Diels-Alder reaction, with pyrones

The use of trifluoromethyl-substituted a-pyrones in Diels-Alder reactions with all types of dienophiles provides an interesting route to trifluoromethyl-benzenes [I/Sj (equation 98)... 

The 2-pyrones can behave as dienes or dienophiles depending on the nature of their reaction partners. 3-Carbomethoxy-2-pyrone (84) underwent inverse Diels-Alder reaction with several vinylethers under lanthanide shift reagent-catalysis [84] (Equation 3.28). The use of strong traditional Lewis acids was precluded because of the sensitivity of the cycloadducts toward decarboxylation. It is noteworthy that whereas Yb(OTf)j does not catalyze the cycloaddition of 84 with enolethers, the addition of (R)-BINOL generates a new active ytterbium catalyst which promotes the reactions with a moderate to good level of enantio selection [85]. 

The a-pyrone (635) undergoes an exothermic Diels-Alder reaction with 1-diethylamino-1-propyne to afford the cycloadduct (636) (77JOC2930). Only a single regioisomer is produced, which is in line with the expected polarization of these reagents (Scheme 144). A Diels-Alder reaction of the same a-pyrone with 1-dibenzylamino-l-propyne affords an aniline derivative which has been employed in a chiral synthesis of the aromatic portion of the ionophore antibiotic lasalocid (80JA6178). 

Salicylate annelatiun.1 A new method involves conversion of a cyclohexanone llllo the annelated 3-carbomethoxy-2-pyrone by reaction of the enolate with dimethyl iliclhoxyincthylcnemalonate2 to form a 3-carbomethoxy-2-pyrone. This product undergoes a facile Diels-Alder reaction with 1,1-dimethoxyethylene with loss of C02 anil ( II, OII to give a salicylate... 

This procedure describes the preparation and inverse electron demand (LUM0(jjene controlled/ Diels-Alder reaction of an electron-deficient diene. While extensive studies on the preparative utility of the normal (HOMOjjg controlled) Diels-Alder reaction have been detailed, few complementary studies on the preparative value of the inverse electron demand Diels-Alder reaction have been described. Table I details representative 3-carbomethoxy-2-pyrones which have been prepared by procedures similar to that described herein and Tables II and III detail their inverse electron demand Diels-Alder reactions with electron-rich dienophiles. 

These pyrones undergo Diels-Alder reactions with electron-deficient alkenes with loss of COj and formation of an aromatic ring. Thus reaction with 1,1-dimethoxyethylene (11, 279-281) provides a regiospecific route to methyl salicylates (e.g., 3), which are convertible in several steps into catechol derivatives (4) or by decarbomethoxylation into phenol ethers (5). Similar reactions with vinylene carbonate or 1, 1,2-trimethoxyethylene provide regiospecific routes to phenols, differentially protected derivatives of catechol, resorcinol, or pyrogallol (equation II). 

Diels-Alder reactions. This pyrone does not react with moderately reactive dienophiles (ethyl acrylate), but does react with reactive symmetrical alkenes to give adducts resulting from addition of 2 equiv. of the dienophile with loss of CO2 from the primary cycloadduct. It also reacts with acetylenic dienophiles to form m-tliincthoxyarencs. 

On the other hand, lower reaction temperature (0-30 °C) was indispensable to decrease the background reaction. Under these conditions, a wide range of other 0C, 3-unsaturated ketones and substituted 2-pyrones had been converted into bicyclic chiral compounds 17 in high yield, diastereomeric ratio, and enantiomeric excess (Table 10.8). Interestingly, theauthors noted that, incontrastto 2-pyrone, electron-rich dienes bearing neither a hydrogen-bond acceptor nor donor such as cyclopentadiene and cyclohexadiene were inactive for the Diels-Alder reaction with benzylideneace-tone catalyzed by lp and TFA. They propose that the activation of 2-pyrone by the multifunctional amine IP is also required for the D-A reaction to occur [30],... 

