Facile One-Pot Parallel Synthesis of 3-Amino-1,2,4-triazoles

Abstract

A 1,2,4-triazole motif is present in numerous commercialized and investigational bioactive molecules. Despite its importance for medicinal chemistry, there is a lack of convenient combinatorial approaches toward this molecular core. Herein, we present a synthetic strategy suitable for the quick preparation of a library of structurally diverse 1,2,4-triazoles in a one-pot setting. The key steps include the formation of thioureas followed by S-alkylation using 1,3-propane sultone and consecutive ring closure leading to the desired 1,2,4-triazoles. Parallel synthesis yields thousands of 1,2,4-triazoles in a cost- and time-efficient manner from commercially available chemicals.

One-Pot Parallel Synthesis of 5-(Dialkylamino)tetrazoles

“…Finally, the resulting S -alkylisothioureas 13 underwent cyclization with NaN 3 leading to the target products 8 , which were further purified by reverse-phase HPLC on the C 18 column. This reaction sequence can be considered as a modification of our previous method for the combinatorial synthesis of 3-amino-1,2,4-triazoles, where hydrazides were used as the nucleophilic reagents instead of NaN 3 …”

“…We have suggested that the low efficiency of the first step (i.e., thiourea 12 preparation) in the isothiocyanate-based method might be a possible reason for its modest success rate. Recently, our group reported the efficient application of bis­(2,2,2-trifluoroethyl)­carbonate (BTC) and -thiocarbonate (BTTC) as reagents for preparation of unsymmetrical ureas , and thioureas, respectively. Therefore, a stepwise reaction of amines 15 and 11 with BTTC was envisaged for the preparation of 12 (BTTC-based method, Scheme A).…”

“…Both primary ( 15 , 378 compounds) and secondary ( 11 , 262 compounds) amines were randomly selected from our building block collection; their representative examples are given in Figure . It should be noted that only aliphatic amines were used, whereas less nucleophilic anilines and heteroaromatic amines were avoided because of their previously noted inefficiency . Further transformations of generated in situ thioureas 12 followed those for the isothiocyanate-based method.…”

“…The current commercial availability and literature coverage of 5-aminotetrazoles was estimated by substructural searches in eMolecules and PubChem databases, which revealed 17 219 and 55 163 compounds, respectively (Figure ). To estimate the number of 5-aminotetrazoles feasible by isothiocyanate-based and BTTC-based methods, the combinations of commercially available secondary amines 11 with isothiocyanates 10 or primary amines 15 , respectively, were selected by in-house developed algorithms based on our previous data on the reactivity of the reagents. − Because the abundance of primary amines is significantly greater than amount of isothiocyanates, it was not surprising that the number of BTTC-derived products (7 097 307) was 20 times larger than that of isothiocyanate-derived products (326 702). Additionally, because the probability of successful preparation of the target products by the BTTC-based method was 67%, these 7 million virtual structures can be considered as REAL substituted 5-aminotetrazoles.…”

Metal‐free Decarboxylative Annulation of 2‐Aryl‐2‐isocyano‐acetates with Aryldiazonium Salts: General Access to 1,3‐Diaryl‐1,2,4‐triazoles

“…[1] Therefore, a vast number of functionalized 1,2,4triazoles have been accessed by means of annulation and cyclization reactions of various synthons and substrates. [1][2][3][4] Among these methods, aryldiazonium salts, [4][5][6][7] which are versatile and readily accessible 'NÀ N' synthons, have been utilized for the synthesis of 1,2,4-triazoles. [5] In 1970's, Masumoto disclosed the first synthesis of 1,3-disubstituted 1,2,4-triazoles via the base-promoted annulation of aryldiazonium salts with methyl isocyanoacetate, [5a] wherein only electronrich aryl groups could be harnessed to deliver methyl 1-aryl-1,2,4-triazole-3-carboxylates (Scheme 1a).…”