The Diels-Alder Reaction Dienophiles

Diels-Alder reactions have long played an important role in synthetic organic chemistry. The reaction of a substituted benzoquinone and 1,3-butadiene, for example, was the first step in one of the early syntheses of steroids. The angular methyl group is introduced from the quinone, and the other functional groups were used for further structural elaboration. 

4d Methyl vinyl sulfone 5e Tetracyanoethylene 6f Diethyl vinylphosphonate 

Substituted alkynes 7f Esters of acetylenedicar-boxylic acid H C( )2CC=CCCKCHj 8E Hexafluoro-2-butyne F3CC=CCF3 9h Dibenzoylacetylene O O II II PhCC=CCPh 

Heteroatomic dienophiles 111 Esters of azodicarboxylic acid 12k 4-Phenyl-l,2,4-triazoline-3,5-dione 131 hninocarbamates 

The synthetic utility of the Diels-Alder reaction can be significantly expanded by the use of dienophiles that contain masked functionality and are the synthetic equivalents of unreactive or inaccessible species (see Section 13.2 for a more complete discussion of the concept of synthetic equivalents). For example, a-chloroacrylonitrile shows satisfactory reactivity as a dienophile. The a-chloronitrile functionality in the adduct can be hydrolyzed to a carbonyl group. Thus, a-chloroacrylonitrile can function as the equivalent of ketene, 

T Maleic anhydride 2 Benzoquinone 0 A 3 Vinyl ketones, acrolein, acrylate esters, acrylonitrile, nitroalkenes, etc. RCH=CH—X 

4 Methyl vinyl sulfone 5 Tetracyanoethylene 6 Diethyl vinylphosphonate 

The synthetic utility of the Diels-Alder reaction can be significantly expanded by the use of dienophiles that contain masked functionality and are the synthetic equivalent of unreactive or inaccessible species. For example, a-chloroacrylonitrile 

Nitroalkenes are good dienophiles, and the variety of transformations that are available for nitro groups make them versatile intermediates. Nitro groups can be coverted to carbonyl groups by reductive hydrolysis, so nitroethylene can be used as a ketene equivalent. 

Vinyl sulfones are reactive as dienophiles. The sulfonyl group can be removed reductively with sodium amalgam. In this two-step reaction sequence, the vinyl sulfone functions as an ethylene equivalent. The sulfonyl group also permits alkylation of the adduct, via the carbanion. This three-step sequence permits the vinyl sulfone to serve as the synthetic equivalent of a terminal alkene.  

Examples of some compounds that exhibit a high level of dienophilic reactivity are collected in Table 7.1 and examples of Diels-Alder reactions of several of them 

Substituted Alkynes 7 Esters of acetylenedicar-boxylic acid 

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Compounds containing a double or triple bond, usually activated by additional unsaturation (carbonyl, cyano, nitro, phenyl, etc.) In the ap position, add to the I 4-positions of a conjugated (buta-1 3-diene) system with the formation of a ax-membered ring. The ethylenic or acetylenic compound is known as the dieTwphile and the second reactant as the diene the product is the adduct. The addition is generally termed the Diels-Alder reaction or the diene synthesis. The product in the case of an ethylenic dienophile is a cyctohexene and in that of an acetylenic dienophile is a cyctohexa-1 4-diene. The active unsaturated portion of the dienophile, or that of the diene, or those in both, may be involved in rings the adduct is then polycyclic. 

In the Diels-Alder reaction (in older literature referred to as the diene synthesis ) a six-membered ring is fonned through fusion of a four-tt component, usually a diene and a two-7C component, which is commonly referred to as the dienophile (Scheme 1.1). 

Despite this overwhelming body of evidence, two-step mechanisms have been suggested for the Diels-Alder reaction, probably inspired by special cases, where highly substituted dienes and/or dienophiles have been found to react through zwitterionic or biradicalintermediates (Scheme 1.2). 

Another form of selectivity can arise when substitirted dienes and dienophiles are employed in the Diels-Alder reaction. Two different cycloadducts denoted as endo and exo can then be formed (Figure 1.2). 

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.

In 1961 Berson et al. were the first to study systematically the effect of the solvent on the endo-exo selectivity of the Diels-Alder reaction . They interpreted the solvent dependence of the endo-exo ratio by consideririg the different polarities of the individual activated complexes involved. The endo activated complex is of higher polarity than the exo activated complex, because in the former the dipole moments of diene and dienophile are aligned, whereas in the latter they are pointing in... 

