6-endo addition

The complexation with Lewis acids or the protonation influences both the energy and the coefficients of carbon atoms of the LUMO orbital of the dienophile. The coefficient of the carbonyl carbon orbital increases (Scheme 1.16) consequently, the stabilizing effect of the secondary orbital interaction is greatly increased and the endo addition is more favored. 

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]. 

When the diene is cyclic, there are two possible ways in which addition can occur if the dienophile is not symmetrical. The larger side of the dienophile may be under the ring endo addition), or it may be the smaller side exo addition) ... 

Most of the time, the addition is predominantly endo that is, the more bulk) side of the alkene is under the ring, and this is probably true for open-chain dienes also. However, exceptions are known, and in many cases mixtures of exo and endo addition products are found. It has been argued that facial selectivity is not due to torsional angle decompression. ... 

Symmetry considerations have also been advanced to explain predominant endo addition. In the case of 2 + 4 addition of butadiene to itself, the approach can be exo or endo. It can be seen (Fig. 15.10) that whether the HOMO of the diene overlaps with the LUMO of the alkene or vice versa, the... 

As is true for most reagents, there is a preference for approach of the borane from the less hindered face of the alkene. Because diborane itself is a relatively small molecule, the stereoselectivity is not high for unhindered alkenes. Table 4.4 gives some data comparing the direction of approach for three cyclic alkenes. The products in all cases result from syn addition, but the mixtures result from both the low regioselectivity and from addition to both faces of the double bond. Even 7,7-dimethylnorbornene shows only modest preference for endo addition with diborane. The selectivity is enhanced with the bulkier reagent 9-BBN. 

Diethoxyphosphoryloxy)-1,3-butadiene and 2-(diethoxyphosphoryloxy)-1,3-pentadiene are good dienes and are compatible with Lewis acid catalysts.50 They exhibit the regioselectivity expected for a donor substituent and show a preference for endo addition with enones. 

Lewis acid catalysis usually substantially improves the stereoselectivity of IMDA reactions, just as it does in intermolecular cases. For example, the thermal cyclization of 4 at 160° C gives a 50 50 mixture of two stereoisomers, but the use of (C2H5)2A1C1 as a catalyst permits the reaction to proceed at room temperature and endo addition is favored by 7 1.125... 

In Entry 9, the initial reaction involves 5-exo addition of the aryl radical to the more-substituted end of the cyclohexene double bond, followed by a 6-endo addition to the phenylthiovinyl group. The reaction is completed by elimination of the phenylthio radical. The product is an intermediate in the synthesis of morphine. 

Imines, on the contrary, proved particularly reactive under these conditions (Fig. 4.34). For example, Jones and Selenski report that the introduction of one equivalent of methyl magnesium bromide to benzaldehyde 5 stirring at —78 °C in the presence of one and half equivalents of the imine that is derived from the condensation of benzyl amine and benzaldehyde proceeds immediately to the aminal 65 in 94% yield.27 Only the trans isomer is observed from this low-temperature cycloaddition. While the relative stereochemistry appears to be result of an exo transition state, we suspect that initial cis adduct from and endo addition may epimerize under these conditions. 

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>. 

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... 

If R and R1 are not a methyl group, the process generates a chiral carbon center (C ). The overall catalytic addition of hydrogen to olefinic bonds generally is nearly always cis (7, p. 407) and to the olefinic face coordinated to the metal. This cis-endo-addition produces a chiral center(s) when one olefinic face is preferentially coordinated. 

Variations to the cis addition have been found in the transtition state in some cases and a mixture of products has been reported. Two possible stereochemical variations have been reported because of endo and exo addition. Thus in the dimerisation of butadiene Hoffmann and Woodward have shown that besides the primary orbital interactions between C, and C4 of the diene and Cj and C2 of the dienophile, there are also secondary interactions (shown by dotted lines and also called endo addition) between C-2 of the dieno and C-3 of the dienophile. Such orientations are only possible in endo orientation and this will stabilize the transition state. 

The indimerization of cyclopentadiene again two products are formed, the major being formed by the endo addition. Here also there are secondaiy bonding interactions. 

Some more examples of endo addition (1) Addition of maleic anhydride to cyclopentadiene. Here also two orientations are possible and the endo product predominates. Sometimes the exo adducts are completely excluded. 

It is to be noted that the endo addition rule is not as universal as the cis-addition rule. It can be finished by the more general rule according to which the reagents approach each other from the less hindered side. If that side appears to correspond to an exo-orientation, then exoaddition will occur both under and thermodynamic conditions. 

The attack from the less-hindered side and in which how the products formed by exo or endo additions vary has attracted great attention and a very interesting case of the reaction between naphthalene derivatives and 4 phenyl-1, 2, 4 triazoline 3, 5 dione (d) acting as dienophile has been reported by B.M. Jacobson in 1973. 

While studying the stereochemistry of the endo addition, it has been found that the bulky side of the olefine is normally under the ring as in the following examples ... 

With the right compounds, the syn addition of the diene and dienophile can lead to two possible adducts, depending on whether the larger side of the dienophile ends up under the ring (leading to endo addition) or the smaller side is under (giving exo addition) as shown in Scheme 7.2. Most of the time, the endo... 

The hydrogenation of hexamethylbicyclo[2.2.0] hexa-2,5-diene over Raney-nickel gives, by exo addition, the more strained product. Consequently, it seems that exo addition is favored in small bicyclic compounds over the endo addition (equation 68)163. 

Stereospecificity of Cycloaddition Not Covered by the Endo-Addition Rule ... 

In some situations, such as in Figure 4-20, two different cis products may form. The two products cire the endo and the exo-product. The endo-product is the major or only product of the reaction. The process leading to the endo-product is Alder endo-addition. The endo-form is more stable than the exo-form. 

Auch auf die in Gl. (19) skizzierte En-Synthese, die im eigentlichen Sinne keine Cycloaddition ist, lassen sich Orbitalsymmetriebetrachtungen anstellen, die mit der gefundenen (35) endo- Addition" (im angegebenen Beispiel etwa 80% stereospe-zifisch) im Einklang stehen. 

Regio and stereochemical preferences in kinetically-controlled reactions may also be expressed as isodesmic processes. For example, the regioselectivity of (endo) addition of 2-methylcyclopentadiene with acrylonitrile comes down to the difference in energy the transition states leading to meta and para products, respectively. 

Similarly, the difference in energy between syn and anti transition states for endo) addition of 5-methylcyclopentadiene with acrylonitrile accounts for the stereochemistry of this reaction. 

The Diels-Alder reaction of cyclopentadiene or isobenzofuran derivatives withlV-acetyl-2-azetine gives cycloadducts (e.g., 1) in high yield by endo addition <99TL443>. 

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