1 mol %) as catalyst in toluene at reflux has also been
reported.16 Although significant advances have been made
in this area, low regioselectivity, longer reaction time, use
of elevated temperature, high catalyst loading, toxic sol-
vents and lower substrate compatibility limit their applica-
tions. Thus there is a need to develop an efficient catalytic
protocol for ring opening of various epoxides with ali-
phatic, aromatic and heteroaromatic amines under ambient
conditions.
In our previous study,17 we introduced Y(NO3)3Á6H2O,
as a novel catalyst for Biginelli and aza-Michael reactions.
The catalyst showed remarkable activity and reusability
affording high yields of the desired products. The co-ordi-
nating ability of Y(NO3)3Á6H2O along with its commercial
availability prompted us to investigate its activity for ring
opening of epoxides. We herein report a general protocol
NH2
OH
+
OH
H
N
H
N
Y(NO3)3.6H2O
O
R
+
R
Solvent-free/R.T.
R
X
X
X
X = Me, OMe, CF3, F
a
b
R = Me, Ph, CH2OPh, CH2Cl
*
Corresponding author. Tel.: +91 22 24145616; fax: +91 22 24145614.
Scheme 1. Aminolysis of epoxides under solvent-free conditions.
E-mail address: bhalchandra_bhanage@yahoo.com (B. M. Bhanage).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.152

M. J. Bhanushali et al. / Tetrahedron Letters 49 (2008) 3672–3676
3673
Table 1
for aminolysis of aliphatic/aromatic epoxides with a wide
variety of amines under solvent-free conditions (Scheme 1).
Initially, the ring opening of styrene oxide with aniline
was chosen as a model and the role of various solvents
and catalysts on the reaction system was investigated.
Solvents such as water, toluene, tetrahydrofuran, methy-
lene dichloride, and methanol (Table 1, entries 1–5) pro-
vided low yields of the desired product (5–12%), while
the same reaction under solvent-free conditions afforded
a 92% yield within 1 h. The high reaction rate observed
could be attributed to the fact that, under solvent-free con-
ditions, the concentration of catalyst is greater leading to
rate enhancement as compared to the same reaction in
the presence of solvent. Further, the effect of various metal
nitrates on the reaction system was examined (Table 1,
entries 6–11). Y(NO3)3Á6H2O and La(NO3)3Á6H2O pro-
vided excellent yields of the desired product within a short
reaction time (1 h). However, since Y(NO3)3Á6H2O
Influence of solvent and catalysta
Entry Solvent
Catalyst
Yieldb (%) Ratioc (a:b )
Influence of solvent
1
2
3
4
5
6
Methanol
Y(NO3)3Á6H2O
7
12
10
7
—
—
—
—
Tetrahydrofuran Y(NO3)3Á6H2O
Dichloromethane Y(NO3)3Á6H2O
Toluene
Water
None
Y(NO3)3Á6H2O
Y(NO3)3Á6H2O
Y(NO3)3Á6H2O
5
—
92
84:16
Influence of catalyst
7
8
9
None
None
None
None
None
Cu(NO3)2.3H2O 42
73:27
79:21
83:17
84:16
78:22
Zn(NO3)2Á6H2O 68
Bi(NO3)3.5H2O
33
10
11
a
Fe(NO3)3.9H2O 70
La(NO3)3Á6H2O 91
Reaction conditions: aniline = 1.2 mmol; styrene oxide = 1 mmol;
solvent = 1 ml, time = 1 h.
b
Yield determined by GC.
Ratios determined by GC–MS analysis.
