Syntheses of Sulfilimines by Iron-Catalyzed Iminations of Sulfides with 2,2,2-Trichloroethyl Sulfamate.

N-protected sulfilimines are prepared by imination of sulfides with a combination of 2,2,2-trichloroethyl sulfamate (H2NTces), (diacetoxyiodo)benzene (PIDA), and a catalytic amount of iron triflate. The reaction proceeds at room temperature, and after only 3 h a wide range of acyclic and cyclic NTces-sulfilimines with various functional groups and (hetero)aryl substituents can be obtained. By subsequent oxidation followed by deprotection, the products are converted into NH-sulfoximines.

Synthesis of Benzo[e][1,4,3]oxathiazin-3-one 1-Oxides from NH-S-(2-Hydroxyaryl)sulfoximines.

Cyclizations of NH-S-(2-hydroxyaryl)sulfoximines with 1,1'-carbonyldiimidazol (CDI) give unprecedented benzo[e][1,4,3]oxathiazin-3-one 1-oxides in good yields. The standard synthetic protocol involves the use of DCE at an increased temperature for 16 h. Under mechanochemical conditions, a representative product was obtained without a solvent at ambient temperature in only 60 min. X-ray single-crystal structure analysis confirmed the molecular scaffold representing a three-dimensional heterocycle.

Unexpected Single-Ligand Occupancy and Negative Cooperativity in the SARS-CoV-2 Main Protease.

Many homodimeric enzymes tune their functions by exploiting either negative or positive cooperativity between subunits. In the SARS-CoV-2 Main protease (Mpro) homodimer, the latter has been suggested by symmetry in most of the 500 reported protease/ligand complex structures solved by macromolecular crystallography (MX). Here we apply the latter to both covalent and noncovalent ligands in complex with Mpro. Strikingly, our experiments show that the occupation of both active sites of the dimer originates from an excess of ligands. Indeed, cocrystals obtained using a 1:1 ligand/protomer stoichiometry lead to single occupation only. The empty binding site exhibits a catalytically inactive geometry in solution, as suggested by molecular dynamics simulations. Thus, Mpro operates through negative cooperativity with the asymmetric activity of the catalytic sites. This allows it to function with a wide range of substrate concentrations, making it resistant to saturation and potentially difficult to shut down, all properties advantageous for the virus' adaptability and resistance.

Mechanochemical Iron-Catalyzed Nitrene Transfer Reactions: Direct Synthesis of N-Acyl Sulfonimidamides from Sulfinamides and Dioxazolones.

A mechanochemical synthesis of sulfonimidamides by iron(II)-catalyzed exogenous ligand-free N-acyl nitrene transfer to sulfinamides is reported. The one-step method tolerates a wide range of sulfinamides with various substituents under solvent-free ambient conditions. Compared to its solution-phase counterpart, this mechanochemical approach shows better conversion and chemoselectivity. Mechanistic investigations by ESI-MS revealed the generation of crucial nitrene iron intermediates.

Molecular Recognition in Mechanochemistry: Insights from Solid-State NMR Spectroscopy.

Molecular-recognition events are highly relevant in biology and chemistry. In the present study, we investigated such processes in the solid state under mechanochemical conditions using the formation of racemic phases upon reacting enantiopure entities as example. As test systems, α-(trifluoromethyl)lactic acid (TFLA) and the amino acids serine and alanine were used. The effects of ball-milling and resonant acoustic mixing (RAM) on the formation of racemic phases were probed by using solid-state Nuclear Magnetic Resonance (NMR) spectroscopy. In a mixer mill, a highly efficient and fast racemic phase formation occurred for both TFLA and the two amino acids. RAM led to the racemic phase for TFLA also, and this process was facilitated upon employing pre-milled enantiopure entities. In contrast, under comparable conditions RAM did not result in the formation of racemic phases for serine and alanine.

A Copper-Catalyzed Interrupted Domino Reaction for the Synthesis of Fused Triazolyl Benzothiadiazine-1-oxides.

