Cycloadditions with Pyrones

Racemic pyrone sulfoxide 52 undergoes a diastereoselective inverse-electron-demand 2 + 4-cycloaddition with 1,1-dimethoxyethylene to afford adduct 53 in > 95% yield (equation 49)100 this is the first example of an asymmetric Diels-Alder cycloaddition using a sulfinyldiene as an electron-deficient enophile101. 

A combination of an intramolecular [5+21-cycloaddition of the pyrone 110 followed by an intermolecular [4 + 2]-cycloaddition with dimethyl-butadiene leads to the fused 6,7,5-tricyclocarboxylic system 112 via 111 as described by Rodriguez et al (scheme 22).1621 The prepared skeleton is found in nature in several terpenes. The starting material for this domino reaction is obtained from maltol 109... 

Finally, in a very recent disclosure, Lee et al. (165) approached the total synthesis of arteminolide using a [5 + 2] cycloaddition strategy with an oxidopyrylium ion. Despite its long history of use, Lee was the first to utilize an allene moiety both in an intra- and an intermolecular cycloaddition with oxidopyrylium ions. By utilizing a pyrone cycloaddition precursor (294) similar to those used in the Wender phorbol synthesis, Lee was able to synthesize various ring sizes and... 

Attempts to effect cycloadditions with a-pyrone as the diene system failed (78JOC315). However, the more electron-deficient a-pyrone-5- (or 6-) carboxylates add slowly (5 days in boiling toluene) to the l//-azepine to furnish a mixture of the [2+4]7t (25%) and the [6 + 4]7r (20%) adducts (153) and (154) respectively. On prolonged heating (7 days) in toluene solution adduct (153) extrudes CO2 to form the benzazepine (155 R1 = CC Me R2 = Et) <78H(11)401). 

However, under our conditions20,35,37 as well as a variety of other conditions,53,54 the formal [3 + 3] cycloaddition reaction of the iminium salt 51 with pyrone 12 failed to provide any desired pentacycle 52. This failure prompted us to think that 51 might be sterically too demanding, thereby obstructing the reaction pathway. 

Reversibility of 67t-Electron Electrocyclic Ring-Closure. The high diastereoselectivity obtained in these reactions here is likely a result of the reversible 67t-electron electrocyclic ring-closure.20,37 41 The best evidence for the reversibility of this ring-closure is described in Scheme 12. We were able to isolate both the desired major isomer 10 and the minor isomer 44 from the formal cycloaddition reaction of the iminium salt 56 with pyrone 12. 

It was not readily apparent that the assignment of keto enal "73-a" was incorrect until we pursued the subsequent formal [3 + 3] cycloaddition of the alleged "73-a."with pyrone 12. The reactions of keto enal "73-a" with... 

The intramolecular thermal [5+2] cycloaddition of 3-alkoxy-4-pyrones with sulfur- (e.g., 416) or silicon- (e.g., 419) tethered alkenes has been shown to occur with complete regio- and stereochemical control to give adducts 417 and 421, respectively. The adducts can be converted by reduction and oxidation, respectively, to the bicyclic products 418 and 421 (Scheme 69) <1993JOC5585>. It should be noted that this thermal [5+2] cycloaddition has not been realized in a bimolecular mode <1977JOC3976>. This methodology serves as an alternative to the reaction of electron-deficient alkenes with pyrone-derived 4-methoxy-3-oxidopyrylium ylides <1992TL2115>. 

Bromo-2-pyrone is not only a valuable precursor for the synthesis of various 3-substituted 2-pyrones,7 but it is also a reactive unsymmetrical diene.8 3-Bromo-2-pyrone undergoes Diels-Alder cycloadditions with a regioselectivity and stereoselectivity that is superior to that of 2-pyrone. Furthermore, 3-bromo-2-pyrone is a chameleon (i.e., ambiphilic) dienophile, undergoing cycloaddition to both electron deficient and electron rich dienophiles. The cycloadducts of bromopyrone with dienophiles are isolable and are useful in the synthesis of diastereomerically pure cyclohexene carboxylates (Scheme 2).8... 

The transformation of a-pyrones to benzene and carbon dioxide upon their cycloaddition with acetylene, and the reaction of 2//-pyrans to yield benzoic acid derivatives when exposed to acetylenecarboxylates are conceptually related processes (see Scheme 2.3). These are, strictly speaking, retro Diels-Alder reactions," some of which embody interesting mechanistic problems. 

Diels-Alder reactions of thiete 1,1-dioxides occur readily as exemplified by the syntheses of 151 ° and 152. Adducts of thiete 1,1-dioxide with tetraphenylcyclopentadienone or a-pyrone ° are thermally unstable. Thiete 1,1-dioxides also undergo 1,3-dipolar additions with diazoalkanes, (e.g., the formation of 153 from which the strained bicyclic thietane sulfone 154 is obtained) " nitrile oxides, and cycloadditions with the MA -dimethylenamine of isobutyraldehyde (e.g., the formation of 155). ° ... 

