Noncovalent Catalysis for Enantioselective Direct Aldol Reaction of 3‐Acetylcoumarins to Pyrazole‐4,5‐diones

Abstract

The first catalytic enantioselective direct aldol reaction of 3-acetylcoumarins to pyrazole-4,5-diones is reported and shown to proceed through noncovalent substrate activation by a quinine-derived bifunctional tertiary amino-amide as the catalyst. The densely functionalized products, consisting of an oxygen-containing quaternary stereocenter and bearing two biologically relevant heterocycles, are generally obtained in high yields with moderate to excellent enantioselectivities.

Recent advances in the applications of pyrazolone derivatives in enantioselective synthesis

“…Recently, the Mukherjee group developed a series of enantioselective nucleophilic additions of nucleophiles to pyrazole-4,5-diones. 64 Using the easily accessible quinine-derived catalyst C30 , the enantioselective nucleophilic additions of allyl ketones 158 or 3-acetylcoumarins 160 to pyrazole-4,5-diones 4a proceeded smoothly (Scheme 35). The corresponding oxygen-containing pyrazolone derivatives 159 and 161 were obtained in moderate to high yields with moderate to excellent enantioselectivities.…”

Recent Advances in Catalytic Enantioselective Synthesis of Pyrazolones with a Tetrasubstituted Stereogenic Center at the 4-Position

“…In 2019, Mukherjee and co-workers reported the enantioselective aldol reaction of 3-acetylcoumarins to pyrazole-4,5-diones with the same quinine-derived bifunctional catalyst used in their previous report, affording 4-hydroxypyrazolones in high yields and medium to excellent enantioselectivities (Scheme 18). 48 It is important to note that the reaction goes through the enol/enolate of the ketone, which is formed by the tertiary amine moiety of the bifunctional catalyst. In this reaction, the ketone is activated by acid-base interaction of the Brønsted base and not by an enamine mechanism.…”

Copper-catalyzed asymmetric alkynylation of pyrazole-4,5-diones using chloramphenicol base-derived hydroxyl oxazoline ligands

“…Therefore, the preparation and functionalization of pyrazolone compounds have attracted enormous attention from the chemical community. 6 In particular, the use of pyrazole-4,5-diones as a C-4 electrophile in asymmetric transformations, including the Friedel–Crafts reaction, 7 vinylogous aldol reaction, 8 [3 + 2] annulation reaction 9 and diorganozinc addition, 10 has recently been studied because of the easy access to pyrazolone derivatives bearing a quaternary stereocenter. In 2019, Wu's group 11 reported the first copper-catalyzed asymmetric alkynylation of pyrazole-4,5-diones with terminal alkynes in the presence of the cyclohexane-based amidophosphine ligand, and chiral propargylic alcohols bearing a pyrazolone motif could be obtained in excellent yields and enantioselectivities.…”