A facile enantioselective synthesis of enantiomerically pure (R)-phenoxybenzamine hydrochloride using the hydrolytic kinetic resolution method

Article abstract of DOI:10.1016/j.tetasy.2010.11.011

A practical and highly efficient enantioselective synthesis of (R)-phenoxybenzamine hydrochloride has been described for the first time using Jacobsen's hydrolytic kinetic resolution of a terminal epoxide as a key step and source of chirality.

Full text of DOI:10.1016/j.tetasy.2010.11.011

Tetrahedron: Asymmetry 21 (2010) 2825–2829
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A facile enantioselective synthesis of enantiomerically pure
(R)-phenoxybenzamine hydrochloride using the hydrolytic kinetic resolution
method
Milind D. Nikalje a, , Murugesan Sasikumar a, Murugan Muthukrishnan b,
⇑
⇑
a Department of Chemistry, University of Pune, Pune 411 007, India
b Division of Organic Chemistry, National Chemical Laboratory, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical and highly efficient enantioselective synthesis of (R)-phenoxybenzamine hydrochloride has
been described for the first time using Jacobsen’s hydrolytic kinetic resolution of a terminal epoxide as
a key step and source of chirality.
Received 6 October 2010
Accepted 8 November 2010
Available online 24 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
resolution of an amine intermediate promoted by tartaric acid as a
resolving agent.7c However, these methods have their own intrinsic
Hypertension or high blood pressure remains a major health
challenge facing us today. It affects all age groups and is one of
the primary risk factors for cardiovascular and renal disorders.1 Re-
cent analyses have shown that there were 972 million people living
with hypertension worldwide and it is estimated that this number
will increase to more than 1.56 billion by the year 2025.2 Many well
recognized and successful antihypertensive medications including
disadvantages such as expensive chiral starting materials, undesired
side products, tedious, and time consuming experiments, and so on.
In this context, as part of our ongoing program aimed at improving
the process for the preparation of various pharmaceutically impor-
tant compounds for industrial applications,8 we herein report a con-
cise and simple synthesis of (R)-phenoxybenzamine hydrochloride
employing Jacobsen’s HKR strategy9 as a key step.
a
-blockersareavailabletotreathypertensioneffectively.
are a group of compounds which block the effects of sympa-
thetic nerves on blood vessels by binding to -adrenoreceptors
located on the vascular smooth muscle (Fig. 1). Among these
-blockers, phenoxybenzamine hydrochloride (dibenzylineÒ) 1 is
a-Blockers
2. Results and discussion
a
A retrosynthetic analysis of (R)-phenoxybenzamine hydrochlo-
ride 1 is outlined in Scheme 1. As shown in Scheme 1, we envisaged
that the b-hydroxy ether (S)-3 would serve as a key intermediate
for the synthesis and it can be extended to the advanced amino
precursor (R)-2 by the Fukuyama–Mitsunobu protocol followed
by simple N-alkylation can lead to the target molecule. However,
the number of methods available for the preparation of enantiome-
rically pure aliphatic b-hydroxy ether with high enantiomeric pur-
ity are rather limited.10 Taking this into consideration, we chose
the (S)-phenyl glycidyl ether (S)-4a as a starting point, as it can
be easily obtained with high enantiopurity from its racemic phenyl
glycidyl ether 4 using Jacobsen’s HKR strategy and can be readily
converted to the desired b-hydroxy ether (S)-3 via a regioselective
reductive ring opening.
The synthesis of the key intermediate (S)-3 began from the
readily available phenol as depicted in Scheme 2. Thus, the reac-
tion of phenol 5 with rac-epichlorohydrin in the presence of
K2CO3 in refluxing acetone gave rac-phenyl glycidyl ether 4 in
90% yield. The glycidyl ether 4 was subjected to Jacobsen’s HKR
conditions with 0.55 equiv of water, using the catalyst (R,R)-Salen
Co(III)OAc (0.5 mol %) at ambient temperature for 30 h. After
a
an important b-chloroethylamine class of drug in this series, which
is widely used in the treatment of hypertension.3 It has also found
application in treating benign prostatic hyperplasia (BPH)4 and
hypoplastic left heart syndrome,5 etc. Furthermore, its possible
use in treating erectile dysfunction (ED) is also under investiga-
tion.6 Although it contains one stereogenic carbon center, it is gen-
erally administered as a racemate. However, the (R)-isomer of
phenoxybenzamine hydrochloride is 14.5 times more potent than
its (S)-isomer.7 The synthesis of drugs in their enantiomerically
pure form becomes very important for the pharmaceutical industry,
due to increased demand for more effective, safer single isomers.
