5-Formyltriazoles as Valuable Starting Materials for Unsymmetrically Substituted Bi-1,2,3-Triazoles

Herein, we present the first synthetic methodologies toward non-symmetrical 5,5′-C, C-linked bi-1,2,3-triazoles starting from 5-formyl-1,2,3-triazole via two related pathways. In a first reaction, 5-formyl-1,2,3-triazole is successfully reacted with a variety of nitroalkanes and organic azides in a one-pot three-component fashion resulting in tetra-ortho-substituted bi-1,2,3-triazoles. In the second, closely related reaction, 5-formyl-1,2,3-triazole is initially converted with nitromethane to the corresponding nitroalkene, and then subsequently oxidatively cyclized with a number of organic azides toward 4-nitro substituted non-symmetrical tetra-ortho-substituted 5,5′-bi-1,2,3-triazoles. The scope of both reactions and furtherr post-functionalizations are examined, and the atropisomeric properties of the obtained bi-1,2,3-triazoles are evaluated.

Next, the three-component reaction was applied as described by our group on 5-formyl-1,2,3-triazole 4 with a variety of nitroalkanes 6a-d and organic azides 2, 7a-e (Figure 1). Firstly, various alkyl and aryl azides were employed with aldehyde 4 and ethyl nitroacetate 6a as model substrates. Good to excellent yields (56-87%) of bi-1,2,3-triazoles 8 were obtained for alkyl azides 7a-d. Interestingly, enantiopure chiral alkyl azide (R)-7b yielded a 2.25:1-diastereomeric mixture, which was successfully separated via silica gel chromatography into single diastereomers 8ba and 8bb. In general, the use of aryl azides 2 and 7e involved an extended reaction time and slightly decreased yields (21-36%) compared to alkyl azides, and the reaction even failed to afford any product when electron-deficient 4-nitrophenyl azide was employed. Secondly, other functional groups were introduced by varying nitroalkanes 6a-6d. Benzoyl-and phenylsulfonyl-appended bi-1,2,3-triazoles 8h and 8i, respectively, were both prepared in 54% yield. The direct three-component reaction toward bromo-derivative 8g seemed cumbersome, in which the formation of the intermediate bromonitroalkene did not proceed. Nevertheless, 8g was isolated in 64% via a two-pot procedure without intermediate purification of the in situ generated bromonitroalkene derivative.
solely nitro derivatives can be obtained, and the crude reaction mixtures are cleaner than the ones obtained from the threecomponentreaction with only the HNO 2 -eliminated derivatives as minor side products.
Several of the obtained bi-1,2,3-triazoles now bear interesting functionalities that could serve as valuable starting point for further derivatization (Scheme 2). Bromo-derivative 8g was subjected to Buchwald-Hartwig amination conditions with pyrrolidine, yet surprisingly the reaction furnished hydrodehalogenated amide 10 in 60% yield. The reactivity of the ester moiety over the bromide of 8g was further exemplified in a substitution reaction with pyrrolidine, in which amide 11 constituting the bromide formed in excellent yields upon reaction at room temperature. Next, hydrolysis of the methyl ester moiety of 9a formed the highly versatile, yet possibly labile, carboxylic acid 12 in 92% yield. Hence, the carboxylic acid was in a next step subjected to heating in order to investigate its thermal stability. Carboxylic acid 12 displayed reasonable stability over the course of several weeks at room temperature, but at 140 • C decarboxylation of 12 nicely furnished 13 in good yields (82%). Finally, the reduction of nitro derivative 9f was investigated. Under standard hydrogenation conditions using Pd/C, the versatile free 4-amino-appended derivative 14 was obtained in 44% yield, without the observation of ring-closed amide 15. Further cyclization toward bis-1,2,3-triazolo-fused 2-pyridone 15 was achieved under acidic conditions at 80 • C, in which 15 was obtained in 76% yield.
compounds show well-separated signals of the diastereotopic benzylic protons at 5.59 (J = 15.0 Hz) and 5.34 ppm (J = 15.0 Hz) for compound 8a, and at 5.67 (J = 14.9 Hz) and 5.42 ppm (J = 14.9 Hz) for compound 9a, both as clear AX spin systems. Moreover, compound 8a also displayed split signals of the diastereotopic methylene protons of the ester group at 4.18 (J = 10.9, 7.1 Hz) and 4.11 ppm (J = 10.9, 7.1 Hz). Subsequently, from the high temperature NMR spectra at 115 • C, it can be observed, based on the chemical shifts, that the diastereotopic signals of both compounds 8a and 9a move closer to each other when the temperature rises, i.e., benzylic signals of  (Figure 3). Unfortunately, or fortunately from the perspective of forming conformationally stable atropisomers, no coalescence was observed for the diastereotopic signals when the maximum temperature of 115 • C (388 K) was reached. Therefore, the corresponding rotational energy barriers G z of these atropisomeric compounds 8a and 9a could not be accurately calculated. Nevertheless, a minimal energy could be tentatively calculated by assuming coalescence at 388 K. Hence, the rotational energy barrier at this temperature for both 8a and 9a is at least 79.5 kJ/mol. In addition, the isolation of both diastereomers via silica gel chromatography was possible for 8ba and 8bb, and 9ba and 9bb. Regrettably, the sets of diastereomers showcased a rather limited rotational stability as they isomerized at room temperature over the course of a couple of days. In future work, the steric hindrance of the orthosubstituents should be increased to create more stable axially chiral compounds. Nevertheless, this is an encouraging result from the perspective of preparing atropisomeric unsymmetrically substituted bi-1,2,3-triazoles.
bi-1,2,3-triazoles. Both reactions displayed a versatile scope toward various alkyl and aryl azides, and via the use of both aforementioned procedures various attractive functional groups can be incorporated. Postfunctionalizations further emphasized their peculiar and interesting chemistries for future applications. Rotational stability tests showed promising characteristics as atropisomers, although the rotational barrier was still rather limited and could be further increased by implementing more sterically hindered ortho-substituents.

DATA AVAILABILITY STATEMENT
All datasets generated for this study are included in the article/Supplementary Material.

AUTHOR CONTRIBUTIONS
RV and TH carried out the experiments, analyzed the data, and wrote the manuscript. MV carried out some of the experiments and analyzed the data. WD directed the project and corrected the manuscript.