Diels-Alder Lewis acid catalysis

This chapter introduces the experimental work described in the following chapters. Some mechanistic aspects of the Diels-Alder reaction and Lewis-acid catalysis thereof are discussed. This chapter presents a critical survey of the literature on solvent ejfects on Diels-Alder reactions, with particular emphasis on the intriguing properties of water in connection with their effect on rate and selectivity. Similarly, the ejfects of water on Lewis acid - Lewis base interactions are discussed. Finally the aims of this thesis are outlined. 

Lewis-acid catalysis of Diels-Alder reactions... 

The regioselectivity benefits from the increased polarisation of the alkene moiety, reflected in the increased difference in the orbital coefficients on carbon 1 and 2. The increase in endo-exo selectivity is a result of an increased secondary orbital interaction that can be attributed to the increased orbital coefficient on the carbonyl carbon ". Also increased dipolar interactions, as a result of an increased polarisation, will contribute. Interestingly, Yamamoto has demonstrated that by usirg a very bulky catalyst the endo-pathway can be blocked and an excess of exo product can be obtained The increased di as tereo facial selectivity has been attributed to a more compact transition state for the catalysed reaction as a result of more efficient primary and secondary orbital interactions as well as conformational changes in the complexed dienophile" . Calculations show that, with the polarisation of the dienophile, the extent of asynchronicity in the activated complex increases . Some authors even report a zwitteriorric character of the activated complex of the Lewis-acid catalysed reaction " . Currently, Lewis-acid catalysis of Diels-Alder reactions is everyday practice in synthetic organic chemistry. 

Studies on solvent effects on the endo-exo selectivity of Diels-Alder reactions have revealed the importance of hydrogen bonding interactions besides the already mentioned solvophobic interactions and polarity effects. Further evidence of the significance of the former interactions comes from computer simulations" and the analogy with Lewis-acid catalysis which is known to enhance dramatically the endo-exo selectivity (Section 1.2.4). 

A combination of the promoting effects of Lewis acids and water is a logical next step. However, to say the least, water has not been a very popular medium for Lewis-acid catalysed Diels-Alder reactions, which is not surprising since water molecules interact strongly with Lewis-acidic and the Lewis-basic atoms of the reacting system. In 1994, when the research described in this thesis was initiated, only one example of Lewis-acid catalysis of a Diels-Alder reaction in water was published Lubineau and co-workers employed lanthanide triflates as a catalyst for the Diels-Alder reaction of glyoxylate to a relatively unreactive diene . No comparison was made between the process in water and in organic solvents. 

What is the scope of Lewis-acid catalysis of Diels-Alder reactions in water An approach of extending the scope by making use of a temporary secondary coordination site is described in Chapter 4. 

What is the effect of micelles on the aqueous Diels-Alder reaction Can micellar catalysis be combined with Lewis-acid catalysis In Chapter 5 these aspects will discussed. 

In order to be able to provide answers to these questions, a Diels-Alder reaction is required that is subject to Lewis-acid catalysis in aqueous media. Finding such a reaction was not an easy task. Fortunately the literature on other Lewis-acid catalysed organic reactions in water was helpful to some extent... 

In organic solvents Lewis-acid catalysis also leads to large accelerations of the Diels-Alder reaction. Table 2.2 shows the rate constants for the Cu -catalysed Diels-Alder reaction between 2.4a and 2.5 in different solvents. 

In summary, the effects of a number of important parameters on the catalysed reaction between 2.4 and 2.5 have been examined, representing the first detailed study of Lewis-acid catalysis of a Diels-Alder reaction in water. Crucial for the success of Lewis-acid catalysis of this reaction is the bidentate character of 2.4. In Chapter 4 attempts to extend the scope of Lewis-acid catalysis of Diels-Alder reactions in water beyond the restriction to bidentate substrates will be presented. 

In Chapter 2 the Diels-Alder reaction between substituted 3-phenyl-l-(2-pyridyl)-2-propene-l-ones (3.8a-g) and cyclopentadiene (3.9) was described. It was demonstrated that Lewis-acid catalysis of this reaction can lead to impressive accelerations, particularly in aqueous media. In this chapter the effects of ligands attached to the catalyst are described. Ligand effects on the kinetics of the Diels-Alder reaction can be separated into influences on the equilibrium constant for binding of the dienoplule to the catalyst (K ) as well as influences on the rate constant for reaction of the complex with cyclopentadiene (kc-ad (Scheme 3.5). Also the influence of ligands on the endo-exo selectivity are examined. Finally, and perhaps most interestingly, studies aimed at enantioselective catalysis are presented, resulting in the first example of enantioselective Lewis-acid catalysis of an organic transformation in water. 

The merits of (enantioselective) Lewis-acid catalysis of Diels-Alder reactions in aqueous solution have been highlighted in Chapters 2 and 3. Both chapters focused on the Diels-Alder reaction of substituted 3-phenyl-1-(2-pyr idyl)-2-prop ene-1-one dienophiles. In this chapter the scope of Lewis-acid catalysis of Diels-Alder reactions in water is investigated. Some literature claims in this area are critically examined and requirements for ejfective Lewis-acid catalysis are formulated. Finally an attempt is made to extend the scope of Lewis-acid catalysis in water by making use of a strongly coordinating auxiliary. 