Copper(I)-catalyzed domino reactions of 2-azido sulfoximines with 1-iodoalkynes yield fused triazolyl-containing benzothiadiazine-1-oxides. The protocol features the synthesis of two fused heterocyclic rings in one step with good to excellent yields and a broad functional group tolerance. Detailed mechanistic investigations indicate that a copper π-complex initiates a cycloaddition and oxidative C-N coupling reaction sequence. The results suggest an interrupted domino process involving an iodinated triazole as a key intermediate.

Disentangling the Effect of Pressure and Mixing on a Mechanochemical Bromination Reaction by Solid-State NMR Spectroscopy.

Mechanical forces, including compressive stresses, have a significant impact on chemical reactions. Besides the preparative opportunities, mechanochemical conditions benefit from the absence of any organic solvent, the possibility of a significant synthetic acceleration and unique reaction pathways. Together with an accurate characterization of ball-milling products, the development of a deeper mechanistic understanding of the occurring transformations at a molecular level is critical for fully grasping the potential of organic mechanosynthesis. We herein studied a bromination of a cyclic sulfoximine in a mixer mill and used solid-state nuclear magnetic resonance (NMR) spectroscopy for structural characterization of the reaction products. Magic-angle spinning (MAS) was applied for elucidating the product mixtures taken from the milling jar without introducing any further post-processing on the sample. Ex situ 13 C-detected NMR spectra of ball-milling products showed the formation of a crystalline solid phase with the regioselective bromination of the S-aryl group of the heterocycle in position 4. Completion is reached in less than 30 minutes as deduced from the NMR spectra. The bromination can also be achieved by magnetic stirring, but then, a longer reaction time is required. Mixing the solid educts in the NMR rotor allows to get in situ insights into the reaction and enables the detection of a reaction intermediate. The pressure alone induced in the rotor by MAS is not sufficient to lead to full conversion and the reaction occurs on slower time scales than in the ball mill, which is crucial for analysing mixtures taken from the milling jar by solid-state NMR. Our data suggest that on top of centrifugal forces, an efficient mixing of the starting materials is required for reaching a complete reaction.

Electro-mechanochemical approach towards the chloro sulfoximidations of allenes under solvent-free conditions in a ball mill.

An electro-mechanochemical protocol for the synthesis of vinylic sulfoximines has been developed. Utilising mechanochemically strained BaTiO3 nanoparticles, the catalytic active system is generated in situ by the reduction of copper(II) chloride. Various combinations of electron-donating and -withdrawing groups are tolerated, and the approach leads to products with difunctionalised double bonds in good to excellent yields. Attempts to add a sulfoximidoyl chloride to an alkyne proved difficult. Additions of a sulfonyl iodide to allenes and alkynes proceeded smoothly in the presence of silica gel without the need for activation by a piezoelectric material.

Synthesis of o-Sulfinylanilines from N-Alkyl Sulfoximines and Arynes.

N-Alkyl sulfoximines react with arynes generated in situ under mild conditions providing o-sulfinylanilines in good yields. The transformation is characterized by a broad substrate scope and a good functional group tolerance. The structure of a reaction product was confirmed by single-crystal X-ray diffraction.

The effect of methyl group rotation on 1H-1H solid-state NMR spin-diffusion spectra.

Fast magic-angle spinning (MAS) NMR experiments open the way for proton-detected NMR studies and have been explored in the past years for a broad range of materials, comprising biomolecules and pharmaceuticals. Proton-spin diffusion (SD) is a versatile polarization-transfer mechanism and plays an important role in resonance assignment and structure determination. Recently, the occurrence of negative cross peaks in 2D 1H-1H SD-based spectra has been reported and explained with higher-order SD effects, in which the chemical shifts of the involved quadruple of nuclei need to compensate each other. We herein report negative cross peaks in SD-based spectra observed for a variety of small organic molecules involving methyl groups. We combine experimental observations with numerical and analytical simulations to demonstrate that the methyl groups can give rise to coherent (SD) as well as incoherent (Nuclear Overhauser Enhancement, NOE) effects, both in principle manifesting themselves as negative cross peaks in the 2D spectra. Analytical calculations and simulations however show that higher-order coherent contributions dominate the experimentally observed negative peaks in our systems. Methyl groups are prone to the observation of such higher order coherent effects. Due to their low-frequency shifted 1H resonances, the chemical-shift separation relative to for instance aromatic protons in spatial proximity is substantial (>4.7 ppm in the studied examples) preventing any sizeable second-order spin-diffusion processes, which would mask the negative contribution to the peaks.

