Recent developments in electrochemical halogenation and dehalogenation reactions.

Organohalides are a prevalent structural motif used as versatile building blocks to access value-added molecules, which could play a vital role in pharmaceutical applications. Newer and greener methods for their synthesis have always been of great interest as they offer unmatched applicability in various fields. Electrochemical reactions are widely recognized as a promising avenue to address the energy crisis, in particular for the development of economically viable and high-performance strategies.

Electrochemical debrominative hydrogenation/deuteration of 2-bromo--arylacetamides.

Herein, we report a facile and efficient electro-reductive debrominative hydrogenation/deuteration of 2-bromo--aryl acetamides using HO/DO as an economical source of hydrogen/deuterium at room temperature. The reactions proceeded efficiently C-Br bond activation, enabling facile synthesis of a range of -substituted amides in moderate to high yields with broad functional group compatibility.

LiBr-Promoted Reaction of β-Ketodithioesters and Thioamides with Sulfoxonium Ylides to Synthesize Functionalized Thiophenes.

An operationally simple and highly efficient synthesis of functionalized thiophenes has been developed by LiBr promoted heteroannulation of β-ketodithioesters and thioamides with bench-stable sulfoxonium ylides in open air for the first time. This one-pot strategy involves formal Csp-H bond insertion/intramolecular cyclization cascade, featuring readily accessible starting materials, TM and additive-free condition, broad substrate scope, high functional group compatibility, and scalability. Moreover, the carbonyl, thiomethyl, and amino groups in the resulting thiophene provide a good handle on downstream transformations.

PIDA-promoted metal-free [3 + 2] heteroannulation of β-ketothioamides with 4-hydroxy coumarins: chemo-/regioselective access to furo[3,2-]chromen-4-ones at room temperature.

Herein, we report a viable protocol to access furo[3,2-]chromen-4-ones by engaging easily accessible 4-hydroxy coumarins as a three-atom CCO unit and thioamides as a C2 coupling partner, mediated by phenyliodine(III) diacetate (PIDA) at room temperature in a highly efficient and pot-/step-economical manner. This strategy not only avoids potential toxicity and tiresome workup conditions, but also features operational simplicity, a broad substrate scope, good functional group tolerance, high yields, easy scalability and exclusive selectivity. A mechanistic study has shown that this metal-free reaction is triggered by PIDA activation of the β-carbon of 4-hydroxy coumarin, followed by a nucleophilic addition/intramolecular cyclization/dethiohydration cascade.

Iridium(III)-catalyzed photoredox cross-coupling of alkyl bromides with trialkyl amines: access to α-alkylated aldehydes.

A C(sp)-C(sp) cross coupling approach based on an iridium-photocatalytic radical process has been developed enabling the synthesis of various α-alkylated aldehydes from easily available/synthesized alkyl bromides and trialkyl amines under mild photocatalytic conditions. The synthesized aldehydes are also explored as a functional handle for various useful products such as carboxylic acid, alcohol and N-heterocycle synthesis.

Aromatic C(sp )-H Functionalization by Consecutive Paired Electrolysis: Dibromination of Aryl Amines with Dibromoethane at Room Temperature.

Herein, we disclose a facile and efficient electrochemical method for the dibromination of aryl amines by double functionalization of aromatic C(sp )-H (both para and ortho) under metal- and external oxidant-free conditions at room temperature for the first time. The reaction is demonstrated using 1,2-dibromoethane to dibrominate a wide range of N-substituted aryl amines in a simple setup with C(+)/Pt(-) electrodes under mild reaction conditions. This transformation proceeds smoothly with a broad substrate scope affording the valuable and versatile N-substituted 2,4-dibromoanilines in moderate to excellent yields with high regioselectivity.

Asymmetric total synthesis of (+)-propolisbenzofuran B.

The first asymmetric total synthesis of (+)-propolisbenzofuran B is accomplished in 11 steps with an overall yield of 11.9%. The key steps are tandem deacetylative Sonogashira coupling-annulation reaction to synthesize the 2-substituted benzofuran core, stereoselective syn-aldol reaction and Friedel-Crafts cyclization to install the desired stereocenters & third-ring, and Stille coupling for -acetylation.

