4362
N. Nishiwaki et al. / Tetrahedron Letters 48 (2007) 4361–4363
Table 1. Optimization of reaction conditions
2g and pyrrolidine 2h, to afford 3g and 3h in high yields
(runs 5 and 6).
NO2
NO2
+
Additive
Br
NHR
Further functionalization could be also performed by
use of amines having an additional functional group
(runs 7–12). The substitution with diamines 2i and 2j
effectively proceeded even though only equimolar di-
amine was employed without any modification of another
amino group. A hydroxy and an ester functions were
also introduced to the amino group by using amino
alcohol 2k and amino acid derivatives 2l and 2m,
respectively.
(5 equiv.)
+
RNH2
+
Solv.
60 °C
N
N
_
2
_
O
O
1
3
Run R (equiv) Solv.
Additive Time (h) Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Pr (2)
Pr (2)
Pr (2)
Pr (2)
Pr (2)
Pr (2)
Pr (2)
Pr (2)
EtOH
MeCN
Na2CO3
Na2CO3
Pyridine Na2CO3
1
1
1
1
1
1
1
1
32
41
51
52
59
28
33
36a
99
41
55
54
62
77
AcOEt
THF
EtOH
Pyridine
THF
THF
THF
THF
THF
Na2CO3
Na2CO3
Recently, Yao et al. carried out the reaction of 3-bromo-
4-nitropyridine with piperazines.13 They isolated three
kinds of substituted pyridines, small amounts of 3-ami-
nated 4-nitropyridine and 4-aminated 3-bromopyridine
in addition to major product, 4-aminated 3-nitropyri-
dine, whose nitro group was migrated from the vicinal
position. To the contrary, N-oxide 1 underwent the
nucleophilic b-amination regioselectively upon treat-
ment with primary or secondary amines 2. On the basis
of these different reactivities, it is considered that the
electron-donating N-oxide increases the electron density
at the a- (2-) and the c- (4-) positions to realize the reg-
ioselective amination at the b- (3-) position. In conclu-
sion, N-oxide 1 is demonstrated to be a useful
precursor for 3-aminopyridine derivatives.
—
—
—
—
—
Pr (2)
24
24
24
i-Pr (2)
i-Pr (2)
i-Pr (2)
i-Pr (5)
i-Pr (10)
b
NEt3
Na2CO3 24
—
—
THF
THF
24
24
a 62% of 1 was recovered.
b 1 equiv of NEt3 was used.
larger amount of 2b was rather effective for improving
the yield of 3b in one day (runs 13 and 14).
Supplementary data
The present reaction was applicable to other amines
2c–m to afford corresponding aminated pyridines 3c–m
as shown in Table 2. Sterically hindered tert-butylamino
group was introduced under the same conditions giving
3c in a moderate yield (run 1). Arylamination was also
possible in cases of aniline 2d and p-anisidine 2f though
triethylamine should be added (runs 2–4). N-Oxide 1
similarly reacted with secondary amines, diethylamine
Supplementary data associated with this article can be
References and notes
1. Recent papers: Penney, J. M. Tetrahedron Lett. 2004, 45,
2667–2669; Narayan, S.; Seelhammer, T.; Gawley, R. E.
Tetrahedron Lett. 2004, 45, 757–759; Bakke, J. M.;
Sletvold, I. Org. Biol. Chem. 2003, 1, 2710–2715.
2. Recent review: Bakke, J. M. J. Heterocycl. Chem. 2005,
42, 463–494.
3. Recent review: Li, J. J.; Gribble, G. W. Palladium in
Heterocyclic Chemistry; Pergamon Press: London, 2000;
pp 183–232.
Table 2. Reactions of 1 with other amines 2c–m
NO2
NO2
+
NR1R2
Additive
(10 equiv.)
Br
R1R2NH
+
+
THF
60 °C, 24 h
(10 equiv.)
N
_
N
_
O
2
O
4. Recent review: Kharchenko, V. G.; Markova, L. I.;
Fedotova, O. V.; Pchelintseva, N. V. Chem. Heterocycl.
Compd. 2003, 39, 1121–1141.
1
3
Run
R1
R2
Additive
Yield (%)
5. Recent reviews: van der Plas, H. C. Adv. Heterocycl.
Chem. 2003, 84, 31–70; Nishiwaki, N.; Tamura, M.; Ariga,
M. J. Synth. Org. Chem. Jpn. 2005, 63, 1232–1239.
6. For example: Kotovskaya, S. K.; Mokrushina, G. A.;
Postovskii, I. Y. Chem. Heterocycl. Compd. 1983, 19, 303–
306 (Translated from Khim. Geterotsikl. Soedin. 1983,
373–376).
7. Azev, Y. A.; Mokrushina, G. A.; Postovskii, I. Y. Chem.
Heterocycl. Compd. 1974, 10, 687–690 (Translated from
Khim. Geterotsikl. Soedin. 1974, 792–795).
8. Matsumura, E.; Ariga, M. Bull. Chem. Soc. Jpn. 1977, 50,
237–241; Matsumura, E.; Ariga, M. Bull. Chem. Soc. Jpn.
1973, 46, 3144–3146.
9. Talik, T.; Talik, Z. Bull. Acad. Pol. Sci., Ser. Sci. Chim.
1968, 16, 1–5 (Chem. Abstr. 1968, 69, 59059).
1
2
3
4
5
6
7
8
9
t-Bu
Ph
p-NO2C6H4
p-MeOC6H4
Et
H
H
H
H
Et
c
d
e
f
—
43
25
0
NEt3
NEt3
NEt3
—
—
—
—
—
NEt3
NEt3
NEt3
55
84
90
89a
70a
28
46
57b
14b
g
h
i
–(CH2)4–
(CH2)2NH2
(CH2)3NH2
(CH2)2OH
CH2COOEt
CH2COOEt
CH(Pri)COOMe
H
H
H
H
H
H
j
k
l
10
11
12
l
m
a 1 equiv of amine was used.
b Reaction time 48 h.