Some Items of Interest to Process R&D Chemists and Engineers

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Takahashi and Seki from the Tokuyama Corporation reported a Cu(II)-catalyzed bromination of free anilines with high selectivity under mild conditions ( Synthesis 2021, 53, 1828). Multiple methods for the direct bromination of free anilines that use either a Br⁺ source (Br₂, N-bromosuccinimide, etc.) or bromide in the presence of an oxidizing agent have been reported. Many of these methods suffer from poor atom economy and/or harsh conditions. The authors recently reported a CuSO₄-catalyzed ortho-selective azidation of free anilines using Na₂S₂O₈ as the oxidant and NaN₃ as the azide source. Applying these conditions to bromination using NaBr in place of NaN₃ resulted in selective bromination of the same substrates but with excellent para selectivity, suggesting a Friedel–Crafts-type mechanism rather than Cu–aniline complexation. Control experiments showed that CuSO₄ was essential for any reaction to proceed and that alternative oxidants (Oxone, H₂O₂) were poorly reactive or gave inferior regioselectivity. The reaction conditions were tested with a range of ortho- and para-substituted anilines, and the monobromination products were predominant in all cases. When the para position is substituted, bromination occurs at the ortho position as expected.

Transition-metal-catalyzed N-arylation of enantiopure α-amino acid derivatives is highly challenging because the requirement of a strong base leads to racemization. Kobayashi and co-workers addressed this issue by translating the known N-arylation of an amine with cyclohexanone to flow conditions ( Chem. - Eur. J. 2021, DOI: 10.1002/chem.202101439). The flow system is composed of a coil in which the substrates and styrene as a hydrogen acceptor are heated at 140 °C before entering a packed-bed reactor charged with palladium hydroxide on carbon and Celite. The residence time was optimized to provide a variety of arylated amino esters in high yield, enantiopurity, and productivity with space-time-yields ranging from 10 to 140 g L^–1 h^–1. The mechanism of the racemization was studied, leading the authors to propose that the rapid preheating and high local concentration of palladium catalyst were the key factors allowing a low loss of enantiomeric purity. Worthy of note is the fact that the reaction can be run for 48 h with minimal palladium leaching.

Ni, Hu, and co-workers from the Shanghai Institute of Organic Chemistry reported the iron-catalyzed fluoroalkylation of arylborates with sulfone reagents ( Angew. Chem., Int. Ed. 2021, DOI: 10.1002/anie.202102597). Fluoroalkyl sulfones have been widely used as fluoroalkyl radical precursors in the alkylation of organic molecules, although to date the single-electron-transfer reduction of sulfones via metal coordination has not been reported. The authors discovered that under iron(II) catalysis a variety of arylsulfones were competent in generating productive fluoroalkyl radicals and that those based upon nitrogen-containing heterocycles were most efficient. The 4,6-dimethylpyrimidine derivative proved to be the best substrate (see the scheme), giving difluoromethylbenzene in 80% isolated yield from the reaction with a borate reagent derived from the combination of PhB(pin) and sBuLi. A wide range of arylborates were demonstrated to be competent substrates in the transformation, including ortho-, meta-, and para-substituted systems and indole derivatives. Difluoroalkylation beyond difluoromethylation was also demonstrated, with difluoroethyl, -propyl, and higher derivatives successfully installed. Three examples of nonfluorinated alkylations were also shown, with both primary and secondary alkyl groups installed in moderate yields. This methodology offers an alternative to other single-electron methods for the installation of valuable fluorinated moieties on aromatic scaffolds.

Sevov and co-workers from The Ohio State University and Boehringer Ingelheim reported the application of electrocatalysis to the Chan–Lam coupling utilizing a substoichiometric redox mediator in the absence of chemical oxidants ( J. Am. Chem. Soc. 2021, 143, 6257). The Chan–Lam coupling is an oxidative cross-coupling that requires an oxidation step to regenerate the active Cu(II) catalyst following reductive elimination. This oxidation is often achieved through molecular oxygen or added chemical oxidants, increasing the complexity and/or limiting the feasibility of this transformation on scale. Chan–Lam couplings have been previously explored using photoredox catalysts or electrochemical systems with Cu electrodes. However, both systems require exogeneous oxidants and are low-yielding in their absence. The authors discovered that the addition of a redox mediator was the key to the successful development of an oxidant-free transformation, with the mediator serving three purposes: (1) to increase the rate of low-valent Cu oxidation; (2) to strip Cu metal from the cathode to regenerate the catalyst and prevent electrode occlusion; and (3) to prevent substrate oxidation by providing anodic overcharge protection. A group of mediators based upon ferrocene were explored, and ferrocenium (Fc⁺) was found to be superior to all neutral ferrocene derivatives. The substrate scope is broad, with aryl, heteroaryl, and alkyl amines all being competent nucleophiles. A range of aromatic boronic acids were demonstrated, including both electron-rich and -poor derivatives. If this methodology is amenable to flow electrochemistry, then it offers a potential alternative to traditional Chan–Lam conditions with added oxidants.

