Acid catalysts Diels-Alder reaction

In a Lewis-acid catalysed Diels-Alder reaction, the first step is coordination of the catalyst to a Lewis-basic site of the reactant. In a typical catalysed Diels-Alder reaction, the carbonyl oxygen of the dienophile coordinates to the Lewis acid. The most common solvents for these processes are inert apolar liquids such as dichloromethane or benzene. Protic solvents, and water in particular, are avoided because of their strong interactions wifti the catalyst and the reacting system. Interestingly, for other catalysed reactions such as hydroformylations the same solvents do not give problems. This paradox is a result of the difference in hardness of the reactants and the catalyst involved... 

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. 

The effect of ligands on the endo-exo selectivity of Lewis-acid catalysed Diels-Alder reactions has received little attention. Interestingly, Yamamoto et al." reported an aluminium catalyst that produces mainly exo Diels-Alder adduct. The endo-approach of the diene, which is normally preferred, is blocked by a bulky group in the ligand. 

This goal might well be achieved by introducing an auxiliary that aids the coordination to the catalyst. After completion of the Diels-Alder reaction and removal of the auxiliary the desired adduct is obtained. This approach is summarised in Scheme 4.6. Some examples in which a temporary additional coordination site has been introduced to aid a catalytic reaction have been reported in the literature and are described in Section 4.2.1. Section 4.2.2 relates an attempt to use (2-pyridyl)hydrazone as coordinating auxiliary for the Lewis-acid catalysed Diels-Alder 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. 

The rate of the Lewis-acid catalysed Diels-Alder reaction in water has been compared to that in other solvents. The results demonstrate that the expected beneficial effect of water on the Lewis-acid catalysed reaction is indeed present. However, the water-induced acceleration of the Lewis-add catalysed reaction is not as pronounced as the corresponding effect on the uncatalysed reaction. The two effects that underlie the beneficial influence of water on the uncatalysed Diels-Alder reaction, enforced hydrophobic interactions and enhanced hydrogen bonding of water to the carbonyl moiety of 1 in the activated complex, are likely to be diminished in the Lewis-acid catalysed process. Upon coordination of the Lewis-acid catalyst to the carbonyl group of the dienophile, the catalyst takes over from the hydrogen bonds an important part of the activating influence. Also the influence of enforced hydrophobic interactions is expected to be significantly reduced in the Lewis-acid catalysed Diels-Alder reaction. Obviously, the presence of the hydrophilic Lewis-acid diminished the nonpolar character of 1 in the initial state. 

The Chiral Lewis Acid-catalyzed Diels-Alder Reaction 9 Fig. 1.1 CAB catalyst 3 and methacrolein Me... 

In 1993, Evans et al. (198) demonstrated that bis(oxazoline)-Cu(II) complexes are effective Lewis acids for Diels-Alder reaction of acryloylimide and cyclopen-tadiene. These Lewis acids are capable of inducing reaction at -78°C with only 5 mol% catalyst loadings, providing the cycloadduct in 86% isolated yield and 98 2... 

A more versatile method to use organic polymers in enantioselective catalysis is to employ these as catalytic supports for chiral ligands. This approach has been primarily applied in reactions as asymmetric hydrogenation of prochiral alkenes, asymmetric reduction of ketone and 1,2-additions to carbonyl groups. Later work has included additional studies dealing with Lewis acid-catalyzed Diels-Alder reactions, asymmetric epoxidation, and asymmetric dihydroxylation reactions. Enantioselective catalysis using polymer-supported catalysts is covered rather recently in a review by Bergbreiter [257],... 

Hubbard and Miller87 used a Lewis acid catalyzed Diels-Alder reaction between y.y-disubstituted o. /i-unsaluralcd esters and cyclopentadiene in their approach toward oligomeric cyclopentanoids. In order for the reaction to proceed, they needed to add trimethylaluminum as a desiccant prior to addition of the Lewis acid catalyst aluminum trichloride. The endo/exo selectivity of the reaction with 97, depicted in equation 29, increased from 98/99 = 75/25 to 88/12 when the reaction temperature was dropped from room temperature to —20 °C. 

