Thiol Surrogate Research Articles

Expedient Synthesis of Alkyl and Aryl Thioethers Using Xanthates as Thiol-Free Reagents.

Thioethers are critical in the fields of pharmaceuticals and organic synthesis, but most of the methods for synthesis alkyl thioethers employ foul-smelling thiols as starting materials or generate them as by-products. Additionally, most thiols are air-sensitive and are easily oxidized to produce disulfides under atmospheric conditions; thus, a novel method for synthesizing thioethers is necessary. This paper reports a simple, effective, green method for synthesizing dialkyl or alkyl aryl thioether derivatives using odorless, stable, low-cost ROCS2K as a thiol surrogate. This transformation offers a broad substrate scope and good functional group tolerance with excellent selectivity. The reaction likely proceeds via xanthate intermediates, which can be readily generated via the nucleophilic substitution of alkyl halides or aryl halides with ROCS2K under transition-metal-free and base-free conditions.

Arylsulfonic Anhydride as Thiol Surrogate for Sulfenylation of sp2 C−H Bond Through De‐oxygenative Reduction with Neutral Ionic Liquid: Scope and Mechanistic Studies

AbstractWe disclosed the dual role of neutral [Hmim]Br towards the direct conversion of arylsulfonic anhydride into arylthiol surrogate for the controlled and regioselective synthesis of 3‐sulfenylindoles from indole derivatives at rt. In addition, 2‐bromo‐3‐sulfenylindoles were synthesized in the presence of catalytic water at 50 °C in a cascade manner i. e. sulfenylation and bromination through de‐oxygenative reduction with [Hmim]Br in the absence of any additional brominating agent. The present method was also utilized for the sulfenylation of other heterocycles including azaindole, coumarin, naphthol, and pyrrole in good to excellent yields. Moreover, mechanistic investigations revealed this reaction was driven by imidazolium cation of neutral ionic liquid i. e. [Hmim]Br, which converts arylsulfonic anhydride into sulfenyl group for sulfenylation/bromination of sp2 C−H bond wherein an acidic ionic liquid [Hmim]pTSA is released as a by‐product.

Development of a Scalable Route for a Key Benzothiazole Building Block via a Pd-Catalyzed Migita Coupling with a Nonsmelly Thiol Surrogate

2-Methylbenzo[d]thiazole-6-carbonitrile was internally identified as an important building block and therefore, kg amounts of it needed to be urgently supplied. As the desired benzothiazole was only available in small quantities for a high price (∼1000 USD/g), a robust and scalable route needed to be rapidly developed. The key to success was the use of a 2-iodophenyl N-acetamide precursor to construct the 2-methylbenzo[d]thiazole core via a Pd-catalyzed Migita coupling followed by subsequent intramolecular condensation of the intermediate thiophenol onto the N-acetyl group. To avoid the use of malodorous thiols on scale, 2-ethylhexyl 3-mercaptopropionate was used as a nonsmelly, inexpensive thiol surrogate. The Migita coupling was extensively optimized and allowed the reaction to be performed in a dose-controlled manner with regard to the addition of the thiol surrogate at 40 °C, by using only 0.1 mol % Pd2dba3. The subsequent intramolecular cyclization step was promoted by the one-pot addition of DBU. After aqueous workup and crystallization, 2-methylbenzo[d]thiazole-6-carbonitrile was obtained in 81% yield and excellent purity (99.7% a/a) on a 2.0 kg scale.

Sulfonyl Chlorides as Thiol Surrogates for Carbon-Sulfur Bond Formation: One-Pot Synthesis of Thioethers and Thioesters.

A method to synthesize thioethers and thioesters directly from readily available sulfonyl chlorides is reported. We demonstrate that a transient intermediate formed during phosphine-mediated deoxygenation of sulfonyl chlorides can be trapped in situ by activated alcohols or carboxylic acids to effect carbon-sulfur bond formation. The method is operationally simple and tolerates a broad range of functional groups. Special attention has been focused on the late-stage diversification of densely functionalized natural products and pharmaceuticals.

