A direct route to 6,6′-disubstituted-2,2′-bipyridines by double Diels-Alder/retro Diels-Alder reaction of 5,5′-bi-1,2,4-triazines

Article abstract of DOI:10.3390/10010274

Inverse electron demand Diels-Alder reaction of functionalized 5,5′-bi-1,2,4-triazines with bicyclo[2.2.1]hepta-2,5-diene in boiling p-cymene leads to a range of 6,6′-disubstituted-2,2′-bipyridines in good yield.

Full text of DOI:10.3390/10010274

Molecules 2005, 10, 274-278
molecules
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A Direct Route to 6,6’-Disubstituted-2,2’-Bipyridines by Double
Diels-Alder/retro Diels-Alder Reaction of 5,5’-bi-1,2,4-Triazines†
Danuta Branowska*
Institute of Chemistry, University of Podlasie, ul. 3 Maja 54, PL-08-110 Siedlce, Poland;
Fax:(+48) 25-644-2045
*Author to whom correspondence should be addressed; e-mail: dankab@ap.siedlce.pl
† Part 29 in 1,2,4-Triazines in Organic Synthesis; for Part 28, see [1]
Received: 5 September 2004; in revised form: 3 January 2005 / Accepted: 3 January 2005 / Published:
31 January 2005
Abstract: Inverse electron demand Diels-Alder reaction of functionalized 5,5’-bi-1,2,4-
triazines with bicyclo[2.2.1]hepta-2,5-diene in boiling p-cymene leads to a range of 6,6’-
disubstituted-2,2’-bipyridines in good yield.
Keywords: 5,5’-bi-1,2,4-triazines, norbornadiene, Diels-Alder reaction
Introduction
2,2’-Bipyridine is one of the most widely used ligands in coordination and supramolecular
chemistry [2]. Particularly interesting and useful are its 5,5’- and 6,6’-disubstituted derivatives in view
of their numerous applications in the construction of many larger supramolecular species [3]. The
preparation of 6,6’-disubstituted-2,2’-bipyridines is generally allowed by the extension of Ullmann
procedure involving Ni- or Pd- catalyzed homo-coupling reactions of the corresponding 6-substituted-
2-halopyridines [4]. Despite their efficiency, these methods have been most widely investigated with
2-bromo-6-methylpyridine [5]. Other derivatives bearing different end groups were obtained by the
further functionalization of substitutes, i.e., methyl or bromine in the combined pyridine rings [5], by
using extrusion procedures involving organophosphorus [6] and organosulfur [7] compounds, or via
ring transformation reactions of bis(triazolo)pyridines [8]. More recent approaches employ the
intermolecular Diels-Alder/retro Diels-Alder (DA-rDA) reaction of 3- or 5-(2-pyridyl)-1,2,4-triazines

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[9] or 5,5’-bi-1,2,4-triazines 2 [10]. Previous studies in this laboratory have shown that the latter
compounds are excellent substrates for the synthesis of symmetrical cycloalkeno[c]fused 2,2’-
bipyridines by the DA-rDA reaction of 2 with cyclic enamines [11]. Now we show that intermolecular
DA-rDA reactions of 3,3’-disubstituted-5,5’-bi-1,2,4-triazines 2a-e with appropriate dienophiles
provide ready access to the symmetrical 6,6’-disubstituted-2,2’-bipyridines 6a-e.
Results and Discussion
The variously substituted 5,5’-bi-1,2,4-triazines 2a-e were prepared using a modified literature
procedure [12], namely the direct dimerization of 3-substituted-1,2,4-triazines 1 (available in
multigram quantities by condensation reactions staring from glyoxal and the corresponding
carbamidrazones [13] or N-alkylthiosemicarbazones [13, 14]), with a 1.5 molar excess of potassium
cyanide in water. The highest yields of the 5,5’-bi-1,2,4-triazines 2a-e were obtained when the
reactions were carried out at room temperature for 1 hour. The bitriazines 2a-e were isolated by
extraction with chloroform, and then used in crude form for the synthesis of 2,2’-bipyridines 6a-e
(Scheme 1, Table 1).
Scheme 1
N
N
N
N
N
3
N
N
N
X
6
+ traces of
+ traces of
N
X
N
X
-N2
N
N
N
N
N
X
5
6
X
2
1
4
_
5
_
N2
N
N
X
X
X = SCH3, SCH(CH3)2, CH3, OCH3, Ph
Table 1. Yields of 5,5’-disubstituted-1,2,4-triazines 2a-e
Comp.
2a
X
-SCH3
-SCH(CH3)2
-CH3
-OCH3
-Ph
Yield (%) M.p. (ºC)
Lit. M.p. (ºC)
168.5-170 [12]
174-175 [15]
151-152 [11]
175-176.5 [12]
-
94
98
67
95
93
166-167
173-174
150-151
175-176
301-302
2b
2c
2d
2e
It has been shown previously that 3,3’-bis(methylsulfanyl)-5,5’-bi-1,2,4-triazine (2a, X=SCH3)
undergoes the regiospecific DA-rDA reaction with 1-vinylimidazole (3) in boiling bromobenzene to
give a single cycloaddition product 5 together with traces of 6,6’-bis(methylsulfanyl)-2,2’-bipyridine

