An efficient route to 5-(hetero)aryl-2,4′- and 2,2′-bipyridines through readily available 3-pyridyl-1,2,4-triazines

Article abstract of DOI:10.1016/j.tetlet.2005.01.135

A new route to substituted bipyridines based on a new method for the synthesis of substituted 3-pyridyl-1,2,4-triazines and their aza-Diels-Alder reactions is shown to be an efficient strategy for the preparation of structurally diverse bipyridine ligands.

Full text of DOI:10.1016/j.tetlet.2005.01.135

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1791–1793
An efficient route to 5-(hetero)aryl-2,40- and 2,20-bipyridines
through readily available 3-pyridyl-1,2,4-triazines
Valery N. Kozhevnikov,* Dmitry N. Kozhevnikov, Olga V. Shabunina,
Vladimir L. Rusinov and Oleg N. Chupakhin
Urals State Technical University, Department of Organic Chemistry, Ekaterinburg 620002, Russia
Received 9 December 2004; revised 18 January 2005; accepted 25 January 2005
Abstract—A new route to substituted bipyridines based on a new method for the synthesis of substituted 3-pyridyl-1,2,4-triazines
and their aza-Diels–Alder reactions is shown to be an efficient strategy for the preparation of structurally diverse bipyridine ligands.
Ó 2005 Elsevier Ltd. All rights reserved.
2,20-Bipyridines (bpy) are undoubtedly among the most
widely used ligands in coordination and supramolecular
chemistry.1,2 In particular, the photophysical properties
of their metal complexes are of special interest. It was
shown in numerous studies that the transition metal
bpy complexes find various applications: from catalysis3
and photocatalysis4 to chemosensors5 and luminescent
probes for biomolecular systems.6 Among bipyridines,
5-aryl-2,20-bipyridines (arbpy) exhibit the best lumines-
cent properties with emission quantum yields (Uf) up
to 0.80, due to the effect of the aromatic substituents
making the bipyridines attractive as chromophores and
ÔantennaeÕ.7 Strong fungicidal activity of 5-aryl-2,20-
bipyridines against different plant diseases is another
application to be described.8 However, the study of
these interesting and useful compounds is hampered
by inefficient chemical synthesis. The typical Kroehnke
synthesis was modified to prepare 5-substituted-2,20-
bipyridines giving mixtures of isomers and poor yields.8
Alternative cross-coupling9 approaches are limited by
inaccessible starting compounds.
6-position of the 1,2,4-triazine ring. It should be noted
that 3-pyridyl-1,2,4-triazines are interesting compounds
in their own right due to their application in transition
metal analysis11 or in the separation of lanthanides
and actinides in the management of nuclear waste.12
We devised a new method for the synthesis of 6-aryl-3-
(2-pyridyl)-1,2,4-triazines 2 starting from readily avail-
able acylarenes 3 bearing various substituents on the
aryl moiety, for example, fluoro-, chloro-, bromo-,
methyl-, methoxy- or nitrophenyl. Nitrosation of 3
yielded the corresponding 1-aryl-2-oximino-1-ethanones
4, then treatment with hydrazine hydrate resulted in the
formation of 1-aryl-1-hydrazono-2-oximinoethanes 5 in
good yields. Condensation of hydrazones 5 with pyri-
dine-2-carboxaldehyde gave 1-aryl-2-oximino-1-(2-pyr-
idylmethylenehydrazono)ethanes 6 in excellent yields.
The open-chain compounds 6 exist in equilibrium with
the cyclic 6-aryl-4-hydroxy-3-(2-pyridyl)-3,4-dihydro-
1,2,4-triazines 7 (the ring-chain isomerism of 4-hydro-
xy-3,4-dihydro-1,2,4-triazines is described elsewhere13).
Dehydration of the dihydrotriazines 7 after brief reflux-
ing in acetic acid yielded the aromatic pyridyltriazines 2.
