1
48
Can. J. Chem. Vol. 83, 2005
Table 3. Bromination of activated pyridine and quinoline derivatives by NBS in the presence of LiClO –SiO .
4
2
Entry
1
Substrate
NBS (equiv.)
2
Product(s)
5-Bromo-2-aminopyridine
,5-Dibromo-2-aminopyridine
5,7-Dibromo-8-aminoquinoline
Yield (%)
2-Aminopyridine
90
10
98
3
2
8-Aminoquinoline
2
Note: Reaction time: 5 min.
Scheme 1.
dibromoarene) was formed in a short reaction time and in
good yield. In all cases, the crude products were monitored
by GC and checked for the presence of any by-products.
Some general trends are apparent from the data in Table 1.
First, the reactivity of the substrate seems to be related to the
electron density on the aromatic ring. Thus, the nucleus
must be sufficiently activated before significant reactions
occurred. This reagent is not effective for benzene, toluene,
or naphthalene, and amino derivatives give slightly easier
and cleaner reaction than hydroxyl derivatives. The presence
of electron-donating or electron-withdrawing groups on the
aniline or phenol did not affect the rates or the yields of the
reactions. For example, p-methylaniline, p-nitroaniline, N,N-
dimethylaniline, and p-(N,N-dimethylamino)benzaldehyde
gave the monobromo product in short reaction times and in
high yields (Table 1, entries 4, 8, 10, and 11). p-Substituted
anilines were brominated at the ortho position. In the case of
aniline (Table 1, entry 2), 1-naphthylamine (Table 2, entry
vents, such as water and ethanol. In the reported procedures,
with the use of common organic solvents such as CH CN,
3
CS , CH Cl , and CCl , mixtures of monobromo and
2
2
2
4
dibromo products were formed, with long reaction times
(19, 20). We have found that NBS/LiClO –SiO is suitable
4
2
for the regioselective monobromination of aminopyridine
and dibromination of 8-aminoquioline with excellent yields
and a reaction time of a few minutes (Table 3).
To extend the scope of this reagent, we have also investi-
gated bromination of anthracene and thiophenol. NBS in
CCl is a common brominating agent for anthracene and af-
4
fords a mixture of mono- and dibromoanthracene in good
yields (21). We found that bromination of anthracene with 2
equiv. of NBS using the NBS/LiClO –SiO reagent yieled
4
2
9,10-dibromoanthracene as the sole product. On the other
hand, bromination of thiophenol was not successful, and
coupling of thiol groups to form the disulfide in excellent
yields was observed (Scheme 1).
In conclusion, we have developed a simple, general, and
efficient method for electrophilic bromination of activated
3
8
), and 4-aminoacetophenone (Table 1, entry 6), as well as
-aminoquinoline (see Table 3, entry 2), in the presence of 2
equiv. of NBS dibromination occurred at the 2 and 4 posi-
tions in high yields. It is noteworthy that the direct
bromination of aniline with bromine in solution often results
in polybromination and requires the protection of amino
groups. The results with the derivatives of phenol are some-
what different. For example, under the above reaction condi-
tions, phenol gave dibromophenol (Table 1, entry 1), while
arenes under mild conditions, mediated by LiClO dispersed
4
on SiO in CH Cl . The absence of side-chain bromination
2
2
2
products in this procedure clearly indicates that an electro-
philic aromatic substitution mechanism operates in this reac-
tion medium; the remarkable enhancement in reaction rates
and regioselectivity could be explained by increased polar-
ization of the N—Br bond of NBS in this ionic process. This
procedure also can be applied to polycyclic aromatic com-
pounds. Furthermore, the LiClO –SiO reagent is cheap, sta-
2
-naphthol (Table 2, entry 1), 2,7-dihydroxynaphthalene
Table 2, entry 4), and p-substituted phenols gave only
(
4
2
monobrominated products in short reaction times and with
high yields (except in the case of 4-nitrophenol). 1-Naphthol
ble, easy to handle, and nontoxic. The present method would
be useful in organic synthesis. We are currently extending
this methodology to the use of NXS (X = Cl, I).
(
Table 2, entry 2) and 3-anisidine (Table 1, entry 13) pro-
duced the corresponding dibromo derivatives. The
bromination of methoxybenzene required a long reaction
time with 1 g of LiClO –SiO (Table 1, entry 9), but 2-
Experimental
4
2
methoxynaphthalene gave the dibromo product in excellent
yield with 1 g of LiClO –SiO (Table 1, entry 13). Compari-
General procedure for the bromination of aromatic
compounds with NBS
4
2
son of our results with those reported in the literature clearly
shows that higher reactivity and higher selectivity are ob-
tained with LiClO –SiO than with SiO (18).
NBS (1–2 eqiuv.) was added slowly to a stirred solution
of an aromatic compound (2 mmol) and 0.4 g of LiClO4–
SiO (1:4) in CH Cl (20 mL). When the addition was com-
4
2
2
2
2
2
We next investigated bromination of 2-aminopyridine and
-aminoquinoline. The most direct approach to the
bromination of pyridine derivatives is the direct electrophilic
halogenation of the activated pyridines in polar protic sol-
plete, the reaction mixture was stirred at room temperature
and the progress of the reaction monitored by TLC and GC.
Complete conversion was achieved for most of the sub-
strates. The reaction mixture was filtered, and the catalyst
8
©
2005 NRC Canada