Nitrones, 1,3-dipolar cycloadditions ethyl vinyl ether

In an analogous study by Meske, the impact of various oxazaborolidinone catalysts for the 1,3-dipolar cycloaddition reactions between acyclic nitrones and vinyl ethers was studied [31]. Both the diastereo- and the enantioselectivities obtained in this work were low. The highest enantioselectivity was obtained by the application of 100 mol% of the tert-butyl-substituted oxazaborolidinone catalyst 3d [27, 32] in the 1,3-dipolar cycloaddition reaction between nitrone la and ethyl vinyl ether 8a giving endo-9a and exo-9a in 42% and 27% isolated yield, respectively, with up to 20% ee for endo-9a as the best result (Scheme 6.10). 

The above described reaction has been extended to the application of the AlMe-BINOL catalyst to reactions of acyclic nitrones. A series chiral AlMe-3,3 -diaryl-BINOL complexes llb-f was investigated as catalysts for the 1,3-dipolar cycloaddition reaction between the cyclic nitrone 14a and ethyl vinyl ether 8a [34], Surprisingly, these catalysts were not sufficiently selective for the reactions of cyclic nitrones with ethyl vinyl ether. Use of the tetramethoxy-substituted derivative llg as the catalyst for the reaction significantly improved the results (Scheme 6.14). In the presence of 10 mol% llg the reaction proceeded in a mixture of CH2CI2 and petroleum ether to give the product 15a in 79% isolated yield. The diastereoselectiv-ity was the same as in the acyclic case giving an excellent ratio of exo-15a and endo-15a of >95 <5, and exo-15a was obtained with up to 82% ee. 

The Lewis acid-catalyzed reaction of nitrone 21 with ethyl vinyl ether 22 (Scheme 8.8) was also investigated for BH3 and AlMe3 coordinated to 21 [32]. The presence of BH3 decreases the activation energy for the formation of 23 by 3.1 and 4.5 kcal mol to 9.6 kcal mol for the exoselective reaction and 11.6 kcal-mol for the endo-selective reaction, respectively, while the activation energy for the formation of 24 increases by >1.4 kcal mol , compared to those for the uncatalyzed reaction. The transition-state structure for the BH3-exo-selective 1,3-dipolar cycloaddition reaction of nitrone 21 with ethyl vinyl ether 22 is shown in Fig. 8.19. 

Fig. 8.19 The calculated transition-state structure for the BH3-exo-selective 1,3-dipolar cycloaddition reaction of nitrone 21 with ethyl vinyl ether 22 [32 ...

The effect of the addition of Lewis acid upon the stereoselectivity of cycloaddition of chiral nitrones 3a and 34 to electron-rich alkene, with ethyl vinyl ether and the further transformation of so-prepared isoxazoli-dine 36b to new fi-amino acid ester 40, has been also investigated by the same team (Fig. 10). The 1,3-dipolar cycloaddition of nitrone 3a with ethyl vinyl ether imder AlMes and Et2AlCl catalysis proceeded diastereoselectively and finished at - 8 °C over 20 h, providing only two diastereoisomers 35a and 36a in a ratio of 90 10 with erythro-cis 35a predominant, although four diastereoisomers are possible. Indeed, cycloaddition in the absence of any Lewis acids proceeded very slowly with excess of ethyl vinyl ether at room temperature over 14 days to give a mixture of all four diastereoisomers 35-38 with a considerable decrease of the stereoselectivity in a ratio of 59 12 14 15, although erythro-cis 35a was still the major adduct. The 1,3-... 

An enantioselective 1,3-dipolar cycloaddition of nitrones 187 with ethyl vinyl ether 194 catalyzed by Brpnsted acid catalyst 195 was reported by Yamamoto and co-workers. Scheme 3.63 [80]. Only 5 mol% of this air-stable catalyst was used, and the reactions were completed within 1 h. The endo-selectivity of this cycloaddition is different to the previously reported cjto-selectivity of the aluminum-catalyzed reaction (Lewis acid catalysis). 

Giomi s group developed a domino process for the synthesis of spiro tricyclic nitroso acetals using a, 3-unsaturated nitro compounds 4-163 and ethyl vinyl ether to give the nitrone 4-164, which underwent a second 1,3-dipolar cycloaddition with the enol ether (Scheme 4.35) [56]. The diastereomeric cycloadducts formed, 4-165 and 4-166 can be isolated in high yield. However, if R is hydrogen, an elimination process follows to give the acetals 4-167 in 56% yield. 

Mukai et al.85 reported an asymmetric 1,3-dipolar cycloaddition of chromium(0)-complexed benzaldehyde derivatives. As shown in Scheme 5 52, heating chiral nitrone 171a, derived from Cr(CO)3-complexed benzaldehyde, with electron-rich olefins such as styrene (173a) or ethyl vinyl ether (173b) generates the corresponding chiral a.v-3,5-disubstitutcd isoxazolidine adduct 174 or... 

Jprgensen and co-workers (247) investigated the asymmetric 1,3-dipolar cycloaddition reaction catalyzed by bis(oxazoline)-copper(II) complexes. In the presence of 25 mol% 269c, nitrone (401) reacts with ethyl vinyl ether and methoxypropene to afford the [3 + 2] adducts in modest diastereoselectivity and high enantioselectivity, Eq. 217. Ethyl vinyl ether preferentially forms the exo adduct while methoxypropene prefers the endo mode for reasons that are unclear. 

