Convenient, easy and highly regioselective preparation of haloalcohols from the reaction of epoxides with elemental halogen catalyzed by hexamethylenetetramine (HMTA)

Article abstract of DOI:10.1002/jccs.200800170

The highly regioselective cleavage of epoxides into corresponding vicinal haloalcohols with elemental halogen has been catalyzed by hexamethylenetetramine (HMTA). This method occurred under neutral and mild conditions with high yields and short reaction times in various aprotic solvents even when sensitive functional groups were present.

Full text of DOI:10.1002/jccs.200800170

1156
Journal of the Chinese Chemical Society, 2008, 55, 1156-1159
Convenient, Easy and Highly Regioselective Preparation of Haloalcohols
from the Reaction of Epoxides with Elemental Halogen Catalyzed by
Hexamethylenetetramine (HMTA)
Hossein Naeimi
Department of Chemistry, Faculty of Science, University of Kashan, Kashan 87317, Iran
The highly regioselective cleavage of epoxides into corresponding vicinal haloalcohols with elemen-
tal halogen has been catalyzed by hexamethylenetetramine (HMTA). This method occurred under neutral
and mild conditions with high yields and short reaction times in various aprotic solvents even when sensi-
tive functional groups were present.
Keywords: Regioselective; Halohydrins; Epoxide; Catalyst; Hexamethylenetetramine.
INTRODUCTION
Vicinal halohydrins are useful compounds in syn-
tions and properties of HMTA have been reviewed.11 This
compound is soluble in water, chloroform, ethanol and
some other organic solvents.
thetic organic chemistry since they contain two functional
groups of alcohol and iodide. A great effort has been made
in the last few years to find new mild procedures for con-
verting epoxides into halohydrins.1
In conjunction with ongoing work in our laboratory
on the preparation of haloalcohols12 and the complex for-
mation of heterocyclic compounds containing donor nitro-
gen atoms, with neutral molecules such as iodine and bro-
mine, we found out that the HMTA compound can be reac-
tive as a new catalyst in the addition of elemental halogen
to epoxides under mild reaction conditions with high regio-
selectivity.
Epoxides are versatile intermediates in organic syn-
thesis and a large variety of reagents are known for the ring
opening of these compounds.2,3 Among the numerous
transformations already reported,4 little attention was
given to the opening of the epoxide ring to the correspond-
ing vicinal haloalcohols. The reaction was typically per-
formed with hydrogen halides, but the strenuous reaction
conditions and the low observed regioselectivity in the
opening of asymmetrical epoxides have prompted a search
for more selective and milder procedures.2 Recently, it has
been found that epoxides can be converted into haloalco-
hols by means of elemental halogen,5 but this method has
some limitations such as low yield, long reaction times, low
regioselectivity and formation of acetonide byproducts in
addition to the expected iodoadduct in acetone solution.
Furthermore, iodination does not occur in other aprotic
solvents.
RESULTS AND DISCUSSION
In this study, we wish to report the synthesis of halo-
alcohols from the reactions of several epoxides with ele-
mental iodine and bromine in the presence of a catalytic
amount of HMTA (Scheme I).
The corresponding results are indicated in Table 1. As
shown in Table 1, in each case, cleavage of the epoxide ring
occurs and, upon thiosulfate-workup, iodoalcohol and
bromoalcohol are obtained. The products were obtained
with this new methodology in good to excellent yields and
very low reaction times. The optimum amount of catalyst
was found to be 0.04 moles for 1 mole of epoxide and
halogen.
Hexamethylenetetramine (HMTA) derived from the
condensation of ammonia and formaldehyde,6,7,8 has a
symmetrical adamantine-like structure and is rather stable,
although dihetero-substituted methylene groups are known
to be highly reactive. The chemical and steric equivalence
of the four nitrogen atoms has been demonstrated by vari-
ous physico-chemical methods.9,10 Large scale prepara-
As indicated in entries 9 and 10 in which only the
trans isomer is obtained, the reactions are completely anti-
stereoselective. As for the regioselectivity, attack of the
nucleophile preferentially occurs at the less substituted
epoxide carbon. This regioselectivity appears to be the op-
* Corresponding author. Fax: +98-361-5552935; E-mail: naeimi@kashanu.ac.ir

