Direct Access to Versatile Electrophiles via Catalytic Oxidative Cyanation of Alkenes

Abstract

Nucleophilic attack on carbon-based electrophiles is a central reactivity paradigm in chemistry and biology. The steric and electronic properties of the electrophile dictate its reactivity with different nucleophiles of interest, allowing the opportunity to fine-tune electrophiles for use as coupling partners in multistep organic synthesis or for covalent modification of proteins in drug discovery. Reactions that directly transform inexpensive chemical feedstocks into versatile carbon electrophiles would therefore be highly enabling. Herein, we report the catalytic, regioselective oxidative cyanation of conjugated and nonconjugated alkenes using a homogeneous copper catalyst and a bystanding N-F oxidant to furnish branched alkenyl nitriles that are difficult to prepare using existing methods. We show that the alkenyl nitrile products serve as electrophilic reaction partners for both organic synthesis and the chemical proteomic discovery of covalent protein ligands.

Ligand-accelerated, branch-selective oxidative cyanation of alkenes

“…Furthermore, this catalytic cyanation reaction has been efficiently scaled up by utilizing a continuousflow microreactor. While the manuscript is in preparation, similar work concerning the oxidative cyanation of alkenes has been published [45].…”

Regio‐ and Stereoselective Thianthrenation of Olefins To Access Versatile Alkenyl Electrophiles

“…[11] Alkenyl nucleophiles are available directly from the C(sp 2 ) À H functionalization of alkenes to give alkenyl silane [12] and boronate [13] species, for example. Michael acceptors such as nitroolefins [14] and alkenyl nitriles [15] can also be synthesized from alkenes. Procter and co-workers disclosed the synthesis of alkenyl sulfoniums via an interrupted Pummerer approach, but the reaction is limited to styrene-like substrates.…”

“…[17] The direct synthesis of versatile alkenyl electrophiles from simple olefins by C(sp 2 )ÀH functionalization, however, is as of yet unknown. [12][13][14][15][16]18] Here we fill this gap, and showcase the utility of the alkenyl sulfonium electrophiles in several crosscoupling reactions. The chemistry differs conceptually from prior art because of the unusual mechanism of olefin functionalization, which sets the chemistry apart from arene thianthrenation and other syntheses of alkenyl sulfonium species.…”

“…Steric bulk in the allylic position does not interfere with productive functionalization (6,7). Functional groups such as imide (11), primary alkyl bromide (8), alcohol (9), ether (15,16), amide (17), ester (26-33), ketone (29), piperidine (30), nitro (31), sulfonamide (32), sulfone (33), and nitrile (33) moieties are all tolerated. Electron-rich arenes can undergo aromatic substitution, [19c] but electron-poor (11,13), electron-neutral (12), and six-membered heterocyclic arenes (26, 27, 31) are tolerated.…”

“…[13b, 18, 21] Internal olefins that are electronically biased such as enol ethers (16) are functionalized regioselectively, as are all a-olefins, but the regioselectivity diminishes for other 1,2-disubstituted olefins. [22] Trisubstituted olefins (15) on the other hand are functionalized regioselectively. Cyclic olefins (18,19,20,21) participate well.…”