A widely applicable synthesis of medicinal chemistry-relevant 2-aminobenzo[b]thiophenes has been achieved from ortho-halo-substituted thioamides of 2-arylacetic acids through a t-BuOK-promoted intramolecular C-S bond formation under transition-metal-free conditions. The operationally simple, high-yielding protocol is based on readily accessible substrates and tolerates a variety of functional groups. Density functional theory (DFT) studies, along with mechanistic investigations, including EPR spin trapping experiments, were conducted to elucidate a plausible reaction mechanism.

The preparation of iodoarenes from arenes with precise chemo- and regioselectivity remains a challenge in organic synthesis. A novel strategy for aromatic C-H-iodination includes the in-situ generation of diaryliodonium salts, followed by the reaction with boron hydrides. Mild conditions and short reaction time allow for the retention of a range of functionalities, including carbonyl groups. An unprecedented mechanism for the reaction of iodonium salts with boron hydrides was proposed based on D-labeling experiments and DFT study.

Substituted isatins exhibit a variety of biological activities and serve as versatile intermediates for accessing diverse medicine-relevant compounds. While N-alkylated isatins are easily obtained through a deprotonation-alkylation sequence, the synthesis of their N-arylated counterparts remains challenging. Herein, we report a new improved method for the N-arylation of isatins with diaryliodonium salts under transition-metal-free conditions. The protocol is scalable, compatible with the most widespread functional groups and applicable to sterically hindered molecules, and may be useful for utilization in medicinal chemistry.

Regioselective C-H-thionation of pyridine and quinoline rings can be achieved through the reaction of the corresponding quaternary azinium salts with sulfur and a base via a radical- or carbene-involved reaction pathway. The selectivity of CS group installation is determined by the reaction mechanism and affected by the base used.

Herein, we report a transition‐metal‐free strategy for the synthesis of O‐alkyl‐S‐(indol‐3‐yl) xanthates, valuable surrogates for indol‐3‐yl thiols. The method relies on the in situ formation of electrophilic (3,5‐dimethylisoxazol‐4‐yl)(indol‐3‐yl)iodonium salts via highly chemo‐ and regioselective C(3)–H functionalization of indoles with (3,5‐dimethylisoxazol‐4‐yl)–I(OH)OTs, a Koser's type reagent. These electrophilic intermediates readily react with potassium O‐alkyl xanthates, delivering the corresponding O‐alkyl‐S‐(indol‐3‐yl) xanthates in good‐to‐high yields. The protocol exhibits good functional group compatibility and is well‐suited for late‐stage functionalization of complex bioactive molecules, as demonstrated by the derivatization of the antiviral agent CCG‐203926 and estradiol, a steroid hormone. This operationally simple protocol provides an efficient approach to otherwise inaccessible indol‐3‐yl xanthates that are both a class of compounds of considerable interest due to their potential biological activity and valuable precursors for other indole derivatives containing organosulfur functional groups at the C(3) position.

A direct synthesis of medicinal chemistry-relevant 2- aminobenzo[b]thiophenes has been achieved from substituted thioamides of 2-arylacetic acids through a fast intramolecular cross-dehydrogenative cyclization, mediated by hydroxy(tosyloxy)iodobenzene (HTIB, Koser’s reagent). This synthetic approach is operationally simple, uses easily accessible substrates, and tolerates a variety of substituents at different sites, providing an opportunity for diversification.

Pyridines and quinolines substituted with sulfur‐containing functional groups are widely used as drugs, drug candidates, organic materials, N,S‐ligands and others. Traditional synthetic routes to produce these compounds are based on nucleophilic aromatic substitution reactions and transition metal‐catalyzed cross‐coupling reactions of (pseudo)halopyridines. While effective in many cases, both approaches are limited due to using forcing conditions and expensive, specifically designed catalytic systems. In the last decade, a number of innovative methods for the functionalization of the pyridine ring via the formation of a C−S bond have been developed. Most of these methods proceed through the direct or indirect C−H functionalization of unfunctionalized pyridines, thus avoiding the use of oftentimes not readily available halopyridines as the starting materials. Deoxygenative C−H functionalization of pyridine‐N‐oxides and deaminative transformation of aminopyridines have been also employed for the introduction of diverse organosulfur functionality into the pyridine ring. All these processes can be easily performed under mild conditions, typically affording value pyridines and quinolines in good to high yields. Usually being highly chemo‐ and regioselective, these methods allow the late‐stage functionalization of complex molecules including drugs and natural products. In this Review, we summarize the most recent synthetic methods for functionalization of pyridines and fused pyridines with sulfur‐containing functional groups reported mostly since 2018. For a better understanding of the processes, the mechanisms of the described reactions are briefly discussed.

