An efficient method for regioselective ring opening of epoxides by amines under microwave irradiation using Bi(NO3)3·5H2O as a catalyst

Article abstract of DOI:10.1039/c6nj03701a

Bismuth(iii)nitrate pentahydrate, a highly efficient environmentally benign catalyst, is used for the nucleophilic ring opening of epichlorohydrin and styrene oxide with aromatic, aliphatic and heteroaromatic amines under solvent free microwave conditions

Full text of DOI:10.1039/c6nj03701a

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An efficient method for regioselective ring
opening of epoxides by amines under microwave
Cite this:DOI: 10.1039/c6nj03701a
irradiation using Bi(NO3)3Á5H2O as a catalyst†
Shobha Bansal, Yogendra Kumar, Parveen Pippal, Dipak K. Das,
Panchanan Pramanik and Prabal P. Singh*
Bismuth(III)nitrate pentahydrate, a highly efficient environmentally benign catalyst, is used for the nucleophilic
ring opening of epichlorohydrin and styrene oxide with aromatic, aliphatic and heteroaromatic amines under
solvent free microwave conditions reducing the reaction time drastically to afford the corresponding b-amino
alcohols in good to excellent yields with high regioselectivity. The products obtained were directly purified
by column chromatography and characterised by 1H & 13C NMR, FTIR and mass spectroscopy.
Received 2nd December 2016,
Accepted 28th February 2017
DOI: 10.1039/c6nj03701a
rsc.li/njc
It is evident from the literature survey that bismuth(III)nitrate
pentahydrate has been used for functional group transformation,22
Introduction
b-Amino alcohol has attracted a large number of researchers in Michael addition,23 synthesis of coumarins24 and nitration.25 The
the synthesis of a good amount of biologically active natural and low toxicity,26 lower cost and versatile nature of bismuth(III)nitrate
synthetic products1,2 including chiral auxiliaries.3a These play an pentahydrate as an efficient catalyst prompted us to investigate its
increasingly vital role in medicinal chemistry, pharmaceuticals activity for epoxide ring opening. Here the present report describes
and organic synthesis. b-Blockers are used in the treatment of a a highly regioselective and efficient protocol for the aminolysis of
wide variety of human disorders, like hypertension, sympathetic aliphatic and aromatic epoxides with a variety of amines under
nervous system disorders, heart failure, and cardiac arrhythmias3b solvent free microwave conditions.
and also as insecticidal agents.3c The ring opening of epoxides
with amines represents one of the most important and straight-
forward methods of preparing these compounds.4 Various Lewis
Results and discussion
acid, viz. Y(NO3)3Á6H2O,5 ZrCl4,6 Sc(OTf)3,7 SmI2,8 RuCl3,9 and
10
NbCl5 catalysed reactions have been examined for this class In our initial efforts to optimise the finest reaction conditions
of reactions. The classical synthesis of b-amino alcohol involves for aminolysis of styrene oxide, aniline and bismuth(III)nitrate
heating of epoxides with amines in excess at elevated tempera- pentahydrate as catalysts were mixed and placed in a micro-
tures11 but high temperature may not be the standard condition wave for the appropriate time intervals as a model reaction.
for molecules having sensitive functional groups. Therefore a Monitoring of the reaction was done by TLC and the completion
milder and improved procedure has been developed using of the reaction was confirmed by the complete disappearance of
alumina,12 metal amides,13 metal alkoxides,14 metal halides,15 the starting materials. To our delight the reaction was completed
and silica perchloric acid.16 Due to the toxicity of metals, a better in much less time with a single isomer. The reaction mixture was
catalyst is still desirable for the nucleophilic ring opening of treated with dichloromethane; the crude product thus obtained
epoxides by various amines to afford the corresponding b-amino was purified by column chromatography to get the regioselective
alcohols. A literature survey also reveals that epoxide ring opening 2-phenyl-2-phenylaminoethanol in an appreciably good amount
reaction can be conducted under microwave irradiation.17–20 (Scheme 1).
Bismuth(III)chloride21 has also been tried earlier for the ring
opening of epoxides but it required a longer reaction time.
To study the effect of catalyst loading and the wattage of the
microwave on the ring opening of epoxides with amines, we
next examined the model reaction in the presence and absence
of the catalyst under varied microwave conditions (Table 1).
The results in Table 1 depict that in the absence of a catalyst,
the reaction did not proceed at all (Table 1, entry 1), while the
desired product was isolated in 85% yield under optimized
Department of Chemistry, GLA University, 17 km Stone, NH-2 Delhi-Mathura Highway,
Chaumuhan, Mathura UP 281406, India. E-mail: prabal.singh@gla.ac.in;
Fax: +91-5662-241687; Tel: +91-5662-250729
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6nj03701a conditions (Table 1, entry 5). Reaction at a higher wattage of
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Table 3 A table of comparison with state of the art protocols
Amount Time (min) Yieldsa (%) Ref.
