Zinc(II) perchlorate hexahydrate catalyzed opening of epoxide ring by amines: Applications to synthesis of (RS)/(R)-propranolols and (RS)/(R)/(S)-naftopidils

Article abstract of DOI:10.1021/jo062674j

(Figure Presented) Commercially available zinc(II) Perchlorate hexahydrate [Zn(ClO₄)₂·6H₂O] was found to be a new and highly efficient catalyst for opening of epoxide rings by amines affording 2-amino alcohols in high yields under solvent-free conditions and with excellent chemo-, regio-, and stereoselectivities. For unsymmetrical epoxides, the regioselectivity was influenced by the electronic and steric factors associated with the epoxides and the amines. A complementarity in the regioselectivity was observed during the reaction of styrene oxide with aromatic and aliphatic amines: aromatic amines provided amino alcohols from nucleophilic attack at the benzylic carbon as major products whereas aliphatic amines resulted in formation of the amino alcohols through reaction at the terminal carbon atom of the epoxide ring as the major/sole products. Reaction of aniline with various glycidic ethers gave the amino alcohols by regioselective nucleophilic attack at the terminal carbon atom of the epoxide ring as the only/major product. Zinc(II) Perchlorate hexahydrate was found to be the best catalyst compared to other metal Perchlorates. The counteranion modulated the catalytic property of the various Zn(II) compounds that followed the order Zn(ClO₄) ₂·6H₂O Zn(BF₄)₂ ～ Zn(OTf)₂ ZnI₂ > ZnBr₂ > ZnCl₂ > Zn(OAc)₂ > Zn(CO₃)₂ in parallelism with the acidic strength of the corresponding protic acids (except for TfOH). The applicability of the methodology was demonstrated by the synthesis of cardiovascular drugs propranolol and naftopidil as racemates and optically active enantiomers.

Full text of DOI:10.1021/jo062674j

Zinc(II) Perchlorate Hexahydrate Catalyzed Opening of Epoxide
Ring by Amines: Applications to Synthesis of (RS)/(R)-Propranolols
and (RS)/(R)/(S)-Naftopidils
Shivani, Brahmam Pujala, and Asit K. Chakraborti*
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research
(NIPER), Sector 67, S. A. S. Nagar 160 062, Punjab, India
akchakraborti@niper.ac.in
ReceiVed December 29, 2006
Commercially available zinc(II) perchlorate hexahydrate [Zn(ClO4)2‚6H2O] was found to be a new and
highly efficient catalyst for opening of epoxide rings by amines affording 2-amino alcohols in high yields
under solvent-free conditions and with excellent chemo-, regio-, and stereoselectivities. For unsymmetrical
epoxides, the regioselectivity was influenced by the electronic and steric factors associated with the
epoxides and the amines. A complementarity in the regioselectivity was observed during the reaction of
styrene oxide with aromatic and aliphatic amines: aromatic amines provided amino alcohols from
nucleophilic attack at the benzylic carbon as major products whereas aliphatic amines resulted in formation
of the amino alcohols through reaction at the terminal carbon atom of the epoxide ring as the major/sole
products. Reaction of aniline with various glycidic ethers gave the amino alcohols by regioselective
nucleophilic attack at the terminal carbon atom of the epoxide ring as the only/major product. Zinc(II)
perchlorate hexahydrate was found to be the best catalyst compared to other metal perchlorates. The
counteranion modulated the catalytic property of the various Zn(II) compounds that followed the order
Zn(ClO4)2‚6H2O . Zn(BF4)2 ∼ Zn(OTf)2 . ZnI2 > ZnBr2 > ZnCl2 > Zn(OAc)2 > Zn(CO3)2 in
parallelism with the acidic strength of the corresponding protic acids (except for TfOH). The applicability
of the methodology was demonstrated by the synthesis of cardiovascular drugs propranolol and naftopidil
as racemates and optically active enantiomers.
Introduction
toris, cardiac arrhythmias, and also other disorders3 related to
the sympathetic nervous system. The versatility of this trans-
formation is recognized well as it constitutes the key step for
synthesis of â2-adrenoceptor agonists,4 novel anti-HIV agents,5
Nucleophilic opening of epoxide rings by amines is an
important reaction for synthetic organic/medicinal chemists as
the resultant 2-aminoalcohols represent a broad range of
â-adrenergic blockers widely used in the management of
cardiovascular disorders,1 including hypertension,2 anginapec-
(3) (a) Owen, D. A. L.; Marsden, C. D. Lancet 1965, 1259. (b) Granville-
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* To whom correspondence should be addressed. Fax: 91-(0)-172 2214692.
Tel: 91-(0)-172 2214683.
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10.1021/jo062674j CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/06/2007
J. Org. Chem. 2007, 72, 3713-3722
3713

Shivani et al
4-demethoxydaunomycin,6 protein kinase C inhibitor balanol,7
glycosidase inhibitor,8 antimalarial agents,9 liposidomycin B
class of antibiotics,10 naturally occurring brassinosteroids,11
taxoid side chain,12 diverse heterocycles, for example, benzo-
diazepinones/benzoxazines/benzoxazepinones13 and indoles,14
a vast range of biologically active natural and synthetic
products,15 unnatural amino acids,16 and chiral auxiliaries.17 The
classical approach for the synthesis of 2-amino alcohols from
epoxides involves the treatment of an epoxide with an amine
under heating.18 However, this procedure has limitations such
as the requirement of excess of amines and elevated temperature,
often works less well with poorly nucleophilic and sterically
hindered amines, lacks appreciable regioselectivity, and poses
problems in dealing with sensitive epoxides because of potential
side reactions such as rearrangement or polymerization. Thus,
there have been incessant efforts to develop methodologies for
opening of epoxide rings by amines as evidenced by recent
reports.19 Still, some of these methods could not overcome the
shortcomings such as the use of solvents, requirement of long
reaction times (2.5 - 24 h), high pressure, and moisture/air
sensitive and costly catalysts. In continuation of our interest
for the development of newer methodologies for epoxide ring
opening by amines,20 we thought that a metal salt of a strong
protic acid should possess a strong Lewis acid property and
activate the epoxide ring more effectively and enable the epoxide
ring-opening reaction under milder conditions and in short times.
