Silver nanoparticle-catalysed phenolysis of epoxides under neutral conditions: Scope and limitations of metal nanoparticles and applications towards drug synthesis

Article abstract of DOI:10.1016/j.molcata.2014.05.011

Chemo- and regio-selective epoxide phenolysis is reported for the first time under neutral condition catalysed by silver nanoparticles. Other metal nanoparticles (e.g., Au, Pd, Cu, In, and Ru) are less effective. The choice of solvent is critical with 2-propanol being the best followed by DEF. Amongst various stabilisers used (surfactants, PEGs, tetra-alkylammonium halides) the tetra-alkylammonium halides are found to be the most effective (TBAF > TBAB > TBACl > TBAI). The role of the silver nanoparticles is envisaged as synchronous mode epoxide-phenol dual activation via a cooperative network of coordination, anion-π interaction, and hydrogen bond. The silver nanoparticles are recovered and reused for five consecutive times. The reaction has been used for the synthesis of propranolol and naftopidil as a few representative cardiovascular drugs.

Full text of DOI:10.1016/j.molcata.2014.05.011

Journal of Molecular Catalysis A: Chemical 392 (2014) 164–172
Contents lists available at ScienceDirect
Journal of Molecular Catalysis A: Chemical
journal homepage: www.elsevier.com/locate/molcata
Silver nanoparticle-catalysed phenolysis of epoxides under neutral
conditions: Scope and limitations of metal nanoparticles and
applications towards drug synthesis
Kapileswar Seth, Sudipta Raha Roy, Damodara N. Kommi, Bhavin V. Pipaliya,
Asit K. Chakraborti∗
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, Punjab 160 062, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Chemo- and regio-selective epoxide phenolysis is reported for the first time under neutral condition
catalysed by silver nanoparticles. Other metal nanoparticles (e.g., Au, Pd, Cu, In, and Ru) are less effective.
The choice of solvent is critical with 2-propanol being the best followed by DEF. Amongst various stabilis-
ers used (surfactants, PEGs, tetra-alkylammonium halides) the tetra-alkylammonium halides are found
to be the most effective (TBAF > TBAB > TBACl > TBAI). The role of the silver nanoparticles is envisaged as
synchronous mode epoxide-phenol dual activation via a cooperative network of coordination, anion–␲
interaction, and hydrogen bond. The silver nanoparticles are recovered and reused for five consecutive
times. The reaction has been used for the synthesis of propranolol and naftopidil as a few representative
cardiovascular drugs.
Received 12 February 2014
Accepted 14 May 2014
Available online 24 May 2014
Keywords:
Silver nanoparticle
Catalyst
Base-free epoxide phenolysis
Synchronous dual activation
Drug synthesis
© 2014 Published by Elsevier B.V.
1. Introduction
2. Experimental
Epoxide phenolysis is a highly sought for organic reaction in
drug discovery and development as it provides direct access to the
essential pharmacophoric feature A present in wide ranges of drugs
such as guaifenesin (1) (used for cold and cough), mephenesin (2)
and chlorphenesin (3) (used as muscle relaxants), and the broad
ranges of ␤-adrenergic blocking agents (cardiovascular drugs), e.g.,
propranolol (4), naftopidil (5), etc. (Fig. 1).
A few existing methodologies for epoxide phenolysis are per-
formed under basic conditions using a large amount of the base
(or the preformed phenolate) and stoichiometric amount or excess
quantities of a phase transfer catalyst or surfactant [1]. Catalyst
systems containing a basic moiety either covalently attached to a
central metal ion [2] or as the counter anion are also reported but
require excess of the epoxide [3]. Herein we report for the first time
epoxide phenolysis under neutral (base-free) condition using silver
nanoparticle (AgNP) as the catalyst.
2.1. General information
The 1H and 13C NMR spectra were recorded on a 400 MHz NMR
spectrometer in CDCl3 with residual undeuterated solvent (CDCl3:
7.26/77.0) using Me4Si as an internal standard. Chemical shifts (ı)
are given in ppm and J values are given in Hz. The IR spectra were
recorded either on KBr pellets (for solids) or neat (for liquids) on
a FTIR spectrometer. The HRMS spectra were recorded on a mass
spectrometer. The UV spectra were recorded on a UV-VIS Spec-
trophotometer. Melting points were measured using melting point
apparatus. Open column chromatography was performed on Silica
gel [60–120 mesh] and the TLC was performed on Silica gel F254.
The solvents were distilled prior to use. Evaporation of solvents
was performed at reduced pressure, using a rotary evaporator. All
chemicals were purchased and used as received. All the TEM images
were taken on carbon coated Cu grids in an instrument equipped
with EDX facility.
2.2. The AgNP-catalysed epoxide phenolysis
Method A: Typical procedure for epoxide phenolysis catalysed
by the in situ generated AgNPs in iPrOH (Table 2, entry 2): The
mixture of TBAF (0.487 g, 2 mmol, 1 equiv) and AgNO3 (1.7 mg,
∗
Corresponding author. Tel.: +91 0172 2214683x686; fax: +91 0172 2214692.
E-mail addresses: akchakraborti@niper.ac.in, akchakraborti@rediffmail.com
(A.K. Chakraborti).
http://dx.doi.org/10.1016/j.molcata.2014.05.011
1381-1169/© 2014 Published by Elsevier B.V.

K. Seth et al. / Journal of Molecular Catalysis A: Chemical 392 (2014) 164–172
165
2.3. Typical procedure for the identification and analysis of the
in situ formed AgNP
Method A: The mixture of TBAF (0.487 g, 2 mmol, 1 equiv) and
AgNO3 (1.7 mg, 0.01 mmol, 0.5 mol%) in distilled iPrOH (4 mL) was
stirred magnetically under reflux (oil bath temp 80 ◦C). An aliquot
portion (3 ␮L) of the reaction mixture was withdrawn after 15 min
on being subjected to UV measurement exhibited absorption at
350 nm indicating formation of the AgNPs. The sample (3 ␮L) sepa-
rately withdrawn from the reaction mixture after 15 min was kept
on carbon coated Cu grid after dilution. The grid was air dried
and was subjected to TEM and EDX analyses to identify the AgNPs
(3–8 nm).
Method B: The mixture of TBAF (0.244 g, 1 mmol, 0.5 equiv)
and AgNO3 (1.7 mg, 0.01 mmol, 0.5 mol%) in DEF (4 mL) was stirred
magnetically at 80 ◦C. An aliquot portion (3 ␮L) of the reaction mix-
ture was withdrawn after ∼5 min and was kept on carbon coated
Cu grid after dilution. The grid was air dried and was subjected to
TEM and EDX analyses to identify the AgNPs (5–8 nm).
Fig. 1. Representative drugs with the structural motif A.
0.01 mmol, 0.5 mol%) in iPrOH (4 mL) was stirred magnetically
under reflux (oil bath temp 80 ◦C) for 15 min. The oil-bath tem-
perature was reduced to 60 ◦C followed by addition of 6a (0.369 g,
2 mmol) and 7a (0.248 g, 2 mmol) and the mixture was further
stirred magnetically at 60 ◦C until completion of the reaction (6 h,
TLC). The reaction mixture was cooled to rt and the iPrOH was
removed under reduced pressure (30 mm Hg). The mixture was
diluted with H2O (10 mL) and extracted with EtOAc (3 × 5 mL).
The EtOAc layer was separated from the aqueous layer, dried (anh
Na2SO4); filtered off and evaporated to dryness under vacuum
(30 mm Hg). The residue was subjected to column chromatog-
raphy (60–120 mesh silica-gel; 93:7 hexane–EtOAc as eluent) to
afford the 8a as off white solid (0.463 g, 75%). mp 79–81 ◦C (lit
79–82 ◦C) [1c] (0.463 g, 75%). IR (KBr) ꢀmax: 3437, 2927, 1509,
824 cm−1; 1H NMR (CDCl3, 400 MHz) ı (ppm): 2.66 (d, 1H, J = 5.0 Hz,
D2O exchangeable), 3.78 (s, 3H), 4.07–4.16 (m, 4H), 4.34–4.39 (m,
1H), 6.84–6.90 (m, 6H), 7.24–7.28 (m, 2H); MS (ESI) m/z: 308.4
(M+).
