A three-step process using flow chemistry to produce acetaminophen is described. First, the use of biodegradable methanesulfonic acid as a promoter enables a mild and metal-free flow approach for the Friedel-Crafts acylation of different phenols, thereby addressing the limited selectivity of this reaction in acetaminophen synthesis. Subsequently, oximation and a Beckmann rearrangement with readily available and inexpensive reagents afford acetaminophen in a viable flow process, utilizing continuous extraction and crystallization as the sole purification methods, thus avoiding the need for chromatography, which is impractical for large-scale processes. Acetaminophen was formed in yields of up to 66% (60 g) in a three-step process and up to 75% (436 g) in a two-step process, with a purity of 99.93% after recrystallization.

A three-step process using flow chemistry to produce acetaminophen is described. First, the use of biodegradable methanesulfonic acid as a promoter enables a mild and metal-free flow approach for the Friedel–Crafts acylation of different phenols, thereby addressing the limited selectivity of this reaction in acetaminophen synthesis. Subsequently, oximation and a Beckmann rearrangement with readily available and inexpensive reagents afford acetaminophen in a viable flow process, utilizing continuous extraction and crystallization as the sole purification methods, thus avoiding the need for chromatography, which is impractical for large-scale processes. Acetaminophen was formed in yields of up to 66% (60 g) in a three-step process and up to 75% (436 g) in a two-step process, with a purity of 99.93% after recrystallization.

The digital transformation of chemical sciences is redefining how reaction optimization is implemented. This article provides a step-by-step guide to closed-loop optimization of organic reactions using Python, Bayesian optimization, continuous-flow chemistry, and in-line spectroscopic analysis. A nucleophilic aromatic substitution case study illustrates how computational tools and experimental chemistry can be integrated for efficient exploration of chemical space and rapid identification of optimal conditions. Key concepts are introduced and fully illustrated in the Supporting Information, with Jupyter Notebooks offering both complete code implementations and partially filled exercises for training. It is assumed that the reader has fundamental knowledge of Python, including conditionals, loops, coding structures as functions, and basic libraries. By bridging coding and practical experimental knowledge, this work highlights Python literacy as a central requirement for the next generation of chemists.

A robust and safe continuous flow synthesis of multi-tail ionizable lipids, key components in LNP formulations for RNA therapeutic delivery, is reported. A nearly quantitative conversion in the epoxidation of long-chain terminal alkenes is safely achieved in continuous flow using the Oxone/acetone system, which prevents the buildup of hazardous dimethyldioxirane. A catalyst-free polyalkylation of amine nucleophiles via high-temperature epoxide ring-opening reduces reaction time dramatically-from several days in batch to just twenty minutes of residence time in continuous flow. Alkylation of the crude epoxidation product enabled the production of representative ionizable lipids with a throughput exceeding 10 g h-1 in a laboratory setting, demonstrating strong potential for rapid and safe lipid manufacturing at scale.

A user-friendly reagent for mild and general activation of alcohols towards bimolecular nucleophilic substitution (SN2) leveraging diverse nucleophiles, including primary and secondary amines is reported herein. The new ion-paired reagent discovery was based upon the putative zwitterionic betaine intermediate of the Mitsunobu reaction and enabled the one-step conversion of enantioenriched alcohols to valuable chiral C-X bonds (where X=N, C, S, O or halide). The described activating reagent has also been applied to a one-step methylation reaction using methanol and to an intermolecular amination/intramolecular cyclization sequence that generates heterocycles, such as tetrahydroisoquinolines. This work provides the first evidence by X-ray crystallography of a protonated betaine as intermediate in the Mitsunobu reaction.

The pentafluorosulfanyl (SF5-) group has been the subject of a surge of interest in the past decade, but there is still little practicality associated with its synthesis and installation. Herein is reported the first continuous flow synthesis of pentafluorosulfanyl chloride (SF5Cl), the most common reagent for the synthesis of SF5-substituted compounds. The synthesis is based on inexpensive and easy-to-handle reagents: sulfur powder (S8), trichloroisocyanuric acid (TCCA) and potassium fluoride (KF). To this end, a custom-made stirring reactor was designed to allow for fast, safe, and highly efficient on-demand synthesis of SF5Cl. The resulting SF5Cl solution is showcased in the radical addition on alkynes in a telescoped fashion.

