Conversion of epoxides to halohydrins with elemental halogen catalyzed by phenylhydrazine

Article abstract of DOI:10.1055/s-2002-33340

The highly regioselective method for the synthesis of β-iodohydrins and β-bromohydrins by the direct ring opening of 1,2-epoxides with elemental halogen in the presence of phenylhydrazine is described. This method occurs under neutral and mild conditions with high yields in various aprotic solvents even when sensitive functional groups are present.

Full text of DOI:10.1055/s-2002-33340

PAPER
1519
Conversion of Epoxides to Halohydrins with Elemental Halogen Catalyzed by
Phenylhydrazine
C
onversion of Epo
a
xide
s
to
H
a
s
lohyrins hem Sharghi,* Mohammad Mehdi Eskandari
Department of Chemistry, College of Science, Shiraz University, Shiraz 71454, I.R. Iran
E-mail: sharghi@chem.susc.ac.ir
Received 19 February 2002; revised 29 May 2002
In order to optimize the reaction conditions, at first, we
Abstract: The highly regioselective method for the synthesis of -
iodohydrins and -bromohydrins by the direct ring opening of 1,2-
epoxides with elemental halogen in the presence of phenylhydra-
zine is described. This method occurs under neutral and mild condi-
examined the effects of elemental halogens in the pres-
ence of phenylhydrazine in different ratio on the styrene
oxide as a model in various solvents (Table 1 and
tions with high yields in various aprotic solvents even when Scheme).
sensitive functional groups are present.
Key word: phenylhydrazine, epoxide, halohydrins
Epoxides are versatile intermediates in organic synthesis;
Scheme
and a large variety of reagents are known for the ring
opening of these compounds.1–2 The most common meth-
Table 1 Addition of Iodine (1 mmol) and Bromine (1 mmol) to Sty-
rene Oxide (1 mmol) Catalyzed by Phenylhydrazine in Different Ra-
tios in Various Solvents at 25 °C
od for the synthesis of 1,2-halohydrins from 1,2-epoxides
is their ring opening either with hydrogen halides or with
hydrohalogenic acid.3 However, these procedures suffer
from limitations 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 ha-
lohydrins. For example, silyl halides can be added to ep-
oxides to give halohydrin.4 In these cases, however, the
primary reaction products are the O-silyl protected deriv-
atives.4 Other methods require the use of a halogen and
triphenylphosphine,5 or disubstituted borane halo-
Entry
Solvent
Catalyst
(mmol)
Iodination
Bromoniation
Time Yield
Time
(h)
Yield
(%)
(h)
1.15
2
(%)
92
80
88
80
90
60
50
1
2
3
4
5
6
7
CH2Cl2
CH2Cl2
CHCl3
C6H6
0.1
0.01
0.1
0.1
0.1
0.1
0.1
0.75
1.5
1.2
1.3
1.1
1.5
1.7
95
80
89
75
85
76
63
1.5
2
genides,6
-bromo bis-(dimethylamino) borane,7
monochloro borane-dimethylsulfide,8 LinMnXn (M = Ni,
Cu, Ti)9 and MXn.10 Recently, it has been found that ep-
oxides can be converted to halohydrins by means of ele-
mental halogen,11 but this method has limitations such as
low yield, long reaction times, low regioselectivity and
formation of acetonides as byproducts, in addition to the
expected iodo adduct in acetone solution. Furthermore,
iodination does not occur in other aprotic solvents. In re-
lation with our pervious works on the use of pyridine-con-
taining macrocyclic compounds,12 we introduce a very
simple, mild, cheap, available and efficient method for the
conversion of epoxides to -halohydrins. We found that
phenylhydrazine catalyzed the addition of elemental halo-
gen to epoxides under mild reaction conditions with high
regioselectivity. In this study, we wish to report the results
of the reactions of some epoxides with elemental iodine
and bromine in the presence of catalytic amount of phe-
nylhydrazine.
CH3CN
Acetone
THF
2
3
3.2
As shown in Table 1 (entry 1) the optimum amount of cat-
alyst was found to be 0.1 mol for 1 mol of epoxide and
halogen. We therefore used this stoichiometric ratio of
PhNHNH2/X2 for conversion of other epoxides to their
corresponding -halohydrins. The results are shown in
Table 2 and are compared with corresponding results ob-
tained in the reaction of the same epoxide in the absence
of catalyst (Table 2, entries 2, 3 and 11). As shown in
Table 2 (entries 7 and 15) where only the trans isomers
were detected, the reactions are completely anti-stereose-
lective. A contra-Markovnikov-type,13,14 regioselectivity
is generally observed in these reactions. In many cases,
this type of regioselectivity appears to be opposite of that
observed in the ring opening of the same epoxides with
aqueous hydrohalogenic acids, under classic conditions15
(entries 1 and 10). Halogenative cleavage of epoxides oc-
curs according to the following four-step mechanism:
Synthesis 2002, No. 11, Print: 22 08 2002.
