Comparative study of the vicinal functionalization of olefins with 2:1 bromide/bromate and iodide/iodate reagents

Article abstract of DOI:10.1016/j.tet.2009.01.095

A comparative evaluation was made on the syntheses of vicinal halohydrins, halo methyl ethers, and halo acetates from olefins using 2:1 Br^-/BrO₃^- and I^-/IO₃^- reagents. In many cases both reagents afforded products selectively in high yields. The highest halogen atom efficiencies attained were 97% and 93% for Br^-/BrO₃^- and I^-/IO₃^-, respectively. Of the two reagents, I^-/IO₃^- was established to be the preferred reagent for vicinal functionalization of linear alkenes and also for halo acetate preparation. However, only Br^-/BrO₃^- was effective for vicinal functionalization of trans-stilbene and chalcones.

Full text of DOI:10.1016/j.tet.2009.01.095

Tetrahedron 65 (2009) 2791–2797
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Comparative study of the vicinal functionalization of olefins with 2:1
bromide/bromate and iodide/iodate reagents
*
Manoj K. Agrawal, Subbarayappa Adimurthy, Bishwajit Ganguly, Pushpito K. Ghosh
Central Salt and Marine Chemicals Research Institute (Council of Scientific and Industrial Research), G. B. Marg, Bhavnagar 364002, Gujarat, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A comparative evaluation was made on the syntheses of vicinal halohydrins, halo methyl ethers, and halo
acetates from olefins using 2:1 Brꢀ/BrO3ꢀ and Iꢀ/IOꢀ3 reagents. In many cases both reagents afforded
products selectively in high yields. The highest halogen atom efficiencies attained were 97% and 93% for
Brꢀ/BrOꢀ3 and Iꢀ/IO3ꢀ, respectively. Of the two reagents, Iꢀ/IOꢀ3 was established to be the preferred reagent
for vicinal functionalization of linear alkenes and also for halo acetate preparation. However, only
Brꢀ/BrOꢀ3 was effective for vicinal functionalization of trans-stilbene and chalcones.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 7 November 2008
Received in revised form 27 January 2009
Accepted 28 January 2009
Available online 4 February 2009
Keywords:
Bromide/bromate
Iodide/iodate
Reagent
Olefins
Functionalization
1. Introduction
Ag(I)carboxylate,16 I2/sulfolane,17 I2/Pb(II) acetate,18 and I2/EPZ-1019
has also been reported. Cornforth and Green used dilute aqueous
Vicinal functionalization of olefins is an important synthetic tool
especially when the reaction affords products in regio- and ster-
eoselective manner.1 Vicinal halohydrins, halo ethers, and halo
esters are versatile synthetic intermediates that provide access to
an array of functional groups.2
solution of iodic acid to oxidize iodide back to iodine and applied
the methodology to obtain iodohydrin and propylene oxide from
propene.20 Among hypervalent iodine-containing reagents, H5IO6/
NaHSO3 has been used wherein the two components of the reagent
participate in a redox process to generate the desired reactive
iodonium species.21
The halide–halate reactions (X¼Br, I) in water represented by
Eq. 1 are well known. The one involving iodine is referred to as the
Dushman reaction,22 and finds useful applications in analysis, while
the reaction involving bromine is known to play an important role
in oscillating chemical reactions.23 The mechanistic pathways for
the reactions are complex and as yet not fully understood.
A large number of reagents such as N,N-dibromobenzene sul-
phonamide,1 ‘selectfluor’-K/KBr,3 p-nitrobenzene-sulphonyl per-
oxide/Brꢀ,4 tribromoisocyanuric acid,5 Agþ/Br2,6 NBS/acid/MeOH,7
and 1,3-dibromo-5,5-dimethylhydantoin (DDH)/MeOH8 have been
reported for synthesis of halo methyl ethers. Alkali halide salts, in
combination with IOꢀ4 and LDH-WO24ꢀ as oxidizing agentsdwhich
generate the halonium iondhave also been reported for prepara-
tion of chloro- and bromo-derivatives.9 Heasley has reported the
BF3-promoted reaction of methyl hypochlorite and methyl hypo-
bromite with olefin to obtain fluoro chloride and fluoro bromide
derivatives.10 Methoxy halides were obtained as side products.
