Regioselective N‐Alkylation of Ethyl 4‐Benzyloxy‐1,2,3‐triazolecarboxylate: A Useful Tool for the Synthesis of Carboxylic Acid Bioisosteres

Abstract

Acidic 4‐hydroxy‐1,2,3‐triazole is a proven bioisostere of acidic functions that has recently been used to replace the acidic moieties of biologically active leads. Straightforward chemical strategies for the synthesis of the three possible N‐alkylated 4‐hydroxy‐1,2,3‐triazole regioisomers have been designed and reported herein, by identifying the optimal conditions under which the alkylation of ethyl 4‐benzyloxy‐1,2,3‐triazolecarboxylate (compound 19) can be regiodirected to the triazole N(b) position and thus produce the only isomer that cannot be obtained via the cycloaddition reaction. Furthermore, an innovative platform for parallel synthesis, called Arachno and which has been patented by the authors' group, has been used to speed up the process, and an NMR study has been carried out to better understand the reactivity of compound 19 towards the N(b) position. A library of benzyloxy protected 4‐hydroxy‐1,2,3‐triazoles has been prepared using the two strategies: regiodirection for the N(b) and N(c) isomers and cycloaddition for the N(a) isomers; the processes are described herein. The three N‐alkylated regioisomer series have been characterized spectroscopically (NMR and MS). The subsequent catalytic hydrogenation of the 4‐benzyloxy protective group on the N‐alkylated‐4‐benzyloxy‐5‐ethoxycarbonyl‐1,2,3‐triazoles provided the corresponding substituted 4‐hydroxy‐1,2,3‐triazoles.

A New NF-κB Inhibitor, MEDS-23, Reduces the Severity of Adverse Post-Ischemic Stroke Outcomes in Rats

“…The relatively large amounts of MEDS-23 needed for the conduction of the in-vivo experiments of the present study necessitated the use of a new synthetic scheme different from the one used in the originally developed protocol [ 11 , 24 ]. The authors took advantage of the recent knowledge acquired from their studies about hydroxylated azoles to improve synthesis and characterization of MEDS-23 [ 25 , 26 ] (for details, see Supplementary Material Section S1 ). MEDS-23 was dissolved in dimethyl sulfoxide (DMSO) in injection volumes that ranged between 0.1–0.2 mL according to animals’ BW.…”

Diazocarbonyl and Related Compounds in the Synthesis of Azoles

“…The limitation of this approach is that aromatic amines fail to react, which is consistent with reduced nucleophilicity (and basicity) of the amino group in aromatic amines. This methodology has been used recently for the preparation of 5-hydroxytriazole derivatives acting as a potential carboxylic acid bioisosters [ 185 , 186 ]. Hydroxytriazole salts can be acidified to afford free 5-hydroxytriazoles 374 , but these compounds are often unstable and undergo ring opening to form parent diazo amide species [ 187 ].…”

Dihydroorotate dehydrogenase inhibitors in anti-infective drug research

“…Compound 55 was obtained via the scaffold hopping of the phenol moiety present in a previously described salicylamide, for which the role of pK a had already been demonstrated (compound 54, Fig. 18) [133]; three acidic hydroxyazoles, with a broad range of pK a values [134,135], were used and the resulting compounds were evaluated for both activity and pK a . Compound 55 (Fig.…”