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A copper-catalyzed coupling of aryl, heteroaryl, and vinyl iodides with α-silyldifluoroamides is reported. The reaction forms α,α-difluoro-α-aryl amides from electron-rich, electron-poor, and sterically hindered aryl iodides in high yield and tolerates a variety of functional groups. The aryldifluoroamide products can be further transformed to provide access to a diverse array of difluoroalkylarenes, including compounds of potential biological interest. Graphical AbstractKeywords enolate arylation; difluoroamide; cross-coupling; fluorine; copper Fluorinated compounds are common in pharmaceuticals, agrochemicals, and materials, due to their favorable biological and physical properties. [1] In medicinal chemistry, fluorinated substituents can alter the lipophilicity, metabolic stability, and overall activity of biologically active compounds, relative to their non-fluorinated counterparts. [2] The difluoromethylene (CF 2 ) group has particular value because it is considered a bioisostere of carbonyl groups and ethers [3] and can modulate the pK a of neighboring functional groups, such as amines. [4] Aryldifluoroamides are present in several biologically active compounds, including the inhibitor of FKBP12 [3] and the modulator of AMPAR [5] shown in Figure 1. Moreover, amides can be transformed into amines, alcohols, acids, esters, and ketones, making aryldifluoroamides versatile precursors to a variety of difluoroalkylarenes. Despite the biological and synthetic potential of this class of compound, current methods for the synthesis of difluoroamides are limited. Aryldifluoroamides can by prepared by ** The authors thank NIH (GM058108) for support of this work. S. I. A. acknowledges the NSF for a graduate fellowship. We thank Dr. Patrick S. Fier for the synthesis of (Z)-iodooctene.
A copper-catalyzed coupling of aryl, heteroaryl, and vinyl iodides with α-silyldifluoroamides is reported. The reaction forms α,α-difluoro-α-aryl amides from electron-rich, electron-poor, and sterically hindered aryl iodides in high yield and tolerates a variety of functional groups. The aryldifluoroamide products can be further transformed to provide access to a diverse array of difluoroalkylarenes, including compounds of potential biological interest. Graphical AbstractKeywords enolate arylation; difluoroamide; cross-coupling; fluorine; copper Fluorinated compounds are common in pharmaceuticals, agrochemicals, and materials, due to their favorable biological and physical properties. [1] In medicinal chemistry, fluorinated substituents can alter the lipophilicity, metabolic stability, and overall activity of biologically active compounds, relative to their non-fluorinated counterparts. [2] The difluoromethylene (CF 2 ) group has particular value because it is considered a bioisostere of carbonyl groups and ethers [3] and can modulate the pK a of neighboring functional groups, such as amines. [4] Aryldifluoroamides are present in several biologically active compounds, including the inhibitor of FKBP12 [3] and the modulator of AMPAR [5] shown in Figure 1. Moreover, amides can be transformed into amines, alcohols, acids, esters, and ketones, making aryldifluoroamides versatile precursors to a variety of difluoroalkylarenes. Despite the biological and synthetic potential of this class of compound, current methods for the synthesis of difluoroamides are limited. Aryldifluoroamides can by prepared by ** The authors thank NIH (GM058108) for support of this work. S. I. A. acknowledges the NSF for a graduate fellowship. We thank Dr. Patrick S. Fier for the synthesis of (Z)-iodooctene.
A copper-catalyzed coupling of aryl, heteroaryl, and vinyl iodides with α-silyldifluoroamides is reported. The reaction forms α,α-difluoro-α-aryl amides from electron-rich, electron-poor, and sterically hindered aryl iodides in high yield and tolerates a variety of functional groups. The aryldifluoroamide products can be further transformed to provide access to a diverse array of difluoroalkylarenes, including compounds of potential biological interest. Graphical AbstractKeywords enolate arylation; difluoroamide; cross-coupling; fluorine; copper Fluorinated compounds are common in pharmaceuticals, agrochemicals, and materials, due to their favorable biological and physical properties. [1] In medicinal chemistry, fluorinated substituents can alter the lipophilicity, metabolic stability, and overall activity of biologically active compounds, relative to their non-fluorinated counterparts. [2] The difluoromethylene (CF 2 ) group has particular value because it is considered a bioisostere of carbonyl groups and ethers [3] and can modulate the pK a of neighboring functional groups, such as amines. [4] Aryldifluoroamides are present in several biologically active compounds, including the inhibitor of FKBP12 [3] and the modulator of AMPAR [5] shown in Figure 1. Moreover, amides can be transformed into amines, alcohols, acids, esters, and ketones, making aryldifluoroamides versatile precursors to a variety of difluoroalkylarenes. Despite the biological and synthetic potential of this class of compound, current methods for the synthesis of difluoroamides are limited. Aryldifluoroamides can by prepared by ** The authors thank NIH (GM058108) for support of this work. S. I. A. acknowledges the NSF for a graduate fellowship. We thank Dr. Patrick S. Fier for the synthesis of (Z)-iodooctene.
The use of unsymmetric diaryliodonium salts as a versatile class of arylating agents has been demonstrated by developing a novel strategy to quickly access α-arylated α-fluoroacetoacetamides. The protocol provides a convenient metal-free method for the α-arylation of a diverse class of fluorinated acetoacetamides, and the products are obtained in good yields. The strategy, upon use of electrondeficient diaryliodonium salts as an arylating agent, provides α-fluoroacetamides through a spontaneous arylation/deacylation cascade. Nowadays, the introduction of fluoroalkyl groups into arenes has become a common practice in medicinal chemistry to improve the biological properties of drug candidates. [1] Obviously, this is attributed to the unique electronic features possessed by fluorine, which, unlike the other halogens, often refine the biological properties, including metabolic stability, permeability, and protein binding affinity. [2] These medicinal applications and the widespread use in material science have fuelled the development of practical methods for introducing fluorinated units into arenes. [3] As such, the past two decades have witnessed remarkable progress in devising strategies for the effective preparation of F-and CF 3-containing arenes. [4,5] However, this field has been dominated by metal-catalyzed trifluoromethylation and fluoroalkylations. [6] Aromatic compounds containing α-fluorocarbonyl groups are of particular interest as non-enolizable analogues of the corresponding arylacetamides. [7] However, a vast majority of the methods to synthesize them utilize Pd or Cu catalyzed coupling reactions of aryl halides with fluoroenolates. [8] Given the importance of this class of compounds in drug discovery, a complementary method that obviates the need of expensive catalysts, harsh conditions and directly uses simple and readily available substrates would be highly important. Recently, diaryliodonium salts have become broadly applied arylating agents for metal-catalyzed and metal-free electrophilic [a] M.
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