An efficient and convenient protocol for highly regioselective cleavage of terminal epoxides to β-Halohydrins

Article abstract of DOI:10.1055/s-0029-1217182

An efficient and facile strategy for the cleavage of terminal epoxides to β-halohydrins using active magnesium halides is described. The conversion proceeds smoothly at room temperature with high regioselectivity and good yields even when sensitive functional groups are present. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217182

LETTER
1511
An Efficient and Convenient Protocol for Highly Regioselective Cleavage of
Terminal Epoxides to b-Halohydrins
Regioselective
C
a
leavage
o
o
f
Terminal Epoxide
W
s
ang, Wen-Hao Ji, Zhong-Yu Xu, Bu-Bing Zeng*
School of Pharmacy, East China University of Science and Technology, Shanghai 200237, P. R. of China
Fax +86(21)64253689; E-mail: zengbb@ecust.edu.cn
Received 18 December 2008
Magnesium bromide hexahydrate supported on silica gel
Abstract: An efficient and facile strategy for the cleavage of termi-
nal epoxides to b-halohydrins using active magnesium halides is de-
scribed. The conversion proceeds smoothly at room temperature
with high regioselectivity and good yields even when sensitive
functional groups are present.
was reported to convert phenyl glycidyl ether into the cor-
responding bromohydrin with excellent yield.4d However,
further studies in our laboratory indicated that the use of
MgBr2·6H2O and MgCl2 led to low yields, and the yields
appeared to be significantly dependent on the structure of
substrates, while anhydrous MgBr2 and MgI2 prepared in
situ could smoothly open the various terminal epoxides to
give corresponding b-halohydrins in satisfactory yields.
Herein, we report an efficient, practical, and rapid proce-
dure for the transformation of terminal epoxides into
bromo- and iodohydrins with a high degree of regioselec-
tivity and chemoselectivity using freshly prepared anhy-
drous magnesium bromide and iodide (Scheme 1).
Key words: epoxide, b-halohydrin, cleavage, regioselectivity,
chemoselectivity
b-Halohydrins, which can be easily prepared from ep-
oxides, are of significant importance as versatile interme-
diates in organic synthesis and building blocks for the
total synthesis of natural products. Specially, the terminal
b-halohydrins are also very useful precursors in organic
transformation of some functional groups1 and broadly
used in the synthesis of halogenated marine natural
products2 and other biologically active molecules.3 More
recently, there is an obvious growing interest in the
research of the conversion between epoxides and b-halo-
hydrins.
A large number of reagents such as halogens,4a,b hydrogen
halides,4c metal halides,3a,4d–4f bromodimethylsulfonium
bromide4g have been developed for the preparation of b-
halohydrins from epoxides. Among these approaches,
ring opening of the epoxides either with hydrogen halides,
or with elemental halogen are the most straightforward
synthetic methods. However, these procedures have limi-
tations when acid-sensitive substrates are used, and many
of which suffered from the utilization of expensive or tox-
ic halogenation reagents and catalysts or additives,4b,d,5,6
complicated procedures, unavoidable side reaction,4a,d
and weak functional-group tolerance.7 Thus, it is still nec-
essary to explore a simpler, milder and more efficient
methodology for the regioselective transformation of ep-
oxides into halohydrins.
Firstly, the effect of solvents on the yield and regioselec-
tivity was studied with (R)-tert-butyldimethyl(oxiran-2-
ylmethoxy)silane as a model reaction in the presence of
magnesium halides. The screening results of reaction
solvents are shown in Table 1. The reaction was highly
solvent-dependent, giving the best result in dichlo-
romethane (Table 1, entry 1). The reaction in other sol-
vents only gave moderate yields even if the reaction time
was extended up to 50 minutes (Table 1, entries 3–6).
Therefore, methylene chloride was employed as the sol-
vent in our further investigations.
Table 1 Ring Opening of Epoxides Using Active Magnesium
Bromide and Iodide in Various Solvents at Room Temperature
OH
MgX2
O
TBSO
X
TBSO
solvent, r. t.
1a,b
Entry Solventa
MgBr2
MgI2
b
b
Time (min) Yield (%) Time (min) Yield (%)
1
2
3
4
5
6
CH2Cl2
MeCN
CHCl3
THF
1
1
92
92
85
80
58
53
1
1
93
92
86
82
60
55
OH
MgX2
O
X
R
R
5
5
CH2Cl2, r.t.
X = Br, I
50
60
60
50
60
60
Scheme 1 Cleavage of terminal epoxides using freshly prepared
MgBr2 or MgI2
Et2O
toluene
a Solvents used in the reaction were all anhydrous.
b MgBr2·THF and MgI2·THF were prepared in situ in THF at r.t. from
Mg, 1,2-dibromoethane and I2, respectively.
