metallacycle intermediate IM2 [12]. Then, the gem-dibromoolefin reacts with IM2 generates the complex IM3, which undergoes a
reductive elimination to afford IM4. Next, IM4 transforms to IM5 through an oxidative addition. Finally, the reductive elimination of
IM5 gives the desired product 3 or 4.
To demonstrate the practicability of our synthetic method, the removal of the directing group was performed [8b]. Gratifyingly, the
2-pyridylmethyl directing group can be readily detached. Adding lithium diisopropylamide (LDA) dropwise in the solution of 3a at -78
ºC and then continuously bubbling O2 for a while, an N-H free γ-lactam 5 was obtained in excellent yield (Scheme 4).
In conclusion, a highly efficient palladium-catalyzed 2-pyridylmethyl-directed β-C(sp3)–H activation and cyclization of aliphatic
amides with gem-dibromoolefins has been developed to construct a variety of γ-lactam derivatives. The reaction can proceed well
under air atmosphere, possessing the merit of operational simplicity. Moreover, the 2-pyridylmethyl directing group can be readily
detached to afford an N-H free γ-lactam. In addition, the Z- and E-isomers of all products could be easily separated and purified after
the reaction, demonstrating the effectiveness and applicability of the method herein developed. In addition, kinetic isotope experiments
indicate that the β-C(sp3)−H cleavage of the amide substrate was involved in the rate-determining step.
Acknowledgment
We are grateful for the financial supports from the National Natural Science Foundation of China (Nos. 21672154 and 21372164).
We thank the Comprehensive Training Platform of Specialized Laboratory, College of chemistry, Sichuan University, for NMR
measurements and HRMS measurements.
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