Conversion of epoxides into halohydrins with elemental halogen catalyzed by thiourea

Article abstract of DOI:10.1016/j.tet.2003.09.033

A highly regioselective method for the synthesis of β-iodohydrins and β-bromohydrins by the direct ring opening of epoxides with elemental halogen in the presence of thiourea is described. This method occurs under neutral and mild conditions with high yields in various solvents even when sensitive functional groups are present.

Full text of DOI:10.1016/j.tet.2003.09.033

Tetrahedron 59 (2003) 8509–8514
Conversion of epoxides into halohydrins with elemental halogen
catalyzed by thiourea
*
Hashem Sharghi and Mohammad Mehdi Eskandari
Department of Chemistry, College of Science, Shiraz University, Shiraz 71454, I. R. Iran
Received 18 March 2003; revised 17 August 2003; accepted 11 September 2003
Abstract—A highly regioselective method for the synthesis of b-iodohydrins and b-bromohydrins by the direct ring opening of epoxides
with elemental halogen in the presence of thiourea is described. This method occurs under neutral and mild conditions with high yields in
various solvents even when sensitive functional groups are present.
q 2003 Published by Elsevier Ltd.
1. Introduction
with elemental iodine and bromine in the presence of
catalytic amount of thiourea.
Epoxides are versatile intermediates in organic synthesis
and a large variety of reagents are known for the ring
opening of these compounds.1,2 The most common method
for the synthesis of 1,2-halohydrins from epoxides is their
ring opening either with hydrogen halides or with hydro-
halogenic acid.3 However, these procedures are limited
when protic acid sensitive substrates are used. A great effort
has been made in the last few years to find new mild
procedures for converting epoxides into halohydrins. For
example, silyl halides can be added to epoxides to give
halohydrins.4 In these cases, however, the primary reaction
products are the O-silyl protected derivatives.4 Other
methods require the use of a halogen and triphenylphos-
phine,5 or disubstituted borane halogenides,6 b-bromo bis-
(dimethylamino) borane,7 monochloro borane–dimethyl-
sulfide,8 LinMnXn (M¼Ni, Cu, Ti)9 and MXn.10 It has been
found that epoxides also can be converted into halohydrins
by means of elemental halogen,11 but this method has some
limitations such as low yield, long reaction times, low
regioselectivity and formation of acetonides as by-products
in addition to the expected iodo adduct in acetone solution.
Furthermore, iodination does not occur in other aprotic
solvents. In relation with our pervious work on the use of
pyridine-containing macrocyclic compounds,12 we intro-
duce a very simple, mild, cheap, available and efficient
method for the conversion of epoxides into halohydrins. We
found that thiourea catalyzed the addition of elemental
halogen to epoxides under mild reaction conditions with
high regioselectivity. In this paper we describe our
successful results that led to a novel and extremely simple
method for the transformation of epoxides into halohydrins
2. Result and discussion
In order to optimise the reaction conditions, we first
examined the effects of elemental halogens in the presence
of different amounts of thiourea on 1,2-epoxy-3-phenoxy-
propane as a model in various solvents (Table 1 and
Scheme 1).
Table 1. Addition of iodine (1 mmol) and bromine (1 mmol) to 1,2-epoxy-
3-phenoxypropane (1 mmol) catalysed by different amounts of thiourea in
various solvents at 258C
Entry
Solvent
Catalyst
(mmol)
Iodination
Bromoniation
Time
(h)
Yielda
(%)
Time
(h)
Yielda
(%)
1
2
3
4
5
6
7
8
CH3CN
CH3CN
CH3CN
CH3CN
THF
0.2
0.1
0.05
0.025
0.1
0.1
0.1
0.1
0.1
2.5
70
70
50
30
55
40
30
33
25
30
50
1.5
75
75
60
40
60
45
50
35
35
40
60
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
Et2O
CH2Cl2
CHCl3
DMSO
HMPA
Dioxane
9
10
11
0.1
0.1
a
Isolated yield.
Keywords: thiourea; epoxide; halohydrins.
