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

Herein, we report a viable protocol to access furo[3,2-c]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 via activation of the ß-carbon of 4-hydroxy coumarin, followed by a nucleophilic addition/intramolecular cyclization/dethiohydration cascade. High-resolution mass spectra (HRMS) study confirms the key intermediates involved during the course of the reaction, elucidating the reaction pathways, and demonstrates the excellent regio- and chemoselectivity of this approach.

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

A C(sp3)-C(sp3) 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.

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 C-acetylation.

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

A one-pot electronically controlled [4 + 2] cycloaddition reaction of in situ 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'H-spiro[indene-2,9'-phenanthren]-1(3H)-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, O2 as a green oxidant, and gram-scale ability. Notably, the final S-S bond formation and cascade ring construction follow a radical pathway, which has been recognized via a radical trapping experiment with BHT during the course of the reaction. Notably, the exocyclic C═N bond at position 3 of 1,2-dithiole possesses Z stereochemistry.

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 ß-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 N,S-heterocyclic frameworks.

Regio- and Chemoselective Access to Dihydrothiophenes and Thiophenes via Halogenation/Intramolecular C(sp2)-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 S-cyclization. This protocol avoids potential toxicity and tedious work-up conditions, and features easy synthesis from readily available starting materials under catalyst-free conditions. Furthermore, 4,5-dihydrothiophenes were aromatized to thiophenes by treatment with KOH in DMF at room temperature. A probable mechanism for the formation of dihydrothiophenes and thiophenes from α-allyl dithioesters has been suggested. Notably, a large-scale experiment and the transformations of products indicated the potential utility of this reaction compared to competing processes for the synthesis of 4,5-dihydrothiophenes and thiophenes.

Magnesium catalyzed [3 + 3] heteroannulation of α-enolic dithioesters with MBH acetate: access to functionalized 3,4-dihydro-2H-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-2H-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-a]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-a]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(sp3)-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%). The allylation protocol is utilized for the short synthesis of coerulescine and various 5'-substituted spiro[pyrrolidine-3,3'-oxindoles].

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. Furthermore, the method is mild, robust, and highly selective, which successfully converted a variety of aryl, alkyl, benzyl, and heterocyclic hydrazides into the corresponding diazirine derivatives.

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. Most importantly, the electrochemical transformation reflected efficient electro-oxidation with an operationally friendly easy procedure with ample functional molecules. Cyclic voltammograms support the mechanism of this electro-oxidative cyclization process.

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 ß-ketothioamides with aryldiazonium salts catalyzed by Ru(bpy)3Cl2 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 Z-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. Despite decades of advancements, the alkynyl sulfides, particularly those composed of polar functionalities and derived from renewable sources, remain unknown. These findings demonstrate the importance of decelerated ketoxime from ß-oxodithioester for the identification of reaction conditions. The method uses mild reaction conditions to generate excited-state photoreductant for the functionalization of an array of alkynyl sulfides. Additionally, a fundamental understanding of elementary steps using electrochemical and spectroscopic techniques/experiments revealed a PCET pathway to this transformation, while the involved substrates and their properties with improved economical tools indicated the translational potential of this method.

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

A metal- and oxidant-free photoinduced strategy for thioxo sulfur-selective trifluoromethylation of ß-ketodithioesters at room temperature is reported. Excellent Z/E-stereoselectivity has been achieved with cheap and viable Langlois' reagent (CF3SO2Na, sodium triflinate) in the presence of eosin Y, which acts as a hydrogen atom transfer (HAT) catalyst. The reaction proceeds via disulfide intermediate disulfanediylbis(3-(alkylthio)-1-phenylprop-2-en-1-one) (a dimer of ß-ketodithioester) followed by complementing proton-coupled electron transfer-mediated reverse HAT cycle of eosin Y. This operationally simple and efficient protocol allows direct access to triflinated α-oxoketene dithioacetals in good to excellent yields bearing diverse synthetically useful functional groups of different electronic and steric nature.

Rhodium(II)-Catalyzed Annulative Coupling of ß-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)2-catalyzed annulative coupling of ß-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 Z-stereochemistry with regard to the exocyclic C═C double bond at the 2-position of the ring. Further, the synthetic utility of the strategy has been revealed to access 2,3-dihydrobenzo[d]thiazoles. Remarkably, atom economy and tolerance of a wide range of functional groups are added characteristics to this strategy.

Visible-Light-Driven Photocatalyst- and Additive-Free Cross-Coupling of ß-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 ß-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 ß-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. A mechanistic rationale for this cascade reaction sequence is well supported by control experiments.

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

Phosphonium ylides are being reported here as a catalyst for the formation of thiazolidines and 1,3-thiazinanes from ß-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 ß-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. The ring size of the skeletally distinct N,S-heterocycles has been efficiently tuned by switching the use of 1,2- and 1,3-dihaloalkanes as α,ß- and α,γ-dielectrophiles. It is noteworthy that the products possess Z-stereochemistry with regard to the exocyclic C[double bond, length as m-dash]C double bond at the 2-position of the ring, revealing exclusive diastereoselectivity. Since phosphorus ylides have found limited use as catalysts, control experiments revealed their behaviour as a catalyst, which not only increase the catalyst tool box, but also would contribute to the field of ylide chemistry.

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 ß-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 ß-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. The developed hydrogen-atom-transfer methodology will be helpful in postsynthetic modification via added synthetic handles.