Method B: Typical procedure for epoxide phenolysis catal-
ysed by the in situ generated AgNPs in DEF in the presence of
TBAF (Table 2, entry 2): The mixture of TBAF (0.244 g, 1 mmol,
0.5 equiv) and AgNO3 (1.7 mg, 0.01 mmol, 0.5 mol%) was stirred
magnetically in DEF (4 mL) at 80 ◦C for ∼5 min. The oil-bath tem-
perature was reduced to 60 ◦C followed by addition of 6a (0.369 g,
2 mmol) and 7a (0.248 g, 2 mmol) and the mixture was further
stirred magnetically at 60 ◦C until completion of the reaction
(6 h, TLC). The reaction mixture was cooled to rt; diluted with
H2O (10 mL) and extracted with dichloromethane (2 × 5 mL). The
dichloromethane layer was separated from the aqueous layer,
dried (anh Na2SO4); filtered off and evaporated to dryness under
vacuum (30 mm Hg). The residue was passed through chro-
matography column (silica-gel; 60–120 mesh) and eluted with
hexane–EtOAc (93:7) to afford the 8a as off white solid (0.438 g,
71%).
2.4. Typical procedure of intermolecular competition study
between 4-methoxyphenol 7a and 4-nitrophenol 7b (Scheme 3)
The mixture of TBAF (0.487 g, 2 mmol, 1 equiv) and AgNO3
(1.7 mg, 0.01 mmol, 0.5 mol%) was stirred magnetically in iPrOH
(4 mL) at 80 ◦C for 15 min. Then the temperature of the mixture was
reduced to 60 ◦C into which were added 6b (0.300 g, 2 mmol), 7a
(0.248 g, 2 mmol, 1 equiv) and 7b (0.278 g, 2 mmol, 1 equiv). After
6 h, the reaction mixture was cooled to rt and iPrOH was removed
in rotary evaporator under vacuum. The crude mixture was diluted
with H2O (10 mL) and extracted with EtOAc (2 × 5 mL). The EtOAc
layer was separated from the aqueous layer, dried (anh Na2SO4); fil-
tered off and evaporated to dryness under vacuum (30 mm Hg). The
residue was passed through chromatography column (silica-gel;
60–120 mesh) and eluted with hexane–EtOAc solvent system to
afford the 1,3-diphenoxy-propan-2-ol 8c as off white solid (0.115 g,
21%) and 1-(4-nitro-phenoxy)-3-phenoxy-propan-2-ol 8b as off
white solid (0.382 g, 66%).
2.5. The AgNP-catalysed intramolecular competition study
Method A: Typical procedure of intramolecular competition
study between phenolic hydroxyl group and alcoholic hydroxyl
group of 4-hydroxybenzyl alcohol, 7c (Scheme 3): A solution of
tetrabutylammonium fluoride (TBAF) (0.487 g, 2 mmol, 1 equiv)
and AgNO3 (1.7 mg, 0.01 mmol, 0.5 mol%) was stirred magnetically
in distilled iPrOH (4 mL) at 80 ◦C for 15 min. Then the temperature
of the solution was reduced to 60 ◦C into which were added 6b
(0.300 g, 2 mmol) and 4-hydroxybenzyl alcohol 7c (0.248 g, 2 mmol,
1 equiv). Upon completion of the reaction (7 h, monitored by TLC),
i
the reaction mixture was cooled to rt and PrOH was removed in
Method C: Typical procedure for epoxide phenolysis catalysed
by the in situ generated AgNPs in DEF in the absence of TBAF
(Table 2, entry 2): The solution of AgNO3 (1.7 mg, 0.01 mmol,
0.5 mol%) was stirred magnetically in DEF (4 mL) at 80 ◦C for ∼5 min.
The oil-bath temperature was reduced to 60 ◦C followed by addi-
tion of 6a (0.369 g, 2 mmol) and 7a (0.248 g, 2 mmol) and the
mixture was further stirred magnetically at 60 ◦C until comple-
tion of the reaction (6 h, TLC). The reaction mixture was cooled to
rt; diluted with H2O (10 mL) and extracted with dichloromethane
(2 × 5 mL). The dichloromethane layer was separated from the
aqueous layer, dried (anh Na2SO4); filtered off and evaporated
to dryness under vacuum (30 mm Hg). The residue was passed
through chromatography column (silica-gel; 60–120 mesh) and
eluted with hexane–EtOAc (93:7) to afford the 8a as off white solid
(0.388 g, 63%).
rotary evaporator under vacuum. The crude mixture was diluted
with H2O (10 mL) and extracted with EtOAc (2 × 5 mL). The EtOAc
layer was separated from the aqueous layer, dried (anh Na2SO4); fil-
tered off and evaporated to dryness under vacuum (30 mm Hg). The
residue was passed through chromatography column (silica-gel;
60–120 mesh) and eluted with hexane–EtOAc solvent system to
afford the 1-(4-hydroxymethyl-phenoxy)-3-phenoxy-propan-2-ol
8d as off white semi-solid (0.362 g, 66%). IR (Neat) ꢀmax: 3437, 2928,
1633, 1490 cm−1; 1H NMR (CDCl3, 400 MHz) ı (ppm): 4.10–4.19 (m,
4H), 4.36–4.40 (m, 1H), 4.61 (s, 2H), 6.90–7.01 (m, 6H), 7.28–7.34
(m, 3H); 13C NMR (CDCl3, 100 MHz) ı (ppm): 64.8, 68.7, 68.8, 68.9,
114.6, 114.6, 121.3, 128.7, 129.6, 133.7, 158.0, 158.4; HRMS (ESI)
[M+Na]+ = 297.1109; Calculated = 297.1103.
Method B: Typical procedure of intramolecular competition
study between phenolic hydroxyl group and alcoholic hydroxyl

166
K. Seth et al. / Journal of Molecular Catalysis A: Chemical 392 (2014) 164–172
group of 4-hydroxybenzyl alcohol, 7c (Scheme 3): A solution of
tetrabutylammonium fluoride (TBAF) (0.244 g, 1 mmol, 0.5 equiv)
and AgNO3 (1.7 mg, 0.01 mmol, 0.5 mol%) was stirred magneti-
cally in DEF (4 mL) at 80 ◦C for ∼5 min. Then the temperature
of the solution was reduced to 60 ◦C into which were added 6b
(0.300 g, 2 mmol) and 7c (0.248 g, 2 mmol, 1 equiv). Upon comple-
tion of the reaction (7.5 h, monitored by TLC), the reaction mixture
was cooled to rt; diluted with water (10 mL) and extracted with
dichloromethane (2 × 5 mL). The dichloromethane layer was sepa-
rated from the aqueous layer, dried (anh Na2SO4); filtered off and
evaporated to dryness under vacuum (30 mm Hg). The residue was
passed through chromatography column (silica-gel; 60–120 mesh)
and eluted with hexane–EtOAc (93:7) to afford the 8d as off white
semi-solid (0.384 g, 70%).
Method C: Typical procedure of intramolecular competition
study between phenolic hydroxyl group and alcoholic hydroxyl
group of 4-hydroxybenzyl alcohol, 7c (Scheme 3): A mixture of
AgNO3 (1.7 mg, 0.01 mmol, 0.5 mol%) was stirred magnetically in
DEF (4 mL) at 80 ◦C for ∼5 min. Then the temperature of the solution
was reduced to 60 ◦C into which were added 6b (0.300 g, 2 mmol)
and 7c (0.248 g, 2 mmol, 1 equiv). Upon completion of the reac-
tion (9 h, monitored by TLC), the reaction mixture was cooled to rt;
diluted with water (10 mL) and extracted with dichloromethane
(2 × 5 mL). The dichloromethane layer was separated from the
aqueous layer, dried (anh Na2SO4); filtered off and evaporated
to dryness under vacuum (30 mm Hg). The residue was passed
through chromatography column (silica-gel; 60–120 mesh) and
eluted with hexane–EtOAc (93:7) to afford the 8d as off white
semi-solid (0.291 g, 53%).