To the best of our knowledge, only two methods have been re-
portedintheliteratureforthepreparationof(R)-phenoxybenzamine
hydrochloride. One is a chiral pool approach using the unnatural
amino acid D
-alanine as a starting material.7a The other is the chiral
⇑
Corresponding authors. Tel.: +91 20 25601225; fax: +91 20 25691728 (M.D.N.).
E-mail addresses: mdnikalje@ymail.com (M.D. Nikalje), m.muthukrishnan@
ncl.res.in (M. Muthukrishnan).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.11.011

2826
M. D. Nikalje et al. / Tetrahedron: Asymmetry 21 (2010) 2825–2829
CH3
H3CO
OEt
O
CH3
N
O
Cl
N
H2NO2S
H
(R)-phenoxybenzamine
(R)-tamsulosin
O
O
R
MeO
S
MeO
O
H
N
H
N
O
O
OMe
OMe
WB 4101 (R=H)
mephendioxan (R= p-tolyl)
benoxathian
Figure 1. Examples of some important a-adrenoreceptor antagonists.
CH3
O
N
H
CH3
OH
CH3
Fukuyama-Mitsunobu
reaction
O
O
N
Cl
(R)-Phenoxybenzamine
(R)-2
(S)-3
O
O
Hydrolytic Kinetic
Resolution
O
O
(S)-4a
(R/S)-4
Scheme 1. Retrosynthetic analysis of (R)-phenoxybenzamine.
OH
OH
O
O
O
OH
O
O
i
ii
(R)-4b
(S)-4a
(R,S)-4
5
CH3
OH
O
O
O
O
iii
iv
CH3
N
v
Ns
(R)-7
(S)-3
(S)-4a
Ns = 2-nitrobenzenesulfonyl
CH3
CH3
CH3
O
O
O
vii
N
N
H
vi
N
.HCl
HO
Cl
(R)-2
(R)-8
(R)-phenoxybenzamine hydrochloride1
Scheme 2. Reagents and conditions: (i) ( )-epichlorohydrin, K2CO3, acetone, reflux, 8 h, 90%; (ii) (R,R)-salen Co(III)-A; (iii) LiAlH4, THF, 0 °C, 30 min, 93%; (iv) N-benzyl-2-
nitro-benzenesulfonamide 6, Ph3P, DIAD, THF, rt, 2 h, 79%; (v) thiophenol, K2CO3, acetonitrile, rt, 2 h, 88%; (vi) bromoethanol, K2CO3, ethanol, 110 °C, sealed tube, 72 h, 82%;
(vii) SOCl2, benzene, reflux, 8 h, 52%.
completion of the reaction, the reaction mixture was chromato-
graphed over a silica gel column to give the enantiomerically pure
epoxide (S)-4a from the racemic mixture in 44% yield and >98% ee
(chiralHPLC){[ D = +5.2(c 7.5, CHCl3)}
D = +5.1(c 7.5, CHCl3);lit.9b
a]
[a]

M. D. Nikalje et al. / Tetrahedron: Asymmetry 21 (2010) 2825–2829
2827
(R)-phenoxybenzamine
CH3
O
N
ii
i
(R)-2
Cl
(R)-9
CH3
O
O
N
H3C
(R)-10
Scheme 3. Reagents and conditions (i) ClCH2COCl, Et3N, DCM, 0 °C, 1 h, 78%; (ii) BH3.SMe2, THF, reflux, 1 h, 81%.
along with its diol (R)-4b in 47% yield. The epoxide (S)-4a was con-
4.2. 2-(Phenoxymethyl) oxirane (racemic) 4
verted into the desired b-hydroxy ether (S)-3 via regioselective
reductive ring opening using lithium aluminum hydride in anhy-
drous THF at 0 °C. The structure of (S)-3 was confirmed by the 1H
NMR spectrum with additional evidence from 13C NMR, IR, and
mass spectral data. The chemical shift of the terminal methyl
group appeared as a sharp doublet at d 1.27 ppm (J = 6.0 Hz) in
its 1H NMR spectrum and d 18.7 ppm in its 13C NMR spectrum.
