Mechanism and Origin of Chemoselectivity of Ru-Catalyzed Cross-Coupling of Secondary Alcohols to β-Disubstituted Ketones

Abstract

Ru-catalyzed cross-coupling of secondary alcohols with only byproducts H 2 and H 2 O provides a green synthetic strategy to prepare β-disubstituted ketones. Density functional theory (DFT) calculations were performed with the coupling of 1-phenylethanol and cyclohexanol as a model reaction to gain deeper mechanistic insights herein. The mechanistic details of the main reaction and the key steps of possible side reactions were clarified, and the obtained results are consistent with reported selectivity. Hydrogenation of α,β-unsaturated ketones and dehydrogenation of ruthenium hydride intermediate are direct chemoselectivity-determining stages. The hydrogenation via 1,4-addition generates more stable intermediates, being favored over that via 1,2-addition, and thus avoids the formation of alkene products. The conjugation and π−π stacking effects of phenyl and the weak electronic effect of alkyls explain the dominance of specific ketone products in the hydrogenation stage. Hydrogenation of ketone products is kinetically operative but not exergonic enough to stop the irreversible dihydrogen release in an open reaction system, and thus alcohol products are absent. Furthermore, water evaporation in aldol condensation is found to be a double-edged sword, as it can accelerate the hydrogenation stage to prevent α,β-unsaturated ketones from being the main products but decrease the selectivity therein from thermodynamics overall.

Phosphine‐Free Pincer Ruthenium‐Catalyzed α‐Alkylation of Ketones with Secondary Alcohols to form β‐Branched Ketones

“…We proposed an in situ formed Ru(II) hydride as the catalytically active species which promote the TH reaction via outer sphere pathway ( vide infra ). On the basis of previous reports, a plausible mechanistic pathway has been proposed and is presented in Scheme 5 [12,14–16] . The reaction involves four steps (a) dehydrogenation of alcohol on active catalyst to form corresponding ketone (b) aldol reaction of ketones to generate aldol product (c) condensation of aldol product to form α, β ‐unsaturated ketone (d) reduction of unsaturated ketones via hydrogenation and/or alcoholysis segment to form β‐branched ketone.…”

“…On the basis of previous reports, a plausible mechanistic pathway has been proposed and is presented in Scheme 5. [12,[14][15][16] The reaction involves four steps (a) dehydrogenation of alcohol on active catalyst to form corresponding ketone (b) aldol reaction of ketones to generate aldol product (c) condensation of aldol product to form α, βunsaturated ketone (d) reduction of unsaturated ketones via hydrogenation and/or alcoholysis segment to form β-branched ketone. Nevertheless, the detailed mechanism and especially the origin of the diastereoselectivity are still not fully clear.…”

Ruthenium‐Catalyzed Selective α‐Alkylation of β‐Naphthols using Primary Alcohols: Elucidating the Influence of Base and Water

“…The catalytic cycle involves three key steps -Deprotonation and hydride abstraction from benzyl alcohol to afford benzaldehyde, aldol condensation of the benzaldehyde with β-naphthoxide, formation of the α-alkylated product by the hydride and proton transfer from Ru-dihydride complex C (Scheme 5). The reaction begins with the deprotonation and hydride abstraction from benzyl alcohol B by the catalytically active ruthenium complex A [16,21] via a concerted transition state TS1 (Scheme 6). This results in the generation of Ru-dihydride complex C and benzaldehyde D. Thereafter, benzaldehyde undergoes aldol condensation with the protonated LiO t Bu and LiO t Bu -coordinated β-naphthoxide E via a sequence of steps.…”

“…Additional references are cited within the Supporting Information. [21][22][23][24][25][26][27][28][29][30][31][32]…”

Catalytic Formal Conjugate Addition: Direct Synthesis of δ-Hydroxynitriles from Nitriles and Allylic Alcohols

“…To decipher the reaction mechanism furthermore, density functional theory (DFT) calculations , were performed for the ruthenium-catalyzed selective formal conjugate addition of nitriles with allylic alcohols at the M06L+SMD/BS2//M06L/BS1 level − (see the Supporting Information). The complete catalytic cycle obtained on the basis of the DFT results is presented in Figure a.…”