Thus, metal triflates should be ideal catalysts as TfOH is the
strongest protic acid (H0 ) -14.1)21 known. However, TfOH
is liberated during the triflate-catalyzed reactions22 and becomes
detrimental because of the potential side reactions such as
dehydration of the resultant amino alcohols and acid-catalyzed
rearrangement of the epoxides. This necessitates the requirement
of solvent, excess of reagent, low temperature (-8 to -60 °C),
and additives (e.g., molecular sieves, MgSO4, TBAB, SDS, etc.)
during the acetylation,23 R-amino phosphonate formation,24 and
epoxide ring-opening19j,p,r,25 reactions carried out in the presence
of metal triflates. Hence, attention is given to metal triflimides
as HNTf2 is a weaker Brønsted acid than TfOH26 and ligand
exchange has not been observed with triflimides.27 However,
triflimides are costly, some are not available commercially and
involve a high cost for preparation, and they are not good
contenders for industrial applications. Since perchloric acid is
the next strongest protic acid, we focused our attention to metal
perchlorates as they are efficient electrophilic activation catalysts
for acylation,28 imine formation,29 thia-Michael addition,30 acylal
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3714 J. Org. Chem., Vol. 72, No. 10, 2007

Zinc(II) Perchlorate Hexahydrate Catalyzed Opening
TABLE 1. Epoxide Ring-Opening Reaction of 1 with 2 in the
Presence of Various Metal Perchloratesa
TABLE 2. Epoxide Ring-Opening Reaction of 1 with 2 in the
Presence of Various Zinc Saltsa
entry
catalyst
time (min)
yield (%)b,c
entry
Zn(II) salt
time (min)
yield (%)b,c
1
2
3
4
5
6
7
8
9
Zn(ClO4)2‚6H2O
Mg(ClO4)2‚xH2O
BiO(ClO4)2‚xH2O
LiClO4‚xH2O
Fe(ClO4)2‚6H2O
Fe(ClO4)3‚6H2O
Co(ClO4)2
15
60
60
60
60
60
60
60
60
100d
48
55
2
81
82
88
73
100
1
2
3
4
6
7
8
9
Zn(ClO4)2‚6H2O
ZnCl2
ZnBr2
15
60
60
60
60
60
60
60
100d
25e,f
52e,f
65f,g
20f
ZnI2
Zn(OAc)2
Zn(OTf)2
Zn(BF4)2
Zn(CO3)2
92
94
ZrO(ClO4)2‚xH2O
Cu(ClO4)2‚xH2O
11f
a 1 (2.5 mmol) was treated with 2 (2.5 mmol, 1 equiv) in the presence
of the zinc salts (2 mol %) at rt under solvent-free conditions. b 3 was the
only product (NMR). c GCMS conversion. d Isolated yield was 99%. e Trace
amount of halohydrine formation was observed. f The unreacted epoxide
remained intact (GCMS). g The iodohydrine was formed in 6% yield.
a 1 (2.5 mmol) was treated with 2 (2.5 mmol, 1 equiv) in the presence
of the metal perchlorate (2 mol %) at rt under solvent-free conditions. b 3
was the only product (NMR). c GCMS conversion. d Isolated yield was 99%.
As the Lewis acid property of a metal salt depends on the
corresponding protic acid, we planned to evaluate the influence
of the counteranion on the catalytic efficiency of various zinc
compounds for the reaction of 1 with 2 (Table 2). The best
result was obtained with Zn(ClO4)2‚6H2O (entry 1, Table 2).
The use of Zn(OTf)2 and Zn(BF4)2‚xH2O (entries 7 and 8) also
gave excellent results but required longer times (compare entry
1 with entries 7 and 8, Table 2). Moderate yield (52% after 60
min, GCMS) of 3 was obtained in the presence of ZnBr2 (entry
3, Table 2) but ZnCl2,19k Zn(OAc)2,35 and ZnCO3 (entries 2
and 6, Table 2) gave poor conversion to 3. The overall catalytic
activity of the various zinc compounds were found to be in the
order Zn(ClO4)2‚6H2O . Zn(BF4)2‚xH2O ∼ Zn(OTf)2 > ZnI2
> ZnBr2 > ZnCl2 > Zn(OAc)2 > ZnCO3 that exhibited
parallelism with the acidity of the corresponding protic acids
(except for TfOH).36
The applicability of Zn(ClO4)2‚6H2O was evaluated for
aminolysis of 1 with various aromatic and aliphatic amines
(Table 3). Excellent results were obtained in each case affording
90-100% yields of the corresponding trans-2-aryl/alkylami-
nocyclohexanols (NMR). The reactions were, in general, faster
(10-60 min, rt) with aromatic amines compared to that for
aliphatic amines (60 min, 80 °C). Electron-rich aromatic amines
(entries 2-5, Table 3) required longer times (30-60 min)
compared to that required for 2 (15 min), but in case of
4-chloroaniline the reaction was faster (10 min).
To establish the benefit of this new method over the standard
epoxide opening by amines, the reactions of 1 with morpholine
and piperidine were separately carried out under solvent-free
conditions at 80 °C for 60 min in the absence of any catalyst.
The corresponding amino alcohols were formed in 20% yields.
The corresponding amino alcohols were prepared in 100 and
97% yields, respectively, under this new method (entries 7 and
9, Table 3). The standard reported uncatalyzed procedure
required heating the mixture of the epoxide and the amine under
reflux for 24 h to afford 85-86% yields of the amino
alcohols.18k
formation,31 and R-aminophosphonate formation32 reactions. We
observed that the potentiality of metal perchlorates for the use
as catalyst for opening of the epoxide rings by amines is
underexplored and only LiClO4 has been used for this purpose.
However, the LiClO4-catalyzed aminolysis of epoxides required
2 equiv of the amines, 1-10 equiv of LiClO4, the use of solvent,
and long times (1-38 h).33 Thus, we planned to evaluate the
catalytic efficiency of various metal perchlorates for opening
of epoxide rings by amines and report that commercially
available zinc(II) perchlorate hexahydrate [Zn(ClO4)2‚6H2O] is
a new and highly efficient catalyst operative under solvent-free
conditions, at room temperature (rt), and in short times.
