Regio-and stereoselective syntheses and cycloadditions of substituted 2 H -pyran-2-ones and their fused derivatives

Microwave-assisted conditions have been shown to be very efficient for the synthesis of a variety of compounds containing 2 H -pyran-2-one skeleton that plays important roles in nature and in synthetic chemistry. Furthermore, such compounds (especially those incorporating a 3-acylamino group) were shown to be efficient partners for the Diels–Alder reactions with a variety of dienophiles including acetylene derivatives, maleic anhydride, substituted maleimides, vinyl-moiety-containing dienophiles, as well as ( Z )-1-methoxybut-1-en-3-yne. Reactions were carried out under conventional thermal conditions, microwave irradiation and under high pressure (13–15 kbar) and resulted in a plethora of different product types: anilines, bi-and terphenyls, indoles, isoindoles, 2-oxabicyclo  2.2.2  oct-5-enes and bicyclo  2.2.2  octenes. Many of the transformations showed remarkable regio-and stereoselectivity, depending primarily on the substitution patterns of the reactants and reaction conditions applied.


Introduction
2H-Pyran-2-ones and their fused derivatives are well-represented structural units of a variety of natural products, 1 their synthetic analogs and many other compounds not having natural counterparts, but nevertheless in many cases exhibiting important biological activity.Furthermore, due to their multifunctional character they display a plethora of potential applications in organic synthesis. 2For example, a recent report by Lee et al. 3 shows a promising in vitro anticancer activity for 6-substituted-4-amino-2H-pyran-2-ones (APO) representing a simplified version of the tanshinlactones, which were shown to be even more potent against the ER+ human breast cancer cell lines than the tamoxifen citrate.In 2009 Cardellina II and coworkers isolated 4 (R)-rugulactone from the plant Cryptocarya rugulosa, possessing 5,6dihydropyran-2-one skeleton and inhibiting nuclear factor κB activation pathway that is active in many types of cancers.(R)-Rugulactone and both epimers of its 4-hydroxy analog have been recently prepared via a stereoselective synthesis by employing proline-catalyzed αaminooxylation, Sharpless epoxidation and Mitsunobu reaction as chirality introducing steps. 5,4,6-Triaryl-2H-pyran-2-ones and their analogs exhibited high in vitro ability to inhibit the cyclooxygenase isozymes COX-1 and COX-2. 6This inhibition is important when treating inflammatory diseases such as rheumatoid arthritis and osteoarthritis.Development of selective COX-2 inhibitors has furthermore brought significant advances in the treatment of colon, breast and prostate cancers.
Anamarine, a polyoxygenated natural product isolated from the flowers and leaves of a plant from the genus Hyptis, was often a target of various synthetic approaches.Recently both enantiomers were prepared: (-)-anamarin was synthesized from D-tartaric acid via β-keto phosphonate intermediate derived from the tartaric acid amide, 7 whereas (+)-anamarin was obtained by a cross-metathesis strategy starting from but-3-en-1-ol and glycidol additionally involving Sharpless asymmetric epoxidation, dihydroxylation and deoxygenation-isomerization through allene rearrangement. 8In the latter synthesis, published by Kumar and Reddy, 8 the formation of the 2H-pyran-2-one ring was achieved by a lactonization of a 5-hydroxyester 1 (PMBO = p-methoxybenzylether) with the use of an acid as the catalyst (p-toluenesulfonic acid) yielding the cyclic intermediate that in three further steps provided the crucial vinyl lactone building block 2 (Scheme 1).The former synthesis of (-)-anamarin developed by Prasad and Penchalaiah 7 relied upon a ring-closing metathesis effected by the first-generation Grubbs catalyst, as described in the case of the preparation of (-)-spicigerolide and (+)-dodoneine (see chapter 2 and Scheme 8).

