DABCO-Catalyzed Michael/Alkylation Cascade Reactions Involving α-Substituted Ammonium Ylides for the Construction of Spirocyclopropyl Oxindoles: Access to the Powerful Chemical Leads against HIV-1

Abstract

A novel Michael/alkylation cascade reaction of Nunprotected 3-bromooxindoles with α,β-unsaturated acyl phosphonates using DABCO as a robust catalyst followed by the derivatization of the acyl phosphonate intermediates in situ has been developed. This scenario enables rapid access to a diverse set of highly functionalized spirocyclopropyl oxindoles in moderate yields with good to excellent diastereoselectivities, which are analogues of a high active non-nucleoside reverse transcriptase inhibitor against HIV-1. The synthetic potential of this tactic has been highlighted by a gram-scale reaction and Suzuki crosscoupling reactions of the product. Moreover, the reaction mechanism has been tentatively elucidated by control experiments and dynamic high-resolution mass spectrometry studies, which indicates that the Michael/alkylation cascade reaction involves DABCO-derived α-substituted ammonium ylides.

Phase‐Transfer Catalytic Strategy: Rapid Synthesis of Spiro‐Fused Heterocycles, Integrated with Four Pharmacophores‐Succinimide, Pyrrolidine, Oxindole, and Trifluoromethyl Group

“…Here, we exhibited the derivatization of 3 l via Pd(II)‐catalyzed Suzuki–Miyaura cross‐coupling reaction with aryl boronic acids 5a ‐ d (Scheme 4). At the outset of probe on the coupling reaction, the substrates 3 l and 5 a appeared to be very sluggish under our former conditions, [31c] and only trace amount of 6 a was observed for 24 h. In order to improve the reaction efficiency as well as execute the phase‐transfer catalytic strategy to the end, we tentatively added the catalytic amount of THAB into the coupling reaction. Surprisingly, this method dramatically accelerated the reaction rate and the target 6 a was gained in 41 % yield within 2 hours.…”

Syntheses and Applications of Spirocyclopropyl Oxindoles: A Decade Review

“…Recently, Chen et al, disclosed Michael/alkylation cascade reaction between α,β‐unsaturated acyl phosphonates 102 and unprotected 3‐bromooxindoles 103 . [ 51 ] Formation of DABCO‐derived ammonium ylide 104 was realised during Michael addition/alkylation cyclization process to provide phosphonate intermediate 105 . Quenching of 105 with nucleophiles (MeOH, EtOH, i PrOH, BnOH) and DBU resulted in the formation of 106 (Scheme 32).…”

Ultrasound-Engineered fabrication of immobilized molybdenum complex on Cross-Linked poly (Ionic Liquid) as a new acidic catalyst for the regioselective synthesis of pharmaceutical polysubstituted spiro compounds

“…2-Oxindoles, especially those spiro-fused to other cyclic frameworks, are structural motifs in organic chemistry due to their widespread bioavailability and pharmacological applications such as HIV protease inhibitor [6] , anti-inflammatory [7] , anti-cancer [8] , antimicrobial [9] , anti-hypertensive [10] , and anti-diabetic [11] . Among various drugs with a 2-oxindole core that have already been developed, only four marketed molecules; namely, Sunitinib proposed in pancreatic neuroendocrine tumors, Ropinirol utilized for Parkinson’s disease treatment, Nintedanib known as a drug against idiopathic pulmonary fibrosis, and HIV protease inhibitor have appeared in Fig.…”