Convenient synthesis of chlorohydrins from epoxides using zinc oxide: Application to 5,6-epoxysitosterol

Article abstract of DOI:10.1002/hc.20529

Efficient synthesis of protected and unprotected chlorohydrins has been achieved by ring opening of epoxides with acetyl/benzoyl chloride and TMSCl using a catalytic amount of ZnO as a reusable catalyst. The applicability of ZnO is further extended by performing the cleavage of the natural product 5,6-epoxysitosterol with acetyl chloride.

Full text of DOI:10.1002/hc.20529

Heteroatom Chemistry
Volume 20, Number 3, 2009
Convenient Synthesis of Chlorohydrins
from Epoxides Using Zinc Oxide: Application
to 5,6-Epoxysitosterol
Firouz Matloubi Moghaddam, Hamdollah Saeidian,
Zohreh Mirjafary, Marjan Jebeli Javan, Mehdi Moridi Farimani,
and Marjan Seirafi
Laboratory of Organic Synthesis & Natural Products, Department of Chemistry, Sharif University
of Technology, P. O. Box 11155-9516, Tehran, Iran
Received 30 November 2008; revised 22 January 2009, 16 February 2009, 18 March 2009
ferrocene, LiClO4, PVP/thionyl-chloride complex,
ABSTRACT: Efficient synthesis of protected and
La(NO3)3·6H2O [5–10], and so on. Most of the men-
unprotected chlorohydrins has been achieved by
tioned procedures have disadvantages such as the
ring opening of epoxides with acetyl/benzoyl chlo-
use of large amounts of toxic reagents, long reaction
ride and TMSCl using a catalytic amount of ZnO
time, and low yields. It is clearly evident that the need
as a reusable catalyst. The applicability of ZnO is
for the development of a new and flexible protocol is
further extended by performing the cleavage of the
required. The surface of many metal oxides exhibits
natural product 5,6-epoxysitosterol with acetyl chlo-
both Lewis acid and base characters, especially TiO2,
ꢀ
C
ride.
2009 Wiley Periodicals, Inc. Heteroatom Chem
Al2O3, ZnO, Fe2O3, etc., and they are excellent adsor-
bents for a wide variety of organic compounds and
they also increase the reactivity of the reactants [11].
ZnO is certainly one of the most interesting metal
oxides, because it has surface properties, which sug-
gests very rich organic chemistry [12–19]. In con-
tinuation of our studies on the preparation of ZnO
and its applications in organic synthesis [20–22], we
became interested in exploring further organic re-
actions catalyzed by ZnO. Herein, we wish to report
the synthesis of protected and unprotected chlorohy-
drins by ring opening of epoxides with acetyl/benzoyl
chloride and TMSCl, respectively, using a catalytic
amount of commercially available ZnO as an ef-
ficient, reusable, and inexpensive heterogeneous
catalyst.
20:157–163, 2009; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20529
INTRODUCTION
Chlorohydrins are useful intermediates for the syn-
thesis of a range of biologically active natural and
synthetic products, along with chiral auxiliaries for
asymmetric synthesis [1]. Furthermore, protected
halohydrins are most important intermediates in the
total synthesis of natural products and in steroid
chemistry [2,3]. Recently reported methodologies
for the synthesis of chlorohydrins include cleavage
of epoxide with hydrogen halides [3], lithium halides
supported on silica gel [4], or with hydrohalogenic
acids in the presence of a Lewis acid such as in-
dium(III) bromide, phosphazirconocene, phospha-
RESULTS AND DISCUSSION
To find optimal conditions, the ring opening of gly-
cidyl phenyl ether (Table 2, entry 2) was investi-
gated as a model substrate with acetyl chloride under
Correspondence to: Firouz Matloubi Moghaddam; e-mail: mat-
loubi@sharif.edu.
2009 Wiley Periodicals, Inc.
c
ꢀ
157

