Synthesis of pyridines from 1,2,4-triazines under high pressure

Article abstract of DOI:10.1007/s11178-008-3016-1

A procedure has been proposed for the synthesis of pyridines from 1,2,4-triazine derivatives and bicyclo[2.2.1]hepta-2,5-diene under high pressure in the presence of lithium perchlorate as catalyst.

Full text of DOI:10.1007/s11178-008-3016-1

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 3, pp. 407–411. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © M.M. Krayushkin, I.P. Sedishev, V.N. Yarovenko, I.V. Zavarzin, S.K. Kotovskaya, D.N. Kozhevnikov, V.N. Charushin, 2008,
published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 3, pp. 411–414.
Synthesis of Pyridines from 1,2,4-Triazines under High Pressure
M. M. Krayushkina, I. P. Sedishevb, V. N. Yarovenkoa, I. V. Zavarzina, S. K. Kotovskayac,
D. N. Kozhevnikovd, and V. N. Charushinc, d
a Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences, Leninskii pr. 47, Moscow, 119991 Russia
e-mail: mkray@ioc.ac.ru
b Mendeleev Russian University of Chemical Technology, Moscow, Russia
c Ural State Technical University, Yekaterinburg, Russia
d Postovskii Institute of Organic Synthesis, Ural Division, Russian Academy of Sciences,
ul. S. Kovalevskoi 20, Yekaterinburg, 620219 Russia
Received March 4, 2007
Abstract—A procedure has been proposed for the synthesis of pyridines from 1,2,4-triazine derivatives and
bicyclo[2.2.1]hepta-2,5-diene under high pressure in the presence of lithium perchlorate as catalyst.
DOI: 10.1134/S1070428008030160
Pyridine derivatives, including fused heterocyclic
compounds containing a pyridine ring, constitute
a number of natural substances and are widely used in
the synthesis of various biologically active compounds
[1–5]. Synthesis and studies on the properties of new
pyridine derivatives may be regarded as a promising
line in the design of effective medical agents. There-
fore, development of new approaches to previously
inaccessible pyridine derivatives attracts considerable
interest.
It is known that electron-deficient 1,2,4-triazines
smoothly react with electron-rich dienophiles [10–13].
In keeping with published data [14] and our own
results [15–18], application of high pressure is effec-
tive in the synthesis of many heterocyclic systems.
While studying the cycloaddition of bicyclo[2.2.1]-
hepta-2,5-diene to thiazolo[4,5-e][1,2,4]triazine, we
previously showed that such reactions cannot be ac-
complished under atmospheric pressure [19]. We also
found that the reaction of 6-(4-chlorophenyl)-3-phenyl-
[1,3]thiazolo[4,5-e][1,2,4]triazine (I) with bicyclo-
[2.2.1]hepta-2,5-diene (II) at a pressure of 1000 MPa
gives the corresponding pyridine derivative III in
44% yield (Scheme 1). In the present communication
we demonstrate that the reaction is general and that
the procedure can be extended to a wide series of
1,2,4-triazines.
Among the existing methods for the preparation of
pyridine compounds, transformations of 1,2,4-triazine
ring into pyridine by the action of alkenes and alkynes
are challenging. Specifically, the use of fused 1,2,4-tri-
azines, which have become accessible via tandem SNH
reactions [6–8], attracts interest. In fact, 1,2,4-triazine
ring can be readily modified with nucleophiles, in-
cluding difunctional ones, and subsequent reactions of
fused 1,2,4-triazines could lead to polyfunctional pyri-
dine derivatives which are difficult to obtain by other
methods [9].
With a view to develop a new general method of
synthesis of pyridine derivatives, we examined reac-
tions of bicyclo[2.2.1]hepta-2,5-diene (II) with both
1,2,4-triazines and fused systems based thereon. The
Scheme 1.
N
N
S
N
S
II
N
Cl
Cl
N
III
Ph
Ph
N
I
407

KRAYUSHKIN et al.
