5
060
T. Xu et al. / Tetrahedron Letters 55 (2014) 5058–5061
Table 2 (continued)
Entry
1
2
Yieldb (%)
60
CN
N
CN
Br
15
16
17
NH
2
N
2o
NH
2
1
o
NO
2
2
Br
NO
2
56
76
68
N
NH
N
2p
NH
2
1
p
CH
3
CH
3
Br
H
3
C
N
NH
2
H
3
C
N
2q
NH
2
1
q
Br
1
8
N
N
N
N
1r
2r
a
Reaction conditions: 2-aminopyridines (0.5 mmol), 1-butylpyridinium bromide (1.5 mmol), p-TSA (0.4 mmol), H
Isolated yields based on substrate 1.
2 2
O (1.2 mmol), DME (2 mL), 80 °C, 24 h.
b
2
-Aminopyridines, its derivatives, and the structures containing
corresponding 5-bromo-pyridines in good to excellent yields
(Table 2, 2b–d). When primary amines of pyridines were subjected
to the conditions, the reactions furnished the desired bromination
products with moderate to high yields (Table 2, 2e–q). 2-Amino-
pyridine 1e gave 5-bromo-2-aminopyridine in 86% yield. When
2-aminopyridines were substituted with electro-donating groups
such as 4-methoxyl (1f), 3-methyl (1g), 4-methyl (1h), 6-methyl
(1i), and 4,6 dimethyl (1q) groups, the desired products were
obtained in 56–85% yields(Table 2, 2f–i, 2q). The present bromina-
tion also was compatible with electron-withdrawing groups on 2-
aminopyridines (halogen, cyan and even nitro), and the respective
products were isolated in 52–77% yields (Table 2, 2j–p). It is note-
worthy that all the transformations showed a high regioselectivity
in the exclusive 5-bromopyridines products. As for some 4-substit-
uented 2-aminopyridines (Table 1, 1f, 1h and 1l), no 3-brominated
or polybrominated product was detected. Multi-substituted
2-aminopyridine, 4,6-dimethylpyridin-2-amine (1q) displayed
the complete regioselectivity to provide the corresponding
product 2q in 76% yield. Encouraged by the above results, we
conducted the bromination of N,N-dimethylpyridin-2-amine (1r)
to examine the application to the tertiary amines of pyridine.
The desirable bromination product 2r was also obtained in a good
yield of 68%. The results demonstrate that this approach is suit-
able for the regioselective bromination of different types of
2-aminopyridines.
them have always been representing a class of compounds which
exhibit various medicinally important properties, such as analge-
2
4
25
sic, anti-inflammatory activities, and beneficial effects in the
2
6
treatment and prevention of central nervous system disorders.
In particular, brominated 2-aminopyridines attracted considerable
attentions for their applications as useful intermediates or build-
ing blocks for pharmaceuticals. Therefore, developing an efficient
and mild method for regioselective bromination of 2-aminopyri-
dines is desirable. We report herein a mild method for the regiose-
lective bromination of 2-aminopyridines. This environmentally
2 2
friendly procedure using 1-butylpyridinium bromide and H O as
green bromination reagents is an important complementary
method for bromination.
Initially, 2-benzylaminopyridine was employed as a model sub-
strate and various bromides were investigated. The reaction was
carried out under the following conditions: 3.0 equiv of bromides,
.4 equiv of TBHP as an oxidant, and 1,2-dimethoxyethane as the
reaction solvent. The reaction mixture was stirred at 80 °C for
4 h under air (Table 1). NBS gave the product 5-bromo-2-benzyl-
aminopyridine 2a in 13% yield, whereas only a trace of 2a was
detected when using TBAB (Table 1, entries 1 and 2). Compared
with NBS and TBAB, 1-butylpyridinium bromide afforded a higher
yield of 19% (Table 1, entry 3), so we chose the 1-butylpyridinium
bromide as the bromine source in the following exploration. Subse-
quently, we investigated various oxidants in this bromination reac-
tion. Oxone and mCPBA led to higher yields of 20% and 40%
respectively compared to TBHP (Table 1, entries 4 and 5). A further
5
6
2
2
Based on our experimental results and the previous reports,7,8,27
a possible mechanism is presented in Scheme 1. First, the bromide
ion of 1-butylpyridinium bromide is oxidized to electrophilic BrOH
improved yield of 46% was obtained with the use of aqueous H
so that it was chosen as the oxidant in the subsequent optimization
Table 1, entry 6). Inspiringly, we found that the yield was
2 2
O
(
H O
2
2
improved to 56% by use of TfOH as an additive (Table 1, entry 7).
PivOH only gave the desired product 2a in 50% yield (Table 1, entry
Br-
BrOH or Br2
H
8
). The yield was dramatically increased (91%) when 0.8 equiv of
Y
R1
R2
R1
R2
R1
R2
Br
H
p-toluenesulfonic acid (p-TSA) was used (Table 1, entry 9). In
addition, the pyridine N-oxide was not detected under oxidative
conditions. The yields of product 2a tend to decrease with chang-
ing the amount of p-TSA (Table 1, entries 10 and 11).
With the optimized conditions in hand (Table 1, entry 9), the
scope and generality of the method were investigated. In addition
to 2-benzylaminopyridine 1a, other secondary amines containing
substituent groups on the phenyl (4-Me, 4-F) or pyridine ring
N
N
N
N
N
N
A
Y= OH or Br
R1
R2
R1
Y-
Br
- H+
-
N
N
Br
N
H
R2
N
B
C
(
4-Me) also underwent bromination smoothly to afford the
Scheme 1. Possible reaction pathway of oxidative bromination.
Xu, Tong