The installation of the N-benzyl moiety was successfully achieved
by treating the b-hydroxy ether (S)-3 with N-benzyl-2-nitro sulfon-
amide 6 via a Fukuyama–Mitsunobu protocol11 and subsequent
denosylation12 to provide the secondary amine (R)-2. To introduce
the chloroethyl moiety on nitrogen, we first acylated the secondary
amine (R)-2 with chloroacetyl chloride in the presence of Et3N to
obtain an amide (R)-9 and then carried out an amide reduction.
However, reduction of amide (R)-9 with a borane-dimethylsulfide
complex was unsuccessful in affording the desired product 1; in-
stead dehalogenated product (R)-10 was isolated as a sole product
(Scheme 3). Finally, the N-alkylation was successfully accom-
plished by treating the secondary amine (R)-2 with bromoethanol
in the presence of K2CO3 as a base in a sealed tube13 at 110 °C for
72 h to give the amino alcohol (R)-8, in which the hydroxyl group
was replaced by a chloride using thionyl chloride to complete the
synthesis of (R)-phenoxybenzamine hydrochloride 1. The structure
of (R)-phenoxybenzamine hydrochloride 1 was confirmed by its IR,
1H NMR, 13C NMR and mass spectroscopic analysis.
To a stirred solution of phenol 5 (4.7 g, 50 mmol) and K2CO3
(13.8 g, 100 mmol) in dry acetone (50 mL) was added ( )-epichloro-
hydrin (5.8 mL, 75 mmol) and the reaction mixture then refluxed
until all of the phenol had been consumed (8 h, TLC). The reaction
mixture was filtered, and washed with acetone, after which the sol-
vent was removed under reduced pressure. The crude residue was
re-dissolved in diethyl ether (100 mL), washed with 1 M NaOH
(2 ꢀ 15 mL) followed by brine, and dried over sodium sulfate. The
solvent was removed under reduced pressure. The crude oil was
distilled under reduced pressure to afford 3 as a colorless oil
(6.8 g, 90%); IR (Neat, cmꢁ1): mmax 3063, 3003, 2926, 1595, 1496,
l
1456, 1346, 1296, 1244, 1174, 1080, 1039, 914, 860, 758, 692; H
NMR (200 MHz, CDCl3): dH 2.72–2.76 (dd, J = 5.0, 2.0 Hz, 1H, OCHH),
2.86–2.91 (apparent t, J = 5.0 Hz, 1H, OCHH), 3.30–3.38 (m, 1H, CH),
3.89–3.97 (dd, J = 11.0, 6.0 Hz, 1H, OCHH), 4.17–4.24 (dd, J = 11.0,
4.0 Hz, 1H, OCHH), 6.89–7.0 (m, 3H, Ph), 7.24–7.33 (m, 2H, Ph);
l3C NMR (50 MHz, CDCl3): dC 158.4 (C), 129.4 (CH, 2 carbons),
121.1 (CH), 114.5 (CH, 2 carbons), 68.6 (CH2), 50.1 (CH), 44.7 (CH2).
4.3. (S)-2-(Phenoxymethyl)oxirane (S)-4a
A mixture of 2-(phenoxymethyl)-oxirane 4 (5 g, 33 mmol) and
(R,R)-salen Co(III)OAc complex-A (0.046 g, 0.07 mmol) was vigor-
ously stirred for 15 min, then cooled to 0 °C, and water added
(0.3 mL, 18 mmol) over a period of 15 min via a micro-syringe.