2-(2-Hydroxy-3-phenoxy-propoxy)-benzoic acid (Table 2,
entry 22): White liquid; IR (Neat) ꢀmax: 3421, 2927, 1675, 1487,
1246 cm−1 1H NMR (CDCl3, 400 MHz) ı (ppm): 2.85 (bs, 1H, D2O
;
exchangeable), 4.06–4.14 (m, 2H), 4.37–4.38 (m, 1H), 4.51–4.58
(m, 2H), 6.86–6.93 (m, 3H), 6.97–6.99 (m, 2H), 7.24–7.31 (m, 2H),
7.44–7.48 (m, 1H), 7.84–7.86 (m, 1H), 10.64 (bs, 1H, D2O exchange-
able); 13C NMR (CDCl3, 100 MHz) ı (ppm): 66.0, 68.5, 68.6, 112.1,
114.6, 117.7, 119.3, 121.5, 129.6, 130.0, 136.1, 158.2, 161.7, 170.1.
HRMS (ESI) [M+Na]+ = 311.0896; Calculated =311.0895.
1-(4-Benzothiazol-2-yl-phenoxy)-3-phenoxy-propan-2-ol
(Table 2, entry 26): Off white solid; mp: 115–117 ◦C; IR (KBr)
ꢀmax: 3438, 2929, 1635, 1492 cm−1 1H NMR (CDCl3, 400 MHz)
;
ı (ppm): 2.67 (bs, 1H, D2O exchangeable), 4.17–4.21 (m, 2H),
4.22–4.29 (m, 2H), 4.45 (bs, 1H), 6.96–7.02 (m, 3H), 7.04–7.07 (m,
2H), 7.30–7.40 (m, 3H), 7.49 (dt, 1H, J = 1.1 Hz, 8.2 Hz), 7.90 (d, 1H,
J = 7.8 Hz), 8.04–8.08 (m, 3H); 13C NMR (CDCl3, 100 MHz) ı (ppm):
68.6, 68.7, 69.0, 114.6, 115.0, 121.4, 121.5, 122.9, 124.9, 126.2,
127.0, 129.2, 129.6, 134.9, 154.2, 158.3, 160.7, 167.6; HRMS (ESI)
[M+Na]+ = 400.0988, Calculated = 400.0983.
2-tert-Butoxycarbonylamino-3-[4-(2-hydroxy-3-phenoxy-
propoxy)-phenyl]-propionic acid ethyl ester (Table 2, entry 27):
Off white semi-solid; IR (Neat) ꢀmax: 3438, 2929, 1711, 1689,
1633, 1490 cm−1 1H NMR (CDCl3, 400 MHz) ı (ppm): 1.25 (t, 3H,
;
J = 7.2 Hz), 1.43 (s, 9H), 2.72 (bs, 1H, D2O exchangeable), 3.02–3.06
(m, 2H), 4.13–4.20 (m, 6H), 4.37–4.40 (m, 1H), 4.51–4.54 (m, 1H),
4.99–5.01 (m, 1H), 6.85–6.88 (m, 2H), 6.94–6.97 (m, 2H), 6.98–7.01
(m, 1H), 7.05–7.08 (m, 2H), 7.28–7.33 (m, 2H); 13C NMR (CDCl3,
100 MHz) ı (ppm): 14.2, 28.3, 37.5, 54.6, 61.3, 68.7, 68.8, 79.8,
114.6, 114.6, 121.3, 128.8, 129.5, 130.4, 155.1, 157.5, 158.4, 171.9;
HRMS (ESI) [M+Na]+ = 482.2160; Calculated = 482.2155.
1-(4-Methoxy-phenoxy)-3-phenylsulfanyl-propan-2-ol
2.6. Typical procedure for the recovery and recyclability of AgNPs
catalytic system for the opening of 6a with 7a
(Table 2, entry 31): Yellow liquid; IR (Neat) ꢀmax: 3437, 2921,
1663, 1277 cm−1 1H NMR (CDCl3, 400 MHz) ı (ppm): 2.89 (bs, 1H,
;
D2O exchangeable), 3.12 (dd, 1H, J = 6.9 Hz, 13.8 Hz), 3.22 (dd, 1H,
J = 5.6 Hz, 13.8 Hz), 3.74 (s, 3H), 3.94–4.01 (m, 2H), 4.04–4.10 (m,
1H), 6.80 (s, 4H), 7.16–7.20 (m, 1H), 7.24–7.28 (m, 2H), 7.38–7.40
(m, 2H); 13C NMR (CDCl3, 100 MHz) ı (ppm): 37.5, 55.7, 68.7, 71.0,
114.7, 115.6, 126.6, 129.1, 129.8, 135.3, 152.6, 154.2; HRMS (ESI)
[M+Na]+ = 313.0879; Calculated = 313.0874.
The mixture of TBAF (0.487 g, 2 mmol) and AgNO3 (1.7 mg,
0.01 mmol, 0.5 mol%) in iPrOH (4 mL) was stirred magnetically
under reflux (oil-bath temp 80 ◦C) for 15 min. The oil-bath tem-
perature was reduced to 60 ◦C followed by addition of 6a (0.369 g,
2 mmol) and 7a (0.248 g, 2 mmol) and the mixture was further
stirred magnetically at 60 ◦C until completion of the reaction (6 h,
TLC). The reaction mixture was cooled to rt and iPrOH was removed
in rotary evaporator under vacuum. The crude mixture was diluted
with H2O (10 mL) and was extracted with EtOAc (2 × 5 mL) to iso-
late the product and other organic contents. The aqueous layer
(contains the AgNPs) was transferred to a round bottom flask
(25 mL) and concentrated under rotary vacuum evaporation to
obtained the recovered AgNPs. The flask containing the recovered
AgNPs was charged with iPrOH (4 mL), 6a (2 mmol) and 7a (2 mmol,
1 equiv) and the mixture was magnetically stirred at 60 ◦C (oil-bath)
for 6 h to obtain 8a in 75% yield after usual workup and purification.
The fresh batches of reaction involving 6a (2 mmol) and 7a (2 mmol,
1 equiv) were repeated for five consecutive times with the recov-
ered AgNPs after each fresh reaction to obtain 8a in 75, 73, 66, 60,
and 53% yields. The decrease in yield after on 5th reuse was due to
the increase of size of the recovered AgNPs as determined by TEM.
2-Hydroxy-3-(4-methoxy-phenoxy)-3-(4-methoxy-phenyl)-
propionic acid methyl ester (Table 2, entry 33): Yellow liquid;
IR (Neat) ꢀmax: 3439, 2958, 1726, 1460, 1277 cm−1
;
1H NMR
(CDCl3, 400 MHz) ı (ppm): 3.37 (bs, 1H, D2O exchangeable), 3.65
(s, 3H), 3.71 (s, 3H), 3.73 (s, 3H), 4.40 (s, 1H), 5.36 (d, 1H, J = 2.8 Hz),
6.67–6.73 (m, 2H), 6.74–6.77 (m, 2H), 6.82–6.87 (m, 2H), 7.29–7.32
(m, 2H); 13C NMR (CDCl3, 100 MHz) ı (ppm): 52.6, 55.2, 55.6, 75.2,
81.4, 114.0, 114.5, 117.4, 128.2, 129.1, 151.6, 154.3, 159.5, 172.4;
HRMS (ESI) [M+Na]+ = 355.1163; Calculated = 355.1158.
Typical procedure for the preparation of 4-benzothiazol-2-
yl-phenol (starting phenol substrate for entry 26, Table 2): To
a magnetically stirred suspension of SDOSS (0.222 g, 0.5 mmol,
5 mol%) in water (50 mL) were added 4-hydroxy benzaldehyde
(1.221 g, 10 mmol) and 2-aminothiophenol (1.502 g, 12 mmol,
1.2 equiv) and the mixture was stirred magnetically at 40 ◦C.
After completion of the reaction (1.5 h, TLC), the mixture was
extracted with EtOAc (2 × 20 mL). The EtOAc layer was sepa-
rated from the aqueous layer, dried (anh Na2SO4); filtered off and
evaporated to dryness under vacuum (30 mm Hg). The residue
was purified by column chromatography (60–120 mesh silica-gel)
using hexane/EtOAc solvent system to afford the 4-benzothiazol-
2-yl-phenol as off white solid (1.977 g, 87%). mp: 213–215 ◦C;
2.7. Characterisation of the unknown compounds
4-(2-Hydroxy-3-phenoxy-propoxy)-benzoic acid (Table 2,
entry 21): Off white solid; mp: 121–123 ◦C; IR (Neat) ꢀmax: 3420,
2933, 1782, 1698, 1595, 1218 cm−1 1H NMR (CD3OD, 400 MHz) ı
;
(ppm): 4.08–4.11 (m, 2H), 4.27–4.30 (m, 1H), 4.38–4.46 (m, 2H),
6.82–6.85 (m, 2H), 6.91–6.96 (m, 3H), 7.24–7.28 (m, 2H), 7.90–7.93
(m, 2H); 13C NMR (CD3OD, 100 MHz) ı (ppm): 66.8, 69.3, 70.2,
115.6, 115.8, 116.2, 122.1, 130.5, 133.0, 160.2, 163.6, 168.2; HRMS
(ESI) [M+Na]+ = 311.0898; Calculated = 311.0895.