Scheme 1
Lam, Hua and Wu with co-workers 9 have recently reported promising cytotoxicity against human non-small-cell lung carcinoma cell lines of various polyene derivatives (the best two cases having IC 50 values of 0.6 and 0.01 µM).All of the compounds synthesized and investigated were of the gymnoconjugatin, auxarconjugatin and isorumbrin classes (of the general structure 3) and all posses a tetraene chain containing a substituted pyrrole ring on one end, with the other end of the chain attached to the position 6 of a substituted 2H-pyran-2-one ring.
It was also demonstrated that 4-alkynyl-6-methyl-2H-pyran-2-ones (AMP) efficiently inhibit the growth of A2780 human ovarian carcinoma and K562 human chronic myelogenous leukemia cell lines at the micromolar level. 10ubstituted 4-methoxy-6-pentyl-2H-pyran-2-one (MPP, R 1 = n-C 5 H 11 ) derivatives were found to be produced by the fungus Pestalotiopsis guepinii that is the causal agent of the socalled "twig-blight", one of the most serious diseases of hazelnut trees (Corylus avellana) in Turkey and consequently one of the main causes of yield loss. 11 4-Methoxy-6-phenyl-2H-pyran-2-one (MPP, R 1 = Ph) was found in the inedible bitter tooth mushroom (Sarcodon scabrosus). 12ll these cases vividly illustrate the importance of 2H-pyran-2-ones and the need for research in the field of their transformations.
There are many possible ways for the synthesis of 2H-pyran-2-ones 4, one of the more traditional ones can be retrosynthetically represented as the hydrolysis of the ester bond in the lactone ring, therefore as the starting material offering hydroxyacid 5 or its tautomeric form 5' (Scheme 2). 13

Scheme 2
Such a direct approach was recently applied in the case of the synthesis of (+)-dodoneine, isolated from Tapinanthus dodoneifolius, a parasitic plant growing on the sheanut trees in West Africa and exhibiting a vasorelaxant effect on preconstricted rat aortic rings.The final step of the synthesis is the construction of the dihydro-2H-pyran-2-one ring executed in two steps via the generation of a Z-configured α,β-unsaturated ester 6 followed by an acid-catalyzed intramolecular transesterification (lactonization) to yield (+)-dodoneine (Scheme 3). 14

Scheme 4
Boháč and co-workers 19 have recently published a useful synthesis of 2H-chromen-2-one derivatives 14 starting from 4-substituted 2-hydroxybenzaldehydes 13, succinic anhydride and sodium succinate under microwave irradiation (250-500 W, 18-50 min) (Scheme 5).The authors report that the microwave-assisted transformations proceed more smoothly and that they provide better yields than those carried out by conventional heating (where 1.5-5 h were necessary).

Scheme 5
2H-Chromen-2-one derivatives 17 were also prepared by a Knoevenagel condensation of suitable carbonyl compounds (substituted 2-hydroxybenzaldehydes 15) and active methylene derivatives in the presence of inorganic supports (on alumina at room temperature, or on KSF clay at 100 or 160 °C); in some cases in addition to the condensation also the hydrolysis of one CO 2 Et group of the starting material 16 occurred (Scheme 6). 20

Scheme 7
An interesting approach to the preparation of a 2H-pyran-2-one ring was recently demonstrated in the case of the synthesis of (-)-spicigerolide ( 23), a natural product isolated from the plant Hyptis spicigera, which was used in traditional Mexican medicine to treat gastrointestinal disturbances, skin infections, wounds and insect bites.The final step of the synthesis consists of a ring-closing metathesis of 22 effected by the second-generation Grubbs ruthenium catalyst (2 mol%) (Scheme 8). 22Similar approach, albeit with the application of the first-generation Grubbs catalyst, was applied by Falomir, Marco and co-workers for the synthesis of (+)-dodoneine. 23Scheme 8

