Synthesis of 2-pyridylpyridines via aza-Diels-Alder reactions between 3-pyridyl-1,2,4-triazines and some vinyl alkanoates

Article abstract of DOI:10.1246/cl.2005.836

New synthetic procedure for 2,ω-bipyridines involving aza-Diels-Alder reaction between 3-(ω-pyridyl)-1,2,4-triazine and vinyl octanoate or decanoate as a dienophile is described. Copyright

Full text of DOI:10.1246/cl.2005.836

8
36
Chemistry Letters Vol.34, No.6 (2005)
Synthesis of 2-Pyridylpyridines via Aza-Diels–Alder Reactions
between 3-Pyridyl-1,2,4-triazines and Some Vinyl Alkanoates
ꢀ
Taichi Shintou, Fumiaki Ikeuchi, Hirokazu Kuwabara, Ken Umihara, and Isamu Itoh
Synthetic Chemistry Research Laboratory, Sankio Chemical Co., Ltd., 5-2-3 Higashiyahata, Hiratsuka 254-0016
(Received February 17, 2005; CL-050215)
New synthetic procedure for 2,!-bipyridines involving aza-
Diels–Alder reaction between 3-(!-pyridyl)-1,2,4-triazine and
vinyl octanoate or decanoate as a dienophile is described.
Table 1. The preparation of 2-pyridylpyridines via the aza-
Diels–Alder reaction of 3-(!-pyridyl)-1,2,4-triazine 1 and 2,5-
norbornadiene (2)
a
b
c
Run
1
Triazine 1
Product 3
Yield/% Purity/%
N
N
N
N
N
In the course of synthetic studies on 2-pyridylpyridine deriv-
atives, which have been well known as fundamental building
80.0
99.2
N
N
1a
3a
3b
3c
1
–3
4
N
N
N
N
N
N
blocks of some potent drugs, Sauer et al. reported the aza-
Diels–Alder reaction of 3-(!-pyridyl)-1,2,4-triazine 1 and 2,5-
norbornadiene (2) as an attractive synthetic procedure of substi-
tuted 2,!-bipyridines 3 in an excellent yield (Eq 1). Their proce-
dure, however, contains two serious problems: i) when !-cyano-
2
3
85.3
88.2
98.9
99.3
N
N
1
b
N
N
N
1
c
ꢁ
pyridine was treated in order with HCl in EtOH at 0 C to rt, with
ꢁ
a
The thermal reaction was carried out with 1 (1 equiv.) and 2 (10
ꢁ
.
hydrazine HCl salt and Et3N, and then with (CHO)2 at ꢂ70 C,
b
equiv.) in xylene at 90 to 120 C for 3 to 5 h. The starting triazine
was prepared from the readily available cyanopyridine. The
5
1
was afforded in only 10% overall yield; ii) 2 as a dienophile
1
pyridine (1 equiv.) was treated with NH NH
requiring 10 equiv. is highly expensive and seems to be unsuit-
able for an industrial application. Accordingly, a synthetic proc-
ess of various 2-pyridylpyridine derivatives via 1,2,4-triazines
using highly reactive (CHO)2 is so difficult that there have been
no reports on the process. We describe herein a general proce-
dure developed by detailed improvement and extension of the
known method.4
.
30 to 70 C for 2 to 5 h to give the amidrazone, which was reacted
H O in H O at
2
2
2
2
ꢁ
ꢁ
with 40% aq (CHO)2 (1 equiv.) in H2O at 60 to 100 C for 1 to 2 h
c
leading to formation of 1. The structure of the product was iden-
d
tified by IR, NMR, and MS. Yield based on the starting triazine 1.
e
The respective purities were determined by HPLC analysis.
,5
R2
N
R2
N
∆
0
+
+
N2
Table 2. The preparation of 2,4 -Pyridylpyridine (3a) via aza-
0
N
R1
(1)
Diels–Alder reaction of 3-(4 -pyridyl)-1,2,4-triazine (1a) and
a
N
R1
N
N
vinyl alkanoates 6 (CH2=CH–OCOR)
1
2
3
0
Reaction Reaction Yield/% Purity/%
b
At first, we established preparation of 3-(4 -pyridyl)-
5
Run
Dienophile 6
6a, R = Me
6b, R = CH2Me
6c, R = CMe3
ꢁ
c
temp/ C time/h
of 3a
of 3a
1
(
,2,4-triazine (1a) by a modification of the Lee procedure
1
2
3
4
5
6
110
127
160
162
166
180
205
210
200
>72
>72
48
42
48
16
3
9.2
15.2
87.8
88.6
87.8
90.4
91.4
90.7
88.9
—
—
Scheme 1). 4-Cyanopyridine (4a 1 equiv.) was reacted with
ꢁ
.
0
NH2NH2 H2O (1 equiv.) in H2O at 50 C for 4 h to give 3-(4 -
pyridyl)amidrazone (5), which, without purification, was treated
98.8
98.5
98.8
99.2
99.2
99.3
98.9
ꢁ
6d, R = (CH2)2Me
6e, R = (CH2)3Me
6f, R = (CH2)4Me
6g, R = (CH2)6Me
6h, R = (CH2)8Me
6i, R = C6H5
with 40% aq (CHO)2 in H2O at 100 C for 2 h providing 1a in
85% overall yield. The aza-Diels–Alder reaction of 1a (1
equiv.) and 2 (10 equiv.) in xylene for 4 h under reflux provided
,4 -bipyridine (3a) in 80.0% yield. The representative synthetic
results of the related 2-pyridylpyridines were revealed in
Table 1.6
As the solution of the next problem, we searched another