Organosodium reagents are seldom used in synthetic organic chemistry despite their appealing properties and low cost. Building upon the works of Asako and Takai and recent reports of on-demand organometallic preparation, Knochel and co-workers from Universität München in Germany succeeded in developing a flow protocol for the generation and in situ trapping of arylsodium reagents ( Angew. Chem., Int. Ed. 2021, DOI: 10.1002/anie.202103031). Sodium-metal-free 0.5 M solutions of (2-ethylhexyl)sodium could be obtained by flowing a hexane solution of the corresponding chloride at room temperature through a packed-bed reactor charged with metallic sodium. This solution was used in flow for sodium/bromide exchange or deprotonation of diverse five- and six-membered (hetero)aromatics. The resulting arylsodium reagents are subsequently trapped in batch with electrophiles such as aldehydes, ketones, Weinreb amides, or disulfides to generate the corresponding addition products in good to high yields. Recourse to flow chemistry overcame the stability issues encountered in batch and expanded the scope of electrophiles thanks to the absence of residual sodium dispersion.

With the steady development of photoredox chemistry, low-cost photocatalysts with improved performance are actively sought. Bonfazi, Davidson and co-workers from Austria and England recently demonstrated the ability of stable and easily synthesized peri-xanthenoxanthene (PXX) to catalyze different benchmark photoredox transformations ( Adv. Synth. Catal. 2021, DOI: 10.1002/adsc.202100030). Thus, conditions were optimized to perform β-arylation of ketones and nickel-catalyzed cross-coupling reactions to forge carbon–nitrogen and carbon–sulfur bonds. Although the scope of each transformation was not studied in detail, the main limitations were highlighted (low yields encountered with primary amines for C–N cross-coupling reactions and the requirement for iodoaryl substrates for thioether formation). Worthy of note is the high reducing potential of PXX, which allows the formation of radicals from a set of (hetero)aryl halides that can subsequently add to different radical traps.

Organometallic reagents, such as n-butyllithium, are commonplace in synthetic laboratories, including those in industrial settings. Although they are typically stored for shorter durations in industrial laboratories than academic ones, the quantification of precise concentration is still important, allowing accurate and reproducible experimentation. Numerous titrating methods currently exist to calculate organometallic reagent concentrations, but new processes that reduce operator time and error would be beneficial. A recent report by Ghiviriga and co-workers ( Org. Lett. 2021, DOI: 10.1021/acs.orglett.1c01006) outlines a convenient method that requires only two NMR spectra, one of the neat organometallic reagent and one of a suitable external standard, such as a solvent like water. The method works by relating the known concentration of the external standard to the unknown reagent concentration using a module common to all major NMR software. Importantly, the use of an external standard eliminates any possible signal overlap from the standard. The method was benchmarked against an alternative NMR method using COD as an internal standard as well as more classical reagent-based titration methods. The NMR methods typically differed by <5%, suggesting good agreement. It is noted that for accurate results, identical NMR tubes must be used for the organometallic reagent and suitable external standard. Furthermore, care must be taken with any method that involves handling of neat organometallic reagents in NMR tubes.

α-Amino aryl ketones constitute an important structural motif that widely exists in pharmaceutically active compounds, clinical drugs, and complex natural products. Furthermore, this functionality serves as a valuable intermediate for the synthesis of versatile 2-amino alcohols and various nitrogen-containing heterocycles. While a number of synthetic procedures have been reported for the synthesis of α-amino aryl ketones, they are not amenable to substrates containing sensitive functional groups. Xu, Xu, and co-workers at Lanzhou University detailed an unprecedented method for the direct cross-coupling of an aroyl radical and an α-amino radical that employs an inexpensive organic photocatalyst ( Org. Lett. 2021, 23, 2846). The reported methodology enabled metal-free α-C(sp³)–H aroylation of saturated aza-heterocycles with commercially available aroyl chlorides in good to excellent yields. Control experiments revealed that light, a photocatalyst, and a base are critical for this radical reaction. Extensive optimization experiments established that 4CzIPN and potassium propionate were the preferred catalyst and base for the reaction, respectively. Lower yields were obtained with Ru- and Ir-containing photocatalysts. The reaction tolerated a variety of substituents on the aroyl chloride partners; substrates containing electron-donating moieties generally afforded the highest yields. Aliphatic acyl chlorides also gave the corresponding cross-coupling products in moderate yields. In summary, the direct α-C(sp³)–H aroylation of tertiary amines via a metal-free radical–radical cross-coupling strategy mediated by an organic photocatalyst was reported.

