Heterodienophile

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 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. 

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. 

The method has then been efficiently used to remove selectively the exocycHc methylsulfanyl group from phosphorylated thiopyranyl derivatives 85 resulting from hetero Diels-Alder reaction of a phosphono-dithioformate or dithioacetate (see Sects. 2.1.2 and 2.2.3). FimctionaHzed thiopyrans 86 [17,18,27a] are thus obtained (Scheme 25). Owing to this selective desulfanylation, phospho-nodithioesters can be used as heterodienophiles in place of the corresponding phosphonothioaldehyde, not described so far and probably very unstable. 

The P-nitroso phosphine oxide 406 behaves as an N-O heterodienophile and reacts with the 1,3-diene part of the molecule in a cycloaddition reaction to form the 2,4 ,5,6,7,8-hexahydro-8-phenyl-[l,2]azaphosphorino[l,6-3][l,2]oxa-zine 8-oxide 407 containing an stereogenic cyclic phosphorus atom (Scheme 64). 31P NMR spectroscopy shows one single peak indicating the formation of only one diastereomer <2002JOG6174>. 

The hetero-Diels-Alder reaction is one of the most important methods of synthesis of heterocycles, yet as a potentially powerful synthetic tool it has found relatively little general use. Microwave irradiation has been used to improve reactions involving heterodienophiles and heterodienes of low reactivity. 

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). 

Jimenez et al. studied the asymmetric Diels-Alder reactions of 1-aryl-1,2-diaza-l,3-butadienes 114, heterodienes derived from sugars, with diethyl azodicarboxylate (115), a heterodienophile [85]. The reactions were performed without solvent in a focused microwave reactor for periods of a few hours. The reaction is stereoselective... 

SCHEME 14. Diels-Alder reaction with acyclic heterodienophiles and heterodienes... 

In Scheme 14 the effect of pressure on Diels-Alder reactions with acyclic heterodienophiles or heterodienes is presented. The application of high pressure leads also in these reactions to an enhancement of rates and improvement of yields. The hetero-Diels-Alder reaction (entry 3) is a good example of the interplay between pressure and temperature. At high pressure the rate of reaction as well as the diastereoselectivity are increased. The pressure-induced acceleration allows the temperature of reaction to be lowered, which leads to a further increase of diastereoselectivity. 

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... 

Acyl nitroso compounds react with 1, 3-dienes as N-O heterodienophiles to produce cycloadducts, which have found use in the total synthesis of a number of nitrogen-containing natural products [21]. The cycloadducts of acyl nitroso compounds and 9,10-dimethylanthracene (4, Scheme 7.3) undergo thermal decomposition through retro-Diels-Alder reactions to produce acyl nitroso compounds under non-oxidative conditions and at relatively mild temperatures (40-100°C) [11-14]. Decomposition of these compounds provides a particularly clean method for the formation of acyl nitroso compounds. Photolysis or thermolysis of 3, 5-diphenyl-l, 2, 4-oxadiazole-4-oxide (5) generates the aromatic acyl nitroso compound (6) and ben-zonitrile (Scheme 7.3) [22, 23]. Other reactions that generate acyl nitroso compounds include the treatment of 5 with a nitrile oxide [24], the addition of N-methyl morpholine N-oxide to nitrile oxides and the decomposition of N, O-diacylated or alkylated N-hydroxyarylsulfonamides [25-29]. 

J0rgensen and co-workers (229,230) examined the use of a-ketoesters and 1,2-diones as heterodienophiles in reactions with Danishefsky s diene. Catalyst 269c was found to exert the highest facial bias in these reactions, and is generally tolerant of substitution on the dione. These reactions may be conducted with as little as 0.05 mol% catalyst loadings. 

The formation of heterocycles by cycloaddition reactions of conjugated dienes is the subject of this chapter. Almost the entire account is devoted to the Diels-Alder reaction of dienes with heterodienophiles to yield six-membered ring compounds (equation 1). Many such reactions have been reported and there is a plethora of reviews. Somela p are general others are cited at appropriate places in the text. This account is highly selective, concentrating on recent work with particular regard to the stereochemistry of these processes. 

Also propiogeninic type macrolide moieties should be accessible via this inverse type hetero-Diels-Alder methodology. This was recently exhibited starting from cis-propenylether as heterodienophile (Schmidt, R.R. Haag-Zeino, B. Hoch, M. Liebigs Ann. Chem., in press). In a highly endo-selective cycloaddition reaction and in subsequent diastereoselective transformations of the methyl substituted dihydropyran obtained a 2,4-dimethyl-... 

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... 

Heterocyclic bases, amination of, 1, 4 in nucleosides, 55, 1 Heterodienophiles, 53, 2 Hilbert-Johnson method, 55, 1 Hoesch reaction, 5, 9... 

Weinreb SM (1991) Heterodienophile additions to dienes. Trost BM, Fleming I (eds) Comprehensive organic synthesis, vol 4. Pergamon, Oxford, pp 401 109... 

The versatility of these [4+2] heterocyclization reactions is a consequence of the wide range of ene and diene components which can be used. In addition to alkenes and alkynes functioning as ene components, a variety of heterodienophiles is available such as electron-deficient imines (e.g. equation 89), nitriles e.g. equation 90), electrophilic carbonyl compounds (e.g. equation 91), thiocarbonyl compounds (e.g. equation 92), singlet oxygen (e.g. equation 93), nitroso compounds (e.g. equation 94), sulfenylsulfonamides (e.g. equation 95) and azo compounds (e.g. equation 96). Many of these reactions proceed with excellent regioselectivity and stereoselectivity, probably because in many instances they involve... 

---