Heterodienophiles aldehydes

The most frequently encountered, and most useful, cycloaddition reactions of silyl enol ethers are Diels-Alder reactions involving silyloxybutadicncs (Chapter 18). Danishefsky (30) has reviewed his pioneering work in this area, and has extended his studies to include heterodienophiles, particularly aldehydes. Lewis acid catalysis is required in such cases, and substantial asymmetric induction can be achieved using either a chiral lanthanide catalyst or an a-chiral aldehyde. 

Examples of the use of heterodienophiles under the action of microwave irradiation are not common. Soufiaoui [84] and Garrigues [37] used carbonyl compounds as die-nophiles. The first example employed solvent-free conditions the second is an example of the use of graphite as a susceptor. Cycloaddition of a carbonyl compound provided a 5,6-dihydro-2H-pyran derivative. These types of reaction proceed poorly with aliphatic and aromatic aldehydes and ketones unless highly reactive dienes and/or Lewis acid catalysts are used. Reaction of 2,3-dimethyl-l,3-butadiene (31) with ethyl glyoxylate (112) occurred in 75% yield in 20 min under the action of microwave irradiation. When conventional heating is used it is necessary to heat the mixture at 150 °C for 4 h in a sealed tube to obtain a satisfactory yield (Scheme 9.33). 

Benzocyclobutene reacts with a range of heterodienophiles under mild conditions through the intermediacy of an o-quinone dimethide the reaction with aldehydes gives high yields of... 

An interesting entry to functionalized dihydropyrans has been intensively studied by Tietze in the 1990s using a three-component domino-Knoevenagel Hetero-Diels-Alder sequence. The overall transformation involves the transient formation of an activated heterodienophile by condensation of simple aldehydes with 1,3-dicarbonyls such as barbituric acids [127], Meldrum s acid [128], or activated carbonyls. In situ cycloaddition with electron-rich alkenes furnished the expected functionalized dihydropyrans. Two recent examples concern the reactivity of 1,4-benzoquinones and pyrazolones as 1,3-dicarbonyl equivalents under microwave irradiation. In the first case, a new three-component catalyst-free efficient one-pot transformation was proposed for the synthesis of pyrano-1,4-benzoquinone scaffolds [129]. In this synthetic method, 2,5-dihydroxy-3-undecyl-1,4-benzoquinone, paraformaldehyde, and alkenes were suspended in ethanol and placed under microwave irradiations to lead regioselectively the corresponding pyrano-l,4-benzoquinone derivatives (Scheme 38). The total regioselectivity was... 

B. Ganem, Chemtracts Org. Chem. 2, 127 -128 (1989) , Role Reversal in the Cyclocondensation of Cyc-lopentadiene with Heterodienophiles Derived from Arylamines and Aldehydes Synthesis of Novel Te-trahydroquinolincs11. 

Unexpectedly, Grieco discovered that immonium ions derived from aryl amines and aldehydes do not function as heterodienophiles toward cyclopentadiene, as was found in the case of simple immonium ions, but rather they acted as 2-azadienes leading to a novel synthesis of tetrahy-droquinolines (88TL5855). 

The HDA reaction allows for rapid access to chiral six-membered heterocyclic structures that serve as valuable intermediates in organic synthesis. The first highly enantioselective HDA reaction promoted by a chiral hydrogen bond donor was reported from the Rawal laboratory. While investigating the cycloaddition reactions of amino-siloxy diene 115, it was observed that this diene was exceptionally reactive to heterodienophiles, and underwent HDA reactions with various aldehydes at room temperature, even in the absence of any added catalyst (Scheme 6.14). Subsequent treatment of the intermediate cycloadducts (116) with acetyl chloride afforded the corresponding dihydro-4-pyrones (117) in good overall yields [101]. Further studies of this reaction revealed a pronounced solvent effect,... 

Grieco PA, Bahsas A (1988) Role reversal in the cyclocondensation of cyclopentadiene with heterodienophiles derived from aryl amines and aldehydes synthesis of novel tetrahydroqui-nolines. Tetrahedron Lett 29 5855-5858... 

