Pyranone syntheses

In this approach to pyranone synthesis, it is thought that the carbanionic site in the betaine attacks the cyclopropenone in a Michael fashion. Subsequent opening of the three-membered ring may lead directly to the pyranone (route a) or the heterocyclic system may form via the ketene (route b Scheme 98). 

Acylation of the dianion of ethyl acetoacetate by an ester is a useful addition to this area of pyranone synthesis. In this reaction and in the formation of the trianions of 2,4,6-triketones the use of lithium diisopropylamide as the base is valuable (76JA7733). The triketo acid from the trianion cyclizes in mineral acids to the pyran-4-one, but in acetic anhydride the pyran-2-one is formed (Scheme 101) (71JA2506). 

Pyran-4-one, 2,2,5-trimethyl-2,3-dihydro-photodimerization, 3, 720 4H-Pyran-4-one, 2,3-dihydro-2,3,5-trimethyl-6-( 1 -methyl-2-oxobutyl)-synthesis, 3, 844 Pyranones alkylation, 2, 56 aromaticity, 3, 632, 633 C NMR, 3, 587, 635 H NMR, 3, 580 cardiac glycosides, 3, 883 chromone synthesis from, 3, 830 colour couplers... 

Pyranones, dihydro-confdrmation, 3, 632 mass spectra, 3, 617 reactions, 2, 62 with halogens, 3, 799 synthesis, 3, 797... 

Compounds in carbohydrate-based synthesis of 2,3-dihydro-4//-pyranones as starting compounds for the preparation of C-saccharides, glycosylstan-nanes, and analogs of tromboxane A2. 98EJ02267. 

Conversion of furfuryl alcohol derivatives 48 to pyranones 49 (Achmatowicz oxidative ring expansion) is employed in the synthesis of spiroketal moiety of a natural product and cyclopentenones <00TL6879>. 

Acetalization of oxo aldehydes is used to protect sensitive aldehyde products, especially in asymmetric hydroformylation preventing racemization of an a-chiral aldehyde product [18-22,27]. Acetal formation can also be applied to the synthesis of monocyclic or spirocyclic pyranes as potential precursors and building blocks for natural products such as pheromones or antibiotics. A representative example is the synthesis of the pyranone subunit of the Prelog-Djerassi lactone. For this purpose, various 1,2-disubstituted homoal-lylic alcohols were used (Scheme 3) [32],... 

In the presence of orthoester and perchloric acid, 3-acetyltropolone (74) with benzaldehydes affords pyranones 76 directly (90JHC891). The reaction is considered to pass through a carbocation (from 74 and orthoester) which is stabilized by electron-donating substituents in the benzaldehyde (Ar). Therefore, the one-step synthesis might be limited to methoxy- and hydro-xybenzaldehydes. These synthons are also used to prepare corresponding... 

Inda-box ent-9a has been used recently in the production of the natural product (-)-malyngolide 265. " The key step of the synthesis by Ghosh and Shirai, as shown in Figure 9.80, is the hetero-Diels-Alder reaction of Danishefsky s diene 112 and cx-ketoester 263 to afford the pyranone derivative 264 in 77% yield and 47% ee that was converted into (—)-malyngolide in several additional steps. The preparation of different pyranones was investigated using different ot-ketoesters. 

Pyranone 127 reacts with alkenes in the presence of cerium ammonium nitrate via a cyclization reaction that leads to the formation of furo[2,3-3]- and furo[3,2-f]-pyranones in moderate yields (Equation 60). This reaction can be extended to the synthesis of furoquinolinones <1999H(51)2881>. Dihydropyran 128, with either / -diketones or /3-keto esters, undergoes cycloaddition reactions promoted by ceric ammonium nitrate to generate furo[2,3-3]pyrans in good yields (Equation 61) <1996T12495>. 

The palladium catalyzed benzannulation reaction, described by Yamamoto, was successfully extended to the synthesis of condensed pyranone derivatives. The precursor to the cyclization underwent the benzannulation spontaneously under the applied Sonogashira coupling conditions (8.40.) on formation, to give the desired dibenzo />,ri pyranone. The functionalities tolerated in the process include unsaturated bonds and polar functional groups, such as hydroxyl.52... 

A nitrile-stabilized carbanion is also involved in a synthesis of a fused pyranone system (81S225). A range of 2-ureidomethylenecyclohexane-l,3-diones, e.g. (308), react with activated acetonitriles in the presence of a strongly basic catalyst to produce 5-oxo-5,6,7,8-tetrahydrocoumarins (309). Since the substrates are readily available from cyclohexane-1,3-diones by reaction with triethyl orthoformate and a urea, the synthesis is attractive (Scheme 88). Furthermore, it has been applied to a pyran-2,4-dione, whereupon the 2,5-dioxopyrano[4,3-6]pyran (310) is formed. 

