Electron-deficient dienophiles

Some electron deficient dienophiles are quinones, maleic ahydride, nitroalkenes, a,p-unsaturated ketones, esters and nitriles. 

More recently, Cheeseman and coworkers have investigated cycloaddition reactions of 2,6-dioxypyrazines (80jCS(Pl)1603). 2,6-Dihydroxy-3,5-diphenylpyrazine (77) reacts with electron deficient dienophiles such as iV-phenylmaleimide, diethyl maleate and diethyl fumarate (Scheme 26) to yield adducts of the 3,8-diazabicyclo[3.2.1]octane class such as (78). This reaction is believed to proceed by way of the betaine (79) and has precedent (69AG(E)604) in that photolysis of the bicyclic aziridine (80) generates analogous betaines which have been trapped in cycloaddition reactions. 

The normal electron-demand reaction is a HOMOdiene-LUMOdienophUeelectron-rich dienes and electron-deficient dienophiles (Scheme 4.2, left dotted line). The inverse electron-demand cycloaddition reaction is primarily controlled by a LUMOdiene HOMOdienophiie inter-... 

The coordination of the dienophile to a Lewis acid (in the calculations a proton was used as the Lewis acid) leads also to an increase in regioselectivity. The re-gioselectivity of reactions of electron-rich, or conjugated dienes, with electron-deficient dienophiles is also controlled hy the diene HOMO-dienophile LUMO interaction. From Fig. 8.2 it appears that the difference in magnitudes of the LUMO coefficients at carhon atoms 1 and 2 of acrolein (Ci -C2 = 0.20) is smaller than the same difference for protonated acrolein (Ci -C2 = 0.30-0.43) so that the reaction of the latter should he considerable more regioselective than the former in accordance with the experimental results [3]. 

The cycloaddition between norbornadiene (23 in Scheme 1.12) and maleic anhydride was the first example of a /mmo-Diels-Alder reaction [55]. Other venerable examples are reported in Scheme 1.12 [56]. Under thermal conditions, the reaction is generally poorly diastereoselective and occurs in low yield, and therefore several research groups have studied the utility of transition metal catalysts [57]. Tautens and coworkers [57c] investigated the cycloaddition of norbornadiene and some of its monosubstituted derivatives with electron-deficient dienophiles in the presence of nickel-cyclo-octadiene Ni(COD)2 and PPhs. Some results are illustrated in Tables 1.4 and 1.5. 

Table 1.4 Ni(COD)2/PPh3 catalyzed Aomo-Diels-Alder reaction of norbornadiene with electron-deficient dienophiles...

Spanish researchers [32] also noted a considerable improvement upon sonica-tion of Diels-Alder reactions of l-dimethylamino-3-methyl-l-azadiene 44 with a variety of electron-deficient dienophiles by using diene as solvent or in acetonitrile (Scheme 4.9). Ultrasound irradiation which allows mild reaction conditions gave good to excellent yields. 

TT-Facial selectivity in the Diels-Alder reactions of thiophen 1-oxides has recently attracted keen attention (Scheme 49). Fallis and coworkers reported in situ generated 2,5-dimethylthiophene 1-oxide 98 reacted with various electron-deficient dienophiles exclusively at the syn face with respect to sulfoxide oxygen [57],... 

Substituted 2-aza-l-(dimethylamino)-3-(inethylthio)-1,3-dienes react readily with a variety of electron-deficient dienophiles to give pyridine derivatives (e.g., 26)... 

Buckminsterfullerene Cgo generally reacts as electron-deficient dienophile or dipolarophile in numerous Diels-Alder or 1,3-dipolar cycloadditions103. The rates of reaction are again enhanced by an increase of pressure so that the yields are usually better at high pressure than at atmospheric pressure (Scheme 12). 

These secondaiy interactions play an important role in cycloadditions having highly electron deficient dienophiles. 

Allenes participate in the Diels-Alder-type [4+2]-cycloaddition mostly as an electron-deficient dienophile. The LUMO energy level of an allene is lowered by the introduction of an electron-withdrawing unsaturated substituent. The largest LUMO coefficient locates on the central carbon (C2) and the next largest on the substituted carbon (Cl). Thus, [4 + 2]-cycloadditions of activated allenes take place at the internal C=C bond of the allene. 