408
Table 1. Reaction conditions and yields of 2-(4-chlorophenyl)-5-phenyl[1,3]thiazolo[4,5-b]pyridine (III) from 6-(4-chloro-
phenyl)-3-phenyl[1,3]thiazolo[4,5-e][1,2,4]triazine (I) and bicyclo[2.2.1]hepta-2,5-diene (II)
Temperature, °C
Pressure, MPa
Solvent
Catalyst
Yield of III, %
Unreacted I, %
100
100
150
150
100
150
150
150
150
150
1000
1500
0500
1000
0500
0500
0500
0500
0500
0500
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
–
44
95
56
05
55
14
85
–
–
–
45
–
86
LiClO4
LiClO4
SnOBu2
SnOBu2
–
15
Et2O
98
CH2Cl2
MeCN
MeCN
Et2O
50
22
13
94
42
–
BF3·Et2O
Tarring
effects of various factors (pressure, catalyst, solvent,
reaction time) on the cycloaddition of compound II to
1,2,4-triazines were estimated. High-pressure reactions
were carried out in Teflon ampules using a setup de-
scribed in [20].
The proposed procedure was successfully extended
to fluorine-containing 1,2,4-benzotriazines IVa–IVc.
These compounds reacted with bicyclo[2.2.1]hepta-
2,5-diene (II) to give the corresponding substituted
quinolines Va–Vc (Scheme 2).
The yields of 2-(4-chlorophenyl)-5-phenyl[1,3]-
thiazolo[4,5-b]pyridine (III) formed in the reaction of
6-(4-chlorophenyl)-3-phenyl[1,3]thiazolo[4,5-e]-
[1,2,4]triazine (I) with bicyclo[2.2.1]hepta-2,5-diene
(II) under different conditions are given in Table 1. It
is seen that the use of BF3·Et2O as catalyst promotes
tarring of the reaction mixture. Dibutyltin oxide
showed no appreciable catalytic activity, though it was
successfully used by us previously to catalyze cycload-
dition processes [15]. The most effective catalyst was
lithium perchlorate which is frequently used as catalyst
in Diels–Alder reactions [16]; in our case, it allowed us
to reduce the pressure from 1500 to 500 MPa, the yield
of III remaining comparable. Lower pressure made
it possible to increase the reaction volume. The reac-
tion volume under a pressure ranging from 1000 to
1500 MPa usually does not exceed a few milliliters,
while at a pressure of 500 MPa the reaction volume
can be increased up to 500 ml. Thus lithium perchlo-
rate as catalyst ensured preparation of required
amounts of the target pyridine derivative.
Table 2 contains the conditions of the reaction of
6-ethoxy-7-fluoro-3-phenyl-1,2,4-benzotriazine (IVb)
with bicyclo[2.2.1]hepta-2,5-diene (II) and the yields
of 7-ethoxy-6-fluoro-2-phenylquinoline (Vb) thus
formed. The data in Table 2 indicate that lithium per-
chlorate also facilitates formation of quinoline Vb and
that the reactivity of benzotriazines IV toward bicyclo-
[2.2.1]hepta-2,5-diene (II) is lower than the reactivity
of thiazolotriazine I. Presumably, compounds IV are
less electron-deficient than I. Under the optimal con-
ditions ensuring 98% yield of thiazolopyridine III
(lithium perchlorate, 500 MPa, 150°C, 6 h), the yield
of quinoline Vb was as poor as 12%. The reactions
with benzotriazines IV required more severe condi-
tions, namely higher pressure and longer reaction time.
When the reactions of compounds IVa and IVc with
bicyclo[2.2.1]hepta-2,5-diene (II) were carried out in
the presence of lithium perchlorate at a pressure of
1000 MPa at 165°C, the yields of quinolines Va and
Vc in 48 h attained 80–90%.
The structure of quinolines Va–Vc was proved by
the NMR and mass spectra and elemental analyses. In
the H NMR spectra of Va–Vc, the 3-H proton in
Scheme 2.
