Synthesis of 4-Pyrones

4-Pyrones result from the acid-catalysed closure of 1,3,5-tricarbonyl precursors. 

The construction of a 4-pyrone is essentially the construction of a 1,3,5-tricarbonyl compound, since such compounds easily form cyclic hemiacetals then requiring only dehydration. Strong acid has usually been used for this purpose, but where stereochemically sensitive centres are close, the reagent from triphe-nylphosphine and carbon tetrachloride can be employed.  

Several methods are available for the assembly of tricarbonyl precursors the synthesis of chehdonic acid (4-pyrone-2,6-dicarboxylic acid) represents the obvious approach of bringing about two Claisen condensations, one on each side of a ketone carbonyl group. Chelidonic acid can be decarboxylated to produce 

A variety of symmetrically substituted 4-pyrones can be made very simply by heating an alkanoic acid with polyphosphoric acid presumably a series of Claisen-type condensations, with a decarboxylation, lead to the assembly of the requisite acyclic, tricarbonyl precursor. 

The Claisen condensation of a 1,3-diketone, via its dianion, with an ester, °° or of a ketone enolate with an alkyne ester, also give the desired tricarbonyl arrays. Applying this principle to 1,3-keto-esters leads through to 2,4-dioxygenated heterocycles.  

1 From 1,3-keto(aldehydo)-acids and carbonyl compounds 

The classical general method for constructing 2-pyrones is that based on the cyclising condensation of a l,3-keto(aldehydo)-acid with a second component which provides the other two ring carbons. 

The long known synthesis of coumalic acid from treatment of malic acid with hot sulfuric acid illustrates this route decarbonylation produces formylacetic acid, in situ, which serves as both 1,3-aldehydo-acid component and the second component. Decarboxylation of coumalic acid is still used to access 2-pyrone itself.  

Conjugate addition of enolates to alkynyl-ketones and to alkynyl-esters are 

2-Pyrone itself can be prepared via Prins alkylation of but-3-enoic acid with subsequent lactonisation giving 5,6-dihydro-2-pyrone which via allylic bromination and then dehydrobromination is converted into 2-pyrone as shown below. Alternative manipulation of the dihydropyrone affords a convenient synthesis of a separable mixture of the important 3- and 5-bromo-2-pyrones (see section 8.2.2.4). 

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A different route to pyrones is the preparative electrochemical oxidation of enamines in acetonitrile in the presence of tetraethylammonium perchlorate (88MI2) (Scheme 46). The synthesis of 2-pyrone derivatives has been carried out by reaction of /3-dicarbonyl compounds with methyl-a-benzoylamino-/3-dimethylaminoacrylate (96JHC751). Thiapyran derivatives can be obtained by interaction of enamines based on (/3-amino-a-cyanoacryloylmethyl)pyridinium chloride derivatives with carbon disulfide (95M711).The synthesis of pyridine derivatives based on analogous enamines has been described as well (95M711). 

Various substituted cyclobutanes and cyclobutenes can be utilized in the synthesis of 2-pyrones . For example, 2-hydroxyl cyclobutylidenes 230 undergo base-promoted rearrangements to afford 2//-pyran-2-ones 231 via formation and ring closure of an intermediate 1,5-keto ester (Scheme 131) <2005TL8237>. 

Because of their aromatic character, pyrones undergo annulation reactions and the introduction of substituents less readily than do most cyclic a,B-unsaturated carbonyl compounds. Nevertheless, some suitable modifications have been developed that allow these compounds to be used effectively in annulation reactions. Some reviews about synthesis of 2-pyrones with 3,4-fused carbocyclic ring systems are currently available (82S337 86G109 92T9111). 

Kishimoto Y, Mitani I (2005) Solvent-free synthesis of 2-pyrone from afkynes and carbon dioxide catalyzed by Ni(l,5-cyclooctadiene)2/trialkylphosphine catalysts. Synlett 14 2141-2146... 

A synthesis of 2-alkyl-2,3-dihydro-y-pyrones (187) from methoxybutenyne and aldehydes has been described (83TL4551). The condensation of lithiomethoxy-butenyne (184) with aldehydes at -78°C leads to the secondary alcohols 185, which form the dihydropyrones 187 via hydration of the acetylenic bond and hydrolysis of the methoxyethenyl group to the ketoenol 186 (0°C, p-TSA, THF, H2O or 30% HCIO4, 20 min) folowed by intramolecular cycloaddition. 