Preparation of iodohydrins, iodo methyl ethers, and iodo
acetates using N-iodosuccinimide (NIS)7b,11 and bis(pyridine)-
iodine(I)tetrafluoroborate12 has been reported. I2/H2O has also
been used successfully in synthesis of iodohydrins and iodo
ethers, especially cyclic ethers, from the corresponding olefins.13
Vicinal functionalization with I2/CuO$HBF4,14 I2/Cu(II)acetate,15 I2/
XOꢀ3 þ 5Xꢀ þ 6Hþ/3X2 þ 3H2O
(1)
The rate equation (r¼rate) can be expressed in the form of Eq.
2.24,25 (The rate equation is still more complex in presence of other
solution species such as acetate ion.) The second term is important
at low concentrations of halide ion but can be ignored otherwise.
The values of k1 for the Brꢀ/BrO3ꢀ and Iꢀ/IOꢀ3 systems are reported to
be 0.81 Mꢀ4 sꢀ1 and 1.3ꢁ109 Mꢀ4 sꢀ1, respectively. In view of the
second order dependence on [Hþ], the reactions can be activated
only in presence of acid. However, since the rate constant of the Iꢀ/
IOꢀ3 reaction is nine orders of magnitude higher than that of the
Brꢀ/BrOꢀ3 reaction, the former reaction is fast even under mildly
acidic conditions.
* Corresponding author. Tel./fax: þ91 2782567562.
E-mail address: pkghosh@csmcri.org (P.K. Ghosh).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.095

2792
M.K. Agrawal et al. / Tetrahedron 65 (2009) 2791–2797
h
ih i h
i
h
ih i h
i
Table 1
2
2
r ¼ k1 XO3ꢀ Hþ Xꢀ 2þk2 XO3ꢀ Hþ Xꢀ
(2)
Synthesis of halohydrins from olefins
Entry Substrate
Product(s)
X
Time (h) Yielda (%)
8630b
The formation of the asymmetric intermediate X2O2 has been
implicated in the mechanism of Eq. 1. The asymmetric structures
shown below were proposed originally for Cl2O2 by Taube and
Dodgen.26 X2O2 is obtained from the reactions of Eq. 3. It can un-
dergo the further reactions of Eqs. 4–6.
OH
X
X
1
2
Br 0.5
(05)b
X
I
2.0
9230a
O
OH
O
X
X
X O X=
3
4
Br 0.5
2.0
9730b
8730a
X
O
I
OH
X
XOꢀ3 þ Hþ/XO3H
(3a)
X
74
5
6
7
8
Br 0.5
(11)b
Cl
Cl
Br
Br
XO3H þ Xꢀ þ Hþ/X2O2 þ H2O
X2O2 þ H2O/XO2H þ XOH
(3b)
(4)
Cl
Br
X
X
X
I
2.5
84
OH
X
747a
Br 0.5
(13)b
XO2H þ Xꢀ þ Hþ/2XOH
XOH þ Xꢀ þ Hþ/X2 þ H2O
(5)
(6)
I
3.0
80
OH
9
10
Br 0.5
937a
CNIc
X
We have shown through recent studies that 2:1 Brꢀ/BrO3ꢀ is
a useful reagent in bromine substitution reactions.27–30 The reagent
can be obtained readily from the intermediate of liquid bromine
manufacture thereby eliminating liquid bromine from the product
lifecycle. TheoverallstoichiometryofthereactionisdepictedbyEq. 7.
I
2.0
syn-dl
OH
O2N
O2N
X
11
12
13
I
2.0
88
OH
3RH þ XOꢀ3 þ 2Xꢀ þ 3Hþ/3RX þ 3H2O
(7)
747a
OH
Br 0.5
(10)b
The rationale for selecting the 2:1 ratio was to avoid the re-
action of Eq. 6 and, instead, to effect the reaction with high
bromine atom efficiency employing the reactive intermediates
formed in Eqs. 3–5. A few studies were also undertaken with 2:1
Iꢀ/IOꢀ3 . Although our efforts were largely focused on substitution
reactions, preliminary studies were carried out to produce
halohydrins from olefins with the above reagents. Unfortunately,
the reactions were found to generate sizable amounts of impu-
rities such as dihalo products. We report herein our studies
aimed at developing a clean and efficient protocol for vicinal
functionalization of olefins with the above reagents. We have
also undertaken a systematic study comparing the Brꢀ/BrO3ꢀ and
Iꢀ/IOꢀ3 reagents. The study was considered to be of interest in
view of the large difference in the values of k1 in Eq. 2 for
the two halogens and the behavioral difference between the
halonium ion intermediates.