158 Moghaddam et al.
TABLE 1 Optimization of the Amount of ZnO for the Catalyzed Model Reaction
Entry
Catalyst (mol%)
Solvent
Time (min)
Yields (%)
1
2
3
4
5
6
No catalyst
ZnO (5%)
ZnO (10%)
ZnO (20%)
ZnO (10%)
ZnO (10%)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Solvent-free
CH2Cl2
300
120
30
30
30
30
83
90
93
60
73a
30
aYield after recycling the catalyst three times.
different conditions at room temperature. In the ab-
sence of catalyst, the product was obtained in low
yield even after a long time (Table 1, entry 1). How-
ever, good results were obtained in the presence of
ZnO (Table 1, entries 2–4). Upon optimization of the
amount of catalyst, we found that 10 mol% of ZnO
could effectively catalyze the reaction to afford the
desired product. Using more than 10 mol% ZnO did
not have any effect on the yield and time of the re-
action (Table 1, entry 4). Reaction in CH2Cl2 was
clean, and the product was obtained without the
formation of any by-products. A low yield of the de-
sired product was observed in the absence of solvent
(Table 1, entry 5). To check the efficiency of the recy-
cled catalyst, glycidyl phenyl ether was subjected to
the ring opening reaction using acetyl chloride and
after three runs, the yield of corresponding protected
chlorohydrin remained relatively high (Table 1,
entry 6).
We then examined the substrate scope under
the optimized reaction conditions. It was found that
ZnO catalyzes the ring opening of both aromatic and
aliphatic epoxides at high rates. As shown in Table 2,
the corresponding protected chlorohydrins were ob-
tained in excellent yields (87%–97%). The regioselec-
tivity for the unsymmetrical epoxides is governed by
both steric and electronic effects. High selectivity for
nucleophilic attack at the less hindered carbon was
observed. Styrene oxide showed a strong preference
for the opposite regioselectivity to that observed in
the aliphatic epoxides, suggesting electronic control
in the ring opening [6]. In this case the reaction likely
proceeds partly through the attack of nucleophile on
the more stabilized “carbocation” with participation
of the phenyl group.
Mechanistically, it is conceivable that the reac-
tion involves the initial formation of an acyl cation
as in Friedel–Crafts reactions and then forms an acyl
oxonium species with the epoxide. The acyl oxo-
nium is attacked by the chloride leading to desired
product.
Furthermore, ZnO was also an effective cata-
lyst for the reaction of epoxides with TMSCl to pro-
vide the corresponding chlorohydrins in high yields
(Table 3).
The applicability of ZnO was further extended
by performing the cleavage of tetrahydrofuran with
acetyl chloride. The reaction worked well, and the
yield of product was satisfactory (Scheme 1).
The superiority of the present protocol can be
seen by comparing our results with those reported
in the literature, as shown in Table 4. The ring open-
ing of styrene oxide with TMSCl was compared in
terms of mol% of the catalyst, solvent, reaction time,
yield, and regioselectivity. Some catalysts such as
LiCl/SiO2 (3 equiv/250 mg) and PVP/thionyl-chloride
complex (190%) require high loading of catalyst,
whereas only low amounts of ZnO are sufficient for
our methodology. Most of the catalysts show low re-
gioselectivity, but ZnO preceded ring opening with a
high regioselectivity.
Many chlorine-containing natural products dis-
play potent antibiotic or cytotoxic properties. There-
fore, it is worth to develop methods for the introduc-
tion of chlorine into organic natural compounds [23–
25]. Encouraged by the results obtained with various
epoxides, we turned our attention to β-sitosterol, a
natural product that has been isolated from Salvia
sahendica in our laboratory [26]. To the best of
our knowledge, this is the first demonstration of
O
O
O
ZnO (10 mol%)
rt , 30 min
Cl
+
H3C
O
H3C
Cl
3
SCHEME 1 Cleavage of tetrahydrofuran with acetyl chloride.
Heteroatom Chemistry DOI 10.1002/hc

Convenient Synthesis of Chlorohydrins from Epoxides using Zinc Oxide: Application to 5,6-Epoxysitosterol 159
TABLE 2 Synthesis of Protected Chlorohydrins Using ZnO as Catalyst
′
OCOR
Cl
O
O
ZnO (10 mol%)
rt , 30 min
+
+
′
R
R
R
R
Cl
′
Cl
OCOR
′
′
1a –j
1a–j
Yield (%)
Entry
1
Epoxide
Acyl Chloride
Product
Ratioa (1a–j:1a’–j’)
97
(00:100)
O
Cl
O
Ph
Ph
H3C
Cl
′
1a
OCOCH3
OCOCH3
2
3
O
O
90
(67: 33)
O
PhO
PhO
H3C
H3C
H3C
Cl
1b
Cl
92
(100:00)
OCOCH3
O
Cl
Cl
Cl
1c
Cl
4
O
89
(100:00)
OCOCH3
O
H3C
Cl
H3C
1d
Cl
5
6
O
87
(cis/trans: 0/100)
O
H3C
Cl
Cl
90
(00:100)
O
O
Ph
Ph
Ph
Cl
′
1f
OCOPh
OCOPh
O
7
87
O
(83:27)
PhO
PhO
Ph
Cl
1g
Cl
Continued
Heteroatom Chemistry DOI 10.1002/hc

