Dienophiles unsymmetric

Step 1. Draw the bare bones of the reaction 3.10, and put in the curly arrows for the forward and backward reactions. Remember that any substituents, even if they make the diene or dienophile unsymmetrical, do not fundamentally disturb the symmetry of the orbitals directly involved. 

Table 2. Distribution of Isomers Produced by the Reaction of Isoprene with Unsymmetrical Dienophiles, CH2=CHX...

From reaction of an unsymmetrically substituted diene 11a, b and dienophile 12, different regioisomeric products 13a, b and 14a, b can be formed. The so-called ortho and the para isomer 13a, resp. 13b, is formed preferentially. 

Most Diels-Alder reactions, particularly the thermal ones and those involving apolar dienes and dienophiles, are described by a concerted mechanism [17]. The reaction between 1,3-butadiene and ethene is a prototype of concerted synchronous reactions that have been investigated both experimentally and theoretically [18]. A concerted unsymmetrical transition state has been invoked to justify the stereochemistry of AICI3-catalyzed cycloadditions of alkylcyclohexenones with methyl-butadienes [12]. The high syn stereospecificity of the reaction, the low solvent effect on the reaction rate, and the large negative values of both activation entropy and activation volume comprise the chemical evidence usually given in favor of a pericyclic Diels-Alder reaction. 

When an unsymmetrical diene reacts with an unsymmetrical dienophile, two regioisomer adducts can be formed depending on the orientation of the substituents in the adduct [37] (Equations 1.16 and 1.17). 

The orbital interaction depicted in Scheme 1.15 shows that the two cr-bonds form at the same time but do not develop to the same extent. The Diels-Alder cycloaddition of unsymmetrical starting materials is therefore concerted but asynchronous. A highly unsymmetrical diene and/or dienophile give rise to a highly unsymmetrical transition state and a stepwise pathway can be followed. 

When an unsymmetrical diene adds to an unsymmetrical dienophile, there are two regioisomeric products (not counting stereoisomers) ... 

Keywords Facial selection. Orbital phase, Secondary orbital interaction. Orbital unsymmetrization. Ketones, Olefins, Diels-Alder dienophiles, Diels-Alder dienes, Michael acceptor. Amine nitrogen atom... 

Cycloaddition of bicyclo[2.2.1]hept-2-ene-2,3-dicarboxylic anhydride 81 with cyclopentadiene was also studied by Bartlett et al., who found exclusive top addition, the top-endo/top-exo ratio being 3 2 [147]. The endolexo ratio is significantly different from that of 80 (60-70 1). The observed top selectivity in norbornadiene (80) and norbomene (81) derivatives is consistent with the inherent top reactivity of norbomanone 25 and norbomene 57. Orbital unsymmetrization of the dienophile... 

Diels-Alder cycloadditions involving norbomene 57 [34], benzonorbomene (83), 7-isopropylidenenorbomadiene and 7-isopropylidenebenzonorbomadiene (84) as dienophiles are characterized as inverse-electron-demand Diels-Alder reactions [161,162], These compounds react with electron-deficient dienes, such as tropone. In the inverse-electron-demand Diels-Alder reaction, orbital interaction between the HOMO of the dienophile and the LUMO of the diene is important. Thus, orbital unsymmetrization of the olefin it orbital of norbomene (57) is assumed to be involved in these top selectivities in the Diels-Alder cycloaddition. 

The sterically unbiased dienes, 5,5-diarylcyclopentadienes 90, wherein one of the aryl groups is substituted with NO, Cl and NCCHj), were designed and synthesized by Halterman et al. [163] Diels-Alder cycloaddition with dimethyl acetylenedicarbo-xylate at reflux (81 °C) was studied syn addition (with respect to the substituted benzene) was favored in the case of the nitro group (90a, X = NO ) (syrr.anti = 68 32), whereas anti addition (with respect to the substituted benzene) is favored in the case of dimethylamino group (90b, X = N(CH3)2) (syn anti = 38 62). The facial preference is consistent with those observed in the hydride reduction of the relevant 2,2-diaryl-cyclopentanones 8 with sodium borohydride, and in dihydroxylation of 3,3-diarylcy-clopentenes 43 with osmium trioxide. In the present system, the interaction of the diene n orbital with the o bonds at the (3 positions (at the 5 position) is symmetry-forbidden. Thus, the major product results from approach of the dienophile from the face opposite the better n electron donor at the (3 positions, in a similar manner to spiro conjugation. Unsymmetrization of the diene % orbitals is inherent in 90, and this is consistent with the observed facial selectivities (91 for 90a 92 for 90b). 

Ohwada extends his theory, unsymmetrization of n orbitals, to Orbital Phase Environment including the secondary orbital interaction (Chapter Orbital Phase Environments and Stereoselectivities by Ohwada in this volume). The reactions between the cyclopentadienes bearing spiro conjugation with benzofluorene systems with maleic anhydride exemplified the importance of the phase environment. The reactions proceed avoiding the out-of-phase interaction between dienophile LUMO and the HOMO at the aromatic rings. The diene 34 with benzo[b]fluorene favored syn addition with respect to the naphtalene ring, whereas the diene 35 with benzo[c]fluorene showed the reverse anti preference (Scheme 22) [28]. 

Overman, Hehre and coworkers reported anti rr-fadal selectivity in Diels-Alder reactions of vinylcyclopenten 73, 74 and 4,5-dihydro-3-etliynylthiophen S-oxide 75 [38] (Scheme 31). These results are not in agreement with the Cieplak effect, at least in Diels-Alder reactions of the dienes having unsymmetrical rr-plane. Yadav and coworkers reported that the reactions between the vinylcyclohexene 76 and dienophiles favor the reactions syn to oxygen, while 77 and 78 favor the reaction anti to oxygen substituents [39], They discuss the Cieplak effect but the reactions are not suitable. 