The aryl substituents of the starting ketones 3 appear ex-
actly at the defined 6-position of the 1,2,4-triazines 2 and
not the 5-position as in 1,2,4-triazine synthesis from
arylglyoxals.14 Isolation of the intermediates 6 and 7
from the reaction mixtures can be omitted to make the
synthetic procedure easier.15
In this letter we report an efficient strategy for the syn-
thesis of 5-(hetero)aryl-2,20-bipyridines 1 based on the
conversion of 3-(2-pyridyl)-1,2,4-triazines to substituted
bpys via an aza-Diels–Alder reaction.10 The key-stepof
our strategy is the regiospecific and easy synthesis of 3-
pyridyl-1,2,4-triazines bearing an aryl substituent at the
Conversion of triazines 2 to arbpys 1 was achieved by
aza-Diels–Alder reactions with a strained dienophile—
2,5-norbornadiene—following a typical procedure.10
Keywords: Bipyridines; Polypyridines; 1,2,4-Triazines; Ligands.
*
Corresponding author. Tel.: +7 343 3754501; fax: +7 343
3740458; e-mail: dnk@htf.ustu.ru
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.135

1792
V. N. Kozhevnikov et al. / Tetrahedron Letters 46 (2005) 1791–1793
Ar
N
N
Ar
N
N
OH
5a-j
Ar
N
N
Ar
O
iv
Ar
O
N
NH2
N
i
ii
iii
93-98%
H
N
N
65-85%
50-70%
N
OH
4a-j
55-70%
OH
OH
3a-j
6a-j
7a-j
Ar
N
Ar
N
v
N
N
85-95%
N
N
2a-j
1a-j
vi
70-90%
N
Ar = C6H5 (a), 4-CH3-C6H4 (b),
4-CH3O-C6H4 (c), 4-F-C6H4 (d),
4-Cl-C6H4 (e), 4-Br-C6H4 (f),
4-NO2-C6H4 (g), 4-pyridyl (h),
2-pyridyl (i), 2-thienyl (j)
Ar
N
8h
Scheme 1. Reagents and conditions: (i) i-PrONO, EtONa, EtOH, 10 °C, then AcOH; (ii) N2H4–H2O, EtOH, rt; (iii) pyridine-2-carboxaldehyde,
EtOH; (iv) AcOH, reflux; (v) 2,5-norbornadiene, xylene, reflux, 8–15 h; (vi) morpholinocyclopentene, dioxane, reflux.
The reaction proceeded slowly and at high temperature
(refluxing in xylene) to give 5-aryl-2,20-bipyridines 1 in
high yields.
Starting from acylheteroarenes, for example, acetylthio-
phene, 2- or 4-acetylpyridines, 3-(2-pyridyl)-1,2,4-tri-
azines 2h–j15 bearing heteroaromatic substituents at
the 6-position were obtained by this method. Next, the
cycloaddition stepgave 5-heteroaryl-2,2 0-bipyridines
1h–j.16
Additional substituent diversity was achieved using ene-
amines as dienophiles in inverse electron demand aza-
Diels–Alder reactions17,18 Pyridyltriazine 2h reacted
Scheme 2. Reagents and conditions: (iv) AcOH, reflux; (v) 2,5-
norbornadiene, xylene, reflux.
with morpholinocyclopentene more readily than with
norbornadiene (refluxing in dioxane instead of xylene)
yielding 8h possessing a fused five-membered ring
(Scheme 1).19
In conclusion it should be noted, that the good yields of
all intermediates and final products, multi-gram scale,
cheapand accessible starting compounds and relatively
easy experimental procedure make these substituted
bipyridines readily available compounds. Substituent
diversity is achieved by variation of three independent
components: the acyl(hetero)arenes, dienophiles and
pyridinecarboxaldehyde.
