4-Sulfanyl-1,2,3-triazole (L1) accelerated the solvent-free CuAAC efficiently with low catalyst loading (0.1 mol% for common azides and 1 mol% for sulfonyl azides). L1 exhibited higher catalytic activity compared to 1,4-substituted 1,2,3-triazole without sulfanyl group (5a) and sulfide, demonstrating that coordination of both sulfanyl and 1,2,3-triazole moieties with copper was critical to enhance the activity of L1. The Cu(OAc)2/L1 catalytic system displayed high selectivity in synthesis of alkynyl- or azido-involved 1,2,3-triazoles. The di-copper system Cu(OAc)2/CuBr/L1 promoted the reaction of electron-deficient and less reactive sulfonyl azides well, generating N-sulfonyl-1,2,3-triazoles in good yields, and L1 showed better performance than 1,3-di-o-tolylthiourea (L '). Other features of this protocol included recyclable ligand, 1:1 substance ratio, high yields, wide substance scope, and easily scaled up and facile purification of most products.

A novel synthetic route was developed to synthesize 6-keto estradiol (2), an intermediate in the synthesis of fulvestrant and analogues. Using norandrostenedione as a starting material, the target 2 was obtained through five step reactions including esterification, hydroxylation, oxidation, enzyme-catalyzed dehydrogenative aromatization, and enzyme-catalyzed reduction. In hydroxylation, phthalic anhydride (PA)/H2O2/pyridine was developed as a catalytic system to give the desired 6a and 6b in 90% yield under mild conditions. The enzyme 3-ketosteroid-Delta(1)-dehydrogenase (Delta(1)-KstD) was utilized for the dehydrogenative aromatization of the A ring in 7, while 17 beta-hydroxysteroid dehydrogenases (17 beta-HSDs) were employed for the stereoselective reduction of 17-keto in 8. The related impurities and process parameters were studied in detail. In addition, the scale-up of this synthetic route was successfully executed on a 300.00 g scale, yielding 159.04 g of 6-keto estradiol (2) with a purity of 99.6% and an overall yield of 50% in five steps. Other notable features of this synthetic route included high yields, mild reaction conditions, and inexpensive and commercially available starting materials.

A novel palladium-catalyzed one-pot multicomponent reaction has been developed for the efficient synthesis of imidazolidinone-fused 3,1-benzoxazine derivatives from simple and readily available starting materials, including 2-aminoarylmethyl alcohols, ethyl glyoxylate, and amines. Notably, this transformation proceeds under mild conditions with a broad substrate scope, high trans-selectivity, and operational simplicity. The method enables the efficient construction of five new bonds and two ring moieties in one pot process, offering straightforward access to structurally diverse polycyclic fused 3,1-benzoxazine derivatives. Density functional theory (DFT) calculations were employed to elucidate the reaction mechanism and rationalize the observed trans-selectivity. Preliminary biological evaluations revealed promising antifungal activity in selected derivatives.

The recombinant 3-ketosteroid Delta(1)-dehydrogenase from Rhodococcus erythropolisPR4 (KstD-Re1) catalyzed the Delta(1)-dehydrogenation of ester (1a) to access vamorolone-21-ester (2a). After modification of the structure and examination of the reaction carefully, the recombinase (KstD-Re1) with position 194 changing from Val to Gly and 318 changing from Tyr to tryptophan (Trp, W) was screened as the best catalyst. Other steroids like androstenedione, progesterone, testosterone, hydroxyprogesterone, and hydrocortisone acetate were also tolerated well in this Delta(1)-dehydrogenation. The molecular docking of 1a with KstD-Re1 was also disclosed. We found that the dual base (NaOH/K2CO3)-mediated hydrolysis of 2a formed vamorolone in 94.0% yield and 99.6% purity, meeting the International Conference Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) quality standards. Staring from the readily available and inexpensive 16 alpha-methyl-4,9-androstadiene-3,17-dione (3), ester 1a could be generated in 80.5% total yield through cyanidation/silyl etherification, in situ silicon nucleophile annelation process (SNAP)/desilylation, and substitution. Notably, a continuous-flow in situ SNAP/desilylation in a microchannel reactor was developed to produce chloride (5) in 91.7% yield, which not only improved the yield dramatically but also avoided the harsh reaction conditions and side reactions such as desilylation, C-Cl bond cleavage and flipping of 16-CH3. Compared to previously reported synthetic routes to vamorolone, our approach offers advantages like low cost, higher yield, mild reaction conditions, excellent product quality, and gram-scale synthesis.

