Vinyl acetates, cycloaddition with

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. 

The simplest nitroalkene, nitroethene, undergoes Lewis acid-promoted [4+2] cycloaddition with chiral vinyl ethers to give cyclic nitronates with high diastereoselectivity. The resulting cyclic nitronates react with deficient alkenes to effect a face-selective [3+2] cycloaddition. A remote acetal center controls the stereochemistry of [3+2] cycloaddition. This strategy is applied to synthesis of the pyrrolizidine alkaloids (+)-macronecine and (+)-petasinecine (Scheme 8.33).165... 

The extremely high selectivity for tandem cycloaddition, the ease of manipulation of the nitroso acetals, and the release of the vinyl ether appendage in the hydrogenolytic cleavage constitute ideal features for asymmetric modifications of the cycloadditions with chiral vinyl ethers. As discussed in Section 8.3.2.1 (Inter [4+2]/inter [3+2] cycloadditions of nitroalkenes), the stereochemical course depends on the Lewis acids. The results are summarized in Scheme 8.38.179 The high levels and complementary selectivity with three chiral vinyl ethers and two kinds of Lewis acids (Ti- and Al-based Lewis acids) are presented in this scheme. 

This regioselectivity is practically not influenced by the nature of subsituent R. 3,5-Disubstituted isoxazolines are the sole or main products in [3 + 2] cycloaddition reactions of nitrile oxides with various monosubstituted ethylenes such as allylbenzene (99), methyl acrylate (105), acrylonitrile (105, 168), vinyl acetate (168) and diethyl vinylphosphonate (169). This is also the case for phenyl vinyl selenide (170), though subsequent oxidation—elimination leads to 3-substituted isoxazoles in a one-pot, two-step transformation. 1,1-Disubstituted ethylenes such as 2-methylene-1 -phenyl-1,3-butanedione, 2-methylene-1,3-diphenyl- 1,3-propa-nedione, 2-methylene-3-oxo-3-phenylpropanoates (171), 2-methylene-1,3-dichlo-ropropane, 2-methylenepropane-l,3-diol (172) and l,l-bis(diethoxyphosphoryl) ethylene (173) give the corresponding 3-R-5,5-disubstituted 4,5-dihydrooxazoles. 

Dipolar cycloadditions of nitrones with vinyl acetate leads to 5-acetoxy-isoxazolidines, which can be easily transformed to isoxazolidinyl nucleosides by the Vorbriieggen methodology (803). 

Diels-Alder reactions between dienes and highly reactive dienophiles such as alkyl vinyl ketones can be carried out using the corresponding acetals in order to prevent polymerization of the dienophile. Activation of the masked dienophiles to undergo ionic [4 + 2] cycloadditions with dienes can be by EGA using the conditions in Scheme 18 [44]. Yields in the range 20 to 85% were obtained depending on the... 

The addition of alkenes to A -methylenium amide cations is stereo-specific in the sense that it obeys the cis principle of Alder and Stein, cis-2-butene giving a cis product (105, R = R = Me) and the trans isomer giving trans product (105, R = R = Me). The cycloaddition of unsymmetrical alkenes is highly regiospecific. Knowing how the alkene will react with a large cation allows prediction of the product (105). Thus styrene, butadiene, and vinyl acetate all react so that its substituent appears at position 6 of the dihydrooxazinium salt (105, R = Ph, vinyl, or OAc). 

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]. 

Cycloaddition of nitrones (e.g. 166, equation 107) to alkoxyaUtenes proceeds in high yield with complete diastereoselectivity, giving 1,2-isoxazolidines of type 167. Similar reactions have been reported for vinyl ethers , vinyl acetate , enamines , vinyl imidazoles , enamides, vinyl sulfones and vinyl sulfides . Since the resultant 1,2-oxazolidines of type 167 and its analogs can be hydrolyzed under acidic conditions, this reaction may also be considered as an approach to O-unsubstituted N-alkylhydroxylamines . 

Chiacchio et al. (43,44) investigated the synthesis of isoxazolidinylthymines by the use of various C-functionalized chiral nitrones in order to enforce enantioselec-tion in their cycloaddition reactions with vinyl acetate (Scheme 1.3). They found, as in the work of Merino et al. (40), that asymmetric induction is at best partial with dipoles whose chiral auxiliary does not maintain a fixed geometry and so cannot completely direct the addition to the nitrone. After poor results with menthol ester-and methyl lactate-based nitrones, they were able to prepare and separate isoxazo-lidine 8a and its diastereomer 8b in near quantitative yield using the A-glycosyl... 

Among a number of other homochiral furanosyl- and isoxazolidinylthymine targets, these workers also applied an achiral cycloaddition approach with vinyl acetate to successfully prepare the antiviral agent d4T (11) and its 2-methyl analogue (Fig. 1.1) (45). In more recent work, similar nitrones [9, R = Me or benzyl (Bn)] were used to prepare hydroxymethyl substituted isoxazolidines [3-(46) and 3,5-substituted (47)] for the preparation of further nucleoside analogues. 