Diels-Alder Reactions with 2H-Pyran-2-ones
Even though 2H-pyran-2-ones 2 24 are somewhat aromatically stabilized, they are appropriate diene components in a variety of Diels-Alder reactions.Due to slightly different reaction pathways, one has to distinguish between two general versions of the cycloadditions taking place on 24 (or their fused derivatives): with alkynes 25 or with alkenes 28 as dienophiles.16f In the former case, the molecule of the alkyne 25 (groups R 5 could be different) acting as the dienophile is in the first reaction step cycloadded to the 2H-pyran-2-one diene system 24 therefore yielding a 2-oxabicyclo[2.2.2]octa-5,7-diene-3-one 26 (Scheme 9).Such adducts (26) contain a CO 2 bridge, which is eliminated in a very facile retro-hetero-Diels-Alder reaction forming a benzene ring 27 as the final product.This retro-cycloaddition (27 → 26) was found to be inevitable in all cases described so far; even under very mild reaction conditions (e.g.under high pressure at room temperature) the CO 2 is spontaneously eliminated.In fact, because of their instability 2-oxabicyclo[2.2.2]oct-5,7-diene-3-ones 26 have not yet been isolated and described in the literature.
elimination / aromatization can occur (when R 6 are suitable and R 6 = R 5 )

Scheme 9
The cycloaddition of alkenes 28, on the other hand, offers a greater variety of products: the initial cycloadduct 29 (2-oxabicyclo[2.2.2]oct-5-en-3-one) is more stable than its analog 26 obtained with alkynes and can be in some cases even isolated (Scheme 9).However, often the reaction conditions applied for the first cycloaddition step (i.e.24 → 29) also result in the elimination (again via the retro-hetero-Diels-Alder reaction) of the CO 2 from 29, yielding cyclohexadiene (dihydrobenzene) systems 30.The latter can also be in some cases isolated, however, they often display high reactivity and therefore undergo further transformations: either serving as a new diene and reacting with a new molecule of the dienophile 28 forming bicyclo[2.2.2]octene systems 31 ("double" cycloadducts), or an aromatization step (via oxidation or elimination if suitable groups are present) takes place yielding benzene derivatives 27 (analogous to those obtained with alkynes).
In many of the above-described cases high regio-and stereoselectivity is observed.Analogous transformations as presented above (Scheme 9) can also be carried out with fused pyran-2-ones (see below).
Microwave irradiation as a way of achieving the necessary activation energies combined with the use of closed vessels in focused microwave reactors was found to be one of the most successful ways to avoid the use of those high-boiling solvents.Namely, it is possible to conduct such transformations either in toluene, water or even as neat reactions, thereby significantly simplifying the isolation procedures and increasing the purity and yields of the products.

