A convenient synthesis of 5,5′-bi-1,2,4-triazines via direct S-arylation and its application in the synthesis of 2,2′-bipyridines

Introduction

Arylthio and heteroarylthio moieties are present in a large number of molecules, which are useful polymeric materials and pharmaceutical compounds. For this reason, the development of efficient S-arylation methods is an important topic. Our research is focused on the synthesis of 3/6-arylthio and 3/6-heteroarylthio-substituted 5,5′-bi-1,2,4-triazines. Known methods of synthesis of such sulfides are rather limited. One approach involves the preparation of monomeric S-substituted 1,2,4-triazine [1] followed by its dimerization [2–4]. Several examples of arylthio- and heteroarylthio-substituted 5,5′-bi-1,2,4-triazines have also been reported by our group [5, 6].

Results and discussion

The treatment of 3,3′-dichloro-5,5′-bi-1,2,4-triazine [7] with benzenethiol in the presence of the equivalent amount of K₂CO₃ in DMSO at ambient temperature furnished the target product, 3,3′-bis(phenylthio)-5,5′-bi-1,2,4-triazine, 2a, in 80% yield (Scheme 1). The 2-pyridyl analog 2b was prepared in a similar way in 90% yield by using 2-pyridinethiol. As shown below, these compounds are important intermediates for the synthesis of thio-substituted 2,2′-bipyridines where the sulfur atoms provide additional sites for metal ion complexation. The X-ray diffraction analysis of 2b confirmed its molecular structure. The view of the molecule and the numbering scheme of the ring atoms are shown in Figure 1. The bond lengths and angles of the triazine and pyridine rings with their thio spacer are in normal ranges [8]. The X-ray analysis of 2b shows that the central bis[1,2,4]triazine moiety adopts the s-anti conformation with respect to the central single C5-C5′ bond. The two 3-(2-pyridylthio) substituents are anti to each other. The 1,2,4-triazine rings are planar to within 0.021(4) Å and the C5-C5′ bond length is 1.485(6) Å, being in good agreement with the corresponding value of 1.4813(7) Å in the related structure of 3,3′-dimethyl-5,5′-bis(1,2,4-triazine) [9]. The conformation of the 3-(2-pyridylthio) substituents are described by the torsion angles N2-C3-S1-C12 and C3-S1-C12-N11 of -2.7(3)° and -92.3(3)°, respectively. These torsion angles indicate that the planar pyridine rings are situated nearly perpendicular to within 0.009(4) Å to the bi-1,2,4-triazine system. The molecular packing in the crystal of 2b is determined by van der Waals forces alone. The molecules form molecular layers that are parallel to the (101) crystallographic plane (Figure 2). The distance between the centers of adjacent layers is approximately 4.63 Å.

Scheme 1

Figure 1

A view of the X-ray molecular structure of 2b with atomic labeling. Non-H atoms are represented by displacement ellipsoids of 30% probability.

Figure 2

A view of the molecular packing in crystal of 2b.

In the study focused on the synthesis of bis-sulfides of 2,2′-bipyridine, we used our experience in Diels-Alder reaction [10–12]. Previously, we have reported the Diels-Alder reaction of dimeric 1,2,4-triazines bearing the methylthio or isopropylthio group with a dienophile as a method for obtaining various substituted 2,2′-bipyridine derivatives in good yield. In this work, we show that the Diels-Alder reaction between 5,5′-bi-1,2,4-triazines 2a,b and a dienophile is regioselective. Thus, the symmetrical substituted 2,2′-bipyridines 3a,b were produced in one step by a double [4+2]-cycloaddition/retro-cycloaddition reaction of 2a,b with N-cyclopent-1-en-pyrrolidine upon heating in a Carius tube for 24 h at 100°C (Scheme 2). The respective compounds 3a,b were obtained in 56% and 31% yield as annulated symmetrical 2,2′-bipyridine. In a similar way, the reactions of 2a,b with norbornadiene as the acetylene furnished the products 4a,b in 62% [5] and 44% yields.

Scheme 2

The bromo-substituted 5,5′-bi-1,2,4-triazine 5 was also allowed to react with benzenethiolate or 2-pyridinethiolate anion to give the expected product 5a or 5b, respectively (Scheme 3). The yields, apparently for steric reasons, were only 70% and 54%.

Scheme 3

Conclusion

A useful and efficient procedure for the preparation of arylthio- and heteroarylthio-substituted 5,5′-bi-1,2,4-triazines in good yield via a classical nucleophilic substitution reaction was developed. This protocol was tested with two thiols. The synthesized compounds undergo Diels-Alder reaction to give symmetrical 2,2′-bipyridine containing arylthio or heteroarylthio substituents.

Experimental

Melting points are uncorrected. ¹H and ¹³C NMR spectra were recorded at 400 MHz and 100 MHz, respectively, on a Varian Gemini spectrometer. Mass spectra were obtained using AMD 604 (AMD Intectra GmbH, Germany) and GC/MS QP 5050 Shimadzu (30 m × 0.25 mm ID-BPX 5 0.25 mm) spectrometers. The elemental analyses were recorded on Perkin-Elmer 2400-CHN. Thin layer chromatography (TLC) was carried out on aluminum sheets coated with silica gel 60 F₂₅₄ (Merck). Column chromatography separations were performed using Merck Kieselgel 60 (0.040–0.060 mm). Solvents were dried and distilled according to standard procedures. All reagents were purchased from Aldrich and used as received.