l-Proline-Catalysed One-Pot aza-Diels–Alder Reaction in Water: Regioselective Synthesis of Spiro(isoxazolo[5,4-b]pyridine-5,5′-pyrimidine) Derivatives

Abstract

A simple and efficient l-proline-catalysed synthesis of spiro(isoxazolo[5,4-b]pyridine-5,5′-pyrimidine) derivatives in water has been accomplished through a pseudo five-component one-pot domino aza-Diels–Alder reaction involving 3-amino crotanonitrile, hydroxylamine hydrochloride, aromatic aldehydes and barbituric acids. The main advantages of the present method are mild reaction conditions, modest purification process involving no chromatographic techniques and high yields. The protocol is a good alternative to prepare spiro derivatives with readily available starting materials, which makes the method highly attractive.

Diels–Alder Cycloaddition Reactions in Sustainable Media

“…The observed diastereoselectivity was rationalized as resulting from the exo-Eanti transition state 229 in the cyclization step, in which both the C=N bond of the diene and the C=C of the dienophile present E-configuration (Scheme 53b). More recently, a different methodology for preparing spiro(isoxazolo [5,4-b]pyridine-5,5 -pyrimidine) derivatives 232 based on an L-proline-promoted one-pot aza-Diels-Alder reaction in water has been disclosed (Scheme 54) [143]. This method has the advantage of generating in situ the 5-amino-3-methylisoxazole (160a) from readily available 3-aminocrotononitrile (230) and hydroxylamine hydrochloride (231).…”

A review of the synthetic strategies toward spirobarbiturate-fused 3- to 7-membered rings

“…It should be noted that the Knoevenagel adducts were used to control the mechanism under optimized conditions, and the same results were obtained (Scheme 50). 95 2.3.1.2. Huisgen's 1,4-dipole strategy for [4 + 2] cycloaddition.…”

Proline and its Derivatives as Organocatalysts for Multi‐ Component Reactions in Aqueous Media: Synergic Pathways to the Green Synthesis of Heterocycles

“…Related spiro systems derived from the spiro(isoxazolo[5,4‐ b ]pyridine‐5,5′‐pyrimidine) ring system (compounds 99 ) were obtained by Dommaraju and co‐workers via a pseudo five‐component reaction starting from 3‐aminocrotonitrile 59 , hydroxylamine hydrochloride 98 , aromatic aldehydes 16 and barbituric acids 95 that was performed in refluxing water, with proline as catalyst (Scheme ). In this case, the authors did not specify the relative configuration of the C‐2 and C‐4 stereocenters, although they can be assumed to be cis according to the precedent mentioned above …”