Coumarins from chromones

Over the years the literature is filled with examples where the initial characterization was incorrect. One example is illustrated below. In 1940, Sethna and Shah presumed that they synthesized coumarins 42 and 43 from a reaction between P-orcacetophenone (44) and its 4-0-methyl ether 45 under standard Kostanecki-Robinson conditions, respectively. Three decades later Bose and Shah synthesized coumarin 43 via another route and concluded that the initial assignment made by Sethna and Shah was incorrect. After the Bose and Shah findings were published, Ahluwalia and Kumar concluded that the Sethna and Shah products were actually chromones 46 and 47 based on proton NMR data and chemical derivatization. Despite these shortcomings, the Kostanecki-Robinson reaction remains an effective method for formation of both coumarins and chromones. 

Spectral data for substituted coumarins and chromones are widely spread in the literature, and references should be sought from the review literature. 

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. 

Ammonia and amines do not convert coumarins into 2-quinolones, nor chromones into 4-quinolones, but isocoumarins do produce isoquinolones. Ring-opened products from chromones and secondary amines can be obtained where the nucleophile has attacked at C-2. 

Synthesis of chromones or coumarins from o-acyloxy aromatic ketones (see 1st edition). 

The Simonis chromone synthesis is the reaction of a phenol la-c with a P-keto ester 2 using an appropriate acid promoter to generate a chromone or benzo-y-pyrone 3 (also called a benzo-l,4-pyrone). While compound 3 is actually a chromenone, for this article, whether the double bond is present or not, the system will be characterized as a chromone. The condensation is related to the Pechmann-Duisberg reaction, which yields coumarins from the condensation of a phenol with a P-keto ester and like its relative, the reaction conditions require the loss of water from the ketone moiety and alcohol from the ester moiety. 

Coumarins and chromones containing pyridine substituents were synthesized from pyridine side-chain acids by employing the Knoevenagel, Pechmann, and Simonis reactions. The chromones XI-106 were obtained from a Simonis condensation of ethyl nicotinoylacetate (XI-105) with a variety of phenols (XI-104), whereas a Pechmann condensation yielded the coumarins (XI-107). 

Coumarins and Chromones from Lomatium macrocarpum. Phytochemistry 12, 2283 (1973). 

Sen and Kakaji synthesized a series of 4-butyrylnaphthocoumarins 48 from l-butyryl-2-naphthols 49 using acetic anhydride and two homolog anhydrides in excellent yields. They also showed that l-propionyl-2-naphthols and l-acetyl-2-naphthols could be converted to their corresponding coumarins using the same three anhydrides. However, l-acetyl-2-naphthol in the presence of acetic anhydride and sodium acetate gave a chromone not a coumarin. 

R] (a) Hauser, C. R. Swamer, F. W. Adams, J. T. Org. React. 1954, 8, 59. [R] (b) Ellis, G. P., Chromenes, Chromanones, and Chromones from The Chemistry of Hetereocylic Compounds, Weissberger, A. and Taylor, E. C., eds John Wiley Sons, 1977, vol. 31, New York, p.495. Note The author in the former reference refers to the formation of chromones, coumarins, and flavones as the Kostanecki acylation while the latter author calls the formation of chromones and coumarins the Kostanecki-Robinson reaction. 

Chromones differ marginally in their chemistry from coumarins (ben-zopyran-2-ones) because the carbonyl group is now conjugated with the oxygen atom via the double bond of the heterocycle (see Box 5.2). This conjugation does not involve the benzene ring. 

Carbonyl stretching frequencies for pyran-2-one, pyran-4-one, coumarin, isocoumarin and chromone derived from the bond orders obtained using EHT agree well with the experimental data (78IJC(A)64). 

The vigorous conditions which are necessary serve to detract from the value of the Perkin synthesis, leading to the production of tarry material which adversely affects the yield of coumarin. Difficulties encountered in the synthesis of substituted o-hydroxybenzaldehydes also limit the application of this route. The obvious advantages of the method are that there are no doubts about the orientation of the product and that, unlike the Pechmann reaction, formation of the isomeric chromones is not possible. 

Hydroxyacetophenone reacts with DMF under Vilsmeier conditions to yield chromone-3-carbaldehyde (72LA(765)8). The reaction appears to be generally applicable, various substituents being acceptable in the aromatic ring (74T3553). Furthermore, acetylhydroxy-naphthalenes yield the corresponding benzochromones, and the pyranochromone (452) is formed from the appropriately substituted coumarin. 

Two disadvantages are associated with this synthesis. Yields range from low to moderate and, of more significance, cyclization of the initially formed ester can give rise to chromones or coumarins or to mixtures of the two heterocycles. With the wide range of analytical techniques now available, it is not difficult to distinguish the isomeric benzopyranones. However, some of the structural assignments in early work have been shown to be erroneous and care is therefore advised in the interpretation of results. 

Coumarins and isocoumarins appear to be of varied origins. Simple coumarins, such as umbelliferone, are formed by the shikimic acid pathway in which hydroxylation of p-hydroxycinnamic acid occurs. Other coumarins, for example alternariol (690), are derived from a polyketide unit, as are a number of chromanones, chromones, pyranones and isocoumarins (B-78MI22400). The biosynthesis of 5-hydroxy-2-methylchromone has been shown to involve the chromanone (60JCS654). However, isocoumarins are also derived from the mixed acetate-shikimate route, through initial cyclization of the polyketide and subsequent lactonization. 

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. 

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