Scheme 10
When one of the reaction components is volatile (or prone to sublimation) the neat conditions, however, are connected with an additional problem.In such cases the volatile reactant tends to evaporate from the lower (hotter) part of the reaction vessel to the upper (colder) parts, where it condenses and is therefore no longer available for the reaction.This problem can be avoided by the use of a larger excess of the volatile component, but such an approach is not recommendable, especially where expensive reagents are used.A much better way to circumvent this problem is to add a minimum amount of an appropriate neutral liquid additive possessing a boiling point close to the reaction temperature; n-butanol is often used).25c,31d Of course, this liquid evaporates as well and also condenses on the upper surfaces of the vessel, but due to its generally lower viscosity it tends to flow down the walls of the reaction vessel, thereby returning the condensed reagent to the seat of the reaction.With this precaution the necessary excess of the reagent can generally be lowered to a few ten percents.
It is of interest to note that cycloadditions of unsymmetrically substituted acetylenes with a hydrogen substituent on one side of the triple bond (33, R 5 = H) generally proceed in a regioselective manner yielding aniline products containing para-positioned hydrogen atoms (e.g. 25 With other alkynes 33, such as N,N-diethylpropynamine and ethyl but-2-ynoate, both regioisomers were obtained providing a rewarding field for an experimental and computational research of their regioselectivity. 26In the case of N,Ndiethylpropynamine used as a dienophile, the results obtained point to a polar and asynchronous two-step mechanism, where 2H-pyran-2-ones act as electrophiles.Less polar and more synchronous concerted mechanism was found in the case of ethyl but-2-ynoate, most probably due to the presence of the electron-withdrawing carboxylic groups decreasing the nucleophilic character of the dienophile.Additionally, we have determined the effects of the 5-substituent (with 3-benzoylamino-2H-pyran-2-one derivatives) on the reactivity: for phenylacetylene as a dienophile we found that 5-acetyl and 5-benzoyl derivatives are far more reactive than 5-(4methoxyphenyl) derivative.On the other hand, diethyl acetylenedicarboxylate and ethyl propynoate showed the inversed reactivity pattern.25b On the basis of these reactivity data for these transformations taking place via polarized asynchronous concerted transition states and possibly also via the formation of zwitterionic intermediates (a polar two-step mechanism) it was possible to classify them according to their electron demand.
Loupy and co-workers 27 have found that cycloadditions of various alkynes (alkyl propiolates and dialkyl acetylenedicarboxylates) with 3-alkoxycarbonyl-2H-pyran-2-ones 36 under solvent-free conditions in general do not proceed regioselectively but instead provide mixtures of 37 and 38 (Scheme 11).The authors made a strict comparison between conventional heating and microwave-assisted conditions.Furthermore, they have discussed the eventual occurrence of a specific microwave effect on the case of 3-methoxycarbonyl-2H-pyran-2-one.

Scheme 11
In some cases it was demonstrated that triple-bond containing dienophiles (e.g.cyclohexyne and cyclooctyne derivatives, hetaryne analog of 2-chloropyridine and indolyne) can be formed in situ from simple precursors and immediately used as efficient partners for a variety of cycloadditions, including those with 2H-pyran-2-ones, additionally enabling a concise synthesis of ellipticine. 28Synthesis of indoles.Further interest in the cycloaddition of alkynes was illustrated by the application of (Z)-1-methoxybut-1-en-3-yne (40) as the dienophile, 29 in this case the triple bond of the dienophile 40 preferentially cycloadds to the 2H-pyran-2-one skeleton 39 (under microwave irradiation, 45-180 min at 150 °C) yielding benzene derivatives 42 with a strategically positioned 2-methoxyethenyl moiety (Scheme 12).Namely, cycloadducts 42 can be easily cyclized into the corresponding substituted indoles 43 by the application of a catalytic amount of a dilute acid (e.g.HCl).This pathway represents a novel and straightforward synthetic route towards 1,5,6-trisubstituted indoles 43 and it enables access to indoles with substitution patterns on the six-membered ring that would be difficult to achieve via other methodologies. 30Scheme 12

Scheme 13
The preparation of such 2-oxabicyclo[2.2.2]oct-5-en-3-ones 29 is feasible especially in those cases where the reactions are taking place under mild conditions (room temperature or at high pressures) or when the electronic demands of the dienophile and diene are correctly matched by the way of appropriate selection of the substituent patterns.3-Phenylsulfenyl-and 3phenylsulfonyl-2H-pyran-2-ones were shown by Posner and co-workers 33 to react with electronrich and electron-poor dienophiles affording such bicyclic lactones suitable as precursors for the syntheses of many natural products and biologically active compounds.Encouraging were also the results obtained by Afarinkia and co-workers 34 while investigating reactions of chloro-and bromo-substituted 2H-pyran-2-ones and related systems with substituted acrylates, fumarates, maleates and their derivatives as dienophiles.The reactions were conducted at ambient temperature, under gentle heating (70-80 °C) or under high-pressure conditions.The regio-and stereochemical preferences of these thermal cycloadditions were investigated computationally (density functional theory calculations with B3LYP/6-31G basis set) providing results that were in agreement with the experimentally observed selectivities.