Finally, the arbpys diversity could be extended by vary-
ing the substituents in the starting pyridinecarboxalde-
hydes, for example, 5-tolyl-60-hydroxymethyl-2,20-
bipyridine 9b was obtained from 6-hydroxymethylpyr-
idine-2-carboxaldehyde (Scheme 2).
Not only 2,20- but 2,40-bipyridines could be obtained
by our method. The condensation of pyridine-4-carbox-
aldehyde with hydrazones 5 followed by dehydration
of the intermediates resulted in the formation of 6-aryl-
3-(4-pyridyl)-1,2,4-triazines 10, then refluxing with nor-
bornadiene yielded 5-aryl-2,40-bipyridines 11 (Scheme
2).
Acknowledgements
The authors thank the Russian Foundation for Basic
Researches (grant no. 04-03-96106) for financial
support.
It is noteworthy, that the reactions could be easily scaled
upto produce multi-gram quantities of arbpys
1 (we
obtained 5 g of the arbpy 1b from one operation). The
relatively harsh conditions (long time (upto 15 h) and
high temperatures (refluxing in xylene) of the reaction
with norbornadiene did not affect the yields or purities
of the arbpys 1.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.01.135.

V. N. Kozhevnikov et al. / Tetrahedron Letters 46 (2005) 1791–1793
1793
with water and recrystallized from ethanol to afford a
yellow crystalline solid (2.66 g, 68%), mp193–194 °C, H
References and notes
1
NMR (250 MHz, DMSO-d6): d = 7.64 (ddd, 1H, J 7.5,
4.7, 1.1 Hz), 8.09 (ddd, 1H, J 7.8, 7.8, 1.8 Hz), 8.26 (m,
2H), 8.52 (br d, 1H, J 7.9 Hz), 8.85 (m, 3H), 9.65 (s, 1H);
C13H9N5 (235.25) calcd C, 66.37; H, 3.86; N, 29.77. Found
C, 66.40; H, 3.91; N, 29.69.
1. von Zelewsky, A. Stereochemistry of Coordination Com-
pounds; Wiley: Chichester, 1996.
2. Constable, E. C. In Comprehensive Supramolecular Chem-
istry; Lehn, J.-M., Ed.; Pergamon, 1996; Vol. 9, pp 213–252.
3. Chelucci, G.; Thummel, R. P. Chem. Rev. 2002, 102, 3129–
3170.
4. Ziessel, R. In Photosensitization and Photocatalysis Using
Inorganic and Organic Compounds; Kalyanasundaram,
K., Gra¨tzel, M., Eds.; Kluwer Academic: Dordrecht,
1993, pp 217–246.
5. Keefe, M. H.; Benkstein, K. D.; Hupp, J. T. Coord. Chem.
Rev. 2000, 205, 201–228.
6. Saha, A. K.; Kross, K.; Kloszewski, E. D.; Upson, D. A.;
Toner, J. L.; Snow, R. A.; Black, C. D.; Decai, V. C.
J. Am. Chem. Soc. 1993, 115, 11032–11033.
7. Loren, J. C.; Siegel, J. S. Angew. Chem., Int. Ed. 2001, 40,
754–757.
8. Kelly-Basetti, B. M.; Cundy, D. J.; Pereira, S. M.; Sasse,
W. H. F.; Savage, G. P.; Simpson, G. W. Bioorg. Med.
Chem. Lett. 1995, 5, 2989–2992.
16. 5-(4-Pyridyl)-2,20-bipyridine 1h. A mixture of 3-(2-pyr-
idyl)-6-(4-pyridyl)-1,2,4-triazine 2h (730 mg, 3.1 mmol),
bicyclo[2.2.1]hepta-2,5-diene (1.58 mL, 15.5 mmol) and
o-xylene (30 mL) was refluxed for 10 h and cooled to
room temperature. The resulting precipitate was filtered
off, washed with benzene and dried to give the title
product (638 mg, 88%), mp 185–187 °C, 1H NMR
(250 MHz, DMSO-d6): d = 7.48 (ddd, 1H, J 7.6, 4.9,
1.2 Hz), 7.85 (m, 2H), 7.98 (ddd, 1H, J 7.9, 7.9, 1.8 Hz),
8.37 (dd, 1H, J 8.2, 2.1 Hz), 8.45 (m, 1H), 8.52 (dd, 1H,
J 8.2, 0.6 Hz), 8.70 (m, 3H), 9.13 (dd, 1H, J 2.1, 0.6 Hz);
C15H11N3 (233.28) calcd C, 77.23; H, 4.75; N, 18.01.
