Diels-Alder reaction endo product

These two aspects of the Dids-Alder are both iteroospecific (Chapter 12) in that the stereochemistry of the product is determined simply by the stereochemistry of the starting materials and not at all by how favourable one reaction pathway may be. There is one more stereochemical aspect of the Diels-Alder reaction—endo selectivity—and that is a stereose/ectiveaspect. 

C, b.p. 170 C (decomp.), has a characteristic odour. It is the Diels-Alder product of cyclopentadiene reacting with itself, the exo-form being formed most rapidly but the endo-form is thermodynamically favoured. At temperatures above ISO C a retro-Diels-Alder reaction occurs and cyclopentadiene monomer is regenerated see diene reactions. 

Under the usual conditions their ratio is kinetically controlled. Alder and Stein already discerned that there usually exists a preference for formation of the endo isomer (formulated as a tendency of maximum accumulation of unsaturation, the Alder-Stein rule). Indeed, there are only very few examples of Diels-Alder reactions where the exo isomer is the major product. The interactions underlying this behaviour have been subject of intensive research. Since the reactions leadirig to endo and exo product share the same initial state, the differences between the respective transition-state energies fully account for the observed selectivity. These differences are typically in the range of 10-15 kJ per mole. ... 

The regioselectivity benefits from the increased polarisation of the alkene moiety, reflected in the increased difference in the orbital coefficients on carbon 1 and 2. The increase in endo-exo selectivity is a result of an increased secondary orbital interaction that can be attributed to the increased orbital coefficient on the carbonyl carbon ". Also increased dipolar interactions, as a result of an increased polarisation, will contribute. Interestingly, Yamamoto has demonstrated that by usirg a very bulky catalyst the endo-pathway can be blocked and an excess of exo product can be obtained The increased di as tereo facial selectivity has been attributed to a more compact transition state for the catalysed reaction as a result of more efficient primary and secondary orbital interactions as well as conformational changes in the complexed dienophile" . Calculations show that, with the polarisation of the dienophile, the extent of asynchronicity in the activated complex increases . Some authors even report a zwitteriorric character of the activated complex of the Lewis-acid catalysed reaction " . Currently, Lewis-acid catalysis of Diels-Alder reactions is everyday practice in synthetic organic chemistry. 

The Diels-Alder reaction provides us with a tool to probe its local reaction environment in the form of its endo-exo product ratio. Actually, even a solvent polarity parameter has been based on endo-exo ratios of Diels-Alder reactions of methyl acrylate with cyclopentadiene (see also section 1.2.3). Analogously we have determined the endo-exo ratio of the reaction between 5.1c and 5.2 in surfactant solution and in a mimber of different organic and acpieous media. These ratios are obtained from the H-NMR of the product mixtures, as has been described in Chapter 2. The results are summarised in Table 5.3, and clearly point towards a water-like environment for the Diels-Alder reaction in the presence of micelles, which is in line with literature observations. 

Table 5.3. Endo-exo product ratios of the Diels-Alder reaction of 5.1c with 5.2 in surfactant solution compared to water and organic solvents.

Another stereochemical feature of the Diels-Alder reaction is addressed by the Alder rule. The empirical observation is that if two isomeric adducts are possible, the one that has an unsaturated substituent(s) on the alkene oriented toward the newly formed cyclohexene double bond is the preferred product. The two alternative transition states are referred to as the endo and exo transition states ... 

An important contribution for the endo selectivity in the carho-Diels-Alder reaction is the second-order orbital interaction [1], However, no bonds are formed in the product for this interaction. For the BF3-catalyzed reaction of acrolein with butadiene the overlap population between Cl and C6 is only 0.018 in the NC-transi-tion state [6], which is substantially smaller than the interaction between C3 and O (0.031). It is also notable that the C3-0 bond distance, 2.588 A, is significant shorter than the C1-C6 bond length (2.96 A), of which the latter is the one formed experimentally. The NC-transition-state structure can also lead to formation of vinyldihydropyran, i.e. a hetero-Diels-Alder reaction has proceeded. The potential energy surface at the NC-transition-state structure is extremely flat and structure NCA (Fig. 8.6) lies on the surface-separating reactants from product [6]. 

The Diels-Alder reaction of a diene with a substituted olefinic dienophile, e.g. 2, 4, 8, or 12, can go through two geometrically different transition states. With a diene that bears a substituent as a stereochemical marker (any substituent other than hydrogen deuterium will suffice ) at C-1 (e.g. 11a) or substituents at C-1 and C-4 (e.g. 5, 6, 7), the two different transition states lead to diastereomeric products, which differ in the relative configuration at the stereogenic centers connected by the newly formed cr-bonds. The respective transition state as well as the resulting product is termed with the prefix endo or exo. For example, when cyclopentadiene 5 is treated with acrylic acid 15, the cw fo-product 16 and the exo-product 17 can be formed. Formation of the cw fo-product 16 is kinetically favored by secondary orbital interactions (endo rule or Alder rule) Under kinetically controlled conditions it is the major product, and the thermodynamically more stable cxo-product 17 is formed in minor amounts only. 

