Regioselectivity in the Diels-Alder reaction

Predict the regioselectivity in the Diels-Alder reactions of acrolein and N-acetyl-2-cyano-4-phenyl-l-azabutadiene with 1-hexene, styrene, ethyl vinyl ether and methyl acrylate. The FOs of the azadiene are given below the others may be found in the Appendix. 

Substituent effects in the Diels-Alder reaction. A. Reaction of acrylonitrile with isoprene. Molecular orbital coefficients for the HOMO and LUMO of each reactant are shown, along with the major mixing (solid arrow) and the minor mixing (dashed arrow). B. Further examples of regioselectivity in the Diels-Alder reaction. 

Chung, W.-S. Wang, J.-Y., Control of regioselectivity in the Diels-Alder reactions of alkyl-substituted 1,4-benzoquinones by p-cyclodextrin and its derivatives, J. Chem. Soc., Chem. Commun., 1995,971-2. 

A typical regioselectivity and endo/exo selectivity has been reported in the Diels-Alder reaction of 2-(/V-acylamino)- 1,3-diene with nitroalkenes (Eq. 8.27).43 Thus, exo products are predominantly formed, which is general for the Diels-Alder reaction of nitroalkenes with sterically hindered dienes. 

In the Diels-Alder reaction between an unsymmetrical diene and dienophile, up to eight stereoisomers can be formed (March, 1992a). It is known that the regioselectivity of the Diels-Alder reaction can be biased so that only the four ori/io-adducts are produced (Fig. 21) through increasing the electron-withdrawing character of the substituent on the dienophile (Danishefsky and Hershenson, 1979). However, stereochemical control of the Diels-Alder reaction to yield the disfavoured exo-products in enantiomerically pure form has proved to be very difficult. 

The following general observations have been made about kinetic regioselection in normal Diels-Alder reactions, i.e., those involving electron-rich dienes and electron-deficient dienophiles (see also discussion in Chapter 9). 

Saigo and co-workers reasoned that, by analogy, high levels of diastereofacial discrimination could be achieved in the Lewis acid-mediated Diels-Alder reaction of dienes with oxazolidinone 108-derived dienophiles. Indeed, excellent regioselectivities (endo. exo) and diastereoselectivities were reached in the Diels-Alder reaction of 109 with cyclic and acyclic dienes using Et2AlCl as the activator (Scheme 24.28).107 The selectivities obtained actually surpassed those reported with cis-1 -amino-2-indanol 1 as the chiral auxiliary (93% de) (see Scheme 24.16).82 The additional bulk... 

Although the use of enzymes, as catalysts in the Diels-Alder reaction, has not been particularly successful,46 102 103 abzymes can be used to control regioselectivity and stereoselectivity in the Diels-Alder reaction.46 104 Biological catalysts have not been used on significant scale in the Diels-Alder reaction. Further, the use of abzymes would require a large investment initially, and any subtle change in the substituents on either the diene or dienophile may dramatically reduce asymmetric induction and yield. 

Explain the stereoselectivity and the complete regioselectivity observed in the Diels-Alder reaction of step n. 

Since the disclosures that the thermal dimerizations of acrolein and methyl vinyl ketone provide the 3,4-dihydro-2//-pyrans (1, 2) derived from 4ir and 2Tt participation of the a,3-unsaturated carbonyl compound in a Diels-Alder reaction, an extensive series of related observations have been detailed. This work has been the subject of several comprehensive reviews - - including the Desimoni and Tacco-ni extensive tabular compilation of work through 1974. Consequently, the prior reviews should be consulted for thorough treatments of the mechanism, scope, and applications of the [4 + 2] cycloaddition reactions of a,3-unsaturated carbonyl compounds. The [4 + 2] cycloaddition reactions of 1-oxa-1,3-butadienes with their 4-it participation in the Diels-Alder reaction exhibit predictable regioselectivity with the preferential or exclusive formation of 2-substituted 3,4-dihydro-2W-pyrans (equation 1). The exceptions to the predicted regioselectivity that have been observed involve the poorly matched [4 + 2] cycloaddition reaction of an electron-deficient l-oxa-l,3-butadiene with an electron-deficient dienophile, e.g. methyl crotonate or methacrolein. - Rigorous or simplified theoretical treatments of the [4 + 2] cycloaddition reaction of 1-oxa-1,3-butadienes predict the preferential formation of 2-substituted 3,4-dihy-dro-2f/-pyrans and accommodate the preferred endo approach of the reactants in which the carbon-carbon bond formation is more advanced than carbon-oxygen bond formation, i.e. a concerted but nonsynchronous [4 + 2] cycloaddition reaction. ... 

Unsymmetrically substituted tropones wherein the substitution is remote from the actual bonding centers have also been the subject of regioselectivity studies. Modest chemical yields accompanied high regioselectivities in the resultant products isolated from the addition of various dienes to 3- and 4-ethoxycarbonyltropones, (18) and (21). So-called even regioselectivity, which completely parallels the regioselectivity observed in the Diels-Alder reaction, prevailed in these cases. Lower selectivities characterized the reactions of 3- and 4-methoxytropones with the same set of electron-rich diene partners. 

Davies and coworkers , for example, used iV-enoyl derivatives of a cw-l-aminoindan-2-ol based L3-oxazolidin-2-one (222) as chiral dienophiles in the Diels-Alder reactions with isoprene (91a) and piperylene (91b) which give 223 (equation 62). Their results have been summarized in Table 6. The reactions proceeded with high endo/exo and regioselectivities. Bidentate co-ordination of the catalyst to both carbonyl groups kept the dienophile in a rigid conformation, which gave rise to the high de values observed. 

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