The reaction mixture was stirred at room temperature for 20 h,
and additional (R,R)-salen Co(III)OAc complex-A (0.046 g,
0.07 mmol) was added and stirring was continued for additional
10 h. The reaction mixture was diluted with ethyl acetate, dried
over Na2SO4, and evaporated under reduced pressure. The residue
was purified by column chromatography (silica gel, petroleum
ether/acetone (95:5). The less polar epoxide (S)-4a eluted first as
3. Conclusion
In conclusion, we have demonstrated the use of a Jacobsen’s
hydrolytic kinetic resolution strategy for the concise asymmetric
synthesis of (R)-phenoxybenzamine hydrochloride 1 for the first
time. Simple procedures, high enantioselectivities, and the ready
availability of the catalyst and starting materials are some of the
salient features of this approach. We envisage that this simple pro-
tocol may find application in the pharmaceutical industry for the
large scale production of (R)-phenoxybenzamine hydrochloride 1.
a pale yellow oil (2.2 g, 44%), ½a D25
ꢂ
¼ þ5:1 (c 7.5, CHCl3) {lit.9b
½
a 2D3
ꢂ
¼ þ5:2 (c 7.5, CHCl3)}; ee >98% [chiral HPLC analysis; CHIRAL-
CEL OD (250 ꢀ 4.6 mm) column; eluent: pet. ether/isopropa-
nol = 90/10; flow rate: 1.0 mL/min; detector: 214 nm [(R)-isomer
tR = 6.95 min; (S)-isomer tR = 10.54 min], followed by diol (R)-4b
4. Experimental
4.1. General
as white crystals (2.35 g, 47%); mp: 51 °C; ½a D25
ꢂ
¼ ꢁ10:5 (c 1, EtOH)
{lit.14
½
a 2D3
ꢂ
¼ ꢁ10:8 (c 1, EtOH)}; IR (CHCl3, cmꢁ1):
m
max 3436, 3020,
1600, 1497, 1215, 1045, 929, 669; NMR (200 MHz, CDCl3): dH 2.03
(t, J = 6 Hz, 1H, OH), 2.60 (d, J = 6 Hz, 1H, OH), 3.70–3.91 (m, 2H),
4.04–4.19 (m, 3H) 6.90–7.02 (m, 3H, Ph), 7.25–7.34 (m, 2H, Ph);
l3C NMR (50 MHz, CDCl3): d 158.4 (C), 129.6 (CH, 2 carbons),
121.3 (CH), 114.5 (CH, 2 carbons), 70.4 (CH), 69.1 (CH2), 63.7 (CH2).
Solvents were purified and dried by standard procedures prior
to use. IR spectra were obtained from Perkin–Elmer Spectrum
one spectrophotometer. 1H NMR and 13C NMR spectra were re-
corded on a Bruker AC-200 NMR spectrometer. Spectra were ob-
tained in CDCl3. Monitoring of reactions was carried out using
TLC plates Merck Silica Gel 60 F254 and visualization with UV light
(254 and 365 nm), I2 and anisaldehyde in ethanol as development
reagents. Optical rotations were measured with a JASCO P 1020
digital polarimeter. Mass spectra were recorded at ionization en-
ergy 70 eV on API Q Star Pulsar spectrometer using electrospray
ionization. Enantiomeric excess was determined by chiral HPLC.
4.4. (S)-1-Phenoxypropan-2-ol (S)-3
To a solution of epoxide (S)-4a (1.5 g, 10 mmol) in dry THF
(10 mL) at 0 °C was added slowly a pre-cooled solution of lithium
aluminum hydride (0.42 g, 11 mmol) in anhydrous THF (10 mL)
with stirring under nitrogen. After 30 min, the reaction mixture

2828
M. D. Nikalje et al. / Tetrahedron: Asymmetry 21 (2010) 2825–2829
was quenched with 1 mL of water and 1 mL of 15% NaOH solution
