Regio‐ and Stereoselective Synthesis of 3‐Pyrazolylidene‐2‐oxindole Compounds by Nucleophilic Vinylic Substitution of (E)‐3‐(Nitromethylene)indolin‐2‐one

Abstract

Vila, C.; Slack, S.; Blay, G.; Muñoz Roca, MDC.; Pedro, JR. (16-0). Regio-and Stereoselective Synthesis of 3-Pyrazolylidene-2-oxindole Compounds by Nucleophilic Vinylic Substitution of (E)-3-(Nitromethylene)indolin-2-one. Advanced Synthesis & Catalysis. 361(8):Abstract. A highly regio-and stereoselective synthesis of 3-alkylidene-2-oxindoles has been described through a nucleophilic vinylic substitution (SNV) of (E)-3-(nitromethylene)indolin-2-one using pyrazol-3-ones as nucleophiles and Et3N as a base. The reaction affords selectively the Z-isomer when pyrazol-3-ones without substituents at the 4 position are used. While the reaction is E-selective with 4-substituted pyrazolones. The stereoselectivity (up to >20:1) and the yields (up to 98%) are very high under mild reaction conditions.

Regio‐, Diastereo‐, and Enantioselective Organocatalytic Addition of 4‐Substituted Pyrazolones to Isatin‐Derived Nitroalkenes

“…By the action of one quinuclidine moieties of (DHQ) 2 Pyr, the pyrazol‐3‐one 2 is activated by hydrogen bonding, for the regioselective nucleophilic addition of the pyrazol‐3‐one to the α‐position of nitroalkene 1 , that could be coordinated to the catalyst by π–π stacking interactions. After the nucleophilic addition of 2 , the intermediate switches to an eclipsed conformation, which is favored by an intramolecular hydrogen bond between the nitro group and the hydrogen of the C‐3 of oxindole through a five‐membered ring , . In this case, in the presence of a base [the quinuclidine moiety of the (DHQ) 2 Pyr catalyst], the hydrogen bond prompts a fast 1,2‐ cis ‐elimination to afford the E ‐3‐alkenyl‐2‐oxindole 3fa as the major product.…”

“…After the nucleophilic addition of 2, the intermediate switches to an eclipsed conformation, which is favored by an intramolecular hydrogen bond between the nitro group and the hydrogen of the C-3 of oxindole through a five-membered ring. [13,14] In this case, in the presence of a base [the quinuclidine moiety of the (DHQ) 2 Pyr catalyst], the hydrogen bond prompts a fast 1,2-cis-elimination to afford the E-3-alkenyl-2oxindole 3fa as the major product.…”

“…Such transformation presents three challenges: the regioselectivity of the nucleophilic addition (attack at the β‐position of the nitroalkene or at the α‐position), the stereoselectivity of the 1,2‐elimination and the enantioselectivity of the reaction. We have recently described a stereoselective addition of pyrazolones to isatin‐derived nitroolefins in a racemic form . As a part of our ongoing interest in the asymmetric addition of pyrazolones, herein, we wish to report the addition of 4‐substituted pyrazolones to isatin‐derived nitroalkenes using a (DHQ) 2 Pyr as an organocatalyst through a nucleophilic vinylic substitution (S N V), leading to chiral heterocyclic compounds containing both 3‐alkylidene‐2‐oxindole and pyrazolone moieties bearing a fully carbon tetrasubstituted stereocenter with good yields, excellent regio‐ and diastereoselectivity and moderate enantioselectivity (Scheme ).…”

Inversion kinetics of some E/Z 3-(benzylidene)-2-oxo-indoline derivatives and their in silico CDK2 docking studies

“…Recent studies have been made for its effective synthesis, and also for the stereoselective synthesis of (E) and (Z) diastereomers. [27][28][29][30][31] Accordingly, the kinetics of the E/Z isomerization of the designed molecules seemed to be of interest.…”

Enantioselective Nucleophilic Vinylic Substitution (SNV) toward 3-Alkenyl-bisoxindoles Facilitated by C6′ Steric Bulk of Cinchona Alkaloid

“…Therefore, we envisioned that the cross coupling between the C­( sp 3 ) of 3-substituted oxindoles 2 and the C­( sp 2 ) of nitro olefins 1 could forge the desired bisoxindole derivatives 3 bearing a vinyl-substituted all-carbon quaternary stereocenter, triggered by the elimination of HNO 2 . However, the regioselectivity of this transformation might be difficult to control, as the reactivity at the α - and β -positions of electrophile 1 is the balance of electron property and steric hindrance . Previous studies have demonstrated that both of these positions are reactive toward nucleophilic partners .…”