Art Id.1437-210X,E;2002,0,11,1519,1522,ftx,en;Z03502SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1520
H. Sharghi, M. M. Eskandari
PAPER
The first step (Equation 1) involves the formation of a 1:2 ed addition of phenylhydrazine to iodine has shown two
or 1:1 molecular complex between phenylhydrazine and strong absorption bands at 286 nm and 364 nm and a
elemental halogen, in which halogen ion (X3 ) exists as a strong band at 271 nm, presumably due to complex forma-
contact ion pair:
tion of this ligand with I2 and Br2. It should be noted that
the bands of 286 nm, 364 nm and 271 nm are characteris-
tic for the formation of I3 and Br3 ions, respectively, in
the process of complex formation of different electron-
pair donor ligands with iodine18–23 and bromine (Fig-
ure).24–26 In conclusion, phenylhydrazine appears to be an
efficient catalyst for ring opening of the epoxides with el-
emental halogens under mild conditions.
In the second step (Equation 2) this complex is further de-
composed to release X3 ion into solution as:
Therefore, in this way, molecular iodine or bromine is
converted to a nucleophilic halogen species in the pres-
ence of a phenylhydrazine and, in the third step (Equation
3, Equation 4), this ion participates in the ring opening re-
action of epoxides:
In addition, the advantages such as high regio- and stere-
oselectivity of the reactions, stability, commercially avail-
ability, inexpensive catalyst, high yield and ease of
workup make this method a useful addition to the present
methodologies in organic syntheses.
These steps occur continuously until all of the epoxides
and halogen are consumed, and after workup, the catalyst
can be recovered easily.
All products are known compounds and yields refer to GC yields,
NMR spectra were recorded in CDCl3 on a Bruker Advanced Dpx-
250 (1H NMR 250 MHz and 13C NMR 62.9 MHz) spectrophotom-
eter 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 Perkin Elmer 781 spectrometer. Cromatogra-
phy was carried out on silica gel 60 (70–230 mesh).
Epoxides to - Halohydrins; General Procedure
Epoxide (1 mmol) in CH2Cl2 (5 mL) was added to a stirred soln of
catalyst (0.1 mmol) in CH2Cl2 (5 mL) at r.t. Next, a solution of ele-
mental halogen (1 mmol) in CH2Cl2 (5 mL) was added in portions
(15 min) to the above mixture. GLC and TLC monitored the
progress of the reaction. After complete disappearance of the start-
ing material, the reaction mixture was washed with 10% aq Na2S2O3
(2 10 mL) and H2O (2 10 mL). The organic layer was dried over
MgSO4 and evaporated to give crude alcohol-catalyst. The crude
Figure Absorption spectra: a) I2. (b) Phenylhydrazine. (c) Phenyl-
hydrazine- I2.
On the basis of our study on the complexation of phenyl-
hydrazine and other work reported on the different products were purified by chromatography on a column of silica
ligands16–26 with elemental halogen, it seems that in these
gel. The solvent was evaporated and pure halohydrin was obtained.
The halohydrins were identified by comparison with authentic sam-
reactions trihalide ion, X3 , was formed and used as the
ples prepared in accordance with literature procedures.9c,10a,27
nucleophile. The electronic absorption spectra of the relat-
Equation 1
Equation 2
Equation 3
Equation 4
Synthesis 2002, No. 11, 1519–1522 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Conversion of Epoxides to Halohydrins
1521
Table 2 Reaction of Various Epoxides with Iodine and Bromine in the Presence of Phenylhydrazine Catalyst in CH2Cl2 at Room Temperature
Entry
1
Epoxide
Catalyst
–
Reaction condition
HI/CHCl3
Product
Reaction time (h) Yield a (%)
0.25
–
>99
–
2
3
–
–
I2 (excess)
CH2Cl2
No reaction
I2/Acetone
25 °C
2
83
4
5
PhNHNH2
PhNHNH2
I2/CH2Cl2
25 °C
1.15
5.5
92
87
I2/CH2Cl2
25 °C
6
7
PhNHNH2
PhNHNH2
I2/CH2Cl2
25 °C
4
75
95
I2/CH2Cl2
25 °C
2.5
8
9
PhNHNH2
PhNHNH2
–
I2/CH2Cl2
25 °C
3
65
60
I2/CH2Cl2
25 °C
3
10
HBr/CHCl3
0.25
>99
11
–
Br2/CH2Cl2
1
31
12
13
PhNHNH2
PhNHNH2
Br2/CH2Cl2
25 °C
1
4
95
90
Br2/CH2Cl2
25 °C
14
15
PhNHNH2
PhNHNH2
Br2/CH2Cl2
25 °C
3
2
85
97
Br2/CH2Cl2
25 °C
16
17
PhNHNH2
PhNHNH2
Br2/CH2Cl2
25 °C
2.5
3
70
65
Br2/CH2Cl2
25 °C
a GC yield.
2-Iodo-1-phenylethanol
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 .
1H NMR: = 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).
1
1H NMR: = 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: = 67.18, 69.67, 70.01, 114.98, 116.87, 121.79, 129.89,
132.86.
13C NMR: = 54.96, 66.90, 128.22, 129.10, 129.21, 138.17.
1-Iodo-2-octanol
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-Iodo-3-phenoxy-2-propanol
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),
1
1
3418 (br s) cm .
Synthesis 2002, No. 11, 1519–1522 ISSN 0039-7881 © Thieme Stuttgart · New York

