A metal-free strategy to construct fluoroalkyl-olefin linkages using fluoroalkanes.

We present a metal-free strategy to access fluoroalkyl-olefin linkages from fluoroalkane precursors and vinyl-pinacol boronic ester (BPin) reagents. This reaction sequence is templated by the boron reagent, which induces C-C bond formation upon oxidation. We developed this strategy into a one-pot synthetic protocol using RCF2H precursors directly with vinyl-BPin reagents in the presence of a Brønsted base, which tolerated oxygen- and nitrogen-containing heterocycles, and aryl halogens. We also found that HCF3 (HCF-23; a byproduct of the Teflon industry) and CH2F2 (HCF-32; a low-cost refrigerant) are amenable to this protocol, representing distinct strategies to generate RCF2H and RCF3 molecules. Finally, we demonstrate that the vinyldifluoromethylene products can be readily derivatized, representing an avenue for late-stage modification after installing the fluoroalkyl unit.

Probing the chemical 'reactome' with high-throughput experimentation data.

High-throughput experimentation (HTE) has the potential to improve our understanding of organic chemistry by systematically interrogating reactivity across diverse chemical spaces. Notable bottlenecks include few publicly available large-scale datasets and the need for facile interpretation of these data's hidden chemical insights. Here we report the development of a high-throughput experimentation analyser, a robust and statistically rigorous framework, which is applicable to any HTE dataset regardless of size, scope or target reaction outcome, which yields interpretable correlations between starting material(s), reagents and outcomes. We improve the HTE data landscape with the disclosure of 39,000+ previously proprietary HTE reactions that cover a breadth of chemistry, including cross-coupling reactions and chiral salt resolutions. The high-throughput experimentation analyser was validated on cross-coupling and hydrogenation datasets, showcasing the elucidation of statistically significant hidden relationships between reaction components and outcomes, as well as highlighting areas of dataset bias and the specific reaction spaces that necessitate further investigation.

High-Throughput Optimization of Photochemical Reactions using Segmented-Flow Nanoelectrospray-Ionization Mass Spectrometry.

Within the realm of drug discovery, high-throughput experimentation techniques enable the rapid optimization of reactions and expedited generation of drug compound libraries for biological and pharmacokinetic evaluation. Herein we report the development of a segmented flow mass spectrometry-based platform to enable the rapid exploration of photoredox reactions for early-stage drug discovery. Specifically, microwell plate-based photochemical reaction screens were reformatted to segmented flow format to enable delivery to nanoelectrospray ionization-mass spectrometry analysis. This approach was demonstrated for the late-stage modification of complex drug scaffolds, as well as the subsequent structure-activity relationship evaluation of synthesized analogs. This technology is anticipated to expand the robust capabilities of photoredox catalysis in drug discovery by enabling high-throughput library diversification.

Preparation and Functionalization of Mono- and Polyfluoroepoxides via Fluoroalkylation of Carbonyl Electrophiles.

We outline a new synthetic method to prepare mono- and polyfluoroepoxides from a diverse pool of electrophiles (ketones, acyl chlorides, esters) and fluoroalkyl anion equivalents. The initially formed α-fluoro alkoxides undergo subsequent intramolecular ring closure when heated. We demonstrated the versatility of the method through the isolation of 16 mono- and polyfluoroepoxide products. These compounds provide unique entry points for further diversification via either fluoride migration coupled with ring opening, or defluorinative functionalization reactions, the latter of which can be used as a late-stage method to install select bioactive moieties. The reaction sequences described herein provide a pathway to functionalize the commonly observed products formed from 1,2-addition into carbonyl electrophiles.

Nucleophilic strategies to construct -CF2- linkages using borazine-CF2Ar reagents.

Using a Lewis acid-quenched CF2Ph- reagent, we show C-C bond formation through nucleophilic addition reactions to prepare molecules containing internal -CF2- linkages. We demonstrate C(sp2)-C(sp3) coupling using both SNAr reactions and Pd-catalysis. Finally, C(sp3)-C(sp3) bonds are forged using operationally simple SN2 reactions that tolerate medicinally-relevant motifs.

Decarboxylative cross-nucleophile coupling via ligand-to-metal charge transfer photoexcitation of Cu(II) carboxylates.