c
Table 2
Ring opening of epoxides with aliphatic and aromatic aminesa
Entry
1
Amine
Epoxide
Productb
Time (h)
1
Yieldc (%)
92 (81)
Ratiod (a:b)
NH2
OH
H
N
O
84:16
Ph
Ph
NH
2
OH
H
N
O
2
3
4
1
3
3
91
89
90
85:15
87:13
89:11
Ph
Ph
H3CO
OCH
3
F
NH
OH
2
H
O
F
N
Ph
Ph
NH
2
2
OH
H
N
O
F C
3
Ph
Ph
CF
3
NH
OH
H
N
O
5
1
92
83:17
Ph
Ph
OH
H
N
O
NH2
6
7
8
4
1
3
88 (82)
90:10
90:10
0:100
Ph
Ph
O
OH
OH
N
91
N
H
Ph
Ph
NH2
H
N
O
75
(continued on next page)

3674
M. J. Bhanushali et al. / Tetrahedron Letters 49 (2008) 3672–3676
Table 2 (continued)
Entry
Amine
Epoxide
Productb
Time (h)
3
Yieldc (%)
81 (77)
Ratiod (a:b)
NH2
F
OH
O
H
F
9
0:100
N
NH2
OH
H
O
O
N
10
11
3
3
72
83
0:100
17:83
H CO
3
OCH3
OH
N
N
H
OH
CH OPh
NH
H
N
2
O
O
12
13
3
3
90
92
0:100
1:99
2
PhOCH
2
OH
N
N
H
PhOCH
2
CH OPh
2
F
OH
NH
H
N
2
O
O
F
14
15
16
17
18
19
5
3
4
4
4
4
86
85
84
82
83
81
1:99
CH2OPh
PhOCH
2
NH2
OH
CH OPh
H
N
F C
3
2:98
2
PhOCH2
CF3
OH
NH
2
H
N
O
0:100
0:100
0:100
0:100
CH Cl
2
ClCH
ClCH
ClCH
ClCH
2
2
2
2
F
OH
CH Cl
NH
2
H
N
O
O
O
F
2
OH
CH Cl
N
N
H
2
NH
2
OH
CH Cl
H
N
F C
3
2
CF
3
NH
2
OH
20
7
90
—
O
NHC6H5

M. J. Bhanushali et al. / Tetrahedron Letters 49 (2008) 3672–3676
3675
Table 2 (continued)
Entry
Amine
Epoxide
Productb
OH
Time (h)
7
Yieldc (%)
92 (89)
Ratiod (a:b)
NH2
21
—
O
NHC10H7
NH
2
OH
22
7
7
91 (88)
—
—
O
O
NHC H -p-OCH
3
6
4
OCH
3
NH
2
OH
NHC H -m-CF
3
23
90
6
4
CF
3
a
Reaction conditions: amine = 3 mmol; epoxide = 2.5 mmol; Y(NO3)3Á6H2O = 0.025 mmol.
Only the major regioisomer is shown.
Yields determined by GC. Yields in parentheses are of isolated products.
Ratios determined by GC–MS analysis.
b
c
d
Table 3
afforded high regioselectivity towards the major isomer (2-
anilino-2-phenylethanol), it was used for further study.
Thus using Y(NO3)3Á6H2O (1 mol %) as the catalyst, the
ring opening of various aliphatic/aromatic epoxides with
structurally and electronically different amines was studied
Ring opening of epoxides with heteroaromatic aminesa
No.
Heterocycle
Productb
Yieldc (%)
Ratiod (a:b)
OH
N
N
1e
92
59:41
N
N
N
18
H
Ph
under ambient conditions (Table 2, entries 1–23). The
reaction of aniline with styrene oxide provided a combined
yield of 92% [2-(phenylamino)-2-phenylethanol + 2-(phen-
ylamino)-1-phenylethanol] with excellent regioselectivity
towards the major isomer, up to 84%.
OH
N
N
H
2
3
4
5
6
86
88
81
90
83
90
7:93
—
N
OH
N
N
H
The structure of the major isomer was confirmed by
GC–MS (base peak at M+À31) and 1H NMR (dd,
d = 3.65 ppm, benzylic proton) indicating attack at the
benzylic position.19 Anilines with electron-donating and
electron-withdrawing groups such as Me, OMe, CF3, F
(entries 2–5) were well tolerated under the present catalytic
system.The aminolysis of styrene oxide with bulky 2-naph-
thyl amine proceeded efficiently to give 88% yield (entry 6).
Indoline also reacted smoothly with styrene oxide within a
short reaction time (entry 7).
In order to explore the generality of the protocol, we
turned our attention towards the ring opening of aliphatic
epoxides such as propylene oxide, phenyl glycidyl ether,
epichlorohydrin, and cyclohexene oxide (entries 8–23).