A series of 2-acyloxybenzamides were synthesized. The structures of the synthesized compounds were characterized by IR, 1H NMR, 13C NMR, and HRMS. Their antifungal activity against plant pathogenic fungi was evaluated. Compound 3i exhibited a 100.0% inhibition rate against M. oryzae, while compound 3b showed 90.0% inhibition against P. capsici. The corresponding EC50 values of compounds 3b (against P. capsici) and 3i (against M. oryzae) were determined to be 3.90 and 8.21 μg/mL, respectively. Molecular docking and MD simulations studies suggested that SCD enzyme may serve as a potential target for compound 3i and its related analogues.

Organic five-membered rings have shown significant applications in the fields of organic synthesis, natural products, organic materials and pharmaceuticals for their unique characteristics. Electrochemical construction of five-membered rings from alkynes attracted increasing attention due to the notable advantages of electrochemical transformations and facile access of alkynes. Indole skeletons were constructed successfully through electrochemical intramolecular coupling of ethynyl-involved ureas, annulation of o-arylalkynylanilines, cyclization of 2-ethynylanilines, selenocyclization of diselenides with 2-ethynylanilines as well as C–H indolization of 2-alkynylanilines with 3-functionalized indoles. Isoindolones were synthesized successfully by electrochemical annulation of benzamides with terminal alkynes, 5-exo-dig aza-cyclization of 2-alkynylbenzamides as well as reductive cascade annulation of o-alkynylbenzamides. Pyrroles and imidazoles were formed efficiently via electrochemical annulation of alkynes with enamides and tandem Michael addition/azidation/cyclization of alkynes, amines and azides, respectively. Imidazopyridines could be obtained by electrochemical [3 + 2] cyclization of heteroarylamines. The electrochemical oxidative [3 + 2] cycloaddition of secondary propargyl alcohols was a simple and efficient access towards 1,2,3-triazoles. In this review, electrochemical cyclizations of alkynes to construct five-membered rings are highlighted. Firstly, the property and application of five-membered rings are simply introduced. After presenting the usefulness of alkynes and the general progress of electrochemical transformations, electrochemical cyclization reactions of alkynes towards five-membered rings are classified and presented in detail. Based on different types of five-membered rings, electrochemical construction of indoles, isoindolinones, indolizines, oxazoles, imidazoles, pyrroles, imidazoles and 1,2,3-triazoles are summarized and the possible reaction mechanisms are disclosed if available.

Mechanochemical and transition-metal-catalyzed reactions of alkynes, exhibiting significant advantages like short reaction time, solvent-free, high yield and good selectivity, were considered to be green and sustainable pathways to access functionalized molecules and obtained increasing attention due to the superiorities of mechanochemical processes and the reactivities of alkynes. The ball milling and CuI-catalyzed Sonogashira coupling of alkyne and aryl iodide avoided the use of common palladium catalysts. The mechanochemical Rh(III)- and Au(I)-catalyzed C–H alkynylations of indoles formed the 2-alkynylated and 3-alkynylated indoles selectively. The mechanochemical and copper-catalyzed azide-alkyne cycloaddition (CuAAC) between alkynes and azides were developed to synthesize 1,2,3-triazoles. Isoxazole could be formed through ball-milling-enabled and Ru-promoted cycloaddition of alkyne and hydroxyimidel chloride. In this review, the generation of mechanochemical and transition-metal-catalyzed reactions of alkynes was highlighted. Firstly, the superiority and application of transition-metal-catalyzed reactions of alkynes were briefly introduced. After presenting the usefulness of green chemistry and mechanochemical reactions, mechanochemical and transition-metal-catalyzed reactions of alkynes were classified and demonstrated in detail. Based on different kinds of reactions of alkynes, mechanochemical and transition-metal-catalyzed coupling, cycloaddition and alkenylation reactions were summarized and the proposed reaction mechanisms were disclosed if available.

Iron compounds, exhibiting high catalytic behavior and excellent compatibility, have been considered as low-toxic, cheap, efficient and green catalysts for many important organic transformations. Organic six-membered rings play a crucial role in the fields of natural products, agricultural chemicals, pharmaceuticals and organic materials due to their significant properties. The construction of six-membered rings from alkynes through iron-catalyzed annulation attracted increasing attention to the remarkable advantages of iron catalysts. Benzenes, pyridines and pyrans could be formed facilely through iron-catalyzed [2+2+2] annulation of alkynes. Pyrimido cycles were afforded successfully via iron-catalyzed [3+2+1] annulation of alkynes, while iron-catalyzed [4+2] cyclization of alkynes could be applied to access quinolones, chromenones, isoquinolone, etc. Iron-catalyzed intramolecular cyclization of alkynes formed isoquinolinium, isocoumarin, phenanthrene, 1,2-dihydroquinolines, and spiro[5.5]trienones. In this review, the generation of six-membered rings from alkynes by iron-catalyzed cyclization was highlighted. Firstly, the property, superiority and application of iron catalysts were briefly introduced. After presenting the usefulness of six-membered rings and the unique reactivities of alkynes, iron-catalyzed synthesis of six-membered rings from alkynes were classified and demonstrated in detail. Based on different kinds of reactions, iron-catalyzed [2+2+2], [3+2+1], [4+2] and intramolecular cyclizations of alkynes were summarized and the plausible reaction mechanism would be also showed if available.