IR (KBr) ꢀmax: 3437, 2926, 1633, 1491 cm−1 1H NMR (CDCl3,
;
400 MHz) ı (ppm): 5.51 (bs, 1H, D2O exchangeable), 6.93–6.95
(m, 2H), 7.34–7.38 (m, 1H), 7.45–7.49 (m, 1H), 7.87–7.89 (m, 1H),
7.98–8.00 (m, 2H), 8.02–8.04 (m, 1H); 13C NMR (CDCl3 + CD3OD,
100 MHz) ı (ppm): 116.5, 122.1, 122.6, 125.3, 125.5, 126.9, 129.8,

K. Seth et al. / Journal of Molecular Catalysis A: Chemical 392 (2014) 164–172
167
134.9, 154.2, 160.9, 169.9; HRMS (ESI) [M+Na]+ = 250.0310; Calcu-
lated = 250.0303.
125.8, 126.4, 127.2, 127.4, 128.5, 128.8, 134.5, 139.8, 154.5; HRMS
(ESI) [M+Na]+ = 631.3517; Calculated = 631.3512. [ee = 97.89%].
HPLC (2-propanol–hexane): Peak 1 tR 21.4 min (area 1.1%); peak 2
tR 24.6 min (area 98.9%).
Typical
procedure
for
the
preparation
of
2-
phenylsulfanylmethyl-oxirane (starting epoxide for entry
31, Table 2): To a magnetically stirred solution of K2CO3 (2.760 g,
20 mmol, 2 equiv) and thiophenol (1.102 g, 10 mmol, 1.03 mL,
1 equiv) in anh CH3CN (20 mL) was added epichlorohydrin
(0.925 g, 10 mmol, 0.78 mL, 1 equiv) and the mixture was stirred
magnetically at 70 ◦C. After completion of the reaction (8 h,
TLC), the reaction mixture was cooled to rt, filtered off and
the solvent was evaporated to dryness under vacuum (30 mm
Hg). The residual was purified by column chromatography
(60–120 mesh silica-gel) using hexane/EtOAc solvent system
to afford the 2-phenylsulfanylmethyl-oxirane as light yellow
Step 3: Typical procedure for the preparation of (S)-propranolol
[23] 4 (Scheme 5): A solution of 10 (0.349 g, 1 mmol) and 10%
Pd/C catalyst (0.040 g) in ethanol (10 mL) was shaken in a Parr
hydrogenator at 60 kg/cm2 hydrogen pressure and at rt for 24 h.
The mixture was filtered through a pad of celite and solvent
was evaporated to dryness under vacuum. The residual was puri-
fied by column chromatography (60–120 mesh silica-gel) using
hexane/EtOAc solvent system to afford the 4 as brown solid
(0.228 g, 88%). IR (KBr) ꢀmax: 3432, 2950, 1647, 1400, 1019 cm−1
;
1H NMR (CDCl3, 400 MHz) ı (ppm): 1.15 (d, 6H, J = 6.3 Hz), 2.59
(bs, 2H, D2O exchangeable), 2.87–2.94 (m, 2H), 3.04 (dd, 1H,
J = 3.4 Hz, 12.2 Hz), 4.13–4.19 (m, 1H), 4.20–4.24 (m, 2H), 6.85 (d,
1H, J = 7.5 Hz), 7.37–7.41 (m, 1H), 7.48–7.54 (m, 3H), 7.82–7.84 (m,
1H), 8.26–8.28 (m, 1H); MS (ESI) m/z: 259.6 (M+). [ee = 97.95%].
HPLC (2-propanol–hexane): Peak 1 tR 14.8 min (area 1.0%); peak
2 tR 17.6 min (area 99.0%).
liquid (0.166 g, 10%). IR (Neat) ꢀmax: 2988, 1654, 1749 cm−1
;
1H NMR (CDCl3, 400 MHz) ı (ppm): 2.51 (dd, 1H, J = 2.4 Hz,
4.9 Hz), 2.76–2.78 (m, 1H), 2.91–2.97 (m, 1H), 3.14–3.19 (m,
2H), 7.20–7.24 (m, 1H), 7.27–7.32 (m, 2H), 7.41–7.44 (m,
2H); 13C NMR (CDCl3, 100 MHz)
ı (ppm): 36.7, 47.4, 51.0,
126.8, 129.0, 130.4, 135.3; HRMS (ESI) [M+Na]+ = 189.0355;
Calculated = 189.0350.
2.9. Preparation of (S)-naftopidil
2.8. Preparation of (S)-propranolol
Step 1: Typical procedure for the preparation of (S)-1-(2-
methoxy-phenyl)-4-oxiranylmethyl-piperazine 11 (Scheme 5): To
a magnetically stirred solution of K2CO3 (2.760 g, 20 mmol, 2 equiv)
and 1-(2-methoxy-phenyl)-piperazine (1.923 g, 10 mmol, 1 equiv)
in anh CH3CN (20 mL) was added (R)-epichlorohydrin (0.925 g,
10 mmol, 0.78 mL, 1 equiv) and the mixture was stirred magnet-
ically at reflux. After completion of the reaction (9 h, TLC), the
reaction mixture was cooled to rt, filtered off and the solvent was
evaporated to dryness under vacuum. The residual was purified
by column chromatography (60–120 mesh silica-gel) using hex-
ane/EtOAc solvent system to afford the 11 as colourless liquid
Step 1: Typical procedure for the preparation of (S)-
benzyl-isopropyl-oxiranylmethyl-amine [23] 9 (Scheme 5): To a
magnetically stirred solution of K2CO3 (2.760 g, 20 mmol, 2 equiv)
and N-iPr benzyl amine (1.492 g, 10 mmol, 1 equiv) in anh CH3CN
(20 mL) was added (R)-epichlorohydrin (0.925 g, 10 mmol, 0.78 mL,
1 equiv) and the mixture was stirred magnetically at reflux.
After completion of the reaction (10 h, TLC), the reaction mix-
ture was cooled to rt, filtered off and the solvent was evaporated
to dryness under vacuum. The residual was purified by column
chromatography (60–120 mesh silica-gel) using hexane/EtOAc
solvent system to afford the 9 as colourless oil (1.499 g, 73%).
(1.738 g, 70%). IR (Neat) ꢀmax: 2924, 1744, 1670, 1597, 1259 cm−1
;
IR (Neat) ꢀmax: 2928, 1677, 1597, 1259 cm−1 1H NMR (CDCl3,
;
1H NMR (CDCl3, 400 MHz) ı (ppm): 2.74–2.82 (m, 6H), 3.08 (bs,
4H), 3.86 (s, 3H), 4.22–4.26 (m, 1H), 4.53–4.57 (m, 1H), 4.82–4.90
(m, 1H), 6.86–6.88 (m, 1H), 6.92–6.94 (m, 2H), 6.99–7.02 (m,
1H); 13C NMR (CDCl3, 100 MHz) ı (ppm): 50.5, 54.2, 55.4, 60.1,
68.0, 75.2, 111.2, 118.2, 121.0, 123.1, 140.9, 152.2; HRMS (ESI)
[M+Na]+ = 271.1427; Calculated = 271.1422. [ee = 99.96%]. HPLC (2-
propanol–hexane): Peak 1 tR 18.7 min (area 0.02%); peak 2 tR
20.9 min (area 99.98%).
400 MHz) ı (ppm): 1.03 (d, 3H, J = 6.6 Hz), 1.06 (d, 3H, J = 6.6 Hz),
2.40 (dd, 1H, J = 2.7 Hz, 5.0 Hz), 2.53–2.58 (m, 1H), 2.60–2.65 (m,
2H), 2.92–2.95 (m, 1H), 3.03–3.08 (m, 1H), 3.53 (d, 1H, J = 14.1 Hz),
3.74 (d, 1H, J = 14.1 Hz), 7.22–7.26 (m, 1H), 7.28–7.32 (m, 2H),
7.36–7.38 (m, 2H); MS (ESI) m/z: 205.5 (M+). [ee = 97.66%]. HPLC (2-
propanol–hexane): Peak 1 tR 6.4 min (area 1.2%); peak 2 tR 12.5 min
(area 98.8%).
