Palladium‐Catalyzed Mono‐α‐arylation of Acetone at Room Temperature

Abstract

The first examples of acetone mono-α-arylation at room temperature are described, enabled by use of a [Pd(cinnamyl)Cl]2 /JosiPhos catalyst system. (Hetero)aryl chloride, bromide, and iodide electrophiles featuring or lacking ortho-substitution, and comprising a range of functionalities (e.g., alkoxy, cyano, fluoro, trifluoromethyl, or alkenyl) and heteroaryl motifs (e.g., pyrrole, pyridine, isoquinoline, quinoline, quinaldine, (benzo)thiophene, benzothiazole, or benzodioxole) were successfully accommodated. Proof-of-principle experiments confirm that other (hetero)aryl methyl ketones can also be employed in such room temperature mono-α-arylations. The established substrate scope is the most extensive reported to date for acetone mono-α-arylation under any conditions, and more generally represents the first room temperature ketone mono-α-arylations employing a structurally diverse set of (hetero)aryl chlorides.

Design of an Indolylphosphine Ligand for Reductive Elimination-Demanding Monoarylation of Acetone Using Aryl Chlorides

“…Later, −PCy 2 -containing P,N-type Zheda-phos and P,N-type di­(ferrocenyl)-2-morpholinophenylphosphine and bidentate Xantphos were also found to promote this reaction. During the completion of our experimental works, a report appeared that Josiphos-type ligand (CyPF- t -Bu) could make this reaction viable at room temperature using 7.5–10 mol % of Pd for 48 h . In fact, the appropriate ligand coordinating number and electronic and steric balance of ligand have been shown to be critical for achieving monoselective α-arylation .…”

Organic Base Enabled Nickel‐Catalyzed Mono‐α‐Arylation of Feedstock Solvents

“…The use of these feedstock chemicals as reagents presents a number of unique challenges, including base‐induced Aldol, Claisen, or other unwanted reactivity, and challenging mono‐α‐arylation, given that the arylated carbonyl product features benzylic CH 2 groups that are more acidic than those in the starting carbonyl reagent (e. g., pKa in DMSO, acetone: 26.5, phenyl acetone: 19.8), [6] which can lead to polyarylation [7] . The selective metal‐catalyzed mono‐α‐arylation of acetone was first reported in 2011, [8] whereby Pd/Mor‐DalPhos catalyst mixtures and Cs 2 CO 3 were employed with (hetero)aryl‐X electrophiles (X=Cl, Br, I, OTs); subsequent advances include use of mesylate electrophiles, [9] and room temperature transformations (using Pd/JosiPhos CyPF‐ t Bu) [10] . Palladium‐catalyzed acetone mono‐α‐arylation has since been applied in the development of D1 positive allosteric modulators for use in the treatment of Lewy body dementia [11] …”

“…[7] The selective metal-catalyzed mono-αarylation of acetone was first reported in 2011, [8] whereby Pd/ Mor-DalPhos catalyst mixtures and Cs 2 CO 3 were employed with (hetero)aryl-X electrophiles (X=Cl, Br, I, OTs); subsequent advances include use of mesylate electrophiles, [9] and room temperature transformations (using Pd/JosiPhos CyPF-tBu). [10] Palladium-catalyzed acetone mono-α-arylation has since been applied in the development of D1 positive allosteric modulators for use in the treatment of Lewy body dementia. [11] An important advance in acetone mono-α-arylation chemistry by Tlili, Amgoune, and co-workers [12] involved development of nickel-catalyzed transformations.…”

“…While these efforts were unsuccessful, we sought improved catalysis by conducting a ligand screen using the stronger organic base BTPP/NaOTf (Figure 4A, entries 1-7). Amongst the ligands surveyed, CyPAd-DalPhos (L3) proved superior (entry 3), and the derived pre-catalyst (L3)Ni(4-CNÀ Ph)Cl was used to examine base/(pseudo)halide scavenger pairings (entries [8][9][10][11][12][13][14]. This secondary portion of the reaction optimization confirmed BTPP/NaOTf as being particularly effective for the formation of 2 a (entry 8), although MTBD (see Figure 2C) was competitive (entries 10 and 11).…”

Valorization of the Primary Building Blocks Ammonia and Acetone Featuring Pd- and Ni-Catalyzed Monoarylations

“…Facing this shortcoming, the group of Stradiotto set out to identify a catalytic system for the α-arylation of acetone . Inspired by various reports on this transformation, they tested frequently used monophosphine ligands such as BrettPhos and Mor-DalPhos in a model reaction in conjunction with [Pd­(cinnamyl)­Cl] 2 as the metal precursor (Scheme ).…”