1
N
N
F
F
II
N
the quinoline ring resonated as a doublet at δ 7.76–
7.78 ppm with a vicinal coupling constant 3J of 8.6 Hz,
which is typical of ortho protons. The 4-H signal in the
spectrum of Vc appeared at δ 8.08 ppm (3J = 8.6 Hz)
separately from signals of the phenyl protons. The
Ph
OR
Ph
N
OR
IVa–IVc
Va–Vc
R = Me (a), Et (b), i-Bu (c).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 3 2008

SYNTHESIS OF PYRIDINES FROM 1,2,4-TRIAZINES UNDER HIGH PRESSURE
409
Scheme 3.
N
N
N
II
X
X
N
N
N
VIa, VIb
VIIa, VIIb
X = Cl (a), MeO (b).
2-(4-Chlorophenyl)-5-phenyl[1,3]thiazolo[4,5-b]-
pyridine (III). A Teflon ampule was charged with
a mixture of 405 mg (4.4 mmol) of bicyclo[2.2.1]-
hepta-2,5-diene (II), 100 mg (0.31 mmol) of
6-(4-chlorophenyl)-3-phenyl[1,3]thiazolo[4,5-e]-
[1,2,4]triazine (I), and 170 mg (1.7 mmol) of lithium
perchlorate in 10 ml of diethyl ether, and the mixture
was kept for 6 h at 500 MPa on heating to 150°C. The
mixture was then applied to a column charged with
silica gel, and the column was eluted with hexane–
ethyl acetate (3:1). A fraction containing compound
III was collected, the solvent was removed under
reduced pressure, and the residue was recrystallized
from hexane. Yield 96 mg (97%), colorless crystals,
mass spectra of Va–Vc contained the molecular ion
peaks.
The high-pressure procedure implying the use of
lithium perchlorate as catalyst was also effective in
reactions with nonfused triazines. The reactions of tri-
azines VIa and VIb with bicyclo[2.2.1]hepta-2,5-diene
(II) at 1000 MPa (100°C) in 1 h gave 92–96% of the
corresponding pyridines VIIa and VIIb (Scheme 3).
Pyridines VIIa and VIIb were synthesized previously
in comparable yields by heating compounds VIa and
VIb in boiling xylene for 10 h [21].
This we have developed a general procedure for the
synthesis of pyridine derivatives by high-pressure reac-
tion of the corresponding 1,2,4-triazines with bicyclo-
[2.2.1]hepta-2,5-diene in the presence of lithium per-
chlorate.
1
mp 234–235°C. H NMR spectrum, δ, ppm: 7.52 m
(5H, Harom), 7.83 d (1H, pyridine, J = 8.4 Hz), 8.20 m
(4H, Harom), 8.32 d (1H, pyridine, J = 8.4 Hz). 13C NMR
spectrum, δC, ppm: 117.47, 126.63, 126.95, 128.47,
128.57, 128.99, 129.19, 131.25, 132.21, 136.55, 138.08,
155.35, 163.94, 169.43. Mass spectrum, m/z (Irel, %):
324 (36) [M + 2]+, 323 (30) [M + 1]+, 322 (100) [M]+,
185 (63), 158 (10), 153 (31), 141 (33), 115 (32), 106
(14), 77 (20), 43 (25). Found, %: C 67.01; H 3.39;
N 8.70; S 9.96. C18H11ClN2S. Calculated, %: C 66.97;
H 3.43; N 8.68; S 9.93. M 322.81.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker
AM-300 spectrometer from solutions in DMSO-d6.
The mass spectra (electron impact, 70 eV) were ob-
tained on a Kratos instrument with direct sample
admission into the ion source. The melting points were
measured on a Boetius hot stage and were not cor-
rected. The progress of reactions was monitored by
TLC on Silufol UV-254 plates using petroleum ether–
ethyl acetate (1:2) as eluent. Column chromatography
was performed on silica gel (0.060–0.200 mm) from
Acros Organics.
Compounds Va–Vc, VIIa, and VIIb were synthe-
sized in a similar way.