and the content stirred for 15 min. The inorganic precipitate was
filtered, washed with ethyl acetate and the solvent evaporated un-
der reduced pressure. The residue was purified by a short filtration
aqueous layer was basified with 1 M NaOH followed by extraction
with diethyl ether (3 ꢀ 15 mL). The combined organic layer was
dried over Na2SO4, concentrated under reduced pressure to give
(R)-2 as a pale yellow oil (0.65 g, 88%); ½a D25
¼ þ10:7 (c 4, EtOH)
ꢂ
column to afford (S)-3 as a colorless oil (1.41 g, 93%); ½a D25
ꢂ
¼ þ36:6
{lit.7a
½
a 2D2
ꢂ
¼ þ10:2 (c 4, EtOH)}; IR (Neat, cmꢁ1): mmax 3433,
(c 1, CHCl3) {lit.15
½
a 2D0
ꢂ
¼ þ30:7 (c 1.32, CHCl3)}; IR (Neat, cmꢁ1):
3327, 3059, 3032, 2962, 2962, 1724, 1597, 1494, 1458, 1481,
1244, 1074, 1039, 725, 696; H NMR (200 MHz, CDCl3): dH 1.18
l
mmax 3414, 3063, 2972, 2926, 1599, 1496, 1456, 1294, 1244,
1151, 1041, 935, 862, 754, 692; 1H NMR (200 MHz, CDCl3): dH
1.27 (d, J = 6.0 Hz, 3H, CH3), 2.40 (d, J = 4.0 Hz, 1H, OH), 3.75–3.83
(apparent t, J = 8 Hz, 1H, OCHH), 3.92–3.98 (dd, J = 10.0,
2.0 Hz,1H, OCHH), 4.13–4.28 (m, 1H, CH), 6.89–7.01 (m, 3H, Ph),
7.24–7.34 (m, 2H, Ph); l3C NMR (50 MHz, CDCl3): dC 158.5 (i-Ph),
129.5 (m-Ph), 121.1 (p-Ph), 114.5 (o-Ph), 73.1 (CH2), 66.2 (CH),
18.7 (CH3); MS: m/z 175 [M+Na]+.
(d, J = 8.0 Hz, 3H, CH3), 1.78 (br s, 1H, NH), 3.09–3.24 (sextet,
J = 6 Hz, 1H, CH), 3.78–3.87 (dd, J = 10.0, 8.0 Hz, 1H, OCHH), 3.90
(s, 2H, CH2-Ph), 3.89–3.97 (dd, 1H, J = 8.0, 6.0 Hz, 1H, OCHH),
6.87–6.98 (m, 3H, PhO), 7.23–7.35 (m, 7H, PhO, and Ph); l3C NMR
(50 MHz, CDCl3): dC 158.8 (C), 140.4 (C), 129.4 (CH, 2 carbons),
128.4 (CH, 2 carbons), 128.1 (CH, 2 carbons), 126.9 (CH), 120.8
(CH), 114.5 (CH, 2 carbons), 71.9 (CH2), 51.7 (CH), 51.3 (CH2),
17.3 (CH3); MS: m/z 241 [M+Na]+.
4.5. N-Benzyl-2-nitro-benzenesulfonamide 6
4.8. (R)-2-Benzyl-N-(2-hydroxyethyl)-1-phenoxyisopropyl-
amine (R)-8
Benzylamine (1.2 mL, 11 mmol) was added slowly to a solution
of 2-nitrobenzenesulfonylchloride (2.2 g, 10 mmol) and triethyl-
amine (2 mL, 15 mmol) in CH2Cl2 (20 mL) at 0 °C. The solution
was stirred for 1 h, then washed with 1 M HCl (10 mL), dried over
Na2SO4 and evaporated under reduced pressure. The crude mate-
rial was recrystallized using EtOAc/PE to yield 6 as white crystals
(2.9 g, 90%), mp = 97 °C; IR (KBr, cmꢁ1): mmax 3302, 3091, 1545,
1435, 1367, 1170, 1126, 1066, 868, 744; 1H NMR (200 MHz,
CDCl3): dH 4.31 (d, J = 6 Hz, 2H, CH2), 5.74 (t, J = 6 Hz, 1H, NH),
7.23 (m, 5H, Ph), 7.59–7.73 (m, 2H, Ns), 7.81–7.85 (m, 1H, Ns),
7.98–8.03 (m, 1H, Ns); l3C NMR (50 MHz, CDCl3): dC 147.7 (C),
135.6 (C), 133.9 (C), 133.4 (CH), 132.7 (CH), 131.0 (CH), 128.6
(CH2, 2 carbons), 128.0 (CH), 127.9 (CH2, 2 carbons), 125.2 (CH),
47.8 (CH2).
A mixture of amine (R)-2 (0.48 g, 2 mmol), bromoethanol
(0.15 mL, 2.2 mmol), and oven dried K2CO3 (0.55 g, 4 mmol) in eth-
anol (10 mL) was heated in a sealed glass tube at 110 °C for 72 h.
