Diels-Alder reactions heterodienophiles

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 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. 

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. 

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]. 

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. 

Diels-Alder reactions of oxazoles afford useful syntheses of pyridines (Scheme 53) (74AHC( 17)99). A study of the effect of substituents on the Diels-Alder reactivity of oxazoles has indicated that rates decrease with the following substituents alkoxy > alkyl > acyl >> phenyl. The failure of 2- and 5-phenyl-substituted oxazoles to react with heterodienophiles is probably due to steric crowding. In certain cases, bicyclic adducts of type (359) have been isolated and even studied by an X-ray method (87BCJ432) they can also decompose to yield furans (Scheme 54). With benzyne, generated at 0°C from 1-aminobenzotriazole and lead tetraacetate under dilute conditions, oxazoles form cycloadducts (e.g. 360) in essentially quantitative yield (90JOC929). They can be handled at room temperature and are decomposed at elevated temperatures to isobenzofuran. 

Ab initio and density functional theoretical studies of the 4 + 2-cycloaddition of 2-azabutadiene with formaldehyde predict a concerted reaction that agrees well with experimental evidence.184 The azadiene A-plienyl-l-aza-2-cyanobuta-l,3-diene reacts with electron-rich, electron-poor, and neutral dipolarophiles under mild thermal conditions.185 5,6-Diliydro-4//-1,2-oxazines have been shown to be usefiil as synthon equivalents of 2-cyano-l-azabuta-1,3-dienes.186 The intramolecular Diels-Alder reaction of 1-aza-l,3-butadienes (106) can be activated by a 2-cyano substituent (Scheme 37).187 Stereoselectivity in the hetero-Diels-Alder reactions of heterobutadienes, nitrosoalkenes, and heterodienophiles has been extensively reviewed.188 The azadiene l-(f-butyldimethylsilyloxy)-l-azabuta-1,3 -diene (107) reacts with halobenzo-quinones, naphthoquinones, and A-phcnylmalcimidc to yield low to good yields of various pyridine heterocycles (108) (Scheme 38).189 The 4 + 2-cycloaddition of homophthalic anhydride with A-(cinnamylidcnc)tritylaminc produces the 3,4-adduct whereas with A -(cinnamylidcnc)bcnzylidinc the 1,2-adduct is produced.190... 

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). 

Clearly, an important feature will be the selectivity of these reactions. In this respect, the control of endo- and exo-selectivity using different Lewis acids, the induced diastereoselectivity with chiral heterobutadienes as well as chiral heterodienophiles and finally the use of chiral Lewis acids for the enantioselec-tive synthesis will be discussed. In recent time some attention has been paid to hetero Diels-Alder reactions in aqueous solutions and in the presence of inor-... 

Table 1-1. Selected heterodienophiles for the Diels-Alder reaction...

Further calculations were performed on 2,3-diaza-1,3-butadiene with different heterodienophiles such as ethene, formaldehyde and formaldimine showing the same exo oxygen or nitrogen lone pair preference [49] as well as on the nitro-soethene/ethene system [50]. Recently, ab initio studies have also been performed for the Lewis acid catalysed hetero Diels-Alder reaction of isoprene and sulfur dioxide by Sordo [51]. 

In a more recent study, Koizumi et al. employed terpene derivatives as chiral auxiliaries attached to thioaldehydes [405], but these heterodienophiles gave only moderate diastereoselectivities in reactions with cyclopentadiene. Mazzan-ti et al. have investigated the hetero Diels-Alder reaction of thioketones bearing an asymmetric silicon atom directly attached to the thiocarbonyl moiety which induced diastereoselectivities up to 50% de [406]. 

Enaminothiones react smoothly with heterodienophiles such as azo esters as well [419]. Very recently, thioacetylindoles which also may be conceived as ena-minothioketones have been subjected to hetero Diels-Alder reactions with numerous electron-deficient dienophiles [420]. 

An asymmetric Diels-Alder reaction of a chiral nitroso dienophile has been employed by Ganem et al. in order to open an elegant access to enantiomerical-ly pure (-t-)-mannostatin A 7-57 and several derivatives thereof [519], The cycloaddition of the heterodienophile 7-54 derived from mandelic acid to 1-me-thylthiocyclopentadiene 7-55 proceeded only in moderate diastereoselectivity, however, the desired product 7-56 was easily separated from its diastereomer. 