6-Fluoro-7-methoxy-2-phenylquinoline (Va). The
reaction mixture was heated for 10 h at 170°C at
a pressure of 1000 MPa. Yield 68 mg (90%), colorless
Table 2. Reaction conditions and yields of 7-ethoxy-6-fluoro-2-phenylquinoline (Vb) from 6-ethoxy-7-fluoro-3-phenyl-
1,2,4-benzotriazine (IVb) and bicyclo[2.2.1]hepta-2,5-diene (II)
Temperature, °C Pressure, MPa
Solvent
Reaction time, h
Catalyst
Yield of Vb, %
Unreacted IVb, %
110
150
160
150
165
160
0000.0.1
0500
PhMe
Et2O
Et2O
Et2O
Et2O
Et2O
48
06
12
12
48
09
–
–
98
86
70
36
–
LiClO4
LiClO4
LiClO4
LiClO4
LiClO4
12
28
61
92
63
0500
1000
1000
1500
35
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 3 2008

KRAYUSHKIN et al.
410
crystals, mp 118–120°C (from hexane). 1H NMR spec-
trum, δ, ppm: 4.08 s (3H, OCH3), 7.40–7.55 m (4H,
Harom), 7.60 d (1H, 5-H, J = 8.2 Hz), 7.78 d (1H, 3-H,
J = 8.6 Hz), 8.06–8.16 m (3H, Harom). 13C NMR spec-
trum, δC, ppm: 56.24, 110.19, 110.92, 111.30, 117.69,
121.74, 121.92, 127.43, 128.89, 129.30, 135.73, 139.63,
146.44, 149.77, 150.78, 151.06, 154.78, 157.01. Mass
spectrum, m/z (Irel, %): 254 (18) [M + 1]+, 253 (100)
[M]+, 238 (13), 222 (6), 210 (23), 209 (21), 183 (8),
149 (6), 127 (7), 43 (12). Found, %: C 75.81; H 4.73;
F 7.46; N 5.54. C16H12FNO. Calculated, %: C 75.88;
H 4.78; F 7.50; N 5.53. M 253.28 .
268 (35) [M + 2]+, 267 (28) [M + 1]+, 266 (100) [M]+ ,
240 (8), 238 (25), 231 (6), 229 (15), 204 (18), 149
(21), 102 (12), 78 (9), 58 (13), 44 (27). Found, %:
C 72.10; H 4.13; Cl 13.32; N 10.49. C16H11ClN2.
Calculated, %: C 72.05; H 4.16; Cl 13.29; N 10.50.
M 266.73.
5-(4-Methoxyphenyl)-2,2′-bypiridine (VIIb).
Yield 78 mg (92%), colorless crystals, mp 124–126°C
1
(from methanol). H NMR spectrum, δ, ppm: 3.88 s
(3H, OMe ), 7.04 d (2H, Harom, J = 8.7 Hz), 7.32 m
(1H, pyridine), 7.62 d (2H, Harom, J = 8.7 Hz), 7.84 m
(1H, pyridine), 8.00 d (1H, 3-H, J = 8.3 Hz), 8.44 m
(2H, 4-H, pyridine), 8.71 d (1H, pyridine, J = 4.5 Hz),
8.89 s (1H, 6-H). Mass spectrum, m/z (Irel, %): 263
(23) [M + 1]+, 262 (100) [M]+, 248 (23), 247 (51), 220
(10), 219 (31), 192 (10), 191 (12), 149 (8), 78 (9), 58
(7), 43 (17). Found, %: C 77.91; H 5.36; N 10.69.
C16H11ClN2. Calculated, %: C 77.84; H 5.38; N 10.68.
M 262.31.
7-Ethoxy-6-fluoro-2-phenylquinoline (Vb). Yield
66 mg (87%), colorless crystals, mp 112–114°C (from
1
hexane). H NMR spectrum, δ, ppm: 1.59 t (3H, CH3,
J = 7.0 Hz), 4.23 q (2H, OCH2, J = 7.0 Hz), 7.40–
7.55 m (4H, Harom), 7.58 d (1H, 5-H, J = 8.2 Hz),
7.78 d (1H, 3-H, J = 8.5 Hz), 8.05–8.17 m (3H, Harom).
