Merging Regiodivergent Catalysis with Atom-Economical Radical Arylation.
ABSTRACT: A titanocene-catalyzed regiodivergent radical arylation is described that allows access to either enantiomerically pure tetrahydroquinolines or indolines from a common starting material. The regioselectivity of epoxide opening that results in the high selectivity of heterocycle formation is controlled by two factors, the absolute configuration of the enantiopure ligands of the (C5 H4 R)2 TiX2 catalyst and the inorganic ligand X (X=Cl, OTs). The overall reaction is atom-economical and constitutes a radical Friedel-Crafts alkylation.
Project description:Reductive cyclization of epoxides tethered to substituted anilines and aminopyridines in the presence of 3 mol % of titanocene dichloride and stoichiometric manganese metal promotes a radical annulation to form 3,3-disubstituted indolines and azaindolines.
Project description:Herein, we report a highly selective C-H olefination of directing-group-free indolines (C5) and tetrahydroquinolines (C6) by Pd/S,O-ligand catalysis. In the presence of the S,O-ligand, a wide range of challenging indolines, tetrahydroquinolines, and olefins was efficiently olefinated under mild reaction conditions. The synthetic potential of this methodology was demonstrated by the efficient olefination of several indoline-based natural products.
Project description:Two regiodivergent approaches to intermolecular cyclization of 2-aminobenzothiazoles with ?-ketoesters and amides have been developed, controlled by the reagents employed. With the Brønsted base KOt-Bu and CBrCl3 as radical initiator, benzo[d]imidazo[2,1-b]thiazoles are synthesized via attack at the ?-carbon and keto carbon of the ?-ketoester moiety. In contrast, switching to the Lewis acid catalyst, In(OTf)3, results in the regioselective nucleophilic attack at both carbonyl groups forming benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ones instead.
Project description:Epoxides are versatile intermediates in organic synthesis, but have rarely been employed in cross-coupling reactions. We report that bipyridine-ligated nickel can mediate the addition of functionalized aryl halides, a vinyl halide, and a vinyl triflate to epoxides under reducing conditions. For terminal epoxides, the regioselectivity of the reaction depends upon the cocatalyst employed. Iodide cocatalysis results in opening at the less hindered position via an iodohydrin intermediate. Titanocene cocatalysis results in opening at the more hindered position, presumably via Ti(III)-mediated radical generation. 1,2-Disubstituted epoxides are opened under both conditions to form predominantly the trans product.
Project description:New N-propargyl tetrahydroquinolines 6a-g have been synthesized efficiently through the cationic Povarov reaction (a domino Mannich/Friedel-Crafts reaction), catalyzed by Indium (III) chloride (InCl3), from the corresponding N-propargylanilines preformed, formaldehyde and N-vinylformamide, with good to moderate yields. All tetrahydroquinoline derivatives obtained were evaluated in vitro as free radical scavengers. Results showed that compound 6c presents a potent antioxidant effect compared with ascorbic acid, used as a reference compound. ADME predictions also revealed favorable pharmacokinetic parameters for the synthesized compounds, which warrant their suitability as potentials antioxidant. Additionally, a theoretical study using Molecular Quantum Similarity and reactivity indices were developed to discriminate different reactive sites in the new molecules in which the oxidative process occurs.
Project description:The regiodivergent addition of substituted phenols to allylic oxides has been demonstrated using C2-symmetric palladium complexes. Complex phenol donors tyrosine, estradiol, and griseofulvin follow the predictive model.
Project description:The single-operation deracemization of 3H indolines and tetrahydroquinolines is described. An asymmetric redox approach was employed, in which a phosphoric acid catalyst, oxidant, and reductant are present in the reaction mixture. The simultaneous presence of both oxidant and reductant was enabled by phase separation and resulted in the isolation of highly enantioenriched starting materials in high yields.
Project description:A method for the regiodivergent arylboration of dienes is presented. These reactions allow for the formation of a diverse range of synthetically versatile products from simple precursors. Through mechanistic studies, these reactions likely operate by initial addition of a Cu-Bpin complex across the diene followed by Pd-catalyzed cross coupling with an aryl halide or pseudohalide.
Project description:Reactions of tethered, tertiary sulfonamides with thermally generated benzynes are reported. Typically, the N-S bonds in the substrates cleave, and saturated heterocycles [tetrahydroquinolines ( n = 2) and indolines ( n = 1)] are formed. The process is accompanied by either sulfonyl transfer or desulfonylation from a zwitterionic intermediate, with the favored pathway being largely dependent upon the size (5- vs 6-membered) of the N-containing ring in the zwitterion.