Sequential Formal [4+1]‐Cycloaddition, C−H Functionalization and Suzuki–Miyaura Cross‐Coupling for the Synthesis of Trisubstituted Isoxazolines

Abstract

Suzuki–Miyaura cross‐coupling reaction of 3‐bromomethyl isoxazolines with arylboronic acids was suggested as final C−C bond forming step in convenient diastereoselective route to trisubstituted isoxazolines. The required bromides were readily available from nitroalkenes and sulfonium ylides through an efficient sequence of formal [4+1]‐cycloaddition and C−H functionalization of intermediate isoxazoline N‐oxides. The synthetic utility of the obtained isoxazolines was demonstrated by their conversion into valuable products such as hydroxy ketone, pyrrolidinone, etc.

Recent advances in the application of ylide-like species in [4 + 1]-annulation reactions: an updated review

“…32 In recent years, our group developed efficient methods for the deoxygenative C–H functionalization of isoxazoline N -oxides 34 (Scheme 14). 32 b ,33,34 One of these methods involves the silylation of N -oxides 34 to give ene-nitrosoacetals 35 , which are then reacted with ZnBr 2 to give 3-bromomethyl isoxazolines 36 via a zinc-promoted S′ N -substitution of the TMSO-group. Bromides 36 are excellent substrates in nucleophilic substitution 33 ( e.g.…”

Reductive Recyclization of sp3-Enriched Functionalized Isoxazolines into α-Hydroxy Lactams

“…A fraction (442 mg, 39% from 3h (1.37 g, 5.53 mmol)) of the compound obtained after the chromatography contained a pure cis-3b diastereomer: colorless solid; mp 108−110 °C; Ethyl 5-((tert-Butoxycarbonyl)amino)-2-hydroxy-4-oxopentanoate (11). The crude compound was purified by flash column chromatography (5 bar) using a gradient of n-hexane−tBuOMe as an eluent and dried upon a flow of gaseous N 2 at 50 °C: 59.8 g (55% from ethyl 3-(((tert-butoxycarbonyl)amino)methyl)-4,5-dihydroisoxazole-5-carboxylate (2n, 108 g, 0.395 mol)), colorless liquid; 1 Ethyl 2-((tert-Butoxycarbonyl)amino)-4-hydroxy-4-(methylsulfonyl)butanoate (20). The hydrogenation proceeded in the presence of Boc 2 O (254 mg, 1.17 mmol).…”

“…Considering the importance of functionalized and alkylsubstituted lactams, especially those bearing a hydroxyl group, efficient synthetic approaches to them with a wide application scope are highly demanded. Among the literature methods for the preparation of 3-hydroxypyrrolidin- by reductive recyclizations of 3-Ph-or 3-CO 2 Et-substituted isoxazoline-5-carboxylates 2a and 2b (performed with H 2 , Pd− C), 15,16 4,5-disubstituted-(NaBH 4 −NiCl 2 ), 17,18 and 3,4,5trisubstituted isoxazolines (PtO 2 , 70 bar, 19,20 or Ni−Ra 21,22 ). Other related methods involved transformations of isoxazoline-N-oxides 23 and hydrogenation of 5-benzoyl-substituted derivatives into 2-phenylpyrrolidin-3-ols.…”

A formal [4 + 1] cycloaddition reaction of Baylis–Hillman bromides with sulfur ylides: facile access to α-alkenyl lactones

“…On the basis of previous related reports 8–12 and our experimental results presented above, as shown in Scheme 6, plausible reaction pathways are illustrated and investigated by density functional theory (DFT) calculation. The corresponding energy data are provided in the ESI †.…”

“…9 After this elegant work, sulfur ylides have been extensively investigated due to their powerful reactivity profile as C1 synthons for the construction of structurally diverse five-membered heterocycles through [4 + 1] cycloaddition. 10,11 Recently, this cycloaddition process has become not limited to pre-formed electron-deficient components. 12 For example, in 2012, Chen and Bolm reported the first example of copper-catalyzed asymmetric formal [4 + 1] cyclization of azoalkenes generated in situ via the dehydrohalogenation of α-halogeno hydrazones with stable sulfur ylides to synthesize chiral dihydropyrazoles (Scheme 1a).…”