Schenone and coworkers have shown in a large number of papers that tertiary aminomethyleneketones react as heterodienes, e.g. with sulphene generated from aliphatic sulphonyl chlorides and triethylamine as a heterodienophile, to yield / -aminosultons in a Diels-Alder reaction. An early simple example is reported by Opitz270 (equation 199). 

The hetero-Diels-Alder reaction is amongst the most efficient processes for the synthesis of six-membered heterocyclic ring systems. Solvent-free conditions have been used to improve reactions of heterodienophiles and heterodynes with low reactivities. Cado et al. (1997) have described the hetero-Diels-Alder reaction of ethyl lH-perimidine-2-acetate as heterocyclic ketene aminal with ethyl propiolate nnder solvent-free conditions with focused microwave irradiation. The new fused perimi-dines (23) were obtained in good yields (67-98%). 

Hetero-Diels-Alder reactions performed with trifluoromethyl-substituled heterodienes or with trifluoromcthyl-substituted heterodienophiles have resulted in the synthesis of a large number of fluoro-heterocyclic compounds. Ketones, thioketones, imincs, nitriles, and their parent a,/3-unsaturated systems have been studied in cycloaddition reactions. Cycloadditions are regioselec-tive. An interesting aspect is the competition with ene-type reactions, aldol reactions and, depending on the partners, with [2 + 2]-cycloaddition reactions. 

Hetero-Diels-Alder reactions of other a, -clhylenic trifluoromethyl ketones provide a good alternative access to trifluoromethyl-substitutcd dihydropyrans (Tabic 7). These cycloadditions occur with inverse electron demand with electron-rich heterodienophiles such as vinyl ethers. They are performed under mild thermal conditions or at room temperature and are chemoselective and rcgioselective. but generally not stereoselective. 

Diels-Alder reactions of heterodienophiles have been known for decades, but only recently has this methodology become widely accepted by the synthetic community. There is enormous diversity in the structural types of compounds which can act as heterodienophiles, and a wide array of heterocyclic adducts can be prepared via these [4 + 2] cycloadditions. It seems clear that hetero Diels-Alder reactions span a range of mechanism from concerted to stepwise ionic processes. In many instances, mechanistic information is totally lacking. The discussion below therefore classifies heterodienophiles by structural rather than mechanistic class. Only the major types of synthetically useful heterodienophiles have been included. Moreover, the significant regio- and stereo-chemical features of the reactions have been exemplified as much as possible using recently reported cases. Other more comprehensive and more specialized reviews should be consulted for older material and more obscure hetero Diels-Alder cycloadditions. 

The initial report of an imine acting as a heterodienophile was briefly mentioned by Alder almost five decades ago. Since that time an ever increasing number of examples of this type of cycloaddition have appeared. The large preponderance of imino Diels-Alder reactions have utilized electron-deficient im-ines, although a few cases of inverse electron demand cyclizations exist. Detailed reviews of this subject have previously been published. ... 

Thiocarbonyl compounds of all kinds are excellent heterodienophiles. There has not been much systematic study of this class of reaction but it seems that such cycloadditions are generally regio-selective. One difference between carbonyl and thiocarbonyl Diels-Alder reactions is that the dihydro-thiopyran adducts from the latter dienophiles often undergo cycloreversion. The slow development of this field is peifaaps mainly due more to lack of methods for generating certain thiocarbonyl compounds than with difficulties in effecting cycloadditions. 

Although carbon disulfide is not reactive as a heterodienophile, thiophosgene and its derivatives do participate in Diels-Alder reactions. - One example is shown in equation (93). 

Multiply bonded phosphorus compounds are often reactive as heterodienophiles. However, diis is a diffuse area of research and little systematic study of these Diels-Alder reactions has been done. A complete listing of the various types of phosphorus dienophiles is beyond the scope of diis review. Some of this material is available in previous summaries. Selected representative examples of recent activity in this area is given in equations (109), (110), (111) and (112). ... 

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