Correction to "Safety Considerations and Proposed Workflow for Laboratory Scale Chemical Synthesis by Ball Milling".

[This corrects the article DOI: 10.1021/acs.oprd.2c00226.].

Direct Amidation of Esters by Ball Milling*.

The direct mechanochemical amidation of esters by ball milling is described. The operationally simple procedure requires an ester, an amine, and substoichiometric KOtBu and was used to prepare a large and diverse library of 78 amide structures with modest to excellent efficiency. Heteroaromatic and heterocyclic components are specifically shown to be amenable to this mechanochemical protocol. This direct synthesis platform has been applied to the synthesis of active pharmaceutical ingredients (APIs) and agrochemicals as well as the gram-scale synthesis of an active pharmaceutical, all in the absence of a reaction solvent.

Building up a Continuous Flow Platform as an Enabler to the Preparation of Intermediates on Kilogram Scale.

The following outlook describes the strategy we followed at Syngenta R&D to build and develop an effective flow chemistry platform which could fit a precise business purpose. In this account, we give insight into specific chemistry challenges encountered and addressed using continuous flow chemistry. The conclusions of the outlook outline the future of our strategy with a perspective on the technology within our business.

Direct Oxidation of Csp3 -H bonds using in Situ Generated Trifluoromethylated Dioxirane in Flow.

A fast, scalable, and safer Csp 3 -H oxidation of activated and un-activated aliphatic chains can be enabled by methyl(trifluoromethyl)dioxirane (TFDO). The continuous flow platform allows the in situ generation of TFDO gas and its rapid reactivity toward tertiary and benzylic Csp3 -H bonds. The process exhibits a broad scope and good functional group compatibility (28 examples, 8-99 %). The scalability of this methodology is demonstrated on 2.5 g scale oxidation of adamantane.

Preparation of homoallylic amines via a three-component coupling process.

A three-component synthesis of homoallylic amines is described. The allylboronic species were generated in situ by homologation of vinyl boroxines with trimethylsilyldiazomethane, then followed by trapping of the allylboron intermediate with imines. Twenty-seven compounds were successfully prepared in moderate to high yields. Imines bearing various functional groups were tolerated, including aliphatic, aromatic and heteroaromatic substituents. Further elaboration of some of the homoallylic amines to form azeditines is also reported.

Mimicking the surface and prebiotic chemistry of early Earth using flow chemistry.

When considering life's aetiology, the first questions that must be addressed are "how?" and "where?" were ostensibly complex molecules, considered necessary for life's beginning, constructed from simpler, more abundant feedstock molecules on primitive Earth. Previously, we have used multiple clues from the prebiotic synthetic requirements of (proto)biomolecules to pinpoint a set of closely related geochemical scenarios that are suggestive of flow and semi-batch chemistries. We now wish to report a multistep, uninterrupted synthesis of a key heterocycle (2-aminooxazole) en route to activated nucleotides starting from highly plausible, prebiotic feedstock molecules under conditions which mimic this scenario. Further consideration of the scenario has uncovered additional pertinent and novel aspects of prebiotic chemistry, which greatly enhance the efficiency and plausibility of the synthesis.

A Versatile Route to Unstable Diazo Compounds via Oxadiazolines and their Use in Aryl-Alkyl Cross-Coupling Reactions.

Coupling of readily available boronic acids and diazo compounds has emerged recently as a powerful metal-free carbon-carbon bond forming method. However, the difficulty in forming the unstable diazo compound partner in a mild fashion has hitherto limited their general use and the scope of the transformation. Here, we report the application of oxadiazolines as precursors for the generation of an unstable family of diazo compounds using flow UV photolysis and their first use in divergent protodeboronative and oxidative C(sp2 )-C(sp3 ) cross-coupling processes, with excellent functional-group tolerance.

Rapid Asymmetric Synthesis of Disubstituted Allenes by Coupling of Flow-Generated Diazo Compounds and Propargylated Amines.

We report herein the asymmetric coupling of flow-generated unstabilized diazo compounds and propargylated amine derivatives, using a new pyridinebis(imidazoline) ligand, a copper catalyst and base. The reaction proceeds rapidly, generating chiral allenes in 10-20 minutes with high enantioselectivity (89-98 % de/ee), moderate yields and a wide functional group tolerance.

Unveiling the role of boroxines in metal-free carbon-carbon homologations using diazo compounds and boronic acids.

By means of computational and experimental mechanistic studies the fundamental role of boroxines in the reaction between diazo compounds and boronic acids was elucidated. Consequently, a selective metal-free carbon-carbon homologation of aryl and vinyl boroxines using TMSCHN2, giving access to TMS-pinacol boronic ester products, was developed.

