Efficient synthesis of chlorohydrins: Ionic liquid promoted ring-opening reaction of epoxides and TMSCl

Article abstract of DOI:10.1016/j.tetlet.2004.01.042

The environmentally benign, highly efficient synthesis of chlorohydrins by cleavage of epoxides using TMSCl in ionic liquid, bmimPF₆, has been studied.

Full text of DOI:10.1016/j.tetlet.2004.01.042

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2435–2438
Efficient synthesis of chlorohydrins: ionic liquid promoted
ring-opening reaction of epoxides and TMSCl
Li-Wen Xu, Lyi Li, Chun-Gu Xia* and Pei-Qing Zhao
State key laboratory of Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences,
Lanzhou 730000, PR China
Received 25 December 2003; revised 7 January 2004; accepted 13 January 2004
Abstract—The environmentally benign, highly efficient synthesis of chlorohydrins by cleavage of epoxides using TMSCl in ionic
liquid, bmimPF6, has been studied.
Ó 2004 Elsevier Ltd. All rights reserved.
Chlorohydrins and other halohydrins are an important
class of organic compounds and versatile intermediates
in the synthesis of a vast range of biologically active
natural and synthetic products, unnatural amino acids,
and chiral auxiliaries for asymmetric synthesis.1 There is
a continued interest in the synthesis of chlorohydrins
and derivatives. Methodologies for preparing these
chlorohydrins include (a) conversion of aldehydes to
chlorohydrins through chloroallylboration,2 (b) cleav-
age of cyclic ketal acids with phosphorus pentachloride,
thionyl chloride, or pivaloyl chloride,3 (c) reaction
of diol with dry HCl or chlorotrimethylsilane,4 (d)
zinc–magnesium- and samarium-mediated reaction of
dichloroacetates with carbonyl compounds,5 (e) olefins
are directly functionalized to chlorohydrins in one-pot
by palladium catalyst6 or the combination of BTSP,
trimethylsilyl (TMS)X (X ¼ Cl), a catalytic amount of
Lewis acid,7 and (f) ring opening of epoxides with dif-
ferent chloride ion sources.8 Although chlorohydrins are
conveniently by an addition of hypohalite-water to
olefins and other substrates, none or low regiospecific
addition was observed. It is therefore not surprising that
the synthesis of chlorohydrins through ring-opening
reaction have received considerable attention. But the
most general method of preparing chlorohydrins by the
ring opening of epoxides with hydrogen halides, metal
chlorides, or other chloride compounds9 also suffers
from one or more disadvantages such as acidity, hand-
ling, and in situ preparation of reagent or relative long
reaction times, pharmacologically inactive chlorohyd-
rins, unwanted byproducts, and low regioselectivity.
Although recent advances10 have made this route more
attractive, development of cheaper, simpler, and more
efficient methods, especially environmentally benign,
highly efficient procedure, is highly desirable.
To minimize the amount of harmful organic solvents
used in chemical processes, much attention has been
devoted to the use of alternative reaction media. Besides
supercritical fluids, water, and solvent-free conditions,
the use of room ionic liquids has been receiving more
attention.11 Room temperature ionic liquid such as
bmimPF6 are finding growing application as an alter-
native media for separation and organic transforma-
tions, and much attention has been focused on organic
reactions promoted by ionic liquid.12 The desirable
advantages of ionic liquids such as the lack of vapor
pressure, wide liquid range, and thermal stability have
made them exceptional reaction media and environ-
mentally benign solvents.13 These factors are especially
important in industry. In addition, several ionic liquids
show enhancement in reaction rates and selectivity,
compared to organic solvents with added benefit of ease
of recovery and reuse of these ionic liquids. Surprisingly
however, there is no report on ionic liquids promoted
ring-opening reaction of epoxides with chlorides ion
sources.
In view of the emerging importance of ionic liquids as
novel reaction media, we wish to report the use of ionic
liquid as efficient promoters for the synthesis of chloro-
hydrins or ring-opening reaction and other reaction.14 In
this letter, we try to explore the catalytic activities of
Keywords: Ionic liquid; Epoxide; Chlorohydrins; TMSCl.
* Corresponding author. Tel.: +86-0931-8276531; fax: +86-0931-827-
7088; e-mail: cgxia@ns.lzb.ac.cn
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.042