Formation of cyclohexadienes.
Many such cases were described starting from maleic anhydride or N-substituted maleimides (of the general structure 46) as dienophiles and various 3-acylamino-2H-pyran-2-ones taking place either under conventional reflux conditions or in closed vessels with the microwave-assisted heating yielding 47.Here generally four stereoisomers can be expected: two containing a plane of symmetry (i.e.exo,exo-47 and endo,endo-47) and a pair of enantiomeric asymmetric products (endo,exo-47 and exo,endo-47).

Scheme 14
Thermal cycloadditions of the majority of the 2H-pyran-2-one derivatives resulted exclusively in the symmetric products exo,exo-47.This type of symmetric product is in agreement with the expected stereostructures of the energetically favored transition states. 37owever, in special cases where severe steric hindrance exists between the two reacting partners, it was suspected that the second cycloaddition step could take place via a different stereochemical course.Indeed, such asymmetric endo,exo-bicyclo[2.2.2]octenes 50 were obtained when an eight-membered ring was fused to the starting 2H-pyran-2-one skeleton (i.e.48) and the dienophile applied was an N-substituted maleimide 49 possessing enough steric hindrance.We found that the methyl substituent (49, R = Me) was the smallest among those examined, to provide such an effect (Scheme 15). 37In contrast, when maleic anhydride (51) cycloadded to the fused 48, symmetric exo,exo adducts 52 were again produced, clearly demonstrating the need for both partners to provide sufficient steric hindrance during the stereochemically crucial reaction step and consequently to change the stereoselectivity of the bicyclo[2.2.2]octene adduct (Scheme 15).Previously such asymmetric endo,exo products were accessible only via photochemical conditions. 38Symmetric adduct 52 can be further transformed with aniline into the corresponding symmetric exo,exo derivative 53 that can be thermally isomerized into asymmetric endo,exo product 50 (R = Ph) (the same as obtained directly with the cycloaddition of 49).This isomerization clearly shows that the asymmetric endo,exo product 50 is thermodynamically more stable than its symmetric endo,exo counterpart 53.These results were further corroborated by computations at the DFT level. 37

Scheme 15
Formation of isoindole derivatives.The last cycloaddition reaction step of the alkene (i.e. 30 → 31) (Scheme 9) can be, at least theoretically, reversible, therefore preserving a certain concentration of the cyclohexadiene intermediate 30 in the mixture throughout the reaction course.Bearing in mind that oxidation (aromatization 30 → 27) (Scheme 9) of the cyclohexadiene intermediate is generally irreversible, it was often experimentally found that in such reactions (with N-substituted maleimides 49 used as dienophiles) the bicyclo[2.2.2]octenes 59 represent the kinetically preferred products, whereas the aromatized isoindoles 58 are thermodynamically favored (Scheme 16).31b Therefore, longer reaction times and higher temperatures generally cause the oxidation to occur, consequently yielding the corresponding isoindole products 58.When suitable dehydrogenation catalysts are applied this oxidation can be the exclusive reaction path.In the case when fused pyran-2-ones 54 was used as a dehydrogenation catalyst, 31b whereas in the cases of other substituted 2H-pyran-2-ones 54 activated charcoal Darco KB was found to be the best choice.31f Further studies have shown that the most important factor influencing the dehydrogenation activity of the catalyst is its specific surface area.It has also been demonstrated that the dienophile (i.e.N-substituted maleimide 49) additionally acts as the sink for the hydrogen eliminated from the cyclohexadiene intermediate 56.Compound 49 is thereafter transformed into the corresponding N-substituted succinimide 57.

