Normal electron demand Diels-Alder

Diels-Alder reactions can be divided into normal electron demand and inverse electron demand additions. This distinction is based on the way the rate of the reaction responds to the introduction of electron withdrawing and electron donating substituents. Normal electron demand Diels-Alder reactions are promoted by electron donating substituents on the diene and electron withdrawii substituents on the dienophile. In contrast, inverse electron demand reactions are accelerated by electron withdrawing substituents on the diene and electron donating ones on the dienophile. There also exists an intermediate class, the neutral Diels-Alder reaction, that is accelerated by both electron withdrawing and donating substituents. 

Hydrogen bonding of water to the activating group of (for normal-electron demand Diels-Alder reactions) the dienophile constitutes the second important effect". Hydrogen bonds strengthen the electron-withdrawing capacity of this functionality and thereby decrease the HOMO-LUMO gap... 

The fact that good correlations are observed with d" rather than with a, is indicative of a strong infiuence of the substituent through a direct resonance interaction with a positive charge in the reacting system. The p-values are positive, which is expected for substituted dienophiles in a normal electron demand Diels-Alder reaction. Furthermore, the p-values do not exceed unity and are not significantly different from literature values reported for the uncatalysed reaction. It is tempting to... 

More complete interpretations of Diels-Alder regioselectivity have been developed. MO results can be analyzed from an electrostatic perspective by calculating potentials at the various atoms in the diene and dienophile. These results give a more quantitatively accurate estimate of the substituent effects. Diels-Alder regioselectivity can also be accounted for in terms of HSAB theory (see Section 1.2.3). The expectation would be that the most polarizable (softest) atoms would lead to bond formation and that regioselectivity would reflect the best mateh between the diene and dienophile termini. These ideas have been applied using 3-2IG computations. The results are in agreement with the ortho rule for normal-electron-demand Diels-Alder reactions. ... 

Since the reactivity depends on the lowest HOMO-LUMO energy separation that can be achieved by the reacting partners, all the factors, steric and electronic, that lower the HOMO-LUMO distance increase the reaction rate and, as a consequence, allow the reactions to be carried out under mild conditions. Thus the normal electron-demand Diels-Alder reaction between 1,4-benzoquinone and 1,3-butadiene (Equation 2.2) proceeds at 35 °C almost quantitatively. 

The combination of thionation by Lawesson s reagent [98] of oxoenamino-ketones 96 with normal electron-demand Diels-Alder reaction of conjugated aldehydes allows a variety of thiopyrans 97 to be synthesized by a regio-selective and chemoselective one-pot methodology [99] (Equation 2.28). Thionation occurred at the more electrophilic ketonic carbonyl group. O O... 

They reported that the DFT calculations of 114 at the B3LYP/6-31G level showed that the ji-HOMO lobes at the a-position are slightly greater for the syn-n-face than for the anti face. The deformation is well consistent with the prediction by the orbital mixing rule. However, the situation becomes the reverse for the Jt-LUMO lobes, which are slightly greater at the anti than the syn-n-face. They concluded that the iyn-Jt-facial selectivity of the normal-electron-demand Diels-Alder reactions... 

In contrast to the above-mentioned cydoadditions, normal electron demand Diels-Alder reactions exclusively form products where the terminal C=C bond of the allene was attacked by the diene. For example, cydoaddition of N-allenylsulfeni-mide 281 with cydopentadiene (282) affords norbornene derivative 283 (Eq. 8.37) [148]. 

The appreciable rate effects in water are generally overpowered by the large accelerations found for Lewis acid catalysis in normal electron demand Diels-Alder... 

The stereoselective normal electron demand Diels-Alder reaction of chiral 13-diaza-13-butadienes 42, derived from acyclic carbohydrates, with diethyl azodicarboxylate 2 yields the corresponding functionalized l,23,6-tetrahydro-133,4-tetrazines 43. The observed stereoselectivity is markedly dependent on the relative stereochemistry at C-1 3 - Reactions proceed slowly in benzene solution at room temperature, but are greatly accelerated by microwave irradiation <99JOC6297>. 