*
Corresponding author. Tel.: þ98-711-2287600; fax: þ98-711-2280926;
e-mail: shashem@chem.susc.ac.ir
Scheme 1.
0040–4020/$ - see front matter q 2003 Published by Elsevier Ltd.
doi:10.1016/j.tet.2003.09.033

8510
H. Sharghi, M. M. Eskandari / Tetrahedron 59 (2003) 8509–8514
Table 2. Reaction of various epoxides with iodine and bromine in the presence of thiourea catalyst in CH3CN at room temperature
Entry
1
Epoxide
Catalyst
Reaction condition
I2/CH3CN/258C
Product
Reaction time (h)
0.83
Yielda (%)
90
Reference
Thiourea
2
3
4
–
–
–
I2 (excess)/CH2Cl2/reflux
I2 (excess)/CH3CN
I2/acetone/258C
No reaction
No reaction
Several days
Several days
2
–
11
11
11
–
83
5
–
LiI/AcOH/THF/rt
1.3
87 (1:2)
10a
6
7
8
–
HI/CHCl3
0.25
2.5
–
.99
15
11
Thiourea
–
I2/CH3CN/258C
I2/acetone/258C
70
94 (1:1)
9
Thiourea
–
I2/CH3CN/258C
I2/acetone/258C
3
–
70
10
79 (1:4)
11
11
Thiourea
I2/CH3CN/258C
1.15
80
12
13
14
Thiourea
Thiourea
Thiourea
I2/CH3CN/258C
I2/CH3CN/258C
Br2/CH3CN/258C
5.5
58
63
95
5.5
0.33
15
16
–
–
Br2/rt/CH2Cl2
1
5
33
11
33
n-Bu4NBr/Mg(NO3)2/CHCl3
78 (5:1)
17
–
(Me2N)2BBr/CH2Cl2/N2
12
75 (1:4.5)
7
18
19
–
HBr/CHCl3
0.25
1.5
.99
15
Thiourea
Br2/CH3CN/258C
75

H. Sharghi, M. M. Eskandari / Tetrahedron 59 (2003) 8509–8514
8511
Table 2 (continued)
Entry
Epoxide
Catalyst
–
Reaction condition
Br2/CH3CN
Product
Reaction time (h)
–
Yielda (%)
66 (1:2)
Reference
11
20
21
22
Thiourea
Br2/CH3CN/258C
0.75
80 (4.5:1)
88 (5:1)
–
Br2/rt/CH2Cl2
–
11
23
24
Thiourea
Thiourea
Br2/CH3CN/258C
Br2/CH3CN/258C
0.75
0.66
75
87
25
26
–
–
Br2/CH2Cl2
–
5
44
90
11
LiBr/AcOH/THF/258C
10a
27
28
Thiourea
Thiourea
Br2/CH3CN/258C
Br2/CH3CN/258C
0.83
0.83
65
75
a
Isolated yield.
As shown in Table 1, yields of both iodination and
bromination with this methodology are quite good. The
optimum amount of catalyst was found to be 0.1 mol for
1 mol of epoxide and halogen.
indicates that an increase in steric hindrance at the epoxide
ring results in a general decrease in the rate of halohydrin
formation (for example, compare Table 2, entry 1 with
entry 11).
The results obtained with some representative epoxides in
the presence of thiourea as catalyst are summarized in Table
2 and are compared with the corresponding results obtained
in the reaction of the same epoxides in the absence of
catalyst (Table 2, entries 2, 3, 4, 8, 10, 15, 20, 22, 25). On the
other hand, for comparison, some other methods for
conversion of epoxides to the corresponding halohydrins
are given in Table 2, entries 5, 6, 16, 17, 18 and 26. When
epoxides were allowed to react in the presence of catalyst,
increases in yield and regioselectivity were observed in all
of the reactions studied. The increase appeared to be largely
dependent on the nature of solvent and amount of catalyst
(Table 1).
The order and rate in which the reagent are combined were
found to exert a subtle influence on yield and regioselec-
tivity in both bromohydrin and iodohydrin formation. For
example, if bromine is added to epoxide before catalyst is
added, two bromohydrin isomers are produced, but if the
epoxide is added to catalyst and then bromine is added
dropwise over a period time, only one isomer is formed.