Reaction of carbanions with dialkynic ketones, the so-called skipped diynes, can produce pyranones through an initial Michael condensation. It should be noted however that diynones are vulnerable to attack at several sites and that mixed products can be formed. Addition of the anions derived from diethyl malonate and ethyl cyanoacetate to hepta-2,5-diyn-4-one (313 R1 = Me) gives the pyranones (314 R2 = C02Et or CN Scheme 91) (74JOC843). The former carbanion reacts similarly with the diynone (313 R1 = Bun) (68T4285). The second alkyne moiety appears to have little effect on the course of the reaction, which parallels the synthesis of pyranones from monoalkynic ketones. 

The Reformatsky reaction has been applied to the synthesis of fused pyranones and provides an example of selective isomer formation by careful choice of substrate. Hydroxy-methylenecyclohexanone (315) and methyl bromoacetate give 5,6,7,8-tetrahydro-l-benzopyran-2-one (316) through alkylation at the hydroxymethylene carbon atom (54JA6388). However, the benzoyl derivative (317) is unable to form an enolate salt and alkylation occurs at the carbonyl carbon atom, leading to 5,6,7,8-tetrahydro-2-benzopyran-3-one (318) (45HCA771). 

The self-condensation of /3-keto esters and related compounds occurs under the influence of either acidic or basic catalysts and constitutes one of the earliest syntheses of pyran-2-ones (l883LA(222)l). It exemplifies a synthesis of type (ii) (Scheme 85). Ethyl acetoacetate, for instance, gives a mixture of 4,6-dimethyl-2-oxopyran-5-carboxylic acid and its ethyl ester other esters behave similarly (59RTC364). Decarboxylation of the pyrancarboxylic acid occurs at 160 °C in sulfuric acid. The formation of the pyranone proceeds through a 5-keto ester which is considered to result from attack of the enolic form of the ester on protonated ethyl acetoacetate (51JA3531). A detailed synthesis of the pyran-5-carboxylic acid is available <630SC(4)549). 

In the presence of a basic catalyst, unsaturated esters react with diethyl oxalate to form an unsaturated 5-keto ester in a synthesis of type (iii) (Scheme 99). In many cases these compounds cyclize spontaneously to the substituted pyranone, but where this is not so, ring closure usually follows hydrolysis under acidic conditions. The pyrancarboxylic acids undergo ready thermal decarboxylation (41JOC566). 

One of the most reliable and widely used syntheses of coumarins involves the acid-catalyzed reaction between a phenol and a jS-keto ester, the Pechmann reaction (45CRV(36)1, 530R(7)l). An important aspect of the reaction is that it shows a dependency on all three reactants, which can be varied widely, thereby optimizing both the scope and conditions of the synthesis. As a consequence, satisfactory yields of coumarins substituted in either the benzene or pyranone ring or both rings can be obtained from readily accessible starting materials. 

Substituents in the pyranone ring are derived from the dicarbonyl component and hence variation in the nature of 3- and 4-substituents is relatively easy. Thus, ethyl benzoylacetate gives 4-phenylcoumarins as for instance in a synthesis of dalbergin (357) (76T2407, 8iiJC(B)9l8) and use of ethyl trifluoroacetoacetate leads to 4-trifluoromethylcoumarins. A study of the reaction of the latter with 3-aminophenol identified the optimum conditions for coumarin formation, but noted the simultaneous formation of the two quinoline derivatives (358) and (359) (80JOC2283). 

The Pechmann synthesis is unsuitable for acid-sensitive phenols, as for example the furo[2,3 -6]benzofuran derivative (373). An alternative approach uses the enhanced electrophilic character of a vinyl bromide in the presence of zinc carbonate to construct a suitable side-chain adjacent to the phenolic group (71JA746). In the examples cited, ring closure occurred under the mild conditions to form the pyranone ring of the aflatoxins (374). Since neither sodium nor potassium carbonate proved effective, it was considered that chelation of the zinc facilitated the carbon-carbon bond formation (Scheme 115). 

A convenient preparation of pyran-4-ones involves heating carboxylic acids or their anhydrides in polyphosphoric acid (67JCS(C)828). Yields are satisfactory, although when the synthesis is applied to a mixture of acids, a mixture of pyranones results. Only symmetrical pyranones (421) are formed, suggesting that the anhydride, rather than the acid, is the precursor of the heterocycle (Scheme 141). 

It has since been shown that the enol ester (451) is an intermediate in the synthesis (69T715). Indeed such esters readily form chromones on treatment with alkali and the ortho acyloxy group becomes part of the pyranone ring as a result of a Baker-Venkataraman rearrangement (Scheme 160) (69T707). 

---