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.

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.

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.

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.

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.

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.

The rapid synthesis of oxazolines and their heterogeneous oxidation to oxazoles under flow conditions.

A rapid flow synthesis of oxazolines and their oxidation to the corresponding oxazoles is reported. The oxazolines are prepared at room temperature in a stereospecific manner, with inversion of stereochemistry, from ß-hydroxy amides using Deoxo-Fluor®. The corresponding oxazoles can then be obtained via a packed reactor containing commercial manganese dioxide.

Cyclopropanation using flow-generated diazo compounds.

We have devised a room temperature process for the cyclopropanation of electron-poor olefins using unstabilised diazo compounds, generated under continuous flow conditions. This protocol was applied to a wide range of different diazo species to generate functionalised cyclopropanes which are valuable 3D building blocks.

A systems approach towards an intelligent and self-controlling platform for integrated continuous reaction sequences.

Performing reactions in flow can offer major advantages over batch methods. However, laboratory flow chemistry processes are currently often limited to single steps or short sequences due to the complexity involved with operating a multi-step process. Using new modular components for downstream processing, coupled with control technologies, more advanced multi-step flow sequences can be realized. These tools are applied to the synthesis of 2-aminoadamantane-2-carboxylic acid. A system comprising three chemistry steps and three workup steps was developed, having sufficient autonomy and self-regulation to be managed by a single operator.

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.

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.

Enhancing the pharmacodynamic profile of a class of selective COX-2 inhibiting nitric oxide donors.

We report herein the development, synthesis, physicochemical and pharmacological characterization of a novel class of pharmacodynamic hybrids that selectively inhibit cyclooxygenase-2 (COX-2) isoform and present suitable nitric oxide releasing properties. The replacement of the ester moiety with the amide group gave access to in vivo more stable and active derivatives that highlighted outstanding pharmacological properties. In particular, the glycine derivative proved to be extremely active in suppressing hyperalgesia and edema.

Integration of enabling methods for the automated flow preparation of piperazine-2-carboxamide.

Here we describe the use of a new open-source software package and a Raspberry Pi(®) computer for the simultaneous control of multiple flow chemistry devices and its application to a machine-assisted, multi-step flow preparation of pyrazine-2-carboxamide - a component of Rifater(®), used in the treatment of tuberculosis - and its reduced derivative piperazine-2-carboxamide.

A machine-assisted flow synthesis of SR48692: a probe for the investigation of neurotensin receptor-1.

Here we report the direct comparison of a conventional batch mode synthesis of Meclinertant (SR48692, 1), a neurotensin receptor-1 antagonist, with its machine-assisted flow chemistry alternative. By using these enabling tools, combined with solid-supported reagents and scavengers, many process advantages were observed. Care, however, must be taken not to convert these techniques into expensive solutions to problems that do not exist.

A class of pyrrole derivatives endowed with analgesic/anti-inflammatory activity.

We report the synthesis and bio-pharmacological evaluation of a class of pyrrole derivatives featuring a small appendage fragment (carbaldehyde, oxime, nitrile) on the central core. Compound 1c proved to be extremely effective in vivo, showing an interesting anti-nociceptic profile that is comparable to reference compounds already marketed, hence representing a great stimulus for a further improvement of this class of molecules.

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.].

MmpL3 is the cellular target of the antitubercular pyrrole derivative BM212.

The 1,5-diarylpyrrole derivative BM212 was previously shown to be active against multidrug-resistant clinical isolates and Mycobacterium tuberculosis residing within macrophages as well as against Mycobacterium avium and other atypical mycobacteria. To determine its mechanism of action, we identified the cellular target. Spontaneous Mycobacterium smegmatis, Mycobacterium bovis BCG, and M. tuberculosis H37Rv mutants that were resistant to BM212 were isolated. By the screening of genomic libraries and by whole-genome sequencing, we found that all the characterized mutants showed mutations in the mmpL3 gene, allowing us to conclude that resistance to BM212 maps to the MmpL3 protein, a member of the MmpL (mycobacterial membrane protein, large) family. Susceptibility was unaffected by the efflux pump inhibitors reserpine, carbonylcyanide m-chlorophenylhydrazone, and verapamil. Uptake/efflux experiments with [(14)C]BM212 demonstrated that resistance is not driven by the efflux of BM212. Together, these data strongly suggest that the MmpL3 protein is the cellular target of BM212.