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We report an improved approach for the integration of flow synthesis and continuous chromatography, for applications in the end-to-end preparation of pharmaceutically-relevant small molecules. It involves the combination of sequential microreactors and twin-column counter-current chromatography based on the often-used C18 columns. The column loading method ensures that the product breaking through a fully loaded first column is loaded onto the second one, avoiding waste of precious material and technological complexity associated with the use of four-to-six columns typical of simulated moving bed chromatography. The system was applied to synthesize biphenyl via Suzuki–Miyaura reaction, and was also demonstrated for other structurally-different compounds. Compared to the discontinuous and other traditional approaches, our method leads to higher isolated yields (ca. +60%), higher productivity (ca. +30%), and reduced solvent consumption (ca. −80%). A circularity and life-cycle analysis was also conducted to demonstrate the environmental benefits of the flow process. Funding from the European Commission (GV, grant agreement 101031710), Bracco Imaging (AS, VR, and GV), Fondazione Bracco (GV), and YMC Japan (TKK and MS) is gratefully acknowledged.

The use of flow technology as an enabling tool for accessing 1-azabicyclo[1.1.0]butanes bearing strained 3-, 4-, and 5-membered O-heterocycles with C3(N-het)–C2(O-het) connectivity is reported.

This minireview covers the recent relevant literature updates on the use of CH2FI as readily available platform for monofluoromethylation strategies.

Recent years have seen a marked increase in the occurrence of sulfoximines in the chemical sciences, often presented as valuable motifs for medicinal chemistry. This has been prompted by both pioneering works taking sulfoximine containing compounds into clinical trials and the concurrent development of powerful synthetic methods. This review covers recent developments in the synthesis of sulfoximines concentrating on developments since 2015. This includes extensive developments in both S-N and S-C bond formations. Flow chemistry processes for sulfoximine synthesis are also covered. Finally, subsequent transformations of sulfoximines, particularly in N-functionalization are reviewed, including N-S, N-P, N-C bond forming processes and cyclization reactions.

In this work we investigated, for the first time, the reactivity of sulfinimidate esters as an electrophilic sulfinimidoyl motif source. The reaction of such sulfinimidate esters with Grignard reagents enables the preparation of protected sulfilimines in high yields and with a remarkable structural variability. Moreover, the transformation can be performed in CPME (cyclopentyl methyl ether) as a green solvent under environmentally responsible conditions.

Two unprecedented transformations of 2-azetines are reported. Varied C2-functionalized 2-azetines, prepared under continuous flow conditions, acted as linchpin for the preparation of either -aminocarbonyls or C3-thiolated azetidines. Interestingly, the two transformations occurred following an ionic or radical pathway depending on the reaction conditions. The ionic pathway is triggered under acidic conditions in the presence of water, while the radical process is initiated using white light irradiation following a thiol-ene reactive scheme. These two methods have been applied to the synthesis of several products including bioactive fragments. Mechanistic evidence for the two pathways is provided.

The reported flow-batch approach enables the easy preparation of 2H-azirines and their stereoselective transformation into highly functionalized NH-aziridines, starting from vinyl azides and organolithium compounds. The protocol has been developed using cyclopentyl methyl ether (CPME) as an environmentally benign solvent, resulting into a sustainable, safe and potentially automatable method for the synthesis of interesting strained compounds.

Since their discovery in the late 1960s, 1-azabicyclo[1.1.0]butanes have demonstrated to be interesting precursors of azetidines, because of the peculiar reactivity of the C3-N bond that allows double functionalization in the 1,3 positions. In particular, the recent advances reported by Baran, Lopchuk, Aggarwal, and others witness the synthetic relevance of such strained azabicycles in the synthesis of highly functionalized azetidines. However, the synthesis and reactivity of 1-azabicyclo[1.1.0]butanes remains a poorly explored topic in organic chemistry. This review aims to furnish a comprehensive knowledge on the preparation of 1-azabicyclo[1.1.0]butanes and the transformation into functionalized saturated four-membered azacycles.

In this work we investigated, for the first time, the reactivity of sulfinimidate esters as an electrophilic sulfinimidoyl motif source. The reaction of such sulfinimidate esters with Grignard reagents enables the preparation of protected sulfilimines in high yields and with a remarkable structural variability. Moreover, the transformation can be performed in CPME (cyclopentyl methyl ether) as a green solvent under environmentally responsible conditions.