2436
L.-W. Xu et al. / Tetrahedron Letters 45 (2004) 2435–2438
Table 1. Ring opening of various epoxides with TMSCl promoted by
ionic liquid bmimPF6
Cl
O
OH
TMSCl
Entrya
Substrates
Chlorohydrins
Yields (%)b
bmimPF /rt
6
O
Cl
1
98 (99:1)
Scheme 1.
OH
O
O
Cl
O
HO
R1
Cl
R2
TMSCl
2c
Trace
OH
bmimPF6/rt
R1
R2
Scheme 2.
Cl
3d
97 (99:1)
OH
ionic liquid in the ring-opening reaction of epoxides with
TMSCl (Schemes 1 and 2), and we reported the efficient
and green synthesis of chlorohydrins through the first
ionic liquid promoted ring-opening reaction of epoxides
with TMSCl. Advantages of the protocol include high-
yielding reaction that can be conducted at low temper-
ature, high regio- and stereoselective ring opened
products was obtained under environmental benign
conditions.
OH
O
O
O
4
5
100 (100:0)
100 (100:0)
Cl
O
OH
O
O
Cl
HO
O
Cl
Initially ring opening of styrene oxide (Scheme 1)15 was
investigated with TMSCl in ionic liquid bmimPF6 and
general organic solvents, such as CH2Cl2. Styrene oxide
was treated with 1.1 equiv of TMSCl at room tempera-
ture in CH2Cl2, and few chlorohydrin products was
obtained even for longer time (yield 6 10%). However,
the ring opening of styrene oxide with TMSCl in
bmimPF6 gave clean conversion to the chlorohydrin,
and styrene oxide was observed to yield chlorohydrin
with chlorine at the more substituted a-carbon atom in
high regioselectivity (99:1). Phosphine compound have
been used in many reaction and include the ring-opening
reactions.16 However, the use of PF6ꢀ as catalyst has not
been reported. We used NaPF6 as a catalyst in the ring-
opening reaction of TMSCl in CH2Cl2 and found the
catalyst was poor in the reaction (low yield). This
enhancement in the reactivity observed in ionic liquid
could be attributed to the strong Lewis acidity of
bmimPF6 in comparison to other organic solvents. To
our knowledge, the result represent one of the highest
regioselectivity reported to date for the nucleophilic
catalytic ring-opening epoxides in the presence of
TMSCl and other chlorine nucleophiles.10e
6
7
98
O
HO
98 (80:20)
Cl
O
HO
8
98 (85:15)
Cl
O
HO
Cl
9
97 (74:26)
99 (99:1)
Cl
O
OH
10
Cl
Cl
O
O
Cl
O
11
12
13
96e (89:11)
89e (78:22)
96
OH
O
O
OH
O
We then turned our attentions to examining the sub-
strate scope under the same reaction condition (Scheme
2). We found that ionic liquid bmimPF6 catalyzed or
promoted the ring opening of epoxides at high rates. In
the first hour, the reaction was carried out completely.
Presented in Table 1 are the results of combining various
epoxides with TMSCl in ionic liquid bmimPF6 followed
by cleavage of the trimethylsilyl group with aqueous
HCl. In all cases the corresponding chlorohydrins were
obtained in excellent yields (96–100%) and chemoselec-
tivity or regioselectivity. The expected two isomers could
not be separated by general column chromatography.
On each occasion, the regioselectivity was determined by
GC–MS and 1H NMR. The stereochemistry of ring
Cl
O
HO
Cl
a All reaction were performed in ionic liquids for 1 h except entry 2.
b Isolated yields, and the ratio of stereochemistry was determined by
1HNMR and GC–MS.
c The reaction was performed in CH2Cl2 and no addition of any cat-
alyst for 5 h.
d The yield after five runs.
e The reaction was performed at 0–5 °C.

