DBU-Mediated Diastereoselective Aldol-Type Cyanomethylation of Isatins

Abstract

An efficient, metal-free approach to 3-substituted 3-hydroxyoxindole by DBU-mediated highly diastereoselective addition of aryl acetonitrile to N-protected isatin under mild conditions has been developed. The reaction proceeds smoothly to produce respective cyanomethylated adducts in good yield and excellent diastereoselectivity. Further transformation of the cyanide group allowed the synthesis of an advance intermediate of corresponding (±) CPC analogue. The mechanistic insight toward the aldol-type cyanomethylation of N-tritylisatin with benzyl cyanide was obtained by DFT calculations.

Nickel‐Catalyzed Cyanoalkylation of Ketone Derivatives

“…Singh and, later on, Zhang et al . both realized the addition of bulkier but more acidic phenyl acetonitriles to isatins using DBU as the base and water as solvent [4d,e] . Worthy of note, the more challenging catalytic addition of disubstituted alkyl cyanide (R 1,2 ≠H) is, so far, best performed thanks to the preformation of silyl ketene imine (SKI) derivatives (R 1,2,3 ≠H, case c) [1a,5] .…”

Krapcho Dealkoxycarbonylation Strategy of Ethyl Cyanoacetate for the Synthesis of 3-Hydroxy-3-cyanomethyl-2-oxindoles and 3,3′-Dicyanomethyl-2-oxindoles in a Reaction with Isatin

“…12 The most common methods employed for oxindolebased alkyl nitriles include base-catalyzed deprotonation of acetonitrile followed by nucleophilic addition to isatin. For example, palladium-catalyzed C-H activation of acetonitrile followed by addition to isatin via aldol type cyanoalkylation, 13 catalytic decarboxylative [1,2] addition of -functionalized acetic acids onto isatin, 14 DBU-mediated diastereoselective aldol-type cyanomethylation of isatins, 15 and recently appeared organocatalytic cyanoarylmethylation of isatin with phenyl acetonitrile 16 are some of the well-documented synthetic protocols for oxindole based alkyl nitriles (Scheme 1).…”

“…The reaction in other solvents like MeCN, DCE, THF, toluene, etc. failed to provide 3a (entries [13][14][15][16][17][18][19].…”

“On Water” Direct Organocatalytic Cyanoarylmethylation of Isatins for the Diastereoselective Synthesis of 3-Hydroxy-3-cyanomethyl Oxindoles

“…In contrast, the use of more challenging ketones as acceptors in cyanoalkylations is rare. To realize such transformations, metal catalysts, metalated alkylnitriles, or excess base were found to be necessary. There are, however, no reports on metal-free catalytic stereoselective addition of simple alkylnitriles to ketone.…”