Preparation of Haloalcohols from Epoxides
J. Chin. Chem. Soc., Vol. 55, No. 5, 2008 1157
Table 1. Reaction of various epoxides with iodine and bromine
in the presence of HMTA catalyst in CH2Cl2 at room
temperature
Scheme I
Substrate
Product
Entry
X2
Time (h) Yielda (%)
(1)
(2)
1
2
3
4
5
6
7
8
a
a
b
b
c
I2
Br2
I2
a
h
b
i
0.2
0.1
0.7
0.15
0.5
0.2
0.3
0.2
95
97
90
92
90
91
92
95
Br2
I2
c
j
c
Br2
I2
d
d
d
k
I
Br2
9
I2
2
87b
O
OH
Br
10
e
Br2
0.7
90b
OH
11
12
13
14
f
f
I2
Br2
I2
f
m
g
2.3
1.3
1.7
1
77b
80b
75b
85b
posite of that observed in ring opening of the same ep-
oxides with hydrohalogenic acids under classic acidic con-
ditions.20
g
g
Br2
n
a Isolated product yields
b GC yields
On the basis of our research on the complex forma-
tion of HMTA and the previous reports on the other lig-
ands21-30 with elemental halogen, it seems that in these re-
-
actions trihalide ion, X3 , was formed and used as a nucleo-
Table 2. Addition of iodine and bromine to styrene oxide by
phile. The electronic absorption spectra regarding addition
of HMTA to iodine has indicated two strong absorption
bands at 292 and 364 nm and a strong band at 272 nm in ad-
dition of HMTA to bromine, presumably due to the interac-
tion of this compound with I2 and Br2 and the formation of
HMTA as catalyst in various solvent at 25 °C
Iodination
Bromination
Entry
Solvent
CH2Cl2
Time/h Yielda/% Time/h Yielda/%
1
2
3
4
5
6
0.2
0.2
0.3
0.6
1
95
92
88
85
75
60
0.1
0.15
2
97
93
90
85
80
65
CHCl3
C6H6
I3 and Br3 ions, respectively,23-30 while none of the initial
reactants show any measurable absorption in these regions.
In order to study the effect of solvent in these reac-
tions, the reaction of styrene oxide in various aprotic sol-
vents was examined. The obtained results are shown in Ta-
ble 2. As can be seen, the above-mentioned reactions ap-
peared to be largely dependent on the type of solvent.
The structure of products has been assigned by spec-
troscopic data. In the IR spectra, the characteristic hydrox-
yl group O-H bond stretching frequency is formed in the re-
gion between u = 3215-3230 cm-1 as a single strong broad
band. The stretching vibration of C-H in the alkyl groups
appear at the region between u = 2800-2900 cm-1. In the 1H
NMR spectra, one proton of O-H has a chemical shift in d =
4.20-4.55 ppm as a singlet broad peak. The signals around
d = 6.5-8.4 are assigned to protons of CH=CH of aromatic
rings.
-
-
CH3CN
CH3COCH3
THF
0.4
0.6
1
1.5
a Isolated product yields
CONCLUSION
This method for preparation of vicinal haloalcohols
has some advantages such as high regioselectivity, high
yields of product, short reaction times relative to other pro-
cedures, and simplicity of workup. This reaction occurs in
neutral and mild conditions on the acid sensitive substrates
and appears to be highly competitive with the other meth-
ods reported in the literature. The haloalcohols were identi-
fied by comparison with authentic samples prepared in ac-
cordance with literature procedures.12-20

