Diels-Alder reactions, pressure effects, high

Whereas maleic anhydride can react with furan (139a) at ambient pressure, citraconic anhydride (140) reacts only at high pressures due to the strong deactivating effect of the methyl group (Schemes 5.21 and 5.22). The two-step synthesis [53] of the palasonin (141), in an overall yield of 96 %, is a good example of the acceleration of the Diels-Alder by high pressure (Scheme 5.21). Previous synthesis [54] based on the thermal Diels-Alder reaction of furan with methoxy carbonyl maleic anhydride required 12 steps. 

Intermolecular befera-Diels-Alder reactions of enamino ketones with highly substituted vinyl ethers. Effect of high pressure on the kinetics and diastereoselectivity [77]... 

The Diels-Alder reaction can be greatly enhanced by high pressure (Chapter 5) but the effect of pressure is generally weaker in aqueous medium than in organic solvent. Results of high pressure-mediated Diels-Alder reactions of furans and acrylates in water and dichloromethane are reported in Table 6.6 [32]. In aqueous medium the cycloadditions occur with lower yields and less diastereoselectivity than in dichloromethane and, in some cases, addition-substitution reactions were observed. 

In Scheme 14 the effect of pressure on Diels-Alder reactions with acyclic heterodienophiles or heterodienes is presented. The application of high pressure leads also in these reactions to an enhancement of rates and improvement of yields. The hetero-Diels-Alder reaction (entry 3) is a good example of the interplay between pressure and temperature. At high pressure the rate of reaction as well as the diastereoselectivity are increased. The pressure-induced acceleration allows the temperature of reaction to be lowered, which leads to a further increase of diastereoselectivity. 

Whilst it is obviously valuable to measure the solubility of reagents in the SCF, it is important to be aware that the solubility in a multicomponent system can be very different from that in the fluid alone. It is also important to note that the addition of reagents and catalysts can have a profound effect on the critical parameters of the mixture. Indeed, at high concentrations of reactants, the mole fraction of C02 is necessarily lower and it may not be possible to achieve a supercritical phase at the temperature of interest. Increases in pressure (i.e. further additions of C02) could yield a single liquid phase (which would have a much lower compressibility than scC02). For example, the Diels-Alder reaction (see Chapter 7) between 2-methyl-1,3-butadiene and maleic anydride has been carried out a pressure of 74.5 bar and a temperature of 50 °C, assuming that this would be under supercritical conditions as it would if it were pure C02. However, the critical parameters calculated for this system are a pressure of 77.4bar and a temperature of 123.2 °C, far in excess of those used [41]. 

While many observations are well understood, e.g. those dealing with the reaction rate or with the selectivity, there are some factors which cannot be generalized. Many transformations of particular reactants or under unusual reaction conditions led to unexpected results. There are often singular explanations for such reactions but no overall concept. For instance, computations on Diels-Alder transition structures and thermodynamics of retro-Diels-Alder reactions confirmed that the activation volume of these [4 + 2]-cycloadditions is negative80. This result, pointing to the compact character of the transition structure, is used to explain the dependence of reactivity and selectivity on internal as well as external pressure81-83. These effects are only observed at relatively high external pressures (Table 5). 

A number of other methods have been reported for the acceleration of Diels-Alder reactions, including the use of a microwave oven,877 water as a solvent (a hydrophobic effect),878 5 M LiC104 in Et20 as solvent,879 absorption of the reactants on chromatographic absorbents,880 and the use of an ultracentrifuge881 (one of several ways to achieve reaction at high pressures).882... 

Diels-Alder reactivity of thiophene and benzothiophene remains poorly understood. AMI semiempirical studies examining the activation of thiophene for this thermally allowed [4+2] cycloaddition process have shown that the usual synthesis approaches (use of highly reactive dienophiles, substitution on thiophene, increased reaction pressures) have only small effects on rate enhancement. However, use of the corresponding S-methylthiophenium salts, which have little aromaticity, should provide excellent activation for Diels-Alder reactions of thiophenes even with poor dienophiles such as ethylene <95JHC483>. This AMI approach has been applied to examine Diels-Alder reactions of benzo[6] and benzo[c]thiophenes the theoretical data agree with experimental results <95JCS(P1)1217>. 

The use of coumarin in Diels-Alder reactions is, by comparison to pyran-2-ones, still largely unexplored. This is likely due to the low reactivity of the double bond at positions 3 and 4. Diels-Alder reactions with 3-substituted coumarins are rare, despite the potential to synthesize tetrahydro-6//-benzo[c]chromen-6-ones, important precursors to functionalized biphenyls and several natural products. Electron-withdrawing substitution at C-3 does not serve to efficiently activate the dienophilic system thus, it has been found that high temperatures and pressures are necessary to effect the reaction (e.g., Equation 25) <2006JOC70>. 

Good results were also obtained with lithium perchlorate in dichloromethane and diethyl ether. It has been shown that the lithium cation acts as a Lewis acid and the effects are not due to an internal pressure [80]. The acceleration is much more pronounced for hetero Diels-Alder reactions as compared to the allcarbon cycloadditions. With chiral aldehydes a high level of chelation control has been observed (see later) [81,82]. 

An effect of high pressure on the diastereoselectivity is also observed for intramolecular hetero Diels-Alder reactions as found for the cycloaddition of the benzylidene-isoxazolone 8-23 to afford the cis-annulated 8-24 as the major product together with the frans-diastereomer 8-25 (Fig. 8-8) [549], However, the difference in activation volume with AAV =1.6 0.2 cm3 mol"1 is rather small. The activation volume with AV = 19.6 0.5 cm3 mol-1 at 343 K lies significantly below the usual values found for intermolecular cycloadditions of 1-oxa-1,3-butadienes, indicating that this reaction may be on the border line to a two-step reaction but see also below. 

Intermolecular [4 + 2] cycloadditions exhibit strongly negative activation volumes and reaction volumes. High pressure, therefore, can be applied to accelerate Diels-Alder reactions and to shift the reaction equilibrium towards the cycloadducts. These effects are of particular advantage to (1) promote odierwise slow [4 + 2] cycloadditions involving heat or Lewis acid sensitive educts or products (2) suppress cycloreversion processes which are eidier thermodynamically favored or would interfere with a kinetically controlled stereochemistry. In view of a recent review (1985) only a few examples are presented here. 

---