Synthesis of Air-stable,Odorless Thiophenol Surrogates via Ni-Catalyzed C−S Cross-Coupling

Thiophenols are versatile synthetic intermediates whose practical appeal is marred by their air sensitivity, toxicity and extreme malodor. Herein we report an efficient catalytic method for the preparation of S-aryl isothiouronium salts, and demonstrate that these air-stable, odorless solids serve as user-friendly sources of thiophenols in synthesis. Diverse isothiouronium salts featuring synthetically useful functionality are readily accessible by nickel-catalyzed C−S cross-coupling of (hetero)aryl iodides and thiourea. Convenient, chromatography-free isolation of these salts is achieved by precipitation, allowing the methodology to be applied directly to large scales. Thiophenols are liberated from the corresponding isothiouronium salts upon treatment with a weak base, enabling an in situ release/S-functionalization strategy that entirely negates the need to isolate, purify or manipulate these noxious reagents.     

Naked metal nanoparticles from metal carbonyls in ionic liquids: Easy synthesis and stabilization

An overview with more than 160 references on the synthesis and stabilization of metal nanoparticles (M-NPs) from metal carbonyls, metal salts in ionic liquids (ILs) and in particular from metal carbonyls in ionic liquids is given. The synthesis of M-NPs can proceed by chemical reduction, thermolysis, photochemical decomposition, electroreduction, microwave and sonochemical irradiation. Commercially available metal carbonyls M_x(CO)_y are elegant precursors as they contain the metal atoms already in the zero-valent oxidation state needed for M-NPs. No extra reducing agent is necessary. The side product CO is largely given off to the gas phase and removed from the dispersion. The microwave induced thermal decomposition of metal carbonyls M_x(CO)_y in ILs provides an especially rapid and energy-saving access to M-NPs because of the ILs significant absorption efficiency for microwave energy due to their high ionic charge, high polarity and high dielectric constant. The electrostatic and steric properties of ionic liquids allow for the stabilization of M-NPs without the need of additional stabilizers, surfactants or capping ligands and are highlighted by pointing to the DLVO (Derjaugin–Landau–Verwey–Overbeek) and extra-DLVO theory. Examples for the direct use of M-NP/IL dispersions in hydrogenation catalysis of cyclohexene and benzene are given.     

Heterocyclic group transfer reactions with I(iii) N-HVI reagents: access to N-alkyl(heteroaryl)onium salts via olefin aminolactonization

Pyridinium and related N-alkyl(heteroaryl)onium salts are versatile synthetic intermediates in organic chemistry, with applications ranging from ring functionalizations to provide diverse piperidine scaffolds to their recent emergence as radical precursors in deaminative cross couplings. Despite their ever-expanding applications, methods for their synthesis have seen little innovation, continuing to rely on a limited set of decades old transformations and a limited subset of coupling partners. Herein, we leverage (bis)cationic nitrogen-ligated I(iii) hypervalent iodine reagents, or N-HVIs, as “heterocyclic group transfer reagents” to provide access to a broad scope of N-alkyl(heteroaryl)onium salts via the aminolactonization of alkenoic acids, the first example of engaging an olefin to directly generate these salts. The reactions proceed in excellent yields, under mild conditions, and are capable of incorporating a broad scope of sterically and electronically diverse aromatic heterocycles. The N-HVI reagents can be generated in situ, the products isolated via simple trituration, and subsequent derivatizations demonstrate the power of this platform for diversity-oriented synthesis of 6-membered nitrogen heterocycles.

Complex N-alkyl (heteroaryl)onium salts are accessed via heterocyclic group transfer reactions of N-ligated I(iii) reagents with alkenoic acids. The reactions proceed in excellent yields, under mild conditions, and with broad substrate scope.     

Modified One‐Pot Protocol for the Preparation of Thioglycosides from Unprotected Aldoses via S‐Glycosyl Isothiouronium Salts*

An efficient one‐pot protocol for the direct preparation of thioglycosides starting from unprotected reducing sugars via S‐glycosyl isothiouronium salts is reported. In this one‐pot methodology, BF₃ · OEt₂ has been used as a general catalyst for both per‐O‐acetylation of sugars and conversion of sugar per‐O‐acetates into S‐glycosyl isothiouronium salts, which was allowed to react with alkylating agents in the presence of a base to furnish thioglycosides in excellent yield.     

