Diels-Alder reactions of enones

Although Lewis acid-catalyzed-Diels-Alder reactions of enones are common, there are few reports on the catalysis of Diels-Alder reaction of nitroalkenes. The reaction of nitroalkenes with alkenes in the presence of Lewis acids undergoes a different course of reaction to give cyclic nitronates (see Section 8.3). Knochel reported an enhanced reactivity and selectivity of the intramolecular Diels-Alder reaction using silica gel as Lewis acid in hexane (Eq. 8.19).31... 

The synthetic strategies used for the preparation of pyrans on insoluble supports have mainly been hetero-Diels-Alder reactions of enones with enol ethers and ringclosing olefin metathesis (Table 15.33). Benzopyrans have been prepared by hetero-Diels-Alder reactions of polystyrene-bound o-quinodimethanes with aldehydes. The required quinodimethanes were generated by thermolysis of benzocyclobutanes, which were prepared in solution [308]. Other solid-phase procedures for the preparation of benzopyrans are the palladium-mediated reaction of support-bound 2-iodo-phenols with 1,4-dienes (Entry 5, Table 15.33) and the intramolecular Knoevenagel... 

The rhodium (II) catalysed thermolysis of e-trimethylsilyloxy-a-diazo-P-ketophosphonates (249) is reported to give rise to a-phosphono- -lactones (250) in moderate to good yields. Diels-Alder reactions of enone phosphonates (251) with different 1,3-dienes give adducts, which are complex phosphonate-contain-ing polycycles with keto function (252) e.g.. Scheme 65). These -keto phosphon-ate systems found interesting synthetic applications. ... 

Table 3. Chiral Lewis acid-catalyzed asymmetric hetero-Diels-Alder reactions of enones with vinyl ethers 26a-c...

Finally, Jacobsen and coworkers developed a highly enantioselective synthesis of indolo- and benzoquinolizidine derivatives via a formal aza-Diels-Alder reaction of enones with cyclic imines utilising catalyst 52 (Scheme 19.59). The products were obtained in high to excellent yields (50-99%) and high enantioselectivities (92-99% enantiomeric excess). 

The 1,5-dicarbonyl functionality is also represented by 2-alkoxy-3,4-dihydro-2H-pyrans (e.g., 162, a masked 5-ketoaldehyde), which are obtained by hetero-DiELS-ALDER reaction of enones and vinyl ethers (c p. 315). On treatment with hydroxylamine, they afford pyridines (e.g., 163) ... 

SCHEME 1.43 Diels-Alder reaction of enones with cyclopentadiene. 

Radical Diels-Alder reactions have been used mainly to synthesize polycyclic molecules. These reactions, like those that involve cations and anions as components, proceed quickly but generally do not give high yields. Thus, the tricyclic enone 14 is the result of an intramolecular Diels-Alder reaction of quenched vinyl radical intermediate 13 obtained by treating the iododienynone 12 with n-tributyltin hydride/2,2 -azobisisobutyronitrile (AIBN) [28] (Equation 1.11). 

The intramolecular Diels-Alder reactions of photochemically generated trans-cycloalk-enones [162]... 

An endo-selective ionic Diels-Alder reaction of a,/f-enone and a,/f-enal acetals catalyzed by electrogenerated acid [99]... 

Diels-Alder reaction of the furan derivative 148 with homochiral bicyclic enone 149 is the key step [56] in the total synthesis of the diterpenes jatropho-lone A and B, 151 and 152, respectively, isolated from Jatropha gossypiifolia L [57], Initial efforts to carry out the cycloaddition between 148 and 149 under thermal or Lewis-acid conditions failed due to diene instability. Application of 5kbar of pressure to a neat 1 1 mixture of diene and dienophile afforded crystalline 150 with the desired regiochemistry (Scheme 5.23). Subsequent aromatization, introduction of the methylene group, oxidation and methylation afforded (-l-)-jatropholones 151 and 152. 

Cycloaddition of 2-cyanoalk-2-enones with several conjugated dienes proceeded under zinc chloride catalysis.636 Zinc halides have also shown reactivity with phenylacetylenes.637 Zinc chloride is an effective Lewis acid catalyst in the Diels Alder reactions of the keto esters and the effects on stereochemistry of catalysts used have been examined.638... 

