Gold(I)-Catalyzed Intramolecular S_EAr Reaction: Efficient Synthesis of Isoxazole-Containing Fused Heterocycles

Abstract

Intramolecular electrophilic aromatic substitution (SAr) reaction at the 5-position of isoxazoles was achieved. The electron-donating heteroatoms (N and O) at the 4-position of isoxazoles, which can be readily prepared based on our originally developed synthetic procedure, and a cationic gold(I) catalyst are essential for the intramolecular SAr reaction to synthesize isoxazole-containing fused heterocycles. Structurally diverse isoxazolopyridines 6 and isoxazolopyrans 9, including base-labile 3-unsubstituted derivatives, were synthesized in good to high yields. The addition of N-phenylbenzaldimine as a hydrogen acceptor improved yields in the synthesis of isoxazolopyridines. Furthermore, synthesis of the tetracyclic fused ring system 12 was achieved by tandem cyclization from the corresponding diyne 11.

Synthesis of 3-Hydroxy-4-Substituted Picolinonitriles from 4-Propargylaminoisoxazoles via Stepwise and One-Pot Isoxazolopyridine Formation/N–O Bond Cleavage Sequence

“…However, there is no report of N–O bond cleavage of 3-unsubstituted isoxazolopyridines. Therefore, the N–O bond cleavage of previously synthesized isoxazolopyridine 9a (19) was first examined under various acidic and basic conditions (Table 1). Among Bro̷nsted acid mediated conditions (entries 1–4), aqueous HCl in MeOH conditions (entry 1) afforded 5a in 70% yield with complete conversion of 9a .…”

“…Column chromatography was performed on Silica Gel 60 N, purchased from Fuji Silysia Chemical Ltd. 4-Propargylaminoisoxazoles 8 and isoxazolopyridines 9 and 10 were prepared in accordance with the previously reported procedure. 19 Spectral data for 8i and 9i (newly prepared compounds) are shown below.…”

“…Our previously reported procedure 19 afforded 8j (84 mg, 0.411 mmol, 48%) as a yellow oil after purification by column chromatography on silica gel (hexane:ethyl acetate = 7:3). 1 H NMR (500 MHz, CDCl 3 ) δ 8.12 (s, 2H), 7.24 (d, J = 4.0 Hz, 1H), 7.17 (d, J = 2.8 Hz, 1H), 6.95 (t, J = 3.6 Hz, 1H), 4.02 (d, J = 4.0 Hz, 2H), 3.29 (br s, 1H); 13 C NMR (125 MHz, CDCl 3 ) δ 144.5, 141.8, 132.3, 129.9, 127.4, 127.0, 122.4, 89.3, 77.7, 37.7; FTIR (neat): 3355, 2923, 1626, 1436, 1093 cm –1 ; HRMS (ESI-TOF): m/z [M + Na] + calcd for C 10 H 8 N 2 NaOS, 227.0255; found, 227.0253.…”

Gold-Catalyzed Homogeneous (Cyclo)Isomerization Reactions

“…Moreover, the authors demonstrated that the addition of an external hydride acceptor as N -phenylbenzaldimine increased the yield in the synthesis of isoxazolopyridines ( 146 , X = NH). Remarkably, the use of bulky gold(I)-complexes, such as [JhonPhosAu] + , is essential for the satisfactory formation of products (Morita et al, 2018).…”

Synthesis of C4-alkynylisoxazoles via a Pd-catalyzed Sonogashira cross-coupling reaction

“…10 Lately, Morita and co-workers reported intramolecular electrophilic aromatic substitution reaction only occurred at the 5-position of isoxazole rather than at the 3-position. 11 Herein, we investigated the effect of the groups at C3 and C5 positions of the isoxazole on the Sonogashira cross-coupling reaction.…”