Aryl sulfinamides allow for aminoarylation of unactivated alkenes

Alkene aminoarylation is a desirable process, but the functionalization of unactivated alkenes has remained a challenge. The use of aryl sulfinamides allows for the functionalization of unactivated alkenes through a radical Smiles-Truce rearrangement.
Published in Chemistry
Aryl sulfinamides allow for aminoarylation of unactivated alkenes

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Arylethylamines are a privileged pharmacophore present in a wide range of biologically active compounds including endogenous neurotransmitters, natural products, and pharmaceuticals. Due to the inherent structural modularity of arylethylamines, rapid exploration of this chemical space in drug discovery would be enabled by development of a one-step synthetic approach for arylethylamines. Alkene functionalization (e.g. carboamination) has become a popular strategy for multicomponent arylethylamine assembly; however, current approaches are limited by the necessity of activating or directing groups, an intramolecular tether, or an azide as the nitrogen source.

In the Stephenson Lab, our own approach to alkene aminoarylation utilizes a radical Smiles-Truce rearrangement of aryl sulfonamides, in which desulfonylative 1,4-aryl migration furnishes a new C–C bond to an arene. Our seminal work in this area relied on capture of the sulfonamide using electron-rich alkenes oxidized to their radical cation form. In 2022, we reported that ortho-substitution of the arene was necessary for intramolecular aminoarylation of unactivated alkenes, as the absence of ortho-groups results in arene dearomatization. As we sought to develop an intermolecular variant of this transformation, we were unfortunately limited by competitive phenol formation. This led us to hypothesize that if we instead used aryl sulfinamides, thus lowering the oxidation state of the sulfur atom, the desired Smiles-Truce rearrangement would occur. We were encouraged by the viability of our hypothesis due to a recent report by the Nevado Lab describing a sulfinyl Smiles-Truce rearrangement.

To test this hypothesis, we subjected the acylated para-tolyl sulfinamide and norbornene to reaction conditions using a weakly oxidizing iridium photocatalyst. Excitingly, this afforded us the aminoarylated norbornene product in 35% yield. Screening conditions on a fluorinated sulfinamide with an unactivated alkene allowed us to find the benefits of using an inorganic base in a biphasic mixture of water and DCE.

The task then became to test the limits of this chemistry! We were pleased to observe the robustness of this approach across a variety of electronically-diverse sulfinamides, including heterocycles and those with halide substitutions. Additionally, a wide range of alkenes were suitable for this chemistry, including those allowing us to access drug targets in an efficient route.

A number of mechanistic studies helped us to propose the following: oxidative N-centered radical generation is followed by alkene addition. At this point, a radical Smiles-Truce rearrangement occurs and reductive N-desulfinylation affords the aminoarylated product. We then tested the power of these chiral sulfinamides to influence the stereochemistry of the products. Gratifyingly, we found significant enantioselectivity when using one enantiomer of a sulfinamide substrate. This enantioselectivity could even be improved by using lower reaction temperatures and longer reaction times!

This study lays the foundation for efficient alkene aminoarylation using mild conditions. We hope this work will add nicely to the field of activating challenging substrates in creative ways. We invite you to read the full study here!

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Physical Sciences > Chemistry > Organic Chemistry > Photochemistry
Organic Chemistry
Physical Sciences > Chemistry > Organic Chemistry
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