Diego Gamba-Sánchez

Herein, we present a mechanochemical approach for the sulfenylation of maleimides to afford sulfenylsuccinimides under solvent-, catalyst-, heating-, and base-free conditions. The reaction proceeds via a thia-Michael addition mechanism and, in several cases, allows product isolation through simple extraction using ethyl acetate. The method also employs LiCl as a grinding auxiliary (with NaCl as a viable alternative in some cases), thereby replacing traditional solvents with less polluting and easily disposable solid materials. The scope of the reaction was evaluated using 30 different substrates, including variations in the nucleophiles, the maleimides, and additional Michael acceptors. Furthermore, we demonstrate selected applications of the resulting sulfenylsuccinimides.

We report a general and efficient mechanochemical protocol for the formation of PO, PN, and PS bonds through the reaction of phosphoryl chlorides with O‐, N‐, and S‐centered nucleophiles. The transformation proceeds under solvent‐free conditions using ball milling in the presence of triethylamine and an inert grinding auxiliary, under ambient atmosphere and short reaction times. A broad range of primary and secondary alcohols, phenols, amines, anilines, and thiols are compatible with the methodology, affording the corresponding phosphates, phosphoramidates, and thiophosphates in moderate‐to‐excellent yields.

Amaryllidaceae alkaloids (AAs) are a valuable class of plant specialized metabolites with diverse pharmacological properties. However, the discovery of enzymes involved in AA biosynthesis through traditional methods has been subjected to several drawbacks over time, demanding labor-intensive screening and optimized growth conditions. Here, we introduce a Support Vector Machine (SVM)-algorithm-based approach that overcomes these challenges by predicting enzyme-substrate interactions based solely on amino acid sequences and molecular fingerprints. We employed a training set of 90 enzyme sequences, equally balanced, where the positive enzymes were selected based on chemical similarity to the substrate of interest (4'-O-methylnorbelladine (4OMET)), and the negative enzymes corresponded to active enzymes toward 4OMET-decoy molecules. Applying this prediction model to transcriptomic data of Crinum asiaticum bulbs identified 19 putative cytochrome P450 enzymes. Functional assays in heterologous systems showed that five candidates reproducibly depleted 4OMET, including a CYP81-like candidate - a P450 class not previously linked to 4OMET turnover. Overall, this strategy bypasses the need for stringent alkaloid accumulation conditions and precise tissue sampling for enzyme discovery, offering a scalable and cost-effective candidate selection alternative for downstream biochemical characterization and pathway elucidation efforts.

Masked formylation using dithiane oxide activated by oxalyl chloride via a thionium ion. It enables efficient substitution in electron-rich arenes and mild dithiane cleavage to aldehydes, offering a simple, versatile alternative to classical methods.

The transamidation (aminolysis) of phthalimide with primary and secondary aliphatic amines is reported, where reactivity is induced by mechanical forces without the need for catalysts, acids, or thermal activation. The reaction proceeds at room temperature to afford N-substituted phthalamides as the major products. It is carried out in a mixer mill using stainless-steel jars and balls. The scope is demonstrated with more than 20 examples, achieving yields of up to 98%.

The halogenation of aromatic and heteroaromatic systems has attracted considerable attention in recent decades owing to the importance of haloaromatics in biologically relevant compounds and their role as essential building blocks for more complex systems. In recent years, various research groups have explored the challenge of developing new synthetic methodologies for electrophilic halogenation. Nevertheless, these methods continue to encounter several challenges, such as waste products from halogenating agents, toxic or contaminating reagents, and problems with low regioselectivity, with polyhalogenation—often the predominant side reaction—occurring in some cases. In this context, organocatalysis has emerged as a promising approach to address these limitations. This review highlights key organocatalytic strategies reported in the last 14 years and discusses experimental aspects, mechanisms, and selectivity issues in chlorination, bromination, fluorination, and iodination of aromatic systems.

A highly chemoselective method for cleaving N-arylphthalimides using nontoxic ammonium carbonate has been developed. The approach enables recovery and reuse of the protecting group, shows complete selectivity over N-alkylphthalimides and common amine-protecting groups, and is effective across 28 substrates. This practical method allows late-stage deprotection, avoids toxic reagents, minimizes waste, and eliminates the need for chromatography, making it a sustainable and efficient alternative for selective deprotection in organic synthesis.

Sulfides are valuable organic compounds and important synthetic intermediates. However, the reduction of sulfoxides to sulfides still lacks general applicability due to challenges such as harsh reaction conditions and the reliance on transition metal catalysts. Here, an extension of a previously reported metal-free reduction of sulfoxides is presented, incorporating a greener approach that, in most cases, eliminates the need for chromatographic purification. This method also enabled to scale up the reduction of albendazole to a multigram scale in excellent yield.

This manuscript presents a regioselective chlorination of arenes, yielding almost exclusively the monochlorinated product. It tolerates free hydroxy groups, 1°, 2° and 3° amines, and carboxylic acids, among other polar and nonpolar functional groups, as well as mono‐ and polysubstituted aromatic rings. Additionally, the utilization of chlorosulfonium salts as the chlorinating agent is demonstrated. The method emerges as an alternative to other processes where organic byproducts must be separated from the reaction mixture. In addition, the main byproducts are gaseous materials such as CO and CO₂. This publication introduces the application of sulfoxides, oxalyl chloride, and aqueous hydrogen peroxide as the chlorination mixture.