Co/Cu Co‐Catalyzed Carbonylation of Alkyl Iodides and Thioesters

AbstractInspired by the unique and ubiquitous nature of thioesters, great attention has been focused on the synthesis of thioesters. However, the harsh reaction conditions and equivalent oxidant required can still limit their applications. Here, a salcomine/IPrCuCl co‐catalyzed carbonylative thioalkylation of alkyl iodides using simple thioesters as a thiol surrogate is developed. This catalytic protocol displayed a good functional groups tolerance. The current work provides an inspiring example of the non‐nobel metal‐catalysed carbonylation for the synthesis of chalcogen‐containing compounds.

Pd‐Catalyzed Intermolecular Transthiolation of Ar‐OTf Using Methyl 3‐(Methylthio) Propanoate as a Thiol Surrogate

AbstractA method for the odorless synthesis of unsymmetrical sulfides via Csp2−O and Csp3−S bond activation is presented. Using methyl 3‐(methylthio) propanoate as a MeSH surrogate, a series of substituted aryl methyl sulfides have been obtained in moderate to good yields. This catalytic protocol can also tolerate methyl 3‐(methylthio)propionate derivatives to afford the corresponding aryl sulfides.

TBAI-catalyzed ring-opening sulfonylations of benzothiazoles and arylsulfonyl hydrazides

An efficient TBAI-catalyzed ring-opening sulfonylation of benzo[d]thiazole and arylsulfonyl hydrazide has been developed. Various benzo[d]thiazole as good thiol surrogates are compatible with the catalytic conditions, providing diversified unsymmetrical thiosulfonates with good yields. This strategy features mild reaction conditions, broad substrate scope, readily available starting materials, and gram-scale synthesis. Importantly, these products can be readily converted to novel o-amino-substituted diaryl sulfides.

Xanthates as Thiol Surrogates for Nucleophilic Substitution with Aryl Halides

AbstractWe herein report an unprecedented xanthate‐based protocol for the preparation of aryl‐alkyl thioethers. Heating xanthates with aryl halides and namely cesium carbonate in methanol provides the target thioethers in generally good yields within short reaction times. This method allows one to avoid contact with odorous thiols and also to introduce substituents of which the corresponding thiols are virtually unavailable or inconvenient in use.

Preparation of glycosyl disulfides and sulfides via the formation of glycosyl Bunte salts as thiol surrogates

A convenient odourless reaction condition has been developed for the preparation of symmetrical glycosyl disulfide derivatives and aryl glycosyl disulfide derivatives from corresponding glycosyl iodides via in situ formation of glycosyl Bunte salts as thiol surrogates. The reaction has been further extended towards the preparation of glycosyl sulfides derivatives from corresponding Bunte salt in the presence of sodium sulphide. Most of the reactions were high yielding and suitable for scaling up.

Facile Synthesis of 2-Acylthieno[2,3-b]quinolines via Cu-TEMPO-Catalyzed Dehydrogenation, sp2-C-H Functionalization (Nucleophilic Thiolation by S8) of 2-Haloquinolinyl Ketones.

An efficient, solvent-free synthesis of 2-acylthieno[2,3-b]quinolines is reported from 2-halo-quinolinyl ketones through Cu-TEMPO catalyzed dehydrogenation, sp2-C-H functionalization using elemental sulfur as thiol surrogate (sulfur source) and tetrabutylammonium acetate as an ionic reaction medium. The optimized reaction conditions give excellent product yields under mild reaction conditions with chemoselectivity and broad functional group tolerance. The synthetic importance of the synthesized molecules is showcased further by Friedländer annulation, reduction, and alkene functionalization reactions.

Comparative reactivity analysis of small-molecule thiol surrogates

Targeted covalent inhibitors represent an increasingly popular approach to modulate challenging drug targets. Since covalent and non-covalent interactions are both contributing to the affinity of these compounds, evaluation of their reactivity is a key-step to find feasible warheads. There are well-established HPLC- and NMR-based kinetic assays to tackle this task, however, they use a variety of cysteine-surrogates including cysteamine, cysteine or acetyl-cysteine and GSH. The diverse nature of the thiol sources often makes the results incomparable that prevents compiling a comprehensive knowledge base for the design of covalent inhibitors. To evaluate kinetic measurements from different sources we performed a comparative analysis of the different thiol surrogates against a designed set of electrophilic fragments equipped with a range of warheads. Our study included seven different thiol models and 13 warheads resulting in a reactivity matrix analysed thoroughly. We found that the reactivity profile might be significantly different for various thiol models. Comparing the different warheads, we concluded that – in addition to its human relevance - glutathione (GSH) provided the best estimate of reactivity with highest number of true positives identified.