Found C, 77.25; H, 4.72; N, 17.96.
17. Rykowski, A.; Branowska, D.; Kielak, J. Tetrahedron
Lett. 2000, 41, 3657–3658.
18. Kozhevnikov, V. N.; Kozhevnikov, D. N.; Nikitina, T. V.;
Rusinov, V. L.; Chupakhin, O. N.; Zabel, M.; Koenig, B.
J. Org. Chem. 2003, 68, 2882–2888.
9. Thompson, A. C. Coord. Chem. Rev. 1997, 160, 1–52.
10. Pabst, G. R.; Pfuller, O. C.; Sauer, J. Tetrahedron 1999,
55, 8045–8064.
11. Croot, P. L.; Hunter, K. A. Anal. Chim. Acta 2000, 406,
289–295.
12. Kolarik, Z.; Mullich, U.; Gassner, F. Solvent Extr. Ion
Exch. 1999, 17, 23–32.
13. Kozhevnikov, D. N.; Rusinov, V. L.; Chupakhin, O. N. In
Adv. Heterocycl. Chem.; Katritzky, A. R., Ed.; Academic,
2002; Vol. 82, pp 261–305.
14. Neunhoeffer, H. In Comp. Heterocycl. Chem. II; Katrizky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon:
Oxford, 1996; Vol. 6, pp 50–574.
15. 3-(2-Pyridyl)-6-(4-pyridyl)-1,2,4-triazine 2h. To a solution
of 1-hydrazono-2-oximino-1-(4-pyridyl)ethane 5h (2.74 g,
16.7 mmol) in AcOH (10 mL) was added 2-pyridinecar-
boxaldehyde (1.79 g, 16.7 mmol). The mixture was stirred
at room temperature for 1 h, heated to reflux, allowed to
cool to room temperature and then diluted with water
(10 mL). The resulting precipitate was filtered off, washed
¨
19. 2-(2-Pyridyl)-5-(4-pyridyl)cyclopenteno[c]pyridine 8h.
A
mixture of 3-(2-pyridyl)-6-(4-pyridyl)-1,2,4-triazine 2h
(400 mg, 1.7 mmol), 1-morpholinocyclopentene (0.3 mL,
287 mg, 1.8 mmol) and 1,4-dioxane (20 mL) was refluxed
for 24 h. Then acetic acid (2 mL) was added and the
reaction mixture was heated at reflux for 1 h, cooled to
room temperature and made basic with an aqueous
solution of NaOH (1 M, 50 mL). The resulting precipitate
was filtered, washed with water and recrystallized from
ethanol–water (1:1) to give the titled compound (320 mg,
79%), mp154–155 °C, 1H NMR (250 MHz, DMSO-d6):
d = 2.02 (p, 2H, J 7.6 Hz), 3.04 (t, 2H, J 7.6 Hz), 3.43 (t,
2H, J 7.6 Hz), 7.42 (ddd, 1H, J 7.3, 4.9, 1.2 Hz), 7.61 (m,
2H), 7.94 (ddd, 1H, J 7.9, 7.9, 1.8 Hz), 8.31 (ddd, 1H, J
7.9, 0.9, 0.9 Hz), 8.59 (s, 1H), 8.70 (m, 3H); C18H15N3
(273.34) calcd C, 79.10; H, 5.53; N. 15.37. Found C, 79.15;
H, 5.42; N, 15.36.