Acidity in Diels-Alder

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. 

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],... 

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 possibility that metallocenes might function as Lewis acids in Diels-Alder reactions was probed with ferrocenium hexafluorophosphate [184]. The answer is affirmative the cycloadditions studied include methacrolein, crotonaldehyde, and methyl vinyl ketone as dienophiles and butadienes and cyclopentadienes as diene components. Yields are in the range 60-80 % with reaction times of 3-36 h at 0 to 20 °C. Fair to good yields were also obtained in reactions of isoprene and cyclopentadiene with acrolein and methyl vinyl ketone in the presence of 1 % [Pd(PPh3)2(MeCN)2](BF4)2 (in CH2CI2, room temperature). Methyl acrylate resulted in low yields, and chiral modification with (5)-BINAP is reported to give the cycloadducts with modest enantioselectivity [164]. 

Kiindig et al [14] have reported the synthesis of the new chiral ruthenium complexes, [CpRu(biphop-F)] (45) and [(Indenyl)Ru(biphop-F)] (46), and have shown their efficiency as Lewis acids in Diels-Alder reactions of methacrolein (24a) with cyclopentadiene (Scheme 16.14, Table 16.3). The corresponding cycloadduct (25) was observed in high exo selectivities. They found that the rate of Diels-Alder reaction varied with the catalyst counteranion and it increased in order BF4 < SbF6 < TFPB (tetrakis[3,5-bis(trifluoromethyl)phenylj borate). 

Diels-Alder Reactions. Diels-Alder reactions are enhanced through the complexation of dienophiles or dienes by Lewis acids. Furthermore, Lewis acids have been successfully employed in asymmetric Diels-Alder additions. Although SnCU is a useful Lewis acid in Diels-Alder reactions, in most instances titanium or aluminum Lewis acids provide higher yields and/or selectivities. The stereoselectivity in Lewis acid-promoted Diels-Alder reactions between chiral a. -unsaturated IV-acy loxazolidinones shows unexpected selectivities as a function... 

Unfortunately, the number of mechanistic studies in this field stands in no proportion to its versatility" . Thermodynamic analysis revealed that the beneficial effect of Lewis-acids on the rate of the Diels-Alder reaction can be primarily ascribed to a reduction of the enthalpy of activation ( AAH = 30-50 kJ/mole) leaving the activation entropy essentially unchanged (TAAS = 0-10 kJ/mol)" . Solvent effects on Lewis-acid catalysed Diels-Alder reactions have received very little attention. A change in solvent affects mainly the coordination step rather than the actual Diels-Alder reaction. Donating solvents severely impede catalysis . This observation justifies the widespread use of inert solvents such as dichloromethane and chloroform for synthetic applications of Lewis-acid catalysed Diels-Alder reactions. 

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. 

What is the effect of water on the rate and selectivity of the Lewis-acid catalysed Diels-Alder reaction, when compared to oiganic solvents Do hydrogen bonding and hydrophobic interactions also influence the Lewis-acid catalysed process Answers to these questions will be provided in Chapter 2. 

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... 

Rate constants for the Diels-Alder reaction of 2.4b-e have also been determined. The results are shown in Table 2.3. These data allow an analysis of the influence of substituents on the Lewis-acid catalysed Diels-Alder reaction. This is interesting, since there are indications for a relatively large... 

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. 

Clearly, complete understanding of solvent effects on the enantioselectivity of Lewis-acid catalysed Diels-Alder reactions has to await future studies. For a more detailed mechanistic understanding of the origins of enantioselectivity, extension of the set of solvents as well as quantitative assessment of the strength of arene - arene interactions in these solvent will be of great help. 

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. 

Throughout this thesis reference has been made to hydrophobic effects. Enforced hydrophobic interactions are an important contributor to the acceleration of uncatalysed and also of the Lewis-acid catalysed Diels-Alder reactions which are described in this thesis. Moreover, they are likely to be involved in the beneficial effect of water on the enantioselectivity of the Lewis-acid catalysed Diels-Alder reaction, as described in Chapter 3. Because arguments related to hydrophobic effects are spread over nearly all chapters, and ideas have developed simultaneously, we summarise our insights at the end of this thesis. 

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. 

Sorbic acid is oxidized rapidly in the presence of molecular oxygen or peroxide compounds. The decomposition products indicate that the double bond farthest from the carboxyl group is oxidized (11). More complete oxidation leads to acetaldehyde, acetic acid, fumaraldehyde, fumaric acid, and polymeric products. Sorbic acid undergoes Diels-Alder reactions with many dienophiles and undergoes self-dimerization, which leads to eight possible isomeric Diels-Alder stmctures (12). 

Nitro compounds have been converted into various cyclic compounds via cycloaddidon reactions. In particular, nitroalkenes have proved to be nsefid in Diels-Alder reactions. Under thermal conditions, they behave as electron-deficient alkenes ind react v/ith dienes to yield 3-nitrocy-clohexenes. Nitroalkenes c in also act as heterodienes ind react v/ith olefins in the presence of Lewis acids to yield cyclic alkyl nkronates, which undergo [3- 2 cycloaddidon. Nitro compounds are precursors for nitnie oxides, alkyl nitronates, and trialkylsilyl nitronates, which undergo [3- 2 cycloaddldon reacdons. Thus, nitro compounds play important roles in the chemistry of cycloaddidon reacdons. In this chapter, recent developments of cycloaddinon chemistry of nitro compotmds and their derivadves are summarized. 

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