Uphill Catalysis
Electron Transfer Mediated Cross-Couplings
C-F Functionalization
Uphill Catalysis
Electron Transfer Mediated Cross-Couplings
C-F Functionalization

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  • August 24, 2017

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Electron Mediated Cross-Couplings

Cross-Coupling technology has revolutionized the synthesis of molecules.  The importance was recognized in the 2010 Nobel Prize.  At the heart of this chemistry is the ability to forge a new C–C between two different components.  However, in its traditional form, cross-coupling chemistry utilizes only preactivated components, i.e. organohalides (or pseudohalides) and organometallics.  Inherently, this restricts the utility of the methodology because it necessitates additional synthetic steps to build the reactive molecules.  A less explored strategy to access these types of products is via electron transfer mechanisms, which have the potential to utilize very simple functionalities, i.e. C–H and C–C   bonds, for selective C–C bond formation.  The ability to use such simple functional groups in selective cross-coupling reactions has vast potential when it comes to accessing important chemical spaces.  Recently we have been exploring the nature of the reactive intermediates which can be accessed via photocatalysis.  For representative publications on this topics, see below.  The most recent work is shown first. 

 

 

Amandeep Arora and Jimmie D. Weaver* "Visible Light Photocatalysis for the Generation and Use of Reactive Azolyl and Polyfluoroaryl Intermediates"  Acc. Chem. Res. 2016, ASAP, DOI: 10.1021/acs.accounts.6b00259.

In this review, we discuss the fundamentals of radical anion fragmentation which provides a mechanistic framework from which all of the results can be understood.

Abstract Image

 

 

Arora, A.; Weaver, J. D.,"Photocatalytic Generation of 2-Azoyl Radicals; Intermediates for the Azoylation of Arenes and Heteroarenes via C-H Functionalization" Org. Lett.2016,18,3996.

In this work we further explore the reactivity and possible chemistry of the photocatalytically generated azolyl radical. Specifically, we utilize the radical for direct arylation via C-H functionalization. The ability to use arenes that have undergone no prefunctionalization makes azolylation and the high yields makes this an attractive approach for late-stage functionalization.

Azole arylation

 

 

Arora, A.; Teegardin, K.; Weaver, J. D., "Reductive Alkylation of 2-Bromoazoles via Photoinduced Electron Transfer; a Versatile Strategy to Csp2–Csp3 Coupled Products." Org. Lett.,2015, 17, 3722.

In this publication we explore the effect of moving from a 2-chloroazole to a 2-bromoazole.  In this case, the reactive intermediate appears consistent with that of a 2-azoyl radical.  The photocatalytic conditions employed allow a relatively rare example of very productive intermolecular radical reactions.  Formally, this is a very selective Csp2-Csp3 cross coupling reaction.  From the alkene perspective it is a hydro(azolation)arylation.  From the 2-bromoazole view it is a reductive alkylation.  It is extremely functional group tolerant and engages a broad range of alkenes.  This method should help facilitate access to this important motiff.  

reductive alkylation TOC

 

 

Singh, A.; Arora, A.; Weaver, J. D., "Photoredox-Mediated C-H Functionalization and Coupling of Tertiary Aliphatic Amines with 2-Chloroazoles" Org. Lett.,2013, 15, 5390.

Use of a photocatalyst allows an electron transfer mediated coupling to occur.  This provides a convient method to selectively functionalize the sterically less hindered C-H bond of the amine and provide extremely rapid access to the biologically relevant carbinamine azoles.  Interestingly, this is chemistry is very specific to the 2-chloroazoles.  Use of the 2-bromoazoles results in a completely different type of reactivity, see below.

Abstract Image