Electronically-controlled diastereoselective synthesis of spirocycles [4 + 2] cycloaddition of 2-arylidene-1-indenones with benzyne.

A one-pot electronically controlled [4 + 2] cycloaddition reaction of generated benzyne with 2-arylidene-1-indenone is unveiled to construct novel spirocyclic frameworks in a regio- and diastereoselective fashion. This protocol features operational simplicity, good functional group tolerance and avoids the use of metal catalysts and external additives. This methodology has extended the synthetic application of 2-arylidene-1-indenones enabling easy access to valuable 10'-spiro[indene-2,9'-phenanthren]-1(3)-ones in good yields.

Radical-Cascade Avenue to Access 1,2-Dithioles Employing Dithioesters and Edman's Reagent.

An operationally simple and efficient domino etiquette has been developed for the facile construction of 1,2-dithioles employing easily accessible dithioesters as a three-atom CCS synthon and aryl isothiocyanates as a two-atom CS unit in the absence of any catalyst and additive at room temperature under open air. The reaction proceeded efficiently affording the desired 1,2-dithioles in good yields having various functional groups of a diverse electronic and steric nature. This approach avoids possible toxicity and tiresome workup conditions and features easy to handle, cheap, and readily accessible reagents, O as a green oxidant, and gram-scale ability.

Access to Functionalized Thiazolothiadiazoles via the Chemoselective Cascade Heteroannulation of Thioamides with Hypervalent Iodine Reagents.

We describe herein a chemo- and regioselective cascade annulation between β-ketothioamides and diazo-substituted hypervalent iodine reagents under transition-metal-free and base-free conditions at room temperature. Thus, a divergent construction of fused-heterocyclic scaffold thiazolothiadiazoles has been achieved with the advantages of operational simplicity, scalability, broad substrate compatibility, and mild reaction conditions. This one-pot strategy not only avoids potential toxicity but also broadens the arsenal of synthetic methods to obtain fused ,-heterocyclic frameworks.

Regio- and Chemoselective Access to Dihydrothiophenes and Thiophenes via Halogenation/Intramolecular C(sp)-H Thienation of α-Allyl Dithioesters at Room Temperature.

An operationally simple, practical, and efficient cascade approach employing α-allyl dithioesters and NBS/NIS has been achieved to access a series of dihydrothiophenes and thiophenes containing diverse functional groups of different electronic and steric natures in good to excellent yields at room temperature in open air. The reaction proceeds via the electrophilic addition of a halogen source (NBS/NIS) to an allylic double bond, followed by intramolecular regio- and chemoselective -cyclization. This protocol avoids potential toxicity and tedious work-up conditions, and features easy synthesis from readily available starting materials under catalyst-free conditions.

Metal-Free One-Pot Annulative Coupling of 2-Hydroxybenzaldehydes with β-Ketothioamides: Access to Diverse 2-Arylimino-2-Chromenes.

A concise and practical one-pot sustainable approach for expedient synthesis of 2-arylimino-2-chromenes by two-component cascade [4 + 2] annulative coupling of easily available 2-hydroxybenzaldehydes with β-ketothioamides has been developed in good yields for the first time. Remarkably, metal- and additive-free conditions, use of simple KCO as a mild base, open atmosphere, exclusive regioselectivity, step/atom economy, nonhazardous reagents, and easy purification are added characteristics to the strategy. This annulative protocol will not only provide an efficient method to access diverse chromene scaffolds, but also enrich the research domain of β-ketothioamides.

Magnesium catalyzed [3 + 3] heteroannulation of α-enolic dithioesters with MBH acetate: access to functionalized 3,4-dihydro-2-thiopyrans.

Magnesium catalysis proved to be efficient towards [3 + 3] chemo- and diastereoselective heteroannulation employing racemic Morita-Baylis-Hillman (MBH) acetate as the C3 unit and α-enolic dithioester as the C2S1 unit, leading to highly substituted 3,4-dihydro-2-thiopyrans in excellent yields. The compatibility with a wide range of functional groups makes this domino formation of C-C and C-S bonds interesting. DFT analyses for the regioselective formation of the intermediate was performed.

