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.

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.

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’-bin class="Chemical">pyridines 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 [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 n class="Chemical">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

Table 1

Yields of 5,5’-disubstituted-1,2,4-triazines 2a-e

Comp.	X	Yield (%)	M.p. (°C)	Lit. M.p. (°C)
2a	-SCH3	94	166-167	168.5-170 [12]
2b	-SCH(CH3)2	98	173-174	174-175 [15]
2c	-CH3	67	150-151	151-152 [11]
2d	-OCH3	95	175-176	175-176.5 [12]
2e	-Ph	93	301-302	-

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 n class="Chemical">1-vinylimidazole (3) in boiling bromobenzene to give a single cycloaddition product 5 together with traces of 6,6’-bis(methylsulfanyl)-2,2’-bipyridine (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’-bin class="Chemical">pyridine (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.	X	Reaction time (hrs)	Yield (%)	M.p. (°C)	Lit. M.p. (°C)
6a	-SCH3	30	80	130-131	130-131 [17]
6b	-SCH(CH3)2	26	48	105-106	105-107 [18]
6c	-CH3	25	88	88-89	88-89 [19]
6d	-OCH3	110	59	117-118	118 [20]
6e	-Ph	28	60	175.5-176	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.

Experimental

General

Melting points are uncorrected. IR spectra were measured with a Magna IR-760 spectrophotometer. The 1H-NMR spectra were recorded in n class="Chemical">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 (

A solution of 3-phenyl-1,2,4-triazine (0.87g, 5.54 mmol) in n class="Chemical">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 give analytically pure compound 2e (0.82 g, 95 %) as a yellow solid, m.p. 301-302°C; 1H-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 . 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 n class="Chemical">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.