Isoxazolines fused

Monoalkylation of Af-tosylallylamine 10 with dibromoalkane 101 proceeded in 60-90% yield (Eq. 10 see also Scheme 3 and Eq. 2) [17]. The bromoalkyl-amines 102 were converted to nitro compounds 103. In situ transformation of 103 into nitrile oxides led to spontaneous cycloaddition with formation of isox-azolines fused to 5-, 6-, and 7-membered ring heterocycles 104 a-c. Under very high dilution conditions, 103 d was converted to 104 d, an isoxazoline fused to an 8-membered azocine, in low (10%) yield. 

Intramolecular cycloaddition of nitrile oxides, prepared from 1,2-isopropy-lidene-protected ether-linked oligo-pentoses leads to the diastereoselective formation of chiral isoxazolines fused to 10-16-membered oxa-cycles (456). 

Starting from the Ni mrao-formyloctaethylporphyrin oxime complex, the meso-cyanooctaethylporphyrin N-oxide complex has been synthesized for the first time. The double addition of the nitrile oxide to 2,5-norbornadiene afford a porphyrin dimer, whose structure has been established by X-ray diffraction analysis (485). The 1,3-dipolar cycloaddition reaction of w< .so-tetraarylporphyrins with 2,6-dichlorobenzonitrile oxide yields isoxazoline-fused chlorins and stereoiso-metric bacteriochlorins. The crystal structure of one of bacteriochlorins has been characterized by X-ray diffraction (486, 487). 

Isoxazoline-fused derivatives (141) absorb at ca. 285 nm this absorption appears to be localized in the isoxazoline moiety <88CCC1060>. Acenaphthene derivative (146) absorbs at 340 (3.66), 315 (3.68), and 250 (4.08) nm, while monocyclic tetrahydrodioxocin (137) displays bands shifted further into the ultraviolet, at 260 (5.51) and 222 (5.33) nm <84IJC(B)1289>. The intensities of the latter absorptions, an order of magnitude higher than those of the corresponding benzo derivatives, appear curious. 

Hassner and coworkers reported a one-pot protocol for the stereoselective synthesis of isoxazolines fused to five- and six-membered carbocycles 204 (Scheme 49) [151]. The method involves conjugate addition of Grignard... 

In another one-pot reaction, chiral isoxazoline-fused benzazepines 31 were formed from the reaction of P-nitrostyrene derivatives 30 and 1,3-dicarbonyl species such as dimethyl malonate. The first step is a nitro-Michael addition reaction between the nitro olefin and dimethyl malonate catalyzed by a chiral thiourea organocatalyst, followed by addition of DMAP and Boc anhydride with heating to promote nitrile... 

Irradiation of the fused ring isoxazoline (27) gave the ring expanded product, oxazepine (28), in 80% yield. 

The reaction of benzonitrile oxide with the bicyclic isoxazoline (451) produced the three fused diisoxazoles shown in Scheme 105 (77JCS(Pi)2222). 

The rearrangement of fused triazole (493) produced a fused aziridine and a fused 4-isoxazoline (494) (75T831). 

Dicarbonylimidazole reacted with the anthranilic acid derivative (498) to produce the fused isoxazolone IV-oxide (499) (77ZOR462). Methyl nitroacetate reacted with indole-3-carbaldehyde to produce (500) (70KGS1505). Treatment of (501) with base gave 3,4,5-triphenyl-2-isoxazoline IV-oxide (Scheme 142) (69JOC984). The reaction was reported to be a direct displacement as (502) did not give a product and no incorporation of deuterium was found using DOMe. 

Reaction of 2-(A -allylamino)-3-formyl-4//-pyrido[l, 2-u]pyrimidin-4-ones 219 in EtOH with HONH2 HCI yielded ( )-oximes 220 at 0°C and 221 (R = PhCH2) under reflux. Heating 220 (R = H) in a boiling solvent afforded cw-fused tetracyclic cycloadducts 221 (R = H). In an aprotic solvent (e.g., benzene or MeCN) the main a>fused cycloadducts 221 (R = H) were accompanied by a mixture of trauA-fused cycloadducts 222, A -oxides 223 and tetracyclic isoxazoline 224 (96T887). The basicity of the 2-allylamino moiety of compounds 219 affected the rate of the conversion. Cycloadditions were also investigated in dioxane and BuOH. 

The intramolecular cycloaddition of a nitrile oxide (a 1,3-dipole) to an alkene is ideally suited for the regio- and stereocontrolled synthesis of fused polycyclic isoxazolines.16 The simultaneous creation of two new rings and the synthetic versatility of the isoxa-zoline substructure contribute significantly to the popularity of this cycloaddition process in organic synthesis. In spite of its high degree of functionalization, aldoxime 32 was regarded as a viable substrate for an intramolecular 1,3-dipolar cycloaddition reaction. Indeed, treatment of 32 (see Scheme 17) with sodium hypochlorite... 

The synthesis of novel heterocycle-fused furo[3,4-d]isoxazoles via ring transformation of 2-isoxazoline-2-oxides by Lewis acids was reported <96H(42)289>. A practical application of the... 