1158 J. Chin. Chem. Soc., Vol. 55, No. 5, 2008
Naeimi
EXPERIMENTAL
(s), 1586 (m), 1611 (m), 2875 (m), 2928 (s), 2962 (m),
3038 (m), 3422 (br, s) cm-1. 1H NMR d 2.15 (s, 1H), 2.49 (s,
3H), 3.02 (d, 2H, J = 5.0 Hz), 3.46 (q, 1H, J = 2.0 Hz), 4.16
(d, 2H, J = 7.0 Hz), 6.95 (d, 2H, J = 7.2 Hz), 7.23 (d, 2H, J =
5.0 Hz).
Chemicals were purchased from the Merck Chemical
Company in high purity. IR spectra were recorded as KBr
pellets on a Perkin-Elmer 781 Spectrophotometer and an
1
Impact 400 Nickolet FTIR Spectrophotometer. H NMR
spectra were recorded in CDCl3 and DMSO with (400
MHz) Spectrometer using of TMS as an internal reference.
Melting points were obtained with a Yanagimoto micro
melting point apparatus and are uncorrected. The purity de-
termination of the substrates and reaction monitoring were
accomplished by TLC on silica-gel polygram SILG/UV
254 plates.
1-Iodo-3-phenoxy-2-propanol (2d)12,15,18
IR (neat): 650 (w), 678 (w), 760 (m), 823 (m), 1038
(s), 1113 (w), 1240 (s), 1375 (m), 1494 (s), 1588 (s), 2877
(m), 2927 (s), 3050 (m), 3418 (br, s) cm-1. 1H NMR: d 3.1
(s, 1 H), 3.48 (d, 2 H, J = 5.0 Hz), 4.06 (tt, 1 H, J1 = 7.0, J2 =
5.0 Hz), 4.13 (d, 2 H, J = 5.6 Hz), 6.78-6.90 (m, 3 H), 7.36
(m, 2 H). 13C NMR: d 67.18, 69.67, 70.01, 114.98, 116.87,
121.79, 129.89, 132.86.
General procedure for preparation of vicinal halo-
hydrins
2-Iodocyclohexanol (2e)15,19
To a stirred solution of HMTAcatalyst (0.04 mmol) in
CH2Cl2 (10 mL) was added epoxide (1 mmol) at room tem-
perature. Then a solution of elemental halogen (1 mmol) in
CH2Cl2 (5 mL) was added dropwise (20 min) to the above
mixture. The progress of the reaction was monitored by
TLC and GLC. After complete disappearance of the start-
ing material, the reaction mixture was washed with 10%
aqueous Na2S2O3 (2 ´ 10 mL) and water (2 ´ 10 mL). The
organic layer was dried over MgSO4 and evaporated to give
crude products. The crude product was purified by crystal-
lization in diethyl ether. After cooling, the catalyst was fil-
tered off and washed with cold ether. The solvent of filtrate
was evaporated and pure haloalcohol was obtained. The
haloalcohols were identified by comparison with authentic
samples prepared in accordance with literature proce-
dures.12-19
IR (neat): 690 (s), 790 (w), 870 (m), 948 (s), 1038
(w), 1082 (br, s), 1123 (m), 1189 (s), 1372 (m), 1462 (s),
2882 (s), 2960 (br, s), 3425 (br, s) cm-1. 1H NMR: d 1.26-
1.44 (m, 3 H), 1.75-1.95 (m, 3 H), 2.15-2.3 (m, 1 H), 2.3-
2.35 (m, 1 H), 2.72 (s, 1 H), 3.58-3.62 (m, 1 H), 3.9-4.0 (m,
1 H). 13C NMR: d 24.51, 26.56, 32.75, 35.40, 59.84, 71, 59.
1-Iodo-2-octanol (2f)15,18
IR (neat): 725 (m), 1015 (br, s), 1105 (m), 1130 (m),
1185 (s), 1385 (s), 1425 (s), 1465 (s), 1475 (s), 2870 (vs),
2940 (vs), 3400 (br, s) cm-1. 1H NMR: d 0.89 (t, 3 H, J = 7.0
Hz), 1.26-1.58 (m, 10 H), 2.24 (s, 1 H), 3.24-3.55 (m, 3 H).
13C NMR: d 14.09, 16.45, 22.62, 25.56, 29.12, 31.70,
36.89, 70.91.
2-Bromo-1-phenylethanol (2h)12-15
IR (neat): 689 (m), 766 (m), 823 (m), 1036 (s), 1115
(w), 1233 (s), 1375 (m), 1494 (m), 1600 (s), 2875 (m),
2935 (s), 3064 (m), 3405 (br, s) cm-1. 1H NMR: d 1.98 (s, 1
H), 4.01 (m, 2 H), 4.98 (t, 1 H, J = 5.0 Hz), 7.19-7.39 (m, 5
H). 13C NMR: d 57.39, 67.97, 128.32, 129.30, 129.37,
138.98.
1-(p-Chlorophenoxy)-3-bromo-2-propanol (2i)15
IR (neat): 649 (m), 664 (m), 695 (m), 743 (m), 768
(w), 821 (m), 938 (m), 1005 (s), 1132 (s), 1245 (m), 1282
(m), 1318 (w), 1449 (m), 1492 (s), 1581 (m), 1596 (m),
1615 (m), 2858 (m), 2928 (s), 2956 (m), 3406 (br, s) cm-1.
1H NMR d 2.21 (s, 1H), 3.42 (d, 2H, J = 5.0 Hz), 3.81 (q,
1H, J = 2.0 Hz), 4.39 (d, 2H, J = 7.0 Hz), 7.26 (d, 2H, J =
7.5 Hz), 7.65 (d, 2H, J = 5.1 Hz).
2-Iodo-1-phenylethanol (2a)12,15
IR (neat): 748 (m), 915 (m), 1032 (s), 1121 (w), 1243
(s), 1365 (m), 1492 (m), 1602 (s), 2885 (m), 2930 (s), 3061
(m), 3398 (br, s) cm-1. 1H NMR: d 2.02 (s, 1 H), 3.76 (d, 2
H, J = 5.5 Hz), 4.78 (t, 1 H, J = 5.0 Hz), 7.17-7.35 (m, 5 H).
13C NMR: d 54.96, 66.90, 128.22, 129.10, 129.21, 138.17.
1-(p-Chlorophenoxy)-3-iodo-2-propanol (2b)12
IR (neat): 632 (w), 648 (w), 667 (s), 694 (m), 742 (m),
818 (s), 893 (m), 936 (m), 1004 (s), 1088 (m), 1167 (s),
1239 (s), 1282 (s), 1374 (w), 1456 (m), 1488 (s), 1580 (m),
1593 (m), 2869 (m), 2925 (s), 2952 (m), 3412 (br, s) cm-1.
1H NMR d 2.25 (s, 1H), 3.38 (d, 2H, J = 5.1 Hz), 3.86 (q,
1H, J = 2.0 Hz), 4.41 (d, 2H, J = 7.0 Hz), 7.22 (d, 2H, J =
7.3 Hz), 7.61 (d, 2H, J = 5.0 Hz).
1-(p-Tolyloxy)-3-bromo-2-propanol (2j)12
IR (neat): 659 (s), 819 (m), 1016 (s), 1075 (w), 1123
(s), 1242 (s), 1285 (m), 1381 (w), 1458 (m), 1512 (s), 1585
(m), 1613 (m), 2875 (m), 2927 (s), 2962 (m), 3035 (m),
3425 (br, s) cm-1. 1H NMR d 2.12 (s, 1H), 2.53 (s, 3H), 3.16
1-(p-Tolyloxy)-3-iodo-2-propanol (2c)12
IR (neat): 665 (s), 743 (w), 814 (m), 1015 (s), 1072
(w), 1123 (s), 1240 (s), 1286 (m), 1378 (w), 1462 (m), 1512

