Diels-Alder reaction hetero-dienophiles

Table 14. Titanium-promoted hetero-Diels-Alder reactions. (Hetero)diene (Hetero)dienophile Titanium sait Product...

In 1951 Gresham and Steadman reported that formaldehyde can be used as a dienophile in Diels-Alder reactions (hetero Diels-Alder reaction). This report led to the investigation of several dienes and aldehydes under thermal reaction conditions. These studies revealed that the reaction is restricted to the use of formaldehyde or aldehydes that contain strong electron-withdrawing groups (such as glyoxal-dehyde) as dienophiles (Scheme 1). 

A review of cycloaddition reactions in carbohydrate chemistry is presented. The use of carbohydrate-derived dienes and dienophiles in the Diels-Alder reaction, hetero-Diels-Alder and dipolar addition reactions of carbohydrates are described. Stereochemical aspects of the cycloaddition processes are also discussed, and applications to the synthesis of natural products are included for each reaction type. Much of the material presented has appeared in the literature within the past five years however, earlier studies are also included in order to give a more representative historical perspective. 

In a combined experimental and theoretical investigation it was found that the / -alkyl group in the dienophile gave a steric interaction in the transition-state structure which supported the asynchronous transition-state structure for the Lewis acid-catalyzed carbo- and hetero-Diels-Alder reactions. The calculated transition-state energies were of similar magnitude as obtained in other studies of these BF3-catalyzed carbo-Diels-Alder reactions. 

The basic concept of activation in hetero-Diels-Alder reactions is to utilize the lone-pair electrons of the carbonyl and imine functionality for coordination to the Lewis acid. The coordination of the dienophile to the Lewis acid changes the FMOs of the dienophile and for the normal electron-demand reactions a decrease of the LUMO and HOMO energies is observed leading to a better interaction with... 

The Diels-Alder reaction is of wide scope. Not all the atoms involved in ring formation have to be carbon atoms the hetero-Diels-Alder reaction involving one or more heteroatom centers can be used for the synthesis of six-membered heterocycles. The reverse of the Diels-Alder reaction—the retro-Diels-Alder reaction —also is of interest as a synthetic method. Moreover and most importantly the usefulness of the Diels-Alder reaction is based on its 5y -stereospecifi-city, with respect to the dienophile as well as the diene, and its predictable regio-and c ifo-selectivities. °... 

The classical Diels-Alder reaction is a cycloaddition between a conjugated diene and a second component, called dienophile, which has at least a n bond (Equation 1.1). When one or more heteroatoms are present in the diene and/or dienophile framework, the cycloaddition is called a hetero-Diels-Alder reaction. 

Avenoza A., Busto J. H., Cativiela C., Peregrina G. M. and Zurbano M. M. The use of 4-Hetaryliden- and 4-Aryliden-5(4H)-Oxazolones as Dienophiles in the Diels-Alder Reactions in Targets in Heterocyclic Systems-Chemistry and Properties vol 3. 1999, Eds. Attanasi O. A. and Spinelli D., Pb. Soc. Chim. Ital. Keywords hetero-Diels-Alder reactions... 

Streith J., Defoin A. Hetero Diels-Alder Reactions With Nitroso Dienophiles Application to the Synthesis of Natural Product Derivatives Synthesis 1994 1107-1117 Keywords chiral dienes, chiral nitroso dienophiles... 

Scheme 24 Use of PS-anthracene to scavenge excess of dienophiles after a hetero Diels-Alder reaction...

Another interesting scavenger is polymer-supported anthracene, developed by Porco for the scavenging of dienophiles [109]. An example of its application to the synthesis of a complex 5,8-dihydro-(l,2,4)triazolo[l,2-a]pyridazine-l,3-diones via hetero-Diels-Alder reaction followed by removal of the excess of triazole-3,5-dione under microwave irradiation is depicted in Scheme 24. For this particular example, moving from thermal heating (toluene, 100 °C) to a microwave-assisted protocol (DCE, 150 °C) reduced scavenging time from 3 h to just 15 min. 

Azadienes undergo Diels-Alder reactions to form pyridine, dihydro- and tetrahydropyridine derivatives. N-Vinyl lactim ethers undergo Diels-Alder reactions with a limited set of dienophiles. " Thioketones react with dienes to give Diels-Alder cycloadducts. The carbonyl group of lactams have also been shown to be a dienophile. Certain heterocyclic aromatic rings (among them furans) can also behave as dienes in the Diels-Alder reaction. Some hetero dienes that give the reaction are -C=C-C=0, 0=C-C=0, and N=C-C=N. ... 

A further hetero-Diels-Alder reaction with inverse electron demand between o-QM 3 as the dienophile and either of the two diastereomers of spiro dimer 9 as the diene provided the spiro trimers 31 and 32 (Fig. 6.25). The absolute configuration was derived from NMR experiments. It was moreover shown that only two of the four possible stereoisomeric trimers were formed in the hetero-Diels-Alder reaction the attack of the o-QM 3 occurred only from the side syn to the spiro ring oxygen.28... 

