Ethyl Vinyl Ether cycloaddition reactions

The perfluoroacetamide catalysts, rhodium(II) trifluoroacetamidate [Rh2(tfm)4] and rhodium(II) perfluorobutyramidate [Rh2(pfbm)4], are interesting hybrid molecules that combine the features of the amidate and perfluorinated ligands. In early studies, these catalysts were shown to prefer insertion over cycloaddition [30]. They also demonstrated a preference for oxindole formation via aromatic C-H insertion [31], even over other potential reactions [86]. In still another example, rhodium(II) perfluorobutyramidate showed a preference for aromatic C-H insertion over pyridinium ylide formation, in the synthesis of an indole nucleus [32]. Despite this demonstrated propensity for aromatic insertion, the perfluorobutyramidate was shown to be an efficient catalyst for the generation of isomtinchnones [33]. The chemoselectivity of this catalyst was further demonstrated in the cycloaddition with ethyl vinyl ethers [87] and its application to diversity-oriented synthesis [88]. However, it was demonstrated that while diazo imides do form isomtinchnones under these conditions, the selectivity was completely reversed from that observed with rhodium(II) acetate [89, 90]. 

The use of enol ethers as dienophiles improves the reaction, however, still high temperature is needed and endo/exo-selectivity is low. Thus, cycloaddition of ethyl vinyl ether 2-83 to cyclopentenecarbaldehyde 2-82 gave the cycloadduct 2-84 as a 1 1 mixture which was used for the synthesis of iridoids (Fig. 2-23) [121]. 

The Knoevenagel products of sufficiently reactive acyclic as well as cyclic 1,3-dicarbonyls can act as oxadienes in hetero Diels-Alder reactions with enol ethers and enamines. Alkenes may be used as dieno-philes if the reaction is performed in an intramolecular mode. The cycloadditions of ethyl vinyl ether... 

Cycloaddition of ethyl vinyl ether to the 3,6-tetrazinedicarboxylic acid disodium salt has been developed as an efficient multigram synthesis of 3,6-pyridazinedicarboxylic acid (Scheme 109). A key feature of this process is that the otherwise facile decarboxylation reactions of acids are minimized by use of their sodium salts, and if required the free acid is obtained by ion exchange <87JHC1285>. 

Heterocyclic o-quinodimethanes are unstable and reactive dienes that must be generated in situ. In solution and in the pre.sence of a dienophile the -quinodimethanes can be intercepted in a Diels-Alder reaction, often in high yield. Most of the dienophiles investigated so far have been electron deficient A-phenylmaleiinide. acrylonitrile, methyl vinyl ketone, acrylate, ftimarate and acetylenedicarboxylic esters are typically used. However, since the objective of most of the work was simply to establish that the o-quinodimethane was being formed, the scope of the reaction has not been adequately explored. The pyridine derived o-quinodimethane 12 has recently been shown to undergo cycloaddition to ethyl vinyl ether (Scheme 2) and to dihydroftiran <96T11889>, and it is thus clear that the scope of the Diels-Alder reaction extends beyond electron deficient alkenes and alkynes. Heterodienophiles (azodicarbonyl compounds and nitrosobenzene) have been added to indole-2,3-quinodimethanes <91T192,S> and this type of hetero Diels-Alder reaction is also potentially of wider application. 

A strategy developed by Tietze and coworkers early in his independent career involved the application of intramolecular or intermolecular inverse electron demand hetero-Diels-Alder reactions to iridoid total synthesis. The intermolecular [4+ 2]-cycloaddition of ethyl vinyl ether and unsaturated aldehyde 31 provided acetal 32, which underwent double bond isomerization to afford 33 (Scheme 1) An intramolecular variant of this reaction is discussed in detail later (Scheme 10). More recently, Jacobsen and Chavez extended this work with the enantio- and diastereoselective synthesis of a range of iridoid natural products. Utilizing tridentate Cr(III) catalyst 34, acetal 35 was prepared in 98% ee with good diastereoselectivity (Scheme 1)P... 