SYNLETT 2009, No. 9, pp 1511–1513
Advanced online publication: 13.05.2009
x
x.
x
x.
2
0
0
9
DOI: 10.1055/s-0029-1217182; Art ID: W19408ST
© Georg Thieme Verlag Stuttgart · New York

1512
T. Wang et al.
LETTER
The reaction proceeded almost completely within one hydrins, but the reaction required longer time in lower
minute in dichloromethane, giving terminal b-bromo- conversion comparing to anhydrous MgBr2 or MgI2
hydrins and iodohydrins in high yields immediately after (Table 2, entry 1). A possible mechanism proposed by
addition of freshly prepared magnesium bromide and Eisch group10 could explain that magnesium halides as
magnesium iodide, respectively. Obviously, the experi- weak Lewis acids could polarize regioselectively the C–
mental procedure was very convenient and simple.8
OMgX bond, leading to the nucleophilic attack of halide
ion by SN2-type at the less hindered terminal carbon. The
reactivity of magnesium halides followed the order of
MgI2 > MgBr2 > MgCl2 owing to the nucleophilicity of
I– > Br– > Cl–. The low yield associated with MgCl2 might
be ascribed to low nucleophilicity of Cl–. This mechanism
also explained that the unstable b-iodohydrins in THF
were partially eliminated into methyl ketone (Table 2, en-
try 3) when the reaction time was prolonged.
Next, the scope and limitations of this novel procedure
with different terminal epoxides bearing various function-
al groups under the condition described above were stud-
ied. The results were summarized in Table 2. Ring
opening of the terminal epoxides by fresh MgX2 (X = Br,
I) were highly regioselective, producing a single product.
This method indicated that the active MgX2 (X = Br, I)
was also chemoselective with respect to other functional
groups such as chiral hydroxyl, benzyl, and trimethylsilyl-
ethynyl (Table 2, entries 1, 2, 4–6). It was observed that
the predominated attack of the reagents occurred at the
less hindered side of the epoxides, whereas the only ex-
ception was in the case of styrene oxide which led to a
mixture of regioisomers (Table 2, entry 7). This exception
could be explained by the formation of a stable positive
charge at the benzylic position.
In conclusion, we reported here an efficient and extremely
simple method for the transformation of epoxides into b-
halohydrins using active magnesium halides. In addition,
high regio- and chemoselectivity, operational simplicity,
neutral and mild reaction conditions without any catalyst
and additive, considerably fast reaction, and high yielding
make this protocol an addition to the existing methods in
the syntheses of b-halohydrins.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
It is worth noting that anhydrous MgCl2 could also open
terminal epoxides to give the corresponding b-chloro-
Table 2 Opening of Terminal Epoxides Using Active Magnesium Halide (X = Br, I)9
Entry
Epoxidea
TBSO
Productb
Yield (%)c
1a X = Br
1b X = I
1c X = Cl
1a X = Br
92
93
OH
O
1
20d
54d
TBSO
BnO
X
X
2a X = Br
2b X = I
90
90
OH
O
2
3
BnO
X
OH
O
3a X = Br
3b X = I
3b/3c X = I
86
O
( )3
Br
Br
85
48/21e
( )3
Br
( )3
OH
O
4a X = Br
4b X = I
80
80
4
X
TMS
Cl
OMOM
TMS
Cl
OMOM
OH
OH
OH
5a X = Br
5b X = I
91
92
5
6
O
O
X
( )5
( )5
TBSO
OTBS
( )5
6a X = Br
6b X = I
95
95
OH
Cl
Cl
X
( )5
OH
X
1
7a¢/7a X = Br
7b¢/7b X = I
60
61
O
X
7
OH
:
Ph
Ph
Ph
2
a All reactions were performed using 2.0 equiv of freshly prepared magnesium halides.
b All reactions finished within one minute.
c Isolated yield through column chromatography on SiO2.
d MgCl2 and MgBr2·6H2O were used in the reaction, respectively.
e The reaction was performed using active MgI2 in dried THF at r.t. for 20 h, and 3c was separated.
Synlett 2009, No. 9, 1511–1513 © Thieme Stuttgart · New York

LETTER
Regioselective Cleavage of Terminal Epoxides
1513
Analytical Data of Compounds 3–6
Acknowledgment
Compound 3a: 1H NMR (400 MHz, CDCl3): d = 3.78 (m, 1
H), 3.53 (dd, J = 12.0, 4.0 Hz, 1 H), 3.43–3.36 (m, 3 H), 2.39
(br, 1 H), 1.92–1.82 (m, 2 H), 1.62–1.51 (m, 4 H). 13C NMR
(100 MHz, CDCl3): d = 70.8, 40.3, 34.1, 33.6, 32.4, 24.3. IR
(neat): 3393, 2941, 2864, 1432, 1259, 1050, 666, 561 cm–1.
