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Aryl substrate reactions reveal more about the field of alkene dicarbofunctionalization

28 July 2022

In 2017, the Giri lab reported a novel method to form two carbon-carbon bonds off an alkene in a single step, known as alkene dicarbofunctionalization, utilizing a removable coordinating group to ward off unwanted side products. Using earth abundant, late first row transition metals, they demonstrated a powerful and efficient synthetic tool useful in the synthesis of pharmaceuticals and other small molecules from simple alkene feedstock chemicals. This coordinating group strategy slows bond rotation in key catalytic intermediates with aliphatic C-H bonds present able to undergo b-H elimination and give Heck type products. Stabilization of these intermediates allow a second carbon group to be installed giving higher utility to the dicarbofunctionalization reaction. 

The original work involved diarylation, in which two aryl groups are installed regioselectively across an alkene. However, aryl substrates were discovered over time to be far easier due to faster reductive elimination and a small number of aliphatic C-H bonds present at key catalytic steps leading to undesired Heck products. With the introduction of more b-H’s, avoiding Heck products with alkylorganometallic reagents is a major challenge that the lab members worked to solve with coordinating strategy due to the presence of alkyl groups in pharmaceuticals.  

In June 2022, the Giri lab published a paper with the online science journal, ACS Publications, highlighting their new discoveries. The paper discusses how they are continuing to work on expanding the scope of this reaction to every possible class of substrate, and each new reaction reveals more about the field of alkene dicarbofunctionalization.  

 

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Challenges of using C(sp3)-organometallic reagents in alkene dicarbofunctionalization reactions 

 

In this paper, the lab group reported nickel-catalyzed regio- and stereoselective alkylarylation of unactivated alkenes in g,d-alkenylketimines in which electron deficient alkenes have a remarkable reaction rate enhancing effect in achieving the dicarbofunctionalized product as observed from monitoring the reaction in real time by in situ 19F NMR.  

 

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Ni-catalyzed alkylarylation reaction using C(sp3)-organometallic reagents and aryl halides in alkenyl ketimines 

 

On exploring the scope of alkylarylation reaction, it allows for use of both terminal as well as internal alkenes with complete stereoselectivity as confirmed from the X-ray crystallography. More importantly, both primary and secondary nucleophilic C(sp3)-alkylorganozinc reagent with or without functional groups works efficiently offering broader scope for use of alkylorganozinc reagents. The reaction also tolerates various functional groups on electrophilic aryl halides regardless of electronic effects of those functional groups in this alkylarylation reaction. Significantly, the potential application of this method can be underlined when applied to synthesizing various drug derivatives as shown below. 

 

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Examples of heterocycles and drug derivatives in alkylarylation reaction

 

Media Contacts
Vivek Aryal
Kathryn Harlow
Chemistry Communications Coordinator