Synthesis of Unsymmetrical Annulated 2,2’-Bipyridine Analogues with Attached Cycloalkene and Piperidine Rings via Sequential Diels-Alder Reaction of 5,5’-bi-1,2,4-triazines†

Synthesis of bisfunctionalized unsymmetrical 2,2’-bipyridines 8 or their sulfonyl derivatives 12a,b are described. They were prepared via the Diels-Alder reaction of 1‑methyl-4-pyrrolidin-1-yl-1,2,3,6-tetrahydropyridine (6) with 3,3’-bis(methyl-sulfanyl)-5,5’-bi-1,2,4-triazine (1). The reaction leads to the single cycloaddition product 7 which undergoes Diels-Alder reaction with cyclic enamines 2a,b to give unsymmetrical 2,2’-bipyridine derivatives 8, consisting of the two different heterocyclic units: cycloalkeno[c]pyridine and 2,6-naphthyridine.


Results and Discussion
This paper describes the extension of the method to the synthesis of annulated 2,2'-bipyridine analogues 8, consisting of the two different heterocyclic units -2,6-naphthyridine and cycloalkeno[c]pyridine (Scheme 2). The preparation of such compounds could involve the regiospecific conversion of the parent 3,3'-bis(methylsulfanyl)-5,5'-bi-1,2,4-triazine (1) to the single cycloaddition product 7 and the subsequent treatment of the latter with the cyclic enamine 2a,b (route a), or alternatively, the IDA reaction of the easily accessible 3a,b with the appropriate dienophile 6 (route b).
Compound 7 was obtained via the single step [4+2]cycloaddition/retro cycloaddition reaction of easily available compound 1 [16] with 1-methyl-4-pyrrolidin-1-yl-1,2,3,6-tetrahydropyridine (6). The reaction was carried out with 1.5 molar excess of 6 in the boiling dioxane for 1h. The product 7 precipitated from the crude reaction mixture in 92 % yield. In the reaction of 1 with 6 the formation of two isomeric 2,6-or 2,7-tetrahydronaphthyridine derivatives can be anticipated considering it involves the use of an unsymmetric enamine. However, the reaction gives only one reaction product in the excellent yield. Its 1 H-NMR spectrum exhibited two signals of isolated aromatic protons at δ=9.97 and δ=7.94 ppm respectively. The former signal belongs to 1,2,4-triazine and the latter one is attributed to the pyridine hydrogen. The separate signal of isolated methylene group appears at δ=3.65, and the multiplet at δ=2.77 can only corresponds to four vicinal hydrogens in saturated pyridine ring. Nuclear Overhauser Enhancement difference spectroscopy provided an unambigous assignment for this compound. It was found that irradiation of a proton in aromatic pyridine ring (δ=7.94 ppm) led to significant NOE for the signal of the isolated methylene group in the saturated pyridine ring (δ=3.65). These results and the lack of such interactions with the multiplet at δ=2.77 provide evidence for spatial closeness of the pyridine hydrogen and CH 2 and confirm the 2,6-tetrahydronaphthyridine derivative structure of 7. Heating 7 with an excess of 1-pyrrolidino-1-cyclopentene (2a, n=1) at 100 ºC for 15 hours gives annulated 2,2'-bipyridine dihydroanalogue 8'a as a reaction intermediate. The latter is simply converted into 8a by heating with acetic acid in boiling toluene for 1 hour. Using less reactive 1-pyrrolidino-1-cyclohexene (2b, n=2) [11] and the similar reaction conditions, the annulated 2,2'bipiridine analogue 8b with a cyclohexene ring attached is prepared in low yield, while the corresponding pyrrolidino derivative 9 is obtained as a main product. This compound is also obtained by treatment of 3,3'-bis(methylsulfanyl)-5,5'-bi-1,2,4-triazine (1) with an excess of 6 without solvent at 100 °C. Compound 9 is obviously formed by conventional nucleophilic replacement of methylsulfanyl group in 1,2,4-triazine part of 7. The single annulation products 3a (n=1) and 3b (n=2) undergo to small extent Diels-Alder reaction with 1-methyl-4-pyrrolidin-1-yl-1,2,3,6-tetrahydro-pyridine (6) to yield compounds 8a and 8b in low yield. Reaction of such derivatives has been found to result in a rather nucleophilic substitution of methylsulfonyl group in 3a and 3b giving compounds 10a and 10b respectively ( Table 1). These results suggest that compound 6 is less reactive and less stable as a dienophile in comparison to cycloalkeno derived enamines 2a and 2b.
In order to help us better characterize the cycloaddition reactions of 3a,b with 6 as well as cyclic enamines 2a,b with 7, we calculated the energy differences (∆E) between the LUMO of diene and HOMO of dienophile, using the AM1 semiempirical method [17]. The results are presented in Table 2. A better orbital overlap should be obtained between the HOMO orbital of cyclic enamines 2a,b and the LUMO orbital of the 7 than in combination of 1-methyl-4-pyrrolidin-1-yl-1,2,3,6-tetrahydropyridine 6 with 3a,b because the energy gaps are smaller and range from 0.02 to 0.05 eV. From the above data it is clear that compounds 3a,b are not suitable intermediates for the synthesis of bipyridine derivatives 8a,b. It is well known however that introduction of electron-withdrawing substiuents increases deficiency in the 1,2,4-triazine ring and enhances its reactivity in Diels-Alder reaction [12]. We have therefore explored the reaction between 6 and methylsulfonyl derivatives 11a,b, easily available by oxidation of 3a,b with KMnO 4 under phase transfer catalysis conditions [18] (Scheme 3). The reaction of 11a,b with heterocyclic enamine 6 is complete within 1 hour at room temperature leading to unsymmetrical annulated 2,2'-bipyridine analogues 12a and 12b in good yield (Scheme 3).

Conclusions
In summary, we have developed a new route to unsymmetrical annulated 2,2'-bipyridine analogues with cycloalkene and piperidine rings attached bearing alkylsulfanyl and alkylsulfonyl groups in both pyridine rings. The presence of such leaving groups makes these compounds attractive as building blocks for the synthesis of macrocycles.

Acknowledgments
The author is grateful to Prof. Andrzej Rykowski of the University of Podlasie for fruitful discussions and to Dr. Zbigniew Karczmarzyk for the calculations using the AM1 semiempirical method.