Highly efficient synthesis and application of aryl diazonium salts via femtosecond laser-tailored 3D flow microfluidic chips

The first example of the microfluidic chips (MFCs) consisting of centimeter-level 3D channels with high-density and large-volume fabricated by femtosecond laser micromachining were utilized to develop a time-saving, economical and hazardless flow synthesis process, and its advantages have been proved by in situ formation of aryldiazonium salts and subsequent borylation with bis(pinacolato)diboron. There are several important advantages in our 3D MFC-based flow synthesis technology, including the following: (1) the reaction temperature was altered from ice bath to room temperature; (2) the residence time was reduced by 10 times; (3) the yield was greatly improved, that is, several arylboronates were successfully obtained with higher yield compared to traditional batch process. Therefore, it can be envisioned that a novel, simplified flow synthetic protocol will be developed toward green organic synthesis via MFCs.     

Visible-light-induced N-heterocyclic carbene mediated cascade transformation of N-alkenoxypyridinium salts

While N-alkenoxypyridinium salts are widely used for the synthesis of α-functionalized ketones via umpolung strategy, such approaches are usually limited to special nucleophiles at high temperatures. Herein, we developed an alternative photoinduced N-heterocyclic carbene (NHC)- mediated functionalization of N-alkenoxypyridinium salts with various nucleophiles, including tetramethylammonium azide, secondary amines, aryl and alkyl thiols, and even the challenging C(sp³)-nucleophiles, under mild conditions. A cascade radical-radical coupling/nucleophilic substitution sequence was proposed, wherein the NHC enabled the formation of a photoactive electron donor-acceptor complex for α-iodo ketone synthesis.     

Synthesis of Purine-Based Ionic Liquids and Their Applications

Bio-based ionic liquids (ILs) are being increasingly sought after, as they are more sustainable and eco-friendly. Purines are the most widely distributed, naturally occurring N-heterocycles, but their low water-solubility limits their application. In this work, four purines (theobromine, theophylline, xanthine, and uric acid) were combined with the cation tetrabutylammonium to synthesize bio-based ILs. The physico–chemical properties of the purine-based ILs were characterized, including their melting and decomposition temperatures and water-solubility. The ecotoxicity against the microalgae Raphidocelis subcapitata was also determined. The ILs show good thermal stability (>457 K) and an aqueous solubility enhancement ranging from 53- to 870-fold, in comparison to their respective purine percursors, unlocking new prospects for their application where aqueous solutions are demanded. The ecotoxicity of these ILs seems to be dominated by the cation, and it is similar to chloride-based IL, emphasizing that the use of natural anions does not necessarily translate to more benign ILs. The application of the novel ILs in the formation of aqueous biphasic systems (ABS), and as solubility enhancers, was also evaluated. The ILs were able to form ABS with sodium sulfate and tripotassium citrate salts. The development of thermoresponsive ABS, using sodium sulfate as a salting-out agent, was accomplished, with the ILs having different thermosensitivities. In addition, the purine-based ILs acted as solubility enhancers of ferulic acid in aqueous solution.     

Carbamoylimidazolium salts as diversification reagents: an application to the synthesis of tertiary amides from carboxylic acids

An efficient method for the preparation of tertiary amides from carbamoylimidazolium salts and carboxylic acids is described. The transformation occurs at room temperature and under relatively mild conditions. The carbamoylimidazolium salts are obtained from the reaction of secondary amines with N,N′-carbonyldiimidazole, followed by methylation with methyl iodide. The utility of this reaction was demonstrated in the formation of Weinreb amides and in a short synthesis of fused bicyclic amides. The introduction of this reaction now permits carbamoylimidazolium salts to be utilized in the formation of tertiary amides, ureas, carbamates and thiocarbamates under a single set of conditions.     

ESCA-untersuchungen zur ladungsverteilung in alkylierten thioharnstoffderivaten und verwandten thiocarbonylverbindungen

The S 2p, N 1s and C 1s electron binding energies of some substituted thiourea derivatives, isothiouronium salts, thiazolthiones, 1,3,5-thiadiazin-2-thiones and 1,3,5-thiadiazinium salts have been measured using the X-ray photoelectron spectroscopy (ESCA). From binding energy shifts information concerning the charge distribution on the atoms in the molecules was obtained. The positive charge of the isothiouronium salts was found to concentrate on carbon and nitrogen atoms. The charge of the 1,3,5-thiadiazinium cations was found to be delocalized demonstrating the pseudoaromatic character of the electronic system.     

