Heterodienes intramolecular

The inverse electron-demand catalytic enantioselective cycloaddition reaction has not been investigated to any great extent. Tietze et al. published the first example of this class of reaction in 1992 - an intramolecular cycloaddition of heterodiene 42 catalyzed by a diacetone glucose derived-titanium(IV) Lewis acid 44 to give the cis product 43 in good yield and up to 88% ee (Scheme 4.31) [46]. 

The /zetero-Diels-Alder reaction permits heterocyclic-six- membered rings to be constructed by the interaction of heterodienes and/or heterodienophiles. Both the intermolecular and intramolecular versions of the /zctcro-Diels Alder reaction are, therefore, very important methods for synthesizing heterocyclic compounds. 

Given their extraordinary reactivity, one might assume that o-QMs offer plentiful applications as electrophiles in synthetic chemistry. However, unlike their more stable /tora-quinone methide (p-QM) cousin, the potential of o-QMs remains largely untapped. The reason resides with the propensity of these species to participate in undesired addition of the closest available nucleophile, which can be solvent or the o-QM itself. Methods for o-QM generation have therefore required a combination of low concentrations and high temperatures to mitigate and reverse undesired pathways and enable the redistribution into thermodynamically preferred and desired products. Hence, the principal uses for o-QMs have been as electrophilic heterodienes either in intramolecular cycloaddition reactions with nucleophilic alkenes under thermodynamic control or in intermolecular reactions under thermodynamic control where a large excess of a reactive nucleophile thwarts unwanted side reactions by its sheer vast presence. 

In the [4 + 2] cycloadditions discussed so far, the enol ether double bond of alkoxyallenes is exclusively attacked by the heterodienes, resulting in products bearing the alkoxy group at C-6of the heterocycles. This regioselective behavior is expected for [4+2] cycloadditions with inverse electron demand considering the HOMO coefficients of methoxyallene 145 [100]. In contrast, all known intramolecular Diels-Alder reactions of allenyl ether intermediates occur at the terminal C=C bond [101], most probably because of geometric restrictions. 

Cyclic alkyl nitronates may be used in tandem [4+2]/[3+2] cycloadditions of nitroalkanes, and this reaction has been extensively studied by Denmark et al. (64,333-335). In recent work, they developed the silicon-tethered heterodiene-alkene 219 (Scheme 12.63). Steric hindrance and the fact that both the nitroalkene and the a,p-unsaturated ester in 219 are electron deficient renders the possibility of self-condensation. Instead, 219 reacts with the electron-rich chiral vinyl ether 220 in the presence of the catalyst 224 to form the intermediate chiral nitronate 221. The tandem reaction proceeds from 221 with an intramolecular 1,3-dipolar cycloaddition to form 222 with 93% de. Further synthetic steps led to the formation of ( )-detoxinine 223 (333). A similar type of tandem reaction has also been applied by Chattopadhyaya and co-workers (336), using 2, 3 -dideoxy-3 -nitro-2, 3 -didehydrothymidine as the starting material (336). 

There are a number of examples of the synthesis of chromans using o-quinone methides as the heterodiene in a hDA reaction. Both pyrano[3 -c]-benzopyrans and cyclopenta[c][l]benzopyrans result from an intramolecular cycloaddition of a substituted o-quinonemethide generated under mild conditions. In the former case, salicylaldehyde and an unsaturated alcohol yield the rra/is-fused tetrahydropyranobenzopyran (Scheme 10) <99JOC9507>. However, the latter synthesis (Scheme 11) is less selective <99BCJ73>. 

Lactone 5 can be obtained in both enantiomeric forms or as a racemate according to the described procedure. The reaction sequence includes the in situ formation of an alkylidene-1,3-dicarbonyl system 7 which can act as a heterodiene in an intramolecular hetero-Diels-Alder addition. A small amount of the ene product 4 with de > 98% is formed at room temperature as well. The remarkable selectivity in formation of diastereomer 3 is explained by an energetically more favorable exo transition state 8 with a pseudo-chair arrangement having the methyl group quasi-equatorial. Polycyclic cis-fused compounds can also be synthesized by the procedure above,9 and a related sequence to the cannabinoid skeleton has been described using appropriate 1,3-dicarbonyl reactants.10... 

Intramolecular heterodiene synthesis used alkyne (22) (Scheme 15) <95B(ECTOC-l)>. 

Sulfinyl dienes and vinyl sulfoxides have rarely been used in asymmetric hete-ro-Diels-Alder reactions [145]. The first example was reported in 1992 and describes an intramolecular cycloaddition using a heterodiene bearing a chiral sulfinyl group [146a]. In this paper, the conversion of a-p-tolylsulfinyl a,ft-unsaturated ketone 176 (prepared by Knoevenagel reaction of 3-methylcitronellal and (S)-p-toluenesulfinylacetone) into the hetero-Diels-Alder adducts 177... 