The reduction of nitroarenes to anilines is one of the most significant reactions in organic chemistry. In this context, various procedures have been developed to obtain anilines via the hydrogenation of nitroarenes. Most of the recent reports on the catalytic hydrogenation of nitroarenes focus on the development and modification of heterogeneous catalysts to improve the chemoselectivity. In contrast, there have been few reports of the utilization of homogeneous catalysts for this transformation. Rueping and co-workers at RWTH Aachen University extended their research on manganese catalysts to include the chemoselective reduction of nitroarenes to anilines under mild conditions ( Org. Lett. 2021, 23, 2742). The air- and moisture-stable manganese catalyst was readily prepared from a commercially available, air-stable PhPNP ligand and the metal precursor. Screening experiments indicated that toluene and K₂CO₃ were the preferred solvent and base for the reaction, respectively. Control experiments indicated that the manganese catalyst and base were both critical for the reduction to proceed. The chemoselectivity was demonstrated with various functional groups, including halogen, double bond, amide, ester, and sulfonamide. Unfortunately, under the general reaction conditions, nitriles, certain ketones, and alkynes were partially reduced. In conclusion, a manganese-catalyzed protocol for the hydrogenation of arenes was developed that uses molecular hydrogen as the reducing agent. This newly developed manganese catalyst exhibited good reactivity and chemoselectivity and tolerated a variety of functional groups.

The pyrrole functional group is a common feature of many agrochemical and pharmaceutical compounds of interest, such as the cholesterol-lowering drug Lipitor. Functionalization can be a challenge, especially the regiochemical functionalization of C3-substituted pyrroles, because of competing C2 and C5 reactivity. Expanding upon a previous report of indole borylation, Houk, Shi, and co-workers ( Angew. Chem., Int. Ed. 2021, 60, 8500) reported a C2-selective C–H borylation of C3-substituted pyrroles. Key to this new method is the requirement for an N-pivaloyl group, with alternate N substituents leading to no product or poor regiocontrol. The reaction proceeds with initial selective borylation at C2 with BBr₃, assisted by the N-pivaloyl group, and further reaction of this intermediate with pinacol to generate the isolated pinacol borane products. A range of substituents at C3 were tolerated (>25 examples, typically >70% yield), such as halogens and alkyl, alkenyl, and aryl groups, but the process was not successful with an electron-deficient group at C3, such as cyano. The process was exemplified by application to the core pyrrole unit of Lipitor on a 4 mmol scale in 93% yield. Furthermore, computational investigation rationalized the selectivity as the result of greater stabilization of the C2 (vs C5)-functionalized reaction intermediate by the electron-donating C3 substituent.

Although amides are ubiquitous in natural products, pharmaceuticals, and functional polymers, they are generally considered to be inert because of the enhanced stability of the C–N bond caused by resonance effects. Various efforts have been devoted to activating and cleaving the amide C–N bond for further transformations. Although some progress has been achieved, a means to activate general amides and utilize the amine moieties is still highly desirable. Tu, Tu, and their co-workers at Fudan University and Zhengzhou University detailed a nickel-catalyzed amination of aryl chlorides with amides under mild reaction conditions ( Org. Lett. 2021, 23, 687). Screening experiments indicated that acenaphthoimidazolium chloride (APr·HCl), an N-heterocyclic carbene precursor, was the preferred ligand. Excellent yields were obtained with Ni(COD)₂ catalyst loadings as low as 1 mol %. The addition of a small amount of water (up to 1 equiv) to the reaction mixture was shown to increase the yield. The reported protocol tolerated a variety of electron-donating and electron-withdrawing groups on the (hetero)aryl chloride. A variety of secondary and tertiary amides, both acyclic and cyclic, were effective amine donors. In all of the coupling experiments, no carbonyl-containing byproducts were generated. In summary, a Ni-catalyzed amination of aryl chlorides with inactive amides as amine sources under mild reactions was described.