The solid was filtered, washed with ethanol (2 ꢀ 5 mL) and the sol-
vent evaporated under reduced pressure. The crude residue was re-
dissolved in diethyl ether (15 mL), extracted with 2 M HCl
(2 ꢀ 5 mL). The aqueous solution was basified with 2 M NaOH,
and then extracted with diethyl ether (2 ꢀ 10 mL). Removal of
the solvent under reduced pressure was followed by purification
over a flash column (silica gel; petroleum ether/ethyl acetate;
85:15) to afford (R)-8 as
a
pale yellow oil (0.465 g, 82%);
¼ þ15:0 (c 4, EtOH)}; IR (Neat,
½
a 2D5
ꢂ
¼ þ15:4 (c 4, EtOH) {lit.7a
½ ꢂ
a 2D2
cmꢁ1):
mmax 3323, 3061, 3061, 3028, 2972, 2928, 2872, 1799, 1730,
4.6. (R)-N-Benzyl-2-nitro-N-(1-phenoxypropan-2-yl)benzene-
sulfonamide (R)-7
1599, 1494, 1379, 1244, 1170, 1059, 1039, 754; lH NMR (200 MHz,
CDCl3): dH 1.11 (d, J = 7.0 Hz, 3H, CH3), 2.65–2.88 (m, 2H, N–
CH2CH2OH), 3.25–3.36 (m, 1H, CH), 3.42–3.62 (m, 1H, –CHH),
3.69 (s, 2H, –CH2Ph), 3.76–3.88 (m, 2H), 3.94–4.03 (dd, J = 10.0,
6.0 Hz, 1H, OCHH), 6.85–6.98 (m, 3H, PhO), 7.22–7.35 (m, 7H, Ph,
PhO); l3C NMR (50 MHz, CDCl3): dC 158.5 (C), 139.7 (C), 129.4
(CH, 2 carbons), 128.6 (CH, 2 carbons), 128.4 (CH, 2 carbons),
127.1 (CH), 120.8 (CH), 114.5 (CH, 2 carbons), 69.5 (CH2), 58.7
(CH2), 54.6 (CH2), 53.3 (CH), 50.9 (CH2), 11.8 (CH3); MS: m/z 285
[M+Na]+.
A solution of DIAD (1.3 mL, 6.5 mmol) in dry THF (10 mL) was
added dropwise to a solution of (S)-3 (0.76 g, 5 mmol), N-benzyl-
2-nitro-benzenesulfonamide 6 (1.75 g, 6 mmol) and triphenyl-
phosphine (1.7 g, 6.5 mmol) in dry THF (25 mL) under N2
atmosphere at room temperature. Stirring was continued until all
of the alcohol had been consumed (2 h, TLC). The reaction mixture
was concentrated under reduced pressure and the residue was
purified by column chromatography (silica gel, petroleum ether/
EtOAc, 90:10) to yield (R)-7 as pale yellow crystals (1.7 g, 79%);
4.9. (R)-Phenoxybenzamine hydrochloride 1
mp: 105–107 °C; ½a D25
ꢂ
¼ þ45:4 (c 1, CHCl3); IR (KBr, cmꢁ1): mmax
3302, 3091, 3026, 1545, 1435, 1367, 1342, 1170, 1126, 1066,
868, 744; lH NMR (200 MHz, CDCl3): dH 1.21 (d, J = 8.0 Hz, 3H,
CH3), 3.66–3.74 (dd, J = 10.0, 6.0 Hz, 1H, OCHH), 3.92–4.01 (dd,
J = 10.0, 8.0 Hz, 1H, OCHH), 4.39–4.54 (m, 1H, CH), 4.62 (d,
J = 2 Hz, 2H, N–CH2–), 6.62 (d, J = 8.0 Hz, 2H, OPh), 6.92 (apparent
t, J = 7 Hz, 1H, PhO), 7.17–7.27 (m, 5H, PhO, and Ph), 7.33–7.39
(m, 2H, Ph), 7.48–7.64 (m, 3H, Ns), 7.89 (d, J = 8.0 Hz, 1H, Ns); l3C
NMR (50 MHz, CDCl3): dC 157.9 (C), 137.4 (C), 134.1 (C), 133.1
(CH), 131.5 (CH), 131.2 (CH), 129.4 (CH, 2 carbons) 128.5 (CH, 2
carbons), 128.3 (CH, 2 carbons), 127.7 (CH), 124.1 (CH),121.1
(CH), 114.2 (CH, 2 carbons), 69.2 (CH2), 53.4 (CH), 48.3 (CH2),
16.4 (CH3); MS: m/z 426 [M+Na]+.
