English

Dehydrogenative Annulation of γ, δ-Unsaturated Amides and Alkynes via Double C―H Activation

• WANG Zhen ^§, ,
• LI En ^§, ,
• HE Zhiqi ,
• CHEN Jiean ^, ,
• HUANG Yong ^,

• State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Shenzhen Graduate School, Peking University, Shenzhen 518055, Guangdong Province, P. R. China

Corresponding author: CHEN Jiean, chenja@pkusz.edu.cn; HUANG Yong, huangyong@pkusz.edu.cn

• Received Date: 27 November 2018
  Accepted Date: 21 December 2018
  Revised Date: 12 December 2018
  Available Online: 01 September 2019
• Fund Project:

  The project was supported by the National Natural Science Foundation of China (21825101, 21572004, 21602007), Shenzhen Basic Research Program, China (JCYJ20170818085510474, JCYJ20170818085438996)

Abstract: Pyridones represent an important family of heterocycles that exhibit a wide range of biological activities. They are often found in pharmaceutical agents and biomolecules. Several transition-metal-catalyzed transformations have been developed to access this family of heterocycles. Among them, C―H bond activation has recently emerged as a general strategy for the construction of substituted pyridones. In most cases, the core nitrogen-containing heterocycle is assembled via the dehydrogenative annulation of α, β-unsaturated amides and alkynes. Such processes involve a cascade sequence of N―H cleavage, sp² C―H activation, and annulation. Despite this progress, the more readily available α, β-saturated amides are rarely used. Ideally, tethering the direct dehydrogenation of an amide with the above-mentioned C―H annulation cascade would give a more practical synthesis of pyridones. Nevertheless, the dehydrogenation of amides under mild conditions is a synthetic challenge due to their intrinsic weak α-acidity. Recently, we have reported a general protocol for the aerobic dehydrogenation of γ, δ-unsaturated amides, acids, and ketones. A key Ir―allyl intermediate was believed responsible for enhancing the α-acidity of the amides studied, which enables the dehydrogenation step to occur under mild reaction conditions. Herein, we describe a new method for the synthesis of polysubstituted pyridones using γ, δ-unsaturated amides and alkynes. In the presence of [RhCp*Cl₂]₂, the dehydrogenation step occurs via β-C―H bond activation. The resulting π-allyl―Rh intermediate undergoes an accelerated dehydrogenation reaction to afford the doubly unsaturated amide. This in-situ generated dienamide undergoes sp² C―H activation at the β-position and a subsequent alkyne insertion/cyclization reaction to yield the target heterocycle. Regeneration of the Rh catalyst is accomplished using an external oxidant and completes the streamlined double C―H activation and double dehydrogenation catalytic cycle. Various functional groups are well tolerated. The γ-alkenyl moiety not only facilitates the direct dehydrogenation of amides, but also serves as a handle for further derivatization of the as-obtained products. To gain a mechanistic insight into the reaction cascade, a set of control experiments were carried out. The results demonstrate that the dienamide is one of the key reaction intermediates. NMR experiments confirmed that the fast dehydrogenation process occurs during the early stage of the reaction. The alkyne insertion is believed to be the rate-determining step in the reaction cascade, as suggested by competition experiments.

Key words:
• Rh(III) catalysis
•  /  C―H activation
•  /  Dehydrogenation
•  /  Annulation
•  / 

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