Carbohydrates have found widespread use as chiral auxiliaries in asymmetric Diels-Al-der reactions156. A recent example is a study conducted by Ferreira and colleagues157 who used carbohydrate based chiral auxiliaries in the Lewis acid catalyzed Diels-Alder reactions of their acrylate esters 235 with cyclopentadiene (equation 66). Some representative results of their findings, including the ratios of products 236 and 237, have been summarized in Table 9. The formation of 236 as the main product when diethylaluminum chloride was used in dichloromethane (entry 3) was considered to be the result of an equilibrium between a bidentate and monodentate catalyst-dienophile complex. The bidentate complex would, upon attack by the diene, lead to 236, whereas the monodentate complex would afford 236 and 237 in approximately equal amounts. The reversal of selectivity on changing the solvent from dichloromethane to toluene (entry 2 vs 3) remained unexplained by the authors. 

The most important development within the field of Diels-Alder chemistry during the past two decades must be considered to be the design and application of chiral Lewis acid catalysts. From the mid 80s on, the number of literature reports about the design and application of chiral Lewis acids in the synthesis of chiral Diels-Alder adducts from achiral precursors grew exponentially, but it started to level off and decrease again in the mid 90s. Several excellent reviews about the application of chiral Lewis acids in Diels-Alder reactions have been published41,43 44. In this section, the recent literature about the chiral Lewis acid catalyzed all-carbon Diels-Alder reactions of dienes with dienophiles is reviewed, which, as such, has not been reviewed before. 

In the preceding paragraphs the advantages of water in uncatalysed Diels-Alder reactions were outlined. An important question is whether these advantages can be transferred to Lewis acid catalysed reactions as well. Since the majority of Diels-Alder reactants are likely to have a negligible tendency to interact with Lewis acid catalysts in water, this issue was addressed only recently. The first step was the development of water-tolerant catalytic systems for [4 + 2]-cycloadditions, and there are now a few examples of Lewis acid catalysed Diels-Alder reactions that not only tolerate the presence of small amounts of water281-284 but even benefit from it285. An example of a Lewis acid catalysed Diels-Alder reaction carried out in water THF mixture is presented in Scheme 12286. 

Lewis acids as catalysts (Diels-Alder reactions),... 

The rac-isomers have a twofold axis and therefore C2-symmetry. The meso-isomer has a mirror plane as the symmetry element and therefore Cs-symmetry. For polymerisation reactions the racemic mixture can be used since the two chains produced by the two enantiomers are identical when begin- and end-groups are not considered. Note When catalysts of this type are to be used for asymmetric synthesis, e.g. as Lewis acids in Diels-Alder reactions, separation of the enantiomers is a prerequisite [25],... 

An extensive review of the use of chiral Lewis acid catalysts in Diels-Alder cycloadditions has been presented. Brpnsted acid-assisted chiral Lewis acids have been shown to be highly efficient catalysts for the enantioselective Diels-Alder reactions of a- and /3-substituted-Q, /i-enals with numerous dienes. The chiral Lewis acid-catalysed Diels-Alder reaction between cyclopentadiene and alkenoyloxazolidi-nones can be catalysed by bis(oxazolone)magnesium catalysts. ... 

Acyloxyboranes. Yamamoto et a/.1 have used the known reactivity of borane with carboxylic acids to activate acrylic acids for Diels-Alder reactions. Thus addition of BH3-THF to acrylic acids at 0° furnishes an acyloxyborane formulated as 1, which undergoes cycloaddition (equations I and II). The reaction proceeds satisfactorily even when borane is used in catalytic amounts. A chiral acyloxyborane, BL, prepared from a tartaric acid derivative, can serve as a catalyst for an asymmetric Diels-Alder reaction (equation III). 

The four possible transition-state structures for the Lewis acid-promoted Diels-Alder reaction of cyclopentadiene with propynal are depicted in Fig. 7. In the chiral Lewis acid-promoted reaction, the enantiomeric excess of an adduct originates in the enantiofacial selectivity of cyclopentadiene, which has prochiral reactive centers. The enantioselective pathway presupposes three characteristics (i) the chiral Lewis acid must sterically shield one enantioface of the coordinated propynal because the open acetylenic jr-face in the chiral catalyst-dienophile complex approaches one face of... 