160 Moghaddam et al.
TABLE 2 Continued
Entry
Yield (%)
Epoxide
Acyl Chloride
Product
Ratioa (1a–j:1a’–j’)
O
OCOPh
O
8
90
(100:00)
Cl
Cl
Ph
Cl
1h
Cl
O
9
O
92
(100:00)
OCOPh
Ph
Cl
H3C
H3C
1i
Cl
O
10
88
(cis/trans: 0/100)
O
Ph
Cl
aRatio obtained from 1H NMR measurement of the crude reaction mixture.
the ZnO-based ring opening of 5,6-epoxysitosterol,
which was synthesized according to reported pro-
cedures for other steroids with epoxide moieties.
The hydroxyl function of β-sitosterol was protected
using acetic anhydride in the presence of catalytic
amount of DMPA in Et2O [27], followed by epoxi-
dation with KMnO4/CuSO4 in CH2Cl2 to afford 5,6-
epoxysitosterol (6) [28,29]. The ring opening of 5,6-
epoxysitosterol with acetyl chloride in the presence
of ZnO gave the corresponding chlorohydrin (7) in
high yield (86%) (Scheme 2). The stereochemistry of
compound 7 was determined in analogy with similar
compounds [30,31].
In summary, we have developed an efficient
procedure for the synthesis of protected and un-
protected chlorohydrin derivatives using ZnO as a
reusable, nontoxic, noncorrosive, inexpensive, and
commercially available heterogeneous catalyst. The
method also offers some advantages such as clean
reaction, low loading of catalyst, high yields of
SCHEME 2 Synthesis of chlorohydrin β-sitosterol.
Heteroatom Chemistry DOI 10.1002/hc

Convenient Synthesis of Chlorohydrins from Epoxides using Zinc Oxide: Application to 5,6-Epoxysitosterol 161
TABLE 3 Synthesis of Chlorohydrins Using ZnO as Catalyst
OH
Cl
O
ZnO (10 mol%)
rt , 30 min
+
TMSCl
R
R
R
2a–e
2a′–e′
Cl
OH
Entry
Epoxide
Product
Yield (%)
Cl
O
Ph
1
95
′
2a
Ph
OH
OH
PhO
O
2
3
86a
2b
PhO
Cl
OH
Cl
O
89
Cl
2c
Cl
OH
O
H3C
4
5
85
2d
H3C
Cl
90 (cis/trans: 0/100)
O
aRatio of isomers = 71:29.
products, short reaction time, and applicability of
various substrates.
General Procedure for the Synthesis
of Protected Chlorohydrins
To a stirred suspension of ZnO (10 mol%) in acetyl
or benzoyl chloride (2 mmol) in CH2Cl2 (0.5 mL),
an epoxide (2 mmol) was added. The reaction mix-
ture was stirred at room temperature for 30 min.
The progress of the reaction was monitored by TLC.
After completion of the reaction, the mixture was fil-
tered and zinc oxide was recovered. (The recovered
ZnO was dried at 100◦C for 4 h before reusing.) The
solvent was removed by a rotary evaporator to give
the desired product. Further purification was carried
out by short column chromatography on silica gel.
EXPERIMENTAL
General
All chemicals were purchased from Fluka and
Aldrich and were used without any further purifi-
cation. NMR spectra were recorded at 500 MHz for
proton and at 125 MHz for carbon nuclei in CDCl3.
The products were purified by column chromatog-
raphy carried out on silica gel by using ethyl ac-
etate/petroleum.
Heteroatom Chemistry DOI 10.1002/hc