New task-specific ionic liquids as bifunctional organocatalysts; Synthesis,characterization, and computational insights

A new class of functionalized imidazolium-based Task-Specific Ionic Liquids (TSILs) is designed as low-cost bifunctional organocatalyst. New alkoxymethylimidazolium ILs are efficiently synthesized under solvent free conditions and extensively characterized by physical and spectral studies. The newly synthesized ILs demonstrate excellent catalytic potential in condensation reactions of high importance, such as the Biginelli reaction for the synthesis of medicinally important dihydropyrimidiones. The effect of the alkoxy group and counter-ions in the imidazolium salts were evaluated in detail. Moreover, computational studies were employed to explore the structural dynamics and physicochemical properties of the prepared ionic liquids. 3-(iso-butoxymethyl)-1-methyl-1H-imidazol-3-ium tetrafluoroborate (ⁱBOMMIMBF₄ 7) exhibited the highest catalytic ability due to the combined influence of the alkoxy group structure, counterion nature, high electrophilicity index, and availability of the reactive C2-H. Some notable advantages of the new TSILs include efficient catalyst preparation, simple work-up procedure, recyclability, short reaction times, and excellent yields.     

S-Benzyl isothiouronium chloride as a recoverable organocatalyst for the direct reductive amination of aldehydes

The direct reductive amination of aldehydes using S-benzyl isothiouronium chloride as a recoverable organocatalyst for the activation of the imine intermediate through hydrogen bonding is described. A mild and operationally simple fragment coupling procedure was accomplished with a wide range of aldehydes as well as amines in good to excellent yields. In addition, the S-benzyl isothiouronium chloride catalyst was easily recovered by simple filtration and reused without any drop in its efficiency.     

Comparative study of chemically immobilized and conventional homogeneous ionic liquids as phase-transfer catalysts for the N-alkylation of heterocyclic compounds

Various ionic liquids (ILs) were screened for their phase-transfer catalytic (PTC) activity using the N-alkylation of nitrogen heterocycles as the model reaction. Immobilized ILs behaved extremely well and proved to be far better catalysts than conventional homogeneous PTCs in terms of their stability, easy recovery, and reusability. The investigation also demonstrated that quaternary tetraalkylammonium salts offer very high catalytic activity, whereas aromatic heterocyclic tetravalent nitrogen catalysts (imidazolium- and pyridinium-based salts) were poorly active.     

Reinvestigation of the stevens rearrangement of 1-benzyl-1,3,4-trimethyl-1,2,5,6-tetrahydropyridinium salts. II. Synthesis of 2-aryl-3-isopropenyl-1,3-dimethylpyrrolidines

cis-2-Aryl-3-isopropenyl-1,3-dimethylpyrrolidines Ha and IIb have been synthesized by an unambiguous way, thus confirming the structure of the methylene derivatives obtained as by-products in the Stevens rearrangement of 1-benzyl-1,3,4-trimethyl-1,2,5,6-tetrahydropyridinium salts Ia and Ib. The synthesis is based on the acid-induced intramolecular cyclization between an iminium salt and the α-position of a ketal group. Thus, condensation between amino ketal XXI, prepared via Gabriel synthesis from 5-chloro-3-methyl-2-pentanone, and the appropriate aldehyde afforded imines XXI. Their treatment with dry hydrogen chloride followed by acid hydrolysis and methylation gave 3-acetylpyrrolidines IV, which were transformed into the isopropenyl derivatives II by reaction with methyl-lithium and further dehydration.     

Ultrasound-assisted synthesis of substituted guanidines using 1H-pyrazole-1-carboxamidine and S-methylisothiouronium sulfate under solvent-free conditions

We have investigated ultrasound-assisted synthesis of guanidine derivatives using 1H-Pyrazole-1-carboxamidine (PyzCA) and S-substituted isothiouronium sulfate (MeITU). The guanylations of several amines are promoted by ultrasound sonication under solvent-free conditions, and proceed under mild conditions. It is of particular interest that the guanylations do not require bases in most cases.     