In summary, the groups of Espenson and Loh observe catalysis of Diels-Alder reactions involving monodentate reactants by Lewis acids in water. If their observations reflect Lewis-acid catalysis, involvirg coordination and concomitant activation of the dienophile, we would conclude that Lewis-acid catalysis in water need not suffer from a limitation to chelating reactants. This conclusion contradicts our observations which have invariably stressed the importance of a chelating potential of the dienophile. Hence it was decided to investigate the effect of indium trichloride and methylrhenium trioxide under homogeneous conditions. 

Scheme 4.6. Schematic representation of the use of a coordinating auxiliary for Lewis-acid catalysis of a Diels-Alder reaction.

In a second attempt to extend the scope of Lewis-acid catalysis of Diels-Alder reactions in water, we have used the Mannich reaction to convert a ketone-activated monodentate dienophile into a potentially chelating p-amino ketone. The Mannich reaction seemed ideally suited for the purpose of introducing a second coordination site on a temporary basis. This reaction adds a strongly Lewis-basic amino functionality on a position p to the ketone. Moreover, the Mannich reaction is usually a reversible process, which should allow removal of the auxiliary after the reaction. Furthermore, the reaction is compatible with the use of an aqueous medium. Some Mannich reactions have even been reported to benefit from the use of water ". Finally, Lewis-acid catalysis of Mannich-type reactions in mixtures of organic solvents and water has been reported ". Hence, if both addition of the auxiliary and the subsequent Diels-Alder reaction benefit from Lewis-acid catalysis, the possibility arises of merging these steps into a one-pot procedure. 

As anticipated from the complexation experiments, reaction of 4.42 with cyclopentadiene in the presence of copper(II)nitrate or ytterbium triflate was extremely slow and comparable to the rate of the reaction in the absence of Lewis-acid catalyst. Apparently, Lewis-acid catalysis of Diels-Alder reactions of p-amino ketone dienophiles is not practicable. 

Careful examination of literature reporting Lewis-acid catalysis of Diels-Alder reactions in combination with kinetic investigations indicate that bidentate (or multidentate) reactants are required in order to ensure efficient catalysis in water. Moreover, studies of a number of model dienophiles revealed that a potentially chelating character is not a guarantee for coordination and subsequent catalysis. Consequently extension of the scope in this direction does not seem feasible. 

With the aim of catalysis of the Diels-Alder reaction of 5.1 with 5.2 by metallo micelles, preliminary studies have been performed using the surfactants 5.5a-c and 5.6 (Scheme 5.2). Unfortunately, the limited solubility of these surfactants in the pH region that allows Lewis-acid catalysis of the Diels-... 

Interestingly, at very low concentrations of micellised Qi(DS)2, the rate of the reaction of 5.1a with 5.2 was observed to be zero-order in 5.1 a and only depending on the concentration of Cu(DS)2 and 5.2. This is akin to the turn-over and saturation kinetics exhibited by enzymes. The acceleration relative to the reaction in organic media in the absence of catalyst, also approaches enzyme-like magnitudes compared to the process in acetonitrile (Chapter 2), Cu(DS)2 micelles accelerate the Diels-Alder reaction between 5.1a and 5.2 by a factor of 1.8710 . This extremely high catalytic efficiency shows how a combination of a beneficial aqueous solvent effect, Lewis-acid catalysis and micellar catalysis can lead to tremendous accelerations. 

First of all, given the well recognised promoting effects of Lewis-acids and of aqueous solvents on Diels-Alder reactions, we wanted to know if these two effects could be combined. If this would be possible, dramatic improvements of rate and endo-exo selectivity were envisaged Studies on the Diels-Alder reaction of a dienophile, specifically designed for this purpose are described in Chapter 2. It is demonstrated that Lewis-acid catalysis in an aqueous medium is indeed feasible and, as anticipated, can result in impressive enhancements of both rate and endo-exo selectivity. However, the influences of the Lewis-acid catalyst and the aqueous medium are not fully additive. It seems as if water diminishes the catalytic potential of Lewis acids just as coordination of a Lewis acid diminishes the beneficial effects of water. Still, overall, the rate of the catalysed reaction... 

Hydrocarbon resins based on CPD are used heavily in the adhesive and road marking industries derivatives of these resins are used in the production of printing inks. These resins may be produced catalyticaHy using typical carbocationic polymerization techniques, but the large majority of these resins are synthesized under thermal polymerization conditions. The rate constants for the Diels-Alder based dimerization of CPD to DCPD are weU known (49). The abiHty to polymerize without Lewis acid catalysis reduces the amount of aluminous water or other catalyst effluents/emissions that must be addressed from an environmental standpoint. Both thermal and catalyticaHy polymerized DCPD/CPD-based resins contain a high degree of unsaturation. Therefore, many of these resins are hydrogenated for certain appHcations. 

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 most frequently encountered, and most useful, cycloaddition reactions of silyl enol ethers are Diels-Alder reactions involving silyloxybutadicncs (Chapter 18). Danishefsky (30) has reviewed his pioneering work in this area, and has extended his studies to include heterodienophiles, particularly aldehydes. Lewis acid catalysis is required in such cases, and substantial asymmetric induction can be achieved using either a chiral lanthanide catalyst or an a-chiral aldehyde. 

Lewis-acid catalysis is effective in intermolecular as well as intramolecular /zomo-Diels-Alder reactions. Thus, complex polycyclic compounds 93 have been obtained in good yield by the cycloaddition of norbornadiene-derived dienynes 92 by using cobalt catalyst, whereas no reaction occurred under thermal conditions [91] (Scheme 3.18). 

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