Synthesis of Aryldifluoroamides by Copper‐Catalyzed Cross‐Coupling

Abstract

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 practical and catalyst-free trifluoroethylation reaction of amines using trifluoroacetic acid

“…However, the use of fluorine in this field is currently limited to a small number of chemotypes with aryl fluorides being dominant56789. Given the beneficial properties of fluorine, practical new methods that allow access to a more diverse range of medicinally relevant fluorinated building blocks are of particular importance1011121314151617181920212223242526. For example, β -fluoroalkylamines are less basic than their hydrocarbon counterparts (p K a H 10.7 versus 5.7 for ethylamine and trifluoroethylamine respectively)27 and often exhibit decreased acute toxicity and increased metabolic stability rendering them very attractive in pharmaceutical contexts (for examples, see Fig.…”

Catalyst‐Free Csp−Csp3Cross‐Coupling of Bromodifluoroacetamides with 1‐Iodoalkynes under Visible‐Light Irradiation

“…N-Difluoroacetylmorpholines are versatile difluoroalkyl building blocks because their amide moieties can be readily transformed into various functional groups. [16] Thus, we investigated the selective carbonyl transformations of the alkynyldifluoroacetamide product with its alkyne moiety preserved. The reduction of 6 aa was carried out using NaBH 4 (2 equiv) in ethanol at room temperature for 3 h to afford the desired alcohol 13 in 87% yield along with trace amounts of 3fluorofuran 14 a (Scheme 8a).…”

Copper-Mediated Cyanodifluoromethylation of (Hetero)aryl Iodides and Activated (Hetero)aryl Bromides with TMSCF2CN

“…Copper-mediated and copper-catalyzed fluoroalkylation reactions have been developed for the synthesis of trifluoromethylarenes, − aryldifluoromethylesters, , and aryldifluoromethylamides . We sought to develop a coupling of aryl halides with a nucleophilic form of the cyanodifluoromethyl group to address the lack of suitable methods to synthesize aryl-α,α-difluoroacetonitriles rapidly, with broad scope, and in a fashion applicable to compounds of potential biological interest.…”