CsF-Mediated Reaction of Trifluorodiazoethane with 3-Nitroindoles Enables Access to Trifluoromethylpyrazolo[4,3-b]indoles.

A mild and metal-free strategy for the construction of trifluoromethylated pyrazolo[4,3-b]indoles through the reaction of N-substituted 3-nitroindoles with trifluorodiazoethane is reported. This operationally simple transformation involves a [3 + 2] cycloaddition of trifluorodiazoethane with 3-nitroindole, followed by the elimination of the nitro group to furnish pyrazole-fused indoles. The synthetic utility of this method is further demonstrated by applying it to other heterocycles, such as 3-nitrobenzothiophene and 2-nitrobenzofuran.

Trapping of Arynes with In Situ Generated Aryltrifluoromethylnitrones Enables Access to Trifluoromethylated Benzoxazolines.

Herein, we report a rare example of trapping arynes using in situ generated aryltrifluoromethylnitrone to access an important class of trifluoromethylated benzoxazolines. This three-component strategy involves a nitrone formation/[3 + 2] cycloaddition/thermal rearrangement cascade and furnishes trifluoromethylated benzoxazolines in high yields. The scope of the reaction is quite broad with respect to aryltrifluorodiazoethanes, nitrosoarenes, and arynes. The proposed reaction pathway is supported through the isolation and characterization of the key reaction intermediates phenyltrifluoromethylnitrone and benzisoxazoline.

Ag-Catalyzed Annulation of o-Alkynylaryl Aldehydes, Amines, and Diazo Compounds: Construction of Trifluoromethyl- and Cyano-Functionalized Benzo[d]azepines.

A Ag-catalyzed three-component annulation protocol, which uses o-alkynylaryl aldehydes, amines, and trifluorodiazoethane or diazoacetonitrile, to forge a new class of trifluoromethyl- and cyano-functionalized benzo[d]azepine is presented in this Letter. The key transformations involved in this reaction are the transient formation of the isoquinolinium intermediate and the subsequent ring-expansive addition of in situ-formed silver trifluorodiazoethylide to this intermediate. The practicality of this protocol is illustrated by realizing access to a wide range of densely functionalized benzo[d]azepines.

Direct Access to Trifluoromethylated Benzo[d]oxepines from o-Alkynylaryl Aldehydes and Trifluorodiazoethane.

Reported in this Letter is a silver-catalyzed reaction between o-alkynylaryl aldehydes and trifluorodiazoethane that enables an expedient synthesis of trifluoromethylated benzo[d]oxepines. The reaction works through a silver-promoted 6-endo-dig cyclization of o-alkynylbenzaldehydes for the generation of an isochromenylium intermediate, which upon a ring-expansive addition of trifluorodiazoethane delivers a novel class of trifluoromethylated benzoxepine frameworks. This strategy was applied to the synthesis of phosphonylated benzo[d]oxepines using the Seyferth-Gilbert reagent.

Incorporation of Trifluoromethyltriazoline in the Side Chain of 4-Aminoquinolines: Synthesis and Evaluation as Antiplasmodial Agents.

Reported herein is the identification of a novel class of 4-aminoquinoline-trifluormethyltriazoline compounds as possible antiplasmodial agents. The compounds were accessed through a silver-catalyzed three-component reaction of trifluorodiazoethane with in situ generated Schiff base from corresponding quinolinylamine and aldehydes. While attempting to incorporate a sulfonyl moiety, the triazoline formed underwent spontaneous oxidative aromatization to afford triazole derivatives. All synthesized compounds were tested for their antimalarial potential in vitro and in vivo. Out of 32 compounds, four showed the most promising antimalarial activity with IC50 values ranging from 4 to 20 nM against Pf3D7 (chloroquine-sensitive) and from 120 to 450 nM against PfK1 (chloroquine-resistant) strains. One of these compounds was also found to be effective in animal studies; it showed a 99.9 % decrease in parasitic load on day 7 post-infection along with a 40 % cure rate and longest host life span.

Additive-free synthesis of fused tricyclic cyanoisoxazolidines using in situ formed cyanonitrones.

Herein, we disclose the first report on the generation of cyanonitrone in situ from diazoacetonitrile and nitrosoarene, and its subsequent [3+2] cycloaddition with oxabicyclic alkenes to access fused tricyclic cyanoisoxazolidines. Further, this methodology could be extended to access fused tricyclic trifluoromethylated and phosphonylated isoxazolidines. Surprisingly, the reductive ring-opening of cyanoisoxazolidines was followed by a spontaneous lactonization to produce fused tricyclic amino lactones. Moreover, the N-O bond of the obtained tricyclic trifluoromethylated isoxazolidines could be cleaved to obtain 1,3-amino alcohols.