Step 2: Typical procedure for the preparation of (S)-1-(benzyl-
isopropyl-amino)-3-(naphthalen-1-yloxy)-propan-2-ol [23] 10
using in situ generated AgNPs (Scheme 5): The mixture of
TBAF (0.730 g, 3 mmol, 1 equiv) and AgNO3 (2.5 mg, 0.015 mmol,
0.5 mol%) was stirred magnetically in iPrOH (6 mL) at 80 ◦C for
15 min. Then the temperature of the solution was reduced to
60 ◦C into which were added 9 (0.616 g, 3 mmol) and 1-naphthol
(0.432 g, 3 mmol, 1 equiv). Upon completion of the reaction (13 h,
TLC), the reaction mixture was cooled to rt and iPrOH was removed
in rotary evaporator under vacuum. The crude mixture was diluted
with H2O (15 mL) and extracted with EtOAc (3 × 5 mL). The EtOAc
layer was separated from the aqueous layer, dried (anh Na2SO4);
filtered off and evaporated to dryness under vacuum (30 mm
Hg). The residue was passed through chromatography column
(silica-gel; 60–120 mesh) and eluted with hexane–EtOAc to afford
the 10 as colourless liquid (0.598 g, 57%). IR (Neat) ꢀmax: 2930,
Step 2: Typical procedure for the preparation of (S)-naftopidil,
5 using in situ generated AgNPs (Scheme 5): The mixture of
TBAF (0.730 g, 3 mmol, 1 equiv) and AgNO3 (2.5 mg, 0.015 mmol,
0.5 mol%) was stirred magnetically in iPrOH (6 mL) at 80 ◦C for
15 min. Then the temperature of the solution was reduced to
60 ◦C into which were added 11 (0.744 g, 3 mmol) and 1-naphthol
(0.432 g, 3 mmol, 1 equiv). Upon completion of the reaction (13 h,
TLC), the reaction mixture was cooled to rt and iPrOH was removed
in rotary evaporator under vacuum. The crude mixture was diluted
with H2O (15 mL) and extracted with EtOAc (3 × 5 mL). The EtOAc
layer was separated from the aqueous layer, dried (anh Na2SO4);
filtered off and evaporated to dryness under vacuum (30 mm Hg).
The residue was passed through chromatography column (silica-
gel; 60–120 mesh) and eluted with hexane–EtOAc to afford the 5
as off white solid (0.565 g, 48%). IR (KBr) ꢀmax: 3433, 2950, 1650,
1400, 1014 cm−1 1H NMR (CDCl3, 400 MHz) ı (ppm): 2.74–2.78
;
1676, 1599, 1263 cm−1 1H NMR (CDCl3, 400 MHz) ı (ppm): 1.09
;
(m, 4H), 2.94–2.97 (m, 2H), 3.16 (bs, 4H), 3.71 (bs, 1H), 3.89 (s, 3H),
4.18–4.21 (m, 1H), 4.24–4.27 (m, 1H), 4.30–4.35 (m, 1H), 6.86–6.91
(m, 2H), 6.94–7.00 (m, 2H), 7.02–7.06 (m, 1H), 7.38–7.42 (m, 1H),
7.46–7.54 (m, 3H), 7.81–7.84 (m, 1H), 8.29–8.32 (m, 1H); MS (ESI)
m/z: 392.7 (M+). [ee = 98.00%]. HPLC (2-propanol–hexane): Peak 1
tR 17.0 min (area 1.0%); peak 2 tR 20.1 min (area 99.0%).
(d, 3H, J = 6.6 Hz), 1.17 (d, 3H, J = 6.6 Hz), 2.78 (d, 2H, J = 6.6 Hz),
3.03–3.11 (m, 1H), 3.61 (d, 1H, J = 13.6 Hz), 3.70 (bs, 1H, D2O
exchangeable), 3.82 (d, 1H, J = 13.6 Hz), 4.06–4.18 (m, 3H), 6.80 (d,
1H, J = 7.5 Hz), 7.29–7.41 (m, 6H), 7.44–7.53 (m, 3H), 7.81–7.83 (m,
1H), 8.18–8.21 (m, 1H); 13C NMR (CDCl3, 100 MHz) ı (ppm): 15.8,
20.3, 50.0, 51.9, 54.7, 66.0, 70.3, 104.7, 120.4, 122.0, 125.2, 125.6,

168
K. Seth et al. / Journal of Molecular Catalysis A: Chemical 392 (2014) 164–172
Ru(III) were also used to determine the efficiency of the respective
metal NPs but were found to be inferior to AgNP.
Further experiments (entries 1, 16–18) revealed that the use
of 1 mol% of AgNO3 along with 1 equiv of TBAB afforded the opti-
mised yield. No improvement in yield was observed in using larger
amount (2 equiv) of TBAB (entry 20) but lesser amount (50 mol%)
gave lesser yield (entry 19). The use of PdCl2 along with 1 equiv
of TBAB afforded lesser (40%) yield (entry 21). The use of AgNO3
along with TBAB is essential as the epoxide phenolysis does not
take place in using either AgNO3 (entry 22) or TBAB (entry 23)
alone. The reaction mixture becomes yellow when both AgNO3 and
TBAB are present indicating the formation of the AgNP and was sup-
ported by the absorption at 350 nm in the UV ([12]; see Supporting
Information).
Scheme 1. Epoxide-phenol synchronous dual activation by AgNP.
3. Results and discussion
A base-free protocol for epoxide phenolysis would require
activation of the substrates. Although the Lewis acid-catalysed elec-
trophilic activation of the epoxide ring remains the mainstay of
epoxide aminolysis [4] and thiolysis [5] the strategy does not work
for the phenolysis [6] and urges for epoxide-phenol dual activation.
The activation of sulfur atom occurs at AgNP surface [7]. It was
anticipated that the AgNP would, on a similar fashion, activate
the oxygen atom of the epoxide ring. This prompted to invoke a
catalytic model (Scheme 1) for ‘epoxide-phenol synchronous acti-
vation’ by AgNP that would induce activation of the epoxide ring
(electrophile) through coordination with the epoxide oxygen lone
pair of electrons and in turn would be involved in charge transfer
(anion–␲ type) interaction with the aromatic ring of the phe-
nol (nucleophile activation) [8]. The phenolic hydroxyl hydrogen
would participate in hydrogen bond (HB) formation in a cooper-
ative manner [9] and render rigidity to the transition state I and
would also further contribute towards the activation of the epoxide
ring.
Alcohols with ␣-hydrogen form metal nanoparticles (MNPs)
from the precursor metal salts under base-free condition [10].
Therefore, in a model study, 4-chlorophenyl glycidyl ether 6a was
treated with 4-methoxyphenol 7a in the presence of various metal
salts and TBAB (1 equiv) as the stabiliser [11] in MeOH under reflux
(oil bath temp 65 ◦C) for 8.5 h to from 8a (Table 1). During prelim-
inary studies various Ag salts were used (10 mol%). The best result
(60% yield) was obtained with AgNO3 and other Ag compounds such
as AgOAc, AgBF4, and AgOTf gave inferior yields (51–52%). The com-
pounds of other metals such as Au(III), Cu(II), Pd(II/0), In(III) and
As the MNP formation under neutral condition is dependent on
the solvent the effect of various solvents in generating the MNPs
from the precursor metal salts was evaluated for the reaction of 6a
with 7a to form 8a (Supporting Information) The epoxide phenoly-
sis was achieved to form 8a in 77% yield in using 0.5 mol% of AgNO3
i
and 1 equiv of TBAB in PrOH (2 mL mmol−1 of 6a) under reflux
(bath temp 80 ◦C) for 8.5 h. A decrease in the amount of AgNO3 (up
to 0.1 mol%) or TBAB (up to 0.25 equiv) gave lesser yields (0–44%).
