Diels-Alder Reaction in Aqueous Medium

Table 4.18 Diels-Alder reactions in aqueous medium in the presence and in the absence of bovine serum albumin...

Engberts [3e, 9] has extensively investigated the Diels Alder reaction in aqueous medium. Recently Engberts and colleagues reported [9c] a kinetic study of a Diels Alder reaction of N-alkyl maleimides with cyclopentadiene, 2,3-dimethyl-1,3-butadiene and 1,3-cyclohexadiene in different solvents. The reaction rates of the cycloadditions with the open-chain diene relative to w-hexane are reported in Table 6.3. The aqueous medium greatly accelerates the Diels Alder reaction and the acceleration increases as the hydrophobic character of the alkyl group of the dienophile increases. These and other kinetic data [3e, 9], along with the observation that the intramolecular Diels-Alder reaction is also accelerated in... 

Fringuelli F., Piermatti O., Pizzo F. Hetero Diels-Alder Reactions in Aqueous Medium Targets in Heterocyclic Systems-Chemistry and Properties 1997 1 57-73, Eds. Attanasi O. A. and Spinelli D., Pb. Soc. Chim. Ital. 

Fringuelli, F., Piermatti, O., Pizzo, F. Hetero Diels-Alder reactions in aqueous medium. Targets in Heterocyclic Systems 1997,1, 57-73. Gonzalez, J., Sordo, J. A. Theoretical results on hetero-Diels-Alder reactions. Recent Research Developments in Organic Chemistry 1997,... 

The Diels-Alder reaction in aqueous medium is much more effective than in organic solvents. The [4 + 2] cycloaddition of the dienophile 7 to diene 8a in benzene at room temperature yields adducts 9a and 10a in 52% yield in a 1 1.2 ratio. The same dienophile reacts with sodium carboxylate 8b in a much shorter time (4 h at ambient temperature) to give a 3 1 mixture of 9b and 10b in 99% yield. Similarly, addition of diene 8a to the dienophile 11 (toluene, 100 C, 36 h, 97%) produces the adducts 12a and 13a in a ratio of 1 1.1, while the addition to diene 8b (water, room temperature, 4.5 h, 90%) provides adducts 12b and 13b in a ratio of 3 116. 

The Diels-Alder reaction in aqueous medium has tremendous synthetic potentialities. This technique has been used in the field of terpenes, steroids and alkaloids. 

Before 1980 only a few examples of Diels-Alder reactions in aqueous medium had been reported because little consideration was given to water as a reaction medium for organic synthesis. ... 

In the last decade of the last century there was great interest toward Lewis acid-catalyzed Diels-Alder reaction in aqueous medium. Many catalysts have been discovered (Cu(ll), Ni(II), Zn(II), Ln(OTf)3, Sc(OTf)3, Bi(OTf)3, InClj, MeReOs, Cu(DS)2, Zn(DS)2) that have also contributed to the development of environmental-friendly organic synthesis this topic was recently reviewed. ... 

The influence of micelle and CDs on the reactivity and selectivity of Diels-Alder reaction in aqueous medium was mainly investigated in the 1990s and has been reviewed. 

Recent examples of Diels-Alder reactions in aqueous medium in a self-assembled coordination cage are the cycloadditions of 1,4-naphthoquinone, enclathrated in the cavity of a cage compound, with isoprene and 1,3-cyclohexadiene the reactions were accelerated 113 and 21 times, respectively, with respect to those carried out in the absence of cage. 

Theoretical studies and computer simulations have also been reported regarding the role of water in Diels-Alder reaction in aqueous medium. 

In a second attempt to extend the scope of Lewis-acid catalysis of Diels-Alder reactions in water, we have used the Mannich reaction to convert a ketone-activated monodentate dienophile into a potentially chelating p-amino ketone. The Mannich reaction seemed ideally suited for the purpose of introducing a second coordination site on a temporary basis. This reaction adds a strongly Lewis-basic amino functionality on a position p to the ketone. Moreover, the Mannich reaction is usually a reversible process, which should allow removal of the auxiliary after the reaction. Furthermore, the reaction is compatible with the use of an aqueous medium. Some Mannich reactions have even been reported to benefit from the use of water ". Finally, Lewis-acid catalysis of Mannich-type reactions in mixtures of organic solvents and water has been reported ". Hence, if both addition of the auxiliary and the subsequent Diels-Alder reaction benefit from Lewis-acid catalysis, the possibility arises of merging these steps into a one-pot procedure. 

The Diels-Alder reaction of nonyl acrylate with cyclopentadiene was used to investigate the effect of homochiral surfactant 114 (Figure 4.5) on the enantioselectivity of the reaction [77]. Performing the reaction at room temperature in aqueous medium at pH 3 and in the presence of lithium chloride, a 2.2 1 mixture of endo/exo adducts was obtained with 75% yield. Only 15% of ee was observed, which compares well with the results quoted for Diels-Alder reactions in cyclodextrins [65d]. Only the endo addition was enantioselective and the R enantiomer was prevalent. This is the first reported aqueous chiral micellar catalysis of a Diels-Alder reaction. 

Also see Diels-Alder reaction in ionic liquids, which is considered to be better than in aqueous medium (Chapter 14). 

