Organocatalytic Enantioselective Hydroxymethylation of Oxindoles with Paraformaldehyde as C1 Unit

Abstract

A bifunctional thiourea-tertiary amine-catalyzed asymmetric hydroxymethylation of 3-substituted oxindoles using paraformaldehyde as the C1 unit was developed. A wide scope of oxindoles, bearing C3 sterically congested quaternary carbon centers, were smoothly obtained in good to excellent yields (up to 99%) and high enantioselectivities (up to 91% ee) under mild reaction conditions. A more significant feature of this approach employs cheap and readily available paraformaldehyde as a hydroxymethylation C1 unit, which is activated by chiral bifunctional thiourea organocatalysts. Chiral 3,3-disubstituted 2-oxindole substructures are present in many biologically active natural products and pharmaceutical compounds.1,2 Recently, some progress has been described in the development of efficient methods to construct functionalized chiral 3,3-disubstituted 2-oxindole scaffolds. 3,4 In this regard, various electrophiles have been investigated for the asymmetric reactions with prochiral 3-substituted oxindoles as donors. However, to the best of our knowledge, only a single example, reported by Feng and co-workers, describes a direct asymmetric aldol-type reaction of 3-substituted oxindoles with aldehyde (phenylglyoxal derivatives) using N,N 0 -dioxide-Sc(OTf) 3 complex as catalyst. 3k Thus, it is evident that there remains further need for synthetic approaches of oxindoles with aldehydes to access diversely structured 3,3-disubstituted 2-oxindoles.Enantioselective hydroxymethylation of carbonyl compounds at their R-position with formaldehyde as the C1 unit is one useful method for constructing chiral building blocks in organic synthesis, and some progress has been obtained (6) For direct aldol reactions involving formaldehyde with organocatalysts, see: (a) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H.

Asymmetric Aldol Reaction with Formaldehyde: a Challenging Process

“…A distinct example of the hydroxymethylation of oxindoles has been recently developed using commercially available paraformaldehyde and a bifunctional amino thiourea catalyst 28 , easily prepared from ( R , R )−1,2‐diphenylethane‐1,2‐diamine (Scheme ) 48…”

Germylene Cyanide Complex: A Reagent for the Activation of Aldehydes with Catalytic Significance

“…Yield: 0.68 g (2.06 mmol), 99 %; m.p. 120 8C; elemental analysis calcd (%) for C 16 Paraformaldehyde (0.022 g) was added to a solution of 2 (0.20 g, 0.61 mmol) in THF (5 mL) and stirred at room temperature for 6 h. All the volatiles were then removed under reduced pressure, the product was extracted into toluene (7 mL), and filtered through a G4 frit. Removal of toluene from the filtrate in vacuo afforded an analytically pure sample of compound 3 as a red solid.…”

“…This is comprehendible, as the insoluble paraformaldehyde releases the monomeric formaldehyde slowly into the solution. [16] Compounds 3-6 are stable in an inert atmosphere of dinitrogen gas and their solubilities are comparable to that of 2. They were characterized by multinuclear NMR and IR spectroscopy and single-crystal X-ray diffraction studies.…”

Recent Advances in Organocatalytic Methods for Asymmetric CC Bond Formation

“…One example for the construction of quaternary centers using substituted oxindoles 10 as aldol donors was developed by Yuan et al. Asymmetric hydroxymethylation with paraformaldehyde 11 under mild conditions achieved the corresponding products in high yields and with high ee values (Scheme ) 13…”

“…[12] One example for the construction of quaternary centers using substituted oxindoles 10 as aldol donors was developed by Yuan et al Asymmetric hydroxymethylation with paraformaldehyde 11 under mild conditions achieved the corresponding products in high yields and with high ee values (Scheme 6). [13] The more common strategy for the construction of quaternary carbon centers via aldol additions is the deployment of ketones as aldol acceptors. Thus tertiary alcohols are the re-action products.…”