Sulfondiimines: synthesis, derivatisation and application.

Sulfondiimines are aza-analogues of sulfones and sulfoximines. In contrast to the latter two compound classes, sulfondiimines are rare in the chemical literature. Although a full understanding of the stability and reactivity of sulfondiimines is wanting, sulfondiimines have recently been recognized as novel bioisosteres for carbonyl moieties enabling expansion of the well-known portfolio of pharmaceutically relevant compounds. In this review, we briefly summarize the structure and stability of sulfondiimines and then focus on syntheses and derivatisations of these interesting compounds with sulfur-nitrogen core units. Furthermore, their use in heterocyclic chemistry and recent applications as bioactive compounds are presented.

Reshuffle Bonds by Ball Milling: A Mechanochemical Protocol for Charge-Accelerated Aza-Claisen Rearrangements.

This study presents the development of a mechanochemical protocol for a charge-accelerated aza-Claisen rearrangement. The protocol waives the use of commonly applied transition metals, ligands, or pyrophoric Lewis acids, e.g., AlMe3. Based on (heterocyclic) tertiary allylamines and acyl chlorides, the desired tertiary amides were prepared in yields ranging from 17% to 84%. Moreover, the same protocol was applied for a Bellus-Claisen-type rearrangement resulting in the synthesis of a 9-membered lactam without further optimization.

Synthesis of N-Monosubstituted Sulfondiimines by Metal-free Iminations of Sulfilimium Salts.

Sulfondiimines are marginalized entities among nitrogen-containing organosulfur compounds, despite offering promising properties for applications in various fields including medicinal and agrochemical. Herein, we present a metal-free and rapid synthetic procedure for the synthesis of N-monosubstituted sulfondiimines that overcomes current limitations in their synthetic accessibility. Particularly, S,S-dialkyl substrates, which are commonly difficult to convert by existing methods, react well with a combination of iodine, 1,8-diazabicyclo[5.4.0]undec-7-en (DBU), and iminoiodinanes (PhINR) in acetonitrile (MeCN) to furnish the corresponding sulfondiimines in yields up to 85 % (25 examples). Valuable "free" NH-N'H-sulfondiimines can then be accessed by N-deprotection under mild reaction conditions. Several experimental observations suggest a mechanistic pathway diverging from the common radical-based iodine/iminoiodinane mechanism. Based on the experimental results in combination with data obtained by 1 H NMR spectroscopy, ESI mass spectrometry, and crystallographic analysis we propose a direct amination from PhINNs and a reaction path via a cationic iodonitrene.

Mechanochemical Synthesis of Stimuli Responsive Microgels.

Mechanochemical approaches are widely used for the efficient, solvent-free synthesis of organic molecules, however their applicability to the synthesis of functional polymers has remained underexplored. Herein, we demonstrate for the first time that mechanochemically triggered free-radical polymerization allows solvent- and initiator-free syntheses of structurally and morphologically well-defined complex functional macromolecular architectures, namely stimuliresponsive microgels. The developed mechanochemical polymerization approach is applicable to a variety of monomers and allows synthesizing microgels with tunable chemical structure, variable size, controlled number of crosslinks and reactive functional end-groups.

Revisiting the bromination of 3ß-hydroxycholest-5-ene with CBr4/PPh3 and the subsequent azidolysis of the resulting bromide, disparity in stereochemical behavior.