More recently the research on the Diels-Alder reaction in the aqueous medium has been focused mainly on the diastereoselectivity of the cycloaddition, particularly the enantiose-lectivity, and on the utilization of biomolecules as highly stereoselective catalysts. 

A Diels-Alderase enzyme that catalyzes the Diels-Alder reaction in biosynthetic processes was isolated in 1995 from cell-free extracts of the fungus Altemaria solani The fungus produces toxins known as solanapyrones that are biosynthesized via Diels-Alder reaction exo selectively. In buffered aqueous medium at pH 7.0 the Diels-Alderase catalyzed the cycloaddition of prosolanapyrone (35) to (-)-solanapyrone A (36) with high exo diastereoselectivity (exo/endo 86 14) and excellent enantioselectivity (ee 99% Scheme 5.9). In sole water the reaction occurred at 30°C and after 3 h a reversed diastereoselectivity (exo/endo 4 96) was observed. 

The aza-Diels-Alder reaction of imines with diene of Danishefsky is an important route to 2,3-dihydro-4-pyridones. A number of Lewis acids have been used to catalyze the reaction in organic solvents. In water the reaction was realized by acid catalysis via iminium salts or by Bronsted acids. The montmorillonite K-10 catalyzed this cycloaddition in water or in aqueous acetonitrile in excellent yield. Recently Kobayashi has performed the reaction in water at room temperature under neutral conditions in two (imine - - diene) or three (aldehyde -b amine -b diene) component versions by using sodium triflate as catalyst. Imine intermediates from the indium-mediated reaction, in aqueous medium at 50° C, between aromatic nitro compounds and 2,3-dihydrofuran undergo aza-Diels-Alder cycloadditions to give tetrahydroquinoline derivatives in good overall yields. ... 

Other recent examples of inverse electron-demand Diels-Alder reactions in water are the cycloadditions of ( )-3-diazenylbut-2-enes 72 with a variety of vinyl ethers. The results of cycloaddition of 72 with ethyl vinyl ether (61) are reported in Table 5.5. The reactions were always faster in heterogeneous aqueous medium than in organic solvent and the endo adduct was the prevalent reaction product. Pyrrole derivatives such as ethyl-2-methyl-1-ureido-lH-pyrrole-3-carboxylates, derived from zwitterionic [3 + 2] cycloaddition reactions, were sometimes observed and a reaction mechanism of their formation has been proposed. In water, as well as in DCM, 72 (R = OEt, Ri = H) behaves like an electron-acceptor heterodiene even with a highly reactive diene such as cyclopentadiene, giving quickly, at 15°C, only the endo adduct. The cycloaddition of 72 (R = OEt, Ri = H) with the chiral vinyl ether (-F)-2-(ethenyloxy)-3,7,7-trimethylbicyclo[4.1.0]heptane (62x) was complete in water in 68 h at 15°C and gave a mixture of 83 17 endo/exo adducts with modest enantioselectivity. This is the first example of an asymmetric inverse electron-demand Diels-Alder reaction performed... 

In the area of cycloaddition reactions in aqueous medium much work has been done on the Diels-Alder reaction and, until 10 years ago, httle attention had been paid to 1,3-dipolar cycloaddition although this reaction shows many similarities to Diels-Alder reaction both are [4jt +2st reversible pericyclic processes with negative volume of activation and the dipolarophiles are the counterpart of dienophiles. 

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... 

The intramolecular /zetero-Diels-Alder reactions of 4-O-protected acyl-nitroso compounds 81, generated in situ from hydroxamic acids 80 by periodate oxidation, were investigated under various conditions in order to obtain the best endo/exo ratio of adducts 82 and 83 [65h] (Table 4.15). The endo adducts are key intermediates for the synthesis of optically active swainsonine [66a] and pumiliotoxin [66b]. The use of CDs in aqueous medium improves the reaction yield and selectivity with respect to organic solvents. 

Bronsted-acid-catalyzed Diels-Alder reactions are not frequent because of the proton sensitivity of many dienes and cycloadducts, especially when long reaction times and high temperatures are required. Examples in aqueous medium involving imines activated by protonation as dienophiles and a proton-promoted Diels-Alder reaction of glyoxylic acid with cyclopentadiene are considered in Section 6.1. 

In 1980, organic chemists recognized the potential of the aqueous medium as a reaction medium when Breslow [2] showed that some Diels-Alder reactions were strongly accelerated when carried out in water in comparison with the same reactions performed in organic solvent. 

Among the organic reactions that have been investigated in aqueous medium, the Diels-Alder cycloaddition has been the most studied owing to its great importance from the synthetic and theoretical point of view [7a, bj. In this section Diels-Alder reactions carried out in water under conventional conditions of temperature and pressure will be illustrated. The use of water at supercritical or near-supercritical conditions will be discussed in Section 6.4. 

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]. 

The aqueous medium also has beneficial effects on the diastereoselectivity of the Diels-Alder reactions. The endo addition that occurs in the classical cycloadditions of cyclopentadiene with methyl vinyl ketone and methyl acrylate is more favored when the reaction is carried out in aqueous medium than when it is performed in organic solvents (Table 6.4) [2b, c]. 

---