A diverse array of novel 2-aryl-3-amidyl-1,3-benzoxazine compounds were synthesized in 54–93

(-)-Epigallocatechin gallate ((-)-EGCG) was successfully afforded through Friedel-Crafts reaction, protection, Sharpless reaction, desilylation, configuration conversion, esterification, and debenzylation, etc. To avoid the use of acyl chloride, a direct esterification of cis-alcohol (8) and carboxylic acid (2) catalyzed by zirconocene was developed. Other features of this synthetic route included facile gram-scale synthesis, convenient purification of intermediates and products, and high yields.

Ursodeoxycholic acid (UDCA) was synthesized from commercially available phytosterol-derived bisnoralcohol with an overall yield of 57% by a six-step process. The absolute configuration of the 3,5,7-stereogenic centers in UDCA was determined using Pd-catalyzed and hydroxysteroid dehydrogenase (HSDH)-catalyzed hydrogenation conducted under normal temperature and atmospheric pressure conditions. To investigate the stereoselectivity and regioselectivity of the catalyst and assess the final purity of the product, all potential impurities were synthesized and analyzed using HPLC with charged aerosol detection (CAD). The developed process demonstrated cost-effectiveness and suitability for large-scale production of UDCA with an ICH-grade quality. Our Pd-catalyzed and HSDH-catalyzed hydrogenation techniques could also be applied in the synthesis of alphaxalone and brexanolone.

Organic sulfone compounds, exhibiting interesting bioactivities, were widely applied in the field of pharmaceutical and medicine. And numerous of sulfuryl group-involved drugs were approved by the Food and Drug Administration (FDA). Odevixibat, maralixibat chloride and belzutifan approved in 2021 could be applied in the treatment of progressive familial intrahepatic cholestasis (PFIC), cholestatic pruritus and clear cell renal cell carcinoma (ccRCC), respectively. In 2022, abrocitinib, pyrukynd and voquezna were approved for the treatment of atopic dermatitis, pyruvate kinase deficiency (PKD) and acid-related disorders, respectively. Defencath for preventing bloodstream infections, sparsentan for treatment of proteinuria related to IgA nephropathy, and xacduro for treatment of hospital-acquired bacterial pneumonia (HABP) were approved in 2023. In this review, the synthesis and therapies of these sulfuryl group-involved drugs approved from 2021 to 2023 are discussed in details.

Sulfur‐containing 1,2,3‐triazoles display bioactivities like antidepressant, antifungal activity, antitumor, etc. Numerous approaches have been established to form sulfur‐containing 1,2,3‐triazoles. 4‐Sulfanyl‐ and 5‐sulfanyl‐1,2,3‐triazoles were produced by metal‐catalyzed azide‐alkyne cycloaddition (AAC), etc. N‐Sulfonyl‐1,2,3‐triazoles were generated via the reaction of acetylides with sulfonyl azides, CuAAC. 4‐Sulfonyl‐1,2,3‐triazoles were produced through [3+2] cycloaddition and reaction of azide with bromovinylsulfonyl fluoride. Although 5‐sulfonyl‐1,2,3‐triazoles were formed successfully via RuAAC, their synthetic approaches were very limited. 1‐Phosphinyl‐2‐sulfanylethynes were suitable substances to access sulfur‐ and phosphorus‐containing triazoles. In this review, the synthesis and properties of sulfur‐containing 1,2,3‐triazoles were highlighted. Initially, the properties of organosulfurs, 1,2,3‐triazoles and sulfur‐containing 1,2,3‐triazoles were briefly introduced. After stating the general procedures to construct 1,2,3‐triazole skeleton, the synthetic approaches and properties of sulfur‐involved 1,2,3‐triazoles were sorted and described in details. According to different kinds of sulfur‐containing 1,2,3‐triazoles, synthetic methods and features of 4‐sulfanyl‐1,2,3‐triazoles, 5‐sulfanyl‐1,2,3‐triazoles, N‐sulfonyl‐1,2,3‐triazoles, 4‐sulfonyl‐1,2,3‐triazoles, 5‐sulfonyl‐1,2,3‐triazoles, sulfur‐ and heteroatom‐containing 1,2,3‐triazoles were summarized.