Results and Discussion
To find the most effective catalyst, cyclohexene oxide 1 was
treated with aniline 2 in the presence of catalytic quantities of
various metal perchlorates, and the results are summarized in
Table 1. The reactions were monitored by tandem gas chroma-
tography mass spectrometry (GCMS). In each case, the trans-
2-phenylaminocyclohexanol 3 was formed as the sole pro-
duct.20
The reaction was best catalyzed by Zn(ClO4)2‚6H2O with
100% conversion (GCMS) to 3 after 15 min at rt. The use of
Fe(ClO4)2‚xH2O, Fe(ClO4)3‚xH2O, Co(ClO4)2‚xH2O, ZrO(ClO4)2‚
xH2O, and Cu(ClO4)2‚xH2O provided 81, 82, 88, 73, and 100%
conversion, respectively, after 60 min (entries 5-9, Table 1).
Moderate yields (GCMS) of 3 were obtained in the presence of
Mg(ClO4)2‚xH2O and BiO(ClO4)2‚xH2O (entries 2 and 3, Table
1), but no significant amount of formation of 3 was observed
after 60 min in the presence of LiClO4‚xH2O (entry 4, Table
1).34
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J. Org. Chem, Vol. 72, No. 10, 2007 3715

Shivani et al
TABLE 3. Zn(ClO4)2‚6H2O-Catalyzed Epoxide Ring-Opening
During the reaction with aromatic amines, an exothermic
reaction occurred which was completed after 15-30 min (entries
1-5, Table 4) affording 90-99% yields of the amino alcohols.
In case of aliphatic amines, the conversion to the amino alcohols
took place in 97-100% yields after heating the reaction mixtures
at 80 °C for 60 min (entries 6-9, Table 4). A complementarity
in the regioselectivity was observed during the reaction with
aromatic and aliphatic amines. Reaction with aromatic amines
afforded the amino alcohols from nucleophilic attack at the
benzylic carbon atom of the epoxide ring as the major products
(entries 1-5, Table 4). In case of aliphatic amines, the major/
exclusive product was the regioisomeric amino alcohol produced
by nucleophilic attack at the less hindered carbon atom of the
epoxide ring (entries 6-9, Table 4). The major regioisomeric
alcohol formed during the reaction of 4 with aromatic amines
was isolated by column chromatography of the crude product
isolated from the reaction mixture. However, the regioisomeric
amino alcohols formed by the reaction of 4 with aliphatic amines
could not be separated by column chromatography. In each case,
the regioselectivity was determined by GCMS.20 The regioiso-
mer formed by the reaction of the amine at the benzylic carbon
atom of the epoxide ring showed the characteristic ion peak at
m/z [M+ - 31] because of the loss of the CH2OH in the GCMS.
The characteristic ion peak was at m/z [M+ - 107] because of
the loss of PhCHOH for the product formed by the reaction at
the terminal carbon atom of the epoxide ring.
Reaction of 1 with Various Aromatic and Aliphatic Aminesa
To establish the generality, various epoxides were treated with
2 in the presence of Zn(ClO4)2‚6H2O (Table 5). Excellent yields
of the 2-amino alcohols were obtained in each case. Cyclopen-
tene oxide (entry 1, Table 5) afforded the trans-2-phenylami-
nocyclopentanol as the only product. In case of glycidic ethers
(entries 2-4, Table 5) and epichlorohydrin (entry 5, Table 5),
excellent regioselectivity was observed. The amino alcohols
derived from nucleophilic attack at the less substituted carbon
atom of the epoxide rings were obtained as the exclusive/major
products (GCMS). The reaction with epichlorohydrin provided
an example of excellent chemoselectivity and no product from
nucleophilic substitution of the chlorine atom was formed
(GCMS). Ethyl phenylglycidate (entry 6, Table 5) afforded the
amino alcohol from nucleophilic attack at the benzylic carbon
atom as the only product (GCMS).19k This observation further
highlighted the influence of electronic factor of the phenyl ring
in controlling the regioselectivity analogous to that observed
during the reaction of aromatic amines with 4 (Table 4).
The role of the metal perchlorates in catalyzing the epoxide
ring-opening reaction by amines is depicted in Scheme 1. The
coordination of the metal cation [M+n] with the epoxide oxygen
atom generates the transition-state I. The positive charge that
is developed on the oxygen atom of the epoxide ring is
delocalized through the adjacent carbon atoms constituting the
epoxide ring and increases the electrophilicity at these two sites.
The nucleophilic attack by the nitrogen atom of the amine at
the carbon atom of the epoxide ring forms the transition-state
II. An intramolecular proton shift takes place via the transition-
state III as the oxyanionic site forms hydrogen bond with one
of the hydrogen atoms of the (R)ArNH2+ moiety. This leads to
the amino alcohol and releases the metal perchlorate to complete
the catalytic cycle. Thus, the efficiency of the methodology
depends on the (1) oxophilicity of the central metal cation so
as to form strong coordinate bond with the oxygen atom of the
epoxide ring and (2) the pKa value of the amine so that the
a 1 (2.5 mmol) was treated with the amine (2.5 mmol, 1 equiv) in the
presence of Zn(ClO4)2‚6H2O (2 mol %) at rt (except for entries 7-10) under
solvent-free conditions. b Isolated yield of the corresponding trans-2-aryl/
alkylaminocyclohexanol. c The products were characterized by IR, NMR,
and MS. d The reaction was carried out at 80 °C. e The desired amino alcohol
was formed in 20% yield when the reaction was carried out in the absence
of any catalyst at 80 °C for 60 min (to compare with the reported standard
procedure under ref 18k).
To determine the regioselectivity, styrene oxide 4 was used
as a representative unsymmetrical epoxide and was treated with
various aromatic and aliphatic amines in the presence of Zn-
(ClO4)2‚6H2O (Table 4).
