Ligand-promoted palladium-catalyzed β-methylene C–H arylation of primary aldehydes

Abstract

The transient directing group (TDG) strategy allowed long awaited access to the direct β-C(sp3)−H functionalization of unmasked aliphatic aldehydes via palladium catalysis. However, the current techniques are restricted to terminal...

Surpassing the Limited Coordination Affinity of Native Amides by Introducing Pyridone-Pd-AgOAc Clusters to Promote Distal γ-C(sp3)–H Arylation

“…Consequently, reductive elimination can occur via a three-membered ring transition state TS3′ , entailing a high barrier of 34.9 kcal mol –1 . Alternatively, the trifluoroacetate-coordinated intermediate Int5 is formed after a thermodynamically favorable and irreversible iodine abstraction by silver trifluoroacetate AgTFA …”

“…Alternatively, the trifluoroacetate-coordinated intermediate Int5 is formed after a thermodynamically favorable and irreversible iodine abstraction by silver trifluoroacetate AgTFA. 29 Int5 then undergoes reductive elimination via TS3 (ΔG ‡ = 27.3 kcal mol −1 ), facilitating C(sp 2 )−C(sp 3 ) coupling between the aryl group and the aliphatic amide to yield a stable intermediate Int6, where the arylated product is coordinated to the Pd(II) center. Finally, Int6 reacts with acetic acid to regenerate 1/ 3(PdOAc 2 ) 3 , 1/2 (AgOAc) 2 , and trifluoroacetic acid (TFA) and release the product.…”

“…This includes iodine abstraction by the AgTFA before reductive elimination, decreasing the possibility of backward conversion and promoting further steps by releasing the AgI precipitate. 29 Coordination of the TFA ligand makes reductive elimination more facile than iodidecoordinated reductive elimination. Experimental findings show that applying TFA as an acidic additive increases the yield by a reasonable amount, corroborating the obtained computational results.…”

C−H Functionalization of Aldehydes and Ketones with Transient Directing Groups: Recent Developments

“…Until recently, only methyl or cyclic CÀ H bonds were successfully activated but, in 2022, Dang, Maiti and Ge reported the first example of palladium-catalyzed methylene β-CÀ H arylation of primary aldehydes 92 (Scheme 24.c). [57] Employing 3-amino-3-methylbutanoic acid as TDG, mono-βarylated primary aldehydes were synthesized in good yield. At the same time, Yu's group reported a regioselective CÀ H arylation of primary aldehyde 94 and, in function of the employed amine which affects the bite angle of the TDG, βor γ-arylation was observed (Scheme 24.d).…”

“…In this case, a [6,5]‐bicyclic palladium intermediate was proposed to explain the regioselectivity. Until recently, only methyl or cyclic C−H bonds were successfully activated but, in 2022, Dang, Maiti and Ge reported the first example of palladium‐catalyzed methylene β‐C−H arylation of primary aldehydes 92 (Scheme 24.c) [57] . Employing 3‐amino‐3‐methylbutanoic acid as TDG, mono‐β‐arylated primary aldehydes were synthesized in good yield.…”