Vinyl sulfones and sulfonamides are valued for their use as electrophilic warheads in covalent protein inhibitors. Conversely, the S(VI) aza-isosteres thereof, vinyl sulfoximines and sulfonimidamides, are far less studied and have yet to be applied to the field of protein bioconjugation. Herein, we report a range of different synthetic methodologies for constructing vinyl sulfoximine and vinyl sulfonimidamide architectures that allows access to new areas of electrophilic chemical space. We demonstrate how late stage functionalization can be applied to these motifs to incorporate alkyne tags, generating fully functionalized probes for future chemical biology applications. Finally, we establish a workflow for determining the absolute configuration of enantioenriched vinyl sulfoximines and sulfonimidamides by comparing experimentally and computationally determined electronic circular dichroism spectra, enabling access to configurationally assigned enantiomeric pairs by separation.

This work reports the preparation of propranolol according to a flow process. Propranolol has been prepared paying attention to tackle the formation of the by-product tertiary amine, resulting from an additional ring opening of the starting epoxide. Remarkably, the use of catalytic amount of water resulted beneficial for the yield and purity of the desired propranolol, and to substantially reducing the amount of tertiary amine byproduct. The high concentration of the solutions allowed for a productivity of several grams/h.

A facile microwave assisted three-component protocol allows the synthesis of chiral aryl-1,2-mercaptoamines in water in a few minutes with high yields, bypassing the use of toxic aziridine intermediates. The chiral 1,2-mercaptoamines were then deracemized through enzymatic resolution of the racemates using monoamine oxidase (MAO-N) biocatalysts.

We report herein a synthetic protocol for the preparation of 1,3-dibromo-1,1-difluoro-2-propanone, a new synthon used for the first time in a reaction with aromatic amines and sodium thiocyanate, leading to thiazoles which are useful candidates in drug discovery programs. The new synthon allows to introduce a bromodifluoromethyl group at the C4 of the thiazole, and it is amenable of further transformation such as the Br/F exchange useful in radiopharmaceutics. Application of the strategy to the preparation of a precursor of the biologically relevant DF2755Y is also reported.

The reaction between configurably stable α-lithiated oxiranes and 3-substituted cyclobutanones allows obtaining enantiomerically enriched cyclobutanols (er > 98 : 2). These adducts, subjected to base-mediated Payne rearrangement, lead to the synthesis of a new class of oxaspirohexanes, useful precursors of 2,4-disubstituted cyclopentanones.

Strained compounds are privileged moieties in modern synthesis. In this context, 1-azabicyclo[1.1.0]butanes are appealing structural motifs that can be employed as click reagents or precursors to azetidines. We herein report the first telescoped continuous flow protocol for the generation, lithiation, and electrophilic trapping of 1-azabicyclo[1.1.0]butanes. The flow method allows for exquisite control of the reaction parameters, and the process operates at higher temperatures and safer conditions with respect to batch mode. The efficiency of this intramolecular cyclization/C3-lithiation/electrophilic quenching flow sequence is documented with more than 20 examples.

In this work we report a new synthetic tactic for the straightforward preparation of hardly accessible sulfinamidines and sulfinamide esters, by using a simple metal-free protocol. The process is robust and uses readily available sulfenamides as the S-donor and sulfonyloxycarbamates as the N-source. The scope and mechanism have also been investigated.

Indole derivatives are among the most useful and interesting heterocycles employed in drug discovery and medicinal chemistry. In addition, flow chemistry and flow technology are changing the synthetic paradigm in the field of modern synthesis. In this review, the role of flow technology in the preparation of indole derivatives is showcased. Selected examples have been described with the aim to provide readers with an overview on the tactics and technologies used for targeting indole scaffolds.

A straightforward flow synthesis of α-chloro aldehydes has been developed. The strategy involves, for the first time, the thermal unstable chloroiodomethyllithium carbenoid and carbonyl compounds. A batch versus flow comparative study showcases the superb capability of flow technology in prolonging the lifetime of the lithiated carbenoid, even at -20 °C. Remarkably, the high chemoselectivity realized in flow allowed for preparing polyfunctionalized α-chloro aldehydes not easily accessible with traditional batch procedures.

