Alkylation of Ketones Catalyzed by Bifunctional Iron Complexes: From Mechanistic Understanding to Application

Abstract

Alkylation of ketones usually involves halides or pseudohalides such as tosylate and triflate derivatives in the presence of a stoichiometric amount of as trong base. [1] Such methodology generates wastes, as all these electrophiles are prepared from alcohols, and requires the use of hazardous chemical materials. Synthetic chemists seek nowadays for more environmentally friendly ways to construct carbon-carbon bonds. In recent years, several efficient strategies were proposed for their creation:i )directly from two simple carbon-hydrogen bonds (catalytic dehydrogenative cross-coupling reaction), [2] andi i) from ketonesa nd alcohols (hydrogen autotransfero rb orrowing hydrogen strategy). [3] Carbon-carbon bond formation via the borrowing hydrogen strategy is ap owerful strategy for the alkylation of ketones (Scheme1). [3] Advantages of this approach are the use of easily-to-handle alcohols, asasourceo fa lkylating reagents, andt he formationo fw ater as the sole byproduct. Indeed, following as implified mechanism,t he alcohol is initially oxidized (dehydrogenation step), and then an aldolizationdehydration step liberates an enone intermediate, whichc an be reduced into ak etone (Scheme 1).Many efficient catalysts are based on expensive noble metals such as iridium, [4] ruthenium [5] or rhodium. [6] Owing to economic constraint and sustainability concerns,t he replacement of platinum metals by first-row-based metals could be an attractive alternative. Recent reports described the use of iron, [7] cobalt [8] and manganese [9] as non preciousm etals in hydrogen autotransfer processes. However,a ll these complexes requiredat emperature threshold of 140 8Ca nd/ore xpensive phosphine ligands. The scope of substrates could also be rather limited. As example, Darcel and co-workers showed recently that only aromatic ketones could be engaged in alkylation reactions in the presence of an in situ iron catalystg enerated from Knçlker's complex and triphenylphosphine. [10] Moreover,y ields were moderate andn om echanism was proposed. [11] Then, even if these works pavet he way to new opportunities in sustainable chemistry,s omel imitationsw ere still present,amechanistic understanding of this iron-catalyzed alkylation reaction and someimprovementwere needed.In our ongoing work on iron-catalyzed reduction, [12] we have recently brought to light that cyclopentadienone iron tricar-Cyclopentadienone iron dicarbonyl complexes were applied in the alkylation of ketones with variousa liphatic and aromatic ketones and alcohols via the borrowing hydrogen strategy in mild reactionc onditions. DFT calculations and experimental works highlight the role of the transition metal Lewis pairs and the base. These iron complexes demonstrated ab road applicability in mild conditions and extended the scope of substrates.Scheme1.Simplified acceptedm echanism of alkylation of ketones.

Recent Catalytic Applications of (Cyclopentadienone)iron Complexes

“…HB α‐alkylation of ketones reported by Sortais, Darcel and co‐workers (A), Poater, Renaud and co‐workers (B), and Morrill and co‐workers (C) …”

“…Using pre‐catalyst 5fa – a modified version of 1f in which one CO is replaced by PPh 3 – Poater, Renaud and co‐workers also developed an effective and general protocol for the chemoselective 1,4‐reduction of α,β‐unsaturated ketones by CTH with i PrOH (Scheme E) . Use of cesium bases was found crucial to achieve the desired reaction, which gave good results also with several natural products.…”

“…No explanation on the role of PPh 3 is provided by the authors. Poater, Renaud and co‐workers also studied the α‐alkylation of ketones using the highly active pre‐catalysts 1f and 5fa (Scheme ), extending the reaction scope to aliphatic ketones (Scheme B) . Moreover, they carried out DFT studies from which the crucial role of the base counterion (Cs + ) in both the HT steps (alcohol dehydrogenation and 1,4‐reduction) emerged.…”

Multi‐Step Reactions Involving Iron‐Catalysed Reduction and Hydrogen Borrowing Reactions

“…32 or 33 ) which permitted to perform the same reaction at lower temperature (Scheme ). Indeed, for the alkylation of (hetero)aromatic ketones with various benzylic alcohols, using 2 mol‐% of 32 and 10 mol‐% of Cs 2 CO 3 in toluene, the reaction can be performed at r.t. under UV‐A light for 2 h, then at 90 °C for 16 h. Using 2 mol‐% of 33 and 10 mol‐% of Cs 2 CO 3, the reaction was conducted at 90 °C for 16 h. Notably, the alkylation of cyclohexanones and hindered alkyl ketones such as 3,3‐dimethylbutan‐2‐one or 3‐methylbutan‐2‐one can be efficiently performed at 90 °C using CsOH instead of Cs 2 CO 3 as the catalytic base . Morrill et al also succeeded to perform efficiently both mono‐ and di‐ α ‐methylation of numerous aromatic and aliphatic ketones using the catalysts 9 or 32 (2 mol‐%) in the presence of Me 3 NO (4 mol‐%) at 80 °C in methanol …”

Cyclopentadienone Iron Tricarbonyl Complexes-Catalyzed Hydrogen Transfer in Water

“…In 2015, we introduced in catalysis the tricarbonyl iron complex Fe2 bearing a diaminocyclopentadienone ligand [21]. Compared to other cyclopentadienone iron carbonyl complexes, this phosphine-free iron complex has, to the best of our knowledge, the highest catalytic activities to date in reductive amination [21], in chemoselective reduction of α,β-unsaturated ketones [22], in the hydrogenation of carbon dioxide [23], in alkylation of ketones [24][25][26][27], amines [25,28], oxindoles [29], indoles [25,30] and alcohols [31,32]. In our ongoing interest in reduction and alkylation, we thought that a water-soluble analog of Fe2 would be more active than our previous water-soluble cyclopentadienone iron complex Fe3 (Figure 1).…”