In 2008, Yamamoto et al. disclosed an asymmetric 1,3-dipolar cycloaddition of diarylnitrones 156 with ethyl vinyl ether (157) (Scheme 66). Under the influence of the bulky chiral A-triflyl phosphoramide (5)-4s (5 mol%, R = 2,6- Prj-4-Ad-C Hj), the enrfo-products 158 were formed as the major diastereomers in good yields and enantioselectivities (66 to >99%, 7 1-32 1 endolexo, 70-93% ee(endo)) [86]. High asymmetric induction was achieved only with electron-deficient aryl groups on the nitrones. 

In order to control the stereochemistry of 1,3-dipolar cycloadditions involving this type of nitrone, the Cu(OTQ2-BOX complex 238 was found to be the most suitable catalyst (Scheme 12.81) (367). The 1,3-dipolar cycloaddition of 256 with the electron-rich ethyl vinyl ether 232a as the dipolarophile in the presence of 25 mol% of 258 proceeded at room temperature to give a high conversion, an exo/ endo ratio of 84 16, and exo-251 was obtained with up to 93% ee. 

Stereoselective 1,3-dipolar cycloaddition of nitrones.1 The cycloaddition of the nitrone 1 with an electron-rich alkene such as ethyl vinyl ether or vinyltrimethyl-silane provides a regioselective route to 3,5-disubstituted isoxazolidines (2) (12, 566), but with low stereoselectivity. 

Dipolar Cycloadditions. 1,3-Dipolar cycloadditions provide a powerful method for the synthesis of five-membered heterocyclic rings. The use of (5,5)-r-Bu-box in combination with Cu(OTf)2 as catalyst for the reaction of a nitrone with ethyl vinyl ether leads to the products in 93% yield (eq 23). The diastere-oselectivity is exo-selective, as the product was obtained in an endo/exo ratio of 83 16. A change of the counterion in the cata-... 

Scheme 3.27 1,3 Dipolar cycloaddition reaction of nitrones with ethyl vinyl ether.

In general, a Lewis acid catalyzed 1,3 dipolar cycloaddition reaction of nitrones with vinyl ethers provides exo isomers predominantly. In fact, the MeAl BINOL catalyzed cycloaddition reaction of ethyl vinyl ether with diaryl nitrone furnished the corresponding product vhth high exo selectivity [121]. However, phosphoramide 6b as the chiral Bronsted acid catalyst exhibited high e-ndo selectivity in the same cycloaddition reaction (see Scheme 3.27). 

Pyrazol-3-one derivatives have taken part in both 1,3-dipolar cycloaddition and Diels-Alder reactions. The 1,3-dipolar cycloaddition between (Z)-pyrazol-3-ones 694a g with an excess of ethyl vinyl ether gave the pyrazol-3-one-4-spiro-3-isoxazolidines 695a-g, in nearly quantitative yield (82G483) (Scheme 203). The kinetics of this reaction was studied by quantitative spectroscopic analysis. The rate of reaction increases with the electron-withdrawing character of the substituent on the aromatic ring and a linear relationship is obtained between logk and op constants. The LUMO nitrone-HOMO vinyl ether is taken as the dominant interaction. 

Scheme 3.63 Organocatalytic 1,3-dipolar cycloadditions of diaryl nitrones and ethyl vinyl ether...

The first example of 1,3-dipolar cycloaddition of nitrones catalysed by a chiral organocatalyst was that developed by Yamamoto et al, concerning the cycloaddition with ethyl vinyl ether promoted by a chiral BINOL-derived phosphoramide. These reactions yielded the endo products as the major diastereomers with high diastereoselectivities of up to 94% de, excellent yields and high enantioselectivities of up to 93% ee, as shown in Scheme 6.14. 

Scheme 6.14 1,3-Dipolar cycloadditions of nitrones to ethyl vinyl ether.

Jiao, P., Nakashima, D., Yamamoto, H. (2008). Enantioselective 1,3-dipolar cycloaddition of nitrones with ethyl vinyl ether The difference between Brpnsted and Lewis acid catalysis. Angewandte Chemie International Edition, 47, 2411-2413. 

A study of the regioselectivity of the 1,3-dipolar cycloaddition of aliphatic nitrile oxides with cinnamic acid esters has been published. AMI MO studies on the gas-phase 1,3-dipolar cycloaddition of 1,2,4-triazepine and formonitrile oxide show that the mechanism leading to the most stable adduct is concerted. An ab initio study of the regiochemistry of 1,3-dipolar cycloadditions of diazomethane and formonitrile oxide with ethene, propene, and methyl vinyl ether has been presented. The 1,3-dipolar cycloaddition of mesitonitrile oxide with 4,7-phenanthroline yields both mono-and bis-adducts. Alkynyl(phenyl)iodonium triflates undergo 2 - - 3-cycloaddition with ethyl diazoacetate, Ai-f-butyl-a-phenyl nitrone and f-butyl nitrile oxide to produce substituted pyrroles, dihydroisoxazoles, and isoxazoles respectively." 2/3-Vinyl-franwoctahydro-l,3-benzoxazine (43) undergoes 1,3-dipolar cycloaddition with nitrile oxides with high diastereoselectivity (90% de) (Scheme IS)." " ... 

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