Synthesis of Cyanamides via a One-Pot Oxidation–Cyanation of Primary and Secondary Amines

Abstract

An operationally simple oxidation–cyanation method for the synthesis of cyanamides is described. The procedure utilizes inexpensive and commercially available N-chlorosuccinimide and Zn­(CN)2 as reagents to avoid direct handling of toxic cyanogen halides. It is demonstrated to be amenable for the cyanation of a variety of primary and secondary amines and aniline derivatives as well as a complex synthetic intermediate en route to verubecestat (MK-8931). Additionally, kinetic measurements and other control experiments are reported to shed light onto the mechanism of this cyanation reaction.

N‐Cyanation of Primary and Secondary Amines with Cyanobenzio‐doxolone (CBX) Reagent

“…Remarkably, ketone functionality was successfully tolerated for the first time as it was usually protected as its ketal pattern to participate the cyanation process in previous works. [12,14] More sterically encumbered acyclic secondary amines including dicyclohexylamine could also react smoothly, albeit with a lower yield (16).…”

“…For this reason, several alternative procedures with the aim to circumvent the handling of cyanogen halides during the synthesis of cyanamides have been developed. [10] For example, an operationally simple oxidation-cyanation procedure with the in situ generation of cyanogen halide for electrophilic N-cyanation was reported by Chen [11] and Kuhl, [12] respectively. Other strategies including deoxycyanamidation, [13] elimination, [14] rearrangement, [15] copper-mediated oxidative N-cyanation, [16] and transition-metalcatalyzed conversion of isocyanides to cyanamides [17] are mutually complementary to electrophilic N-cyanation.…”

Cyanide-Free Synthesis of Air Stable N-Substituted Li and K Cyanamide Salts from Tetrazoles. Applications toward the Synthesis of Primary and Secondary Cyanamides as Precursors to Amidines

“…Since then and to date, conventional methods of synthesis of symmetrical N,N′-disubstituted cyanamides have consisted in the electrophilic cyanation of amines using cyanogen bromide as exemplified by the von Braun reaction (Scheme A), by Cu-mediated cyanation of amines, by variations in the direct alkylation of existing cyanamide salts, and by other methods . In a most recent contribution from the Merck Process group, electrophilic N-cyanation was achieved by treatment of an N -chloroamine with zinc­(II) cyanide (Scheme B) . One of the major concerns of these methods of synthesis of cyanamides relying on cyanide-containing reagents has been the potential hazards of side products such as HCN and HBr produced during the cyanation reaction.…”

“…Treatment of the salts with acidified water led to the corresponding N-monosubstituted cyanamides exemplified by compounds 1u–1y . This offers an alternative two-step cyanide-free method to the Merck protocol from readily available N-substituted tetrazoles toward a variety of functionalized cyanamides. In addition to N -methyl cyanamide first reported by Raap, N -aryl cyanamides have been proposed as intermediates in the decomposition of N -aryl tetrazole in DMSO and NaOH …”

“…13 In a most recent contribution from the Merck Process group, electrophilic Ncyanation was achieved by treatment of an N-chloroamine with zinc(II) cyanide (Scheme 1B). 14 One of the major concerns of these methods of synthesis of cyanamides relying on cyanidecontaining reagents has been the potential hazards of side products such as HCN and HBr produced during the cyanation reaction. In spite of its long-standing history, the direct alkylation of commercially available cyanamide salts cannot be practically controlled to obtain N-monosubstituted 15 To the best of our knowledge, a methodology study to obtain N,N′-differentiated cyanamides without the use of cyanide-containing reagents has not been reported.…”