Silver‐Promoted Fluorination Reactions of α‐Bromoamides

Abstract

Silver‐promoted C−F bond formation in α‐bromoamides by using AgF under mild conditions is reported. This simple method enables access to tertiary, secondary, and primary alkyl fluorides involving biomolecular scaffolds. This transformation is applicable to primary and secondary amides and shows broad functional‐group tolerance. Kinetics experiments revealed that the reaction rate increased in the order of 3°>2°>1° α‐carbon atom. In addition, it was found that the acidic amide proton plays an important role in accelerating the reaction. Mechanistic studies suggested generation of an aziridinone intermediate that undergoes subsequent nucleophilic addition to form the C−F bond with stereospecificity (i.e., retention of configuration). The synthesis of sterically hindered alcohols and ethers by using AgI is also demonstrated. Examples of reactions of α‐bromoamides with O nucleophiles are presented.

Trifluoromethylthiolation of Hindered α-Bromoamides with Nucleophilic Trifluoromethylthiolating Reagents

“…However, this mechanism alone cannot account for the significant role of the amide NH groups of the α-bromoamides (see Scheme ). In our previous work, the silver-promoted fluorination of ( S )- 3f with AgF in the absence of a base showed stereospecificity with double inversion . This result was consistent with those described previously by D’Angeli and Quast, which implies that a double-inversion process takes place through an N- protonated aziridinone intermediate .…”

“…In our previous work, the silver-promoted fluorination of (S)-3f with AgF in the absence of a base showed stereospecificity with double inversion. 17 This result was consistent with those described previously by D'Angeli and Quast, which implies that a double-inversion process takes place through an N-protonated aziridinone intermediate. 20 Since a base was necessary for this trifluoromethylthiolation reaction to proceed, the formation of a neutral aziridinone intermediate C with concomitant ring opening to transform into D as the second intermediate under basic conditions was also predicted.…”

“…All solvents were purchased from Wako Pure Chemical Industries. α-Bromoamides were prepared according to the protocol described in refs , , .…”

“…To address this issue, we previously reported a hydrofluorination reaction of 3-bromooxindole to form a highly reactive electrophilic o -azaxylylene intermediate with a mild HF source . In addition, the silver-promoted nucleophilic substitution reaction of α-bromoamides with AgF to access sterically hindered fluorides have been reported . With these previous studies in mind, we herein report the development of a method for the synthesis of hindered α-SCF 3 -substituted amides by trifluoromethylthiolation of 3-bromo-oxindoles and α-bromoamides with nucleophilic trifluoromethylthiolating reagents (Scheme D).…”

Transition metal-free ether coupling and hydroamidation enabling the efficient synthesis of congested heterocycles

“…15 Moreover, Mizuta reported the Ag-mediated α-alkoxylations of α-bromocarboxamides. 16 During the course of our study, we discovered that α-bromocarboxamides ( 1 ) react with alkynols ( 2 ) containing tertiary alcohol moieties to produce ethers ( 3 ) or heterocycles ( 4 ) in the absence of a transition metal catalyst. Here, etherification is followed by hydroamidation.…”