Substrate-controlled product divergence in the reaction of α-fluoro-ß-ketoamides with arynes.

An interesting substrate-controlled reactivity switch has been observed in the reaction of α-fluoro-ß-ketoamides with arynes. The reaction of secondary α-fluoro-ß-ketoamides with arynes provided access to α-aryl-α-fluoroacetamides through an arylation/deacylation sequence. Interestingly, the reaction of tertiary α-fluoro-ß-ketoamides resulted in the C-C σ-bond insertion reaction to afford 1,2-disubstituted arenes.

Recent advances in pyrazole synthesis employing diazo compounds and synthetic analogues.

Pyrazole is an essential structural component of many pharmaceuticals and agrochemicals. The synthesis of pyrazoles has been a subject of intense research for several decades. Many transformations are now available to conveniently access pyrazoles from readily available starting materials. Conventionally, the synthesis of pyrazoles involves the condensation reaction of hydrazines with 1,3-dicarbonyl compounds or their synthetic equivalents and 1,3-dipolar cycloaddition reactions of diazo compounds with dipolarophiles. The present review provides comprehensive information on the development of synthetic approaches to access pyrazoles via [3 + 2] cycloaddition reactions of diazo compounds and their synthetic equivalents.

Organocatalytic asymmetric nitroso aldol reaction of α-substituted malonamates.

A practical enantioselective N-selective nitroso aldol reaction of α-methylmalonamates with a nitrosoarene is reported. The reaction employs the Takemoto thiourea catalyst for the induction of enantioselectivity, and the corresponding optically active oxyaminated malonamates were obtained in reasonably good yields.

Development of small-molecule PCSK9 inhibitors for the treatment of hypercholesterolemia.

When secreted into the circulation, proprotein convertase subtilisin kexin type 9 (PCSK9) blocks the low-density lipoprotein receptors (LDL-R) and, as a consequence, low-density lipoprotein cholesterol (LDL-C) levels increase. Therefore, PCSK9 has emerged as a potential therapeutic target for lowering LDL-C levels and preventing atherosclerosis. The US Food and Drug Administration (FDA) has approved two monoclonal antibodies (mAbs) against PCSK9, but the expensive manufacturing process limits their use. Subsequently, there have been tremendous efforts to develop cost-effective small molecules specific to PCSK9 over the past few years. These small molecules are promising therapeutics that act by preventing the synthesis of PCSK9, its secretion from cells, or the PCSK9-LDRL interaction. In this review, we summarize recent developments in the discovery of small-molecule PCSK9 inhibitors, focusing on their design, therapeutic effects, specific targets, and mechanisms of action.

Silver-Catalyzed Direct Synthesis of Trifluoromethylated Enaminopyridines and Isoquinolinones Employing Trifluorodiazoethane.

This Letter reports a Ag-catalyzed three-component approach for the N-alkenylation of 2-aminopyridines employing aldehydes and trifluorodiazoethane. Unlike the known reactions of trifluorodiazoethane with imines, which generate Mannich adducts, aziridines, or triazolines depending on the substrates and conditions, this reaction, after Mannich addition, proceeds via a carbene formation and 1,2-aryl migration sequence to afford (E)-enaminopyridines. This surprising selectivity, which is effective for a wide range of aldehydes and 2-aminopyridines, has been subsequently explored to access trifluoromethylated isoquinolinones.

Base-Mediated Intramolecular Cyclization of α-Nitroethylallenic Esters as a Synthetic Route to 5-Hydroxy-3-pyrrolin-2-ones.

An unprecedented Cs2CO3-mediated intramolecular cyclization/rearrangement cascade that transforms α-nitroethylallenic esters to functionalized pyrrolin-2-ones has been uncovered. This reaction provides a new and practical approach for the synthesis of medicinally privileged 5-hydroxy-3-pyrrolin-2-ones under mild conditions. The broad potential of this new method was demonstrated by an efficient Au/Ag-catalyzed heteroarylation of 5-hydroxy-3-pyrrolin-2-ones employing electron-rich heteroarenes to furnish heteroaryl-lactam derivatives.

Utilization of Unsymmetric Diaryliodonium Salts in α-Arylation of α-Fluoroacetoacetamides.

The use of unsymmetric diaryliodonium salts as a versatile class of arylating agents has been demonstrated by developing a novel strategy to quickly access α-arylated α-fluoroacetoacetamides. The protocol provides a convenient metal-free method for the α-arylation of a diverse class of fluorinated acetoacetamides, and the products are obtained in good yields. The strategy, upon use of electron-deficient diaryliodonium salts as an arylating agent, provides α-fluoroacetamides through a spontaneous arylation/deacylation cascade.

The Bestmann-Ohira Reagent and Related Diazo Compounds for the Synthesis of Azaheterocycles.