L.-W. Xu et al. / Tetrahedron Letters 45 (2004) 2435–2438
2437
6. El-Qisairi, A. K.; Qaseer, H. A.; Henry, P. M.
J. Organomet. Chem. 2002, 656, 168.
7. (a) Sakurada, I.; Yamasaki, M.; Gottlich, R.; Lida, T.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122,
1245; (b) Larock, R. C. Comprehensive Organic Transfor-
mations; VCH: New York, 1989; pp 325–326.
opening had several expected and unique features. The
aliphatic epoxides such as cyclic oxides were observed to
yield products with exclusive inversion of stereochem-
istry (entries 6 and 13). And styrene oxide showed a
strong preference for the opposite regioselective to that
observed in the glycidyl aryl ethers and glycidyl alkyl
ethers.
8. (a) Andrews, G. C.; Crawford, T. C.; Contilio, L. G.
Tetrahedron Lett. 1981, 22, 3 803 ; (b) Loreto, M. A.;
Pellacani, L.; Tardella, P. A. Synth. Commun. 1981, 11, 287.
9. (a) Eisch, J. J.; Liu, Z. R.; Ma, X.; Zheng, G. X. J. Org.
Chem. 1992, 57, 5140; (b) Shimizu, M.; Yoshida, A.;
Tamotsu, F. Synlett 1992, 204; (c) Eisch, J. J.; Liu, Z. R.;
Singh, M. J. Org. Chem. 1992, 57, 1618; (d) Azzena, F.;
Calvani, F.; Crotti, P.; Gardelli, C.; Macchia, F.; Pineschi,
M. Tetrahedron 1995, 51, 10601; (e) Ciaccio, J. A.; Heller,
E.; Talbot, A. Synlett 1991, 248.
10. (a) Garrett, C. E.; Fu, G. C. J. Org. Chem. 1997, 62, 4534;
(b) Denmark, S. E.; Barsanti, P. A.; Wong, K. T.;
Stavenger, R. A. J. Org. Chem. 1998, 63, 2428; (c) Ready,
J. M.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 6086;
(d) Reymond, S.; Brunel, J. M.; Buono, G. Tetrahedron:
Asymmetry 2000, 11, 4441; (e) Wang, L. S.; Hollis, T. K.
Org. Lett. 2003, 5, 2543.
11. (a) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025–
1074; (b) Adeyemi, O. G.; Coville, N. J. Organometallics
2003, 22, 2284; (c) Akiyama, T.; Sanada, M.; Fuchibe, K.
Synlett 2003, 1463; (d) Chancharunee, S.; Perlmutter, P.;
Statton, M. Tetrahedron Lett. 2003, 44, 5683–5685; (e)
Firouzabadi, H.; Iranpoor, N.; Nowrouzi, F. Tetrahedron
Lett. 2003, 44, 5343; (f) Mitra, A. K.; Banerjee, K. Synlett
2003, 1509.
12. (a) Welton, T. Chem. Rev. 1999, 99, 2071; (b) Wassersc-
heid, P.; Keim, W. Angew. Chem., Int. Ed. 2000, 39, 3773;
(c) Sheldon, R. Chem. Commun. 2001, 2399; (d) Zhang,
S. B.; Ding, M. X.; Gao, L. X. J. Org. Chem. 2002, 22, 159;
(e) Dupont, J.; de Souza, R. F.; Suarez, P. A. Z. Chem. Rev.
2002, 102, 3669; (f) Chandrasekhar, S.; Narasihmulu, C.;
Jagadeshwar, V.; Reddy, K. V. Tetrahedron Lett. 2003, 44,
3629; (g) Li, Z.; Xia, C. G. Tetrahedron Lett. 2003, 44, 2069.
13. (a) Davis, J. H.; Fox, P. A. Chem. Commun. 2003, 1209;
(b) Davis, J. H.; Fox, P. A. Chem. Commun. 2003, 4281;
(c) Kabalka, G. W.; Venkataiah, B.; Dong, G.; Kim, D.
W.; Song, C. E.; Chi, D. Y. J. Org. Chem. 2003, 68;
Tetrahedron Lett. 2003, 44, 4673; (d) Chen, S.; Ji, S. L.;
Loh, T. P. Tetrahedron Lett. 2003, 44, 2405; (e) Ranu, B.
C.; Dey, S. S. Tetrahedron Lett. 2003, 44, 2865.
To check the efficiency of recycling ionic liquids
(bmimPF6), styrene oxide was subjected to the ring-
opening reaction of TMSCl,17 after five runs, the yield of
corresponding chlorohydrin was very high (97%).
In summary, we have first demonstrated that the ring-
opening reaction of epoxides with TMSCl could be
promoted by simple recyclable bmimPF6 ionic liquid.
The present reaction with its mild reaction conditions
opens a novel entry to synthesis of chlorohydrins com-
pounds using recyclable ionic liquid. And the specific
advantages are that the reactions are carried out under
mild conditions with high stereo-, and chemoselectivity