Furthermore, fast addition of bromine reduced regio-
selectivity, too (Table 2, entry 21).
As shown in Table 2 (entries 11 and 24) in which only the
trans isomers were detected, the reactions are completely
trans-stereoselective. A contra-Markovnikov-type13,14 of
regioselectivity is generally observed in these reactions. In
one case, this type of regioselectivity appears to be opposite
to that observed in the ring opening of the same epoxides
with aqueous hydrohalogenic acids, under classic con-
ditions15 (entries 6 and 18). The regiochemical mode of
epoxide cleavage by elemental iodine or bromine in the
presence of thiourea catalyst can be viewed as occurring via
nucleophilic attack by halide ion on the less sterically
hindered epoxide carbon. This mechanism closely
However, other factors can exert a controlling influence,
such as: (1) steric hindrance of epoxides, (2) the rate of
admixing the reagents and (3) the order in which the
reagents are combined. Each can have pronounced effect on
the observed ratio of halohydrin isomers and overall yield.
A comparison of the reaction of epoxides with elemental
bromine or iodine in the presence of thiourea catalyst

8512
H. Sharghi, M. M. Eskandari / Tetrahedron 59 (2003) 8509–8514
Figure 1. Absorption spectra in CH3CN solution: (a) Thiourea. (b) I2.
(c) Thiourea–I2.
generated should be fostered and transition state b may be
expected to be lower in energy. In this case the cleavage
leads to a mixture of secondary alcohol and primary alcohol
products.14
Scheme 2.
resembles the SN2 model for aliphatic nucleophilic
displacement. On the basis of our study on the complexation
of thiourea and other work reported on the different
ligands11,16 with elemental halogen, halogenative cleavage
of epoxides occurs according to the following four-step
mechanism (Scheme 2).
The variation in yield and rate of cleaving epoxides by
elemental iodine or bromine in the presence of thiourea
can be satisfactory rationalized in terms of the suggested
mechanism.
The first step involves the formation of a 1:2 or 1:1
molecular complex between thiourea and elemental halo-
gen, in which halogen ion (X23 ) exists as a contact ion pair.
In the second step this complex is further decomposed
to release X23 ion into solution. Therefore, in this way,
molecular iodine or bromine is converted to a nucleophilic
halogen species in the presence of a thiourea and, in the
third step, this ion participates in the ring opening reaction
of epoxides. These steps occur continuously until all of the
epoxides and halogen are consumed.
In support of this mechanism, reaction of thiourea with
iodine was followed by UV spectroscopy (Fig. 1). Figure 1
shows the characteristic UV band at 364 nm. This band is
well known to be specific for the formation of triiodide ion,
I23 , in the complex formation process between iodine and
different electron-pair-donating ligands.17–19 The decrease
in regioselectivity that results by merely reversing the order
of mixing of epoxide and halogen, namely the slow addition
of epoxide to bromine or fast addition of bromine to
epoxide, before catalyst was added, can readily be under-
stood from the model. When the initial epoxide was
introduced (in the absence or presence of catalyst), it
would encounter an excess amount of bromine; electrophilic
attack by bromine can then occur, giving the transition state
a, and bromine anions will attack the more substituted
carbon. On the other hand, slow addition of bromine to the
mixture of catalyst and epoxide fosters the four-step
mechanism presented above in which all of the elemental
bromine is converted to Br23 by the catalyst and it then
attacks the less substituted carbon selectively.
On the other hand, when catalyst is not present, cleavage of
epoxides can occur via two limiting mechanistic pathways,
either electrophilic attack by molecular halogen behaving as
Lewis acid, giving the more stable carbonium ion like
transition state a, or via nucleophilic attack by halide ion on
the epoxide–halogen complex, giving the more stable
transition state b (Scheme 3).
The regiochemistry of the cleavage can be selective
depending on the choice of Lewis acid and reaction
conditions. The reaction conditions providing the most
Lewis acidic, namely with titanium halides, foster electro-
philic opening of the epoxide ring to yield transition state a.
