The Effect of the Leaving Group in N-Heterocyclic Carbene-Catalyzed Nucleophilic Aromatic Substitution Reactions

Abstract

We report here that the reactivity order of the leaving group is F > Cl ≥ Br > I in N-heterocyclic carbene-catalyzed CSNAr reactions of aryl halides bearing an α,β-unsaturated amide. Based on a qualitative Marcus analysis, the nature of the transition state in this catalytic CSNAr is primarily determined by the potential energy of the Meisenheimer complex, even though it is not involved as a discrete intermediate in the reaction pathway.

Catalytic C(sp2)–C(sp3) Bond Formation of Methoxyarenes by the Organic Superbase t-Bu-P4

“…1 Indeed, the reaction is frequently used in medicinal chemistry. 2 Catalytic systems with a transition metal and an organocatalyst were established for achieving efficient reactions: 1,3,4 the former uses an electron-deficient ruthenium complex to enhance the electrophilicity of arenes by η 6coordination; 3 the latter employs N-heterocyclic carbene, 4a,b acridinium and xanthylium salts, 4c phosphazene base, 4d and amide base 4e for the activation of arenes or pronucleophiles. The protocol, however, generally requires the use of an additional stoichiometric chemical reagent (base, silane additive, or sometimes an excess amine pronucleophile) to trap the generated acid or prepare a nucleophilic anionic species from the pronucleophile.…”

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

“…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.…”

“…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 . The broad scope of leaving groups led us to envision that α,β-unsaturated amides without any leaving groups at the ortho position would direct the attack of the ylide nucleophile to the most electrophilic ipso carbon of the anilide substrate to undergo the Truce–Smiles rearrangement (Scheme D, attack b).…”

“…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 .…”

“…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.…”