General Platform for the Conversion of Isoxazol‐5‐ones to 3,5‐Disubstituted Isoxazoles via Nucleophilic Substitutions and Palladium Catalyzed Cross‐Coupling Strategies

Abstract

A general platform for the conversion of isoxazol‐5‐ones to 3,5‐disubstituted isoxazoles has been developed via a two‐step strategy. The first step leads to the formation of 5‐(pseudo)halogenated isoxazoles, while in the second, a variety of heteroalkyl‐, heteroaryl‐, alkyl‐, alkenyl‐, alkynyl‐ and aryl‐chains can be installed via nucleophilic substitutions or palladium catalyzed cross‐coupling reactions.

Two‐stage Regioselective Access to Non‐symmetric 3,5‐Diarylisoxazoles: Synthesis of Combretastatin A‐4 analogues

“…In the case of arylated gem ‐dihalocyclopropanes, the nitrosation proceeds highly regioselectively giving access to 3‐aryl‐5‐haloisoxazoles 2 (Scheme 2). [9] The reaction is very promising in view of the availability of the initials and value of the products, 5‐haloisoxazoles [5,7b] . However, this transformation has some limitations.…”

“…With 3‐aryl‐5‐bromoisoxazoles 2 a ‐ k in hand we next studied the opportunity of their arylation under the Suzuki cross‐coupling reaction conditions. Previously we have mentioned that some 5‐bromoisoxazole derivatives have been already tested in the Suzuki reaction, however, it was in the case of 3‐aryl‐5‐bromoisoxazoles that such attempts were unsuccessful [7b] …”

Recent advances in metal catalyzed or mediated cyclization/functionalization of alkynes to construct isoxazoles

“…Recently, Jurberg and co-workers developed a palladiumcatalyzed cross-coupling strategy for the synthesis of 3,5-disubstituted isoxazoles using 5-( pseudo)halogenated isoxazoles as the platform molecule (Scheme 21). 40 With triflate substituted isoxazoles (42) as the optimal substrate, the well-known Sonogashira and Suzuki cross-coupling can be easily achieved, thus generating the corresponding alkynylation products (44) and arylation (46) products in moderate to good yields.…”

“…Firstly, when FeCl 3 and diorganyl diselenide (R 3 Se) 2 were allowed to react in CH 2 Cl 2 at room temperature, reactive species R 3 SeFeCl 2 (Int-38) and R 3 SeCl (Int-39) were obtained. For path a, electrophilic addition of alkynes with R 3 SeCl forms the selenonium intermediate Int- 40, which can undergo sequential anti-nucleophilic attack and the elimination of methyl chloride giving the desired products 71. Alternatively, the coordination of the iron species R 3 SeFeCl 2 with the carbon-carbon triple bond of the alkynes forms the iron complex Int-42.…”

Structural Evidence for Aromatic Heterocycle N–O Bond Activation via Oxidative Addition

“…1 Isoxazoles and related heterocycles containing N-X (X = N, O, S) bonds are widely utilized, [1][2][3][4][5][6][7] rendering crosscoupling of substrates bearing these scaffolds a particularly important transformation. 3,[8][9][10] There are many examples of reactions in which the N-O bond of isoxazoles, benzisoxazoles or anthranils is functionalized, either under thermal, 11,12 Bronsted basic, [13][14][15] Lewis acidic 16 or transition-metal catalyzed conditions. [17][18][19] Isoxazoles are also known to decompose under basic conditions, for example in the Kemp elimination 18 or the Boulton-Katritzky rearrangement.…”