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F. Fu et al. / Tetrahedron Letters 60 (2019) 151020
ipso-bromination of arylboronic acids are relatively scarce. In
addition, many reported methods above are either requiring high
temperature, long reaction time, or large excess of additives/
special ligand and some of them have limited substrate scope or
yields. Therefore, it is very desirable to develop milder, more
efficient, less expensive and environmentally benign alternative
for preparation of haloarenes.
The recent developments of polymer supported reagents have
been growing fast in synthetic organic chemistry [18]. Polymeric
reagents are generally macromolecules to which chemical func-
tional groups are connected. They possess the similar potential
abilities of the low molecular weight analogues. On the other hand,
the main advantages of these polymer-supported species over
their monomeric reagents are (a) easier work-up by simple filtra-
tion and subsequent washing with the solvent because of their
insolubility in the reaction medium, (b) using excess of the
reagents to drive the reaction to completion without any concern
regarding the separation of the desired products from the unused
reagents, (c) recyclability of these polymer supports, (d) lower tox-
icity which makes them environmentally safer, (e) and fine-tuning
the stability and selectivity of the reagents towards different syn-
thetic transformations compared to those carried out on same
functional groups by unsupported reagents [19]. Poly(4-vinylpyri-
dine) (PVP) is one of the most frequently used polymer as a solid
support for various reagents and catalysts because of its commer-
cial availability, its stability, facile complexation with high loading
capacity, fine swelling properties, and good physicochemical char-
acteristics [19]. During the course of our studies, we developed
environmentally benign methods via polymer-supported reagents
such as PVP-HF, PVP-SO,2 PVP-H2O2, PVP-NM (nitrating Mixture),
and PVP-CF3SO3H in recent decades [20]. In continuation of our
efforts using these polymeric complexes for various organic trans-
formations, we decided to explore the application of poly(4-vinyl-
pyridine)- bromine/iodine complexes (PVP-Br2/I2) as effective
reagents for halogenation of aryl boronic acids. PVP-Br2 as a poly-
mer-supported solid complex have been previously studied for
bromination of aromatic rings, alkenes, alkynes, ketones etc [21].
However, the application of PVP-Br2/I2 as polymer supported
reagents for ipso-halogenation reactions has very rarely been
explored in recent years. Herein, we report the preparation and
the use of PVP-Br2/I2 complexes as green and efficient reagents
for ipso-bromination/iodination of arylboronic acids with catalytic
amount of NaNO2 for the synthesis of the corresponding
haloarenes.
Scheme 1. Preparation of PVP:Br2 (1:1) and PVP:I2 (1:1).
weight increment, PVP-Br2 and PVP-I2 complexes are found to
have
a 1:1 M ratio, achieved by the addition of equimolar
amounts of bromine or iodine with respect to monomer unit of
the polymer. During our initial trials, with direct treatment of the
polymer and Br2/I2 without swelling for a day, we got PVP-Br2
and PVP-I2 complexes with 1.5:1 M ratio and 1.2:1 M ratio
respectively. By prior swelling and proper stirring as mentioned
we were able to get the complexes with 1:1 M ratio. The changes
in morphology of the polymer samples because of the formation
of the complexes were further studied through scanning electron
microscopy (SEM) (Fig. 1). The surface morphology of the
complexes changed significantly compared to that of the
precursor PVP polymer. The particle sizes of both PVP-Br2 and
PVP-I2 were found to be much smaller indicating activities of the
complexes with increased reaction surfaces (Fig. 1b, c).
To screen their capabilities as reagents for halogenation, the
complexes were subsequently used for ipso-bromination or iodina-
tion of various arylboronic acids. Preliminary studies showed that
the complex is very effective and convenient halogenating reagent
(for both bromination and iodination) under mild conditions
(Scheme 2).
We began with the screening of reaction conditions such as
amount of the reagents, solvent, temperature and time for bromi-
nation of p-tolylboronic acid with PVP-Br2 complex with molar
ratio 1.5:1 (Table 1). Fortunately, 42% product was formed when
1 equiv. alryboronic acid reacted with 1.5 equiv. PVP-Br2 (1.5:1)
in acetonitrile at room temperature for 17 h (Table 1, entry 1).
Increasing the temperature to 80 °C and reducing the reaction time
to 3 h, showed significant improvement in yield to 67% though not
high as expected (entry 2). Next, we added NaNO2 as additive in
different amounts to see whether it has any impact on the reaction.
In order to improve the yield of the product, reactions with varying
amounts of the complex and the additive with respect to starting
materials were further examined (Table 1, entries 3–7). Reaction
using 1.5 equivalents of PVP-Br2 (1.5:1) with 0.25 equiv. sodium
nitrite at 80 °C for 3 h yielded the ipso-brominated product in
93% yield (Table 1, entry 6). The small amount of sodium nitrite,
0.25 equiv. used in this high yield reaction and much lower yield
in its absence reveal its role as a catalyst (Table 1, entry 6).
For the ipso-halogenation reaction, acetonitrile (CH3CN) was
found to be the solvent of choice in terms of the yield and selectiv-
ity of the reaction (Table 1, entries 3–6, 8). Reaction at a lower tem-
perature led to lower conversion of 4-tolylboronic acid and the
yield of the desired product, 4-bromotoluene (Table 1, entry 8).
Next, four different sodium salts were screened in the presence
of 1.5 equiv. of PVP-Br2 (1.5:1) in acetonitrile at 80 °C for 3 h
(Table 2). Analytically, catalytic amounts of both sodium nitrite
and sodium nitrate provided the products in similar high yields
(Table 2, entries 1 and 3). While conducting the reactions under
similar conditions, results from sodium nitrite and sodium nitrate
did not differ significantly though a slightly better yield was
obtained with sodium nitrite (Table 2, entries 2 and 4).
Results and discussion
We initiated our investigation by preparing poly(4-vinyl-
pryridine)-bromine/iodine complexes or PVP-Br2/I2. Several meth-
ods of making PVP-Br2 had been reported by Zabicky and
Mhasalkar [21g]. Accordingly, commercially available poly(4-
vinylpyridine), 2% cross linked with divinylbenzene, was stirred
with excess hexane as solvent for 24 h so that the polymer was
swollen well. Liquid bromine or solid iodine was then carefully
added to the swollen polymer support in hexane with efficient
cooling and thorough mixing. As complex formation of PVP-Br2
or PVP-I2 proceeds, the color of the solution became lighter and
lighter and stirring was continued till no further significant
change in color was observed (about 24 h). After filtering,
washing and drying under the vacuum, a fluffy, free-flowing,
fresh orange (PVP-Br2) or purple black solid (PVP-I2) was
obtained (Scheme 1). The complexes are almost odorless which is
ready for use as reagent for bromination/iodination, which are
much safer than molecular bromine or iodine. The complex can
be stored in well-closed containers for many months. From the
The optimal reaction conditions for ipso-bromination reaction
using PVP-Br2 (1.5:1) were found to be: 1.5 equiv. PVP-Br2 (1.5:1)