Small, strained carbocyclic systems have fascinated organic chemists from both a theoretical and synthetic standpoint. These systems often challenge conventional wisdom when it comes to molecular structure and tactics for chemical construction. The cyclopropyl motif is one such ring system that remains at the forefront of method development in the modern era. With the advent of an array of non-traditional building blocks, a range of new cyclopropanation processes using one- and two-electron strategies have been developed that not only overcome the synthetic shortcomings of classical approaches but also provide entry into a wide range of new classes of cyclopropanes. This review discusses recent advances in this area with an emphasis on their mechanistic underpinnings and potential applications. Additionally, a concise overview of the properties of and traditional approaches to cyclopropanes is provided. Three's Company: This Concept article presents recent developments in cyclopropanation. Three distinct activation modes (radical, radical-polar crossover, and anionic) of an array of new feedstocks are discussed with a special emphasis on mechanistic similarities. The implication for synthesis, limitations of these methods, and applications to the broader chemical community are detailed. image

Herein we describe an asymmetric synthesis of the pharmacologically relevant natural (-)-trans-CBD and psychoactive (-)-trans-Delta(9)-THC, as well as their synthetic cis diastereomers. The key step is an enantioselective Diels-Alder reaction catalyzed by a prolinol-based catalyst, which provides the cyclohexene carbaldehyde intermediate in good yield and high enantiomeric excess. Optimization of the substituted resorcinol protecting groups to avoid harsh and low-yield deprotection of the acid sensitive resorcinol moiety is also described.

Continuous flow chemistry has become the method of choice for the synthesis of toxic and explosive intermediates such as diazo reagents because they can be generated on demand and readily used, eliminating the need to handle hazardous materials. This inherent increase in safety makes it more feasible to use these reagents in day-to-day synthesis. Herein, we describe a continuous flow, metal-free, easy-to-use method for the preparation of semi-stabilized and unstabilized diazo reagents. The scope of the described continuous flow oxidation of hydrazones using a packed bed column with iodosylbenzene includes 13 semi-stabilized and 13 unstabilized diazo reagents in solution in dichloromethane while producing only 1 equivalent of water and iodobenzene as by-products. These otherwise difficult to access compounds are further reacted either in situ or at the reactor outlet to yield esters and ethers in good to excellent yields (47–96

Abstract Spirocyclic motifs often require multi-step syntheses but are of high value to medicinal chemists due to frequent improvements in potency, selectivity, and physicochemical properties over their planar parent drug molecules. Due to the ubiquity of C‒H and C‒C bonds, an extremely challenging, yet incredibly attractive way to achieve molecular diversity and complexity is through the tandem and predictable activation of inert C‒H and C‒C bonds. Tandem activation/cleavage of these bonds in readily accessible cyclopropanes to access complex motifs is challenging and has only been reported using transition metals. The merging of C‒H activation and C‒C bond cleavage strategies for the regioselective transformation of unactivated cyclopropane building blocks into spirocyclic scaffolds in a metal-free manner could be a valuable addition to the organic chemist’s synthetic toolbox. Here, we demonstrate a regioselective C‒H bond activation and subsequent C‒C bond cleavage of unactivated cyclopropane amine-boranes (CABs) to form spirocyclic amine-boranes (SABs) possessing a rare N-spiroatom in an intramolecular manner using 5 mol% of Tf2NH. The one-pot transformation yields SABs that are amenable to downstream modification and provides access to potential pharmacophores that may have applications in drug discovery.

Continuous flow techniques have been adopted to enhance the efficiency and practicality of using chiral auxiliaries in stereoselective synthesis. One or more of the three steps involved in the generation of stereocenters with chiral auxiliaries (installation, diastereoselective reaction, cleavage) can benefit from continuous flow synthesis making the overall process more practical. This chapter presents a selection of examples to illustrate this concept. Continuous flow synthesis has been applied to chiral auxiliary controlled photocycloadditions, cycloadditions, photocyclizations, enolate fluorination, imine reduction, and alkene reduction.

This work presents the 1,3-dipolar cycloaddition of SF5-alkynes with nonstabilized diazo compounds under mild conditions, producing highly substituted SF5-3H-pyrazoles. Eighteen examples are given, with yields of up to 91%. The two regioisomers were obtained in ratios ranging from 27:73 to 73:27. The products can undergo a Van Alphen-Huttel rearrangement. DFT calculations were performed to understand the selectivities and rearrangements.

The synthesis of trifluoromethyl (CF3)- and pentafluorosulfanyl (SF5)-substituted cyclopropane-fused γ-lactones was carried out through Rh2(esp)2-catalyzed intramolecular cyclopropanation in up to 99% yields. Twelve examples of this interesting scaffold are reported, as well as postfunctionalizations that provide access to highly functionalized CF3- and SF5-substituted cyclopropanes. These novel SF5-substituted analogues join the very short list of available pentafluorosulfanyl intermediates.

