A simple formamide catalyst facilitates the efficient transformation of alcohols into alkyl chlorides with benzoyl chloride as the sole reagent. These nucleophilic substitutions proceed through iminium-activated alcohols as intermediates. The novel method, which can be even performed under solvent-free conditions, is distinguished by an excellent functional group tolerance, scalability (>100 g) and waste-balance (E-factor down to 2). Chiral substrates are converted with excellent levels of stereochemical inversion (99 %→≥95 % ee). In a practical one-pot procedure, the primary formed chlorides can be further transformed into amines, azides, ethers, sulfides, and nitriles. The value of the method was demonstrated in straightforward syntheses of the drugs rac-Clopidogrel and S-Fendiline.

The RNA‐templated extension of oligoribonucleotides by nucleotides produces either a 3′,5′ or a 2′,5′‐phosphodiester. Nature controls the regioselectivity during RNA chain growth with polymerases, but enzyme‐free versions of genetic copying have modest specificity. Thus far, enzymatic degradation of products, combined with chromatography or electrophoresis, has been the preferred mode of detecting 2′,5′‐diesters produced in enzyme‐free reactions. This approach hinges on the substrate specificity of nucleases, and is not suitable for in situ monitoring. Here we report how 1 H NMR spectroscopy can be used to detect the extension of self‐templating RNA hairpins and that this reveals the regioisomeric nature of the newly formed phosphodiesters. We studied several modes of activating nucleotides, including imidazolides, a pyridinium phosphate, an active ester, and in situ activation with carbodiimide and organocatalyst. Conversion into the desired extension product ranged from 20 to 90 %, depending on the leaving group. Integration of the resonances of H1′ protons of riboses and H5 protons of pyrimidines gave regioselectivities ranging from 40:60 to 85:15 (3′,5′ to 2′,5′ diester), but no simple correlation between 3′,5′ selectivity and yield. Our results show how monitoring with a high‐resolution technique sheds a new light on a process that may have played an important role during the emergence of life.

Ein einfacher Formamidkatalysator ermöglicht effiziente Transformationen von Alkoholen zu Alkylchloriden mit Benzoylchlorid als einzigem Reagenz. Diese nukleophilen Substitutionsreaktionen verlaufen über iminiumaktivierte Alkohole als Intermediate. Die neue Methode, die sogar lösungsmittelfrei durchgeführt werden kann, zeichnet sich durch eine exzellente Kompatibilität mit funktionellen Gruppen, Skalierbarkeit (>100 g) und Abfallbilanz aus (E‐Faktor bis zu 2). Chirale Substrate werden unter einem hohen Grad an stereochemischer Inversion in die entsprechenden Chloride überführt (99 %→≥95 % ee). In einem praktischen Eintopfverfahren konnten die primär gebildeten Chloride direkt zu Aminen, Aziden, Ethern, Sulfiden und Nitrilen weiter umgesetzt werden. Der praktische Nutzen der Methode wurde darüber hinaus in kurzen Synthesen von rac‐Clopidogrel und S‐Fendilin bewiesen.

Herein, a method for the nucleophilic substitution (SN) of benzyl alcohols yielding chloro alkanes is introduced that relies on aromatic sulfoxides as Lewis base catalysts (down to 1.5 mol‐%) and benzoyl chloride (BzCl) as reagent. A systematic screening of various sulfoxides and other sulfinyl containing Lewis bases afforded (2‐methoxyphenyl)methyl sulfoxide as optimal catalyst. In contrast to reported formamide catalysts, sulfoxides also enable the application of plain acetyl chloride (AcCl) as reagent. In addition, it was demonstrated that weakly electrophilic carboxylic acid chlorides like BzCl promote Pummerer rearrangement of sulfoxides already at room temperature. This side‐reaction also provided the explanation, why sulfoxide catalyzed SN‐reactions of alcohols do not allow the effective production of aliphatic and electron deficient chloro alkanes. Comparison experiments provided further insight into the reaction mechanism.