Expanding the chemical space of 3(5)-functionalized 1,2,4-triazoles

An efficient approach to the gram-scale synthesis of 3(5)-substituted, 1,3- and 1,5-disubstituted 1,2,4-triazole-derived building blocks is described. The key synthetic precursors – 1,2,4-triazole-3(5)-carboxylates (20 examples, 35–89% yield) were prepared from readily available acyl hydrazides and ethyl 2-ethoxy-2-iminoacetate hydrochloride. Further transformations were performed following the convergent synthetic strategy and allowed the preparation of 1,3- and 1,5-disubstituted 1,2,4-triazole-derived esters (16 examples, 25–75% yield), 3(5)-substituted, 1,3- and 1,5-disubstituted carboxylate salts (18 examples, 78–93% yield), amides (5 examples, 82–93% yield), nitriles (5 examples, 30–85% yield), hydrazides (6 examples, 84–89% yield), and hydroxamic acids (3 examples, 73–78% yield). Considering wide applications of the 1,2,4-triazole motif in medicinal chemistry, these compounds are valuable building blocks for lead-oriented synthesis; they have also great potential for coordination chemistry. Supplementary Information The online version contains supplementary material available at 10.1007/s10593-022-03064-z.

1,2,4-Triazole motif has been embedded into more than 30 approved and marketed medicines as well as more than 100 investigational and experimental drugs. 1 Among them, ribavirin ( Fig. 1) -an antiviral medication used to treat respiratory syncytial virus infection, hepatitis C, and many other viral diseases. [2][3][4] Being one of the safest and most effective remedies needed in a health system, ribavirin has been included into the World Health Organization's List of Essential Medicines. 5 Moreover, recent studies confirmed the successful application of ribavirin as a cure of COVID-19. [6][7][8] Voriconazole is another example of choice used to treat serious fungal infections. [9][10][11][12][13] On the other hand, 1,2,4-triazoles (especially bearing additional functional groups) are very promising ligands for coordination chemistry with multiple coordination modes possible. 14,15 In this view, they were used to obtain coordination polymers, 16 blue-emitting organic lightemitting diodes, 17 chemodynamic therapy agents against cancer cells, 18 spin crossover nanoparticles, 19 and other (potentially) useful materials.
The use of Ph 2 O as the solvent at the cyclization step has several advantages such as: a) completeness of the cyclization reaction; b) prevention of the side reactions; c) decreasing reaction time up to 1 min (the original methods require up to 4 h) and simplification of the work-up procedure; d) reusability of the solvent. In particular, unlike solvent-free procedures (performed by melting at 160-215°C) [33][34][35]37 and those with refluxing diglyme (bp 162°C) 36 or xylenes (bp 139°C) 38,39 as the media, the use of Ph 2 O (bp 259°C) allows achieving better yields (by an average of 10%). The work-up procedure included simple filtration of warm (40°C) reaction mixture followed by washing the precipitate with hexane and subsequent recrystallization of thus obtained Scheme 1. The literature methods for the synthesis of 1,2,4-triazole-3(5)-carboxylates 1 With compounds 1 in hands, we proceeded to evaluation of their chemical properties, concurrently expanding the library of 3(5)-functionalized 1,2,4-triazoles. The alkylation study was conducted first. As expected for the 1,2,4triazole core, nearly equimolar mixtures of products 14 and 15 were obtained after reaction of compound 1 with MeI and K 2 CO 3 in DMF media ( Table 2, entries 1-6). The reaction was more selective with triazole 1q (R = 4-ClC 6 H 4 ) leading to product 14q predominantly (ratio 14q:15q = ca. 3:1), which can be addressed to a steric factor of the aryl substituent. Further chromatographic separation of these mixtures allowed the isolation of pure regioisomers 14 and 15. Their structures were established by NOE, 1 H-13 C, and 1 H-15 N HMBC experiments (Fig. 2). An additional criterion was 1 H NMR shifts of the N-CH 3 protons that were by ca. 0.1-0.2 ppm higher for isomers 14 as compared to isomers 15.
