Regiochemistry of the Diels-Alder reaction

Addition of an unsymmetrical diene to an unsymmetrical dienophile can take place in two ways to give two structurally isomeric products. It is found in practice, however, that formation of one of the regioisomers is strongly favoured and that this can be predicted prior to reaction. Obviously, this is crucial if the Diels-Alder reaction is to be used successfully in synthesis. Cycloaddition of 1 -substituted butadienes with dienophiles such as a,p-unsaturated carbonyl compounds gives rise to 

Correspondingly, in the addition of methyl acrylate to 2-substituted butadienes, the 1,4-adduct is formed predominantly, irrespective of the electronic nature of the substituent (3.58). Addition of alkynyl dienophiles to unsymmetrically substituted butadienes also results in preferential formation of 1,2- or 1,4-adducts. 

In substituted dienes, the magnitude of the orienting effect differs, not only with the nature of the substituent but also with its position on the diene. A substituent at C-1 generally has a more pronounced directing effect than that at C-2. With 1,2-disubstituted butadienes, therefore, the substituent at C-1 often controls the regio-chemical outcome. With 2,3-disubstituted butadienes, the structure of the adducts obtained will depend on the nature of the two substituents. For example, reaction 

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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. 

The regiochemistry of the Diels-Alder reaction of l-alkoxy-3-(rm-butyldimethylsilyl)oxy-2-azadienes and naphthoquinones, as a route to 2-azaanthraquinon-3-ones, has been investigated (91H915). 

The regiochemistry of the Diels-Alder reaction of a thioaldehyde depends on the nature of the substituent directly linked to the sp2-carbon atom [175]. 

The strong directive effect of an allylic silicon in a diene on the regiochemistry of the Diels-Alder reaction proved to be a blessing in synthesis of 11-deoxycarminomycinone [383],... 

At this point it is instructive to examine the regiochemistry of the Diels-Alder reactions of the substituted naphthoquinones 47, 87, and 89 with the dienes 81 and 83 (Scheme 25) [74]. 

Dienes substituted with heteroatoms, X or Y in 145, give allyl (Y in 146) or vinyl (X in 146) derivatives by the Diels-Alder reaction. The heteroatom(s) not only provide latent functionality in the product but also control the regiochemistry of the Diels-Alder reaction itself86. In Danishefsky s vemolepin synthesis87, a compound of type 146 was converted into an enone 147 by hydrolysis since 146 is a 1,3-disub-stituted allyl compounds like the enone precursors in the last section. 

The regiochemistry of the Diels—Alder reaction can then easily be predicted by a careful match of the charges. If an EDG is located at C-1 of a diene, then the dienophile will approach with the EWG group next to the EDG group. This is called a 1-2 or ortho arrangement of the substituents (Scheme 4.15). 

The regiochemistry of the Diels-Alder reaction is also sensitive to the nature of substituents on the diene and dienophile. The combination of an electron donor in the diene and an electron acceptor in the dienophile gives rise to caseA 4 atid B. The preferred orientations are shown in Scheme 11.3. There are also examples where the substituents are reversed so that the electron donor substituent is on the diefiopTiHe and the elecTfon-accepting su is on the diene. These are called... 

When multiple substituents are involved, a new issue arises, that of the regiochemistry of the Diels-Alder reaction. When both the diene and dienophile have a substituent, we can speak in terms of pseudo-ortho, meta, and para patterns for the product, as shown in Figure 15.11. The nomenclature is imperfect, as two different pseudo-meta forms are shown, but usually it is clear in context which isomers are being discussed. Houk and co-workers have... 

Complexes 17-19 can be written in one valence structure as a, /3-unsaturated carbonyl compounds in which the carbonyl oxygen atom is coordinated to a BF2(OR) Lewis acid. The C=C double bonds of such organic systems are activated toward certain reactions, like Diels-Alder additions, and complexes 17-19 show similar chemistry. Complexes 17 and 18 undergo Diels-Alder additions with isoprene, 2,3-dimethyl-1,3-butadiene, tram-2-methyl-l,3-pentadiene, and cyclopentadiene to give Diels-Alder products 20-23 as shown in Scheme 1 for complex 17 (32). Compounds 20-23 are prepared in crude product yields of 75-98% and are isolated as analytically pure solids in yields of 16-66%. The X-ray structure of the isoprene product 20 has been determined and the ORTEP diagram (shown in Fig. 3) reveals the regiochemistry of the Diels-Alder addition. The C-14=C-15 double bond distance is 1.327(4) A, and the... 

