The cyano and trifluoromethyl groups in the 3 position were found to have the highest influence on reactivity of 1-oxa-1,3-butadienes in cycloadditions with enol ethers. It was found that the energy depends on the type and position of a substituent in the 1-oxadiene system.
calculated the influence of various substituents on the energy of LUMO orbitals in 4- N-acetylamino-1-oxa-1,3-butadienes using semiempirical methods. Presence of an electron-withdrawing group in the 1-oxadiene system lowers the lowest energy unoccupied molecular orbital (LUMO) energy level which then can more easily overlap with the highest energy unoccupied molecular orbital (HOMO) orbital of the dienophile. The reactivity of 1-oxa-1,3-butadiene can be enhanced by introducing electron-withdrawing substituents. Enamines can participate in these reactions, providing entry to highly complex molecules. Aza-substituted dienophiles have been used more rarely than their oxygenated counterparts in the HDA reactions of 1-oxa-1,3-butadienes. The use of enol ethers as dienophiles with electron-donating groups improves the cycloadditions but high temperature is needed and diastereoselectivity of these reactions is still low. The reactivity of α,β-unsaturated carbonyl compounds in HDA reactions is low and the reactions must be conducted at high temperature or under high pressure. The presented review is an endeavor to highlight the progress in the HDA reactions with inverse-electron-demand of 1-oxa-1,3-butadienes after the year 2000. The most comprehensive one was written by Tietze and Kettschau in Topics in Current Chemistry in 1997. The reviews on this topic have already been published but they cover the literature until only 1997. These reactions have been classified as cycloadditions with inverse-electron-demand. The HDA reactions of oxabutadienes also show a high regioselectivity. Excellent diastereoselectivity is a characteristic feature of heterocycloaddition of many substituted α,β-unsaturated carbonyl compounds. The second route is the hetero-Diels–Alder (HDA) reactions of electron-deficient α,β-unsaturated carbonyl compounds, representing an 1-oxa-1,3-butadiene system, with electron-rich alkenes. The first one is the cycloaddition of the carbonyl group of aldehydes or ketones, acting as heterodienophiles, with electron-rich 1,3-butadienes. There are two synthetic routes leading to dihydropyran derivatives via cycloadditions. The abundance of carbohydrates in living cells is a reason for the development of new synthetic procedures for the preparation of natural and unnatural sugars. Dihydro- and tetrahydropyran derivatives are prevalent structural subunits in a variety of natural compounds, including carbohydrates, pheromones, alkaloids, iridoids and polyether antibiotics. The use of hetero-substituted diene and dienophiles is important for the application of Diels–Alder cycloadditions towards natural and biologically active product synthesis.
It seems that some of the hetero-Diels–Alder reactions described in this review can be applied in bioorthogonal chemistry because they are selective, non-toxic, and can function in biological conditions taking into account pH, an aqueous environment, and temperature.Ĭycloaddition reactions provide quick and economic methods for the construction of monocyclic, polycyclic and heterocyclic systems. New bioorthogonal ligation by click inverse-electron-demand hetero-Diels–Alder cycloaddition of in situ-generated 1-oxa-1,3-butadienes and vinyl ethers was developed. The reactivity of reactants, selectivity of cycloadditions, and chemical stability in aqueous solutions and under physiological conditions were taken into account to show the potential application of the described reactions in bioorthogonal chemistry. Solvent-free and aqueous hetero-Diels–Alder reactions of 1-oxabutadienes were also investigated. In recent years the use of chiral Lewis acids, chiral organocatalysts, new optically active heterodienes or dienophiles have provided enormous progress in asymmetric synthesis. The domino Knoevenagel hetero-Diels–Alder reactions are also described. Two different modes, inter- and intramolecular, of inverse-electron-demand hetero-Diels–Alder reactions of 1-oxadienes are discussed. This type of reaction is today one of the most important methods for the synthesis of dihydropyrans which are the key building blocks in structuring of carbohydrate and other natural products. The huge number of examples of 1-oxadienes cycloadditions found in the literature clearly demonstrates the incessant importance of this transformation in pyran ring synthesis. This review is an endeavor to highlight the progress in the inverse-electron-demand hetero-Diels–Alder reactions of 1-oxa-1,3-butadienes in recent years.
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