In the presence of electron-deficient dienophiles such as tetracyanoethylene (TCNE), however, vinylallene 198 acts as a diene to afford cross [4+2]-cycloadducts. In the case of 1,4-naphthoquinone, the adduct 199 was converted to 1-methylanthra-quinone 200 in the presence of charcoal [163],... 

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]. 

The starting material is called dicyclopentadiene . Cyclopentadiene itself is not stable it dimerizes to dicyclopentadiene slowly at room temperature by a Diels-Alder reaction. It does this even though it is not an electron-deficient dienophile, demonstrating the enormous reactivity of cyclopentadiene as a diene in the Diels-Alder reaction. 

Unlike thermal homo Diels-Alder reactions in which endo adducts predominate330, the nickel catalyzed reactions of acyclic electron-deficient dienophiles afford the exo isomers as the major cycloadducts. This has been explained by unfavorable steric interactions within intermediate 559 leading to the endo adduct. Cyclic dienophiles, on the contrary, give predominantly the endo isomer, which has again been explained by unfavorable steric interactions within exo 559. The preferred conformation of the dienophile, s-cis or s-trans, has also been suggested to play a role328. 

The Diels-Alder reaction between a 2-fluoroacrylic acid derivative of 8-phenyl-menthol (83) and cyclopentadiene shows high exo- and jr-diastereofacial selectivity (Scheme 30). The C(2) of endocyclic cross-conjugated 2-(acylamino)-l,3-dienes exerts excellent diastereofacial control on the Diels-Alder addition with electron-deficient dienophiles to produce octahydroquinolines. ... 

Okamura and Nakatani [65] revealed that the cycloaddition of 3-hydroxy-2-py-rone 107 with electron deficient dienophiles such as simple a,p-unsaturated aldehydes form the endo adduct under base catalysis. The reaction proceeds under NEtj, but demonstrates superior selectivity with Cinchona alkaloids. More recently, Deng et al. [66], through use of modified Cinchona alkaloids, expanded the dienophile pool in the Diels-Alder reaction of 3-hydroxy-2-pyrone 107 with a,p-unsaturated ketones. The mechanistic insight reveals that the bifunctional Cinchona alkaloid catalyst, via multiple hydrogen bonding, raises the HOMO of the 2-pyrone while lowering the LUMO of the dienophile with simultaneous stereocontrol over the substrates (Scheme 22). 

Table 9-4 Relative Activation Energies of Diels-Alder Cycloadditions of Cyclopentadiene and Electron-Deficient Dienophiles ... 

A second set of comparisons assesses the consequences of use of approximate reactant and transition-state geometries for relative activation energy calculations, that is, activation energies for a series of closely related reactions relative to the activation energy of one member of the series. Two different examples have been provided, both of which involve Diels-Alder chemistry. The first involves cycloadditions of cyclopentadiene and a series of electron-deficient dienophiles. Experimental activation energies (relative to Diels-Alder... 

The following general observations have been made about kinetic regioselection in normal Diels-Alder reactions, i.e., those involving electron-rich dienes and electron-deficient dienophiles (see also discussion in Chapter 9). 

Reaction of l-azirine-3-methylaciylates (155) with imidazoles and pyrazoles under mild conditions results in the formation of 2-aza-1,3-dienes (156), which are useful as dienes in hetero Diels-Alder reactions with electron-deficient dienophiles <99JOC49>. When the related methyl 2-aryl-2ff-azirine-3-carboxylate (157) was used as fee substrate, reaction with an amine induced a ting opening by addition of the amino group onto fee C=N bond followed by cleavage to provide enediamine 158 <99JCS(P1)1305>. 

On the contrary, while working in the synthesis of the alkaloid ru-brolone, Bogerand Zhu (91TL7643) have found 0-alkyl a,/3-unsaturated oximes 98 to participate as effective 4ir components of an intramolecular Diels-Alder reaction with an electron-deficient dienophile. Thus, 98 was prepared from butane-1,4-diol and heated in triisopropylbenzene to furnish 2-pyrindine derivatives 99 by virtue of in situ elimination of alcohol (Scheme 25). 

Hetero-Diels-Alder reactions provide an attractive means of rapidly constructing complex heterocyclic ring systems. Cycloaddition of pyrazolyl imines with a variety of electron-deficient dienophiles has been used to assemble pyrazolo[3,4,1 ]pyridines in a focused microwave reactor under solvent-free conditions53. The reactions proceeded in modest to excellent yield, depending upon the choice of diene and dienophile (Scheme 3.32). 

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