The selective C-3 opening of aromatic 2,3-epoxy alcohols/epoxides with aromatic amines catalysed by β-cyclodextrin in water

Article abstract of DOI:10.1055/s-2005-862359

A simple and mild procedure has been developed for the first time for the C-3 selective ring-opening of aromatic 2,3-epoxy alcohols/epoxides with aromatic amines catalysed by β-cyclodextrin in water at room temperature to afford the corresponding β-aminoa

Full text of DOI:10.1055/s-2005-862359

506
LETTER
The Selective C-3 Opening of Aromatic 2,3-Epoxy Alcohols/Epoxides with
Aromatic Amines Catalysed by b-Cyclodextrin in Water1
S
elective C-3 Ope
.
ning of Arom
S
a
tic 2,3-Epox
u
y
A
lcohols/E
r
poxidesendra, N. Srilakshmi Krishnaveni, K. Rama Rao*
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad-500 007, India
E-mail: drkrrao@yahoo.com
Received 26 August 2004
Herein, we present the first highly regioselective aminol-
Abstract: A simple and mild procedure has been developed for the
first time for the C-3 selective ring-opening of aromatic 2,3-epoxy
alcohols/epoxides with aromatic amines catalysed by b-cyclodex-
trin in water at room temperature to afford the corresponding b-ami-
noalcohols in excellent yields with high regioselectivity.
ysis of trans-disubstituted aromatic epoxides/terminal ep-
oxides with aromatic amines catalysed by b-cyclodextrin
in water. This method provides facile and practical access
to various b-amino alcohols (Scheme 1 and Scheme 2).
Key words: b-aminoalcohols, trans-2,3-epoxy alcohols, epoxides,
aromatic amines, b-cyclodextrin, water
NHR1
O
R
1
R
3
2
β-CD/H2O
R1-NH2
+
OH
C-3
r.t.
b-Aminoalcohols are versatile intermediates in the syn-
thesis of biologically active natural products, unnatural
aminoacids, b-blockers as well as insecticidal agents and
chiral auxiliaries.2 In continuation of the efforts to expand
the synthetic utility of 2,3-epoxy alcohols their reactivities
have been studied extensively with various nucleophiles.3
The utility of these reactions is dependent on the regiose-
lectivity at C-2 and C-3.4,5 Ring-opening of epoxy alco-
hols with a wide variety of nucleophiles show different
ratios of C-2 and C-3 isomers.6 Regiocontrol is generally
difficult to achieve in the ring-opening of substituted
oxiranes and only a few direct and practical approaches to
the ring-opening of substituted epoxides using amines as
nucleophiles have been reported.7
R = OH, OTBDMS, OTHP, COOMe, Br
1 = aryl
R
Scheme 1
OH
β−CD/H2O
O
R1-NH2
NHR1
+
R2
R2
r.t.
R1 = aryl; R2 = Aryloxy, Phenyl
Scheme 2
In general, the reaction was carried out by the in situ for-
mation of the b-CD complex of the epoxide in water fol-
lowed by the addition of amine and stirring for 12 hours at
room temperature to give the corresponding amino alco-
hol in impressive yields (80–92%). The reaction proceeds
smoothly at room temperature without the formation of
any by-products or rearrangements. In the presence of b-
CD, ring-opening of trans-2,3-epoxy alcohols with aro-
matic amines (Table 1) yielded the C-3 opened product as
One of the most straightforward synthetic procedures for
the preparation of b-amino alcohols involves the ring-
opening of epoxides with amines.8 However, these reac-
tions are generally carried out with large excess of the
amines at elevated temperatures utilising expensive and
stoichiometric amounts of reagents with extended reac-
tion times and also entailing undesirable side reactions
and low yields.9 In view of these limitations there is still
need for a widely applicable approach for the C-3 selec-
tive ring-opening of various substituted epoxides prefera-
bly using water as a solvent with a recyclable catalyst and
minimising the use of harmful organic solvents as green
chemistry becomes a central issue in both academic and
industrial research in the 21st century.10
1
the major isomer as detected by H NMR spectroscopic
analysis. This methodology is also compatible with func-
tionalities such as OTBDMS, OTHP, CO2Me, and Br. We
have also examined the opening of terminal aromatic ep-
oxides with aromatic amines (Table 2). These reactions
are highly selective forming b-amino alcohols as the only
products in excellent yields keeping intact functionalities
such as methoxy and acetoxy. Selectivity was also
observed with styrene epoxide where the amine attacks
the terminal carbon. These cyclodextrin-mediated water-
based reactions proceed under mild conditions without the
need for organic solvents. The b-cyclodextrin can be
easily recovered and reused. The compounds were charac-
terised by spectroscopy, elemental analysis or otherwise
compared with the known compounds.7,8
Our earlier expertise in the field of biomimetic modelling
of organic chemical reactions involving cyclodextrins11
prompted us to attempt the regioselective ring-opening of
various substituted oxiranes with amines in the presence
of b-cyclodextrin (b-CD) as this is one of the most useful
synthetic transformations with a variety of applications.
SYNLETT 2005, No. 3, pp 0506–0510
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6.
0
2.
2
0
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Advanced online publication: 04.02.2005
DOI: 10.1055/s-2005-862359; Art ID: D25304ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Selective C-3 Opening of Aromatic 2,3-Epoxy Alcohols/Epoxides
507
Table 1 Synthesis of anti-b-Amino Alcohols from Epoxides in the Presence of b-CD
Entry
1
Substrate
Amine (R)
Producta
Yield (%)b
92
Mp (°C)c
99–101
R
NH2
O
OH
OH
OH
2
3
90
88
92
86
90
86
84
88
90
88
82
80
82
60–62
103–105
105–107
68–70
Oil
R
R
R
R
R
R
R
R
NH2
O
O
O
O
O
O
O
O
OH
OH
F
OH
OH
OH
OH
OH
OH
OH
OH
NH2
OH
OH
Me
4
NH2
OH
OH
Me
5
NH2
OH
OH
OMe
6
NH2
OH
OH
MeO
Br
7
103–105
Oil
NH2
Me
OH
OH
8
NH2
OH
OH
9
Oil
NH2
OTBDMS
OTBDMS
MeO
10
11
12
13
14
Oil
O
O
O
O
O
NH2
R
R
R
R
R
OTHP
OTHP
OTHP
COOMe
Br
OTHP
OTHP
OTHP
COOMe
Br
OH
OH
OH
OH
OH
Oil
NH2
F
Oil
NH2
104–106
110–112
NH2
NH2
MeO
MeO
a Only one regioisomer could be detected by 1H NMR spectroscopy analysis.
b Isolated yields.
c Not corrected.
Synlett 2005, No. 3, 506–510 © Thieme Stuttgart · New York