X
anti-dl
OH
X
OH
OH
I
2.0
93
X
anti-dl
OH
O
O
14
15
Br 0.5
2.0
687a
7933
OH
I
X
anti-dl
OH
O
16
17
Br 1.0
2.5
60
93
O
I
OMe
OMe
X
anti-dl
OH
8430b
(04)b
18d
19d
Br 0.5
2. Results and discussion
X
syn-dl
Scheme 1 is the general representation of vicinal functionali-
zation of olefins with the 2:1 Xꢀ/XOꢀ3 acid-activated reagents
studied in the present work. In our previous attempt to produce
halohydrin, experiments were carried out by adding acid gradually
into the flask containing all of the substrate and reagent. Since this
mode of addition led to substantial formation of dihalo impurity,30
X
I
2.0
8330a
X
syn-dl
OH
X
7130b
(10)b
C4H9
O
R1OH
H+
R1= H/Me/CH3CO
X = I/Br
20d,e
Br 0.5
-
+
2/3 X-
R1
X
1/3 XO3
+
X
R
R
X
C4H9
C4H9
C4H9
X
21d,e
I
2.0
8630a
Scheme 1. Vicinal functionalization of olefins through in-situ acid activation of the 2:1
ꢀ/XOꢀ3 couple.
OH
X

M.K. Agrawal et al. / Tetrahedron 65 (2009) 2791–2797
2793
Table 1 (continued )
Entry
Substrate
Product(s)
X
Time (h) Yielda (%)
OH
X
6930b
(10)b
C6H13
22e
Br 0.5
X
OH
C6H13
C6H13
C6H13
X
23e
I
I
2.0
3.0
7530a
X
Figure 1. MP2/LACVP* optimized three-membered cyclic bromonium (red) and io-
donium (purple) intermediates with (a) 1-hexene and (b) 1-octene, respectively. The
calculated natural charges for C1 and C2 are indicated.
OH
X
C8H17
C8H17
instantaneously with the substrate. Hence the reagent could be
added faster. It can be seen from Table 1 that both reagents give
similar yields for a large number of reactions. However, although
dibromo formation was greatly suppressed, it nonetheless occurred
in several reactions whereas diiodo formation was not seen at all.31
Since the desired reactions presumably proceed via formation of
the halonium intermediates, regioselectivity is expected to be
controlled by the charge differences between the two carbon cen-
ters in the three-membered cyclic intermediates.32 Accordingly,
computational studies were undertaken with 1-hexene and 1-
24e
77
92
C8H17
X
OH
OH
X
C12H25
C12H25
25e
I
3.0
C12H25
X
OH
a
octene (Fig. 1). The computed MP2/LACVP results showed that the
*
Unless specified otherwise, yield refers to total isolated yield of halohydrin.
Yield in parentheses is that of isolated yield of dihalo impurity (note that for all
b
bromonium and iodonium intermediates are unsymmetrical in
nature, the natural charges on C1 and C2 being negative and pos-
itive, respectively, for both bromonium [C1: ꢀ0.460 (1-hexene),
ꢀ0.477 (1-octene); C2: þ0.046 (1-hexene), þ0.034 (1-octene)] and
iodonium [C1: ꢀ0.535 (1-hexene), ꢀ0.536 (1-octene); C2: þ0.096
(1-hexene), þ0.068 (1-octene)] cases. The greater polarization of
charges in iodonium ion intermediates suggests that the regiose-
lectivity would be higher compared to that of bromonium ion in-
termediates, in line with the experimental observations.
entries where dihalo impurity is not shown it implies that no dihalo impurity was
isolated).
c
Desired product observed in GC–MS of crude but could not be isolated.
Four fold excess of substrate was taken.
1-Halo and 2-halo regioisomers were obtained in 82:18, 100:0, 72:28, 100:0,
d
e
98:2 and 79:21 ratios in the crude reaction mixtures of entries 20–25. Note that for
all other entries only single regioisomer was isolated.
we ascribed this to the competing pathway of Eq. 6, which would be
inevitable in presence of large excess of halide ion and, particularly,
if the reactions of Eqs. 3–5 are slow compared to the reaction of
Eq. 6. The problem was mitigated by reversing the addition se-
quence, i.e., stoichiometric amount of acid was taken in a single lot
in the flask along with olefin and the reagent was added gradually.
