A Trialkylphosphine-Derived Palladacycle as a Catalyst in the Selective Cross-Dimerization of Terminal Arylacetylenes with Terminal Propargyl Alcohols and Amides

Abstract

A method for the selective cross-dimerization of terminal aryl alkynes with propargyl alcohols to afford linear (E)enynol products is reported. The complex [Pd(μ-κ 2 -O,O-OAc)(κ 2 -C,P-(t-Bu) 2 PCH 2 C(Me) 2 CH 2 )] 2 selectively affords (E)-5-aryl-2-en-4-yn-1-ol products in good yields under mild conditions with high chemo-, regio-, and stereoselectivity. In contrast, previously reported examples of this reaction afford the branched 4-aryl-2-hydroxymethanol-1-buten-3-yne. Propargyl amides are also selectively cross-dimerized, but with lower regioselectivity for the linear enyne. The method has been applied to the synthesis of (E)-5-phenyl-2-penten-4-yn-1ol, which is a precursor to type 2 diabetes drug candidate NNC 61-4655, in 72% yield from phenylacetylene and propargyl alcohol. The palladacycle precatalyst reacts with aryl alkynes to afford the first example of a dimeric palladacycle complex with a μ-κ 2 -C 1 ,C 1 -bound acetylide ligand. This complex is observed during the catalytic reaction and is a competent precatalyst.

Air-Stable [(R3P)PdCl2]2Complexes of Neopentylphosphines as Cross-Coupling Precatalysts: Catalytic Application and Mechanism of Catalyst Activation and Deactivation

“…The species at 94 ppm is consistent with previous observations from our group of [Pd­(κ 2 - P,C -DTBNpP)­X] 2 species ( 3a ) formed by C–H activation of one of the neopentyl methyl groups (eq ). Neopentylphosphines are known to be prone to metallacycle formation, and the carbonate base would be expected to promote this reaction …”

“…The oil was taken up in pentane, and a white precipitate formed. The white precipitate was collected via filtration and was determined by be a mixture of the known 3a-Br and di- tert -butylneopentylphosphine oxide (DTBNpPO) by 31 P­{ 1 H} NMR spectroscopy in CDCl 3 .…”

Stereo- and Regioselective Dimerization of Alkynes to Enynes by Bimetallic Syn-Carbopalladation

“…The asymmetric bridging mode should result in an uneven charge distribution for both metal centers. 35 The acetylide bridging mode thus differs significantly from the bis-Pd−acetylide complex 4 by Shaughnessy et al 27 shown in the Introduction.…”

“…In contrast to these studies employing neutral ligands, Shaughnessy et al studied the use of acetate-bridged aliphatic C , P -palladacycle catalysts, which were effective in ( E )-selective couplings of propargylic alcohols and amines . Under the reported reaction conditions, an acetate/acetylide-bridged dimeric palladacycle 4 was identified (Figure ).…”

Palladium Acetate Trimer: Understanding Its Ligand-Induced Dissociation Thermochemistry Using Isothermal Titration Calorimetry, X-ray Absorption Fine Structure, and 31P Nuclear Magnetic Resonance

“…It is known to exist as a trimer in noncoordinating solvents (e.g., benzene and toluene) − with an idealized D 3 h -symmetrical cyclic structure of bridging acetate anions between adjacent Pd atoms − (trimer molecular structure in Scheme and in Figure S1). The stability and configuration of the metal complex and the ligand complex − interactions in specific solvent environments have significant effects on the Pd nanoparticle synthesis kinetics and catalytic properties. ,− However, little is known about the Pd 3 (OAc) 6 trimer’s dissociation into monomers in a nucleophilic environment and the binding of such monomers with donor ligands (e.g., phosphines). Challenges of such dissociation studies are as follows: (1) the comparatively high thermodynamic stability of Pd 3 (OAc) 6 trimer in a noncoordinating solvent and (2) even mild heating to facilitate the dissociation can lead to simultaneous reduction of Pd­(II) into Pd(0) .…”