Preparation of Haloalcohols from Epoxides
J. Chin. Chem. Soc., Vol. 55, No. 5, 2008 1159
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7.0 Hz), 6.93 (d, 2H, J = 7.1 Hz), 7.19 (d, 2H, J = 5.2 Hz).
1-Bromo-3-phenoxy-2-propanol (2k)12,15
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IR (neat): 641 (w), 688 (m), 756 (m), 823 (m), 1038
(s), 1112 (w), 1239 (s), 1375 (m), 1494 (s), 1588 (s), 2878
(m), 2925 (s), 3059 (m), 3415 (br, s) cm-1. 1H NMR: d 2.75
(s, 1 H), 3.61 (d, 2 H, J = 5.3 Hz), 4.03 (tt, 1 H, J1 = 7.1 Hz,
J2 = 5.0 Hz), 4.11 (d, 2 H, J = 7.0 Hz), 6.78 (d, 1 H, J = 5
Hz), 6.94 (d, 2 H, J = 8.0 Hz), 7.35 (m, 2 H). 13C NMR: d
69.58, 69.77, 69.93, 115.01, 116.82, 121.86, 129.99, 132.79.
2-Bromocyclohexanol (2l)15,17
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IR (neat): 690 (s), 793 (w), 865 (m), 960 (s), 1038
(m), 1075 (br, s), 1123 (m), 1189 (s), 1372 (m), 1460 (s),
2882 (s), 2960 (br, s), 3425 (br, s) cm-1. 1H NMR: d 1.26-
1.42 (m, 3 H), 1.78-1.98 (m, 3 H), 2.18-2.32 (m, 1 H),
2.32-2.38 (m, 1 H), 2.68 (s, 1 H), 3.58-3.64 (m, 1 H), 3.82-
3.92 (m, 1 H). 13C NMR: d 24.48, 27.02, 33.95, 36.59,
62.13, 75.66.
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IR (neat): 720 (m), 830 (m), 1050 (s), 1075 (s), 1125
(m), 1225 (m), 1265 (m), 1385 (m), 1425 (m), 1470 (s),
2860 (vs), 2935 (vs), 2970 (vs) 3380 (br, s) cm-1. 1H NMR:
d 0.89 (t, 3 H, J = 6.5 Hz), 1.25-1.63 (m, 8 H), 1.86 (q, 2 H,
J = 7.1 Hz), 2.22 (s, 1 H), 3.42 (d, 2 H, J = 7.1 Hz), 3.75-
3.84 (m, 1 H). 13C NMR: d 14.01, 22.52, 25.58, 29.14,
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