To a pre-cooled (0 °C) solution of amino alcohol (R)-8 (0.4 g,
1.5 mmol) in dry benzene (20 mL), HCl gas was bubbled slowly
for 15 min. Then, SOCl2 (0.13 mL, 1.8 mmol) in dry benzene
(5 mL) was added dropwise and the content was refluxed for 8 h.
The solvent and excess SOCl2 was removed under reduced pres-
sure. The crude product was purified by column chromatography
(silica gel; petroleum ether/ethyl acetate; 98:2) to afford (R)-phe-
noxybenzamine hydrochloride 1 (0.26 g, 52%); white crystals; mp
124–26 °C {Lit.7a mp 123–24 °C}; ½a 2D5
ꢂ
¼ þ17:6 (c 4, EtOH) {Lit.7a
½
a 2D5
ꢂ
¼ þ18:0 (c 4, EtOH)}; IR (CHCl3, cmꢁ1): mmax 3437, 3063,
2958, 2928, 2884, 1726, 1595, 1492, 1458, 1284, 1246, 1126,
1074, 1035, 750, 696; lH NMR (200 MHz, CDCl3): dH 1.17, (d,
J = 7.0 Hz, 3H, CH3), 2.84–3.07 (m, 2H, N–CH2CH2Cl), 3.19–3.29
(apparent q, J = 6 Hz, 1H, –CH), 3.34–3.42 (apparent t, J = 7.4 Hz,
2H, –CH2), 3.78 (d, J = 4.0 Hz, 2H, –CH2Ph), 3.82–3.89 (dd, J = 10.0,
6.0 Hz, 1H, –OCHH), 3.99–4.07 (dd, J = 10.0, 6.0 Hz, 1H, –OCHH),
6.86–6.98 (m, 3H, PhO), 7.23–7.39 (m, 7H, Ph, PhO); l3C NMR
(50 MHz, CDCl3): dC 158.8 (C), 140.3 (C), 129.4 (CH, 2 carbons),
128.3 (CH, 4 carbons), 127.0 (CH), 120.7 (CH), 114.5 (CH, 2 car-
bons), 70.3 (CH2), 55.8 (CH2), 54.8 (CH), 53.0 (CH2), 43.1 (CH2),
13.3 (CH3); MS: m/z 322 [M+NH4]+, 268 [MꢁCl]+.
4.7. (R)-N-Benzyl-1-phenoxypropan-2-amine (R)-2
To a solution of free sulfonamide (R)-7 (1.3 g, 3 mmol), K2CO3
(1.2 g, 9 mmol) in acetonitrile (25 mL) thiophenol (0.37 mL,
3.6 mmol) was added. The reaction mixture was vigorously stirred
for 2 h, after which the solvent was evaporated under reduced
pressure. The crude product was dissolved in diethyl ether
(40 mL), and extracted with 1 M HCl (2 ꢀ 15 mL). The combined

M. D. Nikalje et al. / Tetrahedron: Asymmetry 21 (2010) 2825–2829
2829
Muthukrishnan, M.; Garud, D. R.; Borikar, S. P.; Gurjar, M. K. U.S. Patent
7,019,172, 2006; Chem. Abstr. 2006, 144, 108086.; (c) Joshi, R. A.; Garud, D. R.;
Muthukrishnan, M.; Joshi, R. R.; Gurjar, M. K. Tetrahedron: Asymmetry 2005, 16,
3802; (d) Muthukrishnan, M.; Garud, D. R.; Joshi, R. R.; Joshi, R. A. Tetrahedron
2007, 63, 1872; (e) Sasikumar, M.; Nikalje, M. D.; Muthukrishnan, M.
Tetrahedron: Asymmetry 2009, 20, 2814.
Acknowledgement
The authors thank DST, New Delhi for the financial support
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