Heterodienes and Dienophiles

Diene/dienophile combinations incorporating one or more hetero atoms have been studied in some detail. The most extensively investigated example has been the further cyclization of one of the condensation products of citral with olivetol [107]. Other o-vinyl phenols cyclize in similar fashion [108,109]. Unsaturated esters [110], aldehydes [111, 112] and ketones [113] can also serve as dienes. 

Diene-containing heterocycles have also been shown to participate in intramolecular cycloaddition [114-119]. Under some circumstances, initial cycloaddition is followed by elimination [117-119]. One other example appears to belong in this category [120]. 

Hetero atom-containing dienophiles also take part in the intramolecular Diels-Alder reaction [121-122]. With o-quinone methides [123], cyclization proceeds at the temperature required to generate the diene. The reaction of a nitrile as a dienophile with a simple acyclic diene has also been reported [124]. 

Extensive work has been reported by Weinreb [125] and by Keck [126] on the preparation and cyclization of more active heterodienophiles. 

As with bimolecular cycloaddition, the intramolecular Diels-Alder reaction can be catalyzed by Lewis acid [127-129]. In one case, it was reported that trifluoroacetic acid catalyzed cycloaddition [130]. 

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The heterodiene and dienophile behaviours of thioketones have been investigated by Saito in diene-trasmissive112 and transannular113 Diels Alder reactions. 

Diels-Alder reactions are one of the most fundamental and useful reactions in synthetic organic chemistry. Various dienes and dienophiles have been employed for this useful reaction.1 Nitroalkenes take part in a host of Diels-Alder reactions in various ways, as outlined in Scheme 8.1. Various substituted nitroalkenes and dienes have been employed for this reaction without any substantial improvement in the original discovery of Alder and coworkers.2 Nitrodienes can also serve as 4ti-components for reverse electron demand in Diels-Alder reactions. Because the nitro group is converted into various functional groups, as discussed in Chapters 6 and 7, the Diels-Alder reaction of nitroalkenes has been frequently used in synthesis of complex natural products. Recently, Denmark and coworkers have developed [4+2] cycloaddition using nitroalkenes as heterodienes it provides an excellent method for the preparation of heterocyclic compounds, including pyrrolizidine alkaloids. This is discussed in Section 8.3. 

Aiming at the pyranose form of sugars, normal type hetero-Diels-Alder reactions were extensively used for the synthesis of functionally substituted dihydropyran and tetrahydropyran systems (5-10) (see routes A - D in the general Scheme 1) which are also important targets in the "Chiron approach" to natural product syntheses (2.) Hetero-Diels-Alder reactions with inverse electron demand such as a, p-unsaturated carbonyl compounds (l-oxa-1,3-dienes) as heterodienes and enol ethers as hetero-dienophiles, are an attractive route for the synthesis of 3,4-dihydro-2H-pyrans (11). 

The dimerization of o-quinone methides in which one molecule acts as the heterodiene and another as dienophile leads to spiroannelated chromans (equation 12). The driving force for this considerable tendency to dimerize is associated with the ease with which the... 

Most importantly, the scope of the Diels-Alder reaction is very high - not only allowing the synthesis of cyclohexenes and 1,4-cyclohexadienes using 1,3-butadienes and alkenes and alkynes, respectively, but also giving access to a multitude of different heterocycles by exchanging the atoms a-d in the butadiene as well as the atoms e and f in the alkene by hetero atoms such as oxygen, nitrogen and sulfur. However, also dienes and dienophiles with several other atoms as phosphorous, boron, silicone, and selenium have been described. Thus, many different heterodienes and heterodienophiles have been developed over the years (Tables 1-1 and 1-2). 

The formation of pyridazines from 1,2-diaza-1,3-butadienes and electron-rich dienophiles has been reported [308] on the other hand, tetrazine and triazole derivatives have been prepared from these heterodienes and azo esters [309]. Aza Diels-Alder reactions of 1,4-diaza-1,3-butadienes have been employed for the synthesis of unsymmetrical pyrazine derivatives by Heathcock et al. [310]. 

Heteroaromatic systems that possess an electron-deficient azadiene are ideally suited for participation in inverse electron-demand Diels-Alder reactions. 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. 

Hetero Diels-Alder reaction The [4+2] cyclization of a diene or heterodiene and a dienophile or heterodienophile. 204... 

A [4 + 2]/[4 + 2]/[3 + 2] cycloaddition using four different components has also been investigated.The interaction of p-nitrostyrene (81a), diene 92, styrene (96) and A-phenylmaleimide (97) under 1.5 GPa pressure in dichloromethane solution for 16h at room temperature (Scheme 7.24) afforded a mixture of diastereomeric nitroso-acetals 98 and 99. In this case, 92 reacted as a diene, A-phenylmaleimide as a dienophile, p-nitrostyrene as the heterodiene and styrene as a dipolarophile. 

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... 

Attempts have also been made338 346 to find a theoretical explanation of the stereo or positional selectivity in the first stage of the heterodiene synthesis, especially in the interaction between 5-ethoxy-4-methyloxazole and asymmetric dienophiles, e.g., /9-acetylacrylic acid and its ethyl ester. ir-Electron density calculations for the diene and dienophile molecules by the HMO method indicate the formation of the 4-acetylpyridine derivative (187) from ethyl /3-acetylacrylate, while the opposite orientation would be expected in the reaction with the free acid, giving a substituted 5-acetylpyridine as the main product. Indeed, 5-ethoxy-4-methyloxazole on condensation with ethyl /3-acetylacrylate affords only 187, while in the condensation with /3-acetylacrylic acid, only 2-methyl-3-hydroxy-5-acetylpyridine (188) is isolated.338 348... 