1522
H. Sharghi, M. M. Eskandari
PAPER
1H NMR: = 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: = 14.09, 16.45, 22.62, 25.56, 29.12, 31.70, 36.89,
70.91.
References
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2-Iodocyclohexanol
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: = 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: = 24.51, 26.56, 32.75, 35.40,59.84, 71,59.
2-Bromo-1-phenylethanol
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
1
(br s) cm .
1H NMR: = 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: = 57.39, 67.97, 128.32, 129.30,
129.37, 138.98.
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204. (c) Guo, Z. X.; Haines, A. H.; Taylor, R. J. K. Synlett
1993, 607.
1-Bromo-3-phenoxy-2-propanol
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),
1
3415 (br s) cm .
1H NMR: = 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 = 5Hz), 6.94 (d, 2 H, J = 8.0 Hz), 7.35 (m, 2 H).
13C NMR: = 69.58, 69.77, 69.93, 115.01, 116.82, 121.86, 129.99,
132.79.
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1-Bromo-2-octanol
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
1
(vs) 3380 (br s) cm .
1H NMR: = 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: = 14.01, 22.52, 25.58, 29.14, 31.68, 35.05, 40.73,
71.02.
2-Bromocyclohexanol
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
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1
(br s) cm .
1H NMR: = 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: = 24.48, 27.02, 33.95, 36.59, 62.13, 75.66.
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Acknowledgment
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We would like to acknowledge the support of this work by Shiraz
University Research Council.
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Synthesis 2002, No. 11, 1519–1522 ISSN 0039-7881 © Thieme Stuttgart · New York