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

A new method for the synthesis of pyridine- and quinoline-N-oxides containing a ureido or carbamoyl fragment in position 2 is concluded in the oxidation of substituted N,N-dimethyl-N′-(pyridine-2-yl)ureas to the corresponding N-oxides, followed by modification of the dimethylureide moiety. The method produces N-oxides of N-alkyl/aryl-N’-(pyridine-2-yl)ureas in yields up to 99 % (including the ones bearing oxidative-sensitive fragments).

Abstract

A new method for the synthesis of pyridine- and quinoline-N-oxides containing a ureido or carbamoyl fragment in position 2 has been developed. This method concluded in the oxidation of relatively readily available substituted N,N-dimethyl-N′-(pyridine-2-yl)ureas to the corresponding N-oxides, followed by modification of the dimethylureide moiety. Being heated to 90 °C in the presence of amines in a solution of DMF or chlorobenzene, N-oxide of N,N-dimethyl-N′-(pyridine-2-yl)urea undergoes a transamination reaction without loss of the N-oxide function. This produces N-oxides of N-alkyl/aryl-N’-(pyridine-2-yl)ureas in 24–99 % yields, (about 30 examples). Values of the NH protons chemical shifts are a good criterion for the selectivity of the reaction. The reaction is also applicable to N-oxides of ureas substituted in the pyridine ring and to the quinoline congener. N-Oxides of pyridine/quinoline-containing carbamates can be similarly prepared by heating N-oxides of N,N-dimethyl-N′-(pyridine-2-yl)/(quinoline-2-yl)-urea in an appropriate alcohol solution at 120 °C.