162 Moghaddam et al.
TABLE 4 Comparison of the Ring Opening of Styrene Oxide with Previously Reported Methods
OH
Cl
O
+
Catalyst
+
TMSCl
Ph
Ph
Ph
a
b
Cl
OH
Entry
Catalyst (mol%)
Solvent
Time (h)
Yield (a: b)
1
2
3
4
5
LiCl/SiO2 (3 equiv/250 mg)
PVP/thionyl-chloride complex (190%)
Phosphaferrocene (5%)
LiClO4 (10%)
Solvent-free
CH2Cl2
CH2Cl2
MeOH
5 days
10 min
6 min
5
80 (3.7: 1) [4]
95 a [9]
88 (2.7: 1) [7]
82 (7.3: 1) [8]
95a
ZnO (10%)
CH2Cl2
30
4H), 2.67 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ:
General Procedure for the Synthesis
of Unprotected Chlorohydrins
71.29, 46.18.
1
2-Chlorocyclohexanol (2e). H NMR (500 MHz,
To a stirred suspension of ZnO (10 mol%) and TM-
SCl (2 mmol) in CH2Cl2 (2 mL), an epoxide (2 mmol)
was added. The reaction mixture was stirred at room
temperature for 30 min. The progress of the reaction
was monitored by TLC. After completion of the re-
action, 1 mL of water was added to the mixture and
the mixture was stirred for an additional 30 min. The
organic layer was separated and dried with Na2SO4.
The solvent was removed to give the desired prod-
uct. Further purification was carried out by short
column chromatography on silica gel. The structure
of the products was confirmed by 1H NMR, 13C NMR
spectra, and comparison with authentic samples pre-
pared by other reported methods.
CDCl3) δ: 3.71–3.46 (m, 2H), 2.88 (br s, 1H),
2.19–1.23 (m, 8H); 13C NMR (125 MHz, CDCl3) δ:
75.71, 67.70, 35.55, 33.57, 25.99, 24.34; 4-Chlorobutyl
acetate (3).1H NMR (500 MHz, CDCl3) δ: 4.08
(t, J = 6.02 Hz, 2H), 3.54 (t, J = 6.02 Hz, 2H), 2.02
(s, 3H), 1.84–1.60 (m, 4H).
6: 1H NMR (500 MHz, CDCl3) δ: 0.68 (s, 3H, 18-
CH3), 0.85, 0.87 (2d, J = 7.2 Hz, each 3H, 26-CH3
and 27-CH3), 0.94 (d, J = 6.2 Hz, 21-CH3), 1.04 (s,
3H, 19-CH3), 2.07 (s, 3H, CH3COO), 3.11 (m, 1H, 6α-
H), 4.79–4.83 (tt, J1 = 10.4 Hz and J2 = 5.1 Hz, 1H,
3α-H).
1
7: Mp: 127–129˚C; H NMR (500 MHz, CDCl3)
δ: 0.72 (s, 3H, 18-CH3), 0.86, 0.87 (2d, J = 6.8 Hz,
each 3H, 26-CH3 and 27-CH3), 0.96 (d, J = 6.5 Hz,
21-CH3), 1.30 (s, 3H, 19-CH3), 2.13 (s, 3H, CH3COO),
2.14 (s, 3H, CH3COO), 5.15 (m, 1H, 6α-H), 5.37–
5.41 (tt, J1 = 10.6 Hz and J2 = 5.5 Hz, 1H, 3α-H);
13C NMR (125 MHz, CDCl3) δ: 170.71, 170.09, 81.70,
75.95, 70.93, 56.37, 56.05, 46.27, 46.10, 43.11, 40.45,
40.09, 37.74, 36.57, 34.31, 33.44, 31.50, 31.23, 29.56,
28.62, 26.74, 26.43, 24.45, 23.48, 21.78, 21.75, 21.57,
20.23, 19.45, 19.13, 17.95, 12.63, 12.40; Anal Calcd
for C33H55ClO4: C, 71.90; H, 10.06. Found: C, 71.78,
H, 10.13.
Representative Spectroscopic Data. 2-Chloro-2-
phenylethyl acetate (1aꢁ). 1H NMR (500 MHz, CDCl3)
δ: 7.32 (d, J = 7.01 Hz, 2H), 7.27–7.21 (m, 3H), 5.05
(q, J = 6.21 Hz, 1H), 4.42 (m, 2H), 2.05 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ: 170.47, 138.10, 129.32,
129.16, 127.81, 68.27, 59.92, 21.05.
2-Chloro-2-phenylethyl benzoate (1f). 1H NMR
(500 MHz, CDCl3) δ: 8.08 (d, J = 8.44 Hz, 2H), 7.53
(t, J = 7.4 Hz, 1H), 7.50 (d, J = 6.96, 2H), 7.43–733
(m, 5H), 5.27 (q, J = 6.12 Hz, 1H), 4.76–4.69 (m, 2H);
13C NMR (125 MHz, CDCl3) δ: 166.13, 138.28, 133.66,
130.27, 130.24, 129.44, 129.30, 128.92, 127.97, 68.76,
60.32.
REFERENCES
2-Chloro-2-phenylethanol (2aꢁ). 1H NMR (500
MHz, CDCl3) δ: 7.44–7.34 (m, 5H), 4.97 (t, J = 5.62
Hz, 1H), 3.96–3.88 (m, 2H), 2.89 (br s, 1H); 13C NMR
(125 MHz, CDCl3) δ: 138.50, 129.14, 129.10, 127.93,
86.24, 65.03.
[1] Akiyama, Y.; Fukuhara, T.; Hara, S. Synlett 2003,
1530.
[2] Watson, K. G.; Fung, Y. M.; Gredley, M.; Bird, G.
J.; Jackson, W. R.; Gountzos, H.; Mattews, V. Chem
Commun 1990, 1018.
[3] Kulb, H. C.; Sharpless, K. B.; Tetrahedron 1992, 48,
10515.
1,3-Dichloro-2-propanol (2c). 1H NMR (500
MHz, CDCl3) δ: 4.07 (m, 1H), 3.68 (d, J = 5.20 Hz,
Heteroatom Chemistry DOI 10.1002/hc