Considering the ratio of products 14 and 15 in the reaction mixture and their isolated yields, we also studied the alkylation reaction of triazole 1b with higher alkyl halides (i.e. EtI and i-PrI, Table 2, entries 7 and 8). It turned out that with EtI, nearly 1:1 mixture of regioisomers 16a and 17a was obtained, whereas in the case of sterically demanding i-PrI, product 16b was formed preferably (ratio 16b:17b = ca. 3:1). This result demonstrates importance of the electronic effect of the CO 2 Et moiety for the regioselectivity of the alkylation reaction with alkyl halides of lowered reactivity.
Saponification of esters 1, 14, and 15 proceeded smoothly with aqueous alkali at 80°C, but further isolation of the corresponding carboxylic acids was complicated by the partial decarboxylation. Therefore, the corresponding hydrolysis products were isolated as stable sodium or lithium salts 18, 19, and 20 in 80-93% yield ( Table 3).
Finally, the conversion of amides 21, 22, and 23 into the corresponding nitriles required some optimization studies. While N-methylated amides 22b and 23b were successively transformed into the corresponding nitriles 30b and 31b under TFAA-promoted conditions 51-55 at 0-5°C (Scheme 2, method I), this method appeared to be inapplicable for N-1-unsubstituted triazole-derived amides 21 and did not afford the desired product. Another procedure, POCl 3mediated dehydration, 56-60 worked well only for N-unsubstituted substrate 21p possessing aromatic substituent at the C-3 position; the corresponding nitrile 32p was obtained in 86% yield (Scheme 2, method II). However, this method was inefficient for amides with C-3-aliphatic substituent. Specifically, when amides 21b,h were subjected to these reaction conditions, they were converted into the corresponding nitriles 32b,h in 5 and 27% isolated yields, respectively.
Eventually, this was circumvented by one more alternative synthetic approach. In this way, N-unsubstituted ester 1b was treated with 4-methoxybenzyl chloride and K 2 CO 3 in DMF media in order to install the PMB protecting group at the heterocyclic core and prevent side reactions at the dehydration step (Scheme 2, method III). The resulting crude mixture of N-protected regioisomers 33 and 34 was refluxed in ethanolic ammonia that gave a mixture of amides 35 and 36. Subsequent TFAA-mediated dehydratation provided a mixture of PMB-protected nitriles 37 and 38. Ultimately, TFA-promoted cleavage of PMB protecting group afforded the target N-unsubstituted nitrile 32b in 67% overall yield.
Reactions requiring anhydrous conditions were performed with the usual precautions for rigorous exclusion of moisture. All the starting materials were obtained from Enamine Ltd. and UORSY. The solvents were purified according to the standard procedures. 61 Synthesis of ethyl 1,2,4-triazole-3-carboxylates 1a-t (General method). Acyl hydrazide 5a-t (25.0 mmol) was added to a solution of ethyl 2-ethoxy-2-iminoacetate hydrochloride (6) (4.50 g, 25.0 mmol) and Et 3 N (4.20 ml, 3.07 g, 30.3 mmol) in anhydrous EtOH (50 ml), and obtained solution was stirred at room temperature for 12 h. The formed ethyl 2-(2-acylhydrazono)-2-aminoacetate intermediate 2a-t was filtered, washed with EtOH (3×20 ml), and dispersed (except for acetate 2a) in Ph 2 O (50 ml). The resulting mixture was brought to boil and refluxed for 1 min. After the temperature of the reaction mixture had dropped to 40°C, it was filtered. Thus obtained crude product was washed with hexane (3×50 ml) and recrystallized from PhMe to give the title compound 1b-t. Compound 1a was prepared by solvent-free melting of acetate 2a at 150°C for 2 min.