Diethyl acetamidomalonate (DEAM) has been widely used for the synthesis of α-amino acids via C-alkylation under basic conditions followed by hydrolysis/decarboxylation. In contrast, the C-arylation of this reagent remains undeveloped. Herein, we report a novel strategy for the synthesis of racemic α-arylglycines based on the selective arylation of DEAM with diaryliodonium salts under mild, transition metal-free conditions. The reaction features good functional group tolerance and easy scalability and is applicable to the chemoselective C-H-modification of arenes including approved drugs, thus enabling a straightforward approach to complex α-arylglycines that would be challenging to make otherwise.

A new umpolung approach to the C3-H functionalization of indoles with diverse nucleophiles based on the intermediate formation of I(III) reagents is described. The 3,5-dimethylisoxazol-4-yl auxiliary allows for selective indole transfer under catalyst-free conditions, which was impossible using previously reported reagents. Combining the mildness of transition-metal-free conditions and the high reactivity of hypervalent iodine reagents, this protocol tolerates various functional groups and provides access to indoles that are difficult to prepare conventionally.

Visible-light-activated organic reactions unlock novel avenues for complex molecular transformations, impossible under standard "thermal" conditions, which makes them powerful tools in the arsenal of synthetic chemistry. However, transition metal-based or organic photoredox catalysts are often used to ensure productive absorption of visible light, which might be not desirable to medicinal chemistry and industry due to toxicity, low sustainability, and high cost of most photocatalysts. A more environmentally and economically benign approach is based on the formation of transient electron donor-acceptor (EDA) complexes between two reagents or a reagent and an additive, that readily absorb visible light, acting as internal photosensitizers. Within the EDA complex-based arylation strategies, chemical transformations are mediated by noncovalent interaction between two molecules, namely between electron-poor aryl halides or their synthetic equivalents and electron-rich nucleophilic reagents or additives. Moreover, besides stoichiometric EDA complexes between two molecules, EDA complex based organocatalysis can be achieved in certain cases through regeneration of the donor molecules in the course of the reaction. Photoexcitation of the EDA complexes induces a single electron transfer (SET) process to generate aryl radical species for the arylation step. This Review will focus on the state-of-the-art EDA complex-based arylation strategies utilizing aryl halides, aryldiazonium, diaryliodonium, arylsulfonium and arylphosphonium salts as reactants, published mainly in the last five years. Electron donor acceptor (EDA) complexes formed between arylating agents and nucleophilic substrates or additives, undergo photoexcitation to produce aryl radicals. Two main modes of reactivity for such complexes exist: mediation, where EDA complex is formed between two reagents, or catalysis, in which the electron donor additive is used as an organocatalyst. image

Quaternary N-aryl-DABCO salts were introduced for the first time as a highly selective sensing platform for thiols and selenols. By employing this platform, a highly sensitive coumarin based "off-on" fluorescent probe was designed and synthesized. The probe possesses a good solubility in water, low background fluorescence, and, most importantly, demonstrates high selectivity to aryl thiols and selenols over their aliphatic counterparts and other common nucleophiles. A dramatic increase in fluorescence intensity is achieved through the selective cleavage of the quaternized DABCO-ring, yielding a piperazine derivatives with a high fluorescence quantum yield (similar to 72 %). Moreover, stability of the probe to the most used reducing agents DTT and TCEP was demonstrated. The limits of detection for p-thiocresol and phenyl selenide were evaluated to be 22 nM and 6 nM, respectively.

