Acceleration of Pd-Catalyzed Amide N‑Arylations Using Cocatalytic Metal Triflates: Substrate Scope and Mechanistic Study

The Pd/xantphos-catalyzed cross-coupling of amides and aryl halides is accelerated by cocatalytic metal triflate additives. A survey of nitrogen nucleophiles reveals improved yields for a variety of N-aryl amide products when Al­(OTf)₃ is employed as a catalytic additive, with some exceptions. Initial rates of catalysis indicate that the Lewis acid acceleration is more pronounced when bromobenzene (PhBr) is used in comparison with iodobenzene (PhI). The observation of an aryl halide dependence on rate and various qualitative kinetic experiments are consistent with a mechanism in which ligand exchange of halide for amide (“transmetalation”) is turnover limiting. The mechanism may be different depending on whether PhBr or PhI is used as a coupling partner. Oxidative addition complexes (xantphos)­Pd­(Ph)­(X) (X = Br, I; xantphos = 4,5-bis­(diphenylphosphino)-9,9-dimethylxanthene), likely intermediates in catalysis, have been prepared; their differing interactions with Yb­(OTf)₃ in solution resemble the halide dependence of the catalytic mechanism, which we propose originates from a reversible Lewis acid mediated halide abstraction during catalysis

Modular Synthesis of Azabicyclohexanes and Cyclobutenyl Amines

The development of two divergent and complementary Lewis acid catalyzed additions of bicyclobutanes to imines is described. Microscale high-throughput experimentation was integral to the discovery and optimization of both reactions. N-arylimines undergo formal (3+2) cycloaddition with bicyclobutanes to yield azabicyclo[2.1.1]hexanes in a single step; in contrast, N-alkylimines undergo an addition/elimination sequence to generate cyclobutenyl methanamine products with high diastereoselectivity. These new products contain a variety of synthetic handles for further elaboration, including many functional groups relevant to pharmaceutical synthesis. The divergent reactivity observed is attributed to differences in basicity and nucleophilicity of the nitrogen atom in a common carbocation intermediate, leading to either nucleophilic attack (N-aryl) or E1 elimination (N-alkyl)

High-Throughput Discovery and Evaluation of a General Catalytic Method for N-Arylation of Weakly Nucleophilic Sulfonamides

Sulfonamides are poor nucleophiles in Pd C-N coupling catalysis, hindering synthesis of densely-functionalized N,N-diaryl sulfonamide motifs relevant to medicinal chemistry. Through targeted high-throughput experimentation (HTE), we have identified the Pd/AdBippyPhos catalyst system as an effective and general method to construct this difficult to access moiety. In particular, AdBippyPhos is critical for the installation of heteroaromatic groups. Computational steric parameterization of the investigated ligands reveals the potential importance of remote steric demand, where a large cone angle combined with an accessible Pd center is correlated to successful catalysts for C-N coupling reactions.<br /

A Thermally Stable, Alkene-Free Palladium Source for Oxidative Addition Complex Formation and High Turnover Catalysis

Oxidative addition complexes play a crucial role in Pd-catalyzed transformations. They are not only key catalytic intermediates, but are also powerful and robust precatalysts, and effective reactants for late-stage functionalization of complex molecules. However, accessing a given oxidative addition complex is often challenging due to a lack of effective and stable palladium sources with the correct reactivity. Herein, we report an easily prepared and bench stable Pd(II) dialkyl complex, DMPDAB–Pd–BTSM (BTSM = bis[trimethylsilylmethyl]), that is a versatile precursor for generating Pd(II) oxidative addition complexes, and a highly active Pd source for in situ catalyst formation in cross-coupling reactions. A crucial aspect of this structure is the absence of alkene-based stabilizing ligands common to other Pd precursors. We demonstrate the utility of this precursor in the formation of several Pd(II) complexes, including phosphine and diimine-ligated oxidative addition complexes, and in high turnover number catalysis of C–O, Suzuki, and Heck coupling reactions

Selective Isomerization of Terminal Alkenes to (<i>Z</i>)‑2-Alkenes Catalyzed by an Air-Stable Molybdenum(0) Complex

Positional and stereochemical selectivity in the isomerization of terminal alkenes to internal alkenes is observed using the <i>cis</i>-Mo­(CO)₄(PPh₃)₂ precatalyst. A <i>p</i>-toluenesulfonic acid (TsOH) cocatalyst is essential for catalyst activity. Various functionalized terminal alkenes have been converted to the corresponding 2-alkenes, generally favoring the <i>Z</i> isomer with selectivity as high as 8:1 <i>Z</i>:<i>E</i> at high conversion. Interrogation of the catalyst initiation mechanism by ³¹P NMR reveals that <i>cis</i>-Mo­(CO)₄(PPh₃)₂ reacts with TsOH at elevated temperatures to yield a phosphine-ligated Mo hydride (MoH) species. Catalysis may proceed via 2,1-insertion of a terminal alkene into a MoH group and stereoselective β-hydride elimination to yield the (<i>Z</i>)-2-alkene

(DMP)DAB–Pd–MAH: A Versatile Pd(0) Source for Precatalyst Formation, Reaction Screening, and Preparative-Scale Synthesis

We report an easily prepared and bench-stable mononuclear Pd(0) source stabilized by a chelating N,N’-diaryldiazabutadiene ligand and maleic anhydride: DMPDAB–Pd–MAH. Phosphine ligands of all types, including bidentate phosphines and large cone angle biarylphosphines, rapidly and completely displace the diazabutadiene ligand at room temperature to give air-stable Pd(0) phosphine complexes. DMPDAB–Pd–MAH itself is readily soluble and stable in several organic solvents, making it an ideal Pd source for in situ catalyst preparation during reaction screening, as well as solution-dispensing to plate-based reaction arrays for high-throughput experimentation. Evaluation of DMPDAB–Pd–MAH alongside other common Pd(0) and Pd(II) sources in microscale reaction screens reveals that DMPDAB–Pd–MAH is superior at identifying hits across six different C–N, C–C, and C–O coupling reactions. DMPDAB–Pd–MAH, and the phosphine precatalysts derived therefrom, are also effective in preparative-scale cross couplings at low Pd loadings