Lowering the reaction temperature to 65 or 40 ◦C also had detri-
mental effect (69 and 27% yields, respectively. A decrease in the
yield (54%) was observed in carrying out the reaction for lesser time
period (6 h). The use of other silver salts, e.g., AgOAc, AgOTf, AgBF4
as the pre-catalyst afforded inferior yields (34–49%). To assess the
catalytic potential of other MNPs various Pd(II), Au(III), and Cu(II)
compounds were used as the pre-catalysts/precursors for the cor-
responding MNPs. The use of PdCl2, Pd(OAc)2, and Pd(dba)2, gave
poor to moderate yields (16–64%) indicating PdNPs to be less effec-
tive than the AgNPs [13]. The poor yields (37 and 19%, respectively)
were obtained in using HAuCl4 and Cu(OAc)2·H2O demonstrating
the inferior catalytic potential of the Ag/CuNPs.
The importance of the use of iPrOH as the solvent was realised
by the fact that the use of other solvents such as EtOH, ethylene
glycol, glycerol, water, toluene, THF, MeCN, and NMP gave poor
yields (0–34%). However, moderate yields (56–65%) were obtained
in formamide and DMF. A distinct superior effect of the secondary
alcohol was observed when nPrOH (39% yield) was compared with
iPrOH (77% yield). Similarly 2-butanol was the most effective (78%
yield) compared to nBuOH (52% yield) and tBuOH (23% yield). Cyclic
secondary alcohol, e.g., cyclohexanol proved to be ineffective as
it did not lead to epoxide phenolysis. The optimal amount of the
iPrOH was found to be 2 mL per mmol of the epoxide as use of lesser
amount (0.5–1 mL) gave decreased yields (39 and 57%, respectively)
and no significant change in the product yield (76%) in using higher
amounts (4–8 mL) of the solvent (see Supporting Information).
As the stabiliser plays important role during the MNP for-
mation due to their ability to prevent agglomerisation of the
MNPs, various ionic (cationic and anionic), nonionic and Brørnsted
acid stabilisers were used during the AgNP-catalysed reaction of
6a with 7a (Table 2) (see Supporting Information). The TBAF,
TBACl, and TBAB afforded comparable yields (75–77%) in per-
forming the reaction for 8.5 h but TBAI gave lesser yield (60%)
and others were ineffective. However, the use of TBAF proved
to be beneficial as it afforded 75% yield in lesser time (6 h)
whereas TBAB and TBACl afforded lesser yields (54 and 55%,
respectively). The necessity of the catalytic assistance by AgNPs
for epoxide phenolysis is demonstrated by the fact that the
epoxide phenolysis did not take place in performing the reac-
tion in the presence of TBAF (1 equiv) alone (in the absence of
AgNO3).
Table 1
Base-free epoxide phenolysis of 6a with 7a to form 8a.a
Entry
Pre-catalyst (mol%)
Stabiliser (equiv)
Yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
AgNO3 (10)
AgOAc (10)
AgOTf (10)
TBAB (1)
TBAB (1)
TBAB (1)
TBAB (1)
TBAB (1)
TBAB (1)
TBAB (1)
TBAB (1)
TBAB (1)
TBAB (1)
TBAB (1)
TBAB (1)
TBAB (1)
TBAB (1)
TBAB (1)
TBAB (1)
TBAB (1)
TBAB (1)
TBAB (0.5)
TBAB (2)
TBAB (1)
None
60c
51
52
51
41
39
31
44
51
22
20
Trace
14
17
14
61
60
61
21
62
40
0
AgBF4 (10)
HAuCl4 (10)
Cu(OAc)2·H2O (10)
Na2PdCl4 (10)
Pd(OAc)2 (10)
PdCl2 (10)
Pd(PPh3)4 (10)
Pd2(dba)3 (10)
[Pd(PPh3)2Cl2] (10)
Pd/C (10)
InCl3 (10)
RuCl3·xH2O (10)
AgNO3 (5)
AgNO3 (2.5)
AgNO3 (1)
AgNO3 (1)
AgNO3 (1)
PdCl2 (1)
AgNO3 (1)
None
TBAB (1)
0
a
The epoxide 6a (2 mmol) was treated with the phenol 7a (2 mmol) under various
conditions in MeOH (4 mL) for 8.5 h.
The moderate yields (56–65%) obtained in formamide and
DMF indicated their potential to form AgNP and encouraged for
further studies to derive any beneficial effects on the use of
b
Isolated yield of 8a.
c
No reaction took place when 6a was subjected to similar treatment in the
absence of 7a and the starting material was recovered.

K. Seth et al. / Journal of Molecular Catalysis A: Chemical 392 (2014) 164–172
169
Scheme 2. Epoxide-phenolysis performed under basic condition following reported procedure with a few selected base-sensitive substrates.
DMF or formamide as the solvent (see Supporting Information).
It was observed that the amount of TBAF can be reduced to
50 mol% to afford 74% yield in using DEF as the solvent. Fur-
ther, the use of TBAF can be avoided altogether in performing
the reaction in DEF to afford the desired product in 63–65%
yields.
Further studies (see Supporting Information) indicated that
the temperature has significant role in the AgNP formation and
the optimal condition is 80 ◦C forming the NPs in 15 min in
iPrOH and in ∼5 min in DEF. Thereafter the temperature can be
reduced to 60 ◦C for the epoxide phenolysis without any decrease
in the product yield. No significant change in the size of the
AgNPs was observed in preparing the NPs at 80 ◦C and subse-
quently reducing to 60 ◦C. Therefore, the two-stage procedure
was adopted for the subsequent studies on general applica-
tions.
Thus three methods are derived for the AgNP-catalysed epoxide
phenolysis under base-free conditions: (i) formation of the AgNP by
the treatment of the AgNO3 (0.5 mol%) in 2-propanol under reflux
at 80 ◦C for 15 min in the presence of TBAF (1 equiv to the epox-
ide) followed by the addition of the epoxide and the phenol to the
in situ formed AgNPs at 60 ◦C (Method A), (ii) formation of the AgNP
by the treatment of the AgNO3 (0.5 mol%) in DEF under heating at
80 ◦C for ∼5 min in the presence of TBAF (0.5 equiv to the epox-
ide) followed by the addition of the epoxide and the phenol to the
in situ formed AgNPs at 60 ◦C (Method B), and (iii) formation of
the AgNP by the treatment of the AgNO3 (0.5 mol%) in DEF under
heating at 80 ◦C for ∼5 min followed by the addition of the epox-
ide and the phenol to the in situ formed AgNPs at 60 ◦C (Method
C).
Various epoxides (glycidyl and non-glycidyl) on treatment with
differently substituted phenols afforded the epoxide phenolysis
products in good to excellent yields (Table 2). Excellent regioselec-
tivity was observed for exclusive reaction at the terminal (except
for entry 33, Table 2) carbon of the oxirane moiety. Substrates bear-
ing electron withdrawing groups (entries 4–8, 11, 12, 16, 18, and
20–23; Table 2) took lesser time but those with a substituent ortho
to the phenolic OH group required longer time (entries 15, 17, and
19; Table 2). Excellent functional group tolerability is observed.
The N-Boc tyrosine ethyl ester (entry 27) did not undergo competi-
tive ester [14]/N-Boc [14b,15] cleavage and trans esterification. The
glycidyl ester (entry 33; Table 2) exemplified regio- and chemo-
selectivity with exclusive reaction at the benzylic carbon of the
epoxide ring without competitive transesterification with the phe-
nol or iPrOH. No competitive replacement of the thiophenyl group
(entry 31, Table 2) was observed.
(Scheme 2) performed under basic condition following the reported
procedure [1c].
Thus, the reported procedure does not work for pheno-
lic substrate bearing carboxylic acid group and is devoid of
chemoselectivity for substrates containing an ester group (e.g.,
glycidic esters) leading to hydrolytic cleavage of the ester
group.
The TEM analysis of the reaction mixture identified AgNP
(≈3–8 nm) (Fig. 2a) and was characterised by EDX spectra (Fig. 2b).
The AgNP was recovered and reused for four consecutive times
affording 75, 73, 66, and 60% yields, respectively (Table 3). How-
ever the yield decreased to 53% after fifth reuse due to the increase
in size (100–120 nm) of the recovered AgNP (see Supporting Infor-
mation).
The outcome of the reactions (Table 2) can be rationalised by the
mechanistic proposal on ‘epoxide-phenol synchronous dual acti-
vation by the AgNPs’ through cooperative action of coordination,
charge-charge (anion–␲), and HB interaction [16] as depicted in
Scheme 1. The shorter reaction time required for phenols bearing
electron withdrawing substituent (Table 2: compare entries 1–3
with 4–8; 9, 10 with 11 and 12; 13, 14 with 16, 18, 20–23) is due to
the better HB donor ability of the phenolic hydroxyl group in these
substrates that facilitate the formation of I (Scheme 1).