Aldoximes can be oxidatively dehydrogenated to nitrile oxides using a variety of oxidants such as lead tetraacetate [16a], alkali hypohalites [lla],NBS in DMF followed by base treatment [16b], chloramine-T [11b], 1-chlorobenzotriazole [16c], mercuric acetate [ 16 d], etc. However, we employed either NaOCl or chloramine-T for most of our INOC reactions. For instance, a piperidine ring fused to an isoxazoline as in 14 was constructed using the INOC methodology (Scheme 3) [17]. Monoalkylation of N-tosylallylamine 10 with the bromoacetal... 

The versatility of the INOC reaction is evident from the synthesis of tetrahy-drofurans fused to an isoxazoline 22a-f (Eq. 3) [181. a-Allyloxyaldoximes 21, formed by the reduction of jS-nitrostyrenes 19 with SnCl2 2H2O in the presence of an unsaturated alcohol 20, are transformed to isoxazolines 22 in high yield on treatment with NaOCl via stereoselective ring closure of a nitrile oxide intermediate (Table 2). 

Chiral tricyclic fused pyrrolidines 29a-c and piperidines 29d-g have been synthesized starting from L-serine, L-threonine, and L-cysteine taking advantage of the INOC strategy (Scheme 4) [19]. L-Serine (23 a) and L-threonine (23 b) were protected as stable oxazolidin-2-ones 24a and 24b, respectively. Analogously, L-cysteine 23 c was converted to thiazolidin-2-one 24 c. Subsequent N-allylation or homoallylation, DIBALH reduction, and oximation afforded the ene-oximes, 27a-g. Conversion of ene-oximes 27a-g to the desired key intermediates, nitrile oxides 28 a-g, provided the isoxazolines 29 a-g. While fused pyrrolidines 29a-c were formed in poor yield (due to dimerization of nitrile oxides) and with moderate stereoselectivity (as a mixture of cis (major) and trans (minor) isomers), corresponding piperidines 29d-g were formed in good yield and excellent stereoselectivity (as exclusively trans isomers, see Table 3). 

The above methodology has been extremely useful for the synthesis of a variety of INOC precursors. For instance, treatment of 0-trimethylsilyl a-bro-moaldoximes 52b, e, f with F ion in presence of unsaturated alcohols 57 produces oximino ethers 58 which can be readily oxidized using NaOCl (Scheme 8) [29]. The transient nitrile oxide intermediates formed undergo spontaneous cyclization to fused isoxazolines 59. The preferred stereoisomer in the formation of the five-membered ring ethers is trans whereas in the six-membered ring ethers the cis isomer predominates (see Table 5). MM2 calculations helped rationalize the experimentally observed stereoselectivites (see Table 5). 

ISOC reaction was employed to synthesize substituted tetrahydrofurans 172 fused to isoxazolines (Scheme 21) [44b]. The silyl nitronates 170 resulted via the nitro ethers 169 from base-mediated Michael addition of allyl alcohols 168 to nitro olefins 167. Cycloaddition of 170 followed by elimination of silanol provided 172. Reactions were conducted in stepwise and one-pot tandem fashion (see Table 16). A terminal olefinic Me substituent increased the rate of cycloaddition (Entry 3), while an internal olefinic Me substituent decreased it (Entry 4). 

Hassner and coworkers have developed a one-pot tandem consecutive 1,4-addition intramolecular cycloaddition strategy for the construction of five- and six-membered heterocycles and carbocycles. Because nitroalkenes are good Michael acceptors for carbon, sulfur, oxygen, and nitrogen nucleophiles (see Section 4.1 on the Michael reaction), subsequent intramolecular silyl nitronate cycloaddition (ISOC) or intramolecular nitrile oxide cycloaddition (INOC) provides one-pot synthesis of fused isoxazolines (Scheme 8.26). The ISOC route is generally better than INOC route regarding stereoselectivity and generality. 

The relative stereochemistry of tricycle-fused isoxazolines resulting from 1,3-dipolar cycloaddition of cyclo-1,3-diene-tethered nitrile oxides is cis-cis, whereas from cyclohepta-l,3,5-triene-tethered nitrile oxides the cis-trans isomer predominates (412). 

A promising combination of sequential multicomponent Ugi reaction and INOC has been carried out for the preparation of fused isoxazoles and isoxazolines (413). The coupling of these two reactions (Scheme 1.38) provide access to the heterocyclic ring systems in two steps, from easily available starting materials (e.g., R = Ph, R/=PhCH2), in moderate to good overall yields (the yields of Ugi reaction products 354 were 50%-70%, those of the INOC products 355 were 27%-64%). 

A rapid access to carbocyclic nucleosides, containing a fused isoxazoline ring has been proposed, starting from cyclopentadiene. The route involves a het-ero Diels-Alder cycloaddition reaction of nitrosocarbonylbenzene followed by a 1,3-dipolar cycloaddition of nitrile oxides, cleavage of the N-0 tether and transformation of the heterocyclic aminols into nucleosides via construction of purine and pyrimidine heterocycles (457). 

In this approach, the SENA skeleton is assembled from nitroalkene (42) and nucleophile 56.With the exception of two examples (entries 1 and 2 in Table 3.2), the reaction does not stop at SENA 51, which either undergoes intramolecular cyclization through [3 + 2]-cycloaddition to give fused heterocycles (as a rule after elimination of trimethylsilanol) (198-200) or is involved in [3+ 2]-cycloaddition with specially added methyl vinyl ketone or methyl acrylate to form (after elimination of silanol) substituted isoxazolines in rather high yields (201). 

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