Endo rule cycloadditions

The endo rule also applies to some Diels-Alder reactions with inverse electron demand, as in the cycloaddition of butadienylsulfoxide 2.116 with the enamine 2.117, which gives only the adduct 2.118. The amino group is an... 

In addition, Diels-Alder adducts are formed through two types of approaches that lead to endo or exo isomers. The endo isomer is usually favored over the exo isomer, although the exo isomer is generally the thermodynamically preferred product. This is known as the Alder, or endo, rule and can be attributed to the additional stability gained by secondary molecular orbital overlap during the cycloaddition.22 26 27 Again, the use of a Lewis acid catalyst can alter the endo/exo ratio and has even been shown to give the thermodynamic exo adduct as the major product.28... 

Use the endo rule to predict the product of the following cycloaddition. 

One important nitrone is a cyclic compound that has the structure below and adds to dipolarophiles (essentially any alkene ) to give two five-membered rings fused together. The stereochemistry comes from the best approach with the least steric hindrance, as shown. There is no endo rule in these cycloadditions as there is no conjugating group to interact across space at the back of the dipole or dipolarophile. The product shown here is the more stable exo product. 

The Stereoselectivity of Diels-Alder Reactions. One of the most challenging stereochemical findings is Alder s endo rule for Diels-Alder reactions. The favoured transition structure 6.180 has the electron-withdrawing substituents in the more hindered environment, under the diene unit, giving the kinetically more favourable but thermodynamically less favourable adduct 6.181. Heating eventually equilibrates the adducts in favour of the exo adduct 6.182, by a retro-cycloaddition re-addition pathway. 

As the focus of this chapter is on the synthetic utility of the rDA reaction, an overview of mechanism is beyond the scope of this review however, the subject has beoi reviewed previously. Structural and medium effects on the rate of the rDA reaction are of prime importance to their synthetic utility, and therefore warrant discussion here. A study of steric effects cm the rate of cycloreversicHi was the focus of early work by Bachmann and later by Vaughan. The effect of both diene and dioiophile substituticHi on Ae rate of the rDA reaction in anthracene cycloadducts has been reported in a study employing 45 different adducts. If both cycloaddition and cycloreversion processes are fast on the time scde of a given experiment, reversibility in the DA reaction is observed. Reversible cycloaddition reactions involving anthracenes, furans, fulvenes and cyclopentadienes are known. Herndon has shown that the well-known exception to the endo rule in tiie DA reaction of furan with maleic anhydride (equation 2) occurs not because exo addition is faster than endo addition (it is not), but because cycloreversion of the endo adduct is about 10 000 times faster than that of the exo adduct. ... 

The preceding discussion is not meant to imply that stereo electronic effects alone are responsible for determining diastereoselection in the Diels-Alder reaction. Indeed, examples of reactions that do not conform to the endo rule abound, and these cases are not easily explained without invoking alternative hypotheses. For instance, it has been demonstrated that 1,1-disubstituted dien-ophiles can favor formation of the exo product with cyclopentadiene, sometimes to the complete exclusion of the electronically favored endo isomer [19]. There appears to be subtle interplay between steric and electronic factors, as simply switching the diene to cyclohexadiene or an acyclic diene results in a turnover in selectivity to favor the endo isomer. While the exact source of stereocontrol for a given cycloaddition is still a source of debate, this review will emphasize the practical ramifications of diastereoselection, namely, prototypical dienophiles such as a-methacrolein and a-bromoacrolein can be relied on to deliver exo cycloadducts preferentially with cyclopentadiene endo otherwise), while acrylate, crotonate, and cinnamate-derived dienophiles will generally favor the endo tran-... 

In contrast, other reactions are endo selective, as in the cycloaddition 6.354 of an azomethine ylid to dimethyl maleate giving largely (80 20) the endo adduct endo-6.355.869,870 Thus the stereoselectivity depends in a not always predictable way upon the dipole, the dipolarophile and their substituents, in contrast to Diels-Alder reactions, which more often than not obey the endo rule. It is advisable, when planning a synthesis, to look up close analogies before relying upon the exo or endo stereoselectivity of a 1,3-dipolar cycloaddition. 

Acrylates. Cyclopentadiene is often used to evaluate selectivity in asymmetric Diels-Alder reactions. Table 6.4 lists the selectivities found for acrylate cycloadditions using the auxilieuies shown in Figure 6.13 under conditions that are optimized for each auxiliary. Note that there are four possible norbomene stereoisomers, two endo and two exo. In accord with Alder s endo rule, the endo is heavily favored in all these examples. Although several authors report selectivities in these reactions in terms of selectivity for one endo adduct over the other, the selectivities indicated in the table reflect the total diastereoselectivity of the major adduct over the other three, if this information could be deduced from the information provided in the paper. 

The products obtained from the cyclic diene furan and maleic anhydride and from diene addition reactions of fulvene do not obey the endo rule. The reason for this is that the initial endo adducts easily dissociate at moderate temperatures, allowing conversion of the kinetic endo adduct into the thermodynamically more stable exo isomer. In other cycloadditions, prolonged reaction times may lead to the formation of some exo isomer at the expense of the endo. 

The adducts obtained from acyclic dienes and cyclic dienophiles are frequently formed in accordance with the endo rule. A classic example is found in the Woodward synthesis of reserpine, which started with the Diels-Alder reaction of i -pentadienoic acid and benzoquinone (3.67). In this cycloaddition reaction, the endo adduct 78, in which the carboxylic acid and the benzoquinone carbonyl groups become cLs to one another, is obtained as the exclusive product. 