Further, to suppress polymerization under the prevailing acidic
condition when reverse addition was followed, the solvent system
was changed to DMSO–water in the ratio 3:1 (v/v). This solvent
system was also advantageous in as much as it inhibited over-oxi-
dation. The improved procedure was tested initially on styrene
(entries 1 and 2, Table 1). 2-Bromo-1-phenylethanol and 2-iodo-1-
phenylethanol were obtained in 86% and 92% isolated yields, re-
spectively, compared to 79% and 57% obtained previously.30
Dibromo impurity was 4.5% whereas the corresponding diiodo
impurity was not seen at all. The experiment of entry 2 was also
carried out at 15.3 g scale and the column-purified product was
obtained in 90.7% yield. The study was extended to several other
olefins and high yields of desired products were obtained consis-
tently as can be seen from Table 1. The substrate to reagent mole
ratio was 1:1 in all cases except for the reactions with cyclohexene
and 1-hexene for which fourfold excess of substrate was taken
(entries 18–21). It can be seen from the table that the highest
bromine atom efficiency was 97% (entry 3) while the highest iodine
atom efficiency was 93% (entries 13 and 17). The apparently longer
reaction time with Iꢀ/IO3ꢀ arose mainly due to the fact that the
reactions of Eqs. 3–6 are extremely fast when mineral acid is used
and the iodonium intermediates may not have sufficient time to
react fully with the organic substrate. The iodine, too, reacts with
the substrate, albeit more slowly (this was confirmed through in-
dependent studies with I2/KIO3/Hþ), and this necessitates more
gradual addition of the reagent. With Brꢀ/BrO3ꢀ build up of bromine
color was negligible as the bromonium intermediate presumably is
sufficiently long lived to react with the olefin. Any Br2, which is
generated in the side reaction of Eq. 6, would also react
The method was extended to the preparation of halo methyl
ethers from olefins. The reagent to substrate mole ratio was 1.1:1 in
all cases. Acid activation of the Xꢀ/XO3ꢀ reagent in methanol was
carried out with 98% sulfuric acid to provide protons under nearly
dry condition and thereby suppress halohydrin formation. (Note
that since the acid is consumed in the reaction, the solution has
negligible acidity at the end of the reaction.) When styrene was
subjected to reaction with 2:1 [Brꢀ]/[BrO3ꢀ] and [Iꢀ]/[IO3ꢀ],
respectively, through in-situ acid activation in methanol at 0–10 ꢂC,
(2-bromo-1-methoxyethyl)benzene and (2-iodo-1-methoxyethyl)-
benzene were each obtained in 94% isolated yield (entries 1 and 2,
Table 2). A series of substrates were subjected to the halo methyl
ether syntheses and high yields of the corresponding bromo and
iodo derivatives were obtained in most cases. With stilbene and
chalcone as substrates, the bromo methyl ethers were formed in
89% and 97% isolated yields, respectively (entries 13 and 21), but
the reactions were unsuccessful with the iodo reagent. When (E)-1-
(pyridin-2-yl)-3-p-tolylprop-2-en-1-one and 4-methoxy chalcone
were subjected to bromoetherification reaction, the desired prod-
ucts were obtained in 47% and 79% yields, respectively (entries 23
and 25) with anti/syn addition ratios of 1:0.5 and 1:0.58, re-
spectively, as estimated from NMR spectra. As in the case of chal-
cone, the corresponding iodoetherification reactions were
unsuccessful and the desired iodo ether products could not be
isolated (entries 24 and 26). Methyl cinnamate gave high yields of
bromo ether as well as iodo ether (entries 17 and 18). Indene and
cyclohexene gave good-to-moderate yields of the bromo and iodo
methyl ethers (entries 11 and 12, 27 and 28, Table 2). As in the case
of 1-hexene and 1-octene (Fig. 1), the computed MP2/LACVP re-
*
sults for indene show that the bromonium and iodonium in-
termediates are unsymmetrical in nature. The charge density on
