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

Abstract

An efficient and practical 1,3‐dipolar [3+2] cycloaddition of N‐2,2,2‐trifluoroethylisatin ketimines and maleimides has been achieved through phase‐transfer catalytic process by using the cheap quaternary ammonium salt as a catalyst. The strategy grants rapid generation of various complex trifluoromethyl spiro‐fused[succinimide‐pyrrolidine‐oxindole]s in good yields and with excellent diastereoselectivities. The preparative‐scale reaction in conjunction with the optimized Suzuki–Miyaura cross‐coupling derivatizations of the product give prominence to application prospect of this methodology. The investigation on the reaction mechanism implies that the real catalyst in the cycloaddition might be tetrahexylammonium carbonate.

A Tunable Cascade Reaction of Ureidomalonates and Alkenyl Azlactones for the Divergent Synthesis of Hydantoins with Distinct Functional Groups

“…When 1.0 equiv of TBAB was added to the DBU-catalyzed reaction, the reaction pathway changed to produce 4aa (44% yield), whereas only trace 3aa was detected (entry 3). This result strongly suggested that the carbonate ion of tetrabutylammonium carbonate and in situ generated ethoxy anion (EtO – ) underwent almost irreversible ion exchange during the reaction process, hence suppressing the formation of 3aa . It should be noted that the reaction rate of organocatalysis was much faster than that of PTC (15 min vs 2 h).…”

“…Based on previous literature, ,, controlled experiments, and dynamic high-resolution mass spectrometry (HRMS) studies, a plausible mechanism for the tunable cascade reaction was tentatively proposed (Scheme ). First, both organocatalyzed and phase-transfer/sunlight relay catalyzed cascade reactions were found to undergo the same two pathways to access key intermediate M3 : (i) the base assaults α-hydrogen atom at the diesters moiety of ureidomalonate 1a , and the conjugated addition of the carbanion to alkenyl azlactone 2a delivers M1 .…”

Stereoselective synthesis of CF3-containing spirocyclic-oxindoles using N-2,2,2-trifluoroethylisatin ketimines: an update

“…A highly practical phase transfer catalytic approach for the diastereoselective assembly of CF 3 -containing spiro-fused[succinimide-pyrrolidine-oxindoles] was reported by Chen and co-workers ( Scheme 6 ). 55 With the help of 5 mol% of quaternary ammonium salt tetrahexylammonium bromide (THAB) as the phase transfer catalyst and 2 mol% of Cs 2 CO 3 as the base, the respective products 13 derived from the [3+2] cycloaddition of N -2,2,2-trifluoroethylisatin ketimines 1 and maleimides 12 were accomplished in 69–99% yields with excellent diastereoselectivity (up to >99 : 1 dr) within a short duration of time. Investigations on the reactivity of ketimines with maleimides revealed that both N -H free and N -protected ketimines encompassing electron-deficient and electron-rich substances on diverse positions participated in the reaction very smoothly.…”

Recent Advances of N-2,2,2-Trifluoroethylisatin Ketimines in Organic Synthesis

“…A highly efficient and practical diastereoselective [3 + 2] cycloaddition reaction of N -2,2,2-trifluoroethylisatin ketimines 1 with maleimides 88 was reported by the Chen group in 2021 ( Scheme 37 ) [ 55 ]. This reaction affords a series of complex trifluoromethyl spiro-fused[succinimide-pyrrolidine-oxindole] derivatives 89 with good diastereoselectivities (67:33–>99:1 dr) in moderate to excellent yields (69–96%) in the presence of a phase transfer catalyst.…”