A practical access to cyclopropylamines from the corresponding amides is disclosed, according to an electro-induced Hofmann rearrangement. In an undivided cell under galvanostatic conditions, a panel of cyclopropyl amides was readily converted into the corresponding amines (17 examples, 23% to 94% yield). This reaction allowed an easy access to the versatile cyclopropylamines and is complementary to the existing methods.

A total synthesis of the naturally occurring 1,3,6-trigalloyl-β-d-glucose is reported. The highlights of the synthesis include a regioselective benzylation of levoglucosan, followed by a 1,6-ring opening via acetolysis. Galloyl substituents were introduced via esterification, and the mixture of anomers obtained could be fully converted into the targeted β-anomer via selective hydrazinolysis followed by activation of the anomeric position by a trichloroacetimidate of the 1′-anomeric hydroxyl group. 1,3,6-Trigalloyl-β-d-glucose and its synthetic α-anomer were obtained in an overall yield of 31% and 22%, respectively, from levoglucosan or in an overall yield of 37% of the β-isomer exclusively by recycling the α-isomer.

The importance of rapid access to diagnostics tools in the identification of pathogens-including their crucial component, bioreagents-was recently underscored in the COVID-19 pandemic. The currently adopted synthesis of dithiothreitol (DTT) involves four steps in batch with long reaction times and which generates a highly carcinogenic and mutagenic bis-epoxide intermediate. In this work, we have developed an intensified telescoped three-step continuous flow synthesis of DTT involving a base-mediated ring closure epoxidation, a nucleophilic epoxide opening with thioacetic acid, and an acid-mediated deacetylation. One of the key features is that the first two steps are conducted in a telescoped continuous flow fashion, allowing generation and consumption of the hazardous intermediate in situ, suppressing the need for its isolation, and improving the overall safety of the synthesis. The process is completed by an acid-catalyzed deacetylation and a subsequent recrystallization to afford the desired DTT. Flow chemistry allows here to intensify the process by using high temperatures and high pressures while minimizing the number of unit operations and improving the overall safety of the process. Our protocol permits the on-demand production of DTT in case of future outbreaks.

The borosilylcyclopropanation of styrene derivatives using a (diiodo(trimethylsilyl)methyl)boronic ester carbene precursor is reported herein. The key reagent was synthesized in a 4-step sequence using inexpensive and commercially available starting materials. This method enabled the preparation of novel 1,1,2-tri- and 1,1,2,2-tetrasubstituted borosilylcyclopropanes up to excellent yields and diastereoselectivity. The reaction is organocatalyzed by eosin Y in the presence of visible light. A mechanism consistent with the experimental observations was postulated based on density functional theory calculations. The versatility of these entities was highlighted through post-functionalization reactions.

Through a revisited Simmons-Smith type zincocyclopropanation using bromoform as the carbenoid source, the synthesis of 2-, 2,2- and 2,4-substituted bicyclo[1.1.0]butanes is reported. Few antecedents of the derivatives have yet been described. Ultimately, the underexplored scaffolds exhibited a complete discrepency of reactivity.

An expedient and efficient synthesis of acetyl phloroglucinol from phloroglucinol under continuous flow is reported. This compound is an important building block to access numerous flavonoids. The reported acetylation reaction of phloroglucinol is more efficient than under batch conditions (residence time of 1 min in flow vs 10–15 h in batch; ≥ 98 • Development of an efficient continuous flow synthesis of Friedel–Crafts acetylation reactions. • Use of ethyl acetate as a biomass-derived solvent. • Versatility of the acetylating agent (acetic anhydride or acetyl chloride). • Readily available and cheap Lewis acid (BF3•OEt2). • Acetylation of other electron-rich arenes and heteroarenes under homogenous and flow compatible conditions. • Readily scalable (up to 99 g/h) using laboratory scale equipment.

The first diastereo- and enantioselective cyclopropanation reactions of electron-deficient allenes with donor-acceptor and diacceptor diazo reagents are described. The desired enantioenriched alkylidenecyclopropanes (ACPs) were obtained in high yields with high diastereo- and enantioselectivities in the presence of Rh-2((S)-TCPTAD)(4) or Rh-2((R)-BTPCP)(4) catalysts (up to 95 % yield, >95 : 5 d.r. and 99 : 1 e.r.). This methodology gave a direct access to ACPs bearing multiple electron-deficient substituents and allows to further expand the availability of ACPs chemistry. Interestingly, during the examination of the scope of this reaction, the asymmetric intramolecular C-H insertion reaction into tert-butyl group was observed as a side reaction with up to 94 : 6 e.r.