N‐Heterocyclic Carbene Catalyzed Concerted Nucleophilic Aromatic Substitution of Aryl Fluorides Bearing α,β‐Unsaturated Amides

Abstract

Concerted nucleophilic aromatic substitution (CSNAr) has emerged as a powerful mechanistic manifold, in which nucleophilic aromatic substitution can proceed in one step without the need to form a Meisenheimer intermediate. However, all of the CSNAr reactions reported thus far require a stoichiometric strong base or activating reagent, and no catalytic variants have yet been reported. Herein, we report an N‐heterocyclic carbene (NHC)‐catalyzed intramolecular cyclization of acrylamides that contain a 2‐fluorophenyl group on the nitrogen through a CSNAr reaction. By using this catalytic method, it is possible to synthesize an array of quinolin‐2‐one derivatives, which are common structural motifs in pharmaceuticals and organic materials. DFT calculations unambiguously revealed that this reaction proceeds through the concerted nucleophilic aromatic substitution of aryl fluorides, in which a stereoelectronic σ (Cipso‐Cβ)→ σ*(Cipso‐F) interaction critically contributes to the stabilization of the transition state for the cyclization.

Polarity Inversion Catalysis by the 1,4-Addition of N-Heterocyclic Carbenes

“…Recently, polarity inversion of aryl acrylamide 40 has enabled the preparation of 2-quinolones 41 (Scheme 12). [20] In this report, Tobisu and coworkers exploit bespoke high-nucleophilicity NHCs (i.e. 42) to give enediamine 43, which then undergoes a concerted aromatic substitution reaction (CS N Ar, supported by computational studies) to give 44 and ultimately the quinolone 41.…”

N-Heterocyclic Carbene-Catalyzed Truce–Smiles Rearrangement of N-Arylacrylamides via the Cleavage of Unactivated C(aryl)–N Bonds

“…Sterically demanding ortho -substituted anilides 1j – 1m also participated in this organocatalytic C–N cleavage reaction. Interestingly, ortho -chloro and ortho -bromo substituents did not undergo nucleophilic aromatic substitution by the postulated ylide intermediate , under these conditions, but rather C–N bond substitution occurred exclusively to form the corresponding cinnamamides 2j and 2k , respectively. One of the advantages of this organocatalytic method over transition metal and photoredox catalysis is the tolerance of halogen groups, as evidenced in the reactions of 1c , 1j , and 1k , which should serve as a synthetic handle for further functionalization .…”

“…We previously reported on the NHC-catalyzed intramolecular concerted nucleophilic aromatic substitution (CS N Ar) of aryl halides bearing an α,β-unsaturated amide moiety, in which a highly nucleophilic ylide species is involved (Scheme D, attack a) . In these reactions, oxygen-based poor leaving groups, such as a OPh and even an a OMe group, can also participate, although C­(aryl)–O bonds are generally assumed to be inert .…”

“…As mentioned above, an ortho bromo group is tolerated in the N7 -catalyzed Truce–Smiles rearrangement of 1k to afford a cinnamamide 2k exclusively. Interestingly, the use of N9 , instead of N7 , as a catalyst led to the formation of a cyclized product 3 as a major product, which was produced by catalytic nucleophilic aromatic substution (Scheme , bottom). , These results demonstrate that a catalyst-controlled selectivity between C–N and C–Br bond cleavage is possible.…”

“…Interestingly, the use of N9, instead of N7, as a catalyst led to the formation of a cyclized product 3 as a major product, which was produced by catalytic nucleophilic aromatic substution (Scheme 3, bottom). 11,13 These results demonstrate that a catalyst-controlled selectivity between C− N and C−Br bond cleavage is possible.…”