Convenient Synthesis of Chlorohydrins from Epoxides using Zinc Oxide: Application to 5,6-Epoxysitosterol 163
[4] Kotsuki, H.; Shimanouchi, T.; Ohshima, R.; Fuji-
[17] Hosseini-Sarvari, M.; Sharghi, H. Tetrahedron 2005,
61, 10903.
[18] Hosseini-Sarvari, M. Synthesis 2005, 787.
[19] Kim, Y. J.; Varma, R. S. Tetrahedron Lett 2004, 45,
7205.
wara, S. Tetrahedron 1998, 54, 2709.
[5] Yadav, J. S.; Reddy, B. V. S.; Reddy, P. M. K.; Dash,
U.; Gupta, M. K. J Mol Catal A: Chem 2007, 271,
266.
[6] Wang, L. S.; Hollis, T. K. Org Lett 2003, 5,
2543.
[7] Garrett, C. E.; Fu, G. C. J Org Chem 1997, 62,
4534.
[20] Moghaddam, F. M.; Saeidian, H. Mater Sci Eng B
2007, 139, 265.
[21] Mirjafary, Z.; Saeidian, H.; Sadeghi, A.; Moghaddam,
F. M. Catal Commun 2008, 9, 299.
[8] Azizi, N.; Mirmashhori, B.; Saidi, M. R. Catal Com-
mun 2007, 8, 2198.
[9] Tamami, B.; Ghazi, I.; Mahdavi, H. Synth Commun
2002, 32, 3725.
[10] Suresh, V.; Suryakiran, N.; Rajesh, K.; Selyam, J. J.
P.; Srinivasulu, M.; Venkateswalu, Y. Synth Commun
2008, 38, 92.
[11] Tanabe, K. Solids and Bases; Academic Press: New
York, 1970.
[12] Hosseini-Sarvari, M.; Sharghi, H.; Etemad, S. Helv
Chim Acta 2008, 91, 715.
[13] Hosseini-Sarvari, M.; Etemad, S. Tetrahedron 2008,
64, 5519.
[14] Hosseini-Sarvari, M.; Sharghi, H. J Org Chem 2006,
71, 6652.
[22] Saeidian, H.; Mirjafary, Z.; Sadeghi, A.; Moghaddam,
F. M. J Iranian Chem Soc, in press.
[23] Gribble, G. W. J Nat Prod 1992, 55, 1353.
[24] Gribble, G. W. Acc Chem Res 1998, 31, 141.
[25] Gribble, G. W. Am Sci 2004, 92, 342.
[26] Moghaddam, F. M.; Farimani, M. M.; Salahvarzi, S.;
Amin, Gh. Evid Based Complement Alternat Med
2007, 4, 95.
[27] Steglich, W.; Hofle, G. Angew Chem, Int Ed Engl
1969, 8, 981.
[28] Syamala, M. S.; Das, J.; Baskaran, S.; Chandr-
rasekaran, S. J Org Chem 1992, 57, 1928.
[29] McCarthy, F. O.; Chopra, J.; Ford, A.; Hogan, S. A.;
Kerry, J. P.; O’Brien, N. M.; Ryan, E.; Maguire, A. R.
Org Biomol Chem 2005, 3, 3059.
[15] Tamaddon, F.; Amrollahi, M. A.; Sharafat, L. Tetra-
hedron Lett 2005, 46, 7841.
[16] Gupta, M.; Paul, S.; Gupta, R.; Loupy, A. Tetrahedron
Lett 2005, 46, 4957.
[30] Ceccherelli, P.; Curini, M.; Marcotullio, M. C.; Rosati,
O. Tetrahedron 1991, 47, 4211.
[31] Pinto, R. M. A.; Salvador, J. A. R.; Roux, C. L. Tetra-
hedron 2007, 63, 9221.
Heteroatom Chemistry DOI 10.1002/hc