Green and controllable fabrication of nanocrystals from ionic liquids

Nanocrystals are of great value in delivering poorly soluble drugs as a technique enables enhanced dissolution and bioavailability. The bottom-up technique allows better control of particle properties. However, the commonly used organic solvents are hazardous to environment and operators, and always lead to large particle size and wide size distribution due to failure on controlling the nucleation and crystal growth. The situation is exacerbated in scale-up production. Therefore, in the proof-of-concept study, we evaluated the feasibility of green and controllable fabrication of drug nanocrystals by using biocompatible ionic liquids (ILs) as solvents. Choline based ILs (Ch-ILs) were synthesized via metathesis reactions. Pure paclitaxel nanocrystals of high quality were obtained from Ch-ILs with surface tension higher than 42 mN/m. The sizes were below 250 nm, while the polydispersity indexes were lower than 0.25. Compared with ethanol, choline lactate is superior in controlling the size of the nanocrystals in scale-up production, where the drug concentration was increased by 6 times. The underlying mechanism may be due to the high viscosity and low surface tension of the ILs, which are supposed to benefit homogeneous and burst nucleation. Ch-ILs can be recycled from the process and recovery rate reached 91.1%. Moreover, the applicability of the green technique was validated in a wider range of model drugs and Ch-ILs. In conclusion, ILs are potent solvents in bottom-up technique for green and controllable fabrication of nanocrystals.     

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

Isothiouronium salts are easily accessible and stable compounds. Herein, we report their use as versatile deoxasulfenylating agents enabling a stereoselective, thiol-free protocol for synthesis of thioethers from alcohols. The method is simple, scalable and tolerates a broad range of functional groups otherwise incompatible with other methods. Late-stage modification of several pharmaceuticals provides access to multiple analogues of biologically relevant molecules. Performed experiments give insight into the reaction mechanism.

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.     

Low temperature ionic conductor: ionic liquid incorporated within a metal–organic framework

Ionic liquids (ILs) show promise as safe electrolytes for electrochemical devices. However, the conductivity of ILs decreases markedly at low temperatures because of strong interactions arising between the component ions. Metal–organic frameworks (MOFs) are appropriate microporous host materials that can control the dynamics of ILs via the nanosizing of ILs and tunable interactions of MOFs with the guest ILs. Here, for the first time, we report on the ionic conductivity of an IL incorporated within a MOF. The system studied consisted of EMI-TFSA (1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)amide) and ZIF-8 (Zn(MeIM)₂, H(MeIM) = 2-methylimidazole) as the IL and the MOF, respectively. While the ionic conductivity of bulk EMI-TFSA showed a sharp decrease arising from freezing, the EMI-TFSA@ZIF-8 showed no marked decrease because there was no phase transition. The ionic conductivity of EMI-TFSA@ZIF-8 was higher than that of bulk EMI-TFSA below 250 K. This result points towards a novel method by which to design electrolytes for electrochemical devices such as batteries that can operate at low temperatures.     

Efficient synthesis of thioglycosylated kojic acid by s-glycosyl isothiouronium salts

In this study, 7-S-glycosides of kojic acid were designed and synthesized as mimics of its 7-O-glycosides to improve its water solubility and metabolic stability. To achieve this synthesis, a one-pot approach involving S-glycosyl isothiouronium salts generated in situ as key intermediates was developed by using 7-chloro-kojic acid as the alkylation reagent. A series of water soluble 7-S-glycosides of kojic acid, incorporating monosaccharides and disaccharides, were prepared using this protocol. Thus, this work offers a mild, convenient, and efficient approach for the synthesis of 7-S-glycosides of kojic acid in medium to good yields.     

A donor–acceptor complex enables the synthesis of E-olefins from alcohols,amines and carboxylic acids

Olefins are prevalent substrates and functionalities. The synthesis of olefins from readily available starting materials such as alcohols, amines and carboxylic acids is of great significance to address the sustainability concerns in organic synthesis. Metallaphotoredox-catalyzed defunctionalizations were reported to achieve such transformations under mild conditions. However, all these valuable strategies require a transition metal catalyst, a ligand or an expensive photocatalyst, with the challenges of controlling the region- and stereoselectivities remaining. Herein, we present a fundamentally distinct strategy enabled by electron donor–acceptor (EDA) complexes, for the selective synthesis of olefins from these simple and easily available starting materials. The conversions took place via photoactivation of the EDA complexes of the activated substrates with alkali salts, followed by hydrogen atom elimination from in situ generated alkyl radicals. This method is operationally simple and straightforward and free of photocatalysts and transition-metals, and shows high regio- and stereoselectivities.

A visible-light-induced defunctionalization strategy for the synthesis of olefins by using easily available alcohols, amines and carboxylic acids as starting materials is demonstrated.