Highly Modular Synthesis of 1,2-Diketones via Multicomponent Coupling Reactions of Isocyanides as CO Equivalents

Abstract

A one-pot, four-component Pd-catalyzed coupling has been developed for the synthesis of unsymmetrical 1,2-diketones from aryl halides and alkyl zincs employing tertbutyl isocyanide as a CO source. The intermediate 1,2diketones have been elaborated to quinoxalines. Mechanistic studies help to rationalize the high selectivity for the bis-vs monoinsertion product.

Kinetic Analysis of Catalytic Organic Reactions Using a Temperature Scanning Protocol

“…In order to demonstrate this temperature scanning protocol, we chose to study the multi‐component Pd‐catalyzed synthesis of diketones shown in Scheme that employs t Bu isocyanide as a CO equivalent . Our previous kinetic and mechanistic study of this reaction system proposed the reaction mechanism shown in Scheme .…”

“…We monitored the reaction of Scheme using ReactIR spectroscopy by following the isocyanide peak at 2133 cm −1 . Validation by GC analysis of discrete reaction aliquots allowed calculation of all other components from the reaction stoichiometry and mass balance . Figure a (orange symbols) shows a product profile monitored under isothermal conditions.…”

“…In order to demonstrate this temperature scanning protocol, we chose to study the multi-component Pd-catalyzed synthesis of diketones shown in Scheme 1 that employs t Bu isocyanide as a CO equivalent. [11,12] Our previous kinetic and mechanistic study of this reaction system proposed the reaction mechanism shown in Scheme 2. We proposed that oxidative addition of an aryl bromide 1 to the Pd/dppf catalyst is followed by double insertion of the isocyanide and transmetallation of an alkylzinc bromide 2.…”

“…Validation by GC analysis of discrete reaction aliquots allowed calculation of all other components from the reaction stoichiometry and mass balance. [11] Figure 2a (orange symbols) shows a product profile monitored under isothermal conditions. The reaction exhibits a constant rate revealing overall zero-order kinetics, in accordance with the mechanistic proposal of Scheme 2 with reductive elimination of the product as the ratedetermining step.…”

Nickel-catalyzed allylic carbonylative coupling of alkyl zinc reagents with tert-butyl isocyanide

“…Isocyanide is an important array of organic reagent widely used in transition metal catalyzed carbonylations as C-1 source and in heterocycle synthesis [27][28][29][30][31][32][33][34][35][36][37][38] . Despite the progress, the leverage of functionalized alkyl Negishi reagents for transition metal catalyzed carbonylative coupling with isocyanide still remains extremely limited 33 . Recently, Dechert-Schmitt and Blackmond reported a modular unsymmetrical 1,2-diketone synthesis via Pdcatalyzed four-component coupling between an aryl halide, an alkyl zinc reagent and two molecules of t BuNC.…”