Hetero Diels-Alder Reactions

SCHEME 107. Asymmetric hetero-Diels-Alder reaction. 

Heterodiene addition to dienophile or heterodienophile addition to diene. Typical hetero-Diels-Alder reactions are aza-Diels-Alder reaction and oxo-Diels-Alder reaction. 

Example 2, Similar to the Boger pyridine synthesis (see page 59)  

Acid-promoted rearrangement of 4,4-disubstituted cyclohexadienones to 3,4-disubstituted phenols. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 81, Springer-Verlag Berlin Heidelberg 2009 

Interestingly, the same research group also found that a mixture of Lewis acid derived from racemic (23a) and Imol equivalent of (+)-3-bromocamphor (149) efficiently catalyzed hetero Diels-Alder reaction of benzaldehyde to give ds-pyrone in 82% ee. This finding was explained by selective complexation to one of the enantiomers of Lewis acid by ketone (149). 

TiCU (3.0 equiv) TiCl3(0/-Pr) (2.0 equiv) TiCl2(0/-Pr)2 (1.5 equiv) 

---

Vinyl ethers and a,P unsaturated carbonyl compounds cyclize in a hetero-Diels-Alder reaction when heated together in an autoclave with small amounts of hydroquinone added to inhibit polymerisation. Acrolein gives 3,4-dihydro-2-methoxy-2JT-pyran (234,235), which can easily be hydrolysed to glutaraldehyde (236) or hydrogenated to 1,5-pentanediol (237). With 2-meth5lene-l,3-dicarbonyl compounds the reaction is nearly quantitative (238). 

Hetero Diels-Alder reaction of active olefins (enamines) with triazenes, tetrazenes with loss of Nz and formation of new N-heterocycies. 

Chiral Cu(II)-complexes as catalysts in hetero-Diels-Alder reaction 99PAC1407. 

Hetero-Diels-Alder reactions in organic chemistry 97MI35. 

Development and application of hetero Diels-Alder reactions with participation of amino acid-derived chiral acylnitroso compounds 98T1317. 

Metal-catalyzed asymmetric hetero Diels-Alder reactions of unactivated dienes with glyoxylates 98PAC1117. 

Thermal fragmentation of l,3-dioxin-4-ones or acylated Meldrum acids with generation of a-oxoketenes, hetero Diels-Alder reactions of the latter, and their transformations into lactones and lactams, among them macrocyclic 99YGK76. 

Catalytic enantioselective hetero-Diels-Alder reactions are covered by the editors of the book. Chapter 4 is devoted to the development of hetero-Diels-Alder reactions of carbonyl compounds and activated carbonyl compounds catalyzed by many different chiral Lewis acids and Chapter 5 deals with the corresponding development of catalytic enantioselective aza-Diels-Alder reactions. Compared with carbo-Diels-Alder reactions, which have been known for more than a decade, the field of catalytic enantioselective hetero-Diels-Alder reactions of carbonyl compounds and imines (aza-Diels-Alder reactions) are very recent. 

An important contribution for the endo selectivity in the carho-Diels-Alder reaction is the second-order orbital interaction [1], However, no bonds are formed in the product for this interaction. For the BF3-catalyzed reaction of acrolein with butadiene the overlap population between Cl and C6 is only 0.018 in the NC-transi-tion state [6], which is substantially smaller than the interaction between C3 and O (0.031). It is also notable that the C3-0 bond distance, 2.588 A, is significant shorter than the C1-C6 bond length (2.96 A), of which the latter is the one formed experimentally. The NC-transition-state structure can also lead to formation of vinyldihydropyran, i.e. a hetero-Diels-Alder reaction has proceeded. The potential energy surface at the NC-transition-state structure is extremely flat and structure NCA (Fig. 8.6) lies on the surface-separating reactants from product [6]. 

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. 

In a combined experimental and theoretical investigation it was found that the / -alkyl group in the dienophile gave a steric interaction in the transition-state structure which supported the asynchronous transition-state structure for the Lewis acid-catalyzed carbo- and hetero-Diels-Alder reactions. The calculated transition-state energies were of similar magnitude as obtained in other studies of these BF3-catalyzed carbo-Diels-Alder reactions. 

Frontier-molecular-orbital Interactions for Hetero-Diels-Alder Reactions... 

Hetero Diels-Alder reactions can also he classified into two types of cy-... 

