Abstract The strong and polar nature of C–F bonds impart organofluorine compounds with highly desirable properties, making them indispensable in pharmaceutical, agrochemical, and polymer research. While this bond strength makes the modification of organofluorine compounds challenging, it also creates opportunities for the development of innovative strategies for their functionalization. Carbamoyl fluorides represent an emerging class of fluorinated electrophiles, showcasing unique fluoride-enabled reactivity and serving as versatile building blocks for accessing valuable amides and heterocyclic compounds. This review highlights recent progress in the synthesis and reactivity of carbamoyl fluorides, including comparisons to their chlorinated counterparts where relevant.1 Introduction2 Synthesis and Simple Nucleophilic Substitution Reactions of Carbamoyl Fluorides2.1 Direct Use of Difluorophosgene2.2 Use of (Di)fluorophosgene Equivalents2.2.1 From Isocyanates and Thioformamides2.2.2 From Amines2.3 Use of Difluorocarbene Sources2.4 Use of CO2 and Deoxyfluorinating Reagents2.5 Miscellaneous Methods3 Reactivity of Carbamoyl Fluorides3.1 Covalent Inhibition of Enzymes3.2 Nucleophilic Substitution3.3 Transition-Metal-Catalyzed C–F Bond Activation3.4 Lewis Acid and Base Catalyzed Carbamoylation4.0 Outlook and Conclusion

Abstract The synthesis of a 4,4-difluoropiperidine intermediate, a key component of an MRGPRX2 antagonist, is challenging due to the presence of a gem-difluoro moiety adjacent to a stereocenter which also bears a reactive pyridine N-oxide motif. The initial discovery chemistry route required chiral supercritical fluid chromatography (SFC) at the end of the synthesis to provide enantiopure product. XtalFluor-E was used for deoxyfluorination on a ketone adjacent to a p-pyridylmethyl position, resulting in very low yields due to the elimination of HF. After several unsuccessful attempts for a de novo asymmetric synthesis, we focused our attention on the process development for a more practical synthesis than the existing route. A much higher yielding deoxyfluorination was enabled by SF4 and HF. Furthermore, the chiral SFC was replaced by an efficient classical resolution at a much earlier stage of the synthesis, taking advantage of the basicity of the pyridine moiety before oxidation to the pyridine N-oxide. Although not all stages have been scaled up in the plant scale, the new synthesis is much more practical and has improved the overall yield from 12% to 23% for this challenging molecule.

Abstract A one-pot method is proposed for the synthesis of 3-amino-2-arylquinolin-4(1H)-ones based on intermolecular cyclocondensation of isatoic anhydride and 1-(2-oxo-2-arylethyl)pyridinium salts in a basic medium followed by decomposition of pyridinium to amine by the action of hydrazine hydrate. The solutions of all the obtained amines emit in the blue-green region of the visible spectrum with a fluorescence quantum yield of up to 0.59 when irradiated with ultraviolet or violet light.

Abstract An unexpected formation of novel 2,3-bis(methylthio)-1,4-di(het)arylbut-2-ene-1,4-diones is reported, when methyl ketones are reacted with α-oxodithioesters in the presence of sodium hydride in DMF followed by treatment with methyl iodide. A potential application of these key intermediates for the synthesis of unreported 4,5-bis(methylthio)-3,6-di(het)arylpyridazines is explored by reacting them with hydrazine in the presence of potassium hydroxide in isopropyl alcohol. Possible mechanisms for the formation of 2,3-bis(methylthio)-1,4-di(het)arylbut-2-ene-1,4-diones and 4,5-bis(methylthio)-3,6-di(het)arylpyridazines are proposed.

Abstract The oxidation of primary alcohols, sulfides, and trifluoromethyl sulfides using sodium hypochlorite pentahydrate crystals as the oxidizing agent was investigated in detail. The optimal conditions for oxidation to the corresponding carboxylic acids, sulfones, and trifluoromethyl sulfones in high yields were determined. At a reaction medium pH of 9–10, primary alcohols in ethyl acetate and water in the presence of TEMPO or AZADOL were oxidized to aliphatic and aromatic carboxylic acids in high yields. Sulfides were oxidized to sulfones in high yields by using toluene as the solvent, and trifluoromethyl sulfides were oxidized to give the corresponding sulfones in benzotrifluoride in the presence of trifluoroacetic acid.

Abstract An efficient and simple procedure for direct halogenation of nucleoside furanose rings is developed using commercial α-halo ether reagents. The methodology enables simultaneous protection of the N 3-pyrimidine and halogenation of the ribose ring, starting from the corresponding readily accessible anhydro nucleosides. Several 2′- or 3′-halo-nucleoside derivatives are prepared in good yields under very mild reaction conditions.

Abstract Out of the results of the sole large-scale screening for inhibitors of SARS-CoV-1 main protease reported in 2013, attempts to improve the identified 3-pyridyl-bearing hits have been conducted in research laboratories, either on this enzyme or more recently on the closely related SARS-CoV-2 main protease. From the resulting structural information reported, we sought to design analogues featuring some of the components providing an affinity for the active site of these proteases along with a different scaffold, which would allow for further structure-activity relationship studies and/or pharmacological improvements. We describe here the introduction of a bridging component with the aim of stabilizing the ligand conformation adopted when bound to these proteases. Accordingly, this led us to prepare 3,3-disubstituted piperazin-2-ones from an array of ketones, via either a Bargellini reaction or a multistage condensation/cyclization/hydrolysis involving ethylene diamine and potassium cyanide. However, even the most elaborate and lipophilic biphenyl-bearing analogues displayed only a weak effect in a bioluminescence-based SARS-CoV-2 main protease inhibition assay.

Abstract A general and efficient protocol has been developed for the N-alkylation of carbazoles with benzylic alcohols via scandium-catalyzed reaction. This transformation proceeds smoothly under an air atmosphere and features simple reaction conditions and wide substrate scope, which deliver a variety of N-alkylated carbazoles with up to 99% yields and broad functional group compatibilities.

Abstract Alkynylboron compounds are important scaffolds with broad applicability in organic synthesis. In contrast to polar or metal-catalyzed processes, here a radical approach is employed for the addition of nucleophilic boryl radicals to electrophilic SOMOphiles for the construction of the C(sp)–B bond. The reaction renders the corresponding alkynylated amine boranes with broad functional group compatibility. In addition, theoretical studies have been carried out by means of DFT to understand the reactivity and selectivity of the addition process.