Tunable Bifunctional Phosphine–Squaramide Promoted Morita–Baylis–Hillman Reaction of N‐Alkyl Isatins with Acrylates

Abstract

As erieso fh ighly tunable bifunctional phosphine-squaramide H-bond donor organocatalysts 6 has been synthesizedf rom inexpensivea nd commercially available b-amino alcohols in moderate yields.C atalyst 6f can efficiently promote the asymmetric Morita-Baylis-Hillman (MBH) reaction of N-alkyl isatins with acrylate estersp roviding the chiral 3-substituted 3-hydroxy-2-oxindoles in good yields and enantioselectivities( up to 93 % yield and9 5% ee), in which the challenging substrate tert-butyl acrylate 9d,p rovided the best ee value to date.M oreover, this methodology was applied successfully in the synthesis of chiral cyclic spiropyrrolizidineoxindolea nd g-butyrolactone derivatives without enantioselectivity deterioration. Thep ossible mechanism of this MBH reactionw as also investigated by 31 PNMR, ESI-MS and KIE studies.T he KIE experiments show that the electrophilic addition of N-methyl isatin to the complexo f acrylate ester and phophine-squaramide is the ratedeterming step of the asymmetric MBH reaction.

Recent advances in the asymmetric catalytic synthesis of chiral 3-hydroxy and 3-aminooxindoles and derivatives: Medicinally relevant compounds

“…The products were obtained in good to excellent yields and enantioselectivities [118]. The same type of reaction with catalyst C34 (Scheme 25 b) e 5 mol%) was studied by Dong et al, and gave similar results [119]. These two examples illustrate the efficiency of squaramide-phosphine organocatalysts, namely as regards the low catalyst loading compared to other organocatalysts.…”

Recent Advances in Catalytic Asymmetric Synthesis of Tertiary Alcohols via Nucleophilic Addition to Ketones

“…Later on, the groups of Shi, Lu, Wu, and Zhou independently reported asymmetric MBH reactions of isatin with acrylates (Scheme ). The methods of Shi and Lu also involved the use of 10 mol% β‐isocupreidine 120 as the catalyst, which allowed a variety of 3‐hydroxyoxindoles 122 to be achieved in good to excellent yields and high enantioselectivities.…”

Non-Covalent Interactions in Enantioselective Organocatalysis: Theoretical and Mechanistic Studies of Reactions Mediated by Dual H-Bond Donors, Bifunctional Squaramides, Thioureas and Related Catalysts

“…In addition, with the substrate coordinated to the thiourea, the nitroolefin C2 electrophilic carbon atom in TS-S is closer to the bulky diaminocyclohexane moiety than in TS-R. This forces the Hantszch ester, in releasing the hydride, to a hindered area with the ester group repulsively interacts with the 2,5-methyl pyrrole substituents, thus further favoring TS-R. Qiu, Zhao and coworkers described a Morita-Baylis-Hillman reaction of N-alkyl isatins 102 with acrylates 103 catalyzed by a bifunctional phosphine-squaramide (C43) in 2015 (Figure 53) [102]. The catalyst was part of a series synthesized from inexpensive and commercially available β-amino alcohols.…”

“…Although both pathways had been shown to be viable, some questions remained unknown, such as how rearomatization occurred in the nonpolar media commonly used in asymmetric synthesis, and the studies by the Jacobsen group aimed to clarify those issues. Based on a system previously shown by the group to have broad applicability, with 105 and 76, and to afford chiral tetrahydro-β-carboline products 106 with high ees thanks to the cooperative action between a bifunctional chiral thioureabased catalyst (C44) and weak achiral Brønsted acids, such as benzoic acids, new studies Qiu, Zhao and coworkers described a Morita-Baylis-Hillman reaction of N-alkyl isatins 102 with acrylates 103 catalyzed by a bifunctional phosphine-squaramide (C43) in 2015 (Figure 53) [102]. The catalyst was part of a series synthesized from inexpensive and commercially available β-amino alcohols.…”