The ability of the fluorine atom to enhance the metabolic stability of organic molecules by blocking oxidation has led to a dramatic spike in interest in organofluorine molecules in the pharmaceutical and agrochemical industries. Many methods for the fluorination of organic molecules have been developed to address the increasing need for these motifs. However, many of these techniques are plagued by the hygroscopicity, poor atom economy, and high cost of the reagents. Hong, Whittaker, and Schultz at Merck reported a mild, inexpensive, and scalable method to convert heteroaryl chlorides and aryl triflates to aryl fluorides by means of cooperative catalysis ( J. Org. Chem. 2021, 86, 3999). This approach leverages the cooperative action of 18-crown-6 and tetramethylammonium chloride (TMACl) in the presence of alkali-metal fluorides. On the basis of the results of a series of catalyst screening experiments, TMACl and 18-crown-6 were ultimately selected because of their lower cost and ease of handling. Cesium fluoride outperformed potassium fluoride in this displacement reaction. The reaction was performed under mild conditions (acetonitrile solvent at 60 °C), thus avoiding the utilization of dipolar aprotic solvents at high temperature, a potentially problematic combination. The reaction tolerated a variety of functional groups on the heteroaryl chloride, including ketone, nitro, ester, and nitrile. In summary, the utilization of cooperative catalysis facilitated the fluorination of heteroaryl chlorides and aryl triflates under mild conditions in high yields.

Azaindoles are important building blocks for pharmaceuticals and bioactive molecules. The synthesis of variety of N1-substituted azaindoles has been recently reported, particularly in the medicinal chemistry literature. However, there are significantly fewer methods reported that focus on the synthesis of N7-alkylated 7-azaindoles. Bao, Cheng, and their co-workers at Merck and Wuxi AppTec detailed a mild, general, and selective method for the direct alkylation of readily available 7-azaindoles at N7 ( J. Org. Chem. 2020, 85, 7558). Experiments to optimize the various reaction parameters revealed that alkylation at N1 was favored under basic conditions, whereas neutral or acidic conditions strongly favored alkylation at N7. Butanone was the preferred solvent. In general, benzyl bromides afforded the highest yields of the desired products; the corresponding chlorides afforded lower yields, while dialkylation was observed with iodide substrates. A variety of substituents on the 7-azaindole were tolerated, and higher yields were obtained with electron-donating groups. The reaction was successful with both primary and secondary alkyl electrophiles. In summary, a mild and operationally simple protocol for the chemoselective synthesis of N7-substituted 7-azaindoles through direct alkylation of 7-azaindoles with various electrophiles was reported.

Carboxylic acid derivatives with α-aryl stereocenters are important building blocks for bioactive compounds, such as ibuprofen. An appealing synthesis of this motif is via stereoconvergent reductive coupling of racemic α-chloro esters with aryl iodides to form products with high enantiomeric excess. Building upon work by Durandetti, Sigman, Reisman and co-workers ( Chem. Sci. 2021, DOI: 10.1039/D1SC00822F) reported their nickel-catalyzed process, which is complementary to the previously disclosed metallaphotoredox method of Mao, Walsh, and co-workers. Following investigation, the optimum conditions used 10% Ni with a chiral bis(oxazoline) (Box) ligand in THF, with manganese(0) as the reductant and NaBF₄ as a key additive. In contrast to the metallaphotoredox protocol (3.0 equiv), only 1.5 equiv of the aryl iodide with respect to the phenolic ester was required. Methyl and tert-butyl esters gave reduced yields. A range of aryl and heteroaryl iodides were effective, giving typically good-to-excellent yields (11 examples with >60% yield) and good levels of enantioselectivity (typically 80–90% ee). While the reaction was relatively insensitive to the arene partner, modification of the α-chloro ester gave variations in the observed enantioselectivity (>10 examples with 84–98% ee). This was investigated using a workflow previously reported by the Sigman group, which provided a model that could be used to predict the results for a new substrate/ligand combination. Finally, the method was applied to the synthesis of naproxen to demonstrate its utility on a 1 mmol scale.