The regioselective course of the Diels-Alder reaction in supercritical carbon dioxide was investigated. The analysis failed to confirm the previously reported dramatic effect of reaction conditions on Diels-Alder regiochemistry. The results highlighted the importance of verifying phase behavior when sampling CO2 reaction mixtures and the utility of a view-cell reactor that allows direct monitoring of phase behavior (Ren-slo et al., 1997). 

Another aspect of the Diels-Alder reaction that can be rationalized with FMO theory is the regiochemistry observed with unsymmetric dienes or alkenes. Equation 11.45 shows the product distribution from the cycloaddition of 2-phenyl-l,3-butadiene (97) and methyl acrylate (98). The para" product 99 (named by analogy with aromatic compounds) is the major product, but some "meta" product (100) is produced as well. ... 

When both the 1,3-dipoIe and the dipolarophile are unsymmetrical, there are two possible orientations for addition. Both steric and electronic factors play a role in determining the regioselectivity of the addition. The most generally satisfactory interpretation of the regiochemistry of dipolar cycloadditions is based on frontier orbital concepts. As with the Diels-Alder reaction, the most favorable orientation is that which involves complementary interaction between the frontier orbitals of the 1,3-dipole and the dipolarophile. Although most dipolar cycloadditions are of the type in which the LUMO of the dipolarophile interacts with the HOMO of the 1,3-dipole, there are a significant number of systems in which the relationship is reversed. There are also some in which the two possible HOMO-LUMO interactions are of comparable magnitude. 

Functionalized nitroalkenes are important chenophiles in the Diels-Alder ri example, fE -methyl fi-nitroactylate is an impottant reagent in organic synthesis The nitre group can be readily eliminated the Diels-Alder reaction of fi-nitroactylate is equivalent to that of ethyl propiolate with an inverse regiochemistry fEq. 8.4. ... 

Lewis acids are frequently employed in catalyzing the Diels-Alder reaction. Particularly fascinating is the observation of the different regiochemistry arising from monodentate and bidentate chelation of 2-methoxy-5-methyl-l,4-benzoquinone with boron trifluoride and stannic chloride, respectively [177],... 

Alder Ene Reactions. Like the Diels-Alder reaction, Alder ene reactions usually take place only when the enophile has a Z-substituent, the regiochemistry is that expected from the interaction of the HOMO of the ene and the LUMO of the enophile, and Lewis acids increase the rate. All these points can be seen in the reaction of /3-pinene with the moderately activated enophile methyl acrylate, which takes place at room temperature in the presence of aluminium chloride, but which would probably not have taken place easily without the Lewis acid. 

A route to partially hydrogenated phenanthrenes relies on the Diels-Alder reaction of a benzyne to an annulated furan, e.g. (501) - (503) (Scheme 117). However, regiochemistry raises its ugly head when both the furan and the benzyne are nonsymmetrically substituted (Scheme 118). Hence, the [4 + 2] cycloaddition of 3-methylbenzyne with 2>substituted furans (504) gave the anti and syn adducts (506)... 

The Diels-Alder reaction between cyclopentadiene and acryloyloxazolidinone is enantioselectively catalysed by the bis(oxazoline)-magnesiuni perchlorate complex. " Ab initio calculations of the ionic Diels-Alder reactions of triazoloisoquinolinium and tetraniethoxycarbonylqijinoliziniijin ions with electron-rich dienophiles have been reported. The 2 - -4-cycloadditions of arenediazonium ions with ( )-penta-1,3-diene, 2,3-dimethylbutadiene, and ( )-2-methylpenta-l,3-diene produce dihydropyr-idazines and pyridazinium salts. The similarity approach has been applied to predict successfully the preferred regiochemistry of various types of pericyclic reaction including polar and semi-polar Diels-Alder and 2 - - 2-cycloadditions. ... 

A simplistic approach to predicting the regiochemical course of a Diels-Alder reaction is to consider the polarization of the diene and of the dienophile by examining the resonance forms, and then join the atoms with unlike charges to form a six-member ring, as exemplified below. However, this approach fails to account for some reactions that occur with good regiochemistry. ... 

The classical methods of constructing six-membered rings are the Diels-Alder reaction or the Robinson annulation, which consist of the union of two fragments, one with two carbon atoms and the other with four carbons. A conceptually different method from the above involves the condensation of two three-carbon units, one with two nucleophilic sites and the other containing two electrophilic sites. Furthermore, the regiochemistry of the reaction is controlled by the differential reactivities of these sites. 

A route to partially hydrogenated phenanthrenes relies on the Diels-Alder reaction of a benzyne to an annulated furan, e.g. (501) (503) (Scheme 117). However, regiochemistry raises its ugly head ... 

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