INVESTIGATION INTO THE ORTHO-FUNCTIONALIZATION OF 2-ARYLOXYPYRIDINES USING α-KETO AMIDES VIA PLATINUM-ASSISTED C-H ACTIVATION

Abstract

Transition metals are commonly used to catalyze thermodynamically unfavorable reactions, decreasing the activation energy required to break stable bonds and reform new bonds. Activation of a C-H bond can lead to the formation of more reactive C-X bonds, where X=N, O, Cl, Br, I, and Si, allowing for further reactivity or synthesis. Platinum was used as a catalyst as it serves as a soft Lewis acid, in an organic soluble cis-bis(benzonitrile)dichloroplatinate(II), cis-Pt(PhCN)2Cl2, in order to facilitate in C-H activation. Aryloxypyridines have been used as the scaffolding in several bioactive compounds, from insecticides to human enzyme inhibitors. α-keto amides have shown to have anti-inflammatory and anti-cancer properties, rendering them great candidates for study. The α-keto amides were introduced to the reaction as 2-(dialkylamino)-2-oxoacetyl chloride, as chlorine serves a good leaving group. By utilizing the pyridyl nitrogen as a directing group, the platinum catalyst can undergo rapid ligand exchange and bind itself to the aryloxypyridine. The platinum facilitated C-H activation by the interaction with the 2-(dialkylamino)-2-oxoacetyl chloride, functionalizing an ortho-position on the aryl ring. An array of different 2-aryloxypyridines was tested, with different functional groups at the ortho-, meta-, and para-positions, in order to determine the effects of resonance, induction, and steric hindrance had on the overall reaction. Three different α-keto amide containing acylating agents were tested to see how the size of the dialkyl groups performed in reactivity, where alkyl=methyl, ethyl, and isopropyl. A range of 14% to 88% was found for products using 2-(diethylamino)-2-oxoacetyl chloride, a range of 13% to 57% was found for products using 2-(dimethylamino)-2-oxoacetyl chloride, and a range of 19% to 84% was found for products using 2-(diisopropylamino)-2-oxoacetyl chloride. Due to the wide range of product yields from these reactions, a series of thermal degradations studies were conducted to determine how fragile the different 2-(dialkylamino)-2-oxoacetyl chloride were at the reaction temperature of 155°C. While the 2-(dialkylamino)-2-oxoacetyl chlorides were stable by themselves at 155°C, they underwent rapid degradation under the presence of cis-Pt(PhCN)2Cl2, as the acylating agents underwent decarbonylation.