Unnatural α-amino acids are building blocks of high demand for which new synthetic protocols keep being sought. Karkas and co-workers from Sweden and Russia recently described an improvement of a protocol for radical addition to imines initially developed by the Aleman and Baran groups to access this class of compounds ( Chem. Sci. 2021, 12, 5430). The authors succeeded in using unmodified carboxylic acids under blue-light irradiation as the radical source, thereby improving the overall atom and step economy of the method. Keys for the success of the reaction are the use of mesityl imines in conjunction with α,α,α-trifluorotoluene as the solvent, potassium carbonate as the base, and a high loading of the organic acridinium photocatalyst [Mes-2,7-Me₂AcrPh]BF₄ (see the scheme). A number of functionalized carboxylic acids leading to primary, secondary, and tertiary radicals as well as heteroatom-substituted radicals were found to be well-tolerated under the optimized conditions. Mechanistic and computational studies explaining the stereochemical outcomes as well as examples of N-sulfinyl amide deprotection are also provided.

Alkylation reactions can often employ highly sensitive electrophiles under challenging conditions. Gaining a better mechanistic understanding of pathways for trialkylammonium degradation can help to enable the development of gentler methodologies for the alkylation and derivatization of select nucleophilic substrates. Reid and co-workers reported a study of N,N,N-trimethylanilinium salts, including their degradation pathways and factors that determine their stability ( Chem. Sci. 2021, DOI: 10.1039/d1sc00757b). These trimethylaniliniums show promise for expanded utility in direct methylations and as electrophilic methyl sources in transition-metal-catalyzed cross-coupling reactions. It was determined that nucleophilic counteranions led to greater degrees of thermal degradation in the anilinium salts. For the trialkylanilinium iodides, in situ kinetic analyses allowed the observation that they likely act as a masked source of iodomethane, which then behaved as the primary methylating reagent for O-nucleophiles. The possible divergent pathways of arylation and methylation were examined, and the various substituent effects that may determine them were also discussed.

The structural inclusion of 1,3-disubstituted bicyclo[1.1.1]pentanes (BCPs) has taken on increasing interest in the screening of biologically relevant motifs for pharmaceutical development and various medicinal chemistries. Walsh, Hughes, and co-workers revealed a novel methodology for the direct base-mediated 1,3-difunctionalization of [1.1.1]propellane with benzylimines and boronates. The reaction is ostensibly driven by the release of ring strain, with the concomitant creation of new C–C and C–B bonds ( Chem. Sci. 2021, DOI: 10.1039/d1sc01349a). Screening of pinacolboronates revealed that the highest yield of the desired product was selectively formed with the use of ⁱPrOBpin as the boron source and LDA as the deprotonating base. Following 1,3-carboborylation of the propellane, Pd-catalyzed Suzuki coupling was shown to be effective under certain conditions to allow for C–aryl bond formation in moderate to good yields. Additionally, other C–B bond transformation reactions furnished C–O, C–alkyl, and C–N bonds. Subsequent hydrolysis of the imine generates the free benzylamine species.

Organic polymers have shown consistent utility across a range of academic and industrial applications of interest. Certain substituents incorporated within a polymeric backbone can allow for high-density radical generation with promising potential applications for organic radical batteries and charge-density carriers. Rieger and co-workers reported a Cp₃Lu-based catalyst that can efficiently polymerize dialkyl vinylphosphonates into polyvinylphosphonates bearing pendent TEMPO-type moieties ( Macromolecules 2021, 54, 4089). Rare-earth metal-mediated group transfer polymerization (REM-GTP) allows facile access to polyvinylphosphonates with high molecular weight (M_n up to 500 kg/mol) and relatively narrow dispersity (1.19 < PDI < 1.34). Under thermal or direct oxidative conditions (i.e., treatment with mCPBA) the alkyl group is cleaved, revealing a deprotected TEMPO radical. Experimentally, up to 99% deprotection was achieved, leading to a polymeric material with high radical density. New routes to these vinylphosphonate monomers were disclosed, and the choice of toluene as the solvent led to near quantitative monomer conversion.

The continuous development of metal–organic frameworks (MOFs) involving the judicious choice of organic-ligand-based linkers and metal nodes has led to a variety of well-defined, three-dimensional structures with applications in gas storage, catalysis, and chemicals purification. Uemura and Hosono reported the selective separation of linear and cyclic poly(ethylene glycol) (PEG) polymers via the use of a Zn-based MOF ( Angew. Chem., Int. Ed. 2021, 60, 11830). The MOF used, [Zn₂(14-ndc)₂ted]_n, contains regular 1D nanochannels with an aperture diameter of 5.7 Å. Solid, linear PEG (1900 g/mol) and the MOF were mixed together, and heat was applied. The observed changes in melting point due to confinement effects allowed for the quantification of PEG uptake by the MOF. The cyclic PEG variant was synthesized through treatment with KOH and TsCl. When the MOF was used as a stationary phase in a packed column, the linear polymer was selectively taken up over the cyclic variant in near-quantitative fashion. This study shows that MOFs can be used to reliably identify and potentially purify unique polymer morphologies from a mixture of architectures.