Ditertiary phosphane complexes of nickel were found to be effective in the formation of pyrone 108 by cyclocotrimerization of alkynes with carbon dioxide. The formation of the nickelacyclopentadiene 105 from two moles of alkyne and a nickel complex is followed by CO2 insertion into a nickel-carbon bond to give the oxanickelacycloheptadienone 106, which then eliminates 108 with intramolecular C—O coupling. Another route involving [4 + 2] cycloadditions of 105 with CO2 in a Diels - Alder reaction to give 107 cannot be ruled out but is less probable because CO2 does not undergo [4 + 2] cycloaddition with dienes. Addition of another alkyne to 105 results in the formation of a benzene derivative (Scheme 38). ... 

Upon heating, dialkoxycyclopropenes 15 rearrange in solution to 2,2-dialkoxyvinylcarbenes (see Houben-Weyl, Vol. E19b, pp 748 755). These can react with electron-deficient alkenes to form cyclopropylketene acetals 16 (path a). However, due to their 1,3-dipolar character, [3 + 2] cycloadditions with 1,1 -diacceptor-substituted alkenes (path b) or [4 -f 3] cycloadditions with a-pyrones have been observed. ... 

In a similar context, Afarinkia and coworkers have shown that 2-pyrones with a Cl, Br or I substituent at the C4 position have marginal enophilic reactivity, only undergoing cycloadditions with electron-deficient dienophiles <05JOC1122>. For example, the reaction of 4-bromo-2-pyrone 18 with excess methyl acrylate provided a mixture of synlanti and endolexo isomers in 78% combined yield after heating at 50 - 70 °C for two weeks with no solvent (Table 1). 

An additional example can be formd in the cycloadditions of 5-(indol-2-yl)-2-pyrone 26 with various electron-rich and electron-poor dienophiles reported by Passarella and coworkers (Scheme 8) <00T5205>. While the normal electron demand cycloadditions with electron-deficient dienophiles proceeded under solely thermal conditions, reactions with electron-rich dienophiles required the presence of Si02 or lanthanide shift agents, such as Eu(FOD)3 and Pr(FOD)3. 

Notably, the cycloaddition of 3,5-dibromo-2-pyrone is more stereoselective than monobromo-2-pyrone counterparts 4 and 5. For instance, cycloadditions with acrylonitrile and benzyl vinyl ether provided the cycloadducts 44 and 51 in endolexo ratios of 76 24 and 100 0 (entries 4 and 11), respectively, while 5-bromo-2-pyrone 5 afforded the corresponding cycloadducts in ratios of 54 46 and 67 33, respectively. 

Because of the higher reactivity, 3,5-dibromo-2-pyrone can undergo the D-A cycloaddition with sterically hindered silyl enol ethers as summarized in Table 3 <02TL8193>. 

The resultant 3-alkynyl-5-bromo-2-pyrones 83 are potent ambident dienes, undergoing cycloadditions with both electron-rich and electron-poor dienophiles. As exemplied in Scheme 24, 3-[(trimethylsilyl)-ethynyl]-5-bromo-2-pyrone 83a underwent efficient cycloaddition with benzyl vinyl ether, as well as with methyl acrylate, to afford the corresponding cycloadducts 84 and 85, respectively. 

Pyrone derivatives containing a 2-pyridyl substituent at C3 can undergo Lewis-acid catalyzed DA cycloadditions with electron-rich dienophiles. Shown in Scheme 30 is the ZnBrj catalyzed cycloaddition of 100 with BVE. After 48 hours at -20 °C, the reaction afforded endo-cycloadduct 102 as only product in 81% yield. 

The 2-pyrone 116 (Scheme 33), containing the weakly electron-donating carbamate group at C3, has been reported to undergo cycloadditions with alkynes in refluxing decalin or tetralin, providing aniline derivatives 118 upon elimination of CO2 and aromatization... 

Under appropriate conditions, even unactivated alkenes will take part in intermolecular cycloadditions with 3- and 5-bromo-2-pyrones and with 3-methoxycarbonyl-2-pyrone. Reactions can be conducted at 100 °C, or at room temperature under 10-12 kbar and with zinc chloride catalysis. 

Cycloadditions with ynamines proceed readily at room temperature in carbon tetrachloride solution to yield a-pyrones (106) <77S252>. Likewise, a-pyrones (107) are also formed with cyclo-octyne <83TL1481>, whereas with benzyne the a-benzopyrone (108), produced initially, enters into a second [4 + 2] cycloaddition with benzyne to give ultimately the 9,10-disubstituted anthracene (109) (Scheme 12) <77S252>. 

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