Diels-Alder reactions endo addition

While widespread investigations on rate accelerations in Diels-Alder reactions by additives were highly successful, the effect of these additives on the selectivities of [4 + 2]-cycloadditions in water has not received much attention. Scattered reports on this aspect point to an increase in endo/exo selectivity by additives, due to an increase in the hydrophobic interactions209. 

Cycloaddition reactions.l This surfactant increases the rate of Diels-Alder reactions. In addition, the endo/exo ratio is improved in the addition of acrylic acid derivatives to cyclopentadiene. 

There is a second type of stereoselectivity that is characteristic of the Diels-Alder reaction. The addition of a dienophile such as maleic anhydride to a cyclic diene like 1,3-cyclopentadiene could provide two products, the endo-adduct 2 and the exoadduct 3 (Eq. 12.5). However, only the e do-cycloadduct 2, in which the two boldfaced hydrogens are syn to the one-carbon bridge, is observed experimentally, and its preferential formation follows what is now commonly termed the Alder rule. The basis for this result is believed to be stabilization of the transition state 4 by secondary orbital interactions that occur through space between the p-orbitals on the internal carbons of the diene and the carbonyl carbon atoms of the dienophile, as shown by the dashed lines in 4. Analogous stabilization is not possible in transition state 5. Structure 4 is thus characterized as the one being stabilized by maximum orbital overlap. It should be noted that not all Diels-Alder reactions are as stereoselective as the one between l,3maleic anhydride mixtures of endo-and cxo-products are sometimes obtained. 

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 complexation procedure included addition of an equimolar amount of R,R-DBFOX/Ph to a suspension of a metal salt in dichloromethane. A clear solution resulted after stirring for a few hours at room temperature, indicating that formation of the complex was complete. The resulting solution containing the catalyst complex was used to promote asymmetric Diels-Alder reactions between cyclopen-tadiene and 3-acryloyl-2-oxazolidinone. Both the catalytic activity of the catalysts and levels of chirality induction were evaluated on the basis of the enantio-selectivities observed for the endo cycloadduct. 

Effect of water additive was examined in the asymmetric Diels-Alder reactions catalyzed by the J ,J -DBF0X/Ph-Ni(C104)2 complex. After addition of an appropriate amount of water to the anhydrous complex A, the reaction with an excess amount of cyclopentadiene was performed at room temperature. Enantioselectivity was as high as 93% ee for the endo cycloadduct up to five equivalents of water added and the satisfactory level of 88% ee was maintained when 10 equivalents were added. However, enantioselectivity gradually decreased with the increased amounts of water added 83 and 55% ee from 15 and 50 equivalents, respectively (Scheme 7.11). When the reaction temperature went down to -40 °C, the enantioselectivity as high as 98% ee resulted up to 15 equivalents of water additive. The effect of methanol at room temperature was even more surprising. In the presence of 15 and 100 equivalents of methanol, high levels of enantioselectivities of 88% and 83% ee, respectively, were recorded for the reactions at room temperature. 

As an approach to biomimetic catalysis, Sanders and colleagues [67] synthesized a series of 1,1,2-linked cyclic porphyrin trimers that allow the stereo- and regiochemistry of the Diels-Alder reaction of 84 and 85 within the molecular cavity to be controlled, thereby producing prevalently or exclusively the endo 86 or the exo 87 adduct. Two examples are illustrated in Scheme 4.18. At 30 °C and in the absence of 88, the reaction furnishes a mixture of diastereoisomers, while the addition of one equivalent of trimer 88 accelerates the reaction 1000-fold and the thermodynamically more stable exo adduct 87 is the sole detectable product. 

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. 

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]. 

Edman and Simmons [146] synthesized bicyclo[2.2.1]hepta-2,5-diene-2,3-dicar-boxylic anhydride 80 as a facially perturbed dienophile on the basis of the norbornadiene motif, and its top selectivity in Diels-Alder reactions with cyclopentadiene (top-exo top-endo = 60 70 1) was observed by Bartlett (Fig. 14) [147], The most preferred addition was top-exo addition, along with the minor addition modes, top-endo bottom-enrfo addition (Fig. 14). The addition of butadiene to this anhydride preferentially afforded the top-adduct (top bottom = 6 1). In the addition of anthracene, a top-adduct was formed exclusively. 

