Diels-Alder reactions water promoted

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. 

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... 

It is believed that clay minerals promote organic reactions via an acid catalysis [2a]. They are often activated by doping with transition metals to enrich the number of Lewis-acid sites by cationic exchange [4]. Alternative radical pathways have also been proposed [5] in agreement with the observation that clay-catalyzed Diels-Alder reactions are accelerated in the presence of radical sources [6], Montmorillonite K-10 doped with Fe(III) efficiently catalyzes the Diels-Alder reaction of cyclopentadiene (1) with methyl vinyl ketone at room temperature [7] (Table 4.1). In water the diastereoselectivity is higher than in organic media in the absence of clay the cycloaddition proceeds at a much slower rate. 

Catalysts such as Fe(BuEtCHC02)3 have been d eloped that are effective for the heteroatom Diels-Alder reaction. Indium trichloride (InCls) is a good catalyst for imino-Diels-Alder reactions. Hetero-Diels-Alder reactions involving carbonyls have been done in water. Ultrasound has been used to promote the Diels-Alder reactions of 1-azadienes. ... 

A slightly modified synthesis of dihydrobenzo[c]furan was achieved, in which the key reaction involved the exposure of a dibromide to dry alumina and one equivalent of water in toluene instead of in hexanes <07TL3039>. Another synthesis of dihydrobenzo[c]furans was reported by Hashmi and Teles <07SL1747> and an example is depicted below. Base-promoted cycloaddition of 1-aryl- or l-aryl-7-substituted-4-oxahepta-1,6-diynes in DMSO were found to involve an anionic intramolecular Diels-Alder reaction, and also resulted in the formation of dihydrobenzo[c]furans <07JA4939>. 

Applications of the water-promoted aggregation effects in diastereoface controlled or iminium Diels-Alder reactions will be discussed in Section 4.1.5.2 (Scheme 66) and in Ch ter 4.2, respectively. 

For example, an effective procedure for the synthesis of LLB (where LL = lanthanum and lithium) is treatment of LaCls 7H2O with 2.7 mol equiv. BINOL dilithium salt, and NaO-t-Bu (0.3 mol equiv.) in THF at 50 °C for 50 h. Another efficient procedure for the preparation of LLB starts from La(0-/-Pr)3 [54], the exposure of which to 3 mol equiv. BINOL in THF is followed by addition of butyllithium (3 mol equiv.) at 0 C. It is worthy of note that heterobimetallic asymmetric complexes which include LLB are stable in organic solvents such as THF, CH2CI2 and toluene which contain small amounts of water, and are also insensitive to oxygen. These heterobimetallic complexes can, by choice of suitable rare earth and alkali metals, be used to promote a variety of efficient asymmetric reactions, for example nitroaldol, aldol, Michael, nitro-Mannich-type, hydrophosphonylation, hydrophosphination, protonation and Diels-Alder reactions. A catalytic asymmetric nitroaldol reaction, a direct catalytic asymmetric aldol reaction, and a catalytic asymmetric nitro-Mannich-type reaction are discussed in detail below. 

It is noted that the Diels-Alder reaction has been done with supercritical and with supercritical water as solvents. Diels-Alder reactions on solid supports have also been reported, and zeolites have been used in conjunction with catalytic agents. ° Alumina has been used to promote Diels-Alder reactions. ° Diels-Alder reactions can be done in ionic liquids,including asymmetric Diels-Alder reactions. ... 

On the basis of Monte Carlo simulations [40] and molecular orbital calculations [26a], hydrogen bonding was proposed as the key factor controlling the variation of the acceleration for Diels-Alder reactions in water. Experimental differences of rate acceleration in water-promoted cycloadditions were recently observed [41]. Cycloadditions of cyclopentadiene with acridizinium bromide, acrylonitrile and methyl vinyl ketone were investigated in water and in ethanol for comparison (Scheme 3). Only a modest rate acceleration of 5.3 was found with acridizinium bromide, which was attributed to the absence of hydrogenbonding groups in the reactants. The acceleration factor reaches about 14 with acrylonitrile and 60 with methyl vinyl ketone, which is the best hydrogen-bond acceptor [41]. 

Reusability is a characteristic of the sensitizers prepared by stirring Ceo-fullerene with aminomethylated poly(styrene/vinylbenzene). They have been used to promote the standard O2 oxidation processes such as ene and Diels-Alder reactions (Scheme 7), and catalysts suitable for photoxidations in water have been prepared from them by reaction with poly(allylamine). The same reactions have been carried out using a novel solvent-free procedure which involves loading a porphyrin into solvent-swollen polystyrene beads and carrying out the photo-oxidation in neat liquid substrate. The formation of the allylic hydroperoxide (89) from p-pinene, with complete conversion and in 84% yield, is particularly noteworthy, as the standard liquid-phase reaction can be problematic. It is suggested that the possibility of using this approach under solar conditions is further evidence of the sustainable, green chemistry potential of synthetic photochemistry. 

In these cases the size of the activation volumes obviously depends not only on the effective packing probably caused by the restriction of vibrations and rotations in the transition state, but also on the transition-state polarization enhanced by the polar groups leading to a further decrease in volume which is not observed in the less polarized cycloadducts. Blake and Jorgensen [51] have assumed similar effects to explain the acceleration of Diels-Alder reactions in water. Catalytic and solvophobic promotion of high pressure addition reactions will be discussed in Chapter 11. 

Diels-Alder reactions may be accelerated and the selectivities enhanced if the cycloaddition reactions are conducted in water or under high pressure or in the presence of a Lewis acid (see Section 3.1.3). In water at room temperature, cyclopentadi-ene reacts with methyl vinyl ketone 700 times faster than in 2,2,4-trimethylpentane and the endo exo selectivity rises from about 4 1 to more than 20 1. This can be ascribed to hydrophobic effects, which promote aggregation of non-polar species. Diels-Alder reactions in water are normally carried out with (at least partially) water-soluble dienes such as sodium salts of dienoic acids. Thus, a key step in a formal synthesis of vitamin D3 involved the cycloaddition of the sodium salt 46 with methacrolein in water, to give the adducts 47 and 48 in high yield and a ratio of 4.7 1 after 16 h (3.43). In contrast, the corresponding methyl ester of the diene in excess neat methacrolein at 55 °C gave only a 10% yield of a 1 1 mixture of isomers after 63... 

Friedrich Cramer did the first work in this area, and early work was done by Myron Bender. In Bender s studies, a bound ester reacted with a hydroxyl group on the rim of the cyclodextrin to undergo a transesterification, with reasonable geometric selectivity and some rate acceleration. This was followed up with substrates better designed to be accelerated by such a process, and this will be the first part of the review. Then there are some reactions in which cyclodextrin promotes a process but is not itself transformed, and the first example of this was work we reported on selective aromatic substitution, the second section of this review. I also describe the use of cyclodextrins to catalyse Diels-Alder reactions, in which both the diene and the dienophile can bind into the cyclodextrin cavity in water and in water-like solvents. 

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