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

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.

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 [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.

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	-

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 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’-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.	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]

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 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 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 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.