Conversely, when weaker Lewis acids are employed, such
as molecular halogen, nucleophilic attack by the halide ions
In conclusion, thiourea appears to be an efficient catalyst for
ring opening of the epoxides with elemental halogens under
mild conditions. In addition, the advantages such as high
regio- and stereoselectivity of the reactions, stability,
commercially available and cheapness of the catalyst, high
yield and ease of workup make this method a useful addition
to the present methodologies in organic syntheses.
3. Experimental
Yields refer to isolated yields, NMR spectra were recorded
in CDCl3 on a Bruker Advanced Dpx-250 (1H NMR
250 MHz and 13C NMR 62.9 MHz) spectrophotometer
using TMS as internal standard. UV–vis spectra were
obtained with a Philips PU8750 spectrometer. GC spectra
were recorded on a Shimadzu GC-14A. Infrared
spectra were recorded on a Perkin–Elmer IR-157G and a
Scheme 3.

H. Sharghi, M. M. Eskandari / Tetrahedron 59 (2003) 8509–8514
8513
Perkin–Elmer 781 spectrometer. Chromatography was
carried out on silica gel 60 (70–230 mesh).
3.1.11. 1-Bromo-3-iodo-2-propanol. Yellow liquid. Yield¼
58%; spectroscopic data identical to that reported in the
literature.31
3.1. General procedure for conversion of epoxides into
halohydrins
3.1.12. 1-Chloro-3-iodo-2-propanol. Liquid; bp 53–558C
(0.2 mm) (lit.,32 52–548C (0.2 mm). Yield¼63%; spectro-
scopic data identical to that reported in the literature.31
Epoxide (1 mmol) in CH3CN (5 mL) was added to a stirred
solution of catalyst (0.1 mmol) in CH3CN (5 mL) at room
temperature. Next, a solution of elemental halogen
(1 mmol) in CH3CN (5 mL) was added portionwise
(15 min) to the above mixture. The reaction was monitored
by GLCþTLC. After complete disappearance of the starting
material, the reaction mixture was washed with 10%
aqueous Na2S2O3 (2£10 mL) and water (2£10 mL). The
aqueous layer was extracted with CH2Cl2 (3£10 mL). The
combined organic layer was dried over anhydrous MgSO4
and evaporated to give crude halohydrin. The crude
product(s) was purified by column chromatography.
The halohydrins were identified by comparison with
authentic samples prepared in accordance with literature
procedures.9c,10,11,20,22
3.1.13. 2,2-Dimethyl-4-phenyl-1,3-dioxolane. Liquid.
Yield¼83%; spectroscopic data identical to that reported
in the literature.34
3.1.14. 2-Iodo-2-phenylethanol. Yield¼58%; spectro-
scopic data identical to that reported in the literature.35
3.1.15. 2,2-Dimethyl-4-(phenoxymethyl)-1,3-dioxolane.
Liquid. Yield¼44%; spectroscopic data identical to that
reported in the literature.34
3.1.16. 4-Hexyl-2,2-dimethyl-1,3-dioxolane. Liquid.
Yield¼64%; spectroscopic data identical to that reported
in the literature.11
3.1.1. 2-Iodo-1-phenylethanol. White crystal; mp 33–358C
(lit.,21 348C). Yield¼90%; spectroscopic data identical to
that reported in the literature.12
3.1.17. 2-Bromo-2-phenylethanol. White crystal; mp 36–
378C (lit.,36 388C). Yield¼33%; spectroscopic data identical
to that reported in the literature.35
3.1.2. 2-Bromo-1-phenylethanol. Liquid; bp 110–1118C
(4.2 mm) (lit.,22 120–1238C (5 mm). Yield¼95%; spectro-
scopic data identical to that reported in the literature.12
3.1.18.
1-Bromo-3-(4-bromophenoxy)-2-propanol.
Yield¼22%; spectroscopic data identical to that reported
in the literature.11
3.1.3. 1-Bromo-2-octanol. Liquid; bp 115–1178C (15 mm)
(lit.,23 111–1128C (10 mm). Yield¼75%; spectroscopic
data identical to that reported in the literature.20
3.1.19.
