Diels-Alder reaction salts

Breslow supported this suggestion by demonstrating that the cycloaddition can be further accelerated by adding anti cliaotropic salts such as lithium chloride, whereas chaotropic salts such as guanidium chloride led to a retardation " "" ". On the basis of these experiments Breslow excluded all other possible explanations for the special effect of water on the Diels-Alder reaction " . 

Three years after the Breslow report on the large effects of water on the rate of the Diels-Alder reaction, he also demonstrated tliat the endo-exo selectivity of this reaction benefits markedly from employing aqueous media . Based on the influence of salting-in and saltirg-out agents, Breslow pinpoints hydrophobic effects as the most important contributor to the enhanced endo-exo... 

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. 

Furthermore, the number of diene - dienoplrile combinations that can be expected to undergo a Lewis-acid catalysed Diels-Alder reaction is limited. Studies by Wijnen leave little doubt that the rate of typical Diels-Alder reactions, where the dienophile is activated by one or more carbonyl functionalities, does not respond to the presence of Lewis acids in aqueous solution , at least not beyond the extent that is expected for non-specific interactions (salt effects). No coordination of the Lewis acid to the dienophile was observed in these cases, which is perhaps not surprising. Water is... 

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. 

Turning the argument around reactions that do not involve proton transfer steps will only experience a significant effect of the Lewis acids if a direct interaction exists between catalyst and reactant. The conventional Diels-Alder reaction is a representative of this class of reactions. As long as monodentate reactants are used, the effects of Lewis acids on this reaction do not exceed the magnitude expected for simple salt effects, i.e. there are no indications for a direct interaction between Lewis-acid and substrate. 

Table 1.21 Effect of metal salt on enantioselectivity in the Diels-Alder reaction of cyclopentadiene and acryloyloxazolidinone [22 ...

Kobayashi et al. have reported the use of a chiral lanthanide(III) catalyst for the Diels-Alder reaction [51] (Scheme 1.63, Table 1.26). Catalyst 33 was prepared from bi-naphthol, lanthanide triflate, and ds-l,2,6-trimethylpiperidine (Scheme 1.62). When the chiral catalyst prepared from ytterbium triflate (Yb(OTf)3) and the lithium or sodium salt of binaphthol was used, less than 10% ee was obtained, so the amine exerts a great effect on the enantioselectivity. After extensive screening of amines, ds-1,2,6-... 

The complexation procedure included addition of an equimolar amount of R,R-DBFOX/Ph to a suspension of a metal salt in dichloromethane. A clear solution resulted after stirring for a few hours at room temperature, indicating that formation of the complex was complete. The resulting solution containing the catalyst complex was used to promote asymmetric Diels-Alder reactions between cyclopen-tadiene and 3-acryloyl-2-oxazolidinone. Both the catalytic activity of the catalysts and levels of chirality induction were evaluated on the basis of the enantio-selectivities observed for the endo cycloadduct. 

Phosphonium salts containing a benzyl group may be converted into ylides by the use of only moderately strong bases such as sodium ethoxide. The preparation of benzyli-dene derivatives of aldehydes and ketones is therefore easily done. The procedure below is for the preparation of a substituted butadiene, which in turn is ideally suited for use in the Diels-Alder reaction (see Chapter 8, Section I). 

Diels-Alder reactions Neutral ionic liquids have been found to be excellent solvents for the Diels-Alder reaction. The first example of a Diels-Alder reaction in an ionic liquid was the reaction of methyl acrylate with cyclopentadiene in [EtNH3][N03] [40], in which significant rate enhancement was observed. Howarth et al. investigated the role of chiral imidazolium chloride and trifluoroacetate salts (dissolved in dichloromethane) in the Diels-Alder reactions between cyclopentadiene and either crotonaldehyde or methacroline [41]. It should be noted that this paper describes one of the first examples of a chiral cationic ionic liquid being used in synthesis (Scheme 5.1-17). The enantioselectivity was found to be < 5 % in this reaction for both the endo (10 %) and the exo (90 %) isomers. 

The first studies on cation-radical Diels-Alder reactions were undertaken by Bauld in 1981 who showed [33a] the powerful catalytic effect of aminium cation radical salts on certain Diels-Alder cycloadditions. For example, the reaction of 1,3-cyclohexadiene with trans, iraw5-2,4-hexadiene in the presence of Ar3N is complete in 1 h and gives only the endo adduct (Equation 1.14) [33]. 

The cycloaddition between furan and maleic anhydride was the first uncatalyzed aqueous Diels-Alder reaction reported in the literature and was studied by Diels and Alder themselves [11]. This cycloaddition was successfully revised by Woodward and Baer [12] and some years later by De Koning and coworkers [13]. The aqueous medium was also used in the cycloaddition of aromatic diazonium salts with methylsubstituted 1,3-butadienes [14]. 

Rideout and Breslow first reported [2a] the kinetic data for the accelerating effect of water, for the Diels Alder reactions of cyclopentadiene with methyl vinyl ketone and acrylonitrile and the cycloaddition of anthracene-9-carbinol with N-ethylmaleimide, giving impetus to research in this area (Table 6.1). The reaction in water is 28 to 740 times faster than in the apolar hydrocarbon isooctane. By adding lithium chloride (salting-out agent) the reaction rate increases 2.5 times further, while the presence of guanidinium chloride decreases it. The authors suggested that this exceptional effect of water is the result of a combination of two factors the polarity of the medium and the... 

Table 6.2 Sodium and guanidinium salt effects (relative reaction rates) of Diels-Alder reaction of anthracene-9-carbinol and N-ethylmaleimide...

C-Disaccharide analogs of trehalose were recently [20c] prepared by using as a key step an aqueous Diels-Alder reaction between the sodium salt of glyoxylic acid and the water soluble homochiral glucopyranosil-l,3-pentadiene 19 (Equation 6.1). A mixture of four diastereoisomers in a 41 24 21 14 proportion was obtained after esterification with methanol and acetylation. The main diaster-eoisomer 20 was isolated and characterized as benzoyl-derivative. 

Table 6.8 reports the relative reaction rates of Diels-Alder reactions of 2,5-dimethylbenzoquinone with tran -piperylene in different lithium salt solutions. The data show that the reaction rate depends on the concentration of LT and that in 4.0m LT-AC and 4.0m LT-DE the rate accelerations are comparable to that exhibited in 5.0m LP-DE and 5.0m LP-AC. 

Chloroaluminate ionic liquids (typically a mixture of a quaternary ammonium salt with aluminum chloride see Table 6.9) exhibit at room temperature variable Lewis acidity and have been successfully used as solvent/catalyst for Diels-Alder reactions [57]. The composition of chloroaluminate ionic liquids can vary from basic ([FMIM]C1 or [BP]C1 in excess) to acidic (AICI3 in excess) and this fact can be used to affect the reactivity and selectivity of the reaction. The reaction of cyclopentadiene with methyl acrylate is an example (Scheme 6.31). 

Aza-Diels-Alder reactions in aqueous soiutions cycioaddition of dienes with simpie iminium salts generated under Mannich conditions [22]... 

Kumar A. Salt Effects on Diels-Alder Reaction Kinetics Chem. Rev. 20011011 19... 

The salt is a colorless crystalline solid which is virtually insoluble in all common organic solvents. It reacts slowly with chloroform and carbon tetrachloride to give thallium(I) chloride 25), gives a characteristic red coloration with carbon disulfide, and undergoes the Diels-Alder reaction with maleic anhydride 110). It is rapidly decomposed by acids, but is stable to water this latter fact has been interpreted (55) in terms of the small free energy change for the reaction... 

---