A highly selective hydrogenation of 3-keto in steroids to 3-hydroxyl steroids catalyzed by hydroxysteroid dehydrogenases (HSDHs) was demonstrated. The Ct3α-HSDH-catalyzed hydrogenation generated 3α-hydroxyl steroids as the main enantiopure isomers in high yields, while the Ss3β-HSDH catalytic system afforded 3β-hydroxyl steroids in excellent yields. In both catalytic systems, the hydrogenation proceeded regioselectively at 3-keto with 7-, 11-, 17-, and 20-keto almost unreacted, and chemoselectively with the C═C bond and ester group unattacked. Our HSDH-promoted hydrogenation showed advantages like high regio-, chemo-, and enantioselectivity, good yields, mild conditions, a wide substrate scope, and being suitable for gram-scale synthesis. Notably, bioactive molecules like dehydroepiandrosterone, brienolone, and alfaxalone were obtained facilely in high yields via our hydrogenation approach.

Organic cycles play an important role in chemistry, pharmacology and material science for their unique properties. Construction of organic cycles from thioalkynes attracted increasing attention due to the facile access of thioalkynes. 2H-Azirines were synthesized successfully from thioalkynyl oxime ethers. Cyclobutanes were formed through chiral titanium catalyzed cycloaddition of thioalkynes. Cyclopentenes were afforded by annulation of thioalkynes. Thioalkynes could be also applied to synthesize thiophenes, oxazoles, benzo[b]thiophenes, 2H-chromenes, 2-phenylbenzothiazoles, diazacyclobutene, etc. In this review, construction of organic cycles from thioalkynes were highlighted. Firstly, the property and application of organic cyclic compounds were simply introduced. After presenting the general methods to access organic cycles, applications of thioalkynes as synthons to prepare organic cycles were classified and presented in detail. Based on different kinds of organic cycles obtained from thioalkynes, organic reactions for synthesis of three-, four-, five-, six-membered as well as fused cycles would be summarized and the plausible reaction mechanisms could be presented if available.

4-Sulfanyl-substituted 1,2,3-triazoles were provided regioselectively with good yields and broad scope via consecutive t-BuOK-promoted dephosphinylation of 1-phosphinyl-2-sulfanylethynes and copper-catalyzed azide-alkyne cycloadditions (CuAAC) with alkyl azides. Unsymmetrically substituted ditriazoles were successfully obtained using a tandem dephosphinylative CuAAC protocol with diazides. Direct CuAAC of the 1-phosphinyl-2-sulfanylethynes with azides afforded regioisomeric mixtures of 4-phosphinyl-5-sulfanyl- and 5-phosphinyl-4-sulfanyl-1,2,3-triazoles that were easily separable from one another. When the phosphinyl- and sulfanyl-substituted triazoles were treated with t-BuOK, the dephosphination proceeded smoothly, yielding the corresponding 5- and 4-sulfanyltriazoles, respectively. 5-(1-Aryl-1-hydroxymethyl)-4-sulfanyltriazoles were synthesized by stepwise treatment of 5-phosphinyl-4-sulfanyltriazole with MeMgBr and arylaldehydes. Additionally, Ph2P(O) and RS groups in the triazoles were easily converted to Ph2P and RSO2 by PhSiH3-reduction and m-CPBA-oxidation, respectively. Following the dephosphinylative CuAAC of 1-phosphinyl-2-(4-t-butylphenylsulfanyl)ethyne with aryl azides and m-CPBA-oxidation, potent antagonists of pregnane X receptor LC-58 and LC-59 were successfully produced.

Development of nitrogen-rich energetic materials has gained much attention because of their remarkable properties including large nitrogen content and energy density, good thermal stability, low sensitivity, good energetic performance, environmental friendliness and so on. Tetrazole has the highest nitrogen and highest energy contents among the stable azoles. The incorporation of diverse explosophoric groups or substituents into the tetrazole skeleton is beneficial to obtain high-nitrogen energetic materials having excellent energetic performance and suitable sensitivity. In this review, the development of high-nitrogen energetic materials based on tetrazole skeleton is highlighted. Initially, the property and utilization of nitrogen-rich energetic materials are presented. After showing the advantage of the tetrazole skeleton, the high-nitrogen energetic materials based on tetrazole are classified and introduced in detail. Based on different types of energetic materials (EMs), the synthesis and properties of nitrogen-rich energetic materials based on mono-, di-, tri- and tetra-tetrazole are summarized in detail.