The use of catalyst 187 or 188 (see Sch. 43) in cycloadditions requires anhydrous conditions. Recently, several practical alternatives for this requirement have been reported. Evans has shown that the easily manipulated aquo complex prepared from 187 and water can be dehydrated to the active catalyst in the reaction vessel by addition of molecular sieves, without any loss of reactivity or selectivity [87]. Copper(II) perchlorate is available commercially as a hexahydrate. Ghosh and co-workers have reported that a complex 207 prepared from an aminoindanol-derived bisoxazoline and Cu(C104)2 6H2O is an excellent Lewis acid in Diels-Alder reactions (Sch. 46). It is interesting to note that the generally sluggish reactions with oxazolidinone croto-nates proceed with very high selectivity at room temperature [88]. 

The Diels-Alder reaction is one of the most fundamental means of preparing cyclic compounds. Since discovery of the accelerating effect of Lewis acids on the Diels-Alder reaction of a,)3-unsaturated carbonyl compounds [341-344], its broad and fine application under mild reaction conditions has been amplified. Equations (140) [341] and (141) [345], respectively, illustrate typical dramatic effects from an early reaction and from one reported more recently. Lewis acid-promoted Diels-Alder reactions have been reviewed [7,8,346-353]. In addition to the acceleration of the reaction, other important feature is its alteration of chemo-, regio-, and diastereoselectivity this will be discussed below. The titanium compounds used in Diels-Alder reaction are titanium halides (TiX4), alkoxides (Ti(OR)4), or their mixed salts (TiX (OR)4 n = 1-3). A cyclopentadienyl complex such as Cp2Ti(OTf)2 is also documented as a very effective promoter of a Diels-Alder reaction [354], In addition to these titanium salts, a few compounds such as those in Eq. (142) [355] have recently been reported to effect the Diels-Alder reaction. The third, [(/-PrO)2Ti(bpy)(OTf)(i-PrOH)] (OTf), was estimated to be a more active catalyst than Cp2Ti(OTf)2. 

The catalytic role of Mg + in Scheme 12 is ascribed to the 1 1 and 1 2 complex formation of Q and Mg +, which results in an increase in kobs with an increase in [Mg +], exhibiting first- and second-order dependences on [Mg ], respectively (Figure 7). This contrasts with the Lewis acid catalysis in conventional concerted Diels-Alder reactions, in which the catalyst is believed to activate dienophiles (not the radical anions) by coordination to the acidic metal center [208-212]. However, the exact catalytic mechanism of numerous Lewis acid-catalyzed Diels-Alder reactions [208-212] has yet to be clarified, including a possible contribution of Lewis-acid catalyzed electron transfer step. 

Theoretical calculations have also permitted one to understand the simultaneous increase of reactivity and selectivity in Lewis acid catalyzed Diels-Alder reactions . This has been traditionally interpreted by frontier orbital considerations through the destabilization of the dienophile s LUMO and the increase in the asymmetry of molecular orbital coefficients produced by the catalyst. Birney and Houk have correctly reproduced, at the RHF/3-21G level, the lowering of the energy barrier and the increase in the endo selectivity for the reaction between acrolein and butadiene catalyzed by BH3. They have shown that the catalytic effect leads to a more asynchronous mechanism, in which the transition state stmcture presents a large zwitterionic character. Similar results have been recently obtained, at several ab initio levels, for the reaction between sulfur dioxide and isoprene. ... 

Although cycloadditions and rearrangements often proceed without catalysts, the selectivity of the reaction and the reactivity of very reluctant molecules can be enhanced by a Lewis acid. The Diels-Alder reaction can be performed at enhanced reaction rate in ionic liquids with the addition of ZnCl2 (eq. (4)) [42]. The Claisen rearrangement was also reported to be superior if catalyzed by Sc(OTf)3 in ionic liquids [43]. 

The chiral Lewis acid catalyzed cycloaddition of methacrolein 310 to cyclopentadiene predominantly affording exo cycloadduct 322 together with some 323 has been extensively investigated. The apphcation of menthoxyaluminum dichloride (324) as the chiral catalyst in this reaction represents one of the earliest examples of a chiral Lewis acid catalyzed Diels-Alder reaction (equation 90). The authors confinned their results in 1987, but the ee was revised from 72% to 57%20. ... 

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