Asymmetric Organocatalytic Friedel-Crafts Hydroxyalkylation of Indoles Using Electrophilic Pyrazole-4,5-diones
The electrophilic reactivity of a series of novel pyrazole-4,5-dione derivatives in the organocatalytic Friedel-Crafts reaction with various substituted indoles has been tested. The disclosed procedure catalyzed by a cinchona alkaloid derivative allows the conjugation of two very important aza-heterocyclic scaffolds to generate a new class of indolylpyrazolones bearing a tetrasubstituted stereocenter in excellent yields (up to 99%) and with enantioselectivities of up to 94:6 er.
Asymmetric Synthesis of Amino-Bis-Pyrazolone Derivatives via an Organocatalytic Mannich Reaction
A new series of N-Boc ketimines derived from pyrazolin-5-ones have been used as electrophiles in asymmetric Mannich reactions with pyrazolones. The amino-bis-pyrazolone products are obtained in excellent yields and stereoselectivities by employing a very low loading of 1 mol % of a bifunctional squaramide organocatalyst. Depending on the substitution at position 4 of the pyrazolones, the new protocol allows for the generation of one or two tetrasubstituted stereocenters, including a one-pot version combing the Mannich reaction with a base-mediated halogenation.
Squaramide-Catalyzed Asymmetric aza-Friedel–Crafts/N,O-Acetalization Domino Reactions Between 2-Naphthols and Pyrazolinone Ketimines
N-Boc ketimines derived from pyrazolin-5-ones were explored to develop an unprecedented domino aza-Friedel–Crafts/N,O-acetalization reaction with 2-naphthols. The novel method requires a catalyst loading of only 0.5 mol % of a bifunctional squaramide catalyst, is scalable to gram amounts, and provides a new series of furanonaphthopyrazolidinone derivatives bearing two vicinal tetra-substituted stereogenic centers in excellent yields (95–98 %) and stereoselectivity (>99:1 d.r. and 97–98 % ee). A different reactivity was observed in the case of 1-naphthols and other electron-rich phenols, which led to the aza-Friedel–Crafts adducts in 70–98 % yield and 47–98 % ee.
Catalytic Asymmetric Addition of Diorganozinc Reagents to Pyrazole-4,5-Diones and Indoline-2,3-Diones
The catalytic enantioselective diorganozinc additions to cyclic diketones including pyrazolin-4,5-diones and isatins have been developed. In the presence of morpholine-containing chiral amino alcohol ligand, the corresponding chiral cyclic tertiary alcohols were produced in good to excellent yields (up to 97 %) and enantioselectivities (up to 95 % ee). The notable feature of this protocol includes its mild reaction conditions, Lewis acid additives free and broad functional group tolerance.
Organocatalytic Direct Asymmetric Indolization from Anilines by Enantioselective [3 + 2] Annulation
We report the efficient syntheses of chiral tetrahydroindole pyrazolinones by the asymmetric [3 + 2] cascade cyclizations (indolizations) of simple aniline derivatives with pyrazolinone ketimines as 2C synthons. The chiral phosphoric-acid-catalyzed system uses a concerted π-πinteraction/dual H-bond control strategy to catalytically direct the asymmetric aniline, which undergoes a highly chemo-, regio-, and enantioselective [3 + 2] cascade annulation, furnishing a series of optically active tetra-hydroindole pyrazolinones with two contiguous chiral aza-quaternary carbon centers in excellent yields with excellent enantioselectivities. This method features a relatively broad substrate scope for amines and 2-naphthylamines and highlights the emerging value of direct chiral indolizations from simple amine sources in organic synthesis.