Functionalized thiazole-fused thiopyrans can be regio- and diastereose-lectively prepared through [4 + 2] cyclocondensation reactions, in which 5-arylideneisorhodanines are used as heterodienes and crotonic, cinnamic, and propiolic acid derivatives serve as dienophiles (Scheme 80) (14T720). 

A sequence involving double Diels-Alder reaction followed by double retro Diels-Alder reaction that is reiterated again to obtain tetrabenzocyclophane has been reported (Scheme 16.46) [50]. The diene is a heterodiene, and the cycloadduct obtained from it is capable of losing PhNCO in the retro Diels-Alder step. The dienophile is a strained reactive cyclic diacetylene (cyclophyne). 

Different kinds of diene and dienophile are used in the Diels-Alder reactions. Dienes and dienophiles with a heteroatom such as N, O, or S in their Jt systems are known as heterodienes and heterodienophiles, and their cycloaddition reactions are called the hetero-Diels-Alder reactions. Some highly reactive dienes and dienophiles used in Diels-Alder reactions are listed in Table 3.4. 

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... 

Inverse electron-demand Diels-Alder reaction of (E)-2-oxo-l-phenylsulfo-nyl-3-alkenes 81 with enolethers, catalyzed by a chiral titanium-based catalyst, afforded substituted dihydro pyranes (Equation 3.27) in excellent yields and with moderate to high levels of enantioselection [81]. The enantioselectivity is dependent on the bulkiness of the Ri group of the dienophile, and the best result was obtained when Ri was an isopropyl group. Better reaction yields and enantioselectivity [82, 83] were attained in the synthesis of substituted chiral pyranes by cycloaddition of heterodienes 82 with cyclic and acyclic enolethers, catalyzed by C2-symmetric chiral Cu(II) complexes 83 (Scheme 3.16). 

Keywords 1,2-azapyrylium as heterodiene components and aikynes as dienophiles in a Diels-Alder reaction with inverse eiectron demand as cruciai step... 

Both ( )-l-phenylsulfonyl and (5)-(+)-3-p-tolylsulfmyl -alk-3-en-2-ones can exhibit high diastereoselectivity in their reactions with vinyl ethers and styrenes, with the dienophile having a dominant influence on the stereochemical outcome <96T1205,96TL3687>. Indol-2-ylideneacetic acid esters can act as both dienophile and heterodiene in cycloaddition reactions in the latter case pyrano[3,2-h]indoles are formed <96SYN519>. 

Recently, Denmark and coworkers have developed a new strategy for the construction of complex molecules using tandem [4+2]/[3+2]cycloaddition of nitroalkenes.149 In the review by Denmark, the definition of tandem reaction is described and tandem cascade cycloadditions, tandem consecutive cycloadditions, and tandem sequential cycloadditions are also defined. The use of nitroalkenes as heterodienes leads to the development of a general, high-yielding, and stereoselective method for the synthesis of cyclic nitronates (see Section 5.2). These dipoles undergo 1,3-dipolar cycloadditions. However, synthetic applications of this process are rare in contrast to the functionally equivalent cycloadditions of nitrile oxides. This is due to the lack of general methods for the preparation of nitronates and their instability. Thus, as illustrated in Scheme 8.29, the potential for a tandem process is formulated in the combination of [4+2] cycloaddition of a donor dienophile with [3+2]cycload-... 

Ghosez and co-workers (223) illustrated that azadienes could be efficiently used as heterodienes with acryloylimide dienophiles in the presence of chiral cationic Cu(II) catalysts, Eq. 183. The reaction was found to be highly exo- and enantiose-lective, provided the azadiene contains an aryl or vinyl group in the 1-position. Acryloylimide as dienophile affords equal enantioselectivities albeit reduced dias-tereoselectivities (typically 6 1). 

Blechert and co-workers successfully employed the [4 -I- 2] cycloaddition for the transformation of indole derivatives [79-81], For instance, using 2-vinyl-indole derivatives as heterodienes, (3-acceptor-substituted cyclic and acyclic ena-mines (dienophile), and triarylpyrylium tetrafluoroborate as the photosensitizer, the corresponding Diels-Alder adducts were formed in moderate to good yields with complete regiochemical and stereochemical control [79], Alternatively, good results could be obtained in the reaction of indoles and exocyclic 1,3-dienes, thus providing an easy excess to multifunctionalized carbazoles [80], Quantum... 

Intermolecular Allylboration. A tandem aza[4+2] cycloaddition/allyl-boration three-component reaction has been designed based on the prece-dented carbocyclic [4- -2] cycloaddition/allylboration and a snbsequent one-pot variant. Thns, the thermal reaction between hydrazonobutadienes 138, A-substitnted maleimides, and aldehydes provides polysnbstituted a-hydroxy-alkylpiperidines 141 via the cyclic allylboronate intermediate 139 and the proposed chairlike transition stmctnre 140 (Eq. 103). Monoactivated dienophiles like acrylates fail to react with heterodienes 138 bnt the scope of aldehydes is very broad both ahphatic and aromatic aldehydes are snitable, inclnding electron-rich ones. An inverse electron-demand variant to access the corresponding dihy-dropyran derivatives via the intermediacy of enantiomerically enriched pyranyl allylic boronate 76 has been snbsequently developed (see Eq. 64). ° ... 

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