13C NMR spectrum, δC, ppm: 14.63, 64.80, 110.92,
111.29, 117.63, 127.48, 128.92, 129.28, 135.71, 135.82,
139.78, 146.54, 149.99, 150.18, 150.47, 154.99, 157.06.
Mass spectrum, m/z (Irel, %): 268 (8) [M + 1]+, 267
(48) [M]+, 239 (95), 238 (100), 222 (18), 209 (16), 190
(17), 149 (11), 97 (10), 83 (8), 77 (10), 55 (13), 43
(35). Found, %: C 76.41; H 5.29; F 7.04; N 5.17.
C17H14FNO. Calculated, %: C 76.39; H 5.28; F 7.11;
N 5.24. M 267.31.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
nos. 05-03-08077-ofi_a, 07-03-96074a).
REFERENCES
1. Scriven, E.F.V., Toomey, J.E. Jr., and Murugan, R., Kirk–
Othmer Encyclopedia of Chemical Thechnology, New
York: Wiley, 1996, vol. 20, p. 641.
2. Comprehensive Heterocyclic Chemistry II, Katritz-
ky, A.R., Rees, C.W., and Scriven, E.F.V., Eds., Amster-
dam: Elsevier, 1996, vols. 6, 7.
6-Fluoro-7-(2-methylpropoxy)-2-phenylquino-
line (Vc). Yield 58 mg (81%), colorless crystals,
1
mp 65–67°C (from hexane). H NMR spectrum, δ,
ppm: 1.11 d (6H, CH3, J = 6.7 Hz), 2.37 m (1H, CH,
J = 6.7 Hz), 3.98 d (2H, OCH2, J = 6.7 Hz), 7.40–
7.54 m (4H, Harom), 7.58 d (1H, 5-H, J = 8.2 Hz),
7.76 d (1H, 3-H, J = 8.6 Hz), 8.08 d (1H, 2-H, J =
8.6 Hz), 8.12 d (2H, Harom, J = 7.2 Hz). 13C NMR spec-
trum, δC, ppm: 19.24, 28.08, 75.41, 110.90, 111.20,
117.49, 127.42, 128.86, 129.23, 135.63, 135.74, 139.72,
146.48, 150.01, 150.41, 150.69, 155.01, 156.89. Mass
spectrum, m/z (Irel, %): 295 (15) [M]+, 239 (68), 238
(18), 203 (100), 202 (55), 149 (13), 101 (13), 84 (24),
71 (26), 57 (66), 43 (27). Found, %: C 77.17; H 6.09;
F 6.32; N 4.69. C19H18FNO. Calculated, %: C 77.27;
H 6.14; F 6.43; N 4.74. M 295.36.
3. Barker, J.M., Adv. Heterocycl. Chem., 1977, vol. 21,
p. 65.
4. Matsuo, M., Morino, D., and Tsuji, K., US Patent
no. 4885297, 1988; Chem. Abstr., 1989, vol. 111,
no. 77996x.
5. Yamada S.-i., Goto, T., Mashiko, T., Kogi, K., Oguchi, Y.,
and Narita, S., EPV Patent no. 0277701, 1988; Chem.
Abstr., 1988, vol. 110, no. 57654k.
6. Charushin, V.N., Mochulskaya, N.N., Andreiko, A.A.,
Kodess, M.I., and Chupakhin, O.N., Mendeleev Com-
mun., 2002, p. 28.
7. Charushin, V.N., Mochulskaya, N.N., Andreiko, A.A.,
Filyakova, V.I., Kodess, M.I., and Chupakhin, O.N.,
Tetrahedron Lett., 2003, p. 2421.
