Studies On The Dichlorinative Deamidation Of ?-ketoamides In One-pot

In the practice of organic chemistry,both the elongation and shortening of carbon chains possess identical importance.Amides are a significant functional group and capable of being transformed by hydrolyzing the cyano group or oxidizing the ?-carbon of the amino group.Amides can be further derivatized to important functional groups such as carboxylic acids,esters,acyl halides and oxazoles,all of which have been extensively applied in the synthesis of pharmaceuticals,natural products and important organic polymers.Deamidation is of significance in organic synthesis,and the deamidation of the ?-ketoamide derivatives has been applied to the total synthesis of organochlorine insecticides,Martinin,antitumor antibiotics natural products.Halogenation is an important reaction in organic synthesis.The introduction of halogen into the molecules by halogenation enhances the polarity of the molecules and change their reactivity.Organic chlorides play an extremely important role in organic synthesis.For example,?-chloro ketones have emerged as essential building blocks toward natural products and pharmaceutical compounds,pesticides,disinfectants,herbicides,fungicides and others,have a particularly wide range of applications.In this work,an approach for the dichlorinative deamidation of primary ?-ketoamides through a ketonic cleavage process in one-pot is described.In the tentative research of halogenation of the ?-ketoamides,tertiary ?-ketoamide led to dichlorination without deamination,secondary ?-ketoamide provided the dichlorinated amide through an acidic cleavage,and primary ?-ketoamide gave rise to dichlorinated ketone through a ketonic cleavage.For primary ?-ketoamide as subtrates,no dichlorinative deamidation of ?-ketoamide has been developed to date.The reaction conditions are optimized initially,the optimal method is used,NCS(2.0 equiv,1 mmol)is used as a chlorinating agent,under t-BuOK(2.0 equiv,1 mmol)and a series of ?,?-dichloroketones are furnished mostly in the presence of TEMPO(2.0 equiv,1 mmol)in moderate to good yields.To gain an insight into this transformation,several control experiments for the deamidation of ?-chlorinated and ?,?-dichlorinated ?-ketoamides were conducted.Without addition of NCS,the deamidation of 2-chloro-3-oxo-3-phenylpropanamide to obtain an ?-chloroketone did not proceed.When 1.0 equivalent of NCS was added under the same reaction conditions,the deamidation product 2,2-dichloroacetophenone was generated in 77% yield.?,?-dichlorinated ?-ketoamide 2,2-dichloro-3-oxo-3-phenylpropanamide directly underwent deamidation to provide 2,2-dichloroacetophenone in 71% yield,but the deamidation process failed to proceed with the addition of 2.0 equivalents of TEMPO.Thus,we speculate that this deamidative transformation goes through dichlorination and deamidation reactions.In the presence of TEMPO,2,2-dichloro-3-oxo-3-phenylpropanamide did not yield product 2,2-dichloroacetophenone,which indicates that TEMPO facilitates the dichlorination and is detrimental to the second step,i.e.,deamidation.Based on control experiments,a mechanism involving tandem process of dichlorination and deamidation is proposed to interpret the observed reactivity.