the
a
-carbon is positive in both cases (I, 0.195; Br, 0.086) whereas
carbon is negative (I,
the corresponding charge density on the
b

2794
M.K. Agrawal et al. / Tetrahedron 65 (2009) 2791–2797
Table 2
Synthesis of halo methyl ethers from olefins
Entry
Substrate
Product(s)
X
Time (h)
Yielda (%)
947c
94
OMe
X
1
2
Br
I
2.5
0.75
937c
95
OMe
X
3
4
Br
I
2.5
0.6
OMe
X
5
6
Br
I
3.0
1.0
99
92
t-Bu
Cl
t-Bu
OMe
X
7
8
Br
I
2.5
1.0
931
89
Cl
OMe
X
9
10
Br
I
2.5
1.0
967a
91
Br
Br
OMe
X
11
12
Br
I
2.0
0.5
867a
92
syn-dl
OMe
13
14
Br
I
3.0
3.0
893
0
X
anti-dl
OMe O
O
15
16
Br
I
3.0
1.2
90
81
OH
OH
X
anti-dl
OMe O
O
17
18
Br
I
2.5
2.0
971,7a
94
OMe
OMe
OH
X
anti-dl
OMe
19
20
Br
I
3.0
1.25
997c
89
OH
X
anti-dl
OMe O
O
21
22
Br
I
1.0
0.65
97
0
X
anti-dl
OMe O
23b
24
Br
I
2.0
2.0
47
0
O
X
N
N
O
anti-dl + syn-dl
25b
26
Br
I
3.0
2.0
79
0
OMe O
X
anti-dl + syn-dl
MeO
MeO

M.K. Agrawal et al. / Tetrahedron 65 (2009) 2791–2797
2795
Table 2 (continued )
Entry
Substrate
Product(s)
X
Time (h)
2.5
Yielda (%)
OMe
27
Br
697c (09)c
X
syn-dl
X
28
29
I
0.65
2.5
78
X
syn-dl
OMe
X
C6H13
Br
79d,7c (10)c
X
OMe
C6H13
C6H13
X
30
31
I
1.20
2.5
65d
X
C6H13
OMe
X
C4H9
Br
81d,7c (15)c
X
OMe
C4H9
C4H9
X
32
I
2.5
89d
X
C4H9
a
Unless specified otherwise, yield refers to isolated yield of halo methyl ether.
anti/syn ratio was 1:0.5 and 1:0.58 in entries 23 and 25, respectively (estimated from NMR).
Yieldinparenthesesis theyield(GC–MSarea%)ofdihaloimpurity (notethatforallentries wheredihaloimpurity isnotshownitimpliesthatnodihaloimpuritywasobserved).
Ratios of 1-halo and 2-halo regioisomers were 79:21, 89:11, 83:17 and 91:9 in the crude reaction mixtures of entries 29, 30, 31 and 32, respectively (by GC–MS).
b
c
d
ꢀ0.642; Br, ꢀ0.179), which explains the high regioselectivity ob-
served in both reactions. Proton NMR data of the 2-bromo-1-
methoxy indane isolated from the reaction indicated that the
bromo methoxy addition reaction was antiselective as evident from
the low coupling constant of the vicinal hydrogens.32 With 1-
octene and 1-hexene as substrates, the isolated yields of the cor-
responding bromo methyl ethers were 79% and 81%, respectively
(entries 29 and 31), whereas a similar reaction on iodo-methoxy-
addition to 1-octene gave a lower yield of 65% but with higher
regioselectivity toward the 1-halo-2-methoxy derivative [79:21 vs
89:11 for Br and I, respectively (entries 29 and 30)] as in the case of
the corresponding halohydrin syntheses. The highest halogen atom
efficiencies based on the data of Table 2 were 90% (entries 5 and 19)
and 86% (entry 4) for Brꢀ/BrO3ꢀ and Iꢀ/IOꢀ3 , respectively. We also
synthesized the bromo methoxy derivative of citronellol (1) and
utilized it toward synthesis of rose oxide (4) in one pot in 66%
overall yield (Scheme 2). When the synthesis was carried out via
the iodo-methoxy derivative, the product was obtained in 82%
yield.8 We thereafter extended the study to the syntheses of halo
acetates from olefins employing the 2:1 Xꢀ/XO3ꢀ reagent (Table 3).
Acetic acid served the triple role of proton source, nucleophile and
solvent in these reactions.
iodine atom efficiency was found to be 89% (entry 4) whereas the
maximum bromine atom efficiency for desired product was only
40%. We ascribe the results to the large variation in k1 (Eq. 2), which
enables the reaction of Iꢀ/IO3ꢀ to proceed satisfactorily even with
mild acids whereas Brꢀ/BrO3ꢀ requires stronger acidic conditions.
BrOH which may form would not only see the substrate but also Brꢀ
in solution, leading to Br2 formation and build up of dibromo im-
purity. As in the case of halo ether preparation, the iodo acetate of
stilbene proved elusive while the corresponding bromo derivative
could be obtained albeit in low (36%) yield. The iodoesterification
reactions attempted with methyl cinnamate and 4-methoxy chal-
cone were also unsuccessful.
