Alder Reactions Using Heterodienophiles

The use of imines as the dienophilic components of [4 + 2]-cycloaddition reactions was reviewed in 1979 (79H949) and 1982 (82T3087). 

The Kametani group further investigated quinazolone synthesis by cycloaddition of iminoketene with imines based on the concept of retro mass spectral synthesis and applied it to the total syntheses of deoxyvasicinone (24), 

N-Methyldihydro-j3-carboUne (29) was subjected to the imino Diels-Alder reaction in the presence of methyl pentadienoate (31) to give a mixture of adducts 32,34, and 36 (total yield 71 %). The mixture of adducts was alkylated, affording compound 38 as a single diastereomer. 

A similar imino Diels-Alder reaction between dihydro-)9-carboline 30 and diene 31 afforded three products (33,35, and 37) (total yield 88%), which were directly alkylated to afford the 7-methoxyindoloquinolizidine derivative 39 as 

Fukuyama and Yung (81TL3759) used adduct 69 as a key starting material for the synthesis of methyl ( )-3-(3-cyana-6-oxabicyclo[3.I.0]hex-2-en-5-yl)-2-propenoate (81). The reaction of cycloadduct 69 with methyl lithioacetate gave unsaturated ester 77. Reduction in acidic media of the conjugated double 

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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. 

Several electron-deficient ketones are known to participate in Diels-Alder reactions as heterodienophiles. Carbonyl cyanide19 and a-haloge-nated ketonesnb 20 have been used, but relatively little has been done with... 

Six-membered Rings.—Diels-Alder cyclizations using heterodienophiles provide a useful route to 1,2-thiazine derivatives immonium salts (300) derived from 7V-sulphinylmethylamine react across the N=S grouping. 1,3-Thiazinones are prepared " by reaction of thia-acylisocyanates (301) with enamines and enol ethers, and the formation of this ring system is also possible by reaction of JV-monosubstituted dithiocarbamates with a,/8-unsaturated acid chlorides. The reaction involves a series of equilibria, N- to S-transacylation, and cyclization reactions. 

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 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. 

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]. 

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. 

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-... 

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%). 

Ab initio and density functional theoretical studies of the 4 -b 2-cycloaddition of 2-azabutadiene with formaldehyde predict a concerted reaction that agrees well with experimental evidence. " The azadiene A-phenyl-l-aza-2-cyanohuta-1,3-diene reacts with electron-rich, electron-poor, and neutral dipolarophiles imder nuld thermal conditions. 5,6-Dihydro-4//-l,2-oxazines have been shown to he useful as synthon equivalents of 2-cyano-l-azabuta-l,3-dienes. The intramolecular Diels-Alder reaction of 1-aza-1,3-butadienes (106) can be activated by a 2-cyano substituent (Scheme 37). Stereoselectivity in the hetero-Diels-Alder reactions of heterobutadienes, nitrosoalkenes, and heterodienophiles has been extensively reviewed. The azadiene l-(t-butyldimethylsilyloxy)-l-azabuta-l,3-diene (107) reacts with halobenzo-quinones, naphthoquinones, and A/ -phenylmaleimide to yield low to good yields of various pyridine heterocycles (108) (Scheme 38). The 4 -b 2-cycloaddition of homophthalic anhydride with A/ -(cinnamylidene)tritylamine produces the 3,4-adduct whereas with A/ -(cinnamylidene)benzylidine the 1,2-adduct is produced. ... 

There are also special procedures which allow the preparation of sugars with only endo- or only exo-cyclic double bonds. The first group of compounds with endo-cyclic double bond may be prepared by total synthesis from non-carbohydrate precursors. The particularly useful hetero Diels-Alder reaction (O Fig. 3) allows one to obtain the dihydropyran skeleton either by reaction of a diene with a heterodienophile [3,17] or by reaction of a heterodiene with a normal dienophile [18]. 

Aldehydes bearing electron-withdrawing substituents are reactive as heterodienophiles under mild conditions with a range of 1,3-dienes. In particular, glyoxylate derivatives have been widely used in these cycloadditions. Some examples of Diels-Alder reactions of this type are shown in equations (68), (69) and (70). As can be seen, these reactions occur at relatively low temperatures and are regioselective. ... 

Since Danishefsky demonstrated that activated dienes, such as siloxydiene (commonly referred to as Danishefsky s diene) react with a wide spectrum of aldehydes to afford 5,6-dihydro-y-pyrones in 1982 [l],the hetero-Diels-Alder reaction has attracted a great deal of attention over the last two decades [2,3]. The use of asymmetric catalysis in these reactions is overwhelmingly associated with heterodienophiles. Especially, the cyclocondensations of activated dienes with aldehydes or their derivatives are of particular importance, providing a multitude of opportunities for the highly efficient regio- and stereoselective construe-... 

Dienes that contain electron-donating groups (activated dienes) are more reactive in Diels-Alder reactions than unsubstituted or electron-deficient dienes. In molecular orbital formalism, the substituents on the diene perturb the tT-electron density to cause an increase in the energy of the highest occupied molecular orbital (HOMO Figure 1). In a normal-demand Diels-Alder reaction this results in an increase in the interaction between the HOMO of the diene and the LUMO (lowest unoccupied molecular orbital) of the dienophile. This interaction, in turn, lowers the transition state energy of the reaction. Similar arguments have also been used to explain the increased reactivity of activated dienes towards heterodienophiles such as aldehydes. 

Heterocyclic o-quinodimethanes are unstable and reactive dienes that must be generated in situ. In solution and in the pre.sence of a dienophile the -quinodimethanes can be intercepted in a Diels-Alder reaction, often in high yield. Most of the dienophiles investigated so far have been electron deficient A-phenylmaleiinide. acrylonitrile, methyl vinyl ketone, acrylate, ftimarate and acetylenedicarboxylic esters are typically used. However, since the objective of most of the work was simply to establish that the o-quinodimethane was being formed, the scope of the reaction has not been adequately explored. The pyridine derived o-quinodimethane 12 has recently been shown to undergo cycloaddition to ethyl vinyl ether (Scheme 2) and to dihydroftiran <96T11889>, and it is thus clear that the scope of the Diels-Alder reaction extends beyond electron deficient alkenes and alkynes. Heterodienophiles (azodicarbonyl compounds and nitrosobenzene) have been added to indole-2,3-quinodimethanes <91T192,S> and this type of hetero Diels-Alder reaction is also potentially of wider application. 

Heterodienes, in which one or more of the atoms of the conjugated diene is a heteroatom, can be used in Diels-Alder reactions, although these have not been so extensively employed in synthesis as heterodienophiles. 

Hetero-Diels-Alder Reactions. The 02-symmetric bis(oxazoline) Cu(II) cort5)lexes (Figure 1) promoted the enantioselective synthesis of dihydropyrans using a , -unsaturated carbonyl compounds (heterodienes) with electron-rich olefins (heterodienophiles) with high diastereo- and enantioselectivity (eq 22) ... 

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. 

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