Heteroatom Dienophiles

As mentioned in the beginning of this chapter, we have chosen to focus mainly on other areas than the intramolecular 1,3-dipolar cycloadditions, and thus only few examples of these processes will be highlighted here. For a more comprehensive coverage of this area, readers are directed to existing reviews (5,6). 

As for intermolecular 1,3-dipolar cycloadditions, the endo- and exo-isomers of each of the regioisomers can be formed in intramolecular reactions. In most cases, the exo-isomer is favored for steric reasons. 

Nitronates have also been applied in intramolecular 1,3-dipolar cycloaddition reactions. Denmark and Thorarensen (64) extensively studied the application of cyclic alkyl nitronates in tandem[4+2]/[3+2] cycloadditions of nitroalkanes. In most cases, the stereoselectivity of these reactions is directed by a chiral auxiliary and will thus be outlined in Section 12.3.4. The reader is also directed to the excellent chapter by Denmark in Chapter 2. 

The use of alkenyl nitrile oxides is an effective method for the construction of bland polycyclic isoxazolines (2,4,200,236,237). Due to the rigid linear structure of the nitrile oxide, the reaction of alkenyl nitrile oxides almost always proceeds to give bicyclo[X,3,0] derivatives for X = 3-5. Most frequently, the diastereoselec-tivities are controlled by a chiral center on the link between the alkene and the dipole groups. 

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C. Heteroatomic dienophiles 111 Esters of azodicarboxylic acid 12k 4-Phenyl-l,2,4-triazoline-3,5-dione 131 hninocarbamates... 

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 ),... 

Fluorinated heterodienophiles and heterodienes Diels-Alder reactions in which the dienophiles have perfluoroalkyl-substituted multiple bonds between carbon and a heteroatom are quite common Reported earlier were reactions of perfluoroketones, thiones, ketimines, thioesters, nitroso compounds, and nitriles [9] Examples of a-fluoroimines [107], co-hydroperfluorothioaldehydes [108], perfluorosulfines [109, IIO], and selenocarbonyidifluoride [III] (equations 89-92) have been reported recently... 

The 2n component 2, the so-called dipolarophile (analogously to the dieno-phile of the Diels-Alder reaction) can be an alkene or alkyne or a heteroatom derivative thereof. Generally those substrates will be reactive as dipolarophiles, that also are good dienophiles. 

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. °... 

For clarity, the reactions contained in this section can be divided into three categories according to the structure of the carbene complexes (Fig. 4) (i) those in which the dienophile and the diene are tethered through the heteroatom and the carbene carbon of the complex (type 1), (ii) those in which the dienophile and the diene are part of the same carbon chain (type 2), and finally (iii) those where the diene and the dienophile belong to different ligands within the complex (type 3). 

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. 

The reactivity of heterocyclic dienes is determined by the nature and number of heteroatoms and, in the case of heteroaromatic compounds, also by the aromatic character. Furans undergo Diels-Alder reactions with strong dienophiles and generally afford cxo-cycloadducts which are thermodynamically more stable than the kinetically favoured c z/o-adducts. 

Keywords Diels-Alder reactions in which one or both of the dienophile reaction centers are heteroatoms, retro-Diels-Alder reactions... 

Overman, Hehre and coworkers also reported anti tt-facial selectivity in Diels-Alder reactions of the vinylcyclopentenes 73,74 and 4,5-dihydro-3-ethynylthiophen 5 -oxide 75. They attributed the selectivity to destabilizing electronic interaction between the allylic heteroatom and dienophile in the syn attack transition state (Scheme 43) [38],... 

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... 

In most reported cases, the covalently bound chiral auxiliary has been attached to the dienophile via an acyl linkage, but there are also many examples known in which the auxiliary has been attached to the diene via an acyl, alkyl or heteroatom linkage, the first example of the latter being Trost s diene147. Lewis acids are often added to the reaction mixtures when the chiral auxiliary attached to the dienophile contains an additional Lewis basic site. This is not only to enhance the reaction rate, but especially to enhance the diastereofacial selectivity by complexing to the dienophile in a bidentate fashion. This makes the dienophile more conformationally rigid. 

Heteroatom-substituted vinylcarbene complexes are also excellent dienophiles, which usually undergo Diels-Alder reactions under very mild reaction conditions (see Experimental Procedure 2.2.7). Unfortunately the outcome of reactions between Fischer-type vinylcarbene complexes and dienes is difficult to predict ([256] compare, e.g.. Experimental Procedures 2.2.7 and 2.2.9). The course of... 

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