1,3-dipolar Cycloaddition of Pyridynes and Azides: Concise Synthesis of Triazolopyridines

1,3-Dipolar cycloaddition of pyridynes and organic azides was investigated. Thus, 3,4-pyridynes and 2,3-pyridynes were reacted with various organic azides under mild conditions to afford the corresponding [1,2,3]triazolo[4,5-c]pyridines and [1,2,3]triazolo[4,5-b]pyridines, respectively. In the case of the reaction of 3,4-pyridyne, it was also found that a substituent on pyridine ring affected the regioselectivity of the cycloaddition. Benzyne has been recognized as a unique synthon in organic synthesis, and numerous examples of transformations of benzyne into useful organic compounds have been demonstrated. Pyridynes, nitrogen-containing analogs of benzyne, are also attractive synthetic units for the synthesis of poly-substituted pyridine derivatives. However, in contrast to extensive studies on benzyne chemistry, synthetic utilization of pyridynes has been limited. Therefore, the development of a new method for transformation of pyridyne remains a frontier in recent organic synthesis. In this context, we have reported synthesis of isoquinoline derivatives through nickel-catalyzed [2+2+2] cycloaddition of 3,4-pyridines and diynes, in which the triple bond in 3,4-pyridyne was utilized as a reactive alkyne. Furthermore, we also demonstrated a new synthetic approach to pyridodiazepines, pyridodiazocines and pyridooxazepines via addition of cyclic ureas or N-methyloxazolidinone to 2,3or 3,4-pyridynes. 1,3-Dipolar cycloaddition of azides and alkynes has been established as a powerful and efficient methodology for the synthesis of triazole derivatives in modern organic chemistry. Benzyne could also be employed as a 1,3-dipolarophile to give benzotriazole derivatives, and a number of examples of benzotriazole synthesis by this reaction have been reported. On the other hand, there are only a few examples of 1,3-dipolar cycloaddition of pyridyne, and there has been no examples in which azide was as a 1,3-dipolar reagent. Based on the above background, we envisaged that if the 1,3-dipolar cycloaddition of 3,4-pyridyne (1) and 2,3-pyridyne (2) proceeds in a manner similar to that of the reaction of benzyne, [1,2,3]triazolo[4,5-c]pyridines (3 and 4) and [1,2,3]triazolo[4,5-b]pyridines (5 and 6), whose frameworks are often found in some biologically active compounds as well as functional materials, would be produced, respectively (Scheme 1). Scheme 1. Plan for the synthesis of triazolopyridines via 1,3-dipolar cycloaddition of pyridynes and organic azides To examine the feasibility of the above plan, we set out to investigate the reaction of ethyl azidoacetate (8a) and 2-methoxy-3,4-pyridyne precursor 7 since the reaction of 2-methoxy-3,4-pyridyne and cyclic ureas showed good reactivity and regioselectivity as previously reported. First, the reaction of the precursor 7a and 8a was carried out in the presence of KF as a fluoride source and 18-crown-6 in THF (Table 1, run 1). As a result, 1H-[1,2,3]triazolo[4,5-c]pyridine derivative 3aa was produced in 38% yield as a single regioisomer. This result indicated that the C-N bond formation regioselectively occurred between the nitrogen atom with a negative charge and the carbon atom at the 4-position in the pyridine ring depicted as 9. After several screenings of fluoride sources and solvents, it was found that the use of CsF in MeCN gave a good result (run 4). As the amount of azide 8a was increased, the yield of 3aa improved, and finally the reaction of 7a and 10 equivalents of 8a afforded 3aa in 77% yield (run 7). In the reactions that the desired product was obtained in low or moderate yield (runs 1-4), some polymeric by-products of pyridyne were observed. Pyridyne species are known to be highly reactive while the reactivity of azide 8a seemed to be low, which would result in formation of the undesired polymerization of pyridyne rather than the coupling of pyridyne and azide in the case of the reaction using small amounts of azide. With optimal conditions in hand, we set out to conduct scope and limitation studies of the 1,3-dipolar cycloaddition. First, we investigated the reactions of various 3,4-pyridynes and ethyl azidoacetate (8a) (Table 2). The reaction of 3,4-pyridyne 7b having an N,N-diethylcarbamoyl group at the 2-position and 8a also gave 1H-[1,2,3]triazolo[4,5-c]pyridine derivative 3ba in moderate yield, though the regioselectivity was still high (run 1). 2,6-Dimethoxy-3,4-pyridyne 7c reacted with 8a to give the coupling product in 78% yield (run 2). The reaction of 5-methoxy-3,4-pyridyne 7d and azide 8aafforded 3H-[1,2,3]triazolo[4,5-c]pyridine derivative 4da in 17% yield as a single regioisomer (run 3). On the other hand, no regioselectivity was observed in the reaction of simple 3,4-pyridyne 7e or 6-methoxy-3,4-pyridyne 7f, and both regioisomers 3ea and 4ea or 3fa and 4fa were obtained in moderate yields, respectively (runs 4 and 5). Next, 1,3-dipolar cycloaddition of 2-methoxy-3,4-pyridyne and various organic azides was examined (Table 3). The reaction of 7a and aromatic azides 8b-8g in the presence of CsF proceeded smoothly to give the corresponding [1,2,3]triazolo[4,5-c]pyridines 3ab-3ag in good yields (runs 1-6). Cinnamyl azide (8h) was reacted with 2-methoxy-3,4-pyridyne to give triazolopyridine derivative 3ah in 63% yield (run 7). The hydroxy group of azide 8i was tolerated under the reaction conditions, giving the corresponding coupling product 3ai in 63% yield (run 8). Sugar-derived azides 8j and 8k were also applicable to the cycloaddition with 2-methoxy-3,4-pyridyne to afford poly-functionalized triazolopyridines 3aj and 3ak, respectively, in good yields (runs 9 and 10). The structures of the 1H-[1,2,3]triazolo[4,5-c]pyridine derivatives were unambiguously determined by X-ray crystallographic analysis of compound 3ah (Figure 1). monoclinic P21/c (#14) a = 14.492(4) Å b = 7.317(4) Å c = 12.695(4) Å β = 95.07(2)° V = 1341.0(8) Å3 0.0438 0.1530 1.022 Crystal System Space Group Lattice Parameters