Synthesis of Indoline‐Fused 2,5‐Diketopiperazine Scaffolds via Ugi‐4CR in the Basic Mediated Tandem Consecutive Cyclization

Abstract

This study has developed a method to prepare diastereo‐ and regio‐selective indoline‐fused 2,5‐diketopiperazine scaffolds. The synthetic process involved an Ugi four‐component reaction in which readily available starting materials were used and a metal‐free intramolecular post‐Ugi tandem consecutive 5‐exo‐trig/6‐exo‐dig cyclization under basic conditions. The plausible mechanism and substrate structures were elucidated by single‐crystal X‐ray diffraction analysis and supported by density functional theory calculations.

Camphorsulfonic Acid-Mediated One-Pot Tandem Consecutive via the Ugi Four-Component Reaction for the Synthesis of Functionalized Indole and 2-Quinolone Derivatives by Switching Solvents

“…Therefore, the CSA approaches the Ugi adduct through H-bonding, resulting in the conjugate base of CSA formed simultaneously, abstracting the sp 3 acidic proton, stabilizing as enol II . Subsequent nucleophilic attack on the carbonyl carbon formed a five-membered indoline ring III . , Finally, the desired product 6aaa was produced by the elimination of water and cyclohexyl isocyanate through a six-membered transition state. The water molecule was eliminated first when RCH 3 , resulting in the formation of an exocyclic double bond 6aga-int IV , which was further confirmed by single-crystal X-ray diffraction analysis (Figure ).…”

“…The Ugi adduct contains different active sites, such as (i) a carbonyl group, (ii) an alkyne moiety for nucleophilic or electrophilic addition, and (iii) an acidic C­(sp 3 )–H proton. Our previous work described the post-Ugi transformation for the synthesis of 2-quinolone and 2,5-diketopiperazine . In continuation of the study of Ugi adduct, we have interestingly used the Bronsted acids, resulting in five-and six-membered heterocycles by switching aprotic to protic solvents, respectively.…”

“…Our previous work described the post-Ugi transformation for the synthesis of 2-quinolone 20a and 2,5diketopiperazine. 21 In continuation of the study of Ugi adduct, we have interestingly used the Bronsted acids, resulting in fiveand six-membered heterocycles by switching aprotic to protic solvents, respectively. These interesting results encouraged us to investigate further and report herein the synthesis of functionalized indole and 2-quinolone scaffolds using the Ugi-4CR adduct (Scheme 1).…”

A C–H Activation Approach to the Tricyclic Core of Glionitrin A and B

“…The resulting crude residue was purified by column chromatography (50% EtOAc/ n-heptane) to give N-methyl diketopiperazine 35. Yield: 852 (21). 47 A solution of diketopiperazine 35 (362 mg, 747 μmol) in pyridine (4 mL) was added dropwise to stirred hydrofluoric acid (2 mL, 48% w/w) over 12 min.…”

“…Indoline-fused DKPs have been synthesized through several approaches. − Variations drawing on metal-catalyzed bond activation for forming the indoline five-membered ring are particularly attractive as these allow for simple starting materials. − An elegant example is the palladium-catalyzed sp 3 -C–H activation approach by Baudoin and co-workers to form indoline 8 from DKP 7 (Figure B), which has since been applied to total syntheses of several DTDKP natural products. , More recently, Xuan and co-workers described a palladium-catalyzed sp 2 -C–H activation to produce 10 , wherein the amide serving as a directing group for the C–H activation step is also incorporated in the formed ring …”