Palladium-Catalyzed Benzylic Addition of 2-Methyl Azaarenes to N-Sulfonyl Aldimines via C−H Bond Activation

Abstract

An efficient protocol for the generation of amines by palladium-catalyzed nucleophilic benzylic addition of 2-methyl-substituted azaarenes to N-sulfonyl aldimines under neutral conditions via C-H bond activation has been developed. This reaction represents a very efficient methodology for the synthesis of heterocycle-containing amines and thus opens a new way to access amines through C-H bond activation.

Lewis Acid Promoted Benzylic Cross‐Couplings of Pyridines with Aryl Bromides

“…[4][5][6] In addition, whereas 2-picoline (1 a) can be functionalized in this way, the arylation of 4-picoline (2 a) has not been described. The difficulty in forming a new carbon-carbon bond with metalated 2-picoline (3; or 4-picoline) may be due to the nature of the palladium complexes [7] (4 a-c) resulting from the reaction with ArPdX (Scheme 1). We anticipate that all of these possible structures are reluctant to undergo a reductive elimination because of the chelation of the heterocyclic nitrogen with the Pd center.…”

Lewis Acid‐Catalyzed CH Functionalization for Synthesis of Isoindolinones and Isoindolines

“…Intriguingly, the regioselectivity is in sharp contrast to our previous results achieved with palladium as a catalyst, where 1j'a was obtained as the major product. [7] To rationalize this observation, both intermolecular (k H /k D = 1.7) and intramolecular (k H / k D = 1.5) kinetic isotope effects experiments were conducted under the standard conditions (see Supporting Information). The KIE data shown here are much less extensive than those obtained in the case of the Pd-catalyzed protocol.…”

“…[5] While significant success had been achieved, the apparent need for the activation group in all these catalytic reactions requires additional steps which lengthen the procedures. Another intelligent approach reported by Hiyama and Li involved the use of a catalytic amount of a Lewis acid as activator for enhancing the acidity of C2-H. [6] Intrigued by these elegant works and our recent efforts on the Pd-catalyzed benzylic addition of 2-methyl-A C H T U N G T R E N N U N G azaarenes to aldimines, [7] we envisaged that Lewis acids could also enhance the Brønsted acidity of the benzylic C À H bond of 2-substituted azaarenes and the enhanced acidity of the benzylic C À H in complex A would favor C À H cleavage that is facilitated by the endogenous basic counteranion of the Lewis acid or the basic electrophile (external base) to generate the metal enamide B. [8] The in situ formed active metal enamide species B would react with some appropriate electrophiles to afford the C À H functionalized product 1 (Scheme 1).…”

“…To test this possibility, and based on our previous work on the palladium-catalyzed benzylic addition of 2-substituted azaarenes to aldimines for the synthesis of heterocycle-containing amines, [7] we attempted the reaction of 2,6-lutidine 2a with tosylimine 3a in the presence of Lewis acids to provide the addition product 1aa. To our delight, when the reaction mixture was treated with 10 mol% of AlCl 3 , the benzylic addi-tion reaction indeed proceeded readily at 120 8C in 1,4-dioxane to give the desired product in satisfactory yield (Table 1, entry 1, 62% yield).…”

“…The KIE data shown here are much less extensive than those obtained in the case of the Pd-catalyzed protocol. [7] The deuterium exchange of 2j by treatment with ScA C H T U N G T R E N N U N G (OTf) 3 in D 2 O reveals that the benzyl sp 3 site adjacent to the phenyl group exchanges at a significantly faster rate than the methyl sp 3 site (see Supporting Information). This result suggests that the thermodynamically more favored intermediate D should be generated more quickly than intermediate C in the C À H cleavage step.…”