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. 

The stereochemistry of the product formed in the cycloaddition reaction depends on the approach of the substrate. There are two different approaches by which the reaction can proceed - endo and exo. For the reaction of e.g., a / , y-un-saturated a-keto ester with an ethyl vinyl ether there are four possible approaches... 

The chiral BOX-copper(ll) complexes, (S)-21a and (l )-21b (X=OTf, SbFg), were found by Evans et al. to catalyze the enantioselective cycloaddition reactions of the a,/ -unsaturated acyl phosphonates 49 with ethyl vinyl ether 46a and the cyclic enol ethers 50 giving the cycloaddition products 51 and 52, respectively, in very high yields and ee as outlined in Scheme 4.33 [38b]. It is notable that the acyclic and cyclic enol ethers react highly stereoselectively and that the same enantiomer is formed using (S)-21a and (J )-21b as the catalyst. It is, furthermore, of practical importance that the cycloaddition reaction can proceed in the presence of only 0.2 mol% (J )-21a (X=SbF6) with minimal reduction in the yield of the cycloaddition product and no loss of enantioselectivity (93% ee). 

More recently, further developments have shown that the reaction outlined in Scheme 4.33 can also proceed for other alkenes, such as silyl-enol ethers of acetophenone [48 b], which gives the endo diastereomer in up to 99% ee. It was also shown that / -ethyl-/ -methyl-substituted acyl phosphonate also can undergo a dia-stereo- and enantioselective cycloaddition reaction with ethyl vinyl ether catalyzed by the chiral Ph-BOX-copper(ll) catalyst. The preparative use of the cycloaddition reaction was demonstrated by performing reactions on the gram scale and showing that no special measures are required for the reaction and that the dihydro-pyrans can be obtained in high yield and with very high diastereo- and enantioselective excess. 

Our development of the catalytic enantioselective inverse electron-demand cycloaddition reaction [49], which was followed by related papers by Evans et al. [38, 48], focused in the initial phase on the reaction of mainly / , y-unsaturated a-keto esters 53 with ethyl vinyl ether 46a and 2,3-dihydrofuran 50a (Scheme 4.34). 

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 dimerization of the parent ketene gives the P-lactone. One molecule of ketene reacts across the C=C bond as a donor and the other molecule reacts across the C=0 bond as an acceptor. This is similar to the concerted [2+2] cycloaddition reaction between bis(trifluoromethyl)ketene and ethyl vinyl ether to afford the oxetane (Scheme 26) [127], A lone pair on the carbonyl oxygen in the ketene molecule as a donor activates the C=C bond as the alkoxy group in vinyl ether. 

Nitrooxazoles and 4-nitroisoxazoles 480 are versatile substrates for domino cycloaddition reactions with ethyl vinyl ether 481 to form the tricyclic nitroso acetals 482 and 483 (Equation 129) <1999T13809, 2001T4237>. 

It was found that 2-propenyloxymagnesium bromide reacts much more readily with nitrile oxides than other known dipolarophiles of electron-deficient, electron-rich, and strained types, including 3-buten-2-one, ethyl vinyl ether, and norbomene, respectively (147). Therefore, this BrMg-alkoxide is highly effective in various nitrile oxide cycloaddition reactions, including those of nitrile oxide/Lewis acid complexes. 

On the basis of available experimental data, it is impossible to choose a definite pathway of elimination of silanol. However, study of silylation of methyl P -nitropropionate (411) with BSA in the presence of trapping agents rigorously proved that silyl nitronate D is initially formed. This compound can be detected in the [3 + 2]-cycloaddition reaction with methyl acrylate product (413). If silylation of AN (411) is performed in the presence of ethyl vinyl ether, a-nitrosoalkene E can be successfully trapped in as heterodiene a Diels-Alder reaction. Dihydroox-azine (414) is formed, and its silylation affords isolable product (415). 

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. 

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