The inferior catalytic potential of the PdNPs could be due to the
(i) larger size of PdNPs (60–70 nm as compared to 3–8 nm size of
the AgNPs) because of faster reduction of Pd2+ resulting in agglom-
eration, and (ii) better epoxide activation by more oxophilic AgNPs
(compared to PdNPs). The necessity and influence of the HB forma-
tion involving the phenolic hydroxyl group is reflected by the fact
that no competitive epoxide alcoholysis was observed during the
reactions of 6a with 7a performed in MeOH (Table 1) as compared
to the Lewis acid-catalysed processes [17]. No epoxide alcoholysis
was observed during the treatment of 6a separately with equimolar
amount of EtOH and PhCH2OH in place of a phenol in the presence
of AgNP in iPrOH. To further substantiate the importance of the HB
effect in forming the transition state I (i) intermolecular competi-
tion between two phenols with differential electronic effect and (ii)
intramolecular competition between a phenolic and an alcoholic
hydroxyl group for epoxide phenolysis were designed (Scheme 3).
The 76:24 selectivity towards the product of 4-nitrophenol 7b
in preference to that of 7a during the intermolecular competition
study (Scheme 3) and exclusive selectivity for epoxide phenolysis
compared to epoxide alcoholysis during the intramolecular compe-
tition of 4-hydroxybenzyl alcohol 7c established the involvement
of the HB formation in the transition state I (Scheme 1).
Although the tetra-alkylammonium salts are primarily
required/used as stabiliser to prevent agglomerisation of the
MNPs and no specific amounts have been recommended [11]
for this purpose the differential effectiveness of TBAI, TBAB,
The distinct advantage of the AgNP-catalysed epoxide phe-
nolysis performed under neutral (base free) condition can
be demonstrated through the following selective examples

170
K. Seth et al. / Journal of Molecular Catalysis A: Chemical 392 (2014) 164–172
Table 2
The AgNP-catalysed epoxide phenolysis.
Entry
Epoxide
Phenol
Time (h)
Yield (%)a
OH
O
O
HO
R1
O
R
+
O
(R)Ar
R2
R1
R2
1
2
3
4
5
6
7
8
Ar = 4-Cl-C6H4
R1 = R2 = H
6
6
6
5
5
5
4.5
4.5
6
6
4.5
5
6
6
9
5
6.5
5
6.5
5
76b
75c
80
80
81
83
84
84
74d
77e
87
81
78
80
67
81
72
85
74
83
77
70
85
R1 = H, R2 = OCH3
R1 = H, R2 = Br
R1 = H, R2 = CHO
R1 = H, R2 = Ac
R1 = H, R2 = CO2CH3
R1 = H, R2 = CN
R1 = H, R2 = NO2
R1 = R2 = H
9
Ar = 4-Ac-C6H4
Ar = Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
R1 = H, R2 = OCH3
R1 = H, R2 = NO2
R1 = H, R2 = Ac
R1 = R2 = H
R1 = H, R2 = OCH3
R1 = OCH3, R2 = H
R1 = H, R2 = CHO
R1 = CHO, R2 = H
R1 = H, R2 = Ac
R1 = Ac, R2 = H
R1 = H, R2 = CO2CH3
R1 = H, R2 = CO2H
R1 = CO2H, R2 = H
R1 = H, R2 = NO2
4.5
5.5
4.5
24
9
70
OH
25
26
8
8
74
N
S
67f
OH
O
O
OEt
O
27
8
57g
HN
HO
28
29
30
Ar = 2-Furfuryl
Ar = 1-Naphthyl
R = tBu
R1 = H, R2 = OCH3
6.5
8
77
72
66
R1 = H, R2 = OCH3
6.5
OH
R1
R2
O
HO
O
R1
R2
+
R3
OMe
OMe
R3
31
32
33
R1 = CH2SPh, R2 = R3 = H
R1 = R2 = CH3, R3 = H
R1 = CO2CH3, R2 = H
R3 = 4-OCH3-C6H4
8
8
77
71
8.5
61h
a
Isolated yield of the epoxide phenolysis product following Method A unless otherwise mentioned.
Yields were 76 and 60% for under Methods B and C, respectively.
Yields were 73 and 63% yields under Methods B and C, respectively.
Yields were 77 and 62% after 5.5 and 6 h under Methods B and C, respectively.
Yields were 73 and 60% under Methods B and C, respectively.
Yields were 69 and 55% after 7 and 7.5 h under Methods B and C, respectively.
Yields were 54 and 45% after 8 and 9 h under Methods B and C, respectively.
Yields were 65 and 51% after 8 and 9 h under Methods B and C, respectively.
b
c
d
e
f
g
h

K. Seth et al. / Journal of Molecular Catalysis A: Chemical 392 (2014) 164–172
171
Fig. 2. (a) The HRTEM image of the AgNPs (≈3–8 nm) formed after 15 min by treatment of the mixture of AgNO3 (0.01 mmol) and TBAF (2 mmol) in iPrOH (4 mL) under reflux
prior to the addition of 6a (2 mmol) and 7a (2 mmol). (b) The EDX spectra of AgNPs (formed as described in a) on Cu grid.
Scheme 3. AgNP-catalysed selectivity of epoxide phenolysis.
TBACl, and TBAF suggests some other role played by the tetra-
butylammonium halides in addition to act as the stabiliser. The
associated counter anion (halide anion) may provide assistance
during reduction of the pre-catalyst to form the AgNPs through
the involvement of HB with the ␣ hydrogen of the alcohol [18,19].
The better HB acceptor ability of the fluoride anion compared to
that of the bromide/chloride anion makes it most effective [20]
The inefficiency of the cyclic secondary alcohol, e.g., cyclohexanol
(entry 27, Table 2) is due to the fact that the relevant HB formation
of the axially disposed [21] ␣ hydrogen of cyclohexanol would
involve a higher energy transition state [22]. This further suggests
additional role (apart from acting as stabiliser of the in situ formed
AgNPs) of the tetra-alkylammonium salts in assisting the forma-
tion of the AgNPs through ease of transfer hydrogenation of the
pre-catalyst.
To assess the AgNP-catalysed epoxide phenolysis on chiral sub-
strates with respect to any detrimental effect on the optical purity
of the products, (S)-4-acetylphenylglycidyl ether 6c was subjected
to the AgNP-catalysed phenolysis with 7a and 7b to afford 8e and
8f without any significant loss of optical purity (Scheme 4).
A new strategy was devised for the synthesis of the ␤-adrenergic
blockers (S)-4 and (S)-5 following the AgNP-catalysed epoxide phe-
nolysis (Scheme 5).
Table 3
Reusability of AgNPs for the epoxide phenolysis of 6a with 7a.a
Entry
No. of runs
Yield (%)b
1
2
3
4
5
6
1st use
75
75
73
66
60
53
1st reusec
2nd reusec
3rd reusec
4th reusec
5th reusec
a
The mixture of TBAF (2 mmol) and AgNO3 (0.5 mol%) in iPrOH (4 mL) was heated
under reflux at 80 ◦C (oil-bath) to form the AgNP (15 min) followed by lowering the
temperature to 60 ◦C and addition of 6a (2 mmol) and 7a (2 mmol) and continuing
the reaction until complete consumption of the epoxide (TLC).
b
The isolated yield of 8a.
c
The 6a (2 mmol) was treated with phenol 7a (2 mmol, 1 equiv) in iPrOH (4 mL)
at 60 ◦C in the presence of AgNPs recovered from the previous batch of reaction.
Scheme 4. The AgNP-catalysed phenolysis of (S)-6c with 7a and 7b.

172
K. Seth et al. / Journal of Molecular Catalysis A: Chemical 392 (2014) 164–172
Scheme 5. The AgNP-catalysed synthesis of (S)-4 and (S)-5.
4. Conclusion
[2] S. Matsunaga, J. Das, J. Roels, E.M. Vogl, N. Yamamoto, T. Iida, K. Yamaguchi, M.
Shibasaki, J. Am. Chem. Soc. 122 (2000) 2252–2260.