Reactions that enable carbon-nitrogen, carbon-oxygen and carbon-carbon bond formation lie at the heart of synthetic chemistry. However, substrate prefunctionalization is often needed to effect such transformations without forcing reaction conditions. The development of direct coupling methods for abundant feedstock chemicals is therefore highly desirable for the rapid construction of complex molecular scaffolds. Here we report a copper-mediated, net-oxidative decarboxylative coupling of carboxylic acids with diverse nucleophiles under visible-light irradiation. Preliminary mechanistic studies suggest that the relevant chromophore in this reaction is a Cu(II) carboxylate species assembled in situ. We propose that visible-light excitation to a ligand-to-metal charge transfer (LMCT) state results in a radical decarboxylation process that initiates the oxidative cross-coupling. The reaction is applicable to a wide variety of coupling partners, including complex drug molecules, suggesting that this strategy for cross-nucleophile coupling would facilitate rapid compound library synthesis for the discovery of new pharmaceutical agents.

Ultra-High-Throughput Acoustic Droplet Ejection-Open Port Interface-Mass Spectrometry for Parallel Medicinal Chemistry.

High-throughput experimentation (HTE) has emerged as an important tool in drug discovery, providing a platform for preparing large compound libraries and enabling swift reaction screening over wide-ranging conditions. Recent advances in automated high-density, material-sparing HTE have necessitated the development of rapid analytics with sensitivity and resolution sufficient to identify products and/or assess reaction performance in a timely and data-rich manner. Combination of an ultrathroughput (UT) reader platform with Acoustic Droplet Ejection-Open Port Interface-Mass Spectrometry (ADE-OPI-MS) provides the requisite speed and sensitivity. Herein, we report the application of ADE-OPI-MS to HTE in the areas of parallel medicinal chemistry and reaction screening.

Deaminative Reductive Cross-Electrophile Couplings of Alkylpyridinium Salts and Aryl Bromides.

A nickel-catalyzed reductive cross-coupling of alkylpyridinium salts and aryl bromides has been developed using Mn as the reductant. Both primary and secondary alkylpyridinium salts can be used, and high functional group and heterocycle tolerance is observed, including for protic groups. Mechanistic studies indicate the formation of an alkyl radical, and controlling its fate was key to the success of this reaction.

Sulfonamide Synthesis via Calcium Triflimide Activation of Sulfonyl Fluorides.

A method using calcium triflimide [Ca(NTf2)2] as a Lewis acid to activate sulfonyl fluorides toward nucleophilic addition with amines is described. The reaction converts a wide array of sterically and electronically diverse sulfonyl fluorides and amines into the corresponding sulfonamides in good yield.

Transforming Benzylic Amines into Diarylmethanes: Cross-Couplings of Benzylic Pyridinium Salts via C-N Bond Activation.

A nickel-catalyzed cross-coupling of benzylic pyridinium salts with arylboronic acids was developed. Coupled with chemoselective pyridinium formation, this method allows benzyl primary amines to be efficiently converted to di(hetero)arylmethanes. Excellent heteroaryl and functional group tolerance is observed, and a one-pot procedure enables benzylic amines to be converted to diarylmethanes directly.

A platform for automated nanomole-scale reaction screening and micromole-scale synthesis in flow.

The scarcity of complex intermediates in pharmaceutical research motivates the pursuit of reaction optimization protocols on submilligram scales. We report here the development of an automated flow-based synthesis platform, designed from commercially available components, that integrates both rapid nanomole-scale reaction screening and micromole-scale synthesis into a single modular unit. This system was validated by exploring a diverse range of reaction variables in a Suzuki-Miyaura coupling on nanomole scale at elevated temperatures, generating liquid chromatography-mass spectrometry data points for 5760 reactions at a rate of >1500 reactions per 24 hours. Through multiple injections of the same segment, the system directly produced micromole quantities of desired material. The optimal conditions were also replicated in traditional flow and batch mode at 50- to 200-milligram scale to provide good to excellent yields.

Ru/Ni Dual Catalytic Desulfinative Photoredox Csp2-Csp3 Cross-Coupling of Alkyl Sulfinate Salts and Aryl Halides.

A mild Ru/Ni dual catalytic desulfinative photoredox Csp2-Csp3 cross-coupling reaction of alkyl sulfinate salts with aryl halides has been developed. The optimized catalyst system, consisting of Ru(bpy)3Cl2, Ni(COD)2, and DBU, smoothly mediates the coupling of a diverse set of secondary and primary nonactivated alkyl sulfinate salts with a broad range of electron-deficient aryl bromides, electron-rich aryl iodides, and heteroaryl bromides under irradiation with blue light. The procedure is ideal for late-stage introduction of alkyl groups on pharmaceutical intermediates, and the Csp2-Csp3 cross-coupling reaction allowed the rapid synthesis of caseine kinase 1δ inhibitor analogues via a parallel medicinal chemistry effort.