for the synthesis of chlorohydrin derivatives.
Acknowledgements
This study was supported in part by the Natural Science
Founder of National for financial support of the work
(No. 29933050 and 20373082).
References and notes
1. (a) Erden, I. In Comprehensive Heterocyclic Chemistry,
2nd ed.; Padwa, A., Ed.; Pergamon: Oxford, 1996; Vol.
1A, Chapter 1.03; (b) Watson, K. G.; Fung, Y. M.;
Gredley, M.; Bird, G. J.; Jackson, W. R.; Gountzos, H.;
Matthews, B. R. Chem. Commun. 1990, 1018; (c) Kolb, H.
C.; Sharpless, K. B. Tetrahedron 1992, 48, 10515; (d)
Kwon, D. W.; Cho, M. S.; Kim, Y. H. Synlett 2003, 959;
(e) Akiyama, Y.; Fukuhara, T.; Hara, S. Synlett 2003,
1530.
14. Xu, L. W.; Li, L.; Xia, C. G.; Zhou, S. L.; Li, J. W.
Tetrahedron Lett., 2004, 45, 1219.
2. (a) Brown, H. C.; Racherla, U. S.; Liao, Y.; Khanna, V. V.
J. Org. Chem. 1992, 57, 6608; (b) Jayaraman, S.; Hu, S.;
Oehlschlager, A. C. Tetrahedron Lett. 1995, 36, 4765.
3. (a) Newman, M. S.; Chen, C. H. J. Org. Chem. 1973, 38,
1173; (b) Newman, M. S.; Chen, C. H. J. Am. Chem. Soc.
1972, 94, 2149; (c) Robins, M. J.; Mengel, R.; Jones, R. A.
J. Am. Chem. Soc. 1973, 95, 4074.
15. General procedure: A mixture of the epoxide (2 mmol),
TMSCl (2.2 mmol, freshly distilled: argon atmosphere,
pyridine) and 2 mL of bmimPF6, was stirred at room
temperature for 1 h. After completion of the reaction, as
indicated by TLC and GC, the reaction mixture was
diluted with water and aqueous HCl or NH4Cl, and
extracted with diethyl ether. The combined organic layers
were dried over anhydrous Na2SO4, concentrated in
vacuo, and purified by column chromatography on silica
gel (100–200 mesh, ethyl acetate–petroether) to afford
corresponding chlorohydrin. All the known compounds
were characterized by GC–MS (Agilent 6890N GC/5973N
MS, HP-5MS) and usual spectral methods.
16. Some new examples of phosphine catalyzed reaction: (a)
Lu, X. Y.; Zhang, C. M.; Xu, Z. R. Acc. Chem. Res. 2001,
34, 535; (b) Brown, P. M.; Kappel, N.; Murphy, P. J.
Tetrahedron Lett. 2002, 43, 8707; (c) Wende, M.; Gladysz,
J. A. J. Am. Chem. Soc. 2003, 125, 5861; (d) Stewart, I. C.;
Bergman, R. G.; Toste, F. D. J. Am. Chem. Soc. 2003,
125, 8696; (e) Valentine, D. H., Jr.; Hillhouse, J. H.
4. (a) Derbesy, M.; Naudet, M. Bull. Soc. Chim. Fr. 1968,
ꢀ
4531; (b) Eras, J.; Mendez, J. J.; Balcells, M.; Canela, R.
J. Org. Chem. 2002, 67, 8631.
5. (a) Benincasa, M.; Forti, L.; Ghelfi, F.; Libertini, E.;
Pagnoni, U. M. Synth. Commun. 1996, 26, 4113; (b)
Curran, T. T. J. Org. Chem. 1993, 58, 6360; (c) Kim, K. S.;
Qian, L. Tetrahedron Lett. 1993, 34, 7195; (d) Zhang,
X. L.; Han, Y.; Tao, W. T.; Huang, Y. Z. J. Chem. Soc.,
Perkin. Trans. 1 1995, 189; (e) Tanaka, H.; Yamashita, S.;
Yamanoue, M.; Torii, S. J. Org. Chem. 1989, 54, 444; (f)
Utimoto, K.; Takai, T.; Matsui, T.; Matsubara, S. Bull.
Soc. Chim. Fr. 1997, 134, 365; (g) Castagner, B.; Lacombe,
P.; Ruel, R. J. Org. Chem. 1998, 63, 4551.

2438
L.-W. Xu et al. / Tetrahedron Letters 45 (2004) 2435–2438
Synthesis 2003, 317; (f) Fan, R. H.; Hou, X. L. Tetrahe-
17. Recycling study of ionic liquid: After extraction with
diethyl ether to separate the products, the ionic liquid
layer was washed by aqueous NaHCO3, water; the residue
water was removed in vacuum, and the resulting ionic
liquid layer was reused for the next run.
dron Lett. 2003, 44, 4411; (g) Fan, R. H.; Hou, X. L. J.
Org. Chem. 2003, 68, 726; (h) Shi, M.; Chen, L. H. Chem.
Commun. 2003, 1310; (i) Xu, L. W.; Xia, C. G.; Li, J. W.;
Zhou, S. L. Synlett 2003, 2246.