3. Conclusions
In conclusion, we have demonstrated the utility of 2:1 acid-ac-
tivated Xꢀ/XOꢀ3 couple for the efficient syntheses of a wide range of
halohydrins, halo methyl ethers and halo acetates from olefins with
high selectivity in most cases. Although in the present work the
reagents were formulated from the pure salts, these are readily
prepared in cost-effective manner and exhibit high halogen atom
efficiency.29 The highest halogen atom efficiencies attained in the
present work were 97% and 93% for Brꢀ/BrO3ꢀ and Iꢀ/IO3ꢀ, re-
spectively. Other than acid activation, no catalyst was required, as
such. Brꢀ/BrO3ꢀ and Iꢀ/IOꢀ3 gave similar results in most of the hal-
ohydrin and halo-methoxy-addition reactions studied. For re-
actions with linear terminal olefins, the regioselectivity was found
to be better with the iodo reagent and is ascribed to the larger
difference in the charge densities of the C1 and C2 carbons in the
three-membered cyclic iodonium intermediate. Besides the greater
regioselectivity, another advantage of Iꢀ/IO3ꢀ was the complete
elimination of diiodo impurity formation. The reagent also proved
superior in the synthesis of rose oxide from citronellol. Iꢀ/IO3ꢀ was
also found to be a superior reagent for preparation of halo acetates
from olefins and this is ascribed to the facile formation of Iþ from Iꢀ
and IOꢀ3 even under mild acidic conditions such as that encountered
The reagent to substrate mole ratio was 1.1:1 in all cases. As can
be seen from the table, the yields of the bromoacetates were gen-
erally poor (32–44%), with pronounced formation of dibromo im-
purity. In contrast, the iodo acetate derivatives of the same olefins
were achieved cleanly and in high yields (68–98%) in all the re-
actions where direct comparison was possible. The maximum
X-:XO3-/H+
KOH
1MHCl
HO
HO
Hexane
0 °C
MeOH
70 °C
MeOH
0 °C
HO
X
O
OMe
OMe
1
2
3
4
Scheme 2. Single pot synthesis of rose oxide from citronellol via halo methyl ether.

2796
M.K. Agrawal et al. / Tetrahedron 65 (2009) 2791–2797
Table 3
analyses were carried out on a Shimadzu GCMS-QP2010 instrument.
A Restake Bellfonte’s RTX-5 30 mꢁ0.25 mmꢁ0.25 m column was
used for the analysis with a helium carrier gas flow of 1.0 mL minꢀ1
The GC oven was held at 40 ꢂC for 3 min and then ramped at 10 ꢂC/
min to 240 ꢂC where it was held for 10 min. A 0.4
L injection with
a 1:30 split was used throughout. MS conditions: CI reagent gas was
methane at a source pressure of 1 kg. The instrument was calibrated
using PFTBA reference for CI with the CI reagent gas removed in CI
mode. Mass spectra were acquired over the range m/z 85–400 with
an acquisition time of 0.5 s and an inter-scan delay of 0.05 s. The data
were processed using the GC–MS Real-timer. Microanalysis was
carried out on a Perkin–Elmer 2400 instrument. Wherever possible,
the analytical data were matched against reported data.
Synthesis of halo acetates from olefins
m
Time (h) Yielda (%)
.
Entry
Substrate
Product(s)
X
OAc
m
42 (35)b
98
X
X
1
2
3
4
Br 6.0
X
I
3.5
OAc
44 (35)b
96
X
X
Br 6.0
X
I
I
3.0
5.0
OAc
X
4.2. General procedure for synthesis of halohydrins [2-iodo-
1-phenylethanol (entry 2, Table 1)]
5
6
68
anti-dl
OAc
Styrene (1.00 g, 9.61 mmol) and DMSO (12 mL) were taken in
50 mL round bottomed flask and stirred in water bath at 70–80 ꢂC.
To the above solution, stoichiometric amount of H2SO4 (4.8 mmol in
3 mL water) was added, followed by addition of stoichiometric
amount of solid KI/KIO3 [6.44 mmol KIþ3.26 mmol KIO3] in por-
tions over a period of 30 min under vigorous magnetic stirring. The
progress of the reaction was monitored by TLC. Stirring was con-
tinued for an additional 1.5 h under the same conditions. The re-
action mixture was diluted with water and extracted with CH2Cl2
(25 mLꢁ3). The combined organic layers were washed with dilute
solutions of NaHCO3, Na2S2O3 and brine. Finally it was dried over
anhydrous Na2SO4 and concentrated under reduced pressure to get
crude product, which was purified by column chromatography on
silica gel to afford the pure 2-iodo-1-phenylethanol (2.18 g,
8.8 mmol) in 92% yield. Similar procedure was employed for syn-
thesis of bromohydrins listed in Table 1 using bromide/bromate
with required quantity of acid.