HRMS (EI): m/z [M – H]+ calcd for C6H12Br2O: 258.9234;
found: 258.9156.
This work is financially supported by Shanghai Municipal Commit-
tee of Science and Technology (064319022), 111 project (B07023),
the national ‘863’ Project of China (2006AA609Z447 and
2007AA02Z301) and Shanghai Pujian Program (05PJ14035).
References and Notes
Compound 3b: 1H NMR (400 MHz, CDCl3): d = 3.56–3.48
(m, 1 H), 3.42–3.35 (m, 3 H), 3.22 (t, J = 8.0 Hz, 1 H), 2.34
(br, 1 H), 1.90–1.84 (m, 2 H), 1.60–1.48 (m, 4 H). 13C NMR
(100 MHz, CDCl3): d = 70.7, 35.6, 33.7, 32.4, 24.3, 16.4.
Compound 4a: 1H NMR (400 MHz, CDCl3): d = 4.74 (dd,
J = 28.0, 8.0 Hz, 2 H), 3.98–3.92 (m, 1 H), 3.75 (dd,
J = 12.0, 4.0 Hz, 1 H), 3.67 (dd, J = 12.0, 4.0 Hz, 1 H), 3.57
(dd, J = 12.0, 8.0 Hz, 1 H), 3.41 (s, 3 H), 2.75 (br, 1 H), 2.63
(d, J = 4.0 Hz, 2 H), 0.14 (s, 9 H). 13C NMR (100 MHz,
CDCl3): d = 102.6, 96.6, 87.4, 76.7, 72.0, 56.0, 36.4, 22.4,
–0.0(4). IR (neat): 3437, 2958, 2899, 2177, 1420, 1250, 699,
646 cm–1. HRMS (EI): m/z [M – H]+ calcd for C11H21BrO3Si:
307.0443; found: 307.0349.
(1) (a) Piva, O. Tetrahedron Lett. 1992, 33, 2459.
(b) Berkessel, A.; Rollmann, C.; Chamouleau, F.; Labs, S.;
May, O.; Gröger, H. Adv. Synth. Catal. 2007, 349, 2697.
(c) de Jong, R. M.; Tiesinga, J. J. W.; Villa, A.; Tang, L.;
Janssen, D. B.; Dijkstra, B. W. J. Am.Chem. Soc. 2005, 127,
13338.
(2) For reviews, see: (a) Moore, R. E. In Marine Natural
Products, Vol. 1; Scheuer, P. J., Ed.; Academic: New York,
1978, Chap. 2. (b) Fenical, W. In Marine Natural Products,
Vol. 2; Scheuer, P. J., Ed.; Academic: New York, 1980,
174. (c) Barrow, K. D. In Marine Natural Products, Vol. 5;
Scheuer, P. J., Ed.; Academic: New York, 1983, 51.
(3) (a) Righi, G.; Franchini, T.; Bonini, C. Tetrahedron Lett.
1998, 39, 2385. (b) Babudri, F.; Fiandanese, V.; Marchese,
G.; Punzi, A. Tetrahedron 2001, 57, 549. (c) Boukhris, S.;
Souizi, A. Tetrahedron Lett. 2003, 44, 3259.
(4) (a) Sharghi, H.; Eskandari, M. M. Tetrahedron 2003, 59,
8509. (b) Konnaklieva, M. L.; Dahi, M. L.; Turos, E.
Tetrahedron Lett. 1992, 33, 7093. (c) Stewart, C. A.;
Vander Werf, C. A. J. Am. Chem. Soc. 1954, 76, 1259.
(d) Kotsuki, H.; Shimanouchi, T. Tetrahedron Lett. 1996,
37, 1845. (e) Sabitha, G.; Babu, R. S.; Rajkumar, M.; Reddy,
C. S.; Yadav, J. S. Tetrahedron Lett. 2001, 42, 3955.
(f) Pinto, R. M. A.; Salvador, J. A. R.; Roux, C. L.
Tetrahedron 2007, 63, 9221. (g) Das, B.; Krishnaiah, M.;
Venkateswarlu, K. Tetrahedron Lett. 2006, 47, 4457.
(5) (a) Wu, J.; Sun, X.; Sun, W.; Ye, S. Synlett 2006, 2489.
(b) Niknam, K.; Nasehi, T. Tetrahedron 2002, 58, 10259.
