Synthesis of 2‐Isoxazolines: Enantioselective and Racemic Methods Based on Conjugate Additions of Oximes

Abstract

The formation of 3-unsubstituted 2-isoxazolines by means of condensation reactions between α,β-unsaturated aldehydes and oximes proceeds readily in the presence of catalytic amounts of anilinium salts. Mechanistically, the process involves a fast conjugate addition of the oxime and a slower intramolecular oxime-transfer reaction. The rate of oxime transfer was found to correlate with the acidity of the catalyst. This finding enabled us to discover an enantioselective process in which the fragile conjugate-addition product generated in the first stage is rapidly cyclized into the stable isoxazoline under acidic conditions, with conservation of enantiomeric excess. In summary, herein we describe synthetically useful protocols for accessing 3-unsubstituted 2-isoxazolines in both the enantioselective and racemic manner. The mechanism of the condensation reaction catalyzed by the anilinium salt was also investigated by NMR spectroscopy experiments in which the effect of differently substituted aldehydes and oximes as well as water on the reaction rate was studied. The results point to the rate-limiting elimination of water from the 3-hydroxy-2-isoxazolidine intermediate.

Biocatalytic asymmetric ring-opening of dihydroisoxazoles: a cyanide-free route to complementary enantiomers of β-hydroxy nitriles from olefins

“…1b), which caused a sharp decrease in the product ee. Enlightened by these results, an useful method to prepare racemic β-hydroxy nitriles is described from alkenes via a 5-sub-4,5-dihydroisoxazole intermediate 46,47 upon treatment with a methanolic NaOH solution at room temperature (Scheme 3, and detailed data are shown in the ESI, section 5 ‡). The result is consistent with the previous reports that β-hydroxy nitriles were formed by treating dihydroisoxazoles with bases (such as trimethylamine, 48 1,8-diazabicyclo[5.4.0] undec-7-ene, 49 NaOMe, 50 ring-opening of 3-bromo-2-isoxazolines upon treatment with an alkanethiolate.…”

Tandem β-Elimination/Hetero-Michael Addition Rearrangement of an N-Alkylated Pyridinium Oxime to an O-Alkylated Pyridine Oxime Ether: An Experimental and Computational Study

“…Consequently, many acidic pyridinium oximes (p K a values around 7–9) are pharmacologically well-known esterolytic agents used as reactivators of the enzyme acetylcholinesterase initially inhibited by organophosphorus poisons, such as pesticides and nerve gases. , In recent years, there has been a growing interest in the utility of oximes as oxygen nucleophiles (Michael donors) in the selective synthesis of O-substituted pyridine oxime ethers, currently attractive synthetic target molecules used in the molecular design of drugs because of their considerable application potential in medicinal and bioorganic chemistry. − The conventional methods for the synthesis of O-substituted oxime ethers have been based on the base-catalyzed reactions of the respective pyridine oximes with alkyl and aryl halides or on multicomponent one-pot synthesis using carbonyl-, halogen-, and cyano-pyridine derivatives . Novel methods based on transition metal or organo catalyzed Michael additions of oximes to activated − or nonactivated , unsaturated Michael acceptors in nonaqueous solutions have been developed.…”

Synthesis of Diheteroatomic Five‐Membered Heterocyclic Compounds from α,β‐Unsaturated Aldehydes

“…In 2008, Pihko and Pohjakallio elaborated a new method for the synthesis of racemic 5‐substituted 2‐isoxazolines from α,β‐unsaturated aldehydes and readily available oximes in the presence of an anilinium salt catalyst . Later, they studied the same reaction with Jørgensen′s organic catalyst ( 6 ) to control the enantioselectivity and developed a general catalytic procedure for the asymmetric synthesis of 2‐isoxazolines ( 166 ; Scheme ) ,. Although their yields from enals 164 and acetone oxime ( 165 ) were not always high, the preparation of enantiomerically enriched compounds with original structure makes this method rather attractive.…”