In contrast with exo (top) facial selectivity in the additions to norbomene 80 [41], Diels-Alder reaction between isodicyclopentadiene 79 takes place from the bottom [40] (see Scheme 32). To solve this problem, Honk and Brown calculated the transition state of the parent Diels-Alder reaction of butadiene with ethylene [47], They pointed ont that of particular note for isodicyclopentadiene selectivity issue is the 14.9° out-of-plane bending of the hydrogens at C2 and C3 of butadiene. The bending is derived from Cl and C4 pyramidalization and rotation inwardly to achieve overlap of p-orbitals on these carbons with the ethylene termini. To keep the tr-bonding between C1-C2 and C3-C4, the p-orbitals at C2 and C3 rotate inwardly on the side of the diene nearest to ethylene. This is necessarily accompanied by C2 and C3 hydrogen movanent toward the attacking dienophile. They proposed that when norbomene is fused at C2 and C3, the tendency of endo bending of the norbomene framework will be manifested in the preference for bottom attack in Diels-Alder reactions (Schane 38). 

The optically active a-sulfinyl vinylphosphonate 122 prepared in two different ways (Scheme 38) is an interesting reagent for asymmetric synthesis [80]. This substrate is an asymmetric dienophile and Michael acceptor [80a]. In the Diels-Alder reaction with cyclopentadiene leading to 123, the endo/exo selectivity and the asymmetry induced by the sulfinyl group have been examined in various experimental conditions. The influence of Lewis acid catalysts (which also increase the dienophilic reactivity) appears to be important. The 1,4-addition of ethanethiol gives 124 with a moderate diastereoselectivity. 

Zeijden [112] used chiral M-functionalized cyclopentadiene ligands to prepare a series of transition metal complexes. The zirconium derivative (82 in Scheme 46), as a moderate Lewis acid, catalyzed the Diels-Alder reaction between methacroleine and cyclopentadiene, with 72% de but no measurable enantiomeric excess. Nakagawa [113] reported l,T-(2,2 -bis-acylamino)binaphthalene (83 in Scheme 46) to be effective in the ytterbium-catalyzed asymmetric Diels-Alder reaction between cyclopentadiene and crotonyl-l,3-oxazolidin-2-one. The adduct was obtained with high yield and enantioselectivity (97% yield, endo/exo = 91/9, > 98% ee for the endo adduct). The addition of diisopropylethylamine was necessary to afford high enantioselectivities, since without this additive, the product was essentially... 

It should be noted, however, that despite many examples of the acceleration of Diels-Alder reactions by the use of aqueous media, Elguero59 reported that the Diels-Alder reaction between cyclopentadi-ene and methyl (and benzyl) 2-acetamidoacrylates proceeded better in toluene than in water both in yield and in exo/endo selectivity. Additionally, ultrasonic irradiation did not improve the yield. 

Theoretical considerations in the same fashion enable predication of the possible configuration of the transition state. Eq. (3.25 b) for the multicentre interaction is utilized. Hoffmann and Woodward 136> used such methods to explain the endo-exo selectivity of the Diels-Alder reaction (Fig. 7.28). The maximum overlapping criteria of the Alder rule is in this case valid. The prevalence of the endo-addition is experimentally known 137>. 

Another stereochemical point of significance is that in some Diels-Alder reactions there is the possibility of two alternative modes of addition, the exo (30) and the endo (31), e.g. with cyclopentadiene (32), and maleic anhydride (33) as dienophile ... 

Despite the fact that the exo adduct is likely to be the more stable of the two thermodynamically, it is often (though not universally) found in Diels-Alder reactions that the endo adduct is the major, if not the sole, product. To explain this, it has been suggested that in endo addition stabilisation of the T.S. can occur (and the rate of reaction thereby speeds up) through secondary interaction of those lobes of the HOMO in, e.g. (32) and of the LUMO in (33) that are not themselves involved directly in bond-formation, provided these are of the same phase. Such interaction would not, of course, be possible in the T.S. for exo addition because the relevant sets of centres in (32) and (33) will now be too far apart from each other the endo adduct is thus the kinetically controlled product. It is significant in this connection that the relative proportion of exo... 