3716 J. Org. Chem., Vol. 72, No. 10, 2007

Zinc(II) Perchlorate Hexahydrate Catalyzed Opening
TABLE 4. Zn(ClO4)2‚6H2O-Catalyzed Opening of Epoxide Ring of 4 by Aminesa
a 4 (2.5 mmol) was treated with the amine (2.5 mmol, 1 equiv) in the presence of Zn(ClO4)2‚6H2O (2 mol %) at rt (except for entries 6-9) under
solvent-free conditions. b Isolated yield of the corresponding 2-amino alcohols (mixture of regioisomers). c Determined by GCMS. d The yield of the major
regioisomer obtained after column chromatographic purification of the mixture of the regioisomeric amino alcohols. e The reaction was carried out at 80 °C.
f The regioisomeric amino alcohols could not be separated by column chromatography. g The regioisomeric amino alcohol from nucleophilic attack at the
terminal carbon atom of the epoxide ring of 4 was the only product formed.
intramolecular proton transfer in the transition-states II/III takes
place efficiently.
former cation (Zn+2 5.33 and Li+ 1.35 e2 m-10).37 However,
the inferior results obtained in the presence of Mg(ClO4)2‚xH2O,
BiO(ClO4)2‚xH2O, Fe(ClO4)2‚xH2O, Fe(ClO4)3‚xH2O, Co(ClO4)2‚
xH2O, and Cu(ClO4)2‚xH2O were due to the increasing tendency
The results of Tables 1-5 can be rationalized with the help
of the mechanism proposed in Scheme 1. The better catalytic
activity of Zn(ClO4)2‚6H2O compared to that of LiClO4‚xH2O
(Table 1) was due to stronger oxophilicity of Zn+2 compared
to that of Li+ because of the higher charge-to-size ratio of the
(37) Huheey, J. E. Inorganic Chemistry: Principle of Structure and
ReactiVity, 3rd ed.; Harper & Row: Singapore, 1983.
J. Org. Chem, Vol. 72, No. 10, 2007 3717

Shivani et al
TABLE 5. Zn(ClO4)2‚6H2O-Catalyzed Ring Opening of Various Epoxides by 2a
a The epoxide (2.5 mmol) was treated with 2 (2.5 mmol, 1 equiv) in the presence of Zn(ClO4)2‚6H2O (2 mol %) at rt under solvent-free conditions.
b Isolated yield of the corresponding 2-amino alcohols. c The products were characterized by IR, NMR, and MS. d The trans-2-phenylaminocyclopentanol
was formed as the only product. e The 2-amino alcohol from nucleophilic attack at the less substituted carbon atom of the epoxide ring was formed as the
only product. f The 2-amino alcohol from nucleophilic attack at the less substituted carbon atom of the epoxide ring was formed as the major product along
with the regioisomeric product in ∼2% yield (GCMS and NMR). g The 2-amino alcohol from nucleophilic attack at the less substituted carbon atom of the
epoxide ring was formed as the major product along with the regioisomeric product in 6% yield (GCMS and NMR). h The 2-amino alcohol from nucleophilic
attack at the benzylic carbon atom of the epoxide ring was formed as the only product (GCMS and NMR).
compared to that of Zn+2 ion.38 The water molecules in these
SCHEME 1. The Role of Metal Perchlorates in Catalyzing
the Epoxide Ring-Opening Reaction by Amines
metal perchlorate hydrates decrease the oxophilicity of the
central metal cation. It has been reported that in case of Mg-
(ClO4)2 (anhydrous from) the catalytic efficiency decreases on
repeated exposure of the catalyst to air.27c,e The ability of the
Fe+2, Fe+3, Co+2, and Cu+2 ions to form strong coordination
complexes with an amine also reduces the catalytic activity of
the perchlorate salt of these cations.
The relative catalytic efficiency of various zinc compounds
(Table 2) may be explained by taking into consideration the
fact that the Lewis acid property (oxygen affinity) of the central
metal cation is influenced by the counteranion and a salt of a
stronger protic acid should be a better Lewis acid. Thus, the
(38) (a) Yatsimirksii, K. B.; Vasil’ev V. P. Instability Constants of
Complex Compounds; Pergamon: Elmsford, NY, 1960. (b) Stability
Constants of Metal-Ion Complexes: PartII. Inorganic Ligands;
Bjerrum, J.; Schwarzenbach, G.; Sillen, L. G., Eds.; The Chemical
Society: London, 1958.
of the corresponding metal ions to hydrolyze compared to that
of Zn+2 ion as evidenced by the lower pKh values of these ions
3718 J. Org. Chem., Vol. 72, No. 10, 2007

Zinc(II) Perchlorate Hexahydrate Catalyzed Opening
SCHEME 2. Chemoselective Nucleophilic Opening of the
Epoxide Ring in Epichlorohydrine by 2
order of the catalytic activity Zn(ClO4)2‚6H2O . Zn(BF4)2‚
xH2O ∼ Zn(OTf)2 . ZnI2 > ZnBr2 > ZnCl2 > Zn(OAc)2 >
ZnCO3 is in compliance with the acidic strength of the respective
protic acids.36 Surprisingly, Zn(OTf)2 was found to be inferior
to Zn(ClO4)2‚6H2O although triflic acid is a stronger protic acid
than perchloric acid.36 A similar comparative catalytic activity
between Mg(ClO4)2 and Mg(OTf)2 was observed during acy-
lation reaction.20c The requirement of 50 mol % of LiOTf for
epoxide ring opening by amines further exemplifies the inferior
catalytic property of metal triflates.39
The longer time (60 min) required for 4-methoxyaniline (entry
2, Table 3) was because of sluggishness of intramolecular proton
transfer in the transition-states II/III because of increased pKa
value. The resonance effect of the 4-OMe group decreases/
neutralizes the positive charge on the nitrogen atom of the
substrates of entries 6-8 (Table 4), the nucleophilic attack at
the benzylic and terminal carbon atom of the epoxide ring of 4
by benzyl amine was less discriminatory.
+
4-MeOC6H4NH2 moiety in the transition-states II/III. This
decreases the hydrogen bond formation ability of the hydrogen
The excellent yield (81%) of the amino alcohol corresponding
to nucleophilic attack at the terminal carbon atom of the epoxide
ring obtained during the reaction of 2 with epichlorohydrin 8
(entry 5, Table 5) demonstrates the importance of the counter-
anion of the metal catalyst in controlling the chemoselectivity.