Among the most commonly applied chiral moiety for nitrones (2) is the N-a-methylbenzyl substituent (Scheme 12.6) (18-25). The nitrones 8 with this substituent are available from 1 -phenethylamine, and the substituent has the advantage that it can be removed from the resulting isoxazolidine products 9 by hydrogeno-lysis. This type of 1,3-dipole has been applied in numerous 1,3-dipolar cycloadditions with alkenes such as styrenes (21,23), allyl alcohol (24), vinyl acetate (20), crotonates (22,25), and in a recent report with ketene acetals (26) for the synthesis of natural products. Reviewing these reactions shows that the a-methylbenzyl group... 

The irradiation of benzenes with alkenes provides a fascinating array of photochemical reactions, not least because it converts the aromatic substrates into polycyclic, non-aromatic products. In principle, benzene can undergo reaction across the 1,2-(ortho). 1,3-(meta), or 1,4-(para) positions the 1,3-cycloaddition is structurally the most complex, but it is the predominant mode of reaction for many of the simplest benzene/alkene systems. The products are tricyclic compounds with a fusion of two five-membered rings and one three-membered ring, and an example is the reaction of benzene with vinyl acetate (3.411. For monosubstituted benzenes there can be a high... 

Triazines react also with electron-rich dienophiles such as ethyl vinyl ether (401 R = Et) or vinyl acetate (401 R = Ac) in boiling dioxane to yield the pyridine derivatives (376). After the usual [4 + 2] cycloaddition and nitrogen elimination from the bicyclic compound (402), the dihydropyridines (403) eliminate ethanol or acetic acid to give the aromatic pyridines (376). The dienophiles (401) can therefore be used as alkyne equivalents (69TL5171). 

The first examples of ortho cycloaddition can be found in a U.S. patent of Ayer and Buchi [1], Benzonitrile and 2-methylbut-2-ene are reported to yield 7,8,8-trimethylbicyclo[4.2.0]octa-2,4-diene-l-carbonitrile upon irradiation under nitrogen with a mercury resonance arc. Similar reactions, all leading to derivatives of bicyclo[4.2.0]octa-2,4-diene-l-carbonitrile occurred when benzonitrile was irradiated in the presence of 2,4,4-trimethylpent-l-ene, ethyl vinyl ether, vinyl acetate, methyl vinyl ketone, and methyl acrylate. The addend pairs para-tolunitrile/oct-l-ene, ort/m-dicyanobenzene/2-methylbut-2-ene, para-dicyanobenzene/but-l-ene, 2,3-dimethylbenzonitrile/propene, and 3,4,5-trimethylbenzonitrile/ethene likewise produced ortho photocycloadducts. 

Utilizing a commercially available microreactor, fabricated from FOR-TURAN glass, Fukuyama et al. (2004) evaluated a series of [2 + 2] cycloadditions as a means of reducing the reaction times conventionally associated with the synthetic transformation (Table 27). Using a high-pressure mercury lamp (300 W), the reaction of cyclohex-2-eneone 179 with vinyl acetate 168 (Scheme 51), to afford the cycloadduct 180, was used to compare photochemical efficiency within the microreactor [1,000 pm (wide) x 500 pm (deep)] and a conventional batch reactor (10 ml). 

Scheme 51 Photochemical [2 + 2] cycloaddition of cyclohex-2-eneone 179 with vinyl acetate 168.

Fukuyama, Ryu and coworkers reported intermolecular [2 + 2]-type cycloaddition of various cyclohexenone derivatives and alkenes using a micro reactor made entirely of glass, which was supplied by Mikroglas (Scheme 4.26) [39]. The device was equipped with a heat exchanger channel system through which water flowed to maintain isothermal reaction conditions. The remarkable photochemical efficiency of this device was manifested in rapid cycloaddition of vinyl acetate to cyclohex-2-enone. With this device, the desired product was obtained in 88% yield after 2 h, whereas the same reaction carried out in a Pyrex flask was very sluggish (only 8%... 

As an extension of this work, photoinduced [2+2]-cycloadditions of 1-acetylisatin (13) with cyclic enolethers (furan, benzofuran, 2-phenylfuran, 8-methoxypsoralen), and acyclic enolethers (//-butyl vinyl ether and vinyl acetate) were investigated which afforded the spiro-oxetanes in high yields (82-96%) and with high regio- and diastereoselectivity (Sch. 4) [19]. Treatment of the furan-derived oxetane 15 with acid resulted in oxetane ring opening and yielded the 3-(furan-3-yl)indole derivative 16. 

A large number of 3-lactams have been prepared - by this method (equations 56-61). Cycloadditions of CSI with 1,5-hexadiene, allyl iodide and vinyl acetate - yield azetidinones which have been used as starting materials in the synthesis of carbapenems and penems. In some cases the cycloaddition must be conducted at low temperature to avoid open-chain products (equations 61 and 62). 

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