Ligand-Metal Cooperation Enables C–C Activation Cross-Coupling Reactivity of Cyclopropyl Ketones

Abstract

Activation of C–C bonds has the potential to revolutionize how molecules are made by altering the carbon skeleton and enabling new synthetic routes. Stereodefined cyclopropyl ketones have become readily available and would be an ideal source of linear 3-carbon fragments, but this reactivity is unknown. In this study we show how a new type of C–C activation catalyst, that relies upon a different, metalloradical mechanism, can enable new subsequent reactivity: the cross- coupling of cyclopropyl ketones with organozinc reagents and chlorotrimethylsilane to form 1,3- difunctionalized, ring-opened products. A mixture of experiment and theory sheds light on how cooperation between the redox-active ligand and the nickel catalyst enables the C–C bond activation step, suggesting how this approach could be applied in other systems.

Nickel-Catalyzed Defluorinative Coupling of Aliphatic Aldehydes with Trifluoromethyl Alkenes

“…Ring opening of either a cyclopropylcarbinyl radical or the corresponding organonickel intermediate VI would be expected, but in this case, further rearrangement of the cyclopropane fragment led to the production of compound 11 in 25% isolated yield. A recent study from Weix illustrates ring-opening processes of cyclopropyl aldehydes, and provides deep insights into the mechanism of how intermediate VII can be produced directly from 1q under conditions similar to those described in this report. Additionally, we attributed reactivity of 1a with redox-active esters to be derived from intermediates similar to VII in our recent report of aldehyde/redox-active ester couplings .…”

“…We attribute this difference to be the result of the changes in the ligand structure between redox-active ester couplings (BiOx) and trifluoromethyl alkene couplings ( L1 ). While we originally envisioned that VII was likely derived from VI , the recent evidence from Weix illustrating the direct formation of VII from 1q is detailed and convincing . Formation of a ketyl radical through homolysis of VI would not afford the rearranged constitution of 11 unless recombination of the radical with nickel again leads to intermediate VII .…”

AlCl3‐Promoted Conia‐Ene‐Related Cyclization of α,ω‐Diethylenic Ketones and 1,2‐ or 1,3‐Hydroalkenylation of Unactivated Cyclopropanes

“…[22] Recently, Weix merged the use of redox-active ligands and Nicatalyzed cross-couplings to develop a general CÀ C activation of cyclopropyl ketones, notably able to provide hydroalkenylation products. [23] Inoue performed an oxidative radical alkenylation of 1-cyclopropyl-1-ethanol, where the secondary alcohol was essential for generating the initial radical. [24] Schröder performed the intramolecular hydroalkenylation of a non-functionalized trisubstituted cyclopropane, whose activation by a gem-dimethyl group afforded a tertiary carbocation after ring-opening.…”

Nickel-Catalyzed Decarboxylative Coupling of Redox-Active Esters with Aliphatic Aldehydes

“…In this case, we attribute ring-opening of the cyclo- propane unit to a nickel-catalyzed process involving the intermediacy of 15, potentially involving the initial oxidative addition of a low-valent nickel species to the aldehyde, promoted by Et 3 SiCl. 15,22 An experiment employing stoichiometric Ni(cod) 2 but lacking the zinc reductant resulted in the formation of product 3a in high yield, suggesting that key organonickel intermediates involved in product formation do not require reduction at the nickel center but rather that the zinc reductant is involved in catalyst regeneration (Scheme 2D).…”