[2 + 3] Annulative Coupling of Tetrahydroisoquinolines with Aryliodonio diazo compounds To Access 1,2,4-Triazolo[3,4-]isoquinolines.

Base promoted one-pot annulative coupling of 1,2,3,4-tetrahydroisoquinolines (THIQs) with hypervalent iodine(III) species aryliodonio diazo compounds has been devised for the direct construction of 1,2,4-triazolo[3,4-]isoquinoline derivatives at room temperature in open air for the first time. This approach involves [2 + 3] cascade annulation of nucleophilic THIQ with an electrophilic aryliodonio diazo compound via N-H and α-C1(sp)-H difunctionalization of THIQ.

Selective C3-Allylation and Formal [3 + 2]-Annulation of Spiro-Aziridine Oxindoles: Synthesis of 5'-Substituted Spiro[pyrrolidine-3,3'-oxindoles] and Coerulescine.

Brønsted acid- and/or Lewis acid-catalyzed selective C3-allylation and formal [3 + 2]-annulation of spiro-aziridine oxindoles with allylsilanes have been demonstrated to deliver direct access to 3-allyl-3-aminomethyl oxindoles and 5-silyl methyl spiro[pyrrolidine-3,3'-oxindoles], respectively. The acid-catalyzed methods do not provide any stereoselectivity when chiral spiroaziridines are used. However, the reaction of nonracemic sprioaziridines with allyl-Grignard reagent under catalyst-free conditions afforded 3-allyl-3-aminomethyl oxindoles with good stereoselectivity (ee up to 80%).

Base Mediated Diazirination via Iodine(III) Reagents.

Herein, we described an efficient method for the construction of highly functionalized diazirines from the carbohydrazide and diazo-substituted hypervalent iodine reagents. Unambiguous transformation has been designed with user applicable and easy practicable conditions. Remarkably, d-glucose, menthol, aspirin, proline, and lithocholic acid were efficiently diazirinated.

Electrochemical Synthesis of 1,2,3-Thiadiazoles from α-Phenylhydrazones.

We have developed an electrochemical approach for the synthesis of fully substituted 1,2,3-thiadiazoles from α-phenylhydrazones at room temperature, which is very challenging and complementary to the conventional thermal reactions. The key step involves anodic oxidation of phenylhydrazone derivatives at a constant current followed by N,S-heterocyclization. The protocol is remarkable in that it is free of a base and free of an external oxidant and can be converted to a gram scale for postsynthetic drug development with functional thiadiazoles.

Photo-oxidative Ruthenium(II)-Catalyzed Formal [3 + 2] Heterocyclization of Thioamides to Thiadiazoles.

An operationally simple and sustainable one-pot photo-oxidative formal [3 + 2] heterocyclization of β-ketothioamides with aryldiazonium salts catalyzed by Ru(bpy)Cl has been realized to provide 2,4-disubstituted 5-imino-1,2,3-thiadiazoles in good to high yields under mild reaction conditions for the first time. The reaction proceeded via an α-phenylhydrazone adduct of thioamides leading to 1,2,3-thiadiazoles via N-S bond formation at room temperature. Notably, the products possess -stereochemistry with regard to the exocyclic C═N double bond at the 5-position of the ring.

Unusual Behavior of Ketoximes: Reagentless Photochemical Pathway to Alkynyl Sulfides.

The unique properties of ketoximes are used prominently for the synthesis of heterocycles. In contrast, their potential to absorb light and photoelectron transfer processes remains challenging. Widespread interest in controlling direct excitation of ketoxime tacticity unlocks unconventional reaction pathways, enabling photochemical intramolecular skeletal modification to constitute alkynyl sulfides that cannot be realized via traditional activation.

Visible-Light Photocatalysis of Eosin Y: HAT and Complementing MS-CPET Strategy to Trifluoromethylation of β-Ketodithioesters with Langlois' Reagent.