Parallel Synthesis of 1H-Pyrazolo[3,4-d]pyrimidines via Condensation of N-Pyrazolylamides and Nitriles.

A novel parallel medicinal chemistry (PMC)-enabled synthesis of 1H-pyrazolo[3,4-d]pyrimidines employing condensation of easily accessible N-pyrazolylamides and nitriles has been developed. The presented studies describe singleton and library enablements that allowed rapid generation of molecular diversity to examine C4 and C6 vectors. This chemistry enabled access to challenging alkyl substituents, expanding the overall chemical space beyond that available via typical C(sp2)-C(sp2) coupling and SNAr transformations. Furthermore, monomer group interconversions allowing the use of larger and more diverse amides and carboxylic acids as precursors to nitriles are discussed.

Selective Access to Heterocyclic Sulfonamides and Sulfonyl Fluorides via a Parallel Medicinal Chemistry Enabled Method.

A sulfur-functionalized aminoacrolein derivative is used for the efficient and selective synthesis of heterocyclic sulfonyl chlorides, sulfonyl fluorides, and sulfonamides. The development of a 3-step parallel medicinal chemistry (PMC) protocol for the synthesis of pyrazole-4-sulfonamides effectively demonstrates the utility of this reagent. This reactivity was expanded to provide rapid access to other heterocyclic sulfonyl fluorides, including pyrimidines and pyridines, whose corresponding sulfonyl chlorides lack suitable chemical stability.

The Synthesis of Alkyl and (Hetero)aryl Sulfonamides From Sulfamoyl Inner Salts.

An approach to the synthesis of sulfonamides from sulfamoyl inner salts and organometallic species is presented. A range of sulfamoyl carbamates, amines, and metals are explored. Primary, secondary, and tertiary alkyl-, aryl-, and heteroaryllitihium and magnesium nucleophiles were successful. This approach yields bench-stable intermediates and avoids many of the functional group incompatibilities, regioselectivity issues, and high-energy reagents generally associated with the synthesis of sulfonamides. Additionally, the products may be purified by basic extraction or salt formation, avoiding chromatography.

A Case Report: Jacobsen Syndrome Complicated by Paris-Trousseau Syndrome and Shone's Complex.

A preterm infant presenting with a congenital cardiac malformation and thrombocytopenia was found to have a karyotype showing a terminal deletion of the long arm of chromosome 11 of the segment 11q24.1-11qter consistent with Jacobsen syndrome. The infant was later diagnosed with Paris-Trousseau syndrome, commonly associated with Jacobsen syndrome. Because children with cardiac malformations often require high-risk surgical procedures in the early neonatal period, those with platelet dysfunction require prompt identification at birth.

Shining light on photoredox catalysis: theory and synthetic applications.

Photoredox catalysis is emerging as a powerful tool in synthetic organic chemistry. The aim of this synopsis is to provide an overview of the photoelectronic properties of photoredox catalysts as they are applied to organic transformations. In addition, recent synthetic applications of photoredox catalysis are presented.

Tandem visible light-mediated radical cyclization-divinylcyclopropane rearrangement to tricyclic pyrrolidinones.

Visible light promoted single electron reduction of bromocyclopropyl cyclization scaffolds enabled by photoredox catalysis initiates a novel tandem radical cyclization/sigmatropic rearrangement to generate tricyclic pyrrolidinones having considerable molecular complexity from simple, readily available starting materials. Furthermore, subtle variations to substrate structure afford a wide array of reaction diversity.

Intermolecular atom transfer radical addition to olefins mediated by oxidative quenching of photoredox catalysts.

Atom transfer radical addition of haloalkanes and α-halocarbonyls to olefins is efficiently performed with the photocatalyst Ir[(dF(CF(3))ppy)(2)(dtbbpy)]PF(6). This protocol is characterized by excellent yields, mild conditions, low catalyst loading, and broad scope. In addition, the atom transfer protocol can be used to quickly and efficiently introduce vinyl trifluoromethyl groups to olefins and access 1,1-cyclopropane diesters.