Inverse electron demand hetero-Diels-Alder reaction

The Diels-Alder reaction, inverse electronic demand Diels-Alder reaction, as well as the hetero-Diels-Alder reaction, belong to the category of [4+2]-cycloaddition reactions, which are concerted processes. The arrow pushing here is merely illustrative. 

Diels-Alder reaction, inverse electronic demand Diels-Alder reaction, hetero-Diels-Alder reaction... 

The two transition states in Figs 8.5 and 8.6 correspond in principle to a metal-catalyzed carho-Diels-Alder reaction under normal electron-demand reaction conditions and a hetero-Diels-Alder reaction with inverse electron-demand of an en-one with an alkene. The calculations by Houk et al. [6] indicated that with the basis set used there were no significant difference in the reaction course. 

Inverse electron-demand controlled hetero-Diels-Alder reactions... 

Inverse Electron-demand Hetero-Diels-Alder Reactions... 

The final class of reactions to be considered will be the [4 + 2]-cycloaddition reaction of nitroalkenes with alkenes which in principle can be considered as an inverse electron-demand hetero-Diels-Alder reaction. Domingo et al. have studied the influence of reactant polarity on the reaction course of this type of reactions using DFT calculation in order to understand the regio- and stereoselectivity for the reaction, and the role of Lewis acid catalysis [29]. The reaction of e.g. ni-troethene 15 with an electron-rich alkene 16 can take place in four different ways and the four different transition-state structures are depicted in Fig. 8.16. 

The domino reaction consists of a Knoevenagel condensation giving an intermediate which immediately undergoes an intramolecular hetero-Diels-Alder reaction with inverse electron demand [18]. 

The spiro dimer of a-tocopherol (9, see also Fig. 6.4) is formed as mixture of two diastereomers by dimerization of the o-QM 3 in a hetero-Diels-Alder reaction with inverse electron demand. Both isomers are linked by a fluxion process (Fig. 6.22), which was proven by NMR spectroscopy.53 The detailed mechanism of the interconversion, which is catalyzed by acids, was proposed to be either stepwise or concerted.53-55... 

A further hetero-Diels-Alder reaction with inverse electron demand between o-QM 3 as the dienophile and either of the two diastereomers of spiro dimer 9 as the diene provided the spiro trimers 31 and 32 (Fig. 6.25). The absolute configuration was derived from NMR experiments. It was moreover shown that only two of the four possible stereoisomeric trimers were formed in the hetero-Diels-Alder reaction the attack of the o-QM 3 occurred only from the side syn to the spiro ring oxygen.28... 

While disilene 5 does not undergo Diels-Alder reactions with 1,3-dienes, the [4+2]-cycloaddition products are formed with heterodienes, e.g. 1,4-diazabutadienes [17] or a-ketoimines [19]. It can be deduced that the electron deficient properties of such dienes cause them to readily take part in hetero-Diels-Alder reactions, which have inverse electron demands. This is corroborated by theoretical calculations which predict an inverse electron demand of the Si-Si double bond it is strongly electron donating rather than electron accepting towards butadienes and other compounds [24,25]. 

Furthermore, Akiyama and coworkers applied phosphoric acid (/ )-3m (10 mol%, R = 9-anthryl) to the asymmetric inverse-electron-demand hetero-Diels-Alder reaction of A-2-hydroxyphenyl-protected aldimines 8 with vinyl ethers 99 (Scheme 38) [61], Tetrahydroquinolines 100 were obtained in good yields (59-95%), excellent yyn-diastereoselectivities (24 1-99 1), and high enantioselec-tivities (87-97% ee). 

Aiming at the pyranose form of sugars, normal type hetero-Diels-Alder reactions were extensively used for the synthesis of functionally substituted dihydropyran and tetrahydropyran systems (5-10) (see routes A - D in the general Scheme 1) which are also important targets in the "Chiron approach" to natural product syntheses (2.) Hetero-Diels-Alder reactions with inverse electron demand such as a, p-unsaturated carbonyl compounds (l-oxa-1,3-dienes) as heterodienes and enol ethers as hetero-dienophiles, are an attractive route for the synthesis of 3,4-dihydro-2H-pyrans (11). 

Recently, the first examples of catalytic enantioselective preparations of chiral a-substituted allylic boronates have appeared. Cyclic dihydropyranylboronate 76 (Fig. 6) is prepared in very high enantiomeric purity by an inverse electron-demand hetero-Diels-Alder reaction between 3-boronoacrolein pinacolate (87) and ethyl vinyl ether catalyzed by chiral Cr(lll) complex 88 (Eq. 64). The resulting boronate 76 adds stereoselectively to aldehydes to give 2-hydroxyalkyl dihydropyran products 90 in a one-pot process.The diastereoselectiv-ity of the addition is explained by invoking transition structure 89. Key to this process is the fact that the possible self-allylboration between 76 and 87 does not take place at room temperature. Several applications of this three-component reaction to the synthesis of complex natural products have been described (see section on Applications to the Synthesis of Natural Products ). 