508
K. Surendra et al.
LETTER
Table 2 Synthesis of b-Amino Alcohols from Epoxides in the Presence of b-CD
Entry
1
Substrate
Amine (R)
Product
Yield (%)a
92
Mp (°C)b
OH
59–61
52–54
62–64
65–67
O
O
O
NH2
O
O
R
R
2
3
4
90
86
90
OH
OH
NH2
O
O
O
O
F
NH2
R
O
OH
NH2
CH3
O
O
R
Me
Me
5
88
60–62
NH2
OH
O
O
O
R
OCH3
MeO
O
MeO
O
6
7
89
85
56–58
85–87
OH
O
NH2
O
O
R
H3CO
H3C
O
NH2
OH
O
O
R
O
O
8
82
131–133
OH
NH2
O
O
O
R
O2N
O2N
9
86
82
57–59
55–57
O
NH2
OH
O
O
R
R
F
10
O
OH
NH2
a Isolated yields.
b Not corrected
These reactions do take place with a-CD as well with the complex and freeze-dried reaction mixtures of the b-CD
same regioselectivity and stereochemistry; however, b- complex of trans-epoxy cinnamyl alcohol with amines at
CD was chosen as the catalyst since it is inexpensive and 6 hours and 12 hours was undertaken. There is a clear up-
easily accessible. These reactions do not proceed in the field shift of H3 (0.028 ppm) and H5 (0.036 ppm) protons
absence of cyclodextrin. The C-3 selectivity in the reac- of b-cyclodextrin in b-CD–trans-epoxy cinnamyl alcohol
tion of trans-2,3-epoxy alcohols with aromatic amines in complex as compared to b-CD indicating the formation of
the presence of b-CD in water has been postulated and inclusion complex of epoxide with b-CD.12 However, it is
confirmed as follows: the role of CD appears to be not observed from the spectra of the reaction mixtures of b-
only to activate the epoxides but also form a CD–epoxide CD–epoxide complex and amines at 6 hours and 12 hours
complex through hydrogen bonding. These studies were that these complexes apart from retaining the upfield char-
undertaken with trans-epoxy cinnamyl alcohol as a repre- acter of H3 and H5 protons with subtle changes, there is
sentative example. A comparison of the 1H NMR spectra also an upfield shift of the H6 proton of 0.030 ppm at 6
(D2O) of b-CD, b-CD–trans-epoxy cinnamyl alcohol hours and 12 hours, indicating the complexation of the
Synlett 2005, No. 3, 506–510 © Thieme Stuttgart · New York

LETTER
Selective C-3 Opening of Aromatic 2,3-Epoxy Alcohols/Epoxides
509
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O
H
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Figure 1
Thus, it has been shown for the first time that amino alco-
hols can be obtained with high regioselectivity from easily
accessible oxiranes and inexpensive amines in the pres-
ence of b-cyclodextrin in water. This methodology de-
scribes a simple, convenient and highly efficient method
for the synthesis of amino alcohols. The notable features
of this method are cleaner reaction profiles, high yields
and operational simplicity. Above all, these reactions are
carried out in water. This methodology will be a useful
addition to the modern synthetic methodology with the
ever-growing demand for eco-conscious chemical pro-
cesses and increasing interest in green chemistry.
General Procedure
b-Cyclodextrin (1 mmol) was dissolved in H2O (15 mL) at 60 °C,
epoxide (1 mmol) dissolved in acetone (1 mL) was added slowly
with stirring and cooled to r.t. Amine (1.0 mmol) was then added
and stirring was continued at r.t. After completion of the reaction
the organic material was extracted with EtOAc, the organic phase
was separated, filtered and washed with brine. The organic phase
was then dried (Na2SO4), filtered and the solvent was removed
under vacuum. The crude product was purified by silica gel column
chromatography using EtOAc–n-hexane (2:8) as eluent.
Acknowledgment
K S. thanks CSIR, New Delhi, India, for the award of a research
fellowship.
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