Microwave heating has also been employed for performing retro-Diels-Alder cycloaddition reactions, as exemplified in Scheme 6.94. In the context of preparing optically pure cross-conjugated cydopentadienones as precursors to arachidonic acid derivatives, Evans, Eddolls, and coworkers performed microwave-mediated Lewis acid-catalyzed retro-Diels-Alder reactions of suitable exo-cyclic enone building blocks [193, 194], The microwave-mediated transformations were performed in dichloromethane at 60-100 °C with 0.5 equivalents of methylaluminum dichloride as catalyst and 5 equivalents of maleic anhydride as cyclopentadiene trap. In most cases, the reaction was stopped after 30 min since continued irradiation eroded the product yields. The use of short bursts of microwave irradiation minimized doublebond isomerization. 

Both enantiomers of the bicyclic enone 78 and their derivatives have been proved to be useful chiral building blocks for the synthesis of natural products [29], among them y-butyrolactones. 78 is readily available in either enantiomeric form by a Diels-Alder reaction of furan with a-acetoxyacry-lonitrile and subsequent hydrolysis, followed by a resolution of the racemate... 

Danishefsky dienes [98] cycloadd to Cjq in refluxing toluene or benzene [5, 38, 99-101]. The diene 103 adds in 60% yield to Cjq to give the desilylated ketone 104 [5,101]. Acid-catalyzed methanol elimination then furnishes the enone 105 in 82% yield (Scheme 4.17). As already described, this enone can be reduced by DIBAL-H to the corresponding alcohol for further functionalization. The same a,(3-un-saturated alcohol can also be obtained in better yield by Diels-Alder reaction of Cg0 with butadiene, followed by oxidation with singlet oxygen to the allylic hydroperoxide and PPhj reduction to the desired alcohol [101]. This sequence yields the allylic alcohol in 53%, starting from Cjq without the need of isolating intermediates. 

The chiral organocopper compound (186) adds diastereoselectively to 2-methyl-2-cyclopentenone, allowing the preparation of optically active steroid CD-ring building blocks (Scheme 68).202-204 A related method was applied to a synthesis of the steroid skeleton via an intramolecular (transannular) Diels-Alder reaction of a macrocyclic precursor.203 Chiral acetone anion equivalents based on copper azaeno-lates derived from acetone imines were shown to add to cyclic enones with good selectivity (60-80% ee, after hydrolysis).206-208 Even better ee values are obtained with the mixed zincate prepared from (187) and dimethylzinc (Scheme 69). Other highly diastereoselective but synthetically less important 1,4-additions of chiral cuprates to prochiral enones were reported.209-210... 

Mechanistically it is proposed that the reaction proceeds via an initial Knoevena-gel condensation of the aldehyde with Meldrum s acid followed by a Diels-Alder reaction of the resulting arylidene Meldrum s acid with an in situ generated chiral dienamine, which is formed in the reaction of the enone with the aminocatalyst. 

The intermolecular Diels-Alder reaction between the dibromoenone (111) and dienes (112) provides access to bicyclo[5.4.0]undecane systems (113) that are common core structures of many natural products (Scheme 32).118 The alio-threonine-derived O-(/ -biphenyl carbonyl oxy)-/i-phenyloxazaborolidi none catalyses the enan-tioselective Diels-Alder reaction of acyclic enones with dienes.119 The reversal of facial selectivity in the Diels-Alder cycloaddition of a semicyclic diene with a bro-moenone was induced by the presence of the bromo substituent in the dienophile.120 Mixed Lewis acid catalyst (AlBr3/AIMe3) catalyses the Diels-Alder reaction of hindered silyloxydienes with substituted enones to produce highly substituted cyclohexenes.121 Chiral /V-enoyl sultams have been used as chiral auxiliaries in the asymmetric Diels-Alder reactions with cyclopentadiene.122... 