[3] (a) D.A. Annis, E.N. Jacobsen, J. Am. Chem. Soc. 121 (1999) 4147–4155;
(b) K. Venkatasubbaiah, X. Zhu, E. Kays, K.I. Hardcastle, C.W. Jones, ACS Catal. 1
(2011) 489–492.
[4] (a) B. Pujala, S. Rana, A.K. Chakraborti, J. Org. Chem. 76 (2011) 8768–8780;
(b) Shivani, B. Pujala, A.K. Chakraborti, J. Org. Chem. 72 (2007) 3713–3722;
(c) A.K. Chakraborti, A. Kondaskar, S. Rudrawar, Tetrahedron 60 (2004)
9085–9091;
Epoxide phenolysis is reported for the first time under neutral
(base-free) condition catalysed by the MNPs formed in situ from
the corresponding precursor metal salts through transfer hydro-
genative reduction by the solvent. Amongst the various MNPs, the
AgNPs proved to be the best catalyst system. Excellent chemose-
lectivity is observed with substrates bearing functionalities such
as ester, N-Boc, thiazoline, and carboxylic acid groups that are not
affected due to the potential side reactions, e.g., transesterification
with the alcohol/phenol, N-Boc deprotection, cleavage of the thia-
zoline moiety and ester formation with the carboxylic acid (Method
A). Reactions with non-symmetrical epoxide exhibited excellent
regio-selectivity affording the exclusive formation of the prod-
uct through selective epoxide phenolysis at the terminal carbon
of the epoxide ring with glycidyl ethers and 2-methylpropylene
oxide and at the benzylic carbon of the epoxide ring in methyl 4-
methoxyphenyl glycidate. The AgNP-catalysed epoxide phenolysis
constitutes a new model for synchronously epoxide-phenol dual
activation through cooperative action of coordination (involving
the AgNP and the epoxide oxygen lone pair), anion–␲ interac-
tion, and hydrogen bond formation (between the phenolic OH
and the other lone pair of electron of the epoxide oxygen). The
AgNP-catalysed epoxide phenolysis offers a new synthetic strat-
egy for construction of the essential pharmacophoric feature of a
wide range of therapeutic agents and has been exemplified through
the synthesis of cardiovascular drugs propranolol and naftopidil in
enantio enriched forms.
(d) A.K. Chakraborti, S. Rudrawar, A. Kondaskar, Eur. J. Org. Chem. (2004)
3597–3600;
(e) A.K. Chakraborti, S. Rudrawar, A. Kondaskar, Org. Biomol. Chem. 2 (2004)
1277–1280;
(f) A.K. Chakraborti, A. Kondaskar, Tetrahedron Lett. 44 (2003) 8315–8319;
(g) For review: C. Schneider, Synthesis (2006) 3919–3944.
[5] Shivani, A.K. Chakraborti, J. Mol. Catal. A: Chem. 263 (2007) 137–142.
[6] M. Pineschi, F. Bertolini, R.M. Haak, P. Crotti, F. Macchia, Chem. Commun. (2005)
1426–1428.
[7] W. Gan, B. Xu, H.-L. Dai, Angew. Chem. Int. Ed. 50 (2011) 6622–6625.
[8] A. Kumar, S. Mandal, S.P. Mathew, P.R. Selvakannan, A.B. Mandale, R.V. Chaud-
hari, M. Sastry, Langmuir 18 (2002) 6478–6483.
[9] T. Steiner, Angew. Chem. Int. Ed. 41 (2002) 48–76.
[10] A. Roucoux, J. Schulz, H. Patin, Chem. Rev. 102 (2002) 3757–3778.
[11] (a) J. Kiwi, M. Grätzel, J. Am. Chem. Soc. 101 (1979) 7214–7217;
(b) Z. Deng, D.E. Irish, J. Phys. Chem. 98 (1994) 11169–11177;
(c) S. Özkar, R.G. Finke, J. Am. Chem. Soc. 124 (2002) 5796–5810;
(d) D. Astruc, F. Lu, J.R. Aranzaes, Angew. Chem. Int. Ed. 44 (2005) 7852–7872.
[12] D.D. Evanoff Jr., G. Chumanov, J. Phys. Chem. B 108 (2004) 13948–13956.
[13] K. Seth, S. Raha Roy, B.V. Pipaliya, A.K. Chakraborti, Chem. Commun. 49 (2013)
5886–5888.
[14] (a) M. Namikoshi, B. Kundu, K.L. Reinhart, J. Org. Chem. 56 (1991) 5464–5466;
(b) U. Jacquemard, V. Bénéteau, M. Lefoix, S. Routier, J.Y. Mérour, G. Coudert,
Tetrahedron 60 (2004) 10039–10047.
[15] S. Routier, L. Saugé, N. Ayerbe, G. Coudert, J.Y. Mérour, Tetrahedron Lett. 43
(2002) 589–591.
[16] (a) Cooperativity of charge-charge and HB interaction involving the catalyst and
the reactants has been demonstrated during catalysis by ionic liquids: A. Sarkar,
S. Raha Roy, N. Parikh, A.K. Chakraborti, J. Org. Chem. 76 (2011) 7132–7140;
(b) S. Raha Roy, P.S. Jadhavar, K. Seth, K.K. Sharma, A.K. Chakraborti, Synthesis
(2011) 2261–2267;
Acknowledgments
(c) A. Sarkar, S. Raha Roy, A.K. Chakraborti, J. Chem. Soc. Chem. Commun. 47
(2011) 4538–4540;
(d) S. Raha Roy, A.K. Chakraborti, Org. Lett. 12 (2010) 3866–3869;
(e) A.K. Chakraborti, S. Raha Roy, J. Am. Chem. Soc. 131 (2009) 6902–6903;
(f) A.K. Chakraborti, S. Raha Roy, D. Kumar, P. Chopra, Green Chem. 10 (2008)
1111–1118.
KS, SRR, and DNK thank CSIR (New Delhi) for senior research
fellowships and BVP thanks DST (New Delhi) for INSPIRE junior
research fellowship. Financial support from DST (New Delhi) (no.
SR/S1/OC-33/2008) is also gratefully acknowledged.
[17] (a) A. Dhakshinamoorthy, M. Alvaro, H. Garcia, Chem. Eur. J. 16 (2010)
8530–8536;
Appendix A. Supplementary data
(b) D. Jiang, A. Urakawa, M. Yulikov, T. Mallat, G. Jeschke, A. Baiker, Chem. Eur.
J. 15 (2009) 12255–12262;
(c) C. Schneider, A.R. Sreekanth, E. Mai, Angew. Chem. Int. Ed. 43 (2004)
5691–5694;
(d) J. Barluenga, H. Vázquez-Villa, A. Ballesteros, J.M. González, Org. Lett. 4
(2002) 2817–2819.
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.molcata.
2014.05.011.
[18] H. Hirai, J. Macromol. Sci. Chem. A 13 (1979) 633–649.
[19] (a) Influence of HB during fluoride anion promoted reactions: A.K. Chakraborti,
L. Sharma, M.K. Nayak, J. Org. Chem. 67 (2002) 2541–2547;
(b) M.K. Nayak, A.K. Chakraborti, Chem. Lett. (1998) 297–298.
[20] A. Allerhand, P.V.R. Scheleyer, J. Am. Chem. Soc. 85 (1963) 1233–1237.
[21] J.A. Hirsch, Top. Stereochem. 1 (1967) 199–222.
[22] (a) E.L. Eliel, S.H. Schroeter, T.J. Brett, F.J. Biros, J.-C. Richer, J. Am. Chem. Soc. 88
(1966) 3327–3334;
(b) P. Müller, J.-C. Perlberger, J. Am. Chem. Soc. 98 (1976) 8407–8413.
[23] X.-L. Hou, B.-F. Li, L.-X. Dai, Tetrahedron: Asymmetry 10 (1999)
2319–2326.
References
[1] (a) B. Das, M. Krishnaiah, P. Thirupathi, K. Laxminarayana, Tetrahedron Lett. 48
(2007) 4263–4265;
(b) M.A. Brimble, Y.-C. (William) Liu, M. Trzoss, Synthesis (2007) 1392–
1402;
(c) K. Surendra, N.S. Krishnaveni, Y.V.D. Nageswar, K. Rama Rao, J. Org. Chem.
68 (2003) 4994–4995;
(d) A. Zvagulis, S. Bonollo, D. Lanari, F. Pizzo, L. Vaccaro, Adv. Synth. Catal. 352
(2010) 2489–2496.