An arylation of anions of active methylene compounds with aryl halides provides an access to synthetically versatile alpha-arylated 1,3-diketones, beta-keto esters, beta-keto nitriles, beta-cyano esters, etc. Previously, these C-C cross-coupling reactions have been accomplished only using transition metal-based catalysts. Herein, we demonstrate that these arylations can be successfully realized under catalyst-free conditions employing the electron donor-acceptor (EDA) complex photoactivation strategy. The protocol was further optimized for a semi-one pot synthesis of indole derivatives via an intramolecular C-C coupling. image

Arylation of amino-, diamino- and triaminophosphines with aryl(mesityl)iodonium triflates under blue light irradiation followed by oxidative P-N bond cleavage in the insitu generated amino phosphonium salts under hydrolytic conditions represent a method for the synthesis of substituted arylphosphine oxides, arylphosphinic and arylphosphonic amides respectively. The proposed approach is based on using visible light as the only promoter for the C-P bond formation, accommodates a variety of functional groups, and can be applied to the late-stage C-H functionalization of drug molecules.

Most existing methods for the synthesis of alkyl arylthioethersrequire the use of mercaptans as the starting materials, which comeswith practical limitations. Reactions of diaryliodonium salts withxanthate salts, easily prepared from the corresponding alcohols andCS(2), under the developed conditions represent an operationallysimple, thiol-free method for the synthesis of these valuable compounds.The protocol features high functional group tolerance and can be appliedto the late-stage C-H functionalization and for the introductionof a CD3S group.

Preparation of S-aryl xanthates via transition-metal-catalyzed or SNAr reactions is complicated by their further transformations under the utilized conditions. In contrast, S-arylation of potassium O-alkyl xanthates with diaryliodonium salts proceeds under mild conditions, enabling access to substituted S-aryl xanthates. The method exhibits good functional group tolerance and can be applied to the late-stage C-H functionalization of drug molecules. Divergent transformations of the resulting S-aryl xanthates provide rapid access to a range of medicinal chemistry-relevant organosulfur compounds.

Quinoline-2-thiones valuable for synthetic and medicinal chemistry applications were obtained with excellent regioselectivity employing a deoxygenative C-H functionalization of readily available quinoline-N-oxides with thiourea upon activation with triflic anhydride. Unlike the current methods, this approach provides general access to diverse quinoline-2-thiones functionalized with groups of different electronic natures. Experimental simplicity and good to high yields are advantages of this protocol. Given the high reactivity of quinoline-2-thiones, this method provides an entry point for the synthesis of diverse organosulfur quinoline scaffolds.

Reactions of acceptor-substituted aryl iodides and bromides with potassium thiocarboxylates under white light irradiation allow for the preparation of S-aryl thioesters including synthetically versatile S-aryl thioacetates. This transition-metal and external photocatalyst-free method features extremely mild reaction conditions compared with those used in transition-metal-catalyzed protocols. Reactions proceed via the initial formation of an electron donor-acceptor (EDA) complex in the ground state, which was supported by UV-vis spectra. Electron paramagnetic resonance (EPR) spin-trapping experiments using phenyl-N-tert-butylnitrone (PBN) have revealed the radical nature of the reaction.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

The formation of carbon–heteroatm bond is the key step of synthesis of numerous organic compounds, including socially important products such as pharmaceuticals, crop protection agents and organic functional materials. These reactions proceed most efficiently when catalyzed by compounds of transition metals, first of all palladium. However, this approach has considerable drawbacks, in particular, high cost and toxicity of transition metal compounds and harsh reaction conditions required in some cases, resulting in limited functional group tolerance. This review describes the recent advances in the development of methodology of transition metal-free carbon–heteroatom bond-forming cross-coupling. It is shown that single-electron transfer and homolytic bond cleavage result in the generation of highly reactive radical and/or radical ion intermediates, enable the formation of new carbon–heteroatom bonds. These intermediates are generated using either visible light or electricity as energy sources or simple organic compounds acting as electron donors. Methods for carbon–heteroatom bond formation based on radical reactions proceeding under mild conditions and in the presence of labile functional groups are considered. The key mechanistic aspects of the reactions are highlighted. The review mainly covers the original publications of the current decade. The bibliography includes 302 references.

Arylation of tertiary aryl and alkyl phosphines bearing 2-cyanoethyl group with aryl(mesityl)iodonium triflates under blue light irradiation followed by retro-Michael reaction of the in situ generated quaternary phosphonium salts initiated by DBU represent a novel efficient and general method for the preparation of distinctly substituted tertiary arylphosphines. An operationally simple, one-pot protocol features mild, transition-metal-free conditions, high selectivity, broad functional group compatibility, as well as scalability and would be applied to substrates with different electronic and steric nature.