Iodine-Promoted Thioylation and Dicarbonylation of Enaminone α-C Sites: Synthesis of Fully Substituted Thiazoles via C═C Bond Cleavage.

A novel iodine-promoted difunctionalization of α-C sites in enaminones was demonstrated as a means of synthesizing a variety of fully substituted thiazoles by constructing C-C(CO), C-S, and C-N bonds. This transformation allows the realization of enaminones as unusual aryl C2 synthons and simultaneously allows the thioylation and dicarbonylation of α-C sites. A preliminary mechanistic study was performed and indicated that the cleavage of C═C bonds in enaminones involves a bicyclization/ring-opening and oxidative coupling sequence.

I2-DMSO-Mediated Construction of 2,3- and 2,4-Disubstituted Pyrimido[1,2-b]indazole Skeletons.

An efficient synthetic method for constructing 2,3- and 2,4-disubstituted pyrimidio[1,2-b]indazole skeletons through I2-DMSO-mediated and substrate-controlled regioselective [4 + 2] cyclization is reported. The reaction conditions are mild, its operation is simple, and the substrate scope is wide. More than 60 pyrimidio[1,2-b]indazole derivatives have been synthesized, providing a new methodology for constructing related molecules and potentially enriching bioactive-molecule libraries.

Azide-free cyclization reaction access to 4-aryl-NH-1,2,3-triazoles: P-toluenesulfonyl hydrazide and sulfamic acid as nitrogen sources.

An iodine-mediated cyclization has been developed to 4-aryl-NH-1,2,3-triazoles, with p-toluenesulfonyl hydrazide and sulfamic acid used as nitrogen sources. Sulfamic acid plays a crucial role in this reaction by both acting as a substrate and providing an acidic environment. This reaction offers a metal- and azide-free strategy to access NH-1,2,3-triazoles.

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.

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.

Successive Promotion of Formal [3+2] Cycloaddition of Aryl Methyl Ketones by I2 and Zn: Access to 2-Hydroxy-4-morpholin-2,5-diarylfuran-3(2H)-ones with a Quaternary Carbon Center.

2-Hydroxy-4-morpholin-2,5-diarylfuran-3(2H)-one derivatives were constructed sequentially using iodine and zinc dust from simple and readily available methyl ketone and morpholine as the starting materials. Under mild conditions, C-C, C-N, and C-O bonds formed in a one-pot synthesis. A quaternary carbon center was successfully constructed, and the active drug fragment morpholine was introduced into the molecule.

One Stone, Three Birds: One-Pot Synthesis of Pyrido[3,2-a]phenoxazin-5-one Derivatives from o-Aminophenols with Triple Roles, Paraformaldehyde, and Enaminones via the Povarov Reaction.

A novel multicomponent cascade cyclization reaction in one pot for the preparation of pyrido[3,2-a]phenoxazin-5-ones from simple o-aminophenols, paraformaldehyde, and enaminones has been established. It is noteworthy that o-aminophenol plays multiple roles serving as both a bis-nucleophile and an iminoquinone precursor, which can in situ generate aminophenoxazinones to undergo the Povarov reaction for the first time to yield pyrido[3,2-a]phenoxazin-5-ones with a high efficiency. Moreover, the photoluminescence of pyrido[3,2-a]phenoxazin-5-ones has polarity sensitivity and features aggregation-induced emission (AIE) characteristics, which is promising for bioimaging and theranostic applications.

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.

An I2-DMSO catalytic manifold enabled aromatization for C-ring editing of podophyllotoxone.

The precise aromatization of the C-ring of podophyllotoxone to access value-added dehydropodophyllotoxin derivatives conventionally requires the use of equivalent amounts of unsustainable oxidants and suffers from inefficiencies. Taking advantage of the hydridic character of the C8 and C8' of podophyllotoxone, we have developed an I2-DMSO catalytic manifold that enables a green and selective dehydrogenative aromatization to overcome these synthetic challenges. An unprecedented dehydrogenative amination of podophyllotoxone derivatives was also realized using aniline as the reaction partner.

Synthesis of primary propargylic alcohols from terminal alkynes using rongalite as the C1 unit.

Here, an efficient leaving group-activated methylene alcohol strategy for the preparation of primary propargyl alcohols from terminal alkynes by employing the bulk industrial product rongalite as the C1 unit has been described. The reaction avoids the low-temperature reaction conditions and inconvenient lithium reagents required for the classical method of preparing primary propargylic alcohols. Preliminary mechanistic studies showed that the reaction may not proceed via formaldehyde intermediates, but through the direct nucleophilic attack of the terminal alkyne on the carbon atom of rongalite by activation through SO2- as a leaving group.

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.

Switching Over of the Chemoselectivity: I2-DMSO-Enabled α,α-Dichlorination of Functionalized Methyl Ketones.