(6) Bajwa, J. S.; Anderson, R. C. Tetrahedron Lett. 1991, 32,
3021.
Compound 4b: 1H NMR (400 MHz, CDCl3): d = 4.77–4.68
(m, 2 H), 3.75–3.66 (m, 2 H), 3.49–3.45 (m, 1 H), 3.40 (d,
J = 8.0 Hz, 3 H), 3.35–3.31 (m, 1 H), 2.75 (br, 1 H), 2.61 (d,
J = 8.0 Hz, 2 H), 0.12 (d, J = 8.0 Hz, 9 H). 13C NMR (100
MHz, CDCl3): d = 102.6, 96.7, 87.4, 78.4, 72.2, 56.1, 22.4,
11.0, –0.0(0).
Compound 5a: 1H NMR (400 MHz, CDCl3): d = 3.79–3.72
(m, 2 H), 3.59 (dd, J = 12.0, 4.0 Hz, 1 H), 3.51–3.43 (m, 2
H), 3.35 (dd, J = 12.0, 8.0 Hz, 1 H), 2.76 (br, 2 H), 1.55–1.43
(m, 6 H), 1.40–1.30 (m, 4 H). 13C NMR (100 MHz, CDCl3):
d = 71.3, 71.0, 50.4, 40.4, 34.9, 34.0, 29.3, 29.2, 25.4, 25.3.
Compound 5b: 1H NMR (400 MHz, CDCl3): d = 3.78–3.73
(m, 1 H), 3.57 (dd, J = 8.0, 4.0 Hz, 1 H), 3.50–3.42 (m, 2 H),
3.32 (dd, J = 8.0, 4.0 Hz, 1 H), 3.21–3.17 (m, 1 H), 3.04 (br,
2 H), 1.55–1.39 (m, 6 H), 1.38–1.26 (m, 4 H). 13C NMR (100
MHz, CDCl3): d = 71.3, 70.8, 50.3, 36.4, 34.0, 29.2, 25.5,
25.4, 16.3.
Compound 6a: 1H NMR (400 MHz, CDCl3): d = 3.85–3.79
(m, 2 H), 3.56 (dd, J = 12.0, 4.0 Hz, 1 H), 3.48–3.38 (m, 3
H), 2.14 (d, J = 4.0 Hz, 1 H), 1.61–1.50 (m, 4 H), 1.43–1.32
(m, 6 H), 0.91 (s, 9 H), 0.10 (d, J = 8.0 Hz, 6 H). 13C NMR
(100 MHz, CDCl3): d = 72.4, 71.0, 48.5, 40.6, 35.0, 34.8,
29.5, 25.8, 25.5, 24.7, 18.1, –4.5, –4.6. IR (neat): 3393,
2931, 2857, 1463, 1255, 1099, 837, 777 cm–1.
(7) (a) Ranu, B. C.; Banerjee, S. J. Org. Chem. 2005, 70, 4517.
(b) Ranu, B. C.; Adak, L.; Banerjee, S. Can. J. Chem. 2007,
85, 366.
(8) General Procedure
To the solution of epoxide (5 mmol) in CH2Cl2 (8 mL) was
added active MgX2·THF (2.0 equiv, M = 1.78 mol/L) at r.t.
The reaction was stirred at the same temperature for 1 min
and then quenched with sat. aq NH4Cl. The solvent was
removed under vacuum. and the residue was extracted with
EtOAc. The combined organic layer was washed with H2O
and brine, dried over anhyd Na2SO4, and concentrated under
reduced pressure. Purification of the residue was by
chromatography on SiO2 to give the product.
Compound 6b: 1H NMR (400 MHz, CDCl3): d = 3.85–3.80
(m, 1 H), 3.56–3.48 (m, 1 H), 3.46–3.38 (m, 3 H), 3.25 (dd,
J = 12.0, 8.0 Hz, 1 H), 2.03 (d, J = 8.0 Hz, 1 H), 1.66–1.53
(m, 4 H), 1.46–1.31 (m, 6 H), 0.91 (s, 9 H), 0.10 (d, J = 4.0
Hz, 6 H). 13C NMR (100 MHz, CDCl3): d = 72.4, 70.9, 48.5,
36.5, 34.8, 29.5, 25.8, 25.6, 24.7, 18.1, 16.6, –4.4, –4.6.
(10) Eisch, J. J.; Liu, Z. R.; Zheng, G. X. J. Org. Chem. 1992, 57,
5140.
(9) Spectral Data of Compounds 1a–c, 2a,b, 3c, 7a, 7a¢, 7b,
7b¢ matched in all respects with reported data.
Synlett 2009, No. 9, 1511–1513 © Thieme Stuttgart · New York

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