Stereoselective synthesis of gem-dihalopiperidines via the halo-aza-Prins cyclization reaction: access to piperidin-4-ones and pyridines.

An efficient methodology for the synthesis of 4,4-dihalopiperidine derivatives in excellent yields has been developed using N-(3-halobut-3-en-1-yl)-4-methylbenzenesulfonamide and an aldehyde catalyzed by In(OTf)3. The reaction involves an initial formation of a six-membered carbocation via the aza-Prins cyclization reaction followed by a nucleophilic attack by a halide ion to give 4,4-dihalopiperidine. The dihalopiperidine is converted to tetrahydropiperidinone using Ac2O/Et3N in DCM/H2O (1 : 1). It is also utilized for the synthesis of pyridine scaffolds by treatment with DBU. Furthermore, the dihalopiperidine is transformed to its enol ether derivatives using KOH in alcohol.

Base-Promoted [4 + 2] Annulation Reaction of In Situ-Generated Azadienes from N-Propargylamines with Active Methylene Compounds: Access to Highly Functionalized 2-Pyridones.

A facile and efficient synthesis of structurally diversified 2-pyridones is demonstrated using the [4 + 2] annulation of in situ generated azadienes from N-propargylamines and active methylene compounds. The reaction is promoted by an inorganic base giving moderate to good yields. The developed methodology is applicable for the direct and formal synthesis of various bioactive molecules. The synthetic utility of the protocol was also illustrated by late-stage functionalization of the products.

Diastereoselective Synthesis of 2,6-Disubstituted Tetrahydropyranones via Prins Cyclization of 3-Bromobut-3-en-1-ols and Aldehydes.

Tetrahydropyranones are synthesized from 3-bromobut-3-en-1-ols and aldehydes in good yields with excellent diastereoselectivity at -35 °C. The reaction involves an initial formation of a most stable six-membered chairlike tetrahydropyranyl carbocation followed by nucleophilic attack of the hydroxyl group and subsequent elimination of HBr to give tetrahydropyranone. The carbonyl moiety of the tetrahydropyranone is converted to enol ether and esters using Wittig reaction. It is also transformed into 4-hydroxy-2,6-disubstituted tetrahydropyran with 2,4- and 4,6-cis configuration by lithium aluminum hydride in up to 96% diastereoselectivity. Furthermore, the methodology is extended toward the synthesis of novel anticancer aminoguanidine compounds.

Synthesis of Spiro[furan-2,1'-isoindolin]-3'-ones from 2-(4-Hydroxybut-1-yn-1-yl)benzonitriles and Aryl Aldehydes under the Action of Triflic Acid.

The synthesis of spiro[furan-2,1'-isoindolin]-3'-ones from 2-(4-hydroxybut-1-yn-1-yl)benzonitriles and aryl aldehydes is demonstrated. It involves the initial formation of dihydrofuranylideneisoindolinone via intramolecular sequential Prins and Ritter reactions, followed by the ring opening of the furanyl moiety to generate N-acyliminium ions and alcohols for the final cyclization reaction, and the spiro-cyclic compounds are produced in moderate to good yields. It is a one-pot, three-component reaction in which one new quaternary carbon, two five-membered rings, one C-N bond, two C-O bonds, and one C-C bond are formed. The reaction is carried out with a Brønsted acid from 0 °C to room temperature within a short period of time.