Precise control of the chemoselectivity of the halogenation of a substrate equipped with multiple nucleophilic sites is highly demanding and challenging. Most reported chlorinations of methyl ketones show poor compatibility or even exclusive selectivity toward electron-rich arene, olefin, and alkyne residues. This is attributed to the direct or in situ employment of electrophilic Cl2/Cl+ species. Here, we reported that, even bearing those competitive residues, methyl ketones can still undergo dichlorination to afford α,α-dichloroketones in a chemo-specific manner. Enabled by the I2-dimethyl sulfoxide catalytic system, in which hydrochloric acid only acts as a nucleophilic Cl- donor, this straightforward dichlorination reaction is safe and operator-friendly and has high atomic economy, giving access to structurally diverse α,α-dichloroketones in good yields and with good functional-group tolerance.

Pd-Catalyzed Hydroxyl-Directed Cascade Hydroarylation/C-H Germylation of Nonterminal Alkenes and Aryl Iodides.

Pd-catalyzed cascade hydroarylation and C-H germylation of nonterminal alkenes and aryl iodides enabled by hydroxyl assistance have been developed. The key step in this C-H germylation cascade is the formation of a highly reactive oxo-palladacycle intermediate, which markedly restrained the ß-H elimination process. Mechanistically, control experiments indicated that the hydroxyl group played an important role in this process. This transformation shows excellent reactivity and selectivity for most substrates investigated.

One-Pot Synthesis of Diaryl 1,2-Diketones via Zn-Mediated Reductive Coupling.

A reductive coupling reaction was established for the synthesis of diaryl 1,2-dicarbonyl compounds from aryl methyl ketones in good yields. The mechanistic study showed the reaction undergoes C(CO)-C(sp3) bond cleavage, with the reductive coupling reaction occurring through an electron transfer process. Notably, the reaction not only is simple to operate but also has mild reaction conditions and a wide range of applicable substrates.

I2-Promoted In Situ Cyclization-Rethiolation Reaction: Synthesis of 2-Aliphatic- or Aromatic-Substituted Indolizines.

An efficient I2-promoted one-pot one-step three-component reaction for the synthesis of sulfhydryl indolizines from methyl ketones, 2-pyridylacetate derivatives, and sulfonyl hydrazides via an in situ cyclization-rethiolation strategy has been developed. This protocol shows excellent substrate compatibility, including for chain and cyclic aliphatic methyl ketones, natural product pregnenolone acetate, and phosphorus-containing methyl ketones, affording a series of valuable aliphatic-substituted indolizines in good yields.

Iodine-Promoted Oxidative Cyclization of Methyl Azaarenes and α-Amino Ketones for One-Pot Synthesis of 2-Azaaryl-5-aryl Oxazoles.

A high efficiency protocol was developed for the synthesis of 2,5-disubstituted oxazoles via iodine-promoted oxidative domino cyclization. These reactions were performed with readily available methyl azaarenes and α-amino ketones under metal-free conditions. This protocol is a simple method with high functional group compatibility, a wide range of substrates, and excellent yield, providing a new way to synthesize azaarene-attached oxazoles.

Iodine-catalyzed oxidative annulation: facile synthesis of pyrazolooxepinopyrazolones via methyl azaarene sp3 C-H functionalization.

An iodine-catalyzed methyl azaarene sp3 C-H functionalization has been developed for the synthesis of a seven-membered O-heterocyclic architecture containing three different heterocyclic aromatic hydrocarbons. This method can be applied to a wide range of substituted methyl azaarenes and diverse 2,4-dihydro-3H-pyrazol-3-ones, and brings about the efficient preparation of 2,9-dihydrooxepino[2,3-c:6,5-c']dipyrazol-3(7H)-ones in high yields with the merits of low catalyst loading, good functional group tolerance and metal-free conditions.

Synthesis of Diversified Pyrazolo[3,4-b]pyridine Frameworks from 5-Aminopyrazoles and Alkynyl Aldehydes via Switchable C≡C Bond Activation Approaches.

A cascade 6-endo-dig cyclization reaction was developed for the switchable synthesis of halogen and non-halogen-functionalized pyrazolo[3,4-b]pyridines from 5-aminopyrazoles and alkynyl aldehydes via C≡C bond activation with silver, iodine, or NBS. In addition to its wide substrate scope, the reaction showed good functional group tolerance as well as excellent regional selectivity. This new protocol manipulated three natural products, and the arylation, alkynylation, alkenylation, and selenization of iodine-functionalized products. These reactions demonstrated the potential applications of this new method.

I2/CuCl2-Copromoted Formal [4 + 1 + 1] Cyclization of Methyl Ketones, 2-Aminobenzonitriles, and Ammonium Acetate: Direct Access to 2-Acyl-4-aminoquinazolines.

We herein report an I2/CuCl2-copromoted diamination of C(sp3)-H bonds for the preparation of 2-acyl-4-aminoquinazolines from methyl ketones, 2-aminobenzonitriles, and ammonium acetate. This reaction features operational simplicity, commercially available substrates, mild reaction conditions, and good functional group compatibility. Mechanistic studies indicate that CuCl2 plays a pivotal role in this transformation. This study uses a methyl group as a novel input to construct 2-acyl-4-aminoquinazoline derivatives for the first time.

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.