The reaction, in principle, may proceed via two distinct
pathways: (1) direct displacement of chlorine (path a) leading
to the formation of the oxiran 9 or (2) nucleophilic attack on
the least substituted carbon atom of the epoxide ring leading to
opening of the epoxide ring followed by protonation of the
alkoxide anion to form the amino alcohols (path b) or extrusion
of the chlorine atom through intramolecular nucleophilic
substitution by the adjacent alkoxide anion (path c) to give 9
(Scheme 2).40 It is anticipated that the perchlorate anions in
Zn(ClO4)2‚xH2O make the Zn+2 ion sufficiently electrophilic
so as to hold the negative charge of the alkoxide anion generated
after the nucleophilic attack of the amine on the metal-
complexed epoxide. Thus, the free alkoxide anion is not
available for subsequent elimination of the chloride anion to
make “path c” to be operative, and the amino alcohol 10 is
obtained as the sole/major product.
The applicability of this newly developed methodology is
demonstrated for the synthesis of cardiovascular drugs such as
propranolol and naftopidil as racemates and optically active
enantiomers. The common synthetic strategy for these cardio-
vascular agents involve the nucleophilic opening of the epoxide
ring of 1-naphthyl glycidyl ether 11 with isopropyl amine and
1-(2-methoxyphenyl)piperizine 12, respectively, (Scheme 3).
The key starting material (RS)-11 was prepared in 80% yield
by the reaction of 1-naphthol with (RS)-8, in the presence of
K2CO3 in MeCN under reflux by modification of the reported
procedure.41 The treatment of (RS)-11 with iPrNH2 (1 equiv) at
rt for 1 h in the presence of Zn(ClO4)2‚6H2O under neat
conditions afforded (RS)-propranolol in 72% yield. The synthesis
of (RS)-naftopidil was achieved by the Zn(ClO4)2‚6H2O-
catalyzed opening of the epoxide ring of (RS)-11 by 12 (1
equiv), prepared following reported procedure.42 An initial
attempt in carrying out the reaction of (RS)-11 with 12 at rt
under solvent-free condition led to incomplete conversion
probably because of improper mixing of 12 (floppy solid) with
11 (liquid). However, the use of dichloromethane (DCM)
afforded the desired product in 92% yield at rt after 16 h. To
+
atoms attached to the nitrogen atom of the 4-MeOC6H4NH2
moiety and makes the intramolecular proton transfer sluggish
which eventually retards the rate of the reaction. The relatively
faster rate of reaction with 4-chloroaniline (entry 6, Table 3)
compared to that with the more nucleophilic amines such as
aniline and methoxy/methyl substituted anilines (entries 2-5,
Table 3) supports the importance of the intramolecular proton
transfer in the transition-states II/III. The reactions with aliphatic
amines that are better nucleophiles than the aromatic amines
required heating because of the weak acidic property of the
amino group that did not permit formation of the transition-
state III at rt.
The regioselective outcome (Tables 4 and 5) can be explained
by the steric and electronic factors associated with the epoxide
and the amine. Complex formation between the epoxide oxygen
atom of 4 and the Zn+2 generated the transition-state I (R1 )
Ph; R2 ) R3 ) R4 ) H; Scheme 1) in which the positive charge
was accumulated on the oxygen atom and was delocalized
through the carbon atoms of the epoxide ring. The benzylic
carbon atom of the epoxide ring exhibited better carbocationic
character and became more electrophilic compared to the less
substituted carbon atom. Since aromatic amines were less
nucleophilic compared to the aliphatic amines, selective nu-
cleophilic attack took place at the more electrophilic benzylic
carbon atom of the epoxide ring. The preference of nucleophilic
attack by 2 on the benzylic carbon atom of ethyl phenylglycidate
(entry 6, Table 5) further supports the influence of resonance/
electronic effect of the phenyl group in controlling regioselec-
tivity. In the absence of such resonance effect in glycedic ethers
(entries 2-4, Table 5), and epichlorohydrin (entry 5, Table 5),
the regioselectivity is controlled by the steric factor and selective
nucleophilic attack took place at the less substituted/terminal
carbon atom of the epoxide ring.
The preferential reaction at the non-benzylic position of 4
(Table 4) by aliphatic amines was due to the complex formation
between the nitrogen atom and the catalyst (as aliphatic amines
were stronger bases compared to the aromatic amines) that made
the effective nucleophilic species sterically hindered, and the
reaction took place at the less hindered position. This is
supported by the result obtained during the reaction of 4 with
benzyl amine (entry 9, Table 4) in which case the selectivity of
benzylic versus terminal carbon of the epoxide ring in 4 was
44:56. As the steric factor surrounding the nitrogen atom of
benzyl amine was less compared to that of the secondary amine
(40) McClure, D. E.; Arison, B. H.; Baldwin, J. J. J. Am. Chem. Soc.
1979, 101, 3666.
(41) Bose, D. S.; Reddy, A. V. N.; Chavhan, S. W. Synthesis 2005, 2345.
(42) Kothakonda, K. K.; Bose, D. S. Chem. Lett. 2004, 1212.
(39) Auge´, J.; Leroy, F. Tetrahedron Lett. 1996, 37, 7715.
J. Org. Chem, Vol. 72, No. 10, 2007 3719

Shivani et al
SCHEME 3. The Application of Zn(ClO4)2‚6H2O-Catalyzed
Epoxide Ring Opening by Amine for the Synthesis of
(RS)-Propranolol and (RS)-Naftopidil
SCHEME 5. Synthesis of (R)-(-)-Propranolol and
(R)-(-)-Naftopidil from (R)-11
enantiomeric distribution of ∼91:9 [ee ) 82%] eluting at 10.9
and 14 min, respectively. The formation of (R)-11 from (S)-8
revealed that 11 is not obtained following a direct alkylation
route by nucleophilic substitution of the chlorine atom in (S)-8
by the 1-naphthoxide anion (path a, Scheme 4) but is formed
via the opening of the epoxide ring by nucleophilic attack at
the unsubstituted carbon atom of the epoxide ring forming the
intermediate alkoxide anion followed by 1,2 elimination of the
chlorine atom to form (R)-9 (path b, Scheme 4).