Anti TT-facial selectivity with respect to the sterically demanded substituent in the Diels-Alder reactions of dienes having unsymmetrical tt-plane has been straightforwardly explained and predicted on the basis of the repulsive interaction between the substituent and a dienophile. However, there have been many counter examples, which have prompted many chemists to develop new theories on the origin of 7t-facial selectivity. We have reviewed some theories in this chapter. Most of them successfully explained the stereochemical feature of particular reactions. We believe that the orbital theory will give us a powerful way of understanding and designing of organic reactions. 

It was also well established that silenes could take part as the dienophile in Diels-Alder reactions. In many cases, particularly with unsymmetric dienes such as isoprene, the reactions were not clean because, in addition to formation of the [2+4] cycloadduct 61, the possibility exists for the formation of it regioisomer 62, products of an ene reaction 63, and conceivably the [2+2] cycloaddition product 64, as shown in Eq. (23). Wiberg... 

Ethoxy)-allylidenecyclopropane (136a) readily underwent Diels-Alder reaction with activated dienophiles under mild conditions (Table 14) [33]. Only one regioisomer was formed with unsymmetrically substituted dienophiles such as methyl maleic anhydride (137), and quinones 138-141 (entries 2 and 3-6). AH the cycloadducts 143-147 derive from an endo approach between the two reagents. Two site-isomers were obtained in 96 4 ratio with 3-isopropyl-6-methyl-p-quinone (141) (entry 6) and the high site-selectivity observed in this... 

Such a conclusion is, nevertheless, connected with the synchronous character of the mechanism. If a stepwise process is involved (nonsimultaneous formation of the two new bonds), as for unsymmetric dienes and/or dienophiles or in hetero Diels-Alder reactions, a specific microwave effect could intervene, because charges are developed in the transition state. This could certainly be so for several cycloadditions [47, 48] and particularly for 1,3-dipolar cycloadditions [49]. Such an assumption has... 

A systematic exploration of the intramolecular [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles was described. The studies permit the use of unsymmetrical dienophiles, dipolarophiles, and oxadiazoles as well as to control the cycloaddition regioselectivity and diastereoselectivity. The scope and utility of the reaction were defined <2006JA10589>. The tandem intramolecular [4+2]/[3+2] cycloaddition cascade reaction of 1,3,4-oxadiazole was applied to the syntheses of a series of natural products including a total synthesis of (-)- and ent-(+)-vindoline <2006JA10596>. 

Reactions of unsymmetrical dienes and/or dienophiles have also been studied101 103 104. For these reactions ab initio calculations predict concerted non-synchronous mechanisms. The values of the potential energy barriers are very sensitive to the level of calculation and reasonable values are only obtained when electron correlation is included up to the MP3 level103. 

Diels-Alder reactions with unsymmetrical dienes and/or dienophiles can lead to the formation of different isomers. One of the most interesting aspects in these systems is stereoselectivity, observed in reactions involving cyclic dienes. In these cases, two different stereoisomers can be formed endo and exo. 

A question of regioselectivity arises when both the diene and alkene are unsymmetrically substituted and two different orientations are possible. Thus a 1-substituted diene with a mono substituted dienophile may form an ortho and a meta adduct. The same dienophile with a 2-substituted diene can yield a meta and a para product. Actually it has been observed that 1 sustituted dienes preferentially form ortho adducts whereas with 2-substituted derivatives para adducts are formed. 

With an unsymmetrical electron-deficient dienophile, the electron-rich central carbon of vinylallene preferentially adds to the more electron-deficient carbon of the dienophile. Moderate regioselectivities were observed in the reactions of methyl vinyl ketone with vinylallenes at 100 °C [164]. 

Finally, it should be pointed out that the diaryne reactions of 1,2,4,5-tetrabromobenzene are stepwise. Thus the procedure described here, but using half the amounts of furan and butyllithium, can be used to prepare 6,7-dibromonaphthalene 1,4-endoxide (mp 115-117°C) in 70% yield.17 This versatile intermediate can then be used as a benzyne precursor, to make unsymmetric adducts 7 13 17 it also can be used as a dienophile.15 18... 

In the Diels-Alder reaction between an unsymmetrical diene and dienophile, up to eight stereoisomers can be formed (March, 1992a). It is known that the regioselectivity of the Diels-Alder reaction can be biased so that only the four ori/io-adducts are produced (Fig. 21) through increasing the electron-withdrawing character of the substituent on the dienophile (Danishefsky and Hershenson, 1979). However, stereochemical control of the Diels-Alder reaction to yield the disfavoured exo-products in enantiomerically pure form has proved to be very difficult. 

For an unsymmetrical dienophile, there are two possible stereochemical orientations with respect to the diene. The two possible orientations are called endo and exo, as illustrated in Fig. 6.3. In the endo transition state, the reference substituent on the dienophile is oriented toward the % orbitals of the diene. In the exo transition state, the substituent is oriented away from the % system. For many substituted butadiene derivatives, the two transition states lead to two different stereoisomeric products. The endo mode of addition is usually preferred when an electron-attracting substituent such as a carbonyl group is present on the dienophile. The empirical statement which describes this preference is called the Alder rule. Frequently, a mixture of both stereoisomers is formed, and sometimes the exo product predominates, but the Alder rule is a useful initial guide to prediction of the stereochemistry of a Diels-Alder reaction. The endo product is often the more sterically congested. The preference for the endo transition state... 

When 39 was trapped with unsymmetrical dienophiles such as acrylonitrile a mixture of regioisomers was obtained with some selectivity for 6-substituted benzothiazoles 41 over 5-substituted benzothiazoles 42 <98EJOC2047>. 

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