2-Bromo-3-(4-bromophenoxy)-1-propanol.
Yield¼44%; spectroscopic data identical to that reported
in the literature.11
3.1.4. 1-Iodo-2-octanol. Yellow liquid. Yield¼70%; spec-
troscopic data identical to that reported in the literature.20
Acknowledgements
3.1.5. 2-Iodocyclohexanol. White crystal; mp 41.5–438C
(lit.,24 41.5–42.58C). Yield¼80%; spectroscopic data
identical to that reported in the literature.20
We would like to acknowledge the support of this work by
Shiraz University Research Council.
3.1.6. 2-Bromocyclohexanol. Liquid; bp 84–868C (10 mm)
(lit.,25 88–908C (7 mm). Yield¼87%; spectroscopic data
identical to that reported in the literature.20
References
3.1.7. 1-Bromo-3-phenoxy-2-propanol. Odourless liquid;
bp 160–1618C (15 mm) (lit.,26 167–1698C (16 mm). Yield¼
75%; spectroscopic data identical to that reported in the
literature.12
1. Bonini, C.; Righi, G. Synthesis 1994, 225–241.
2. (a) Shimizu, M.; Yoshida, A.; Fujisawa, T. Synlett 1992,
204–206. (b) Iranpoor, N.; Mohammadpour Baltork, I. Synth.
Commun. 1990, 20, 2789–2797.
3. For an exhaustive list of methods for the preparation of 1,
2-halohydrins from epoxides see: Fieser and Fieser’s Reagent
for Organic Synthesis; Smith, J. G., Fieser, M., Eds.; Wiley:
New York, 1990; Collective Index for Vols. 1–12.
3.1.8. 1-Iodo-3-phenoxy-2-propanol. Odourless liquid; bp
176–1808C (16 mm) (lit.,26 177–1818C (16 mm). Yield¼
70%; spectroscopic data identical to that reported in the
literature.12
4. (a) Kricheldorf, H. R.; Morber, G.; Regel, W. Synthesis 1981,
383–384. (b) Andrews, G. C.; Crawford, T. C.; Contillo, L. G.
Tetrahedron Lett. 1981, 22, 3803–3806. (c) Detty, M. R.;
Seidler, M. D. Tetrahedron Lett. 1982, 23, 2543–2546.
5. (a) Palumbo, G.; Ferreri, C.; Caputo, R. Tetrahedron Lett.
1983, 24, 1307–1310. (b) Caputo, R.; Ferreri, C.; Noviello, S.;
Palumbo, G. Synthesis 1986, 499–501.
3.1.9. 1,3-Dibromo-2-propanol. Yellow liquid; bp 103–
1068C (15 mm) (lit.,27 1058C (16 mm). Yield¼65%;
spectroscopic data identical to that reported in the
literature.28
3.1.10. 1-Bromo-3-chloro-2-propanol. Liquid; bp96–988C
(15 mm) (lit.,29 95–988C (15 mm). Yield¼75%; spectro-
scopic data identical to that reported in the literature.30
6. (a) Guindon, Y.; Therien, M.; Girard, Y.; Yoakim, C. J. Org.
Chem. 1987, 52, 1680–1686. (b) Joshi, N. N.; Srebnik, M.;
Brown, H. C. J. Am. Chem. Soc. 1988, 110, 6246–6248.

8514
H. Sharghi, M. M. Eskandari / Tetrahedron 59 (2003) 8509–8514
7. Bell, T. W.; Ciaccio, J. A. Tetrahedron Lett. 1986, 27,
827–830.
20. Masuda, H.; Takase, K.; Nishio, M.; Hasegavw, A.;
Nishiyama, Y.; Ishii, Y. J. Org. Chem. 1994, 59, 5550–5555.
21. Golumbic, C.; Cottle, D. L. J. Am. Chem. Soc. 1939, 61,
996–1000.
8. Bovicelli, P.; Mincione, E.; Ortaggi, G. Tetrahedron Lett.
1991, 32, 3719–3722.