Lactone (170) is reduced to aldehyde (171) and used as a heterodieneophile in a Diels-Alder reaction with diene (14), with ZnCh in THF as a catalyst, to give (172 Scheme 48). The major product of this cycloaddition is the syn pyrone derived from a Cram-Felkin attack (syn-CF) 27% of the syn-ACF product is also produced. The jyn-CF pyrone (172) is ozonized and subjected to an oxidative work-up fol-... 

Diels-Alder reactions. 2-Pyrone can undergo thermal Diels-Alder reactions but generally requires such high temperatures (100-200°) that the adducts lose C02. High-pressure cycloadditions have also been effected, but the products are usually unstable. In contrast, this 3-substituted derivative 1 can undergo thermal Diels-Alder reactions with electrophilic dienophiles at 24-90° to give mainly enrfo-adducts that are stable to chromatography. 

Loupy et al. studied possible speciflc MW effects in irreversible Diels-Alder reactions with acetylenic dienophiles under solvent-free conditions [73]. Strict comparisons of microwave irradiation and conventional heating were conducted and substantial speciflc kinetic MW effects were observed for the reaction of 3-carbomethoxy-2-pyrone with acetylenic compounds (Scheme 11.22). This were in... 

JCycloadditions. Posner et al. have reviewed Diels-Alder reactions with 2-pyrones and 2-pyridones in detail, with special attention to the selectivity (213 references). 

Diels-Alder reactions have also been reported in which phosphaal-kynes function as the dienophile component to yield phosphaben-zenes. An AMI semiempirical study comparing aU nes and phosphaalkynes as dienophiles has been published recently. It has also been reported that ethyl cyanoformate and p-toluenesulfonylcy-anide undergo Diels-Alder reaction with some pyrones to yield pyrido[3,4- >]-indoles 14 and isoquinolines 15. This methodology was limited in scope, however, and it could not be extended to other nitriles (R = COPH, Me, Ph, Py, MejN) nor to imines. 

Various other nonconjugated dienes have been used as the dieno-phile component in tandem Diels-Alder processes. In these cases, the first cycloaddition occurs as usual. Then cycloreversion with loss of COj is followed by intramolecular Diels-Alder reaction with the remaining pendant alkene to yield bicyclo[2.2.2]octene structures. For example, methyl coumalate (5-methoxycarbonyl-2-pyrone 26) reacts with 1,5-cyclooctadiene under thermal conditions to give the cage compound 27. ... 

In order to prepare the cyclohexenaldehyde 8, 3-hydroxy-2-pyrone 14 and ethyl 4-hydroxy-2-methyl-2-butenoate 15 are subjected to a Diels-Alder reaction in the presence of phenylboronic acid which arranges both reactants to the mixed boro-nate ester 19 as a template to enable a more efficient intramolecular Diels-Alder reaction with optimal control of the regiochemical course of the reaction. Refluxing in benzene affords the tricyclic boronate 20 as primary product. This liberates the intermediate cycloadduct 21 upon transesterification with 2,2-dimethylpropane-l,3-diol which, on its part, relaxes to the lactone 22. Excessive i-butyldimethyl-silyltriflate (TBSTf) in dichloromethane with 2,6-lutidine and 4-7V,A-dimethyl-aminopyridine (DMAP) as acylation catalysts protects both OH goups so that the primary alcohol 23 is obtained by subsequent reduction with lithiumaluminum-hydride in ether. 

In the first step, the oxaloacetic acid is decarboxylated.Thereby, the enolate form of the pyruvic acid is stabilised with a magnesium ion in the macro-phomate-synthase. This then undergoes the DIels-Alder reaction with the pyrone favourably positioned for the cycloaddition, while the enzyme is activated by hydrogen bonding. The anf/ -elimlnation of water and carbon dioxide leads ultimately to macrophomic acid. 

Pyrone is a reactive diene for Diels-Alder reactions. The resulting cycloadducts are generally unstable and undergo loss of COj to yield aromatic products [36]. 2-Pyrone is known to undergo Diels-Alder reaction with l ti(trrmethylstannyl)acetylene (Scheme 16.34) [37]. This reaction offers a method for the synthesis of 1,2-distannyl aromatic compounds. 