The basic concept of activation in hetero-Diels-Alder reactions is to utilize the lone-pair electrons of the carbonyl and imine functionality for coordination to the Lewis acid. The coordination of the dienophile to the Lewis acid changes the FMOs of the dienophile and for the normal electron-demand reactions a decrease of the LUMO and HOMO energies is observed leading to a better interaction with... 

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

Very few theoretical studies of hetero-Diels-Alder reactions have been performed [25] and, furthermore, theoretical studies of the Lewis acid-catalyzed hetero-Diels-Alder reactions are even more limited. 

The transition-state structure of the hetero-Diels-Alder reaction is generally found to be unsymmetrical. Houk et al. have for the reaction of formaldehyde with 1,3-butadiene calculated the C-C and C-0 bond lengths to be 2.133 A and 1.998 A, respectively, in the transition state using ab-initio calculations shown in Fig. 8.12 [25 bj. The reaction of formaldimine follows the same trend for the transition-state structure. 

The hetero-Diels-Alder reaction of formaldehyde with 1,3-butadiene has been investigated with the formaldehyde oxygen atom coordinated to BH3 as a model for a Lewis acid [25 bj. Two transition states were located, one with BH3 exo, and one endo, relative to the diene. The former has the lowest energy and the calculated transition-state structure is much less symmetrical than for the uncatalyzed reaction shown in Fig. 8.12. The C-C bond length is calculated to be 0.42 A longer, while the C-0 bond length is 0.23 A shorter, compared to the uncatalyzed reac-... 

Fig. 8.12 Calculated transition-state structure for the hetero-Diels-Alder reaction of formaldehyde with butadiene [25 bj...

The mechanism for the hetero-Diels-Alder reaction of benzaldehyde 9 with the very reactive diene, Danishefsky s diene 10, catalyzed by aluminum complexes has been investigated from a theoretical point of view using semi-empirical calculations [27]. The focus in this investigation was to address the question if the reaction proceeds directly to the hetero-Diels-Alder adduct 11, or if 11 is formed via a Mukaiyama aldol intermediate (Scheme 8.4) (see the chapter dealing with hetero-Diels-Alder reactions of carbonyl compounds). 

The reaction was studied in the absence, and presence, of (MeO)2AlMe as a model catalyst for the BINOL-AlMe system. The change in relative energy for the concerted hetero-Diels-Alder reaction, and formation of the hetero-Diels-Alder adduct 11 via a Mukaiyama aldol reaction, is shown in Fig. 8.13. The conclusion of the study was that in the absence of a catalyst the concerted reaction is the most... 

Fig. 8.13 Schematic representation of the change in energies for the concerted hetero-Diels-Alder reaction of benzaldehyde with Danishefsky s diene and the step-wise reaction...

The hetero-Diels-Alder reaction of aldehydes 12 with 2-azabutadienes 13 (Scheme 8.5) has been studied using high-level ab-initio multiconfigurational molecular orbital and density functionality calculation methods [28]. 

To determine the preferred pathway for the [4-r-2]-hetero-Diels-Alder reaction model reactions using formaldehyde (R =H for 12 in Scheme 8.5) as the carbonyl compound and 2-azabutadiene (R -R" = H for 13 in Scheme 8.5) for the hetero... 

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 number of theoretical investigations of hetero-Diels-Alder reaction is very limited. The few papers dealing with this class of reactions have shown that the influence of the Lewis acid on the reaction course can to a high extent be compared to those found the carbo-Diels-Alder reactions. At the present stage of investigations, however, more work is needed if we are to understand the influence and control of selectivity in Lewis acid-catalyzed hetero-Diels-Alder reaction - we are probably at the beginning of a new era in this field. 

The theoretical investigations of Lewis acid-catalyzed 1,3-dipolar cycloaddition reactions are also very limited and only papers dealing with cycloaddition reactions of nitrones with alkenes have been investigated. The Influence of the Lewis acid catalyst on these reactions are very similar to what has been calculated for the carbo- and hetero-Diels-Alder reactions. The FMOs are perturbed by the coordination of the substrate to the Lewis acid giving a more favorable reaction with a lower transition-state energy. Furthermore, a more asynchronous transition-structure for the cycloaddition step, compared to the uncatalyzed reaction, has also been found for this class of reactions. 

---