9. (a) Ciaccio, J. A.; Heller, E.; Talbot, A. Synlett 1991, 248.
(b) Shimizu, M.; Yoshida, A.; Fugisawa, T. Synlett 1992,
204–206. (c) Guo, Z. X.; Haines, A. H.; Taylor, R. J. K.
Synlett 1993, 607–608.
22. Guss, C. O.; Rosenthal, R. J. Am. Chem. Soc. 1955, 77, 2549.
23. Forgo, I.; Buechi, J. Chem. Abstr. 1970, 72, 110733k.
24. Winstein, S.; Grunwald, E.; Buckles, R. E.; Hason, C. J. Am.
Chem. Soc. 1948, 70, 816–821.
10. (a) Bajwa, J. S.; Anderson, R. C. Tetrahedron Lett. 1991, 32,
3021–3024. (b) Kotsuki, H.; Shimanouchi, T. Tetrahedron
Lett. 1996, 37, 1845–1848.
25. Naqui, S. M.; Horwitz, J. P.; Filler, R. J. Am. Chem. Soc. 1957,
79, 6283–6286.
26. Pfeiffer, P.; Bauer, K. Chem. Ber. 1947, 80, 7. Chem. Abstr.
1947, 41, 3098d.
11. Konnaklieva, M. I.; Dahi, M. L.; Turos, E. Tetrahedron Lett.
1992, 33, 7093–7096, and references therein.
12. Sharghi, H.; Niknam, K.; Pooyan, M. Tetrahedron 2001, 57,
6057–6064.
27. Lide, R. D. CRC Handbook of Chemistry and Physics, 80th ed.
1999–2000.
28. WWW.aist.go.jp/RIODBS/SDBS/sdbs/owa/sdbs-Sea.Ere-
Frame-Sea.
13. Dela More, P. B. D.; Bolton, R. Electrophilic Addition to
Unsaturated System; Elsevier: Amsterdam, 1982.
14. Eisch, J. J.; Liu, Z. R.; Ma, X.; Zheng, G. X. J. Org. Chem.
1992, 57, 5140–5144.
29. Koelsch, C. F.; Mc Elvain, S. M. J. Am. Chem. Soc. 1929, 51,
3390–3394.
30. Lamrrd, P. B. D. D. E.; Naylor, P. G.; Williams, D. L. H.
J. Chem. Soc. 1962, 443–449.
15. Chini, M.; Crotti, P.; Gardelli, C.; Macchia, F. Tetrahedron.
1992, 48, 3805–3812.
31. Woolard, F. X.; Moore, R. E. Tetrahedron 1976, 32,
2843–2846.
16. (a) Sharghi, H.; Massah, A. R.; Abedi, M. Talanta 1999, 49,
531. (b) Semnani, A.; Shamsipur, M. J. Chem. Soc. Dalton
Trans. 1996, 2215–2218. (c) Gangali, M. R.; Sharghi, H.;
Eshghi, H.; Shamsipur, M. J. Electronal. Chem. 1996, 405,
177.
32. Cornforth, J. W.; Green, D. T. Chem. Abstr. 1970, 72,
121250b.
33. Dawe, R. D.; Molinski, T. F.; Turner, J. V. Tetrahedron Lett.
1984, 25, 2061–2064.
17. Serguchev, Y. A.; Petrenko, T. I. Teor. Eksp. Khim. 1977, 13,
705.
34. Iranpoor, N.; Zeynizadeh, B. J. Chem. Res. 1998, 466–467,
and references therein.
18. Andrews, L. J.; Keefer, R. M. J. Org. Chem. 1987, 52,
2690–2694.
35. Bonini, C.; Giuliano, C.; Righi, G.; Rossi, L. Synth. Commun.
1992, 22, 1863–1870, and references therein.
36. Cowell, A.; Stille, J. K. J. Am. Chem. Soc. 1980, 102, 4193.
and references therein.
19. Mizuno, M.; Tanaka, J.; Harada, I. J. Phys. Chem. 1981, 85,
1789–1794.