Steric control of the Diels-Alder reaction of the enone 56 has been reported (82H2053). The ene adduct 57 (4.5%) was obtained in a reaction with 1,3-bis(trimethylsilyloxy)butadiene at 180°C, together with the main product 58 (39.5%) resulting from an ene addition. Under the same conditions, the analogous indolizidine derivative 59 gave only ene adducts. 

This group has used the same reaction conditions with diynes 182 and cyclic dienes like cyclopentadiene to form tetracyclic enone 183 which was transformed into triquinane 184 by means of an oxidative cleavage of the double bond. When phenyl groups at the alkyne terminus were substituted by H or Me they observed a competitive [2 + 2 + 1]/[2+ 2 + 2] process, with the participation of two diyne molecules giving compounds 185 (Scheme 54) [171]. No mechanistic hypothesis appears in this work but the formation of a norbornene derivative by means of the Diels-Alder reaction of cyclopentadiene and the diyne that would react with the other triple bond of the diyne seems attractive in this case. 

Thus optically pure shikimic acid (347) has been synthesized via the addition of 1,4-diacetoxybuta-diene (345) to (340a), whereas the Diels-Alder reaction of )V-dienylcarbamate (348) to hydroxy enone (340b) served as the key step for a synthesis of the enantiomer (350) of naturally occurring pumiliotoxin C (142) (c/. Scheme 35). 

The Diels-Alder reaction of 3,6-dimethoxybenzocyclobutene 30 with some dienophiles was studied (Scheme 9). A mixture of benzocyclobutene 30, A -phenyl-maleimide 54, and benzene was heated at 210 in a sealed tube. The adduct 55 was obtained in 53% yield. The reaction of 30 and cyclohexenone 56 similarly gave the adduct 57 in 36% yield. In the case of dienone 58, however, the desired product could not be obtained. On the other hand, the Diels-Alder reaction with tranj-enone 59 afforded adduct 60 in a good yield (76% yield). Therefore, we felt confident that the reaction of benzocyclobutene 30 with enone (+)-31 would give the desired adduct with a tetracyclic skeleton. 

Hersh and co-workers reported that catalysis for the Diels-Alder reactions of cy-clopentadiene with a, ff-unsaturated enones was induced by (Me3P)(CO)3(NO)W-FSbFs. In order to probe the mechanism of the Diels-Alder catalysis, a single-crystal X-ray diffraction study of [(Me3P)(CO)3(NO)(acrolein)W] SbF was carried out, and CT-type coordination was found to be present in the solid state [25]. This structure provides clear evidence for the preferred s-trans conformation of the a,//-unsaturated aldehyde unit, which would be expected by theoretical studies (Fig. 1-7). 

Another diastereoselective intramolecular Diels-Alder reaction of furan was studied by Keay wherein the methyl group in the tether of (—)—12 directed the facial selectivity of the cycloaddition. Equilibrating conditions using a catalytic amount of Lewis acid gave the tricyclic enone (—)-13, Eq. 10 [23]. 

Both 9-epiamino derivatives of 9-deoxyquinine and 9-deoxyquinidine promote exo-selective Diels-Alder reaction of 3-hydroxy-2-pyrones with enones. Actually, great latitude exists for tuning the reaction by partial structural changes of the catalysts. ... 

In addition to studies detailing the effective use of electron-deficient a, 3-unsaturated aldehydes, a number of related investigations have described the inverse electron demand Diels-Alder reactions of additional ,/3-un-saturated carbonyl compounds bearing a C-3 (a) electron-withdrawing substituent and include 2-acetylcyclohex-2-enone [Eq. (19)],104... 

A variety of other heterogeneously catalyzed Diels-Alder reactions has been reported. Nafion-H, a perfluorinated resinsulfonic acid, catalyzed several Diels-Alder reactions and the isolated yield of the adducts was 80-95% [46]. We have found that a recently described Nafion-silica composite catalyst containing 13 % (w/w) Nafion [47] was approximately 30 times more active than the pure resin in the Diels-Alder reaction of 2,3-dimethylbutadiene with 1,4-naphthoquinone [48]. We also showed that another strong heterogeneous Brpnsted acid, tung-stophosphoric acid supported on silica gel, is a very active catalyst of Diels-Alder reactions of quinones [49] and other enones [50]. 

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