Scheme 16
In some cases, where aromatization is energetically very favorable, the heterogeneous dehydrogenation catalyst might not be needed at all; however, there is still the need for the presence of some other molecule possessing a suitable double bond to act as the hydrogen sink.Tsuboi and co-workers, for example, have described some elegant cases of cycloaddition of various 3-hydroxy-2H-pyran-2-ones with 1,4-quinones, which were used as dienophiles and concomitantly enabled the aromatization into the final naphtho-and anthra-quinones. 39In some other examples aromatization is achieved by the elimination of a small, stable molecule, such as ethanesulfinic acid, as described by Haider et al. 40 Cycloadditions of vinyl-containing dienophiles.Sometimes it would be useful if acetylene could be used as the dienophile.However, because of its gaseous nature and negligible polarization it is very unreactive and therefore often unsuitable for cycloadditions as the dienophile.Therefore, some synthetic equivalents of acetylene would be of certain interest: vinyl-moiety containing ethers and esters 60 as well as amides 61 proved to be suitable masked equivalents of acetylene readily reacting as dienophiles with a variety of electron-deficient substituted 2H-pyran-2-ones 39 (Scheme 17). 32,41The initially formed 2-oxabicyclo[2.2.2]oct-5en-3-ones 44 and 45 could be isolated only in the cases where the cycloadditions took place at high pressure (13-15 kbar) and at room temperature; the necessary reaction times were therefore rather longca.15 days.It is of additional interest that the stereoselectivity of the cycloadditions depended upon the dienophiles used: ethyl vinyl ether (60, R 4 = Et) (and other dienophiles 60) yielded exclusively endo adducts 44, whereas with 1-vinyl-2-pyrrolidone (61, n = 1) and N-vinylcaprolactam (61, n = 3) (both with the vinyl moiety attached to a nitrogen atom) mixtures of both endo and exo adducts 45 were observed, the exo adduct predominating in the majority of cases (Scheme 17).

Scheme 17
When these cycloadditions (Scheme 17) were conducted under microwave irradiation, the resulting reaction temperature caused the elimination of CO 2 from 44 and 45 via the retro-hetero-Diels-Alder reaction.The cyclohexadienes 62 and 64 produced proved to be of low stability and were prone to spontaneous aromatization yielding the final aromatic systems 63 corresponding to those that would be obtained by the application of acetylene as the dienophile.The reaction towards such aromatic systems 63 was found to be further accelerated by the application of a suitable base acting as an organocatalyst.Among the bases examined DABCO (1,4-diazabicyclo[2.2.2]octane) was shown to be the most appropriate; additionally it was proved that DABCO has no effect on the cycloaddition step (i.e.39 → 44 and 39 → 45) and that it acts only in the last elimination step (formation of 63).The same synthetic strategy of using ethyl vinyl ether (60, R 4 = Et) as a masked equivalent of acetylene was later extended also to the cases of fused pyran-2-ones, where only final, aromatized products of type 63 were isolated. 42pplication of a vinylated sugar (an appropriately protected D-glucofuranose derivative) as the dienophile for a cycloaddition with 3-methoxycarbonyl-2H-pyran-2-one afforded either the CO 2 -bridged primary adduct (after 6 days at 65 °C) or a cyclohexadiene system (after 2 days at 100 °C) amenable for the further transformation into a carbasugar-sugar pseudodisaccharide. 43

Selected examples of other transformations of 2H-pyran-2-one derivatives
One of the key steps for the preparation of biologically important compounds belonging to the gymnoconjugatin, auxarconjugatin and isorumbrin classes (see chapter 1) was a microwaveassisted oxidation of a 6-methyl group on a 2H-pyran-2-one ring 65 into the corresponding aldehyde moiety taking place with SeO 2 in dioxane (at 150-160 °C) (Scheme 18). 9 Instead of using conventional heating in a sealed tube, as was reported earlier, 44 Lam, Hua and Wu with coworkers 9 decided to use microwave irradiation; in this way reaction times were shortened and yields of the products 66 improved.

