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S. P. Pathare, K. G. Akamanchi / Tetrahedron Letters 54 (2013) 6455–6459
Table 2
OH
OH
H
N
Comparison of different catalysts for the formation of 2-(phenylamino)cyclohexanola
H
N
O
O
O
Entry Catalyst
Wtb
(%)
Solvent Temperature /
Time in min
Yieldc
(%)
O
H2N
O
1
2
Amberlite
40
60
DCM
DCM
25 °C /150
25 °C /360
89
85
Bisoprolol
Atenolol
Mesoporous
aluminosilicate
Sulfamic acid
Montmorillonite
K10
3
4
16
12
Neat
Neat
70 °C /120
25 °C /60
95
95
O
O
N
H
O
N
H
OH
OH
H3CO
5
6
Sulfated zirconia
Sulfated tungstate
17
10
Neat
Neat
25 °C /60
25 °C /15
94
96
N
H
a
b
c
Data were taken from the literature (Refs. 17–21).
For ready comparison converted into wt %.
Isolated yield.
Carvedilol
Propranolol
S
H
N
N
N
O
HO
HN
compiled in Table 2. Among the various catalysts viz amberlite,
mesoporous aluminosilicate, sulfamic acid, montmorillonite K10
and sulfated zirconia, only sulfated tungstate was found to be the
most efficient in terms of amount required, time and yield (Table 2,
entries 1–6).
N
OH
O
O
N
O
N
O
Ranolazine
Timolol
With the optimized conditions in hand, a number of structurally
diverse epoxides and amines were screened to demonstrate gen-
eral applicability and efficacy of this protocol46 and results are
summarized in Table 3. To determine the regioselectivity, styrene
oxide was used as a representative unsymmetrical epoxide and
was treated with various aromatic and aliphatic amines in the
presence of sulfated tungstate. During the reaction with aromatic
amines, an exothermic reaction occurred, and the reaction was
completed within 15 min (Table 3, entries 1–4) affording 86–92%
yields of the b-amino alcohols. However in case of aliphatic
amines, the reaction was slow and required heating to give b-ami-
no alcohols in 87–90% yields at 70 °C for 30 min (Table 3, entries 5–
8). This is attributed to interaction of strongly basic aliphatic
amines with the catalyst resulting in reduced nucleophilicity. As
far as regioselectivity of epoxide opening is concerned a comple-
mentarity was observed with aromatic and aliphatic amines. Reac-
tion with aromatic amines afforded b-amino alcohols from
nucleophilic attack at the benzylic position of the epoxide ring as
the major products (Table 3, entries 1–4), whereas in case of ali-
phatic amines, the major/exclusive product was the regioisomeric
amino alcohol produced by nucleophilic attack at the less hindered
carbon atom of the epoxide ring (Table 3, entries 5–8). The ring
opening of cyclohexene oxide was attempted with various aro-
matic and aliphatic amines. Excellent results were obtained in each
case affording in high yields of the corresponding trans-2-aryl/
alkylaminocyclo hexanols. The reactions were, in general, faster
(15–45 min, rt) with aromatic amines compared to that for cyclic
aliphatic amines (60 min, 70 °C) (Table 3, entries 9–13). Epichloro-
hydrin (Table 3, entries 14–17) and glycidyl ethers (Table 3, entries
18–20) reacted smoothly with amines to afford the corresponding
b-amino alcohols in excellent yields with high regioselectivity. In
both cases the main product was regioisomer arising out of attack
at the less hindered carbon atom of the epoxide ring. The reaction
with epichlorohydrin provided an example of excellent chemose-
lectivity and no product derived from nucleophilic substitution of
the chlorine was formed.
Figure 1. Examples of active pharmaceutical ingredients containing a b-amino
alcohol unit.
H2N
OH
Sulfated tungstate
O
+
N
H
Scheme 1. Epoxide opening of cyclohexene oxide with aniline.
Table 1
Results of optimization studiesa
Entry
Solvent
Sulfated tungstate (wt%)
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
9
Neat
Neat
Neat
Neat
—
1
5
10
20
20
20
20
20
720
60
60
15
15
60
60
60
60
15
19
69
96
96
90
62
79
58
Neat
Ethyl acetate
Chloroform
Ethanol
Toluene
a
Reaction conditions: cyclohexene oxide (1 g, 10.18 mmol) and aniline (0.95 g,
10.18 mmol) at 25 °C.
b
Isolated yield.
Thus, when a mixture of cyclohexene oxide (1 equiv), aniline (1
equiv) and sulfated tungstate (10 wt%) was stirred at rt, a fast reac-
tion ensued and got completed in just 15 min to give 96% yield of
2-(phenylamino)cyclohexanol (Table 1, entry 4). A control experi-
ment was performed in the absence of catalyst and the reaction
did not occur (Table 1, entry 1) thus proving the catalytic role of
sulfated tungstate. Next, experiments were conducted to optimize
quantity of sulfated tungstate and found that use of just 10 wt% of
catalyst is sufficient to produce an excellent yield of the product in
short reaction time (Table 1, entries 2–5). Regarding the use of sol-
vent, ethyl acetate was found to be most suitable (Table 1, entry 6)
and whereas other solvents such as chloroform, ethanol and tolu-
ene were found to be relatively inferior in terms of yield and time
taken for the completion of reaction (Table 1, entries 7–9).
Reusability study of the catalyst was performed, by following
standard protocol previously reported by us,39 and found that the
catalyst was stable and reusable four times without any significant
loss of activity with marginal drop in yield from 96% to 92% with
respect to fresh and fourth recycle respectively (Table 4).
Applicability of the methodology is demonstrated for the syn-
thesis of various b-adrenergic blocking agents such as atenolol,
propranolol and ranolazine (Fig. 1). b-Adrenergic blocking agents
are effective life-saving medicines in the management of cardio-
vascular disorders, including hypertension, angina pectoris, cardiac
To assess the standing of sulfated tungstate among other cata-
lysts for the formation of 2-(phenylamino)cyclohexanol, compara-
tive experimental data were taken from the literature and is