Entry Catalyst
1
2
3
4
5
6
Y(NO3)3Á6H2O
1 mol% 180–420
5 mol% 15
5 mol% 120–300
81–92
92–98
82–95
25–85
71–92
75–92
5
6
7
19
ZrCl3
Sc(OTf)3
Montmorillonite 0.2 gm
BiCl3
Bi(NO3)3Á5H2O
Scheme 1 Synthesis of b-amino alcohol under optimized conditions.
1
15 mol% 60–270
10 0.2–4
21
Our work
Table 1 Optimal conditions of catalyst loading and wattage used for
microwave irradiation
a
Reported yields.
Entry
Watt
Catalyst loadinga (mol%)
Yieldsb (%)
1
2
3
4
5
6
7
100
100
100
100
100
300
900
No catalyst
1
3
NR
60
60
70
85
83
82
5
10
10
10
Scheme 2 Aminolysis of epoxides with aromatic and aliphatic amines.
a
Reaction conditions: epoxide (1 mmol), amine (1 mmol), solvent free
b
microwave irradiation. Isolated yield.
Table 4 Microwave assisted ring opening of epoxides with various amines
in the presence of a catalyst
Producta Time (s) Yieldsb (%)
900 W did not show any remarkable change in the yield of the
product.
Entry R1
R2
R3
H
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
A
A
A
A
150
30
50
85
85
85
92
87
88
90
86
84
76
82
92
92
78
80
75
We also examined the model reaction in various solvents in
the presence of 10 mol% of catalyst (Table 2). The reaction did
not proceed even with longer irradiation times when toluene was
taken as a solvent (Table 2, entry 1) while other polar solvents gave
similar regioselectivity, but required a longer reaction time with
low yield of the product as compared to our optimized solvent free
microwave assisted reaction conditions (Table 2, entries 2–6). We
examined the above model reaction under neat conditions at
50 1C, 100 1C and 150 1C also. But under all these conditions the
products were isolated in poor yields (Table 2, entries 7–9).
On comparison of the developed method with the state of
the art protocols, the results obtained by our newly developed
methodology were very much exciting and inspiring in terms of
being solvent free and less time consuming, and yielding the
products in appreciably good amounts (Table 3).
N-Methyl piperazine
Piperadine
4-Methyl piperazine
Isopropyl
n-Propyl
a-Naphthyl
2-CH3C6H4
n-Butyl
27
Isopropyl A
n-Propyl
H
H
Me
H
H
H
110
160
55
150
56
150
180
240
50
120
60
A
A
A
A
B
B
B
B
9
10
11
12
13
14
15
16
17
18
–CH2Cl Ph
–CH2Cl 4-CH3C6H4
–CH2Cl 2-CH3C6H4
–CH2Cl a-Naphthyl
–CH2Cl n-Propyl
–CH2Cl Piperadine
–CH2Cl N-Methyl piperazine
–CH2Cl 2,4,6-BrC6H2
Ph 2,4,6-BrC6H2
H
n-Propyl
B
B
B
30
H
H
NR
NR
>2 h
>2 h
a
b
Purity of isolated regioisomers was determined by HPLC. Isolated
yield.
The versatility of this protocol was studied by using various
substituted amines and epoxides under optimized reaction
conditions (Scheme 2, Table 4). The desired product was obtained
in good to very good yields and also in a shorter reaction time.
Solvent free conditions are found to be the best as the effective
concentrations of the reagents are always maximum under solvent
free conditions. The results also indicate the effect of both steric
and electronic factors on the regioselectivity of the reaction.
The reaction of styrene oxide with both aromatic and aliphatic
amines afforded a high ratio of regioisomer A by nucleophilic
attack at the benzylic carbon (Table 4, entries 1–9), which could
be due to the localized positive charge on the more highly
substituted benzylic carbon, and yields the major product.27
While the regioselectivity was reversed when an aliphatic epoxide
like epichlorohydrin was treated with aromatic and aliphatic
amines to afford the regioisomer B (Table 4, entries 10–16). This
behaviour may be due to steric factors predominating over
electronic factors. Aniline having electron withdrawing groups
at the ortho and para positions did not yield any product even in
trace amounts (Table 4, entries 17 and 18).
