Organocatalyzed Enantioselective Decarboxylative Mannich Reaction of β‐Ketoacids with Pyrazolinone Ketimines for the Construction of Chiral β‐Amino Ketone‐Pyrazolinone Derivatives

Abstract

An organocatalytic enantioselective decarboxylative Mannich reaction of pyrazolin‐5‐one derived ketimines with β‐ketoacids using quinine‐derived bifunctional squaramide as a catalyst has been developed. With the developed protocol, a series of chiral β‐amino ketone‐pyrazolinone derivatives were obtained in excellent yields (up to 99 %) with good enantioselectivities (up to 94:6 er). The enantioselective decarboxylative aldol reaction of pyrazole‐4,5‐dione with β‐ketoacids was also realized under the standard reaction conditions.

Pd‐Catalyzed Asymmetric Addition of Arylboronic Acids to Pyrazolinone Ketimines

“…For example, Enders group pioneered squaramide‐catalyzed enantioselective Strecker reaction of pyzazolin‐5‐one derived ketimines with trimethylsilyl cyanide toward chiral pyrazolone α‐aminonitriles [8] . Subsequently, a few organocatalytic or metal‐catalyzed versions of pyzazolin‐5‐one‐derived ketimines with various nucleophiles, such as naphthols, [9] 2,4‐dihydro‐3H‐pyrazol‐3‐one, [10] 1H‐indol‐4‐ols, [11] β‐ketoacids, [12] silyl enol ethers [13] and benzyl but‐3‐ynoates, [14] were reported. Despite these significant advances, asymmetric addition of arylboronic acids as aryl pronucleophiles to pyrazolinone ketimines remains unexplored so far, probably because of the lack of effective asymmetric catalytic system.…”

Recent advances in the applications of pyrazolone derivatives in enantioselective synthesis

“…In 2019, Yuan and co-workers also realized several examples utilizing ketoacids 164 as nucleophiles, affording chiral pyrazolones 165 in moderate yields and with moderate enantioselectivities (Scheme 35). 66…”

Recent Advances in Squaramide‐Catalyzed Asymmetric Mannich Reactions

“…We have introduced the decarboxylative Mannich reaction to isatin‐derived ketimines 6 in previous section (Scheme 3), here we will introduce another decarboxylative Mannich reaction of β‐keto acids 5 to pyrazolone‐derived imines 69 reported by Yuan group [59] in 2019 (Scheme 33). This enantioselective reaction wascatalyzed by squaramide catalyst C3 , and the products 74 containing β‐amino ketone and pyrazolone scaffolds were obtained in excellent yields (95–99%) with moderate to high enantioselectivities (60:40–94:6 er).…”