2-Acetylthienopyridine Synthesis via Thiolation and Copper-Catalyzed Cyclization of o-Propynol Fluoropyridine Using Xanthate as a Thiol Surrogate.

2-Acylthienopyridines and related heterocycles are readily prepared in moderate to good yields under mild conditions by a nucleophilic thiolation, copper-catalyzed cyclization, and an oxidation cascade process using potassium xanthate as the thiol source. Moreover, excellent chemoselectivity, broad substrate scope, and good functional group tolerance are prominent features of this transformation.

ChemInform Abstract: Fe—Cu Catalyzed Synthesis of Symmetrical and Unsymmetrical Diaryl Thioethers Using 1,3‐Benzoxazole‐2‐thiol as a Sulfur Surrogate.

An efficient Fe–Cu catalyzed approach is herein developed using 1,3-benzoxazole-2-thiol as a thiol surrogate for the synthesis of symmetrical and unsymmetrical diaryl thioethers. This method provides an odorless and inexpensive strategy which can be applied to various aryl and nitrogen containing aryl halides in moderate to excellent yields up to 90%.

ChemInform Abstract: Microwave‐Assisted Synthesis of 3‐Sulfenylindoles by Sulfonyl Hydrazides Using Organic Ionic Base‐Broensted Acid.

AbstractSulfenylindoles are prepared via a DBU‐based ionic liquid‐promoted sulfenylation of indoles using sulfonyl hydrazides as thiol surrogate.

Microwave-assisted synthesis of 3-sulfenylindoles by sulfonyl hydrazides using organic ionic base-Brønsted acid

3-Sulfenylation of indoles by sulfonyl hydrazides using organic ionic base-Bronsted acid sulfonyl hydrazides as thiol surrogate.

Fe–Cu catalyzed synthesis of symmetrical and unsymmetrical diaryl thioethers using 1,3-benzoxazole-2-thiol as a sulfur surrogate

An efficient Fe–Cu catalyzed approach is herein developed using 1,3-benzoxazole-2-thiol as a thiol surrogate for the synthesis of symmetrical and unsymmetrical diaryl thioethers.

ChemInform Abstract: Deep Eutectic Mixture Catalyzed the Synthesis of Disulfides Using Bunte Salts as Thiol Surrogates.

AbstractAn eutectic mixture of choline chloride and toluenesulfonic acid is used for the synthesis of disulfides from Bunte salts in the presence of an oxidant.

ChemInform Abstract: An Odorless Thia‐Michael Addition Using Bunte Salts as Thiol Surrogates.

AbstractThe synthesis of various β‐sulfido carbonyl compounds via hydrolysis of Bunte salts is described.

ChemInform Abstract: Iodine‐Catalyzed Regioselective Thiolation of Imidazo[1,2‐a]pyridines Using Sulfonyl Hydrazides as a Thiol Surrogate.

Iodine-catalyzed regioselective sulfenylation of imidazo[1,2-a]pyridines via C(sp2)–H bond functionalization has been achieved using sulfonyl hydrazides as a thiol surrogate. A library of 3-sulfanylimidazopyridines with broad functionalities was synthesized under metal and oxidant-free practical reaction conditions. This methodology is also applicable for the regioselective sulfenylation of imidazo[2,1-b]thiazole and benzo[d]imidazo[2,1-b]thiazole.

Deep Eutectic Mixture Catalysed the Synthesis of Disulfides Using Bunte Salts as Thiol Surrogates

Bunte salts, easily prepared from odourless sodium thiosulfates and various alkyl and aryl halides, acted as thiol surrogates for preparation of disulfides in the presence of hydrogen peroxide and a Brønsted-acidic deep eutectic mixture. The reaction proceeded smoothly to give the corresponding disulfide products in moderate to good yields, leaving odourless sodium bisulfite and water as the by-products. Moreover, this catalytic system could be readily recovered and reused several times without significant loss in activity.