Annual Volume 71 contains 30 checked and edited experimental procedures that illustrate important new synthetic methods or describe the preparation of particularly useful chemicals. This compilation begins with procedures exemplifying three important methods for preparing enantiomerically pure substances by asymmetric catalysis. The preparation of (R)-(-)-METHYL 3-HYDROXYBUTANOATE details the convenient preparation of a BINAP-ruthenium catalyst that is broadly useful for the asymmetric reduction of p-ketoesters. Catalysis of the carbonyl ene reaction by a chiral Lewis acid, in this case a binapthol-derived titanium catalyst, is illustrated in the preparation of METHYL (2R)-2-HYDROXY-4-PHENYL-4-PENTENOATE. The enantiomerically pure diamines, (1 R,2R)-(+)- AND (1S,2S)-(-)-1,2-DIPHENYL-1,2-ETHYLENEDIAMINE, are useful for a variety of asymmetric transformations hydrogenations, Michael additions, osmylations, epoxidations, allylations, aldol condensations and Diels-Alder reactions. Promotion of the Diels-Alder reaction with a diaminoalane derived from the (S,S)-diamine is demonstrated in the synthesis of (1S,endo)-3-(BICYCLO[2.2.1]HEPT-5-EN-2-YLCARBONYL)-2-OXAZOLIDINONE. 

According to recent quantum mechanical calculations, die importance of secondary orbital interactions, which have also been frequently used to explain die endo diastereoselectivity of Diels-Alder reactions, seems to be questionable and to be reserved for special cases like the addition of cyclopropene to various dienes. T. Karcher, W. Sicking, J. Sauer and R. Sustmann, Tetrahedron Lett., 33, 8027 (1992) R. Sustmann and W. Sicking, Tetrahedron, 48, 10293 (1992) Y. Apeloig and E. Matzner,./. Am. Chem. Soc., 117, 5375 (1995). 

Despite the fact that Diels and Alder carried out a cycloaddition in water [2], it was not until 1980 that it was reported that large accelerations in the rates of the Diels-Alder reaction could be achieved in water [3], In addition, selectivity towards the endo product was also increased [4], For example, a 700-fold acceleration in the rate of reaction between cyclopentadiene and 3-buten-2-one (Scheme 7.3) was found in water as compared to reaction in 2,2,4-trimethylpentane. The addition of lithium chloride as a salting-out reagent... 

The endo selectivity in many Diels-Alder reactions has been attributed to attractive secondary orbital interactions. In addition to the primary stabilizing HOMO-LUMO interactions, additional stabilizing interactions between the remaining parts of the diene and the dienophile are possible in the endo transition state (Figure 3). This secondary orbital interaction was originally proposed for substituents having jr orbitals, e.g. CN and CHO, but was later extended to substituents with tt(CH2) type of orbitals, as encountered in cyclopropene57. 

Hubbard and Miller87 used a Lewis acid catalyzed Diels-Alder reaction between y.y-disubstituted o. /i-unsaluralcd esters and cyclopentadiene in their approach toward oligomeric cyclopentanoids. In order for the reaction to proceed, they needed to add trimethylaluminum as a desiccant prior to addition of the Lewis acid catalyst aluminum trichloride. The endo/exo selectivity of the reaction with 97, depicted in equation 29, increased from 98/99 = 75/25 to 88/12 when the reaction temperature was dropped from room temperature to —20 °C. 

Gedanken and colleagues136 investigated the Diels-Alder reactions of trichloromethyl allenyl sulfoxides 203 and cyclopentadiene under ultrasound irradiation. Allenes 203 are generally very sluggish in reactivity. However, when ultrasound was applied, the reactions of allenes 203 with cyclopentadiene were completed within 2 hours (equation 57). Mixtures of endo (204) and exo (205) isomers were obtained in all instances. When the y-position of the allenyl sulfoxides was substituted, additional mixtures of E and Z isomers were obtained. 

Okamura and coworkers151 studied the base catalyzed Diels-Alder reactions between 3-hydroxy-2-pyrone (224) and chiral l,3-oxazolidin-2-one based acrylate derivatives. Catalysis of the reaction between 224 and 225 by triethylamine gave fair to good de values, somewhat dependent on the solvent system used (equation 63, Table 7). Addition of 5% of water to the solvent isopropanol, for example, increased the de of the endo adduct 226 substantially. When the amount of water was increased, however, the triethylamine catalyzed reaction became less endo and diastereofacially selective, a small amount of exo 227 being obtained. Replacing triethylamine by the chiral base cinchonidine also improved the de, but now independently of the solvent system used. 

Lewis-acid catalysis of Diels-Alder reactions involving bidentate dienophiles in water is possible also if the beneficial effect of water on the catalyzed reaction is reduced relative to pure water. There are no additional effects on endo-exo selectivity. As expected, catalysis by Cu ions is much more efficient than specific-acid catalysis.Using a-amino acids as chiral ligands, Lewis-acid enan-tioselectivity is enhanced in water compared to organic solvents. Micelles, in the absence of Lewis acids, are poor catalysts, but combining Lewis-acid catalysis and micellar catalysis leads to a rate accelaration that is enzyme-like. 

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