The use of catalysts for a Diels-Alder reaction is often not necessary, since in many cases the product is obtained in high yield in a reasonable reaction time. In order to increase the regioselectivity and stereoselectivity (e.g. to obtain a particular endo- or exo-product), Lewis acids as catalysts (e.g. TiCU, AICI3, BF3-etherate) have been successfully employed." The usefulness of strong Lewis acids as catalysts may however be limited, because they may also catalyze polymerization reactions of the reactants. Chiral Lewis acid catalysts are used for catalytic enantioselective Diels-Alder reactions. ... 

Eee has used chloroaluminate(III) ionic liquids in the Diels-Alder reaction [36]. The endo. exo ratio rose from 5.25 to 19 on changing the composition of the ionic liquid from X(A1C13) = 0.48 to X(A1C13) = 0.51 (Scheme 5.1-16). The reaction works well, giving up to 95 % yield, but the moisture-sensitivity of these systems is a major disadvantage, the products being recovered by quenching the ionic liquid in water. 

Another stereochemical feature of the Diels-Alder reaction is that the diene and dienophile partners orient so that the endo product, rather than the alternative exo product, is formed. The words endo and exo are used to indicate relative stereochemistry when referring to bicyclic structures like substituted norbornanes (Section 4.9). A substituent on one bridge is said to be exo if it is anti (trans) to the larger of the other two bridges and is said to be endo if it is syn (cis) to the larger of the other two bridges. 

Endo products result from Diels-Alder reactions because the amount of orbital overlap between diene and dienophile is greater when the reactants lie directly on top of one another so that the electron-withdratving substituent on the dienophile is underneath the diene. In the reaction of 1,3-cyclopentadiene with maleic anhydride, for instance, the following result is obtained ... 

More detailed stereochemical studies on the Diels-Alder reaction between cyclopen-tadiene and 2-phenylsulphinylacrylic acid 560 revealed that the formation of endo-syn products 561 is strongly favoured (75-80%) over that of the endo-anti forms661 (equation 359). 

This route provides a convenient method for synthesizing deltacyclenes 89 which have been proven to be useful in the synthesis of highly strained unnatural products of theoretical interest [88]. Diels-Alder reactions of norbornadiene (88) have been successfully activated by a nickel catalyst [89] (Scheme 3.17). Amarked influence of the catalyst on the endo-exo diastereoselectivity has been observed. 

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. 

Diels-Alder reaction is one of the most fundamental reactions for organic synthesis. Its synthetic utility is unquestioned. The stereochemistry of the reactions has attracted much attention. The retention of stereochemistry in the diene and the dienophile, the predominant formation of endo-attack products in the reactions of cyclic dienes, and highly controlled regioselectivity in the reactions of substimted dienes and... 

Fujisawa et al. [Ill] have reported that the magnesiiun complex prepared from chiral 2-[2-[(tolylsulfonyl)amino]phenyl]-4-phenyl-l,3-oxazoline 81 and methyl-magnesium iodide was efficient, in a stoechiometric amount, for promoting the enantioselective Diels-Alder reaction of 3-alkenoyl-l,3-oxazohdin-2-one with cyclopentadiene (Scheme 45) leading exclusively to the endo adducts in up to 92% ee. The use of 10 mol% of the complex led to an important decrease in enantioselectivity of the product (51% ee). 

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... 

Apart from the cyclopropanation reaction, only one example has been published of the application of ionic liquids as reaction media for enantio-selective catalysis with bis(oxazoline) ligands. In this case, the complex 6b-ZnCl2 was used as a catalyst for the Diels-Alder reaction between cyclopen-tadiene and N-crotonyloxazolidin-2-one in dibutyUmidazoUiun tetrafluorob-orate (Scheme 9) [48]. Compared with the same process in CH2CI2, the reaction was faster and both the endofexo selectivity and the enantioselectivity in the endo product were excellent. However, experiments aimed at recovering the catalysts were not carried out. 

The stereoselectivity of some Diels-Alder reactions was also strongly affected in water.26 At low concentrations, in which both components were completely dissolved, the reaction of cyclopentadiene with butenone gave a 21.4 1 ratio of endo/exo products when they were stirred at 0.15 M concentration in water, compared to only a 3.85 1 ratio in excess cyclopentadiene and an 8.5 1 ratio with ethanol as the solvent. Aqueous detergent solution had no effect on the product ratio. The stereochemical changes were explained by the need to minimize the transition-state surface area in water solution, thus favoring the more compact endo stereochemistry. The results are also consistent with the effect of polar media on the ratio.27... 

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... 

A typical regioselectivity and endo/exo selectivity has been reported in the Diels-Alder reaction of 2-(/V-acylamino)- 1,3-diene with nitroalkenes (Eq. 8.27).43 Thus, exo products are predominantly formed, which is general for the Diels-Alder reaction of nitroalkenes with sterically hindered dienes. 

GuoetaLhavereported Diels-Alder reaction of differently substituted2-acetyl-[l, 2,3] diazaphospholes, 6 with cyclopentadiene and obtained both endo and exo cycloadducts in moderate yields depending on the reaction conditions (Scheme 28). By quenching the room temperature reaction after only 5 min, endo product 89 was obtained exclusively in 65-75% yields, while prolongation of reaction time to 3 days led to the isolation of only exo product 90 in 50-75% yields [19]. 

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