Regiochemistry of Diels—Alder reaction

Kuzuya M., Noguchi A. The Nature of Substituent Effects on Tautomeric Equilibria of 2-Pyridones and Their Reactions Trends Org. Chem. 1991 2 73-92 Keywords chemo- and regiochemistry of Diels-Alder reactions with benzyne,... 

Kahn and Hehre stated that the regiochemistry of Diels-Alder reactions of electron-rich dienes and electron-withdrawing dienophiles follows from matching the nucle-ophilicity of the dienes and the electrophilicity of the dienophiles, although it has... 

The regiochemistry of Diels-Alder reactions with 3.3.3-trifluoropropene (1) shows that the inductive effect of a trifluoromethyl group increases the magnitude of the molecular orbital coefficient of the unsubstituted terminus, but the effect is not great enough to achieve high regioselectivity with dienes other than l-methoxy-3-(trimethylsiloxy)buta-l,3-diene (Danishefsky s diene, 4) compare the reaction of 1 with 2, 3, and 4. ... 

To rigorously predict the regiochemistry of Diels-Alder reactions, one has to apply frontier molecular orbital theory. 

An interpretation based on frontier molecular orbital theory of the regiochemistry of Diels Alder and 1,3-dipolar cycloaddition reactions of the triazepine 3 is available.343 2,4,6-Trimethyl-benzonitrile oxide, for example, yields initially the adduct 6.344... 

The electronic structures of the diene and dienophile also influence the regioselectivity of the reaction The regiochemistry of Diels-Alder products 27, 29. and 31, derived from the variously substituted dienes 25, 28, and 30, is illustrated by the scheme in the margin. 

Fig. 6. Controlling stereochemistry and regiochemistry in Diels-Alder reactions by the application of very high pressure. The potential for using elevated pressures to obtain asymmetric induction is based upon exploiting the different volumes of activation between the competing diastereoisomeric transition states [48, 54]. In the first example, a AAV of 0.9 cm3 mol-1 favors the formation of diastereoisomer 15 over diastereoisomer 16 as the pressure is increased. In the second example, the increased ratio of 18 relative to 17 illustrates the importance of pressure variations in the control of regiochemistry...

Regiochemistry and stereochemistry When both components of a cycloaddition reaction are unsymmetrically substituted, two regioisomeric cycloadducts are possible. In the case of Diels-Alder reactions, these are shown in the reactions of both C-1 and C-2 substituted dienes and monosubstituted dienophiles. Isomeric adducts can be referred as ortho, meta and para in reference to similar disubstitution isomers of benzene. 

Mechanistic studies in this area are essentially nonexistent. Recently, the regiochemistry of some [4 + 2] cycloadditions of thioaldehydes has been rationalized based on FMO theory.2 It is difficult to generalize the resulting stereochemistry of this type of Diels-Alder reaction since systematic studies are lacking and since many structurally diverse kinds of thiocarbonyl dienophiles have been used as 277 components. 

The rates, regiochemistry, and stereochemistry of Diels-Alder reactions are affected by the solvent, and are often correlated to solvent polarity scales. In Chapter 15, we will cover orbital interactions that dictate the dominant regio-isomers of Diels-Alder reactions similar to that given below. The diene A is considered to be a nucleophile and... 

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. 

Calculations at several levels of theory (AMI, 6-31G, and MP2/6-31G ) find lower activation energies for the transition state leading to the observed product. The transition-state calculations presumably reflect the same structural features as the frontier orbital approach. The greatest transition-state stabilization should arise from the most favorable orbital interactions. As discussed earlier for Diels-Alder reactions, the-HSAB theory can also be applied to interpretation of the regiochemistry of 1,3-dipolar cycloaddi-... 

