Pyrones and Chromones

The presence of a benzene unit fused to a pyrone ring affects the chemistry of both coumarins and chromones, but there are subtle differences in reactivity between the two types of compounds. 

Although pyridones are usually resistant to alkali, pyrone rings are often easily opened. Pyran-2-ones are reversibly ring-opened by aqueous alkali to acid anions (222). Hydroxide ions convert coumarins (223) reversibly into salts of coumarinic acids (224) which can be converted into the trans isomers (225), and chromones (226) into 3-dicarbonyl compounds (227). 

The pyrylium salts (76) are the six-membered oxygen heteroaromatic compounds. The 2- and 4-pyrones [(77) and (78) respectively] and the corresponding benzo analogues [coumarins (79) and chromones (80)] are represented by examples which further illustrate the usefulness of retrosynthetic analysis in the derivation of preparative methods. 

Few of these species are strictly aromatic, but reactivity with electrophiles resembles that of aromatic compounds. Much of the discussion that follows will be devoted to the pyrones and thiopyrones (the fused benz-derivatives, coumarins, chromones, flavones, and isoflavones, will be covered in Part 3). 

Ketones derived from pyrans are called pyranones (also commonly pyrones), and the parent compounds are pyran-2-one 17 and pyran-4-one 18. Trivial names are used for the related benzo analogs coumarin 19, isocoumarin 20, dihydrocoumarin 21, chromone 22, xanthone 23, and chromanone 24. 

The pyrilium cation 9.1, 2-pyrone 9.2, 4-pyrone 9.3, and their benzo-fused analogues the benzopyrilium cation 9.4, coumarin 9.5, chromone 9.6, are the parent structures of a series of six-membered ring heterocycles containing one oxygen atom. The impetus for research in this area comes from the enormous number of plant-derived natural products based on the benzopyrilium, coumarin, and chromone structures. 

Coumarin (11.46), iscoumarin (11.47), and chromone (11.48) should each be more reactive than the corresponding pyrone, and consideration of conjugative effects indicates substitution to be preferred at the 3-position of 11.46 and 11.48, and at the 4-position of 11.49. Isocoumarin (11.47), in which the oxygen lone pair is less readily delocalized into the benzenoid ring, should be more reactive than the other two isomers. Substituents in these molecules will have very marked directional effects because of significant bond fixation. 

Pyrylium salts, pyrone derivatives, and their benzo derivatives show various interesting reactivities and appear in many natural products. Therefore, many organic chemists have an interest in the chemistry of pyrylium salts 1 and 2 and pyrones 3 and 4 (Scheme 1) (82AHC66 83AHC187). This review is a survey of the literature from 1980 onward, concentrating especially on nucleophilic reactions and carbocyclic annulation reactions that retain the resulting pyran ring. Related benzopyrone derivatives, coumarins (5) and chromones (6), are also included. 

The simple y-pyrones are quite stable crystalline substances, whereas the a-pyrones are much less stable, a-pyrone itself, which has the smell of fresh-mown hay, polymerising slowly on standing. There are relatively few simple pyrone natural products in great contrast with the widespread occurrence and importance of their benzo-derivatives, the coumarins and chromones, in nature. 2- and 4-Hydroxypyrylium salts are quite strongly acidic and are therefore much better known as their conjugate bases, the 2- and 4-pyrones. 

The first pyrylium salt without hydroxy or alkoxy substituents made by the protonation or alkylation of 4-pyrones was obtained in 1911 by Baeyer and Piccard fi"om 4-pyrones and Grignard reagents. Isolation of these compounds was often difficult, and their characterization was confiised by a lack of a clear understanding of their electronic structure. However, there was much interest in benzopyrenes (coumarins, flavones, and chromones) and benzopyrylium (flavylium, chromylium) salts isolated fi om plants (anthocyanins, anthocyanidines) to which they conferred a large diversity of colors. 

Ganguly, A.K., Kaur, S., Mahata, P.K., Biswas, D., Pramanik, B.N., Chan, T.M. 2005. Synthesis and properties of 3-acyl-y-pyrones, a novel class of flavones and chromones. Tetrahedron Letters 46(23) 4119-4121. 

The major part of this review concerns chromones which possess a carboxyl or related group at C-2 but a few derivatives of the 3-carboxylic acids are known and discussed. Compounds in which the heterocyclic oxygen or the pyrone carbonyl oxygen is replaced by sulphur are also mentioned. The chemistry of chromones has been reviewed up to 1948 [1] and a survey (without references) of the synthesis of coumarins and chromones of therapeutic interest appeared in 1970 [2], Naturally-occurring chromones are covered in a chapter of a book by Dean [3]. The chromone-2- and -3-carboxylic acids have not been reviewed previously, although an early review of chromones [4] contains a short section on chromone carboxylic acids. 

Analysis of the published data demonstrates that of the diverse fluorine-containing pyrones, chromones and coumarins, 2-(trifluoromethyl)-4-pyrones and 2-(polyfluo-roalkyl)chromones, as well as 3-(polyfluoroacyl)chromones and chromones with the... 

Sosnovskikh VY, Korotaev VY, Chizhov DL, Kutyashev IB, Yachevskii DS, Kazheva ON, Dyachenko OA, Charushin VN (2006) Reaction of polyhaloalkyl-substituted chromones, pyrones, and furanones with saUcylaldehydes as a direct route to fused 2//-chromenes. J Org Chem 71 4538-4543... 

However, chromones react differently, because the phenolic hydroxy group in the ring-opened intermediate is unreactive. Thus, isoxazoles (264) result from the reaction with hydroxylamine, and a pyrazole is formed with hydrazine. y-Pyrones also give pyrazoles with hydrazine. 

The ketones derived from the pyrans are known as pyranones (17) and (18), although the name pyrone has enjoyed much usage. Trivial rather than systematic names are in general use for the benzologues (19), (20) and (21) and these, too, are used throughout. The 2-phenyl derivative of chromone is known as flavone (22). 

Aloe (Aloe arborescens) is a medicinal plant rich in aromatic polyketides such as pharmaceutically important aloenin (a hexaketide pyrone), aloesin (a heptaketide chromone), and barbaloin (an octaketide anthrone) (Fig. 4a). Pentaketide chromone synthase (PCS) and octaketide synthase (OKS) are novel plant-specific type III PKSs, which were obtained from the aloe plant by RT-PCR cloning using degenerate oligonucleotide primers based on the conserved sequences of known CHS enzymes [30-33]. The deduced amino acid sequences of PCS and OKS are 91% identical (368/403), and show 50-60% identity to those of other CHS superfamily type III PKSs of plant origin OKS shares 60% identity (240/403) with CHS from... 

Polyhaloalkyl-substituted chromones and 7-pyrones react with salicylaldehydes in the presence of piperidine to give a variety of fused 277-chromenes in good yields (Scheme 58) <2006JOC4538>. Although it is conceivable that this reaction could proceed through a Baylis-Hillman reaction pathway, studies of this reaction point to the mechanism being a tandem intramolecular oxa-Michael addition and subsequent Mannich condensation. 

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