I2-DMSO-Mediated Transannulation of Benzo[d]isoxazol-3-amine: Direct Access to 2,4,5-Substituted Pyrimidine Derivatives.

An I2-DMSO-mediated multicomponent [3+1+2] cascade annulation reaction using aryl methyl ketones, enaminones, and benzo[d]isoxazol-3-amine as substrates has been developed. This metal-free reaction involved the transannulation of benzo[d]isoxazol-3-amines with the formation of two C-N bonds and a C-C bond in one pot. Notably, a pyrimidine ring with a 1,4-dicarbonyl scaffold could efficiently transform into a pyrimido[4,5-d]pyridazine skeleton. The phenolic hydroxyl group of the target product could undergo further modification with pharmaceuticals, demonstrating the utility of this method.

Base-Controlled Synthesis of Fluorescent Acridone Derivatives via Formal (4 + 2) Cycloaddition.

A transition-metal-free formal (4 + 2) cycloaddition for the direct assembly of acridone derivatives has been developed from simple and easily accessible o-aminobenzamides and 2-(trimethylsilyl)aryl triflates. The base played an important role in the selective controlled synthesis of N-H and N-aryl acridones. A preliminary study on the fluorescence properties of N-aryl acridones demonstrated that they could be used as fluorescent materials with a broad emission range.

A Pummerer Reaction-Enabled Modular Synthesis of Alkyl Quinoline-3-carboxylates and 3-Arylquinolines from Amino Acids.

Concise synthesis of functionalized quinolines has received continuous research attention owing to the biological importance and synthetic potential of bicyclic N-heterocycles. However, synthetic routes to the 2,4-unsubstituted alkyl quinoline-3-carboxylate scaffold, which is an important motif in drug design, remain surprisingly limited, with modular protocols that proceed from readily available materials being even more so. We herein report an acidic I2-DMSO system that converts readily available aspartates and anilines into alkyl quinoline-3-carboxylate. This method can be extended to a straightforward synthesis of 3-arylquinolines by simply replacing the aspartates with phenylalanines. Mechanistic studies revealed that DMSO was activated by HI via a Pummerer reaction to provide the C1 synthon, while the amino acid catabolized to the C2 synthon through I2-mediated Strecker degradation. A formal [3 + 2 + 1] annulation of these two concurrently generated synthons with aniline was responsible for the selective formation of the quinoline core. The synthetic utility of this protocol was illustrated by the efficient synthesis of human 5-HT4 receptor ligand. Moreover, an unprecedented chemoselective synthesis of 2-deuterated, 3-substituted quinoline, featuring this reaction, has been established.

Aniline assisted dimerization of phenylalanines: convenient synthesis of 2-aroyl-3-arylquinoline in an I2-DMSO system.

We herein report an efficient synthesis of 2-aroyl-3-arylquinolines from phenylalanines and anilines. The mechanism involves I2-mediated Strecker degradation enabled catabolism and reconstruction of amino acids and a cascade aniline-assisted annulation. Both DMSO and water act as oxygen sources in this convenient protocol.

Copper-Catalyzed Oxidative C(sp3)-H/C(sp3)-H Cross-Coupling Reaction of 3-Methylbenzo[c]isoxazoles with Methyl Ketones: Access to Indigoid Analogues.

A copper-catalyzed oxidative C(sp3)-H/C(sp3)-H cross-coupling reaction of methyl ketones and 3-methylbenzo[c]isoxazoles has been developed for the direct synthesis of 3-oxoindolin-2-ylidene derivatives. This process involves an intermolecular nucleophilic addition/ring-opening/aza-Michael addition cascade, providing indigoid analogues with high atom economy and as single isomers exclusively under mild conditions.

I2-DMSO mediated oxidative amidation of methyl ketones with anthranils for the synthesis of α-ketoamides.

An I2-DMSO mediated oxidative amidation of methyl ketones using anthranils as masked N-nucleophiles has been developed for the direct synthesis of α-ketoamides with high atom-economy. This metal-free process involves reductive N-O bond cleavage of anthranils and oxidative C-N bond formation of methyl ketones under mild conditions. The iodo group and electrophilic formyl group provide multiple possibilities for further functionalization of α-ketoamides.

Acid-Promoted Multicomponent Tandem Cyclization to Synthesize Fully Substituted Oxazoles via Robinson-Gabriel-Type Reaction.

An acid-promoted multicomponent reaction for the synthesis of diverse fully substituted oxazole derivatives from simple and readily available arylglyoxal monohydrates, nitriles, and various C-nucleophiles has been developed. This protocol features wide functional group diversity which is capable of installing 4-hydroxycoumarin, 2-naphthol, and 1,3-cyclohexanedione motifs to oxazoles. Mechanistic analysis indicates that a classical Robinson-Gabriel reaction served as the key step for this tandem transformation.

Acid-Catalyzed Multicomponent Tandem Double Cyclization: A One-pot, Metal-free Route to Synthesize Polyfunctional 4,9-Dihydropyrrolo[2,1-b]quinazolines.

