Carboxy‐ and Cyano‐Hydroxylation of Alkenes. Synthesis of 3‐Hydroxy‐4‐amino Acids and Butyrolactones via the Isoxazoline Route

Abstract

Dichloro‐ and dibromoformaldoximes are useful 1,3‐dipolar cycloaddition reagents. They are conveniently preparated in situ, in high yields by dihalogenation of glyoxalic acid aldoxime with N‐bromo‐ and N‐chlorosuccinimide or tert‐butyl hypochlorite. Dehydrohalogenation with potassium hydrogen carbonate in the presence of alkenes gives 3‐halo‐isoxazolines in a one‐pot reaction. Reduction with iron pentacarbonyl gives β‐hydroxynitriles. Methoxylation and catalytic reduction give β‐hydroxy esters. Allyl alcohols and allylamines are transformed with halonitrile oxides into butyrolactones (DL‐angelica lactone) and DL‐3‐hydroxy‐4‐amino acids (carnitine, 4‐amino‐3‐hydroxybutyric acid), respectively. The lactonization is best effected by heating the γ‐silyloxy ester in acetic acid with potassium hydrogen sulfate as catalyst. A synthesis of N‐Boc‐dihydromuscimol is described.

Synthesis and Reactivity of 3‐Halo‐4,5‐dihydroisoxazoles: An Overview

“…This strategy has also been widely explored to afford recently patented 3‐aryloxy‐Δ 2 ‐isoxazolines based fatty acid amide hydrolase (FAAH) inhibitors using aryl alcohols [103] . Similar reactivity was also observed for 3‐chloro isoxazolines in presence of hydroxy or alkoxy ions [37] …”

“…Instead, the great majority of the cases in the literature reported the use of the convenient [3+2] 1,3‐dipolar cycloaddition reaction between a properly decorated alkene, i. e., the dipolarophile, and chloronitrile oxide, i. e., the 1,3‐dipole (Scheme 2e). This unstable intermediate is predominantly generated in situ under the Huisgen [37–42] conditions, which involve the treatment of its stable precursor 1,1‐dichloroformaldoxime (DCF) with a weak base, leading to a dehydrohalogenation reaction to afford chloronitrile oxide. Notably, DCF, also known as phosgene oxime, is a toxic, hazardous and very unhandy intermediate obtained through direct decarboxylative chlorination of 2‐hydroxyiminoacetic acid with chlorinating agents such as NCS or tert ‐butyl hypochlorite (Scheme 2e) [37,38] .…”

“…This unstable intermediate is predominantly generated in situ under the Huisgen [37–42] conditions, which involve the treatment of its stable precursor 1,1‐dichloroformaldoxime (DCF) with a weak base, leading to a dehydrohalogenation reaction to afford chloronitrile oxide. Notably, DCF, also known as phosgene oxime, is a toxic, hazardous and very unhandy intermediate obtained through direct decarboxylative chlorination of 2‐hydroxyiminoacetic acid with chlorinating agents such as NCS or tert ‐butyl hypochlorite (Scheme 2e) [37,38] . On the other hand, Zapol'skii and co‐workers [43] reported an alternative possibility to generate chloronitrile oxide in situ by treatment of 1,1,2‐trichloro‐2‐nitroethene with powdered sodium hydroxide in anhydrous solvents at 60 °C, followed by rapid and spontaneous release of chloride ion, chloridric acid and CO 2 (Scheme 2f).…”

“…One point of strength of the use of the 1,3‐dipolar cycloaddition reaction for the synthesis of 3‐bromo 4,5‐dihydroisoxazoles is represented by the key features of DBF. Besides being a handleable and stable precursor of the 1,3‐dipole, DBF is also cheaply available commercially and can be easily synthesized through a one‐pot reaction, by amination of glyoxylic acid with hydroxylamine, followed by decarboxylation and bromination with Br 2 [38,51,59–62] or NBS [37] . These conditions were also optimized by the use of flow‐chemistry reactors [63] …”

Chemistry of Polyhalogenated Nitrobutadienes, Part 7: A Novel Synthetic Access to Chlorinated Nitrile Oxides

“…It is remarkable that only dihydroisoxazoles 31 and 33 are known so far. 25 This important class of heterocycles can be easily converted into isoxazoles, which also show synthetic potential due to their weak nitrogen-oxygen bond. 8 Additionally, these five-membered heterocycles are often structural units in biologically active compounds, for example, the antitumor antibiotic Acivicin (AT-125) or the cholinergic channel activator ABT 418.…”