Cycloadditions with these heterodienophiles are usually regioselective and are in accord with FMO theory. The reactions are syn selective with the diene component. Other stereochemical features of the process are outlined in some of the examples described below, as well as in previous reviews. -" It should also be mentioned that only aldehydes and some ketones act as dienophiles. Except for rare exceptions, other types of carbonyl compounds apparently do not participate in Diels-Alder cycloadditions. 

Several years later Danishefsky introduced l-methoxy-3-trimethylsilyloxy-l,3-butadiene, a highly reactive diene, which upon reaction with (not activated) aldehydes catalyzed with mild Lewis acids [(Eu(fod)3] afforded cyclic a, -unsaturated ketones [19]. Another method involved reaction of l,4-di-alkoxy(acyloxy)-butadiene with an activated heterodienophile, which led to more functionalized derivatives (Schmidt) [20]. This methodology may be illustrated by the classical synthesis of the precursor of purpurosamine B (3) and higher sugar... 

Aldehydes bearing electron-withdrawing substituents are reactive as heterodienophiles under mild conditions with a range of 1,3-dienes. In particular, glyoxylate derivatives have been widely used in these cycloadditions. Some examples of Diels-Alder reactions of this type are shown in equations (68), (69) and (70). As can be seen, these reactions occur at relatively low temperatures and are regioselective. ... 

Since Danishefsky demonstrated that activated dienes, such as siloxydiene (commonly referred to as Danishefsky s diene) react with a wide spectrum of aldehydes to afford 5,6-dihydro-y-pyrones in 1982 [l],the hetero-Diels-Alder reaction has attracted a great deal of attention over the last two decades [2,3]. The use of asymmetric catalysis in these reactions is overwhelmingly associated with heterodienophiles. Especially, the cyclocondensations of activated dienes with aldehydes or their derivatives are of particular importance, providing a multitude of opportunities for the highly efficient regio- and stereoselective construe-... 

Dienes that contain electron-donating groups (activated dienes) are more reactive in Diels-Alder reactions than unsubstituted or electron-deficient dienes. In molecular orbital formalism, the substituents on the diene perturb the tT-electron density to cause an increase in the energy of the highest occupied molecular orbital (HOMO Figure 1). In a normal-demand Diels-Alder reaction this results in an increase in the interaction between the HOMO of the diene and the LUMO (lowest unoccupied molecular orbital) of the dienophile. This interaction, in turn, lowers the transition state energy of the reaction. Similar arguments have also been used to explain the increased reactivity of activated dienes towards heterodienophiles such as aldehydes. 

Two reports of the use of heterodienophiles, amidines100 and aldehyde N,N-dimethylhydrazones,l00b in [4 + 2] cycloadditions with 1,2,4-triazines have been detailed (Table 10-IX). 

The combination of europium catalysts and high pressure (15 kbar) makes amino aldehydes available as heterodienophiles in 4 + 2] cycloadditions (Scheme 7.4) [7]. 

Other reactive heterodienophiles include electron-rich hydrazones and cyanamides, oxazolines, thiazolines, pyr-azolines, donor-substituted benzonitriles, thioketones and aldehydes, thioformic acid derivatives, and thionylimines <1996CHEC-II(6)901>. 

Carretero and coworkers have further extended the scope of N-sulfonyl imine heterodienophiles in enantioselective copper-catalyzed aza-Diels-Alder reactions (Scheme 17.65) [94]. In contrast to previous work that had been limited to the highly reactive N-tosyl imine of ethyl glyoxylate, chiral Cu(I) complexes of phosphino sulfenyl ferrocenes catalyze cycloaddition of Danishefsky s diene (286) to N-tosyl imines (292) of both aromatic and aliphatic aldehydes. Phosphorous substitution proved to play a critical role in both reactivity and enantioselectivity of the reaction with complex [151 CuBr]2 bearing 1-naphthyl substituents on the phosphorous... 

In this scheme, the character of the aldehyde is altered by the lanthanide cation so that it can act as a potent heterodienophile. This promotion can be attributed to the oxophilicity of the europium species, which, appropriately complexed, can exploit favorable solubihty properties. 

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