Broad-Scope Rh-Catalyzed Inverse-Sonogashira Reaction Directed by Weakly Coordinating Groups

Area of Science:

• Organic Chemistry
• Catalysis
• Synthetic Methodology

Background:

• Direct C-H functionalization offers a more atom-economical approach to molecule synthesis compared to traditional cross-coupling methods.
• The inverse-Sonogashira reaction, involving alkynylation of C-H bonds, remains an underexplored area in synthetic chemistry.
• Developing robust catalytic systems for directed C-H alkynylation is crucial for expanding synthetic capabilities.

Purpose of the Study:

• To develop a rhodium-catalyzed inverse-Sonogashira reaction for the alkynylation of C(sp2)-H bonds.
• To investigate the scope of directing groups for this transformation, including common and less common functionalities.
• To elucidate the reaction mechanism, focusing on the C-H activation step.

Main Methods:

• Rhodium-catalyzed cross-coupling reaction between C(sp2)-H bonds and bromoalkynes.
• Utilizing directing groups such as esters, ketones, ethers, amines, thioethers, and sulfoxides to guide the regioselectivity of C-H activation.
• Performing mechanistic studies, including kinetic analyses and isotopic labeling, to understand the reaction pathway.

Main Results:

• Successful alkynylation of C(sp2)-H bonds was achieved using a variety of directing groups, including synthetically useful ester, ketone, and ether functionalities.
• The reaction demonstrated tolerance for less common directing groups like amine, thioether, sulfoxide, sulfone, phenol ester, and carbamate.
• Mechanistic investigations revealed that the reaction proceeds via a turnover-limiting C-H activation step, consistent with an electrophilic-type substitution pathway.

Conclusions:

• The developed rhodium-catalyzed inverse-Sonogashira reaction provides an efficient method for C(sp2)-H alkynylation.
• The broad scope of directing groups highlights the versatility and practical applicability of this synthetic strategy.
• Understanding the C-H activation mechanism offers insights for further catalyst design and reaction optimization.