Scheme 18
4-Hydroxy-6-methyl-2H-pyran-2-one (69) can be used as an efficient partner for a threecomponent reaction with N-substituted isatins 67 and 1,3-dicarbonyl compounds 68 catalyzed by an appropriate Lewis acid yielding products 70 (Scheme 19 also presents the suggested mechanism). 45Stephenson and co-workers have investigated many possible Lewis acids (including TiCl 4 , BF 3 •OEt 2 and SnCl 4 , the last being found to be the most efficient) and various conditions (including conventional heating in 1,2-dichloroethane at 60 °C or with microwave irradiation at 80 °C in the same solvent).The most appropriate were found to be the microwave conditions enabling the decrease of the necessary reaction times from 12-20 h to just 80 min and in most cases providing the products 70 with increased yields.
Furopyrimidines and furopyranones as well as furocoumarins (the latter two represented by the general structure 74) can be prepared by a three-component solvent-free condensation between various 2H-pyran-2-ones or coumarins 71, substituted benzaldehydes 72 and isonitriles 73 on montmorillonite K10 as the solid support in DMF (Scheme 20).The otherwise necessary reaction times (14-16 h for furopyranones and 16-24 h for furocoumarins) were drastically reduced to just 4-5 min with the application of microwave irradiation. 46

Scheme 20
Furopyranones and furocoumarins similar to those above were also obtained by the cyclization of 4-hydroxy-2H-pyran-2-ones or related coumarins with substituted benzaldehydes and nitriles in DMF under microwave irradiation for 3 min. 47u et al. have reported the condensation of arylaldehydes with two molecules of 4hydroxy-6-methyl-2H-pyran-2-one (69) under microwave irradiation in refluxing ethylene glycol yielding tricyclic systems 75 in 4-5 min with yields generally higher than those reported (Scheme 21). 48

Scheme 21
Pyrazolecarboxaldehydes were also used for reaction with 4-hydroxy-6-methyl-2H-pyran-2-one and a related 4-hydroxycoumarin catalyzed by Zn(proline) 2 as a Lewis acid under solventfree conditions (or alternatively in water). 49However, the expected Knoevenagel condensation products were not detected and instead of them pyrazolopyrones were produced.With the application of microwave irradiation, the authors were able to decrease the necessary reaction times from 45-120 min (conventional heating in the aqueous medium) to 5-9 min with the concomitant increase of yields.

Scheme 22
The temperature attained with microwave irradiation was 150 °C; however, when CaSO 4 was used as the additive only 110 °C was needed.Reaction times of microwave-accelerated reactions varied between 5 and 90 min and were significantly shorter than those needed under thermal conditions at 80 °C (up to 25 h).Albeit the obtained yields of 78 were in some cases lower than under conventional conditions, the microwave approach offers significant time savings and thus enables more rapid access to large libraries of such heterocyclic systems 78 that are related to natural products of the pyripyropene family (Scheme 22).
Stoyanov and Ivanov 51 have published a transformation between 4-hydroxycoumarin (79) or 4-hydroxy-6-methyl-2H-pyran-2-one (69) and a set of substituted amines including morpholine under microwave-irradiation (850 W, 1.5-10 min).It is noteworthy that the fused pyran-2-one moiety of the coumarin 79 did not open during this transformation and therefore the 2H-pyran-2one-moiety-containing product 80 was obtained.On the other hand, the 2H-pyran-2-one ring 69 was transformed into the 2-pyridone ring 81 (Scheme 23).It should be noted that these reactions were carried out in a closed vessel in an ordinary kitchen microwave oven, so the reaction parameters (temperature, pressure) are not reported; this might lead to certain problems with the reproducibility.

Transformations of bicyclo[ [ [ [2.2.2] ] ]
]octenes Bicyclo[2.2.2]octenes of type 82 36 that are easily accessible by the Diels-Alder reactions of a variety of 2H-pyran-2-ones and appropriate N-substituted maleimides or maleic anhydride represent very rewarding substrates for the investigations of the regio-and stereoselectivity of hydrogenation reactions in the presence of suitable heterogeneous catalysts: various LDH (layered double hydroxides)-supported Pd and Rh salts were applied to study the chemoselectivity: the hydrogenation can take place at the double bond; alternatively acetyl group can be reduced to the 1'-hydroxyethyl group (i.e.formation of 83 versus 84) (Scheme 24).31c, 52 Additionally, silica sol-gel heterogenized synphos modified Pt nanoclusters 53 and iron oxide colloids 54 were evaluated and successfully applied for an analogous hydrogenation.It is important to mention that hydrogenations of these bicyclo[2.2.2]octenes under standard conditions proceed poorly, at best.