SCHEME 4. Formation of (R)-(11) from (S)-8
Having (R)-11 on hand, we planned to extend the applicability
of the Zn(ClO4)2‚6H2O-catalyzed epoxide ring-opening reaction
for the synthesis of (R)-propranolol and (R)-naftopidil (Scheme
i
5). The treatment of (R)-11 with PrNH2 at rt for 1 h under
solvent-free condition in the presence of Zn(ClO4)2‚6H2O
afforded (R)-propranolol in 75% yield. The enantiomeric product
mixture was analyzed by HPLC and tandem liquid chromatog-
raphy mass spectrometry (LCMS) on a chiral column and was
compared with the HPLC and LCMS data of (RS)-propranolol.
These indicated an ee of 82%. However, the optical purity was
found to be 87.5% on comparison of the observed value of the
optical rotation of the product with the reported value of optical
rotation of (R)-propranolol (Experimental Section). The reaction
of (R)-11 with 12 at 80 °C under neat conditions for 10 min in
the presence of Zn(ClO4)2‚6H2O afforded (R)-naftopidil in 82%
yields. However, the optical rotation was found to be -11.7 [c
1.5, MeOH] as compared to the reported42 value of -3.94 [c
1.5, MeOH]. To establish the optical and chemical integrity,
the product was subjected to HPLC and LCMS studies on chiral
column, and the results were compared with those of (RS)-
naftopidil. The product showed the enantiomeric distribution
of 94.5:5.5 (89% ee) with tR ) 54.6 min and tS )75.1 min
(hexane:2-propanol:diethylamine ) 80:20:0.1) on chiral HPLC.
In the case of the LCMS studies using a chiral column, the
enatiomers eluted at tR ) 60.3 min and tS ) 85.0 min (hexane:
2-propanol:diethylamine ) 85:15:0.1) with the corresponding
m/z of 437 [(M - H)++ 2Na].
Finally, we planned to demonstrate the effectiveness of the
Zn(ClO4)2‚6H2O-catatlyzed epoxide ring-opening reaction for
the synthesis of (S)-naftopidil (Scheme 6). The key starting
material (S)-11, prepared by the reaction of (R)-8 with 1-naph-
thol following the modified procedure, on treatment with 12 at
80 °C under neat conditions for 10 min in the presence of Zn-
(ClO4)2‚6H2O afforded (S)-naftopidil in 95% yield. However,
similar to the case of the (R)-enatiomer, the optical rotation was
found to be +11.7 [c 1.5, MeOH] instead of the reported42 value
of +3.8 [c 1.5, MeOH]. Thus, HPLC and LCMS studies of the
claim a solvent-free synthesis, the reaction of (RS)-11 with 12
was carried out at 80 °C under neat condition, and (RS)-
naftopidil was obtained in 85% yield after 10 min. Being
encouraged by the results of the syntheses of (RS)-propranolol
and (RS)-naftopidil, we planned to extend this methodology for
the synthesis of the chiral drugs. Although currently these drugs
are therapeutically used as racemates, it is reported that the (S)-
isomers are more potent than the (R)-isomers.43 Thus, we
planned to synthesize (S)-propranolol and (S)-naftopidil from
(S)-11. The reaction of 1-naphthol with (S)-8 following the
modified procedure (Scheme 4) afforded the 1-naphthylglycedic
ether in 78% yield with an [R]D value of - 28.8 (c ) 1, MeOH)
indicating it to be (R)-11 with 85% optical purity on comparison
with the reported [R]D value of - 33.9 (c ) 1.55, MeOH).44 In
the chiral high-performance liquid chromatography (HPLC), the
(RS)-11 exhibited the enantiomers in a ratio of 48:52 eluting
after 12 and 14.5 min, respectively. The 1-naphthylglycedic ether
obtained from the reaction of 1-naphthol with (S)-8 showed the
(43) (a) Sheldon, R. A. Chirotechnology, Industrial Synthesis of Optically
ActiVe Compounds; Marcel Dekker: New York, 1993. (b) Scott, A. K. Drugs
News Perspect. 1991, 4, 476. (c) Main, B. G. In Problems and Wonders of
Chiral Molecules; Simomyi, M., Ed.; Academia Kiado: Budapest, Hungary,-
1990; pp 329-348. (d) Barrett, A. M.; Cullum, V. A. Br. J. Pharmacol.
1968, 34, 43. (e) Howe, R.; Shanks, R. G. Nature 1966, 1336. (f) Black, J.
W.; Stephenson, J. S. Lancet 1962, 311.
(44) Bevinakatti, H. S.; Banerji, A. A. J. Org. Chem. 1991, 56, 5372.
3720 J. Org. Chem., Vol. 72, No. 10, 2007

Zinc(II) Perchlorate Hexahydrate Catalyzed Opening
SCHEME 6. Synthesis of (S)-(+)-Naftopidil from (S)-11
MeCN (10 mL) was added (RS)-epichlorohydrin 8 (0.29 mL, 3.75
mmol), and the reaction mixture was heated under reflux for 16 h.
The cooled (rt) reaction mixture was filtered, the filtrate was
concentrated under vacuum, and the residue was purified by passing
through a column chromatography of silica gel (60-120 mesh) and
eluting with EtOAc:hexane (1:19) to affored (RS)-11 (400 mg,
80%), 1H NMR (300 MHz, CDCl3): δ 2.84-2.87 (m, 1 H), 2.95-
2.98 (m, 1 H), 3.48-3.49 (m, 1 H), 4.15 (dd, 1 H; J ) 5.5, 11.0
Hz), 4.40 (dd, 1 H; J ) 3.0, 11.0 Hz), 6.81 (d, 1 H; J ) 7.5 Hz),
7.36 (t, 1 H; J ) 8.0 Hz), 7.43-7.52 (m, 3 H), 7.78-7.81 (m, 1
H), 8.28-8.31 (m, 1 H) identical with those reported in the
literature.41 The (RS)-11 was subjected to HPLC on CHIRAL OD-H
column and was eluted with hexane:2-propanol (85:15) containing
diethyl amine (0.1%). The two enantiomers eluted after 11.9 and
14.5 min and were present in a ratio of 48:52.