A synthesis of unprecedented and stable glycosyl sulfoximines is reported. The developed strategies represent the first example of highly stereoselective sulfoximine formation directly from thioglycosides. This synthetic protocol has been tested on several β-thioglycosides bearing different aromatics and alkyls as S-substituents, and bearing glucose, mannose and galactose as glycosyl units. The process has been extended to a lactose derived thioglycoside and to a glucose derived sulfenamide. The process was chemo- and stereoselective, and X-ray analysis confirmed the structure and provided stereochemical information on the configuration at the sulfur atom. A model for the stereochemical outcome is proposed based on the steric environment of the sulfide.

Nuclear Magnetic Resonance (NMR) is an analytical technique extensively used in almost every chemical laboratory for structural identification. This technique provides statistically equivalent signals in spite of using spectrometer with different hardware features and is successfully used for the traceability and quantification of analytes in food samples. Nevertheless, to date only a few internationally agreed guidelines have been reported on the use of NMR for quantitative analysis. The main goal of the present study is to provide a methodological pipeline to assess the reproducibility of NMR data produced for a given matrix by spectrometers from different manufacturers, with different magnetic field strengths, age and hardware configurations. The results have been analyzed through a sequence of chemometric tests to generate a community-built calibration system which was used to verify the performance of the spectrometers and the reproducibility of the predicted sample concentrations.

The production of biodiesel at the industrial level is mainly based on the use of basic catalysts. Otherwise, also acidic catalysis allowed high conversion and yields, as this method is not affected by the percentage of free fatty acids present in the starting sample. This work has been useful in assessing the possible catalytic pathways in the production of fatty acid methyl esters (FAMEs), starting from different cooking waste oil mixtures, exploring particularly acidic catalysis. It was possible to state that the optimal experimental conditions required concentrated sulfuric acid 20% w/w as a catalyst, a reaction time of twelve hours, a temperature of 85 &deg, C and a molar ratio MeOH/oil of 6:1. The role of silica in the purification method was also explored. By evaluating the parameters, type of catalyst, temperature, reaction time and MeOH/oil molar ratios, it has been possible to develop a robust method for the production of biodiesel from real waste mixtures with conversions up to 99%.

The development of a multistep continuous-flow process, consisting of a direct α-lithiation stage and subsequent hydroxylation by aerobic oxidation, is reported. The protocol is applied to the synthesis of cyclopentylmandelic acid (CPMA), the main building block for the anticholinergic glycopyrronium bromide (glycopyrrolate). We demonstrate the safe utilization of organolithium reagents and molecular oxygen in combination by using a continuous-flow protocol. The first stage involves the formation of a di-lithium enolate intermediate, which was either pre-formed in batch or formed in flow by using n-hexyllithium as a cost-effective and industrially safe base. The subsequent hydroxylation stage utilized molecular oxygen under homogeneous and mild conditions (atmospheric pressure and room temperature) to give the desired product. A diluted form of oxygen gas, consisting of less than 10% O2 in N2 (“synthetic air”), is used in pharmaceutical batch manufacturing to effectively address safety concerns when handling molecular oxygen. The telescoped flow process afforded the target intermediate in 65% solution NMR yield (50% isolated yield after re-crystallization). The continuous-flow process opens up new opportunities for the manufacture of CPMA, with a protocol which can safely handle pure O2, and compares favorably with existing Grignard-based batch processes.

A continuous-flow reduction of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide, involved in the synthetic pathway of Mirabegron, has been developed. This study demonstrated the possibility to safely handling BH3 complexes within microfluidic reactors using 2-MeTHF as greener alternative to traditional solvents, and without requiring any additive such as DMI. In addition, NMR and HPLC purity analysis revealed that the sole by-product of this process is the diamine 3, which wouldn’t affect the following synthetic steps towards Mirabegron.

Aryl thiols can be selectively converted to sulfonimidates or sulfonamides with three new S-X connections being made selectively in one pot. Using hypervalent iodine reagents in the presence of ammonium carbamate, NH- and O-groups are transferred under mild and practical conditions. Reducing the loading of ammonium carbamate changed the product distribution, converting the sulfonimidate to the sulfonamide. Studies into the possible intermediate species are presented, suggesting that multiple pathways may be possible via sulfinate esters, or related intermediates, with each species forming the same products.

A convenient synthesis of 2- and/or 3-oxazolines has been developed depending on the structure and stereochemistry of the starting amino alcohol. PhI(OAc)2 acted as oxidant on the intermediate imine, as supported by NMR investigation. The findings demonstrate a new route providing access to unusual 3-oxazolines.