A metal- and oxidant-free photoinduced strategy for thioxo sulfur-selective trifluoromethylation of β-ketodithioesters at room temperature is reported. Excellent /-stereoselectivity has been achieved with cheap and viable Langlois' reagent (CFSONa, sodium triflinate) in the presence of eosin Y, which acts as a hydrogen atom transfer (HAT) catalyst. The reaction proceeds disulfide intermediate disulfanediylbis(3-(alkylthio)-1-phenylprop-2-en-1-one) (a dimer of β-ketodithioester) followed by complementing proton-coupled electron transfer-mediated reverse HAT cycle of eosin Y.

Rhodium(II)-Catalyzed Annulative Coupling of β-Ketothioamides with α-Diazo Compounds: Access to Highly Functionalized Thiazolidin-4-ones and Thiazolines.

An operationally simple and efficient one-pot protocol for the synthesis of highly functionalized thiazolidin-4-ones and thiazolines has been devised via Rh(OAc)-catalyzed annulative coupling of β-ketothioamides with diazo compounds under mild reaction conditions for the first time. This double functionalization of diazo compounds proceeds via selective S-alkylation followed by intramolecular N-cyclization enabling the formation of C-S and C-N bonds at moderate temperature. Notably, the products possess -stereochemistry with regard to the exocyclic C═C double bond at the 2-position of the ring.

Visible-Light-Driven Photocatalyst- and Additive-Free Cross-Coupling of β-Ketothioamides with α-Diazo 1,3-Diketones: Access to Highly Functionalized Thiazolines.

A photocatalyst- and additive-free, visible-light-mediated chemoselective domino protocol was devised to access fully substituted thiazoline derivatives from β-ketothioamides and α-diazo 1,3-diketones at moderate temperature in open air. The reaction proceeds through in situ generation of electrophilic carbenes from α-diazo 1,3-diketones by a low-energy blue LED (448 nm), which undergoes selective coupling with nucleophilic β-ketothioamides to give thiazolines by successive formation of C-S and C-N bonds in one stretch. Notably, the benign and clean conditions, operational simplicity, sustainability, 100 % carbon economy, high yields, and wide functional-group tolerance are further attributes of the strategy.

Phosphonium ylide catalysis: a divergent diastereoselective approach to synthesize cyclic ketene acetals [thia(zolidines/zinanes)] from β-ketothioamides and dihaloalkanes.

Phosphonium ylides are being reported here as a catalyst for the formation of thiazolidines and 1,3-thiazinanes from β-ketothioamides (which act as a three atom N, C, and S synthon) with dihaloalkanes via [3 + 2] and [3 + 3] annulations under metal-free conditions. An N,C,S-centred chemoselective dihaloalkane-controlled cascade process has been identified for the preparation of cyclic N,S-heterocycles (thiazolidines and 1,3-thiazinanes) from identical β-ketothioamides. The reaction proceeds via consecutive sulfur and nitrogen nucleophilic attack of the thioamide on dihaloalkanes enabling the formation of S-C and N-C bonds.

Organocatalytic Domino Reaction of Spiroaziridine Oxindoles and Malononitrile for the Enantiopure Synthesis of Spiro[dihydropyrrole-3,3'-oxindoles].

The first organocatalytic regio- and stereoselective domino reactions of spiroaziridine oxindoles and malononitrile have been developed using DBU as a catalyst without any metal/Lewis acid activation for the enantiopure synthesis of spiro[dihydropyrrole-3,3'-oxindoles] (ee up to >99%). The protocol is also equally effective for the phenyl aziridine with excellent regio- and stereoselectivity.

Visible-Light-Mediated Synthesis of 1,2,4-Dithiazolidines from β-Ketothioamides through a Hydrogen-Atom-Transfer Photocatalytic Approach of Eosin Y.

An efficient protocol for visible-light-mediated synthesis of a specific class of 1,2,4-dithiazolidines from β-ketothioamides is devised employing eosin Y as a photoinitiator at ambient temperature in an open pot. The reaction proceeds via an in situ-generated thiyl radical followed by dimerization/deaminative cyclization cascade, enabling the creation of a dithiazolidine ring through successive formation of S-S and N-C bonds under metal- and additive-free conditions. Remarkably, the benign conditions, sustainability, and quantifying forbearance of wide horizons of functional groups are added characteristics to the strategy.