Cholesterol reacts under Appel conditions (CBr4/PPh3) to give 3,5-cholestadiene (elimination) and 3ß-bromocholest-5-ene (substitution with retention of configuration). Thus, the bromination of cholesterol deviates from the stereochemistry of the standard Appel mechanism due to participation of the Δ5 π-electrons. In contrast, the subsequent azidolysis (NaN3/DMF) of 3ß-bromocholest-5-ene proceeds predominantly by Walden inversion (SN2) affording 3α-azidocholest-5-ene. The structures of all relevant products were revealed by X-ray single crystal structure analyses, and the NMR data are in agreement to the reported ones. In light of these findings, we herein correct the previous stereochemical assignments reported by one of us in the Beilstein J. Org. Chem. 2015, 11, 1922-1932 and the Monatsh. Chem. 2018, 149, 505-517.

Factors Governing the Catalytic Insertion of CO2 into Arenes - A DFT Case Study for Pd and Pt Phosphane Sulfonamido Complexes.

The potential of Pd/Pt complexes for catalytic carboxylation of arenes with CO2 is investigated by means of computational chemistry. Recently we reported that the bis[(2-methoxyphenyl)phosphino]-benzenesulfonamido palladium complex 1 inserts CO2 reversibly in its Pd-C(aryl) bond generating carboxylato complex 2. In the present work we study how geometric and electronic factors of various ligands and substrates influence the overall activation barrier (energy span, ES) of a potential catalytic cycle for arene carboxylation comprising this elementary step. The tendency of the key intermediates to dimerize and thus deactivating the potential catalysts is examined as well as the role of the base, which inevitably is needed to stabilize the reaction product. We show that Pd and Pt complexes I(Pd)-L16-S1 and I(Pt)-L16-S1 do not dimerize, enable the computation of complete catalytic cycles, and show interestingly low ES values of 26.8 and 24.5 kcal/mol, respectively.

Mechanistic Insights on the Mechanosynthesis of Phenytoin, a WHO Essential Medicine.

In recent years, mechanochemistry has enriched the toolbox of synthetic chemists, enabling faster and more sustainable access to new materials and existing products, including active pharmaceutical ingredients (APIs). However, molecular-level understanding of most mechanochemical reactions remains limited, delaying the implementation of mechanochemistry in industrial applications. Herein, we have applied in situ monitoring by Raman spectroscopy to the mechanosynthesis of phenytoin, a World Health Organization (WHO) Essential Medicine, enabling the observation, isolation, and characterization of key molecular-migration intermediates involved in the single-step transformation of benzil, urea, and KOH into phenytoin. This work contributes to the elucidation of a reaction mechanism that has been subjected to a number of interpretations over time and paints a clear picture of how mechanosynthesis can be applied and optimized for the preparation of added-value molecules.

Visible Light-Promoted Synthesis of ß-Keto Sulfoximines from N-Tosyl-Protected Sulfoximidoyl Chlorides.

Under visible light, N-tosyl-protected sulfoximidoyl chlorides react with aryl alkynes to give ß-keto sulfoximines. The reaction is characterized by a high functional group tolerance and good yields. It can be improved by the presence of a ruthenium photocatalyst. Air is the source of the ketonic oxygen in the products.

Iron-Catalyzed Intramolecular Arene C(sp2 )-H Amidations under Mechanochemical Conditions.

In a ball mill, FeBr3 -catalyzed intramolecular amidations lead to 3,4-dihydro-2(1H)-quinolinones in good to almost quantitative yields. The reactions do not require a solvent and are easy to perform. No additional ligand is needed for the iron catalyst. Both 4-substituted aryl and ß-substituted dioxazolones provide products with high selectivity. Mechanistically, an electrophilic spirocyclization followed by C-C migration explains the formation of rearranged products.

Selective Approaches to α- and ß-Arylated Vinyl Ethers.

We developed simple and efficient protocols for palladium-catalyzed regioselective α- and ß-arylations of structurally diverse vinyl ethers. Both catalytic methods proceed under relatively mild reactions conditions applying to a broad substrate range including more complex compounds providing arylated glucal or isochromene. Lacking the common requirement of a large reagent excess, the transformations are highly economic and limiting the waste production. Results from computational studies (DFT) provided insight into the key factors determining the pronounced regioselectivities of the investigated reactions.