The enantioselective hetero Diels-Alder reaction of 1-oxa-1,3-butadienes using chiral non-racemic Lewis acids is a widely unexplored field. The first successful example was the intramolecular cycloaddition of the heterodiene 2-194,... 

Due to their two electron-withdrawing groups, / ,/ -diketoenamines are reactive towards nucleophilic reagents. Attack usually occurs at the a-carbon. With dinucleophiles, the substitution of the amino group is followed by ring closure to 5- or 6-membered heterocycles. However, due to the enaminedione structure, few successful reactions with electrophiles are known. Only if an electrophilic group is incorporated into the enaminone molecule is such intramolecular reaction observed. Enaminediones are also suitable heterodienes in 4 + 2-cycloaddition. Their electron-deficient character as heterodienes requires the use of electron-rich dienophiles. The result is a Diels-Alder reaction with inverse electron demand. 

Several triflates and metal salt hydrates were tested as Lewis acid catalysts (each 10 mol%) and the best results were obtained using Yb(OTf or Ni(C104)2-6H20. The stereoselective formation of bicyclic y-lactones (7) could be obtained from bicyclic nitronate (9) via the hydrolytic process by the action of a strong acid generated from Lewis acid with a small amount of water in both nitroalkene (5) and the Lewis acid. This new methodology of one-pot reaction also involves a new type of intramolecular HAD reaction of nitroalkenes as heterodienes, which provides stereochemically defined bicyclic nitronates. 

Wada, E. and Yoshinaga, M. 2003. A new methodology of intramolecular hetero-Diels-Alder reaction with (3-alkoxy-snbstituted conjugated nitroalkenes as heterodienes Stereoselective one-pot synthesis of tra -fused bicyclic y-lactones. Tetrahedron letters, 44(43) 7953-6. 

The entropic assistance provided in the intramolecular Diels-Alder reaction often is sufficient to promote heterodiene 4ir participation in poorly matched [4 + 2] cycloaddition reactions, including those with unactivated and electron-deficient dienophiles. - " ... 

Reaction of iV,A -unsubstituted selenoureas with a 1,2-diaza-l,3-butadiene affords 2-amino-4,5-dihydro-l,3-selenazol-4-ones 81 mainly in the hydrazono form. The reaction proceeds via nucleophilic addition of the selenium atom to the terminal carbon atom of the heterodiene. The subsequent intramolecular nucleophilic attack by the imidic NH at the carboxylate group with the loss of methanol leads to the selenazole ring closure (Scheme 14) <2002EJO2323, 2001SL144>. 

Dimethylsulfoxonium methylide reacts with AT-selenoacylamidines to give 4,5-dihydro-l,3-selenazoles 33. The reaction pathway involves the addition of the sulfur ylide to the imine bond of the heterodienes, and then cyclization by a subsequent intramolecular substitution of the dimethylsulfoxonium leaving group (Scheme 17) <1998T2545>. 

Hetero-Intramolecular Diels- Alder Reactions Heterodiene-Homodienophile Reactions... 

The additional substitution of the heterocyclic azadiene system with electron-withdrawing groups accents the electron-deficient nature of the heterodiene and permits the use of electron-rich, strained, or even simple olefins as dienophiles.3 415 6 Substitution of the heterocyclic azadiene with strongly electron-donating substituents in many instances is sufficient to overcome the electron-deficient nature of the azadiene and permits the use of conventional electron-deficient dienophiles in normal (HOMCWne controlled) Diels-Alder reactions.4 6 The entropic assistance provided by the intramolecular Diels-Alder reaction is sufficient in most instances to override the reluctant azadiene participation in Diels-Alder reactions.7 The incorporation of the heterocyclic azadiene, or the dienophile, into a reactive system, e.g., heterocumulene, allows a number of specialized [4 + 2] cycloaddition processes which are best characterized as stepwise addition-cyclization [4 + 2] cycloadditions.8... 

One such strategy exploits 142 for construction of the heterodiene 149, derived from azide 148, in which the stereochemistry of the intramolecular Diels—Alder cycloadducts is controlled by the configuration of the dienophile olefin. Treatment of 142 with diphenylpho-sphoryl azide in the presence of diisopropyl azodicarboxylate and triphenylphosphine affords the epoxy azide 148 with inversion of chirality. This is then converted in six steps to the heterodiene intermediate 149, which undergoes an intramolecular cycloaddition to fiimish a single adduct that is subsequently converted to 150. Transformation of 150 into 151 in seven steps completes the synthesis [59] (Scheme 36). 

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