5-(4-Chlorophenyl)-2,2′-bipyridine (VIIa). The
reaction mixture was heated for 1 h at 110°C under
a pressure of 1000 MPa. Yield 81 mg (96%), colorless
8. Mochul’skaya, N.N., Andreiko, A.A., Kodess, M.I.,
Vasil’eva, E.B., Filyakova, V.I., Gubaidullin, A.T., Litvi-
nov, I.A., Sinyashin, O.G., Aleksandrov, G.G., and Charu-
shin, V.N., Izv. Ross. Akad. Nauk, Ser. Khim., 2004,
p. 1228.
1
crystals, mp 148–149.5°C (from MeOH). H NMR
spectrum, δ, ppm: 7.29 m (1H, pyridine), 7.42 d (2H,
H
arom, J = 8.4 Hz), 7.63 d (2H, Harom, J = 8.4 Hz),
7.85 m (1H, pyridine), 8.02 d (1H, 3-H, J = 8.3 Hz),
8.51 m (2H, 4-H, pyridine), 8.72 d (1H, pyridine, J =
4.5 Hz), 8.91 s (1H, 6-H). Mass spectrum, m/z (Irel, %):
9. Neunhoeffer, H., Comprehensive Heterocyclic Chemistry
II, Katritzky, A.R., Rees, C.W., and Scriven, E.F.V., Eds.,
Amsterdam: Elsevier, 1996, vol. 6, p. 507.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 3 2008

SYNTHESIS OF PYRIDINES FROM 1,2,4-TRIAZINES UNDER HIGH PRESSURE
411
10. Taylor, E.C., J. Org. Chem., 1987, vol. 52, p. 4287.
11. Charushin, V.N., van Veldhuizen, B., van der Plas, H.C.,
17. Sedishev, I.P., Shorunov, S.V., Krayushkin, M.M., Luik-
saar, S.I., and Irie, M., Abstracts of Papers, Vserossii-
skaya konferentsiya “Sovremennye problemy organiche-
skoi khimii” (All-Russian Conf. “Current Problems in
Organic Chemistry), Novosibirsk, June 5–9, 2007,
p. 109.
and Stam, C.H., Tetrahedron, 1989, vol. 45, p. 6499.
12. Charushin, V.N., Alexeev, S.G., Chupakhin, O.N., and
van der Plas, H.C., Adv. Heterocycl. Chem., 1989,
vol. 46, p. 73.
18. Konovalov, A.I. and Kiselev, V.D., Izv. Ross. Akad.
Nauk, Ser. Khim., 2003, p. 279.
13. Chupakhin, O.N., Alexeev, S.G., Rudakov, B.V., and
Charushin, V.N., Heterocycles, 1992, vol. 33, p. 931.
19. Krayushkin, M.M., Yarovenko, V.N., Sedishev, I.P., An-
dreyko, A.A., Mochulskaya, N.N., and Charushin, V.N.,
Mendeleev Commun., 2005, p. 151.
14. Matsumoto, K., Sera, A., and Katsura, H., Heterocycles,
1998, vol. 47, p. 1135.
15. Yarovenko, V.N., Eskov, A.A., Kondrashev, P.A., Igna-
tenko, A.V., Zavarzin, I.V., Vorontsova, L.G., Sedi-
shev, I.P., Krayushkin, M.M., and Starikova, Z.A.,
Heterocycles, 2005, vol. 65, p. 1601.
20. Nikishin, G.I., Spektor, S.S., Shakhovskoi, G.P., Glu-
khovtsev, V.G., and Zhulin, V.M., Izv. Akad. Nauk SSSR,
Ser. Khim., 1976, p. 1664.
21. Kozhevnikov, V.N., Kozhevnikov, D.N., Shabuni-
na, O.V., Rusinov, V.L., and Chupakhin, O.N., Tetra-
hedron Lett., 2005, p. 1791.
16. Krayushkin, M.M., Yarovenko, V.N., Sedishev, I.P.,
Zavarzin, I.V., Vorontsova, L.G., and Starikova, Z.A.,
Russ. J. Org. Chem., 2005, vol. 41, p. 875.
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