Lucia De Crescentini

A new class of heterocyclic N,O-aminal and hemiaminal scaffolds was successfully obtained by means of a three-component reaction (3-CR) of 1,2-diaza-1,3-dienes (DDs), α-aminoacetals and iso(thio)cyanates. These stable imine surrogates are generated from key-substituted (thio)hydantoin intermediates through selective FeCl₃-catalyzed intramolecular N-annulation.

A practical and environmentally benign protocol for the assembly of poly substituted-thiazolo[3,2-a]indoles from 3-alkylated indoline-2-thiones and 2-halo-ketones has been developed. This metal-free approach consists in a complete chemo/regioselective formal [3 + 2] annulation that occurs in air, at 60 °C, and in water as the sole reaction medium. The opportunity to vary the substitution pattern up to six different positions, odorless manipulation of sulfurylated compounds, very easy product isolation, and mild reaction conditions are the main synthetic features of this method. The scaled-up experiment and the successive transformations of the products further demonstrate the utility of this chemistry.

An oxidative cyclization of electron‐rich α‐arylhydrazones promoted by phenyliodine bis(trifluoroacetate) (PIFA) has been accomplished. This metal‐free, chemoselective transformation allows to obtain synthetically and medicinally important N‐amino‐1H‐indoles, obviating the need for pre‐functionalization of substrates.

A novel protocol for the assembly of polysubstituted 2,3‐dioxo‐1,4,5,6‐tetrahydropyrazines and 2,3‐dioxo‐hydro‐1H‐cycloalkyl[b]pyrazines has been developed by the sequential three‐component reaction of primary aliphatic amines, 1,2‐diaza‐1,3‐dienes (DDs) and oxalyl chloride. This synthetic sequence proceeds by initial aza‐Michael addition of the amine to the azo‐ene compounds and subsequent ring closure involving the oxalyl chloride. The ready availability of the starting materials as well as the high level of practicability of the reaction and work‐up make this approach an attractive opportunity towards these uncommon systems.

The direct synthesis of pyrrolo[2,3- b ]indoles is developed using a Cu/Fe cocatalyzed intramolecular cycloamination of α-indolylhydrazones. This transformation proceeds cleanly and selectively at 50 °C in air, with water as the only reaction medium.

New and valuable indole based sulfurylated bi‐heterocyclic systems such as 4‐((1H‐indol‐2‐yl)thio)‐5‐oxo‐4,5‐dihydro‐1H‐pyrazoles and 3,3‐dimethyl‐3′H‐spiro‐indoline‐2,2′‐thiazoles are regioselectively obtained under very mild conditions employing 1,2‐diaza‐1,3‐dienes and not smelly indoline 2‐thiones as starting materials.

A metal-free strategy towards thieno [2,3-b] indoles from 1,2-diaza-1,3-dienes and indoline 2-thione is described. The mild reaction conditions required make this method amenable for a one-pot approach to thienodolin, a valuable natural alkaloid.

An unprecedented synthesis of polysubstituted indole-fused pyridazines (azacarbolines) from α-indolylhydrazones under oxidative conditions using a combination of iodylbenzene (PhIO₂) and trifluoroacetic acid (TFA) has been developed. This transformation is conducted without the need for transition metals, harsh conditions, or an inert atmosphere.

Here we report the synthesis of interesting 3-alkyl-4-hydroxy-1-aryl-4-(propa-1,2-dienyl)1H-pyrazol-5(4H)-ones and 9-alkyl-7-aryl-1-oxa-7,8-diazaspiro[4.4]nona-3,8-dien-6-ones, starting from 1,2-diaza-1,3-dienes (DDs) and propargyl alcohol. The reaction proceeds through a sequence Michael-type nucleophilic attack/cyclization/[2,3]-Wittig rearrangement. In the same way, the reaction between the aforementioned DDs and allyl alcohol furnished 4-allyl-4-hydroxy-3-alkyl-1-aryl-1H-pyrazol-5(4H)-ones. A DFT study was also carried out, in order to have decisive clarifications about the mechanism.