An acid-catalyzed multicomponent tandem double cyclization protocol has been developed for the synthesis of polyfunctional 4,9-dihydropyrrolo[2,1-b]quinazolines from simple and readily available arylglyoxal monohydrates, 2-aminobenzylamine, and trans-ß-nitrostyrenes. This practical and metal-free reaction proceeds through an imine formation/cyclization/Michael addition/Henry cyclization protocol, resulting in the construction of four new bonds and two ring moieties directly in one pot.

N-Benzylhydroxylamine as a novel synthetic block in "C1N1" embedding reaction via α-C(sp3)-H activation strategy.

A novel process using N-benzylhydroxylamine hydrochloride as a "C1N1 synthon" in [2+2+1] cyclization for the construction of 1,2,5-trisubstituted imidazoles has been described for the first time. The key to realizing this process lies in capturing arylamines by in situ generated novel acyl ketonitrone intermediates. Subsequent tautomerization activates the α-C(sp3)-H of N-benzylhydroxylamines, and thus breaks through its inherent reaction mode and achieves N, α-C site-selective cyclization. Furthermore, this method enables scale-up synthesis and late-stage modification of complex molecules.

Direct Hydrodefluorination of CF3-Alkenes via a Mild SN2' Process Using Rongalite as a Masked Proton Reagent.

A concise and efficient hydrodefluorination process was developed for the synthesis of gem-difluoroalkenes. This reaction employs rongalite as a masked proton source and does not require any additional catalysts or reductants. Notably, trifluoromethyl alkenes having both terminal and internal double bonds are compatible with this process, allowing for a wider range of substrates. The successful late-stage functionalizations of pharmaceuticals and gram-scale syntheses were used to demonstrate the viability of this method.

Rongalite as C1 Synthon and Sulfone Source: A Practical Sulfonylmethylation Based on the Separate-Embedding Strategy.

Rongalite has been used in several challenging synthetic transformations with operationally simple and effective protocols. However, the employment of multiple characteristics of rongalite in synthetic chemistry is comparatively little known. Herein we report a separate-embedding type sulfonylmethylation of sulfoxonium ylides in which rongalite concurrently acted as a sulfone source, C1 synthon, radical initiator, and potential reducing reagent for the first time. Notably, this facile and easy-handling reaction does not require a catalyst or prefunctionalized sulfonylmethylation reagents.

Synthesis of Tetrahydro-2H-thiopyran 1,1-Dioxides via [1+1+1+1+1+1] Annulation: An Unconventional Usage of a Tethered C-S Synthon.

An unprecedented [1+1+1+1+1+1] annulation process has been developed for the construction of tetrahydro-2H-thiopyran 1,1-dioxides. Notably, rongalite acted as a tethered C-S synthon in this reaction and can be chemoselectively used as triple C1 units and as a source of sulfone. Mechanistic investigation indicated that two different carbon-increasing models are involved in this reaction in which rongalite serves as C1 units.

I2-DMSO Mediated Multicomponent [3+2] Annulation Reaction: An Approach to Pyrrolo[2,1-a]isoquinoline Derivatives with a Quaternary Center.

An I2-DMSO mediated multicomponent [3+2] cascade annulation reaction using methyl ketones, 1,2,3,4-tetrahydroisoquinolines (THIQ) and cyclopropenones as readily available substrates has been developed. This metal-free process involves N-H/α-C(sp3)-H trifunctionalization of THIQ and C-C bond cleavage of cyclopropenone, providing a direct approach to obtain pyrrolo[2,1-a]isoquinoline derivatives with a quaternary carbon center. Two C-C bonds and one C-N bond are formed efficiently in one pot.

I2-DMSO-Mediated N-H/α-C(sp3)-H Difunctionalization of Tetrahydroisoquinoline: Formal [2 + 2 + 1] Annulation for the Construction of Pyrrolo[2,1-a]isoquinoline Derivatives.

An I2-DMSO-mediated cascade reaction using methyl ketones and 1,2,3,4-tetrahydroisoquinolines (THIQs) as commercially available substrates has been developed for the construction of pyrrolo[2,1-a]isoquinoline derivatives. This metal-free process involves N-H/α-C(sp3)-H difunctionalization of THIQ. Two C-C bonds and one C-N bond are formed in one pot under mild conditions. Besides, a quaternary carbon center has been constructed in this transformation efficiently.

Rongalite as a sulfone source: a novel copper-catalyzed sulfur dioxide anion incorporation process.

A novel copper-catalyzed sulfur dioxide anion incorporation cascade for the synthesis of 1-thiaflavanone sulfones has been disclosed using rongalite as an economic and safe sulfone source. A series of 1-thiaflavanone sulfones were synthesized from easily prepared 2'-iodochalcone derivatives in excellent yields. This transformation proceeds through consecutive formation of two C-S bonds, which is the first example of SO- being used to construct sulfone motifs under copper-catalyzed conditions.