Because the fluorine substituents both inductively and hyperconjugatively withdraw electron density from the C(2)-C(3) tt bond, the LUMO is located there, and Diels-Alder reactions take place exclusively with this bond [25] 1,1 -Difluoro allene and fluoroallene reaet readily with a large selection of cyclic and acyclic dienes, and acyclic dienes, [2+2] cycloadditions compete with the Diels-Alder processes As shown in the example in equation 79, a significantly different regiochemistry is observed for the [2+4] cycloaddition compared with the [2+2]... 

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. ... 

Tamariz and coworkers [42] have described a versatile, efficient methodology for preparing N-substituted-4,5-dimethylene-2-oxazolidinones 42 (Figure 2.5) from a-diketones and isocyanates and have also studied their reactivity in Diels-Alder reactions. This is a method for synthesizing polycyclic heterocyclic compounds. Some of the reactions of diene 42 are summarized in Scheme 2.18. The nitrogen atom seems to control the regiochemistry of the reaction. 

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. 

Diels-Alder reaction of the furan derivative 148 with homochiral bicyclic enone 149 is the key step [56] in the total synthesis of the diterpenes jatropho-lone A and B, 151 and 152, respectively, isolated from Jatropha gossypiifolia L [57], Initial efforts to carry out the cycloaddition between 148 and 149 under thermal or Lewis-acid conditions failed due to diene instability. Application of 5kbar of pressure to a neat 1 1 mixture of diene and dienophile afforded crystalline 150 with the desired regiochemistry (Scheme 5.23). Subsequent aromatization, introduction of the methylene group, oxidation and methylation afforded (-l-)-jatropholones 151 and 152. 

The aqueous aza-Diels-Alder reaction of an aldehyde and an amine hydrochloride with a diene is catalyzed by lanthanide(III) trifluoromethane sulfonates (Ln(OTf)3, triflates [24]). Some examples are reported in Schemes 6.12 and 6.13. With respect to uncatalyzed reactions, the lanthanide catalyst allows milder reaction conditions, increases the reaction yield and does not affect the diaster-eoselectivity of the reaction, but influences the regiochemistry as in the cycloaddition of 25 with 1,3-dimethyl-1,3-butadiene (Schemes 6.10 and 6.12). These results have been applied [24b-d] to the synthesis of azasugars (Scheme 6.14). 

Minuti L., Taticchi A., Costantini L. High Pressnre Diels-Alder Reactions of Cycloalkenones in Organic Synthesis Recent Res. Dev. Org. Chem. 1999 3 105-116 Keywords ketones, regiochemistry, stereoselectivity, reactivity... 

Similar results were obtained for analogous complexes of the de-( er -butyl)ated macrocycle (L24)2-. The ter7-butyl substituents do not affect the regiochemistry of this particular Diels-Alder reaction, but they clearly increase its rate. The observed trend is indicative of a small stabilization of the transition-state by hydrophobic effects (AAG 3 kJ/mol k coinpiex/k l) lckgr(nin(i = expiAAG /RT)). This would be consistent with our earlier observation that complexes bearing less polar carboxylate anions have the higher stability constants (see Section III.E). 

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). 

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]. 

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],... 

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],... 

Ab initio calculations of the ionic Diels-Alder reactions of tiiazoloisoquinolinium and tetramethoxycarbonylquinohzinium ions with electron-rich dienophiles have been reported.215 The 2++ 4-cycloadditions of arenediazonium ions with (T)-penta-l,3-diene, 2,3-dimethylbutadicnc, and ( )-2-methylpenta-l,3-diene produce dihydropyr-idazines and pyridazinium salts.216 The similarity approach has been applied to predict successfiilly the preferred regiochemistry of various types of pericyclic reaction including polar and semi-polar Diels-Alder and 2 + 2-cycloadditions.217... 

Very few mechanistic studies have appeared on this subject and Houk group has studied the hetero-Diels-Alder reaction between thioformaldehyde and butadiene475, using ab initio calculations, to show that the reaction is concerted and nearly synchronous. In the case of unsymmetrical dienes, several rules are known to establish the regiochemistry of the cycloadducts1 471. 

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