Visible Light Activation of Boronic Esters Enables Efficient Photoredox C(sp2 )-C(sp3 ) Cross-Couplings in Flow.

We report herein a new method for the photoredox activation of boronic esters. Using these reagents, an efficient and high-throughput continuous flow process was developed to perform a dual iridium- and nickel-catalyzed C(sp2 )-C(sp3 ) coupling by circumventing solubility issues associated with potassium trifluoroborate salts. Formation of an adduct with a pyridine-derived Lewis base was found to be essential for the photoredox activation of the boronic esters. Based on these results we were able to develop a further simplified visible light mediated C(sp2 )-C(sp3 ) coupling method using boronic esters and cyano heteroarenes under flow conditions.

Enabling Technologies for the Future of Chemical Synthesis.

Technology is evolving at breakneck pace, changing the way we communicate, travel, find out information, and live our lives. Yet chemistry as a science has been slower to adapt to this rapidly shifting world. In this Outlook we use highlights from recent literature reports to describe how progresses in enabling technologies are altering this trend, permitting chemists to incorporate new advances into their work at all levels of the chemistry development cycle. We discuss the benefits and challenges that have arisen, impacts on academic-industry relationships, and future trends in the area of chemical synthesis.

Iterative reactions of transient boronic acids enable sequential C-C bond formation.

The ability to form multiple carbon-carbon bonds in a controlled sequence and thus rapidly build molecular complexity in an iterative fashion is an important goal in modern chemical synthesis. In recent times, transition-metal-catalysed coupling reactions have dominated in the development of C-C bond forming processes. A desire to reduce the reliance on precious metals and a need to obtain products with very low levels of metal impurities has brought a renewed focus on metal-free coupling processes. Here, we report the in situ preparation of reactive allylic and benzylic boronic acids, obtained by reacting flow-generated diazo compounds with boronic acids, and their application in controlled iterative C-C bond forming reactions is described. Thus far we have shown the formation of up to three C-C bonds in a sequence including the final trapping of a reactive boronic acid species with an aldehyde to generate a range of new chemical structures.

A multicomponent approach for the preparation of homoallylic alcohols.

Here we report the in situ generation of transient allylic boronic species, by reacting TMSCHN2 and E-vinyl boronic acids, followed by their subsequent trapping with aldehydes as electrophiles to yield homoallylic alcohols. This metal-free reaction was initially discovered by the use of a flow chemistry approach to generate a variety of homoallylic alcohols in a straightforward fashion and then transferred to a batch protocol.

Dynamic flow synthesis of porous organic cages.

The dynamic covalent synthesis of two imine-based porous organic cages was successfully transferred from batch to continuous flow. The same flow reactor was then used to scramble the constituents of these two cages in differing ratios to form cage mixtures. Preparative HPLC purification of one of these mixtures allowed rapid access to a desymmetrised cage molecule.

Machine-Assisted Organic Synthesis.

In this Review we describe how the advent of machines is impacting on organic synthesis programs, with particular emphasis on the practical issues associated with the design of chemical reactors. In the rapidly changing, multivariant environment of the research laboratory, equipment needs to be modular to accommodate high and low temperatures and pressures, enzymes, multiphase systems, slurries, gases, and organometallic compounds. Additional technologies have been developed to facilitate more specialized reaction techniques such as electrochemical and photochemical methods. All of these areas create both opportunities and challenges during adoption as enabling technologies.

Machines vs Malaria: A Flow-Based Preparation of the Drug Candidate OZ439.

An efficient preparation of the antimalarial drug candidate OZ439, which was obtained by integrating a machine-assisted approach with batch processes, is reported. This approach allows a rapid and cost-effective production of the key intermediates that were readily elaborated into the target molecule.

A Versatile Room-Temperature Route to Di- and Trisubstituted Allenes Using Flow-Generated Diazo Compounds.

A copper-catalyzed coupling reaction between flow-generated unstabilized diazo compounds and terminal alkynes provides di- and trisubstituted allenes. This extremely mild and rapid transformation is highly tolerant of several functional groups.

Design, Synthesis, and Evaluation of Tetrasubstituted Pyridines as Potent 5-HT2C Receptor Agonists.

A series of pyrido[3,4-d]azepines that are potent and selective 5-HT2C receptor agonists is disclosed. Compound 7 (PF-04781340) is identified as a suitable lead owing to good 5-HT2C potency, selectivity over 5-HT2B agonism, and in vitro ADME properties commensurate with an orally available and CNS penetrant profile. The synthesis of a novel bicyclic tetrasubstituted pyridine core template is outlined, including rationale to account for the unexpected formation of aminopyridine 13 resulting from an ammonia cascade cyclization.