Typical Procedure for Preparation of (R)-Naphthylglycidic
Ether (11). The reaction of 1-naphthol (360 mg, 2.5 mmol) with
(S)-(8) (290 mg, 3.75 mmol) followed by the usual workup and
purification as stated for the (RS)-11 afforded (R)-11 (390 mg, 78%).
The product was subjected to chiral HPLC analysis using chiral
OD-H column and the two enantiomers were eluted at tR ) 10.9
min and tS ) 14.0 min (85:15 hexane: 2-propanol containing 0.1%
diethylamine) with peak areas of 91 and 9%, respectively, indicating
the optical purity of 82%. However, the ee was found to be 85%
on the basis of the observed [R]D value of -28.8 (c ) 1, MeOH)
isolated product were carried out on a chiral column and were
compared with those of (RS)-naftopidils to determine the optical
and chemical integrity. In the HPLC using a chiral column, the
product was found to be a 9.7:90.3 mixture of the two
enantiomers (ee ∼80%) eluting (hexane:2-propanol:diethylamine
) 80:20:0.1) at tR ) 62.2 min and tS )75.1 min. In the LCMS
on the chiral column, the corresponding values were tR ) 70.54
min and tS ) 86.21 min (hexane:2-propanol:diethylamine )
85:15:0.1) with the m/z of 437 [(M - H)++ 2Na].
1
[lit.44 ) -33.9 (c ) 1.55, MeOH)]. H NMR (CDCl3): δ 2.84-
2.87 (m, 1 H), 2.95-2.98 (m, 1 H), 3.48-3.49 (m, 1 H), 4.15 (dd,
1 H; J ) 5.5, 11.0 Hz), 4.40 (dd, 1 H; J ) 3.0, 11.0 Hz,, 6.81 (d,
1 H; J ) 7.5 Hz,), 7.36 (t, 1 H; J ) 8.0 Hz,), 7.43-7.52 (m, 3 H),
7.78-7.81 (m, 1 H), 8.28-8.31 (m, 1 H). MS (APCI) ) 200.9
(MH+).
Conclusions
In summary, we have described herein Zn(ClO4)2‚6H2O as a
new and highly efficient catalyst for opening of epoxide ring
by amines affording â-amino alcohols. The advantages include
high yields, short reaction times, excellent regio-, chemo-, and
stereoselectivities, and the use of a cheap and commercially
available catalyst. The extension of this methodology for the
synthesis of (RS)-propranolol, (RS)-naftopidil, (R)-propranolol,
(R)-naftopidil, and (S)-naftopidil demonstrated the potentiality
of industrial applications for the synthesis of cardiovascular
drugs. The use of LCMS with a chiral column along with the
chiral HPLC unambiguously established the optical purity of
the chiral products.
Typical Procedure for the Preparation of (RS)-Propranolol.
The mixture of (RS)-11 (200 mg, 1 mmol), isopropyl amine (58
mg, 1 mmol), and Zn(ClO4)2‚6H2O (7.4 mg, 2 mol %) was stirred
magnetically at rt under nitrogen. After completion of the reaction
(60 min, TLC, GCMS), the reaction mixture was diluted with Et2O
(15 mL), was washed with water (5 mL), was dried (Na2SO4), and
was concentrated under vacuum to afford (RS)-propranolol (189
mg, 72%). 1H NMR (300 MHz, CDCl3): δ 1.14 (s, 3 H), 2.60 (bs,
1 H, OH), 2.90-3.02 (m, 3 H), 4.19 (m, 3 H), 6.82 (d, 1 H; J )
6.6 Hz), 7.25-7.46 (m, 5 H), 7.78 (m, 1 H), 8.22 (m, 1 H), identical
with an authentic sample.41 The product on subjection to HPLC
analysis uisng CHIRAL OD-H column and elution with 85:15
hexane:2-propanol containing 0.1% diethylamine showed to be a
1:1 mixture (peak areas of 49.45 and 50.55%) of the two
enantiomers eluting at 12.2 and 24.3 min. The LCMS under similar
condtion exhibited the two enantiomers eluting at 14.89 and 23.09
min with the corresponding m/z of 260 (MH+).
Experimental Section
Typical Procedure for Epoxide Ring Opening by Amine.
trans-2-(Phenylamino)cyclohexanol (3). To the mixture of 1 (245
mg, 2.5 mmol) and 2 (233 mg, 2.5 mmol), Zn(ClO4)2‚6H2O (18
mg, 2 mol %) was added and the mixture was magnetically stirred
at rt under nitrogen. After completion of the reaction (15 min, TLC,
GCMS), the reaction mixture was diluted with Et2O (15 mL), was
washed with water (5 mL), was dried (Na2SO4), and was concen-
trated in vacuo to afford 3 (472 mg, 99%), mp 57-59 °C; 1H NMR
(CDCl3, 300 MHz) δ 1.03-1.42 (m, 4 H), 1.72-1.78 (m, 2 H),
2.10-2.16 (m, 2 H), 28-3.0(m, 2 H, D2O exchangeable), 3.13 (ddd,
1 H, J ) 3.9, 10.0, 10.1 Hz), 3.33 (ddd, 1 H, J ) 4.2, 10.4, 10.5
Hz), 6.7-7.2 (m, 5 H). 13C NMR (CDCl3, 75 MHz) δ 24.3, 25.0,
31.6, 33.2, 60.2, 74.5, 114.4, 118.4, 129.3, 147.8. EIMS (m/z) 191
(M+) identical with an authentic sample.20 The remaining reactions
were carried out following this general procedures. On each
occasion, the spectral data (IR, NMR, and MS) of prepared known
compounds were found to be identical with those reported in the
literature. The unknown compounds (entry 5, Table 3; entries 3
Typical Procedure for the Preparation of (RS)-Naftopidil. The
mixture of (RS)-11 (200 mg, 1 mmol), 1-(2-methoxyphenyl)-
piperizine 12 (190 mg, 1 mmol), and Zn(ClO4)2‚6H2O (7.4 mg, 2
mol %) in DCM (2 mL) was stirred magnetically at rt under
nitrogen. After completion of the reaction (16 h, TLC, GCMS),
the reaction mixture was diluted with Et2O (15 mL), was washed
with water (5 mL), was dried (Na2SO4), and was concentrated under
1
vacuum to afford (RS)-naftopidil (360 mg, 92%). H NMR (300
MHz, CDCl3): δ 3.36-3.71 (m, 8 H), 4.01 (s, 3 H), 4.26-4.36
(m, 5 H), 6.96 (d, 1 H; J ) 7.3 Hz), 7.08-7.14 (m, 2 H), 7.29 (t,
1 H; J ) 7.5 Hz), 7.41 (t, 1 H; J ) 7.6 Hz), 7.52 (t, 1 H; J ) 7.6
Hz), 7.58-7.67 (m, 3 H), 7.97 (d, 1 H; J ) 8.5 Hz), 8.39 (d, 1 H;
J ) 8.5 Hz). The treatment of the reaction mixture at 80 °C under
neat conditions for 10 min afforded (RS)-naftopidil (321 mg, 82%).