Thus, Ghosez et al. were successful in showing that A,iV-dimethyl hydrazones prepared from a,/3-unsaturated aldehydes react smoothly in normal electron demand Diels-Alder reactions with electron-deficient dienophiles [218, 219]. Most of the more recent applications of such 1-aza-l,3-butadienes are directed towards the synthesis of biologically active aromatic alkaloids and azaanthra-quinones [220-224] a current example is the preparation of eupomatidine alkaloids recently published by Kubo and his coworkers. The tricyclic adduct 3-19 resulting from cycloaddition of naphthoquinone 3-17 and hydrazone 3-18 was easily transformed to eupomatidine-2 3-20 (Fig. 3-6) [225]. 

Similarly to the homologous 1-oxa-1,3-butadienes, 1-thia-1,3-butadienes are known to be very suitable and reactive substrates for hetero Diels-Alder reactions. However, in contrast to the oxa-1,3-butadienes which in general act as electron-deficient component in such cycloadditions, thia-1,3-butadienes predominantly undergo normal electron demand Diels-Alder reactions with electron-deficient dienophiles. Nevertheless, also some reactions of thia-1,3-butadienes involving electron-rich dienophiles have been described [412,413], Thia-1,3-butadienes considerably tend to dimerize due to their high reactivity in hetero Diels-Alder reactions [414]. 

It is reported that electron-poor 2- or 3-nitrothiophene can react as dienophiles with Danishefsky s diene in normal electron demand Diels-Alder reactions <2004MI369>. 

EWG normal electron-demand Diels-Alder reaction... 

Heteroatomic dienophiles such as aldehydes and imines also participate in Diels-Alder reactions. Heteroatomic dienophiles have low-energy MOs, so they undergo normal electron-demand Diels-Alder reactions with electron-rich dienes. Singlet 02 ( 02, 0=0) also undergoes normal electron-demand Diels-Alder reactions. Atmospheric 02 is a triplet, best described as a 1,2-diradical ( 0-0 ),... 

Some cycloadditions proceed thermally, whereas others require hv. The dependence of certain cycloadditions on the presence of light can be explained by examining interactions between the MOs of the two reacting components. Frontier MO theory suggests that the rate of cycloadditions is determined by the strength of the interaction of the HOMO of one component with the LUMO of the other. In normal electron-demand Diels-Alder reactions, HOMOdiene ( Ai) interacts with LUMOdienophiie (< >i ) There is positive overlap between the orbitals where the two cr bonds form when both components of the reaction react from the same face of the tt system (suprafacially). 

A four-component [4 + 2]/[4 + 2]/[3 + 2] cycloaddition reaction, reported by Scheeren et is another application of multicomponent reactions. The interaction of 2-methoxy-l,3-butadiene (92) (1 equiv.) with p-nitrostyrene (81a) (3 equiv.) at 1.5 GPa led to a mixture of nitroso-acetals 93-95. In this reaction, p-nitrostyrene (81a) first reacts as a dienophile in the normal electron-demand Diels-Alder reaction, it then reacts as a heterodiene in the inverse electron-demand hetero-Diels-Alder reaction and, finally, it acts as a dipolarophile in the [3 + 2] cycloaddition (Scheme 7.23). 

Hetero-Diels-Alder reactions are not as straightforward as ordinary Diels-Alder reactions. In an ordinary (normal electron demand) Diels-Alder reaction we are accustomed to having an electron-rich diene and an electron-deficient dienophile. In asymmetric catalysis, early successes with a hetero-Diels-Alder reaction58 typically needed a very electron rich diene, such as Danishefsky s diene 248, or very electron deficient dienophiles like a glyoxylate 249. 

Fig. 10.6. Schematic diagram illustrating substituent effect on reactivity in terms of FMO theory. HOMO-LUMO gap narrows, transition state is stabihzed, and reactivity is increased in normal electron-demand Diels-Alder reaction as the nucleophilicity of diene and the electrophihcity of dienophile increase.

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