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Molecules 2005, 10
(6a) [16]. The reaction took a different course during microwave irradiation of the reaction mixture.
Under these conditions the proportion of compound 6a increased considerably and bipyridine 6a was
obtained in 35% yield when the reaction mixture was irradiated for 4 hrs at 150˚C. Attempts to
increase the cycloaddition yields failed, even when longer times are used. In our search for a more
effective route to 6a, we explored the DA-rDA reaction between 2a and bicyclo[2.2.1]hepta-2,5-diene
(4), which can be considered as an acetylene equivalent. When this dienophile was used instead of
1-vinylimidazole (3), a mixture was obtained that contained compound 6a as its major component. In
order to optimize this step, a variety of solvents were tested under various conditions. The progress of
the reaction was followed on TLC after workup of an aliquot. The highest yield of 6,6’-bis(methyl-
sulfanyl)-1,2,4-triazine (6a), isolated by column chromatography from the reaction mixture, was
obtained when the reaction was carried out in p-cymene at 170 ˚C. The utility of this reaction was
further demonstrated by the one step synthesis of a range of 6,6’-disubstituted 2,2’-bipyridines 6b-e
(Scheme 1).
The treatment of sterically crowded 2b with 4 under the same reaction conditions affords 6b in
reasonable yield. The extension of this study by using 3,3’-bis(methyl)- (2c) and 3,3’-bis(methoxy)-
(2d) -5,5’-bi-1,2,4-triazines clearly showed the generality of this ring transformation process, since the
2,2’-bipyridines 6c and 6d were obtained in good to moderate yields. The formation of 6,6’-
bis(methoxy)-2,2’-bipyridine (6d) was less favorable, and more time for its completion was required
than the reaction which yielded methyl or methylsulfanyl derivatives. 3,3’-Bis(phenyl)-5,5’-bi-1,2,4-
triazine (2e) also reacted smoothly with 4, affording 2,2’-bipyridine (6e), respectively. Table 2 shows
the reaction conditions, yields and melting points of compounds 6a-e.
Table 2. Reaction times and yields of 6,6’-disubstituted-2,2’-bipyridines 6a-e
Comp.
6a
X
-SCH3
-SCH(CH3)2
-CH3
-OCH3
-Ph
Reaction time (hrs)
Yield (%) M.p. (ºC) Lit. M.p. (ºC)
30
26
25
110
28
80
48
88
59
60
130-131
105-106
88-89
117-118
175.5-176
130-131 [17]
105-107 [18]
88-89 [19]
118 [20]
6b
6c
6d
6e
176-177 [21]
Conclusions
In summary, we described a new, simple method of gaining access to 6,6’-disubstituted 2,2’-
bipyridines 5, which are valuable components for the construction of larger supramolecular species.
Acknowledgments
The author is grateful to Prof. Andrzej Rykowski of the University of Podlasie for fruitful
discussions.

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Molecules 2005, 10
Experimental
General
Melting points are uncorrected. IR spectra were measured with a Magna IR-760
1
spectrophotometer. The H-NMR spectra were recorded in deuteriochloroform on a Varian-Gemini
200 MHz spectrometer. Mass spectra were measured with an AMD 604 (AMD Intectra GmbH,
Germany). Column chromatography was performed on silica gel (230-400 mesh, 60 Merck). All the
solvents used were dried and distilled according to standard procedures [22]. Merck 60F254 plates were
used for analytical (TLC) chromatography.
Typical procedure: Preparation of 3,3’-Bis(phenyl)-5,5’-bi-1,2,4-triazine (2e)
A solution of 3-phenyl-1,2,4-triazine (0.87g, 5.54 mmol) in water (50 mL) was stirred until
complete dissolution. An excess of KCN (0.54 g, 8.31 mmol, 1.5 eq) was then added as a solid in 5
portions. A precipitate (intensively colored) was formed immediately. The reaction mixture was
extracted with chloroform (30 x 20 mL). The combined organic extracts were dried over MgSO4, then
filtered and concentrated in vacuo. The crude product was purified by recrystallization from ethanol to
1
give analytically pure compound 2e (0.82 g, 95 %) as a yellow solid, m.p. 301-302˚C; H-NMR δ:
.
7.62-7.65 (m, 6 H), 8.68-8.73 (m, 4 H), 10.36 (s, 2 H); Anal. Calcd for C18H12N6 0.25 H2O: C, 67.96;
H, 4.19; N, 26.23. Found: C, 68.25; H, 3.95; N, 26.54.
The synthesis of 6,6’-disubstituted-2,2’-bipyridines 6a-e. General procedure.
The solution of the corresponding 3,3’-disubstituted-5,5’-bi-1,2,4-triazine (1 mmol) in p-cymene
(10 mL) and bicyclo[2.2.1]hepta-2,5-diene (10 eq) was heated at reflux (for the reaction times see
Table 2). The crude products were purified by column chromatography on silica gel (Merck type 60,
230-400 mesh), using a 10:1 hexane-chloroform mixture as eluent, followed by recrystallization from
ethanol to give compounds 6a-e as white solids.
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Sample Availability: Available from the author.
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