Br 6.0
36 (22)b
X
anti-dl
X
X
anti-dl
OAc
7
8
Br 6.0
32 (43)b
X
syn-dl
X
I
I
3.0
3.0
89
X
syn-dl
OAc
X
9
89
91
4.2.1. Scale up of the reaction of entry 2, Table 2
Br
Styrene (15.3 g, 147.1 mmol) and DMSO (80 mL) were taken in
250 mL round bottomed flask and stirred in water bath at 70–80 ꢂC.
Tothe above solution, H2SO4 (88.3 mmol in 25 mL water) was added,
followed by addition of solid KI/KIO3 [98.5 mmol KIþ53.8 mmol
KIO3] in portions over a period of 45 min under vigorous magnetic
stirring. The progress of the reaction was monitored by TLC. Stirring
was continued for an additional 2.0 h under the same conditions.
The reaction mixture was diluted with water (100 mL) and extracted
with CH2Cl2 (50 mLꢁ2). The combined organic layer was washed
with dilute Na2S2O3, dried over anhydrous Na2SO4 and the solvent
stripped off under reduced pressure to get crude product, which was
purified by column chromatography on silica gel to afford 33.1 g
(133.5 mmol, 90.7% yield) of pure 2-iodo-1-phenylethanol.
Br
OAc
OH
OH
10
I
3.0
X
anti-dl
a
Unless specified otherwise, yield refers to isolated yield of halo acetate.
Yield inparentheses is the isolated yield ofdihaloimpurity(note that forallentries
b
where dihalo impurity is not shown it implies that no dihalo impurity was isolated).
with use of acetic acid as nucleophile-cum-proton source. In all of
the reactions studied, trans-stilbene and chalcones did not give the
iodo ethers with Iꢀ/IO3ꢀ whereas high yields of the bromo ethers
were achieved with Brꢀ/BrO3ꢀ. Thus with both reagents having their
respective merits, the two together offer a useful protocol for vic-
inal functionalization of olefins. The salt which precipitates in the
course of the reaction comprises the counter cation of the reagent
and the counter anion of the acid. If these are selected suitably in
the halohydrin and halo ether preparations, one can ensure that the
by-product salt also finds useful applications.
4.3. General procedure for synthesis of halo methyl ethers [1-
(2-iodo-1-methoxyethyl)-4-methyl-benzene (entry 4, Table 2)]
4-Methyl styrene (1.00 g, 8.47 mmol) and MeOH (10 mL) were
taken in 50 mL round bottomed flask cooled with 5–10 ꢂC water
taken in a water bath. To the above solution, 8.47 mmol of concd
H2SO4 was added slowly, followed by addition of 1.1 equiv of solid
KI/KIO3 [6.09 mmol KIþ3.05 mmol KIO3] in portions over a period
of 30 min under vigorous magnetic stirring. The progress of the
reaction was monitored by TLC. Stirring was continued for an ad-
ditional 35 min under the same conditions. The solvent was re-
moved under reduced pressure. Water was added to dissolve
inorganic salts present in the residue and thereafter the residue
was extracted with CH2Cl2 (25 mLꢁ3). The combined organic layers
were washed with dilute solutions of NaHCO3, Na2S2O3 and brine.
Finally it was dried over anhydrous Na2SO4 and concentrated under
4. Experimental section
4.1. General
All the reagents used were analytical reagents purchased from
commercial sources and used as received. 1H and 13C NMR spectra
were recorded on a spectrometer operating at 200 and 50 MHz,
respectively, in CDCl3 unless otherwise stated. Chemical shifts are
reported in parts per million relative to the appropriate standard,
and TMS as internal standard for 1H and 13C NMR spectra. GC–MS

M.K. Agrawal et al. / Tetrahedron 65 (2009) 2791–2797
2797
reduced pressure to get crude product, which was purified by
Supplementary data
column chromatography on silica gel to afford the pure 1-(2-iodo-
1-methoxyethyl)-4-methyl-benzene (2.23 g, 8.09 mmol) in 95%
yield. Similar procedure was employed for synthesis of bromo
methyl ethers listed in Table 2 using bromide/bromate with re-
quired quantity of acid.
Electronic supplementary information (ESI) on 1H and 13C NMR
data, elemental analysis (of solid products) and NMR spectra/GC–
MS of synthesized compounds is available free of charge. Supple-
mentary data associated with this article can be found in the online
version, at doi:10.1016/j.tet.2009.01.095.
