High-throughput experimentation (HTE) has revolutionized the pharmaceutical industry, most notably allowing for rapid screening of compound libraries against therapeutic targets. The past decade has also witnessed the extension of HTE principles toward the realm of small-molecule process chemistry. Today, most major pharmaceutical companies have created dedicated HTE groups within their process development teams, invested in automation technology to accelerate screening, or both. The industry's commitment to accelerating process development has led to rapid innovations in the HTE space. This review will deliver an overview of the latest best practices currently taking place within our teams in process chemistry by sharing frequently studied transformations, our perspective for the next several years in the field, and manual and automated tools to enable experimentation. A series of case studies are presented to exemplify state-of-the-art workflows developed within our laboratories.

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Enantiopure C(1)-symmetric bis(imino)pyridine cobalt chloride, methyl, hydride, and cyclometalated complexes have been synthesized and characterized. These complexes are active as catalysts for the enantioselective hydrogenation of geminal-disubstituted olefins.

Oligomerization is kinetically favored in RCM reactions catalyzed by RuCl2(PCy3)(IMes)(CHPh), for a range of unhindered α,ω-dienes leading to large or medium-sized rings, even at dilutions designed to minimize intermolecular reaction. Reversible metathesis (i.e., ethenolysis) is inhibited by rapid volatilization of ethylene. At appropriately high dilutions, however, the RCM products are efficiently liberated by backbiting.

The synthesis of NiCl­(o-tolyl)­(TMEDA) (3; TMEDA = tetramethylethylenediamine) and its application in coupling reactions is described. In combination with a suitable ligand, precatalyst 3 was applied to a wide range of transformations, such as Suzuki, amination, Kumada, Negishi, Heck, borylation, and reductive coupling. Yields of products obtained with 3 are equal or superior to those obtained with common Ni sources such as Ni­(cod)2 (1) and NiCl2(dme) (2). Importantly, and unlike 1, complex 3 is stable for months in air as a solid, which eliminates the need for a glovebox and greatly facilitates the reaction setup. Thus, complex 3 is the first highly versatile Ni source that combines the broad applicability of 1 with the air stability of 2.

The synthesis, characterization, and reactivity of intermediates formed in the Ni-catalyzed Suzuki–Miyaura cross-coupling (SMC) of an aryl chloride are described. Oxidative addition of 1-chloro-4-trifluoromethylbenzene (1) to a mixture of Ni(cod)2 and PCy3 afforded NiCl(4-CF3Ph)(PCy3)2 (2), which then cleanly provided dimeric [Ni(4-CF3Ph)(μ–OH)(PCy3)]2 (3) by reaction with aqueous KOH. Reactivity studies of 2 and 3 with phenylboronic acid (4) revealed that, while 2 affords only traces of the biphenyl coupling product after 24 h, the same reaction with 3 is complete within minutes at room temperature. In contrast, the reaction of 3 with potassium phenyltrihydroxyborate (6) is much slower than that with boronic acid 4, and significantly lower yields of the cross-coupling product are obtained. We show that formation of the hydroxo species 3 is the rate-determining step in the present SMC.

Reported is the first study of the influence of reactor configuration on the efficiency of a challenging ring-closing metathesis (RCM) reaction. With the intention of increasing the generality of RCM scaleup and reducing its dependence on substrate modification, macrocyclization of an unmodified, low effective-molarity diene was explored using different reactor types, in conjunction with a commercial, homogeneous Grubbs catalyst. Optimized performance is compared for a conventional batch reactor (BR), a continuous plug-flow reactor (PFR), and a continuous stirred-tank reactor (CSTR). In the PFR, maximum conversion is achieved most rapidly, but product yields and selectivity are adversely affected by co-entrapment of ethylene with the catalyst, substrate, and product in the traveling "plug". Use of the CSTR, in which ethylene is efficiently swept out, affords an order-of-magnitude increase in total turnover numbers, and reduces the required catalyst loadings by 25× relative to the BR (to 0.2 mol %), while improving RCM yields and selectivity to quantitative levels. Continuous-flow methodologies that support liberation of the ethylene co-product thus show great promise for industrial uptake of RCM.

Olefin metathesis catalysts containing chelating aryloxide donors, RuXX‘(IMes)(py)(CHPh) (5, XX‘ = 3,5-dichloro-2-oxidobenzenesulfonate; 6, XX‘ = catecholate), are accessible in high yield by reaction of o-sulfonato aryloxide or catecholate salts, respectively, with RuCl2(IMes)(py)2(CHPh). Isomerization to π-bound aryloxides, as found with phenoxide ion or 2‘-(diphenylphosphino)-1,1‘-binaphthyl-2-olate, is suppressed by use of these smaller, more rigid, chelate rings. Preliminary investigations indicate that the catecholato derivative exhibits metathesis activity approaching that of the recently reported, highly active catalyst RuCl(OC6Br5)(IMes)(py)(CHPh).