Scheme 2.5. Synthesis of the ionic dienophiles 2.4f and 2.4g. features of the nncatalysed reaction will be discussed The kinetics of the Diels-Alder reaction of 2,4...

The rate of the uncatalysed reaction in all four solvents is rather slow. (The half-life at [2.5] = 1.00 mM is at least 28 hours). However, upon complexation of Cu ion to 2.4a-g the rate of the Diels-Alder reaction between these compounds and 2.5 increases dramatically. Figure 2.2 shows the apparent rate of the Diels-Alder reaction of 2.4a with 2.5 in water as a lunction of the concentration of copper(II)nitrate. At higher catalyst concentrations the rate of the reaction clearly levels off, most likely due to complete binding of the dienophile to the catalyst. Note that in the kinetic experiments... 

The mechanism by which Lewis-acids can be expected to affect the rate of the Diels-Alder reaction in water is depicted in Scheme 2.6. The first step in the cycle comprises rapid and reversible coordination of the Lewis-acid to the dienophile, leading to a complex in which the dienophile is activated for reaction with the diene. After the irreversible Diels-Alder reaction, the product has to dissociate from the Lewis-acid in order to make the catalyst available for another cycle. The overall... 

In the kinetic runs always a large excess of catalyst was used. Under these conditions IQ does not influence the apparent rate of the Diels-Alder reaction. Kinetic studies by UV-vis spectroscopy require a low concentration of the dienophile( 10" M). The use of only a catalytic amount of Lewis-acid will seriously hamper complexation of the dienophile because of the very low concentrations of both reaction partners under these conditions. The contributions of and to the observed apparent rate constant have been determined by measuring k pp and Ka separately. ... 

Studies of the Diels-Alder reaction of the ionic dienophile 2.4g have demonstrated that the acpieous acceleration of the uncatalysed reaction as well as the catalysed reaction is not significantly affected by the presence of the ionic group at a site remote from the reaction centre. 

In summary, when using a ligand catalyst ratio of 1.75 1 at pH 5-6 the enantioselectivity of the Diels-Alder reaction between 3.8c and 3.9 is dictated by the activated complexes involving ligand, copper(ir) ion, dienophile and diene. Considering that four different products are formed in this reaction (see Scheme 3.5), at least four different activated complexes are involved However, each of these complexes hus two degrees of freedom that determine the stereochemical outcome of the... 

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 this section the influence of micelles of cetyltrimethylammonium bromide (CTAB), sodium dodecylsulfate (SDS) and dodecyl heptaoxyethylene ether (C12E7) on the Diels-Alder reaction of 5.1a-g with 5.2 in the absence of Lewis-add catalysts is described (see Scheme 5.1). Note that the dienophiles can be divided into nonionic (5.1a-e), anionic (5.If) and cationic (5.1g) species. A comparison of the effect of nonionic (C12E7), anionic (SDS) and cationic (CTAB) micelles on the rates of their reaction with 5.2 will assess of the importance of electrostatic interactions in micellar catalysis or inhibition. 

The Diels-Alder reaction of dienophiles 5.1a-e, containing neutral, cationic or anionic substituents, with diene 5.2 in the absence of Lewis acids is retarded by micelles of CTAB, SDS and C12E7. In the situation where the dienophile does not bind to the micelle, the reaction is inhibited because uptake of... 

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... 

A second question involves the influence of ligands on the rate and selectivity of the Lewis-acid catalysed Diels-Alder reaction in water. In Chapter 3 we have demonstrated that nearly all the ligands studied induce a significant decrease in the affinity of the catalyst for the dienophile. This effect is accompanied by a modest reduction of the rate of the Diels-Alder reaction of the ternary dienophile -catalyst - ligand complex. 

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... 

Also the arene-arene interactions, as encountered in Chapter 3, are partly due to hydrophobic effects, which can be ranked among enforced hydrophobic interactions. Simultaneous coordination of an aromatic oc amino acid ligand and the dienophile to the central copper(II) ion offers the possibility of a reduction of the number of water molecules involved in hydrophobic hydration, leading to a strengthening of the arene-arene interaction. Hence, hydrophobic effects can have a beneficial influence on the enantioselectivity of organic reactions. This effect is anticipated to extend well beyond the Diels-Alder reaction. 

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