Endo selectivity in Diels-Alder reactions

Wiberg reported the Diels-Alder reaction of butadiene and cyclopropene [53] and Baldwin estimated from the reaction between cyclopropene and 1-deuteriobutadiene at 0°C that 99.4% of the formed cycloadduct was the endo isomer [54], There are many suggestions which attempt to explain endo selectivity in Diels-Alder reactions (Alder s rule [55]), but none are firmly established. According to Woodward and Hoffmann [56], the preference is the result of favorable Secondary Orbital Interactions (SOI) or secondary orbital overlap [57-59] between the diene and dienophile in the corresponding transition state structure. One can also find an explanation for the reaction preference in the difference between primary overlap [60], volumes of activation [61], and the polarity of the transition states [62]. Secondary orbital overlap between the diene and the dienophile does not lead to bonds in the adduct, but primary orbital overlaps do. 

It has been reported that Cplex-isoelectronic theory predicts endo selectivity in Diels-Alder reactions. Phosphorylated nitroso alkenes react with cycUc dienes to give hetero Diels-Alder-type cycloadducts and subsequent aza-Cope rearrangement gives 5,6-dihydro-4H-l,2-oxazines (Scheme 20). ... 

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. 

Diels-Alder catalysis.1 This radical cation can increase the endo-selectivity of Diels-Alder reactions when the dienophile is a styrene or electron-rich alkene. This endo-selectivity obtains even in intramolecular Diels-Alder reactions. Thus the triene 2, a mixture of (Z)- and (E)-isomers, cyclizes in the presence of 1 to 0° to the hydroindanes 3 and 4 in the ratio 97 3. Similar cyclization of (E)-2 results in 3 and 4 in the ratio 98 2 therefore, the catalyst can effect isomerization of (Z)-2 to (E)-2. Even higher stereoselectivity is observed when the styrene group of 2 is replaced by a vinyl sulfide group (SC6H5 in place of QHtOCT ). 

FIGURE 2. The Diels-Alder reaction of cyclopentadiene with methyl vinyl ketone. The selectivity leading to the endo-product (endo-selectivity of Diels-Alder reactions) is rationalized by secondary orbital interactions in the endo-transition state... 

Alkene- and alkyne-substituted Fischer carbenes participate as dienophiles in Diels-Alder reactions. The conditions are usually mild and the reaction proceeds smoothly at room temperature. Similar isomeric ratio and rate acceleration is observed to that of Lewis acid-promoted Diels-Alder reactions between methyl acrylates and dienes when compared to the uncatalyzed reactions. The reactions are endo-selective. Asymmetric Diels-Alder reactions are... 

One characteristic stereochemical feature of the Diels-Alder reaction is endo selectivity. The origin of the endo preference in Diels-Alder reactions can be ascribed to secondary orbital interactions [167]. If the carbonyl functions of dienophilic a -unsaturated carbonyl substrates are effectively shielded by complexation with ATPH, secondary interaction is reduced, thereby disfavoring the hitherto preferred endo transition state (Fig. 2). 

The reasons for the endo-selectivity of Diels-Alder reactions are only useful for the reactions of dienophiles bearing substituents with lone pairs without a Lewis basic site no secondary orbital interactions are possible. But even in reactions of pure hydrocarbons the endo-selectivily is observed, requiring alternative explanations. For example, the endo-preference of the reactions of cyclopropene with substimted butadienes have been rationalized on the basis of a special type of secondary orbital interactions . Apart from secondary orbital interactions which are probably the most important reason for the selectivities of Diels-Alder reactions, recent literature also advocates other interpretations. 

Table 11.5. endo/exo Selectivity in Diels-Alder Reactions of Cyclopentadiene... 

Water as solvent is shown to enhance both the rate and the selectivity in Diels-Alder reactions using several water-soluble trans buta-l,3-dienyl derivatives of carbohydrates from the simplest one with only one asymmetric center, derived from D-glyceraldehyde to partially protected buta-l,3-dienyl glucosides. In each case, virtually complete endo selectivity was observed, and it is shown that the facial stereoselectivity can be modulated through chemical manipulation of the sugar moiety. It is also shown that the rate enhancement in such aqueous cycloadditions has an entropic origin. 