More recently, it has been described the synthesis of new Diels-Alder adducts by reaction of bis(2-pyrone) with bismaleimides [327,328]. The reaction is a double Diels-Alder reaction with formation of structures such as those presented in Scheme (62). Tractable polymers were formed only for bismaleimides possessing flexible spacers. 

The latter reacting with P2O5 gave rise to fluoroalkylthio(trifluoroacetyl)ketenes 13, which were demonstrated to act as heterodienes in the Diels-Alder reaction with phenylacetylene to form 4-pyrones 14 [ 11], Langer et al. reported that the McsSiOTf-mediated cyclization of l,3-bis(trimethylsilyloxy)-l,3-butadienes 15 with4,4-dime-thoxy-l,l,l-trifluorobut-3-en-2-one resulted in the formation of trifluoromethylated pyran-4-ones 16 [12] (Scheme 7). 

The presence of the carbomethoxy and ttifluoromethyl groups in (he diene system of the pyrone 87 inaeases its electrophilicity and its ability to undergo Diels-Alder reactions with inverse electron demand. The reaction of 87 with l-(A(-pytrolidino)-l-cyclopentene at 30 C gives rise to the tricyclic lactone 88. When 88 is treated with HCl/dioxane, (he indane derivative 89 is obtained. This compound was prepared directly in the reaction of 87 with l-(trimethylsilyloxy)cyclopentene at 180 °C in 90 % yield. More reactive tetramethoxyethylene adds at 100 °C to 87 to afford 90. With 2,5-dihydrofiiran at 130 °C, 91a is formed as the sole isomer. Endo-adducts of this type result also with cyclopentene (91b, 120 °C), cyclooctene (91c, 150 °C), and indene (91d, 80 C). All four possible regio- and stereoisomers can be identified in the reaction of 87 with vinylacetate at 150 °C (79 % yield) (Scheme 28). 

Another feature of 2-pyrone 87 is its ability to undergo Diels-Alder reactions with acetylenes. The cycloadducts decarboxylate spontaneously to form benzene rings bearing the CF3 group. The substitution pattern is determined by the regioselectivity of the [4-1-2] cycloaddition step. Thus, the reaction of 87 with l-(NJ -diethylamind)-l-propyne takes place at 0 °C to produce 92 as a single isomer. Less electron rich acetylenes require heating at 140-200 C. Treatment of 87 with acetylene at 200 C leads to 93, while with dimethyl acetylenedicarboxylate triester 94 is formed [37] (Scheme 28). 

As important hetero Diels-Alder reactions catalyzed by aluminum Lewis acid, two kind of reactions, namely, [4 + 2] cycloaddition of Danishefski s diene with carbonyls and [4 + 2] cycloaddition of nitroalkenes with electronic rich alkenes, have been well known. The former reaction provides highly functionalized pyrones. As the first example of pyrone synthesis through catalytic asymmetric hetero Diels-Alder reaction with chiral aluminum complexes, in 1987, Quimpere and Jankowski reported the reaction of oxomalonate with 1-methyl-1,3-butadiene using Koga s catalyst (48). However, the asymmetric induction and chemical yield were quite poor (Scheme 6.147) [175]. 

In a direct approach for the synthesis of occidentalol, Corey and Watt used the Diels-Alder reaction with an a-pyrone for establishing the c/5-fused decalin system, followed by elimination of the lactone bridge in the adduct for generation of the homoannular 1,3-diene unit. 

Barrelene was obtained via a double Diels-Alder reaction from a-pyrone with methyl acrylate (H.E. Zimmerman, I969A). The primarily forming bicyclic lactone decarboxylates in the heat, and the resulting cyclohexadiene rapidly undergoes another Diels-Alder cyclization. Standard reactions have then been used to eliminate the methoxycarbonyl groups and to introduce C—C double bonds. Irradiation of barrelene produces semibullvalene and cyclooctatetraene (H.E. Zimmerman. 1969B). 

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