A novel use of a chlorofluorocarbon is in the synthesis of a pyrone (30) from 1,1,1-trichlorotrifluoroethane. The key step involves Cu(I) catalysis. Pyrone (30) is a useful CF3 aromatic synthon, as it readily underwent (4 + 2) cycloaddition followed by spontaneous elimination of C02 (85-TL3947). 

Posner G. H. Stereocontrolled Synthesis of Functionalized Cyclohexenes Via Diels-Alder Cycloadditions of 2-Pyrones and 2-Pyridones-Applications to Synthesis of Physiologically Active Compounds in Stereocontrolled Org. Synth. 1994 177, Ed. Trost B. M., Pb. Blackwell Oxford... 

THE SYNTHESIS OF 2-ALKYL-4-PYRONES FROM MELDRUM S ACID... 

CONTENTS The Synthesis of Seven-Membered-Rings General Strategies and the Design and Development of a New Class of Cycloaddition Reactions, Paul A. Wender and Jennifer A. Love. Recent Advances in Diels -Alder Cycloadditions of 2-Pyrones, Benjamin T. Woodard and Gary H. Posner. The Inter- and Intramolecular [4 + 4] Photocycloaddition of 2-Pyridones and Its Application to Natural Product Synthesis, Scott McN. Sieburth. 3 + 4 Annulations Between Rhodi- J s... 

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... 

Evidence for the preferential formation of the rraRS-substituted product of selenium dioxide allylic oxidation is seen in the synthesis of part of (13Z)-retinoic acid (equation 48). Reaction took place exclusively at the exocyclic double bond without rearrangement. Allylic oxidation of this nature has also been used in the synthesis of 6-conjugated 2-pyrones (equation 49). This intermediate was employed in the total synthesis of natural pyrones such as yangonin. 

The catalytic conversion of alkynes with CO2 represents the sole example until now of a homogeneous catalytic reaction which yields C-C bond formation with CO2 and selective formation of eyclooligomers using a eheap 3d-metal complex catalyst. The variation of alkyne substituents allows the synthesis of a wide range of 2-pyrones (mono- and disubstituted alkynes and alkynes with functional groups such as -OR and -OOR [18]). 

Michael addition of diethyl cyanomethylphosphonate to a-nitroalkenes in the presence of LDA (1 eq) followed by treatment with Mc,SiOI provides a one-pot synthesis of 2-isoxazoline derivatives. The reaction proceeds through a 1,3-dipolar cycloaddition of trimethylsilyl nitronate with an a-cyanovinylphosphonate. Similarly, the 1,4-addition of the sodium diethyl cyanomethylphosphonate to the azo-ene system of conjugated alkenes results in the formation of l,2-diamino-3-(dietlioxyphosphinyl)pyrroles in moderate to good yields via a hydrazonic intermediate. - In a route to phosphonylated pyrones, the sodium diethyl cyanomethylphosphonate reacts with 3-anilinometliylene derivatives of 4-hydroxycouinaiins in DMF with displacement of aniline. ... 

The intramolecular Diels-Alder (IMDA) cycloadditions <05CR4779 02AC(E)1668> of 2-pyrones have not been exhaustively explored, due to the lack of synthetic methods to incorporate requisite tethered dienophiles. Only a few examples can be found in the literature and they have been employed mostly in the synthesis of aromatic compounds. 

Scbeme 42. Synthesis and IMDA cycloadditions of 2-pyrones tethered with acrylamide... 

Cycloaddition of 2-pyrones 5 to vinyl ethers 6 serves a key reaction in the synthesis of the important chiron 9, being an A-ring precursor to la-hydroxyvitamin D3. The best diastereose-lectivities were obtained when the appropriate chiral auxiliary was used in the diene component22 or a stereochemically matched pair of chiral diene and chiral catalyst was applied22. 

Synthesis of 3,5-difunctionalized l-methyl-lW-pyrazolo[3,4-fc]pyridines involving palladium mediated coupling reactions has been reported <04TL6633>. A novel synthesis of pyrazolo[3,4-ijjpyridines by condensation of 2-pyrone with 3-aminopyrazolone has been described <04SC2195>. 

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