The hetero-Diels-Alder reaction has also utilized dienophiles in which both reactive centers are heteroatoms. Kibayashi reported that the intramolecular hetero-Diels-Alder cycloaddition of chiral acylnitroso compounds, generated in situ from periodate oxidation of the precursor hydroxamic acid, showed a marked enhancement of the trans-selectivity in an aqueous medium compared with the selectivity in nonaqueous conditions (Eq. 12.55).125 The reaction was readily applied to the total synthesis of (—)-pumiliotoxin C (Figure 12.5).126... 

The ability of the Si=P bond to serve as a dienophile for a [2+4]-cycloaddition (hetero-Diels-Alder reaction) has been verified by the reaction of 15a with cyclopentadiene (Eq. 10).14 The components react at 60°C in benzene to give a quantitative yield of 25, which was isolated as a colorless solid. Interestingly, a Br0nsted acid (C—H)/base (Si=P) reaction, as in the case of 15a and phenylacetylene, was not observed. In the mass spectrum of25, the molecular peak but also the free phosphasilene 15a+ have been detected. Similar behavior was observed for related ad-... 

So far, only those domino Knoevenagel/hetero-Diels-Alder reactions have been discussed where the cycloaddition takes place at an intramolecular mode however, the reaction can also be performed as a three-component transformation by applying an intermolecular Diels-Alder reaction. In this process again as the first step a Knoevenagel reaction of an aldehyde or a ketone with a 1,3-dicarbonyl compound occurs. However, the second step is now an intermolecular hetero-Diels-Alder reaction of the formed 1 -oxa-1,3 -butadiene with a dienophile in the reaction mixture. The scope of this type of reaction, and especially the possibility of obtaining highly diversified molecules, is even higher than in the case of the two-component transformation. The stereoselectivity of the cycloaddition step is found to be less pronounced, however. 

Another combination of hetero-Diels-Alder reactions and a [3+2] cycloaddition of a nitroalkene was described by Avalos and coworkers [46]. Using the chiral substrate 4-134 derived from a sugar, the domino process can be performed as a three-component transformation using an electron-rich dienophile and an electron-poor... 

The Hall group [52] has developed a new three-component domino reaction of 1-aza-4-borono-1,3-butadiene 4-152, a dienophile and an aldehyde to give a-hydroxy-methylpiperidine derivatives. In the first step, a hetero-Diels-Alder reaction takes place, which is followed by allylboration. As an example, reaction of 4-152 with the maleimide 4-153 in the presence of benzaldehyde furnished 4-154 in yields of up to 80% using the three substrates in a 1 2 1 ratio (Scheme 4.32). 

Hetero Diels-Alder reactions using nitroalkenes followed by 1,3-dipolar cycloadditions provide a useful strategy for the construction of polycyclic heterocycles, which are found in natural products. Denmark has coined the term tandem [4+2]/[3+2] cycloaddition of nitroalkenes for this type of reaction. The tandem [4+2]/[3+2] cycloaddition can be classified into four families as shown in Scheme 8.31, where A and D mean an electron acceptor and electron donor, respectively.149 In general, electron-rich alkenes are favored as dienophiles in [4+2] cycloadditions, whereas electron-deficient alkenes are preferred as dipolarophiles in [3+2] cycloadditions. 

Hetero substituted 2-cyclopropylideneacetates are ring-strain activated acrylates, highly reactive dienophiles in Diels-Alder reactions, but also powerful Michael acceptors. The reactivity of these compounds is enhanced by the same strain release in the Diels-Alder cycloadditions as well as in the 1,4-additions, and indeed the borderline between tandem Michael-cyclization and Diels-Alder-type cycloaddition is not well defined in many cases. 

Such a conclusion is, nevertheless, connected with the synchronous character of the mechanism. If a stepwise process is involved (nonsimultaneous formation of the two new bonds), as for unsymmetric dienes and/or dienophiles or in hetero Diels-Alder reactions, a specific microwave effect could intervene, because charges are developed in the transition state. This could certainly be so for several cycloadditions [47, 48] and particularly for 1,3-dipolar cycloadditions [49]. Such an assumption has... 

Methods have been described that involve microwave-assisted graphite-supported dry media for the cycloaddition of anthracene, 1-azadienes and 1,2,4,5-tetrazines with several C-C dienophiles and carbonyl compounds in hetero-Diels-Alder reactions [35], This technique leads to a shortening of reaction times, a situation that enables work to be undertaken at ambient pressure in an open reactor to avoid the formation of unwanted compounds by thermal decomposition of reagents or products. 

The carbonyl group in a ketone or aldehyde is an extremely versatile vehicle for the introduction of functionality. Reaction can occur at the carbonyl carbon atom using the carbonyl group as an electrophile or through enolate formation upon removal of an acidic proton at the adjacent carbon atom. Although the carbonyl group is an integral part of the nucleophile, a carbonyl compound can also be considered as an enophile when involved in an asymmetric carbonyl-ene reaction or dienophile in an asymmetric hetero Diels-Alder reaction. These two types of reaction are discussed in the next three chapters. 

An example for the combination of mechanistically different reactions is the anionic-pericydic process such as the domino-Knoevenagd-hetero-Diels-Alder reaction. In the inter-intramolecular version of this process an aldehyde 1 containing a dienophile moiety and a 1,3-dicarbonyl compound 2 can be mixed together to give unusual heterocycles of diversified structures such as 4 via the intermediate formation of an 1-oxa-l,3-butadiene 3 (scheme 1).[41... 

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