more effective dienophiles in place of 2, which is rather toxic
to human being, highly costs, and requires 10 equiv. amount
for completion of the reaction. Eventually, we found that, when
6
d
7
d
0
2
8
2
6
9
aThe representative reaction was as follows; the mixture of 1a (1
equiv.) and vinyl decanoate 6h (2 equiv.) in diisopropylbenzene
ꢁ
was heated at 210 C for 2 h, diluted with toluene, and washed with
1 M HCl. The aq layer was basified with 9 M NaOH and extracted
with toluene to give 3a as crystals in 90.7% yield (Run 8). The struc-
b
ture of 3a was identified by IR, NMR, and MS. Yield based on the
c
starting triazine 1. The respective purities were determined by HPLC
ꢁ
H O
(CHO)2
, H O
2
2
NH NH2•
2
H NHN
NH
CN
2
d
analysis. The melting point of 3a was 60.6–61.4 C. (reference: P.
ꢁ
H O, 50 °C
2
100 °C, 2 h
Kraumholz, J. Am. Chem. Soc., 73, 4449 (1951). 61.1–61.5 C.)
4
h
N
N
N
N
N
N
5
1a
4a
vinyl acetate 6a was used as a dienophile, the aza-Diels–Alder
reaction proceeded rather slowly (>72 h) but to give the desired
0
Scheme 1. Efficient preparation of 3-(4 -pyridyl)-1,2,4-triazine
(1a).
7
3
a though in 9.2% yield (Table 2, Run 1). Accordingly, we
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.6 (2005)
837
dienophile.8,9 It should be emphasized that the new method is
quite suitable for an industrial production for supply of valuable
2,!-bipyridine derivatives as versatile technical synthetic
intermediates.
Table 3. The preparation of 2-pyridylpyridines via aza-Diels–
Alder reaction of 3-(!-pyridyl)-1,2,4-triazine 1 and vinyl dec-
anoate 6h
Run
Triazine 1
Product 3
Yield/% Purity/%
1
2
1b
1c
3b
3c
89.8
93.3
99.1
99.5
References
N
N
N
N
N
1
D. R. Sidler, R. D. Larsen, M. Chartrain, N. Ikemoto, C. M.
Roberge, C. S. Taylor, W. Li, and G. F. Bills, WO 99/07695
1999).
K. Kamei, N. Maeda, and T. Tatsuoka, WO 99/03847
1999).
3
4
5
88.7
89.4
90.8
99.0
99.3
98.9
N
N
N
N
(
N
N
2
3
(
N
N
N
N
N
N
N
N
D. Cui, M. R. Davis, M. Dunn, B. E. Evans, H. P. Kari, B.
Lagu, D. Nagarathnam, K. P. Vyas, and K. Zhang, U. S.
Patent 6,274,585 B1 (2001).
N
N
N
4
G. R. Pabst and J. Sauer, Tetrahedron Lett., 39, 6687 (1998);
G. R. Pabst, K. Schmid, and J. Sauer, Tetrahedron Lett., 39,
examined to use various related vinyl alkanoates 6. The
results are summarized in Table 2. The yield of 3a depends on
a reaction temperature and amounted to 91.4% or 90.7% yield
with a high purity (>99.2% from HPLC) in the case of vinyl
octanoate 6g or decanoate 6h (Runs 7 and 8). Accordingly, some
other triazines were treated with 6h and the results were summa-
rized in Table 3. The yields were more than 89% with excellent
purity in all triazines.
6
8
3
691 (1998); G. R. Pabst and J. Sauer, Tetrahedron Lett., 39,
817 (1998); O. C. Pfuller and J. Sauer, Tetrahedron Lett.,
9, 8821 (1998); G. R. Pabst, O. C. Pfuller, and J. Sauer, Tet-
rahedron Lett., 39, 8825 (1998); J. Sauer, D. K. Heldmann,
and G. R. Pabst, Eur. J. Org. Chem., 1993, 313.
J.-K. Lee, S.-N. Kim, and S.-G. Lee, J. Korean Chem. Soc.,
5
3
9, 755 (1995).
6
7
F. Ikeuchi, T. Shintou, and H. Suda, WO 00/76975 (2000).
T. Shintou and F. Ikeuchi, Jpn. Patent 2001-158773 A
(2001).
For a sole precedent of aza-Diels–Alder reaction using vinyl
acetate 6a as a dienophile: W. Dittmar, J. Sauer, and A.
Steigel, Tetrahedron Lett., 59, 5171 (1969).
Review of preparation of pyridine derivatives by using tri-
azines via aza-Diels–Alder reaction: D. L. Boger and S. M.
Weinreb, ‘‘Hetero Diels-Alder Methodology in Organic
Synthesis,’’ Academic Press, New York (1987), pp 323–
335; ‘‘Comprehensive Organic Synthesis,’’ ed. by B. M.
Trost and I. Fleming, Pergamon Press, Oxford (1991),
Vol. 5, Chap. 4.3.5.
O
N
N
R2
R1
CN
N
R
O
R2
R1
8
9
N
N
(2)
N
N
Thus, we developed the new efficient procedure for the syn-
thesis of various 2,!-bipyridine derivatives (Eq 2). The process
consists of the preparatory step of 3-(!-pyridyl)-1,2,4-triazine 1
from !-cyanopyridine 4 in H2O and the synthetic step of 2,!-
pyridylpyridine 3 by the aza-Diels–Alder reaction from the
1,2,4-triazine 1 and vinyl octanoate 6g or decanoate 6h as a
Published on the web (Advance View) May 21, 2005; DOI 10.1246/cl.2005.836