Excellent yields of the desired amino alcohols were
obtained with a reversal of regioselectivity indicating
attack at the less substituted carbon of the epoxide. The
probable reason may be that in styrene oxide the positive
charge on oxygen appears to be localized on the more
highly substituted benzylic carbon leading to the major
product. Whereas in case of aliphatic epoxides steric fac-
tors predominate over electronic factors thereby facilitating
the attack at the less hindered carbon atom of the epoxide
ring.3
N
N
OH
OH
N
N
H
3:97
26:74
10:90
—
N
N
N
CH2Cl
N
N
N
N
N
H
Ph
N
OH
N
H
OH
N
N
7
N
H
N
a
Reaction conditions: heterocycle = 1.2 mmol; epoxide = 1 mmol;
Y(NO3)3Á6H2O = 0.025 mmol; time = 24 h.
b
Only the major regioisomer is shown.
Yields determined by GC.
Ratios determined by GC–MS analysis.
Y(NO3)3Á6H2O = 3 mol %; time = 8 h.
c
d
e
Chemoselective aminolysis of epichlorohydrin was
observed, with desired product resulting from attack at
the less substituted carbon on the epoxide ring (entries
16–19). The ring opening of cyclohexene oxide was also
successfully achieved giving 90–92% yields of the desired
amino alcohols (entries 20–23).
The reaction of propylene oxide with amines such as
aniline, 2-fluoroaniline, p-anisidine and indoline afforded
good yields with complete regioselectivity (entries 8–11).

3676
M. J. Bhanushali et al. / Tetrahedron Letters 49 (2008) 3672–3676
5. (a) Khosropour, A. R.; Khodaei, M. M.; Ghozati, K. Tetrahedron
Encouraged by the above results, we next investigated
Lett. 2004, 33, 3525–3529; (b) Ollevier, T.; Lavie-Compin, G.
Tetrahedron Lett. 2002, 43, 7891–7893.
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2004, 45, 8253–8256.
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Tetrahedron Lett. 2005, 46, 2675–2677.
8. Rampalli, S.; Chaudhari, S. S.; Akamanchi, K. G. Synthesis 2000, 78–
80.
9. Sagawa, S.; Abe, H.; Hase, Y.; Inaba, T. J. Org. Chem. 1999, 64,
4962–4965.
10. Chandrasekhar, S.; Ramachandar, T.; Prakash, S. J. Synthesis 2000,
1817–1818.
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8317.
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Catal. A: Chem. 2007, 261, 207–212.
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Commun. 2004, 34, 3673–3681.
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Tetrahedron Lett. 2007, 48, 6249–6251.
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H. A. Synthesis 2007, 902–910; (b) Mojtahedi, M. M.; Saidi, M. R.;
Bolourtchian, M. J. Chem. Res. 1999, 128–129.
16. Williams, D. B. G.; Lawton, M. Tetrahedron Lett. 2006, 47, 6557–
6560.
17. (a) Bhanushali, M. J.; Nandurkar, N. S.; Jagtap, S. R.; Bhanage, B.
M. Catal. Commun. 2008, 9, 1189–1195; (b) Nandurkar, N. S.;
Bhanushali, M. J.; Bhor, M. D.; Bhanage, B. M. J. Mol. Catal A:
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18. General procedure for aminolysis of epoxides: A mixture of amine (1.2
equiv), epoxide (1 equiv) and Y(NO3)3Á6H2O (1 mol %) was stirred at
room temperature. The progress of the reaction was monitored using
a gas chromatograph (Chemito 1000). After completion, the product
was isolated by silica gel chromatography usingchloroform/methanol
as eluent.
the ring opening of epoxides with heterocyclic amines such
as pyrazole and imidazole (Table 3, entries 1–7). There are
very few reports in the literature for the ring opening of
epoxides with heterocyclic amines.20 These methods require
high temperature and pressure. The products obtained are
of pharmaceutical importance and thus a milder protocol
was desired for the synthesis of such hetero-amino alco-
hols. Initially, we studied the ring opening of various
epoxides such as styrene oxide, propylene oxide,
epichlorohydrin and cyclohexene oxide with pyrazole and
excellent results were obtained. The reaction of pyrazole
with styrene oxide and propylene oxide afforded 92% and
86% yields, respectively (entries 1 and 2). The ring opening
of cyclohexeneoxide and epichlorohydrin with pyrazole
afforded the desired amino alcohol in good yields (entries
3 and 4). The aminolysis of these epoxides was next inves-
tigated with imidazole which gave excellent yields in the
range of 83–90% under ambient conditions (entries 5–7).
