Stable and easily available sulfide surrogates allow a stereoselective activation of alcohols

Merad, Jérémy; Matyašovský, Ján; Stopka, Tobias; Brutiu, Bogdan R.; Pinto, Alexandre; Drescher, Martina; Maulide, Nuno

doi:10.1039/d1sc01602d

Cited by 16 publications

(16 citation statements)

References 41 publications

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“…Our group recently reported the reaction of thiouronium salts with alcohols to afford thioethers without requiring the use of thiol reactants. 16 The formation of a stable urea (CO) in exchange for a less stable thiourea (CS) derivative was identified as a plausible thermodynamic driving force of the reaction. 17 By analogy, we surmised that the reaction of thiouronium ylides with carbonyl compounds might also be thermodynamically biased toward the formation of a urea byproduct and thus favor an olefination pathway, in a manner akin to the Wittig reaction.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Direct Stereodivergent Olefination of Carbonyl Compounds with Sulfur Ylides

et al. 2022

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The reactivity of phosphorus and sulfur ylides toward carbonyl compounds constitutes a well-known dichotomy that is a common educational device in organic chemistrythe former gives olefins, while the latter gives epoxides. Herein, we report a stereodivergent carbonyl olefination that challenges this dichotomy, showcasing thiouronium ylides as valuable olefination reagents. With this method, aldehydes are converted to Z-alkenes with high stereoselectivity and broad substrate scope, while N-tosylimines provide a similarly proficient entry to E-alkenes. In-depth computational and experimental studies clarified the mechanistic details of this unusual reactivity.

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Section: ■ Results and Discussionmentioning

confidence: 99%

“…Our group recently reported the reaction of thiouronium salts with alcohols to afford thioethers without requiring the use of thiol reactants . The formation of a stable urea (CO) in exchange for a less stable thiourea (CS) derivative was identified as a plausible thermodynamic driving force of the reaction …”

Section: Results and Discussionmentioning

confidence: 99%

Direct Stereodivergent Olefination of Carbonyl Compounds with Sulfur Ylides

et al. 2022

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“…[ 42 , 43 ] Similarly to O ‐alkyl isoureas generated from alcohols and carbodiimides,[ 44 , 45 , 46 , 47 , 48 ] isouronium salts can act as reactive intermediates in nucleophilic displacement reactions. [ 49 , 50 ] However, none of these alcohol‐activation techniques have been previously attempted under solvent‐free conditions or utilized for the synthesis of amines. Here we report for the first time the application of an air‐stable and non‐hygroscopic solid TFFH reagent[ 50 , 51 , 52 ] for activation of alcohols towards nucleophilic substitution with amines, halogens, and some oxygen nucleophiles under essentially solvent‐free conditions provided by mechanochemistry.…”

Section: Introductionmentioning

confidence: 99%

Mechanochemical Nucleophilic Substitution of Alcohols via Isouronium Intermediates**

et al. 2022

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An expansion of the solvent‐free synthetic toolbox is essential for advances in the sustainable chemical industry. Mechanochemical reactions offer a superior safety profile and reduced amount of waste compared to conventional solvent‐based synthesis. Herein a new mechanochemical method was developed for nucleophilic substitution of alcohols using fluoro‐N,N,N′,N′‐tetramethylformamidinium hexafluorophosphate (TFFH) and K2HPO4 as an alcohol‐activating reagent and a base, respectively. Alcohol activation and reaction with a nucleophile were performed in one milling jar via reactive isouronium intermediates. Nucleophilic substitution with amines afforded alkylated amines in 31–91 % yields. The complete stereoinversion occurred for the SN2 reaction of (R)‐ and (S)‐ethyl lactates. Substitution with halide anions (F−, Br−, I−) and oxygen‐centered (CH3OH, PhO−) nucleophiles was also tested. Application of the method to the synthesis of active pharmaceutical ingredients has been demonstrated.

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“…38,39 Similarly to O-alkyl isoureas generated from alcohols and carbodiimides, [40][41][42][43][44] isouronium salts can act as reactive intermediates in nucleophilic displacement reactions. 45,46 However, none of these alcohol-activation techniques have been previously attempted under solvent-free conditions or utilized for the synthesis of amines. Here we report for the first time the application of an air-stable and non-hygroscopic solid TFFH reagent [46][47][48] for activation of alcohols towards nucleophilic substitution with amines, halogens and some oxygen nucleophiles under essentially solvent-free conditions provided by mechanochemistry.…”

Section: Introductionmentioning

confidence: 99%

Mechanochemical Nucleophilic Substitution of Alcohols via Isouronium Intermediates

Dalidovich

Nallaparaju

Shalima

et al. 2021

Preprint

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An expansion of the solvent-free synthetic toolbox is essential for advances in the sustainable chemical industry. Mechanochemical reactions offer a superior safety profile and reduced amount of waste compared to conventional solvent-based synthesis. Herein we report a new mechanochemical method for nucleophilic substitution of alcohols using fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TFFH) and K2HPO4 as an alcohol-activating reagent and a base, respectively. Alcohol activation and reaction with a nucleophile were performed in one milling jar via reactive isouronium intermediates. Nucleophilic substitution with amines afforded alkylated amines in 40–91% yields. The complete stereoinversion occurred for the SN2 reaction of (R)- and (S)-ethyl lactates. Substitution with halide anions (F−, Br−, I−) and oxygen-centered (CH3OH, PhO−) nucleophiles was also tested. Application of the method to the synthesis of active pharmaceutical ingredients (APIs) has been demonstrated.

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Stable and easily available sulfide surrogates allow a stereoselective activation of alcohols

Abstract: A simple and scalable method for stereoselective synthesis of thioethers directly from alcohols using isothiouronium salts is presented. The utility of this thiol-free reaction was exemplified by late-stage modification of complex molecules.

Cited by 16 publications

References 41 publications

Direct Stereodivergent Olefination of Carbonyl Compounds with Sulfur Ylides

Direct Stereodivergent Olefination of Carbonyl Compounds with Sulfur Ylides

Mechanochemical Nucleophilic Substitution of Alcohols via Isouronium Intermediates**

Mechanochemical Nucleophilic Substitution of Alcohols via Isouronium Intermediates

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