Scheme 24
Bicyclo[2.2.2]oct-7-ene-2,3,5,6-tetracarboxylic acid dianhydride derivatives 85 (obtained by simple cycloaddition between 2H-pyran-2-ones and maleic anhydride (51)) can be efficiently converted into the corresponding tetraesters 86 by microwave-assisted and ionic-liquid-catalyzed transformation (Scheme 25). 55Base-catalyzed isomerization of these tetraesters 86 takes place with the retention of symmetry and yields the products 87 that are appropriate substrates for catalytic hydrogenation.This hydrogenation proceeds under far milder conditions (5 h at room temperature, 3 bar of H 2 and with standard Pd/C as the catalyst) as were necessary for the above mentioned bicyclo[2.2.2]octenes 82 (analogous to those before the isomerization) indicating that the isomerization (86 → 87) strongly decreases the steric hindrance around the double bond.

Scheme 25
Additionally, bicyclo[2.2.2]octenes, such as 85, resulting from the cycloaddition of maleic anhydride are also interesting substrates for derivatizations with amines 56 as well as with hydrazine and its derivatives. 57We have focused special attention to those bicyclo[2.2.2]octenes that incorporate acetyl moiety.When 88 reacts with amines the resulting products differ according to the conditions applied: neat reaction conditions (with an addition of a minor amount of a non-polar liquid, such as toluene) under microwave irradiation yield the product 89 (representing an example of a succinimide derivative with the acetyl group transformed into an imine moiety) (Scheme 26).On the other hand, similar reaction of 88 carried out in an aqueous suspension leads to the product 90, which is an example of a succinimide derivative with the acetyl group remaining unchanged.Transformations with hydrazine and its substituted derivatives, on the other hand, provided derivatives 91 with the acetyl group transformed into the corresponding hydrazone moiety also in the case when water was used as the solvent.

Conclusions
We have presented 2H-pyran-2-one derivatives as naturally occurring and biologically important compounds; furthermore a very versatile one-pot synthesis of many 3-acyl-2H-pyran-2-one derivatives was considered in the light of some other more recent preparation procedures.Then we turned our attention to the application of 2H-pyran-2-ones as dienes useful for a plethora of Diels-Alder reactions with alkynes and alkenes (with special consideration to maleic anhydride and N-substituted maleimides) discussing the regio-and stereoselectivities observed.A novel preparation of substituted indoles and the application of vinyl-moiety containing dienophiles as masked synthetic equivalents of acetylene are also presented.Cycloadditions of 2H-pyran-2-ones often yield bicyclo[2.2.2]octene derivatives that are interesting targets for further reactions: hydrogenation, transformations with amines and hydrazines, isomerizations etc.The introduction of contemporary synthetic tools, including principles of green chemistry and the microwave irradiation, keeps the field of synthesis and transformations of 2H-pyran-2-one a very vital research area and we suppose that novel results will appear in the near future.committees (MC) of different COST actions (D2, D12, D24, D40); currently he is a member of the MC COST Action CM0905 Organocatalysis (ORCA).Since 1996 he is a secretary general of the Slovenian Chemical Society.In the period of time 2008−09 he was a national representative in the committee of the IUPAC Organic and Biomolecular Chemistry Division (III), and since 2010 he is IUPAC Fellow.In 1999, he was awarded the Hanus Medal by the Czech Chemical Society in recognition of his contribution to the field of chemistry.Currently, he is a member of the American Chemical Society and the International Society of Heterocyclic Chemistry and also a member of several advisory boards of different journals, among them of Editorial Advisory Board of Current Organic Chemistry.