Alcohols as Fluoroalkyl Synthons: Ni‐catalyzed Dehydrogenative Approach to Access Polyfluoroalkyl Bis‐indoles

Abstract

An acceptorless dehydrogenative strategy for the synthesis of polyfluoroalkylated bis‐indoles is described by employing an earth‐abundant nickel‐based catalytic system under air. The notable feature of the present transformation is the use of bench stable and easily affordable polyfluorinated alcohols without any pre‐functionalization for the introduction of precious polyfluoroalkyl groups. The developed straightforward protocol accomplished biologically relevant fluoroalkyl bis‐indoles in a sustainable fashion. Extensive DFT study predicts the unique role of indole molecules which stabilizes the transition states during the dehydrogenation process of polyfluorinated alcohols, presumably through non‐covalent π⋅⋅⋅π and H‐bonding interactions.

Recent Advances in Nonprecious Metal Catalysis

“…A direct approach for the synthesis of polyfluoroalkylbis­(indole) systems was developed by Arun, Roy, and De Sarkar . The strategy is based on nickel-catalyzed dehydrogenative coupling of indoles with polyfluorinated alcohols.…”

“…A direct approach for the synthesis of polyfluoroalkylbis-(indole) systems was developed by Arun, Roy, and De Sarkar. 44 The strategy is based on nickel-catalyzed dehydrogenative coupling of indoles with polyfluorinated alcohols. The reaction requires an elevated temperature (135 °C) for an extended time (24 h) to form the dimeric structures in moderate to good yields.…”

Regio-Selective C3- and N-Alkylation of Indolines in Water under Air Using Alcohols

“…Owing to the appealing importance of functionalized indoles, using alcohols, C–H bond functionalization of indoles has been studied extensively. , Also, the N–H bond functionalization of indolines with alcohols is well documented in literature studies. , Recently, Wang and Rueping group reported a remarkable synthesis of C3- and N-alkylated indoles from indolines and alcohols. , However, most of the C3-/N-alkylation reactions of indoles/indolines were carried out in organic solvents such as toluene, , trifluoroethanol, o -xylene, and so forth. − Hence, to develop a greener protocol and inspired by the recent advancement on C–H functionalization in water, we were interested to explore the dehydrogenative alkylation of indolines using alcohols in water which is still out of common.…”

Tertiary Amides as Fluoroalkyl Aldehyde Surrogates: Access to meso-Fluorinated Bis(heteroaryl)methanes

“…The most common reagent, commercially available trifluoroacetaldehyde hemiacetal, is moisture-sensitive, leading to the formation of a less reactive hydrate that needs acidic activation or dehydration under harsh conditions (high temperature) and desiccants . Another strategy is based on in situ oxidation of trifluoroethyl alcohol by Cu- or Ni-catalyzed couplings. , This elegant approach utilizes inexpensive transition metal salts and ligands but requires a high temperature and a large amount of fluorinated alcohol, which could be discouraging. An intriguing reagent capable of being a trifluoroalkyl donor is halothane, which undergoes a sulfinatodehalogenation, providing fluorinated radicals amenable to reaction with pyrroles .…”

“…10 Another strategy is based on in situ oxidation of trifluoroethyl alcohol by Cu-or Ni-catalyzed couplings. 11,12 This elegant approach utilizes inexpensive transition metal salts and ligands but requires a high temperature and a large amount of fluorinated alcohol, which could be discouraging. An intriguing reagent capable of being a trifluoroalkyl donor is halothane, which undergoes a sulfinatodehalogenation, providing fluorinated radicals amenable to reaction with pyrroles.…”