1.3- Cyclopentadiene, Diels-Alder reactions

Keck and Krishnamurthy have shown that the Diels-Alder reaction of cy-clopentadiene and bromoacrolein is facilitated by a Lewis acid derived from titanium tetraisopropoxide and S-BINOL (59) (Scheme 47) [126]. The cycloaddition may be conducted with isoprene at slightly lower levels of enantioselectivi-ty methacrolein-cyclopentadiene Diels-Alder reactions are only moderately selective. 

A stable diaquo titanocene catalyzes aldehyde-cyclopentadiene Diels-Alder reactions in moderate to good enantioselectivities Odenkirk W, Bosnich B (1995) J Chem Soc Chem Commim 1181... 

A C2-symmetric bridged ferrocene catalyzes the methacrolein-cyclopentadiene Diels-Alder reaction in 10% ee Gibis K-L, Helmchen G, Huttner, G, Zsolnai L (1993) J Organomet Chem 445 181... 

Chlordane is prepared by reacting hexachlorocyclopentadiene (40) formed as the main product in the chlorination of cyclopentadiene (42) with hypochlorite or in the high temperature chlorination (470°C) of pentane, neopentane or cyclopentane with cyclopentadiene (Diels-Alder reaction), and chlorinating the 4,5,6,7,8,8-hexa-chloro-4,7-methano-3a,4,7,7a-tetrahydroindene (chlordene, 43) yielded by this reaction until two additional chlorine atoms are absorbed, obtaining 4,7-methano-... 

C, b.p. 170 C (decomp.), has a characteristic odour. It is the Diels-Alder product of cyclopentadiene reacting with itself, the exo-form being formed most rapidly but the endo-form is thermodynamically favoured. At temperatures above ISO C a retro-Diels-Alder reaction occurs and cyclopentadiene monomer is regenerated see diene reactions. 

Figure 1.2. Endo and exo pathway for the Diels-Alder reaction of cyclopentadiene with methyl vinyl ketone. As was first noticed by Berson, the polarity of the endo activated complex exceeds that of the exo counterpart due to alignment of the dipole moments of the diene and the dienophile K The symmetry-allowed secondary orbital interaction that is only possible in the endo activated complex is usually invoked as an explanation for the preference for endo adduct exhibited by most Diels-Alder reactions.

Figure 1.5. Chemical potential of the initial state, the transition state and the product of the Diels-Alder reaction between methyl vinyl ketone and cyclopentadiene in water as compared to 1-propanol The data are taken from r. 56.

Breslow studied the dimerisation of cyclopentadiene and the reaction between substituted maleimides and 9-(hydroxymethyl)anthracene in alcohol-water mixtures. He successfully correlated the rate constant with the solubility of the starting materials for each Diels-Alder reaction. From these relations he estimated the change in solvent accessible surface between initial state and activated complex " . Again, Breslow completely neglects hydrogen bonding interactions, but since he only studied alcohol-water mixtures, the enforced hydrophobic interactions will dominate the behaviour. Recently, also Diels-Alder reactions in dilute salt solutions in aqueous ethanol have been studied and minor rate increases have been observed Lubineau has demonstrated that addition of sugars can induce an extra acceleration of the aqueous Diels-Alder reaction . Also the effect of surfactants on Diels-Alder reactions has been studied. This topic will be extensively reviewed in Chapter 4. 

Fortunately, azachalcone derivatives (2.4a-g, Scheme 2.4) turned out to be extremely suitable dienophiles for Lewis-add catalysed Diels-Alder reactions with cyclopentadiene (2.5). This reaction is outlined in Scheme 2.4 and a large part of this thesis will be devoted to the mechanistic details of this process. The presence of a chromophore in 2.4 allows kinetic studies as well as complexation studies by means of UV-vis spectroscopy. Furthermore, the reactivity of 2.4 is such that also the... 

Interestingly, G jrey et al.", employing a similar tryptophan-derived catalyst (3.4), observed a 99% enantiomeric excess (ee) in the Diels-Alder reaction of 2-bromoacrolein with cyclopentadiene... 