Interestingly, the cycloaddition of 10 and methyl vinyl ketone is also highly stereoselective with respect to the acetyl side chain in 59. Analogous double diastereoselectivity (endo face attack, Alder endo rule [139,202-204]) is observed for the cycloaddition of 10 to methyl acrylate (Scheme 7). As expected [179-184,205], the Diels-Alder additions of 10 are ortho regio-selective. 

Product stereochemistry of [4-i-2]-cycloaddition, e.g., cyclopentadiene plus maleic anhydride, infers a lineup of the diacyloxy moiety of maleic anhydride with the central atoms of the diene. Thus, it is evident that the harder atoms lie in proximity in space and so do the soft components. Although secondary n-orbital interactions (30) are invoked to account for endo stereospecificity, these are not indispensable conditions. Cases which still obey the endo rule are known where direct n interactions are absent. 

Diels-Alder cycloadditions follow the endo rule... 

In Summary The Diels-Alder reaction is a concerted cycloaddition that proceeds best between electron-rich 1,3-dienes and electron-poor dienophiles to furnish cyclohexenes. It is stereospecific with respect to the stereochemistry of the double bonds and with respect to the arrangements of the substituents on diene and dienophile It follows the endo rule. 

The Diels-Alder reaction is a concerted stereospecific cycloaddition reaction of an s-cis diene to a dienophUe it leads to cyclohexene derivatives. It follows the endo rule. 

The thermal Diels-AIder reactions of perfluorocyclopentadiene with diethyl maleate and diethyl fumarate have been shown to proceed in accordance with the cis principle enunciated by Alder and Stein. Further evidence for the normal behaviour of perfluorocyclopentadiene in such 1,4-additions is provided by the observation that hydrolysis of the amide produced by treatment of the diene with A-allyltrifluoroacetamide at 50 °C yields the azatri-cyclononane (19) (see Scheme 4) obviously, Alder s endo rule applies to this cycloaddition. The same technique has been used to show that the Diels-AIder adduct obtained from perfluorocyclohexa-1,3-diene and A-allyltri-fluoroacetamide at 110°C is predominantly or even exclusively the endo-isomer. ... 

The first examples of hetero-Diels-Alder additions of SO2 involved highly reactive dienes 139 and 140. In 1992, Deguin et al. reported that simple 1,3-dienes undergo het-ero-Diels-Alder addition below 60°C in the presence of a large excess of SO2 and of a protic or Lewis acid promoter (Scheme 22.40). For instance, in the presence of CF3COOH, ( , )-deuteriopiperylene 141 equilibrates with sultine 142 at — 80°C. At —60°C, 142 is converted into the more stable isomeric sultine 143, thus, demonstrating the suprafaciality of the cycloadditions that obey the Alder endo) rule. ... 

In general, stereochemical predictions based on the Alder rule can be made by aligning the diene and dienophile in such a way that the unsaturated substituent on the dienophile overlaps the diene n system. The stereoselectivity predicted by the Alder rule is independent of the requirement for suprafacial-suprafacial cycloaddition, since both the endo and exo transition states meet this requirement. 

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

MA cycloaddition to metalloles seems to be always stereospecific and, according to Alder s rule, the endo configuration has been attributed to the adduct125. When two different groups R1 and R2 are present (equation 43), the major adduct results from the sterically more suitable transition state, i.e. the more bulky group is preferentially syn with respect to the C=C bond of the norbornene6,67c. 

Cycloadditions are easier to treat than unimolecular reactions they only require an evaluation of the best FO overlap (rule 4). Let us look at the cyclodimerization of butadiene. Woodward and Hoffmann suggested that the experimentally observed endo compound is due to secondary interactions (shown by the double arrows above), which increase the stabilizing the FO s interaction.23 Cisoid configurations are often adopted by the dienophile in Diels-Alder reactions,24 as first suggested by Dewar.20 For... 

The usual rule of endo-selectivity is not observed in the cycloaddition of cyclo-pentadiene with methacrolein (equation II). In this reaction both DAD and MAD enhance exo-selectivity because of steric repulsion between the bulky catalyst and... 

The primary adducts (156) and (157) of oxazoles with alkenes and alkynes, respectively, are usually too unstable to be isolated. An exception is compound (158), obtained from 5-ethoxy-4-methyloxazole and 4,7-dihydro-l,3-dioxepin, which has been separated into its endo and exo components. If the dienophile is unsymmetrical the cycloaddition can take place in two senses. This is usually the case in the reactions of oxazoles with monosubstituted alkynes with alkenes on the other hand, regioselectivity is observed. Attempts to rationalize the orientation of the major adducts by the use of various MO indices, such as 7r-electron densities or localization energies and by Frontier MO theory (80KGS1255) have not been uniformly successful. A general rule for the reactions of alkyl- and alkoxy-substituted oxazoles is that in the adducts the more electronegative substituent R4 of the dienophile occupies the position shown in formula (156). The primary adducts undergo a spontaneous decomposition, whose outcome depends on the nature of the groups R and on whether alkenes or alkynes have been employed. 

A recent example of an intermolecular [3 + 4] cycloaddition starts with an allylic acetal, as shown in Eq. (167) [419,420]. Other Lewis acids, for example AlEt Cl3 (n = 0-3), TMSOTf, TfOH, SbCL, SnCL were less effective. Although the exact nature of the transition state is still uncertain, the stereochemistry of the product might be explained on the basis of the rule of endo addition with the least hindered approach of the diene. The possibility of asymmetric synthesis starting with the same substrate with a chiral acetal moiety has been mentioned (see Table 15). 

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