Dihydrofuran reacts with /3,7-unsaturated a-keto esters with copper or zinc complex catalysts to generate furo[2,3-/ ]pyran derivatives in good yields with high stereoselectivity. The synthesis proceeds via an inverse electron demand hetero-Diels-Alder reaction <2000CC459>. 

Hanessian and Compain have also reported a Lewis acid-promoted inverse electron demand hetero-Diels-Alder reaction between dihydrofurans and dihydropyrans with a-keto-/3,7-unsaturated phosphonates to give stmcturally related products <2002T6521>. High-pressure OTr/o-selective hetero-Diels-Alder reactions between a,/3-unsaturated aldehydes and enol ethers in the presence of lanthanide catalysts have also been reported and give 3,4-dihydro-27/-pyrans. Examples include the use of cyclic enol ethers to give 2,3,4,4a,5,8a-hexahydro-277,577-pyrano[2,3-. ]pyrans <1995T8383>. 

A novel formal inverse-electron-demand hetero-Diels-Alder reaction between 2-aryl-a,/3-unsaturated aldehydes and ketones produces dihydropyran derivatives stereo-specifically.161 The inverse-electron-demand Diels-Alder reaction of 3,4-r-butylthio-phene 1-oxide with electron-rich dienophiles shows vyn-jr-face and endo selectivity.162 (g) The inverse-electron-demand Diels-Alder reaction of dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate with a variety of dienophiles produces phthalazine-type dihydrodiol and diol epoxides which were synthesized as possible carcinogens.163... 

Aminoindanol-derived Schiff bases were developed as tridentate ligands for the chromium-catalyzed hetero Diels-Alder reaction between weakly nucleophilic dienes and unactivated aldehydes.24 The generality of the utility of these Schiff bases, readily obtained by condensation of 1 with the corresponding aldehyde, was later demonstrated in the hetero Diels-Alder reaction between Danishefsky s diene and chiral aldehydes,25 in the inverse electron-demand hetero Diels-Alder reaction of a,P-unsaturated aldehydes with alkyl vinyl ethers,26 and in hetero-ene reactions.27... 

Chromium complex 53 was also shown to efficiently catalyze the inverse electron-demand hetero Diels-Alder reaction of a,(3-unsaturated aldehydes with alkyl vinyl ethers (Scheme 17.19).26 Although the uncatalyzed process required elevated temperatures and pressures to give dihydropyrans in good yields but poor endo. exo selectivities, the reaction proceeded at room temperature in the presence of 5 mol% of ent-53 and 4A molecular sieves in dichloromethane of tert-butyl methyl ether with excellent diastereoselectivity (endo. exo >96 4) and promising enantioselectivities (72-78% ee). Optimal results were achieved using a solvent-free system and excess vinyl ether. 

Crystal structure of 60 revealed that the complex existed as a dimeric species where the two chromium centers are bridged through the indane oxygen and each chromium metal bears one molecule of water (Figure 17.6). It was therefore proposed, as for the inverse electron-demand hetero Diels-Alder reaction, that the barium oxide desiccant removed one molecule of bound water from the catalyst dimer, which opened one coordination site for binding of the substrate carbonyl.26... 

The domino reaction consists of a Knoevenagel condensation giving an intermediate that immediately undergoes an intramolecular hetero-Diels-Alder reaction with inverse electron demand [31]. As aldehydes, rac-dtronellal, an aromatic aldehyde, and two commercially available 1,3-diketones, 1,3-dimethylbarbituric add and Meldrum s acid, were seleded. By combinations of these reactants, different cycloadducts were generated. 

The hetero Diels-Alder reaction of nitrosoalkenes with electron-rich olefins has been known for a long time [363]. A detailed mechanistic study carried out by Reissig et al. has given evidence that this inverse electron demand cycloaddition is a concerted process [364]. Recent ab initio calculations dealing with the reaction between ethylene and nitroso ethylene strongly corrobate this view [365]. In this work, Jursic and Zdravkovski have also investigated the influence of BH3 as Lewis acid catalyst. However, cycloadditions of nitrosoalkenes already pro-... 

The inverse electron demand hetero Diels-Alder reaction of 1-oxa-l,3-butadienes and electron-rich dienophiles is an extremely versatile tool in natural product synthesis. This cycloaddition represents the key step of numerous approaches not only to carbohydrates, but also to terpenes, alkaloids, polyethers, steroid derivatives and various biologically active metabolites. 

Narsaiah and Krishnaiah (2002) reported that the hetero-Diels-Alder reaction of A(-acetyl perflnoroalkyl substituted 2(1//) pyridones with DMAD on neutral alumina under solvent-free microwave irradiation conditions extended to undergo an inverse electron demand hetero-Diels-Alder reaction, resulting exclusively in E, Z isomers (3 1) of Michael-type A-adducts. 

Krishnaiah, A. and Narsaiah, B. 2002. Studies on inverse electron demand hetero Diels-Alder reaction of perfluoroalkyl 2(1H) pyridones with different dienophiles under microwave irradiation. Journal of Fluorine Chemistry, 113 133-37. 

---