Thus, the catalyst Y(NO3)3Á6H2O enabled efficient cou-
pling of heteroaromatic amines with various epoxides pro-
viding excellent yields of desired products.
In summary, the first example of selective ring opening
of aliphatic/aromatic epoxides with aliphatic, aromatic
and heteroaromatic amines catalyzed by Y(NO3)3Á6H2O
under ambient conditions is described. The protocol offers
several advantages such as low catalyst loading (1 mol %),
high reaction rate, solvent-free conditions and wider sub-
strate compatibility making it an important addition to
previously reported methods.
19. Spectral data of selected products: Table 2, entry 4: 1H NMR
(300 MHz, CDCl3, 25 °C) d = 3.65 (dd, J = 7.1 Hz, J = 11.1 Hz, 1H),
3.84 (dd, J = 3.8 Hz, J = 11.1 Hz, 1H) 4.39 (dd, J = 4 Hz,
J = 6.9 Hz, 1H), 6.55 (d, J = 8 Hz, Ar 1H), 6.71 (s, Ar 1H), 6.80 (d,
J = 7.7 Hz, Ar 1H), 7.05 (t, J = 7.8 Hz, Ar 1H), 7.16–7.26 (m, Ar 5H).
13C NMR (75 MHz, CDCl3, 25 °C) d = 60.1, 67, 110.5, 114.1, 116.5,
122.5, 126.1, 126.7, 127.7, 128.8, 129.6, 139.5, 147.4. MS (EI, 70 eV):
281 (9) (M+), 250 (100), 172 (28). MS/MS analysis (Àve ESI mode):
calcd for (MÀ1) = 280.26, found (MÀ1) = 280.07. Table 2, entry 9:
d = 1.22 (d, J = 6.2 Hz, 3H), 2.98 (dd, J = 8.4 Hz, J = 12.9 Hz, 1H)
3.16 (dd, J = 3.3 Hz, J = 12.8 Hz, 1H) 3.95–4.05 (m, 1H), 6.60–6.99
(m, Ar 4H). 13C NMR (75 MHz, CDCl3, 25 °C) d = 20.7, 51.3, 66.2,
112.8, 114.7, 118.5, 124.6, 136.3, 150.2. MS/MS analysis (+ve ESI
mode): calcd for (M+1) = 170.19, found (M+1) = 170.07. MS (EI,
70 eV): 169 (25) (M +), 124 (100), 77 (20). Table 2, entry 23:d = 1.01–
1.04 (m, 1H), 1.2–1.4 (m, 3H), 1.6–1.76 (m, 2H), 2.05 (m, 2H), 3.11
(ddd, J = 4 Hz, J = 9.75 Hz, J = 10.1 Hz, 1H), 3.33 (ddd, J = 4 Hz,
J = 9.75 Hz, J = 10.1 Hz, 1H), 6.80 (d, J = 8.1 Hz, Ar 1H), 6.87 (s, Ar
1H), 6.92 (d, J = 7.7 Hz, Ar 1H), 7.22 (t, J = 7.7 Hz, Ar 1H). 13C
NMR (75 MHz, CDCl3, 25 °C) d = 24.1, 24.6, 31.4, 33.4, 59.7, 74.3,
110.1, 114.2, 116.8, 122.5, 126.1, 129.7, 148.1. MS/MS analysis (Àve
ESI mode): calcd for (MÀ1) = 258.26, found (MÀ1) = 258.13. MS
(EI, 70 eV): 259 (46) (M+), 216 (12), 200 (100), 174 (33).
20. (a) Duprez, V.; Heumann, A. Tetrahedron Lett. 2004, 45, 5697–5701;
(b) Glas, H.; Thiel, W. R. Tetrahedron Lett. 1998, 39, 5509–5510; (c)
Kotsuki, H.; Wakao, M.; Hayakawa, H.; Shimianouchi, T.; Shiro, M.
J. Org. Chem. 1996, 61, 8915–8920; (d) Kotsuki, H.; Hayashuda, K.;
Shimianouchi, T.; Nishizawa, H. J. Org. Chem. 1996, 61, 984–990.
Acknowledgment
The financial assistance from the University Grants
Commission, India for a major research project (Project
No. 32-273/2006 (SR)) is acknowledged.
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