¹⁴C radiolabeling of organic molecules is a powerful tool that is often used in investigations of drug absorption, distribution, metabolism, and excretion (ADME) properties of new pharmaceuticals. A desirable strategy for ¹⁴C incorporation is through late-stage functionalization of the pharmaceutical compound. Toward this goal, Audisio and co-workers reported a Ni-catalyzed reversible decyanation/cyanation protocol that employs a radiolabeled Zn([¹⁴C]CN)₂ reagent to incorporate ¹⁴C-nitriles into pharmaceuticals via aryl nitrile exchange ( J. Am. Chem. Soc. 2021, 143, 5659). While the reaction was optimized and initially explored using a nonradioactive Zn([¹³C]CN)₂ reagent and catalytic Ni loading, when ¹⁴C labeling was performed, a stochiometric loading of the Ni catalyst was used to operationally simplify the process and preclude the use of a glovebox. After the ¹⁴C labeling of several functionally complex pharmaceuticals was demonstrated, a series of stoichiometric experiments were conducted and intermediates were isolated to probe the reaction and propose a plausible mechanistic pathway. This method is an attractive approach for late-stage isotopic labeling that utilizes a nongaseous ¹⁴C source.

Minisci-type alkylation of heteroarenes is a valuable strategy for the introduction of increased 3D complexity into aromatic systems that is amenable to both convergent and late-stage functionalization approaches. Phipps and co-workers reported a new method employing a hydrogen atom transfer (HAT) manifold for the enantioselective alkylation of heteroarenes that effects an overall net coupling of two C–H bonds ( J. Am. Chem. Soc. 2021, 143, 4928). Under the reaction conditions, the activated heteroarene undergoes reversible radical addition followed by an enantiodetermining deprotonation step that is controlled by the chiral phosphoric acid (CPA) catalyst. Diacetyl, excited by visible light, functions as both the HAT catalyst to form the α-amino radical and the terminal oxidant. The reaction scope was demonstrated with quinoline and pyridine heterocycles to afford enantioenriched benzylamine products. An attractive feature of the method is the ability to tap into the large supply of commercial primary amine building blocks.

Ray and Hartwig reported a new class of oxalohydrazide ligands for the Cu-catalyzed C–O coupling of aryl halides (Cl, Br, I) with phenols and aryl bromides and iodides with aliphatic alcohols ( Angew. Chem., Int. Ed. 2021, 60, 8203). These oxalohydrazide-ligated Cu species proved to be highly active catalysts that could generate aryl ethers at relatively low catalyst loadings (between 0.0125 and 2.5 mol %) with high turnover numbers (between 1000 and 8000), all while maintaining activity over a long lifetime. The scope and functional group compatibility were thoroughly explored, and productive coupling was observed for a variety of substituted phenyl, pyridine, and quinoline cores, including both electron-rich and -poor aryl chlorides. Additionally, selectivity was observed for biaryl ether formation over potentially competitive N-arylation of primary or secondary amides.

Palladium-mediated cross-coupling has widespread application across synthetic chemistry, and screening of palladium sources and ligands to identify the optimum system is commonplace. This can be most efficiently done via high-throughput experimentation by combining the free ligand with a suitable palladium precursor. While the use of a Pd(0) precursor is mechanistically the simpler option, the limitation to the use of Pd₂dba₃ often necessitates exploring the more diverse Pd(II) precursors. A recent report by Leitch and co-workers ( ACS Catal. 2021, 11, 5636) outlines a new Pd(0) precursor, ^DMPDAB–Pd–MAH, to complement the already well established use of Pd₂dba₃. ^DMPDAB–Pd–MAH is an air- and moisture-stable mononuclear Pd(0) complex that is soluble and stable in a range of organic solvents, although it undergoes decomposition in chloroform or acetonitrile (25–30% remaining after 24 h). The complex was benchmarked against other common palladium precursors in six different reaction classes for C–N, C–C, and C–O bond formation, and successful hits were identified in all cases, in some instances outperforming the common Pd(OAc)₂. Preparative-scale examples (>1 mmol) were also demonstrated, and the likely forthcoming commercialization of the complex should offer researchers a viable Pd(0) precursor to consider when screening reactions.