Table 2 Screening of the solvent and thermal conditions for the ring
opening of styrene oxide with aniline using Bi(NO3)3Á5H2O (10 mol%)
Entry
Solvent
Time (s)
Yieldsd (%)
1
2
3
4
5
6
PhMe
H2O
THF
DCM
7200
2400
7200
3600
1500
150
NR
25
20
70
80
85
MeCN
Microwave 100 W solvent free
Thermal conditions
7
8
9
—
—
—
3600a
3600b
3600c
20
23
24
All the products were produced in very good yields despite
the lower reactivity of aromatic primary amines, while cyclic
a
Solvent free thermal conditions at 50 1C. b 100 1C. c 150 1C. d Isolated yield. secondary amines took much less time for the completion of
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the reaction yielding the product in excellent yield (Table 4,
entries 7–9 and 15–16). Aromatic amines bearing electron
withdrawing groups did not react to give the desired product
even after prolonged exposure to microwave irradiation
(Table 4, entries 17 and 18). Aminolysis of epoxides afforded
b-amino alcohol with high regioselectivity with a single isomer
only. The 1H NMR spectrum of all the products is pure enough
to confirm the presence of a single isomer which is also
supported by HPLC data.
Scheme 4 Plausible mechanism for the regioselective ring opening of
epoxide by amines as a nucleophile.
Inspired by the above result, we next examined the ring
opening of epoxides with heteroaromatic amines like imidazole. The
literature survey of such reports suggests the requirement of high
temperature28 and high pressure29 to obtain this pharmaceutically
important entity and thus milder conditions for the synthesis of
such hetero-amino alcohols are required. Therefore we studied
the ring opening of styrene oxide and epichlorohydrin with
imidazole to afford heteroamino alcohols in excellent yield in
much less time (Scheme 3).
The actual mechanism of these reactions is not clear at this
stage. The possible mechanism for the ring opening of epoxides
with bismuth(III)nitrate pentahydrate as the catalyst under
microwave irradiation conditions occurred through a weak
interaction between the catalyst and epoxide. In order to
understand the role of the nitrate ion in the reaction we here
performed the following sets of reactions under our optimized
reaction conditions, and the results are summarised in Table 5.
These observations indicate that both nitrate and Bi3+ play
an active role in the transition state to initiate the reaction
(Table 5, entry 4). In our preliminary mechanistic investigation the
secondary effect of the nitrate anion may be attributed to the
unusual catalytic behaviour of the bismuth metal ion (Scheme 4).
The regioselectivity of products A and B depends upon both
steric and electronic factors.
To our curiosity we also studied the role of water of crystal-
lisation of bismuth nitrate pentahydrate in the formation of
b-amino alcohol, by replacing the water molecule with a DMF
molecule.30 It is very interesting to report that the reaction did
not proceed at all indicating that water of crystallization is also
playing a notable role in proton exchange at the transition state
to form b-amino alcohol by the ring opening of epoxides with
both aliphatic, aromatic and heteroaromatic amines.
Experimental
Materials and methods
All the solvents and reagents were used as supplied by commercial
sources. The recorded melting points are uncorrected. IR spectra
were recorded in KBr on a Schimadzu FTIR 8401 spectrometer and
Perkin Elmer version 10.03.06 for the liquid samples. H and 13C
1
spectra were recorded on a Bruker DRX 300 spectrometer operating
at 300 MHz for 1H NMR and 75 MHz for 13C NMR as solutions in
CDCl3 and DMSO-d6. The ESI mass spectra were measured on a
Waters UPLC-TQD spectrometer. TLC was performed on a silica
coated glass plate, spots were developed in an I2 Chamber or
visualized in a UV chamber. A CEM Discover microwave was used
for irradiation purposes. A HPLC system (Cyberlab, 20, Salo
Terrace, Milbury, MA 01527, USA) was used with a HISEIDO C18
column, MG 5 mm, size – 4.6 mm ID Â 250 mm, and an injection
system, 7725i (Rheodyne) made in USA, with an injection volume of
20 mL, and a flow rate of 0.5 mL. Pure HPLC grade methanol was
used as an eluent.
General procedure for the synthesis of b-amino alcohols
An epoxide (1 mmol), amine (1 mmol) and catalyst (10 mmol%) were
mixed thoroughly at room temperature and afterwards the mixture
was intermittently irradiated in a microwave for the appropriate time
period. The reaction was monitored by TLC; after the completion of
the reaction, the obtained crude product was purified by column
chromatography to afford the corresponding b-amino alcohols. All
Scheme 3 Synthesis of heteroamino alcohols.
Table 5 Table analysing the role of nitrate ions in catalysing the reaction
1
synthesized compounds were fully characterized by FTIR, H & 13C
Entry
Catalysta
Result
NMR and mass spectroscopy (ESI†).
1
2
3
4
Bi(OH)3
No reaction
No reaction
No reaction
Effective reaction
Al(NO3)3Á9H2O
Fe(NO3)3Á6H2O
Bi(OH)3 and KNO3
Conclusions
a
Bi(NO3)3Á5H2O, an environmentally benign and cheaper catalyst,
Reaction conditions: epoxide (1 mmol), amine (1 mmol), catalyst (10 mol%),
solvent free microwave irradiation.
effectively prompts the ring opening of epoxides under solvent
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