Aqueous media, reactions Diels-Alder reaction

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... 

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. 

Among the pericychc reactions investigated in aqueous medium, the Diels-Alder cycloadditions and the 1,3-dipolar cycloadditions have been the most widely studied. Beneficial effects ofaqueous medium were also observed for (2 -I- 2] and [4- - 4] cycloaddition reactions and sigmatropic rearrangements. 

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 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. 

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. 

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

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. 

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]. 

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... 

The nitroso moiety of the N-acylnitroso function is a powerful dienophile and therefore N-acylnitroso compounds are trapped rapidly, especially in an intramolecular reaction, with a diene allowing the Diels Alder reaction to occur also in water, although N-acylnitroso compounds are short-lived in aqueous medium. 

Lanthanide triflates catalyze the Diels-Alder reaction of imines, generated from anilines and aldehydes, with both dienes and alkenes [26]. Thus N-benzyl-ideneaniline in the presence of Yb(OTf)3 (Scheme 6.16) reacts in organic solvent with open-chain dienes, such as Danishefsky s diene, to give tetrahy-dropyridine derivatives, while with cyclopentadiene and vinylethers and vinylthioethers it works like azadiene in both organic solvent and aqueous medium, affording tetrahydroquinoline derivatives. 

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. 

After the discovery of the remarkable acceleration of some Diels Alder reactions performed in water, a number of polar non-aqueous solvents and their salty solutions were investigated as reaction medium. This revolutionized the concept that the Diels-Alder reaction is quite insensitive to the effect of the medium and emphasized that a careful choice of the solvent is crucial for the success of the reaction. The polarity of the reaction medium is an important variable which also provides some insights into the mechanism of the reaction. If the reaction rate increases by using a polar medium, this means that the transition state probably has polar character, while the absence of a solvent effect is generally related to an uncharged transition state. 

Diels-Alder reactions using supercritical water as an aqueous solvent medium [79]... 

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. 

The Diels-Alder reaction between oxazolone and cyclopentadiene in water was investigated by Cativiela (Eq. 12.35).96 Although the reaction is very slow, the ( )-5(4H)-oxazolone reacted with cyclopentadiene in an aqueous medium for six days at room temperature to form the corresponding sprioxazolones in a 95% yield. The cycloadducts were then readily converted into amino-norbomane carboxylic acids. 

The hetero-Diels-Alder reaction has also utilized dienophiles in which both reactive centers are heteroatoms. Kibayashi reported that the intramolecular hetero-Diels-Alder cycloaddition of chiral acylnitroso compounds, generated in situ from periodate oxidation of the precursor hydroxamic acid, showed a marked enhancement of the trans-selectivity in an aqueous medium compared with the selectivity in nonaqueous conditions (Eq. 12.55).125 The reaction was readily applied to the total synthesis of (—)-pumiliotoxin C (Figure 12.5).126... 

An intramolecular hetero-Diels-Alder reaction of enantiomerically pure iV-acyl nitroso derivatives 78, prepared from hydroxamic acids 77 by oxidation on treatment with Pr4NI04 in an aqueous medium, afforded a mixture of diastereomeric pyrido[l,2-A][l,2]oxazin-8-ones 79 and 80 (Scheme 5) <1996J(P1)1113, 20000L2955,... 

The starting material was prepared with the modification on the epibatidine bicychc ring system by repositioning the nitrogen atom to a methylene group. We carried out the Hetero-Diels Alder reaction of cyclopentadiene and iminium ion generated from ammonium chloride and formaldehyde in the aqueous medium and protected resulted unstable secondary amine with benzoyl chloride to provide (3) in good yields [5] (Scheme 38.1). 

Savitha G, Perumal PT (2006) An efficient one-pot synthesis of tetrahydroquinoline derivatives via an aza Diels-Alder reaction mediated by CAN in an aqueous medium and oxidation to heteroaryl quinolines. Tetrahedron Lett 47 3589-3593... 

The 4 + 2-cycloaddition of 2-substituted 1,2-dihydropyridines with nitrosoben-zene produces [2.2.2]bicycloadducts, which are readily reduced by alane to trans-2-substituted 3-amino-l,2,3,6-tetrahydropyridines stereospeciflcally.123 The intramolec- (g) ular nitroso-Diels-Alder reaction of a-acetoxynitroso derivatives in aqueous medium produces 3,6-dihydro-l,2-oxazines in high yield.124 The nitroso-Diels-Alder reaction of acyclic OTIPS-dienes (115) and 6-methyl-2-nitrosopyridine (114) in the presence of (g) [Cu(MeCN)4(difluorosegphos)]PF6 yielded the dihydro 1,2-oxazine cycloadduct (116) with high yield and enantioselectivity (Scheme 33). 125 (Fe)... 

Nitrocoumarins underwent intermolecular Diels-Alder reaction with substituted dienes, followed by sequential hydrolysis / decarboxylation / Nef reaction / cyclodehydration to afford dihydrodibenzo[f>,. 

In an extension of this work, we have shown that 1,3-dienylborates including compounds (19), (20), (21) are exceptionally reactive and stereoselective dienes, far more reactive than dienylboronates (15) in Diels-Alder reactions 25. Interestingly, the reaction could be carried out in aqueous medium in some cases and led to the adducts (22), (23), (24) (figure 11). 

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