Azaheterocycles are one of the most prevalent classes of compounds present in numerous bioactive compounds, natural products, and agrochemicals, and undoubtedly, new methods to access them are always in high demand. Among the methods available, the 1,3-dipolar cycloaddition reactions involving diazo compounds are particularly attractive because of their ability to rapidly construct densely functionalized azaheterocycles in a regioselective manner. In this context, the Bestmann-Ohira reagent has become a well-known reagent for the 1,3-dipolar cycloaddition reactions to produce phosphonylated heterocycles, besides its widespread use as a homologating agent for the conversion of aldehydes to alkynes. This account details our efforts toward broadening the synthetic utility of the Bestmann-Ohira reagent and related compounds for the preparation of azaheterocycles such as pyrazoles, spirooxindoles, triazoles, triazolines, and spiropyrazolines, emphasizing on domino multicomponent reactions employing readily available feedstock reagents.

Substrate-controlled, PBu3-catalyzed annulation of phenacylmalononitriles with allenoates enables tunable access to cyclopentenes.

Divergence in the PBu3-catalyzed [3+2] annulation of phenacylmalononitriles with allenoates, controlled by the γ-substitution on allenoates, offers a tunable synthesis of multifunctionalized cyclopentene carboxamides and cyclopentenols. An unprecedented formation of cyclopentene carboxamide was observed when allenic esters bearing a substitution at the γ-position were employed, while unsubstituted allenoates produced cyclopentenols. The former reaction likely involves a Michael/aldol/nucleophilic cyclization sequence in a domino manner.

Ag-Catalyzed Trifluoromethylative Ring Expansion of Isatins and Isatin Ketimines with Trifluorodiazoethane.

A general method for the construction of trifluoromethylated 2-quinolinones has been established herein by using a trifluoromethylative ring expansion of isatin with trifluorodiazoethane. The strategy provides a platform for the rapid synthesis of a wide range of substituted 3-hydroxy-4-trifluoromethyl-2-quinolinones. This operationally simple and robust Ag-catalyzed protocol successfully transforms isatin ketimines to 3-amino-4-trifluoromethylquinolinones in excellent yields. The utility of this novel method is further illustrated by the conversion of the products into various synthetically and medicinally relevant molecules.

Metal-free α-arylation of α-fluoro-α-nitroacetamides employing diaryliodonium salts.

Herein, we present a mild and efficient metal-free arylation of α-fluoro-α-nitroacetamides employing diaryliodonium salts. A broad range of diaryliodonium salts and α-fluoro-α-nitroacetamides containing sensitive functional groups was successfully employed in this protocol to yield the arylated products in good yields. The synthetic value of this novel protocol was further highlighted by extending the α-arylation to α-cyano-α-fluoroacetamides.

Silver-Catalyzed Three-Component Route to Trifluoromethylated 1,2,3-Triazolines Using Aldehydes, Amines, and Trifluorodiazoethane.

A novel silver-catalyzed domino three-component synthetic route to trifluoromethyl-substituted 1,2,3-triazolines has been realized by employing 2,2,2-trifluorodiazoethane as a 1,3-dipole for the cycloaddition reaction with the Schiff base formed from aldehydes and amines. This step and atom-economic protocol requires only a very low catalyst loading (3 mol %), displays a broad substrate scope with good functional group tolerance, and provides good to excellent yields with high diastereoselectivities.

Additive-Free Three-Component Synthesis of Spiro-isoxazolidine-oxindoles Employing Trifluorodiazoethane.

An efficient three-component protocol for the synthesis of trifluoromethylated spiro-isoxazolidine-oxindoles has been developed. This approach employs the 1,3-dipolar cycloaddition of trifluoromethyl nitrone, generated in situ from trifluorodiazoethane and nitrosoarene, with phenacylideneoxindoles. A range of phenacyclideneoxindoles and nitrosoarenes can be subjected to this reaction to generate the spiro-isoxazolidine-oxindole derivatives. The reductive ring-opening reaction of isoxazolidines carried out to demonstrate the synthetic potential of our strategy resulted in an interesting rearrangement to yield pyrroloquinoline derivatives.

Fluoride-Mediated α-Selective 1,6-Conjugate Addition of Allenic Esters to p-Quinone Methides.

An efficient and expedient fluoride-mediated α-selective 1,6-conjugate addition of allenic esters to para-quinone methides has been developed. The reaction exhibited an excellent substrate scope, and a wide range of α-diarylmethylated allenic esters were obtained in good to excellent yields. It was further shown that the strategy could be extended to isatin-derived quinone methides yielding allenic esters containing 3,3-disubstituted oxindoles. The tert-butyl ester of α-diarylmethylated allenoate was effectively converted into γ-butenolide through a Au/Ag catalyzed cyclization strategy.