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.

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.

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.