O-Methyl-N-nitroisourea as a NCO Surrogate in Cu-Catalyzed Alkane C–H Amidination. A Masked Isocyanate Strategy

Abstract

The Cu-catalyzed C−H activation of alkanes in the presence of O-methyl-N-nitroisourea allows a facile entry to Omethyl-N-alkylnitroisoureas, which are shelf-stable isocyanate precursors. The latter are then readily converted into carbamates and ureas via an uncommon chloride-mediated demethylation process. O-Methyl-N-nitroisourea is available in two steps and on a large scale from urea and constitutes an easy to handle NCO surrogate. The methodology has also been applied to the synthesis of a methylisocyanate (MIC) precursor, a valuable synthon for pharmaceutical and agrochemical purposes and for the postfunctionalization of polyolefins.

Mechanistic Insights into the Origins of Selectivity in a Cu-Catalyzed C–H Amidation Reaction

“…Recently, our group and others have reported copper-catalyzed aminations of alkyl C–H bonds with peroxides as oxidants (Figure b) − under conditions similar to the Kharasch–Sosnovsky oxidation of allylic C–H bonds . Such amination reactions produce N -alkyl amides, carbamates, imides, sulfonamides, amines, sulfoximines, and ureas.…”

“…(a) Recent developments in the amination of C­(sp 3 )–H bonds. (b) Copper-catalyzed aminations of C­(sp 3 )–H by Hartwig and others. − (c) Identification of key processes that determine selectivity . (d) Uncovering design principles for C–H functionalization through a combined computational/experimental study.…”

Copper‐Mediated Decarboxylative Amidination: Synthesis of O‐Methyl‐N‐Alkylnitroisoureas

“…They have also attracted a great deal of interest as precursors for the preparation of insecticides, including dinotefuran 2 , the latest generation of neonicotinoid guanidines [2] . More recently, our laboratory has taken an interest in these compounds as isocyanate precursors [3] . Isocyanates are known for their irritant properties and their perceived carcinogenicity.…”

“…Carboxylic acids (and their peroxide derivatives), are abundant, exhibit little or low toxicity, therefore constituting raw materials of choice for many chemical transformations, including the formation of C−N bonds [4] . Such a process would also allow the formation of nitroisoureas such as I bearing functional groups, a limitation of the Cu‐catalyzed C−H amidination developed earlier [3] …”

Methyl Pyruvate Oxime as a Carbonyl Synthon: Synthesis of Ureas, Carbamates, Thiocarbamates, and Anilides

“…These strategies are based on different starting materials or novel reagent systems. Examples include the generation of isocyanates from amines using CO 2 , or methanol, azides using CO, carbamates by degradation, amides by the Curtius reaction, hydroxamic acids by the Lossen reaction, isonitriles by oxidation, formamides by N–H activation, o -methyl-N-nitroisourea by Krapcho-type dealkylation, and aryl chloride and sodium cyanates by Pd-catalyzed cross-coupling . Nevertheless, the development of a dependable synthesis under mild conditions for isocyanates, along with their use in the preparation of N -containing unsymmetrical carbonyl compounds, remains a significant subject …”