Evans and co-workers investigated the effect of a number of -symmetric bis(oxazoline) ligands on the copper(II)-catalysed Diels-Alder reaction of an N-acyloxazolidinone with cyclopentadiene. Enantiomeric excesses of up to 99% have been reported (Scheme 3.4). Evans et al." suggested transition state assembly 3.7, with a square planar coordination environment around the central copper ion. In this scheme the dienophile should be coordinated predominantly in an cisoid fashion in... 

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. 

Tire results of a study of the effect of these catalysts on the model Diels-Alder reaction of methyl vinyl ketone (4.8) with cyclopentadiene (4.6) are summarised in Table 4.1... 

We chose benzyli dene acetone (4.39, Scheme 4.11) as a model dienophile for our studies. The uncatalysed Diels-Alder reaction of this compound with cyclopentadiene is slow, justifying a catalytic approach. Reaction of 4.39 with paraformaldehyde and dimethyl amine under acidic conditions in an aqueous ethanol solution, following a literature procedure, produced the HCl salt of 4.42 (Scheme 4.11). The dienophile was liberated in situ by adding one equivalent of base. 

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. 

Fortunately, in the presence of excess copper(II)nitrate, the elimination reaction is an order of magnitude slower than the desired Diels-Alder reaction with cyclopentadiene, so that upon addition of an excess of cyclopentadiene and copper(II)nitrate, 4.51 is converted smoothly into copper complex 4.53. Removal of the copper ions by treatment with an aqueous EDTA solution afforded in 71% yield crude Diels-Alder adduct 4.54. Catalysis of the Diels-Alder reaction by nickel(II)nitrate is also... 

This chapter describes the effects of micelles on the Diels-Alder reaction of compounds 5,1 a-g (see Scheme 5.1) with cyclopentadiene (5.2). As far as we know, our study is the first detailed kinetic analysis of micellar catalysis of a Diels-Alder reaction. 

The Diels-Alder reaction provides us with a tool to probe its local reaction environment in the form of its endo-exo product ratio. Actually, even a solvent polarity parameter has been based on endo-exo ratios of Diels-Alder reactions of methyl acrylate with cyclopentadiene (see also section 1.2.3). Analogously we have determined the endo-exo ratio of the reaction between 5.1c and 5.2 in surfactant solution and in a mimber of different organic and acpieous media. These ratios are obtained from the H-NMR of the product mixtures, as has been described in Chapter 2. The results are summarised in Table 5.3, and clearly point towards a water-like environment for the Diels-Alder reaction in the presence of micelles, which is in line with literature observations. 

Finally, in Chapter 5, micellar catalysis of Diels-Alder reactions is discussed. In view of the nonpolar nature of most Diels-Alder reactants, efficient micellar catalysis of this reaction was anticipated However, this has not been observed. The results for the Diels-Alder reaction between cyclopentadiene and substituted 3-phenyl-l-(2-pyridyl)-2-propene-l-one dienophiles, discussed in... 

Chapter 5, may provide a rationale. Conclusions derived from a number of H-MVIR measurements indicate that cyclopentadiene has a high affinity for the interior of the micelles that were investigated, whereas the dienophile prefers the outer regions. In view of the structures of most dienes and dienophiles such a spatial separation can be expected for the majority of Diels-Alder reactions. This arrangement accounts for the unexpectedly small influence of micelles on the rates of Diels-Alder reactions as reported in the literature. 

In summary, the work in this thesis provides an overview of what can be achieved with Lewis-acid and micellar catalysis for Diels-Alder reactions in water as exemplified by the reaction of3-phenyl-l-(2-pyridyl)-2-propene-l-ones with cyclopentadiene. Extension of the observed beneficial effect of water on rates and particularly enantioselectivities to other systems is envisaged. 

Acrolein a.s Dienophile. The participation of acrolein as the dienophile in Diels-Alder reactions is, in general, an exothermic process. Dienes such as cyclopentadiene and l-dieth5laniino-l,3-butadiene react rapidly with acrolein at room temperature. 

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