4.4. General procedure for synthesis of halo acetates [2-iodo-
1-phenyl-ethyl ester (entry 2, Table 3)]
References and notes
Styrene (1.00 g, 9.61 mmol) and acetic acid (20 mL) were taken in
50 mL round bottomed flask and 1.1 equiv of solid KI/KIO3
[6.92 mmol KIþ3.55 mmol KIO3] added in portions over a period of
30 min under vigorous magnetic stirring at room temperature. The
progress of the reaction was monitored by TLC. After completion of
the reaction (3.5 h) the solvent was removed at 60–65 ꢂC under
reduced pressure, the crude residue was treated with water and the
product extracted with CH2Cl2 (25 mLꢁ3). The combined organic
layers were washed with dilute solutions of NaHCO3, Na2S2O3 and
brine, followed by drying over anhydrous Na2SO4 and concentration
under reduced pressure to get acetic acid 2-iodo-1-phenyl-ethyl
ester (2.73 g, 9.41 mmol) in 98% yield. Similar procedure was
employed for synthesis of other iodo acetates. The same procedure
was also followed for the syntheses of bromoacetates listed in Table
3 using the corresponding bromide/bromate salt in acetic acid.
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4.5. General procedure for one pot synthesis of rose oxide
Citronellol (1.56 g, 10.0 mmol) and MeOH (20 mL) were taken
in 50 mL round bottomed flask and the contents were stirred at
5–10 ꢂC. To the above solution, 5.5 mmol of concd H2SO4 was added
slowly followed by the addition of 1.1 equiv of solid KI/KIO3
[7.2 mmol KIþ3.7 mmol KIO3] in portions over 30 min under vigor-
ous stirring at 5–10 ꢂC. The progress of the reaction was monitored
by TLC and no starting material was left after 2.5 h. Solid KOH (0.9 g,
16.0 mM)wasthenaddedintothesameflaskunderstirringandonce
dissolution was complete the contents were refluxed for 2.5 h. The
solvent was removed under reduced pressure. 10 mL of hexane and
10.0 mL of 1.2 N HCl were then added into the flask and the contents
stirred at 0 ꢂC for 3 h. The organic and aqueous layers were separated
and aqueous layer was extracted once with 25 mL of dichloro-
methane. The combined organic layers were dried over anhydrous
Na2SO4 and concentrated under reduced pressure to obtain crude
product, which was purified by column chromatography on silica gel
to obtain 1.263 g (8.20 mmol, 82% yield) rose oxide. The product was
characterized by 1H and 13C NMR, IR and GC–MS.
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4.6. Computational methods
All calculations were performed with the Spartan’ 06 version,
using MP2 electron correlated method.34 Pseudopotential (LACVP
)
*
and 6-31G
basis sets were used for the calculations.35 All species
*
were fully optimized with these basis sets, and harmonic vibra-
tional frequency calculations were used to confirm that the opti-
mized structures were minima, as characterized by positive
vibrational frequencies. The natural population analysis was per-
formed with NBO method.36
32. Optimized geometry of trans 2-bromo-1-methoxy indane at MP2 level of
theory exhibits a dihedral angle of 78ꢂ between the 1,2-vicinal protons. Using
the Karplus equation, the coupling constant is computed to be 0.105 Hz, i.e., the
value is negligible as observed experimentally.
Acknowledgements
33. Anand, N.; Kapoor, M.; Koul, S.; Taneja, S. C.; Sharma, R. L.; Qazi, G. N. Tetra-
hedron: Asymmetry 2004, 15, 3131.
We thank Dr. P. Paul, Mr. V. P. Boricha, Mr. H. Brahmbhatt and Mr.
V. Agrawal of our Analytical Division for analyses and Dr. A. Das for
a sample of the chalcone used in Entry 23/24 of Table 2. We are also
grateful to Dr. P. Ray and Dr. B. C. Ranu for helpful discussions and to
the referees for their valuable suggestions. M.K.A. wishes to thank
UGC, New Delhi for support under UGC-NET fellowship.
34. (a) Hehre, W. J.; Radom, L.; Schleyer, P. V. R.; Pople, J. A. Ab Initio Molecular
Orbital Theory; Wiley: New York, NY, 1986; Spartan’ 06. Wavefunction: Irvine,
CA; (b) Hehre, W. J. A Guide to Molecular Mechanics and Quantum Chemical
Calculations, 2nd ed.; Wavefunction: Irvine, CA, 2006; (c) Carpenter, J. E.;
Weinhold, F. J. Mol. Struct. (Theochem) 1988, 169, 41.
35. Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 270.
36. Reed, A. E.; Weinhold, F. J. Chem. Phys. 1985, 83, 1736.