The product on subjection to HPLC analysis using CHIRAL OD-H
column and elution with 80:20 hexane:2-propanol containing 0.1%
diethylamine showed to be a 1:1 mixture of the two enantiomers
eluting at 57.1 and 71.6 min. The LCMS under similar condition
exhibited the two enantiomers eluting at 66.5 and 84.2 min with
the corresponding m/z of 437 [(M - H)++ 2Na].
1
and 4, Table 4) were characterized by spectral (IR, H and 13C
NMR, and MS) and elemental data.
Typical Procedure for the Preparation of (RS)-Naphthylg-
lycidic Ether (11). To a magnetically stirred solution of 1-naphthol
(360 mg, 2.5 mmol) and K2CO3 (690 mg, 5 mmol) in anhydrous
J. Org. Chem, Vol. 72, No. 10, 2007 3721

Shivani et al
Typical Procedure for the Preparation of (R)-Propranolol.
The reaction of (R)-11 (200 mg, 1 mmol) with isopropyl amine
(58 mg, 1 mmol) in the presence of Zn(ClO4)2‚6H2O (7.4 mg, 2
mol %) followed by usual workup and purification as described
OD-H column), the enantiomers eluted at tR ) 60.3 min and tS )
85.0 min (hexane:2-propanol:diethylamine ) 85:15:0.1) with the
corresponding m/z of 437 [(M - H)++ 2Na].
Typical Procedure for the Preparation of (S)-Naftopidil. The
reaction of (S)-11 (200 mg, 1 mmol) with 1-(2-methoxyphenyl)-
piperizine 12 (190 mg, 1 mmol) in the presence of Zn(ClO4)2‚
6H2O (7.4 mg, 2 mol %) at 80 °C under neat condition under
nitrogen for 10 min followed by usual workup and purifiaction as
described for (RS)-naftopidil afforded (S)-naftopidil (372 mg, 95%).
[R]D: +11.7 (c ) 1.5, MeOH) [lit.42 ) +3.8 (c ) 1.5, MeOH)].
The ee of the product was determined to be ∼80% by chiral HPLC
analysis using chiral OD-H column with the enantiomeric distribu-
tion of 9.7:90.3 eluting (hexane:2-propanol:diethylamine ) 80:20:
0.1) at tR ) 62.2 min and tS )75.1 min. In the LCMS (chiral OD-H
column), the enantiomers eluted (hexane:2-propanol:diethylamine
) 85:15:0.1) at tR ) 70.54 min and tS ) 86.21 min, respectively,
with the corresponding m/z of 437 [(M - H)++ 2Na].
1
for (RS)-propranolol afforded (R)-propranolol (200 mg, 75%). H
NMR (CDCl3): δ 1.12 (s, 6 H), 2.44 (bs, 1 H, OH), 2.89-3.03
(m, 3 H), 4.18-4.45 (m, 3 H), 6.82 (m,1 H), 7.36-7.47 (m, 4 H),
7.80 (m, 1 H), 8.24 (m, 1 H). MS (APCI) ) 260 (MH+). The
product on subjection to HPLC analysis uisng CHIRAL OD-H
column and elution with 85:15 hexane:2-propanol containing 0.1%
diethylamine showed to be a 91:9 mixture of the two enantiomers
eluting at 11.6 and 21.4 min, respectively, indicating the optical
purity of 82%. However, the ee was calculated to be 87.5% on the
basis of the observed [R]D value of +22.5 (c ) 1, EtOH) [lit.45
)
+25.7 (c ) 1.23, EtOH)]. The LCMS under similar condition
exhibited the two enantiomers eluting at 14.59 and 25.16 min,
respectively, with the corresponding m/z of 260 (MH+).
Typical Procedure for the Preparation of (R)-Naftopidil. The
reaction of (R)-11 (200 mg, 1 mmol) with 1-(2-methoxyphenyl)-
piperizine 12 (190 mg, 1 mmol) in the presence of Zn(ClO4)2‚
6H2O (7.4 mg, 2 mol %) at 80 °C under neat condition under
nitrogen for 10 min followed by usual workup and purifiaction as
described for (RS)-naftopidil afforded (R)-naftopidil (321 mg, 82%).
[R]D: -11.7 (c ) 1, MeOH) [lit.42 ) -3.94 (c ) 1, MeOH)]. The
ee of the product was determined to be 89% by chiral HPLC
analysis using chiral OD-H column with the enantiomeric distribu-
tion of 94.5:5.5 and tR ) 54.6 min and tS )75.1 min, respectively,
(hexane:2-propanol:diethylamine ) 80:20:0.1). In the LCMS (chiral
Acknowledgment. Shivani and Brahmam thank CSIR, New
Delhi, India for Senior and Junior Research Fellowship,
respectively. Financial support from the Organisation for the
Prohibition of Chemical Weapons (OPCW), Hague, Netherland
is also gratefully acknowledged.
Supporting Information Available: Experimental details,
scanned spectra, and spectral data of all known and unknown
compounds. This material is available free of charge via the Internet
at http:// pubs.acs.org.
(45) Klunder, J. M.; Ko Soo, Y.; Sharpless, K. B. J. Org. Chem. 1986,
51, 3710.
JO062674J
3722 J. Org. Chem., Vol. 72, No. 10, 2007