A theoretical study of endo-selectivity in the Diels-Alder reaction between butadienes and cyclopropene has shown that neither electron delocalization nor the electrostatic interaction shows preference of enrto-addition over e o-addition. l-Amino-3-siloxybuta-1,3-dienes are highly reactive dienes which show high endo-selectivity in Diels-Alder additions. The aldehyde 2-methylene-5-trimethylsilyl-pent-4-yn-l-al (161) has been shown to be a versatile dienophile reacting with Danishefsky s diene (162) to produce 4 + 2-cycloadducts (163) with endo-selectivity (Scheme 62). " ... 

This thesis describes a study of catalysis of Diels-Alder reactions in water. No studies in this field had been reported at the start of the research, despite the well known beneficial effects of acpieous solvents as well as of Lewis-add catalysts on rate and endo-exo selectivity of Diels-Alder reactions in organic solvents. We envisaged that a combination of these two effects might well result in extremely large rate enhancements and improvements of the endo-exo selectivity. 

There are few examples of the influence of micelles on reactivity and selectivity of Diels-Alder reactions, and the observed effects are sometimes capricious. Compared to the reaction in pure water, modest [71] and exceptional [72] accelerations and even retardations [65e, g, 73] have been observed, and little [73b, 74] and high [75] endo/exo diastereoselectivities were found. 

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). 

This explains the experimentally confirmed predictions that polar solvents attenuate the endo-preference, while non-polar solvents increase the cwdo-selectivity of Diels-Alder reactions. The strong correlation between the polarity of the solvent and the endo/exo ratios in the Diels-Alder reaction led to the empirical polarity scale 2 = log endo/exo) using the reaction of cyclopentadiene with methyl acrylate as the standard144. The importance of solvent polarity has also been discerned on the basis of experimental142 and theoretical investigations145. Dependence on the polarizability was also noted146. 

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. 

An extensive review of the hetero-Diels-Alder reactions of 1-oxabuta-1,3-dienes has been published. Ab initio calculations of the Diels-Alder reactions of prop-2-enethial with a number of dienophiles show that the transition states of all the reactions are similar and synchronous.Thio- and seleno-carbonyl compounds behave as superdienophiles in Diels-Alder reactions with cyclic and aryl-, methyl-, or methoxy-substituted open-chain buta-1,3-dienes.The intramolecular hetero-Diels-Alder reactions of 4-benzylidine-3-oxo[l,3]oxathiolan-5-ones (100) produce cycloadducts (101) and (102) in high yield and excellent endo/exo-selectivity (Scheme 39). A density functional theoretical study of the hetero-Diels-Alder reaction between butadiene and acrolein indicates that the endo s-cis is the most stable transition structure in both catalysed and uncatalysed reactions.The formation and use of amino acid-derived chiral acylnitroso hetero-Diels-Alder reactions in organic synthesis has been reviewed. The 4 + 2-cycloadditions of A-acylthioformamides as dienophiles have been reviewed. ... 

Diets-Alder catalysis.2 This cation radical enhances the reactivity of a neutral or electron-rich eis-1,3-diene in Diels-Alder reactions. Thus 1,3-cyclohexadiene undergoes Diels-Alder dimerization only at temperatures around 200°. The presence of 5-10 mole % of this salt effects dimerization even at —78°, with the usual endo/ exo selectivity (5 1). It also permits facile condensation of 1,3-cyclohexadiene with a hindered dienophile such as 2,5-dimethyl-2,4-hexadiene (equation 1) the dimer of the former diene is a minor product (20% yield). 

The competition C=0 vs C=S in Diels-Alder reactions is represented in the case of thioxoethanal, generated by FVT, and which only reacts through the C=S bond when trapped with a variety of dienes20,373,377 (equation 138). In the case of cyclic dienes, endo selectivity was observed and a-oxothiones behaved similarly20,379 as well as a-oxosulfines20,378. 

Ghosh has also shown that cis- l-(arylsulfonamido)-2-indanols could be used as excellent chiral auxiliaries in Diels-Alder reaction.85 Reaction of 80 with cyclopentadiene using a variety of Lewis acids led to 81 in good yield, with endo. exo ratios superior to 99 1 and diastereoselectivities ranging from 72% to 92%. The best selectivities were observed using titanium tetrachloride as the Lewis acid. The high degree of diastereoselection was presumed to result from effective metal chelation (Scheme 24.17). 

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