“Urea to Urea” Approach: Access to Unsymmetrical Ureas Bearing Pyridyl Substituents

Abstract

A protocol for the synthesis of unsymmetrical ureas substituted by pyridyl/quinolinyl moiety has been developed. This method concluded in metal‐ and base‐free reamination of N,N‐dimethyl‐N‘‐hetaryl ureas with a wide range of aryl and alkyl amines. The isolated yields vary from 40 to 96% depending on the nucleophilicity of the amines. The scope of this method includes more than 50 examples. The reaction is not hindered by either donor or acceptor groups as well as diverse functionalities. The synthesis can be easily scaled to gram quantities. Theoretical calculations supported by experimental data allowed us to propose a plausible mechanism for the process. This reaction takes place through the intermediate formation of hetaryl isocyanate.

N‐Pyridylureas as Masked Isocyanates Fort the Late‐Stage Diversification of Pyridine‐N‐Oxides

“…Note, that 5 in the crystalline state adopts the same curled conformation (see Figure S3 in ESI). Additionally, an intramolecularly bound conformation was previously reported for a related methylsubstituted compound [78] (CCDC code DERXUX). In contrast, the optimized geometry of 4 dg does not contain similar intramolecular hydrogen bonds.…”

“…Next, we preceded to the functionalization of the synthesized aminocarbonyl derivatives of N ‐oxides. First of all, we checked whether the conditions we proposed earlier [78] for the “urea‐to‐urea” transformation can be used in this case. p ‐Toluidine was taken as a model amine.…”

“…[75,76] Moreover, it has found that such ureas are able to react with N-and O-nucleophiles acted like masked hetaryl isocyanates. [77][78][79][80] We hypothesized that involving N-oxides of these ureas into similar transformations can be a good "late-stage modification" approach to rise the diversity of azine-N-oxides. The results of this study are presented in this paper.…”

“…Previously, we developed a simple method [70–72] for the preparation of N , N ‐dialkyl‐ N’ ‐pyridylureas and utilized these compounds as ligands to obtain metal‐based anti‐cancer agents [73,74] and catalysts [75,76] . Moreover, it has found that such ureas are able to react with N ‐ and O ‐nucleophiles acted like masked hetaryl isocyanates [77–80] . We hypothesized that involving N ‐oxides of these ureas into similar transformations can be a good “late‐stage modification” approach to rise the diversity of azine‐ N ‐oxides.…”

Room Temperature Synthesis of Bioactive 1,2,4-Oxadiazoles

“…For example, Boyarskiy et al reported the successful synthesis of 1,2,4-oxadiazoles substituted by pyridine N -oxides [ 115 ], and the N -oxide functionality was compatible with both “ester” and “acid” protocols. Furthermore, these N -oxides were converted into corresponding N -pyridyl ureas [ 115 , 116 ], which are valuable “masked isocyanates” [ 117 , 118 ] and ligands of metal-based anticancer drugs [ 119 , 120 ]. Krasavin et al continued the exploration of 1,2,4-oxadiazole motif for the design of carbonic anhydrase inhibitors [ 14 , 114 ].…”