Chromones, formation

In a later paper (81TL1749) the same group has shown that the lactone structure is not a prerequisite for chromone formation, since the enol ester (478) yields a chromone on irradiation. ... 

Chromones, formation from pyri-dineacetic acid derivatives, 357, 494-497... 

Kojic acid — see also Pyran-4-one, 5-hydroxy-2-hydroxymethyl-, 3, 611 acylation, 3, 697 application, 3, 880 occurrence, 3, 692 reactions, 3, 714, 715 with amines, 3, 700 with phenylhydrazine, 3, 700 synthesis, 3, 810 Kokusagine occurrence, 4, 989 Kokusaginine occurrence, 4, 989 synthesis, 4, 990 Koopmans theorem, 2, 135 Kostanecki-Robinson reaction chromone and coumarin formation in, 3, 819-821 mechanism, 3, 820 flavones, 3, 819... 

Although the literature refers to the formation of chromones/coumarins as the Kostanecki reaction (and often the Kostanecki-Robinson reaction) and the synthesis of flavones as the Allan-Robinson reaction, others have chosen to merge the two reactions and refer to both transformations as the Kostanecki-Robinson reaction. This section will follow the latter school of thought, and use the Kostanecki-Robinson (K-R) nomenclature. 

Flavone formation is believed to proceed through a similar mechanism as the synthesis of chromones, albeit aromatic acid anhydrides and their corresponding salts are used. The first step is benzoylation of 12 to give the ester 14. Enolization and o-alkylation then affords the enolbenzoate 15. Enolbenzoate 15 then undergoes an acyl transfer to yield... 

Typically, the K-R reaction is run at temperatures that often exceed 160 "C. However, a mild variation has been developed using acetic formic anhydride where the transformation occurs at ambient temperature. Okumara and coworkers smoothly converted hydroxyl ester 25 to chromone 26 in 76% yield with acetic formic anhydride and sodium formate at room temperature.Beckett and Ellis also used these conditions to synthesize two chromones in high yield when 27 and 28 were converted to 29 and 30, respectively. ... 

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. 

In the course of synthesizing DNA-gyrase inhibitors Hogberg, Mitscher, and coworkers determined that an effective means of constructing the core of their inhibitors was via a K-R reaction. Under mild conditions, keto ethylester 52 was acylated using acetic formic anhydride in the presence of sodium formate to deliver chromone 53 in 75% yield. 

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. 

Cyclisation of o-hydroxyphenyl ethynyl ketones under basic conditions is known to produce benzopyran-4-ones and benzofuranones by 6-endo-dig and 5-exo-dig processes, respectively. However, both cyclisations are reversible in aprotic media thereby generating anions, of which that derived from the pyranone is rapidly and irreversibly protonated and hence selective formation of the chromone results <96T9427>. 

Chromones are also Michael acceptors, and Scheme 18 shows how 3-bromochromone reacts with 1,3-diketones in basic media. The reaction is fairly general and the yields can be as high as 90%, moreover, phenolic furans are not common and the approach provides an effective way of protecting the phenolic hydroxy group during furan ring formation.100... 

Chromones react with ethylenediamine to give dihydrodiazepines (71KGS17 82MI1 82M12 85S339 87MI1). This presumably involves the customary attack of an amine at the 2-position of the chromone, which leads to formation of an oxoenamine that can cyclize to give the dihydrodiazepine. 

A similar route to 3-substituted chromones and isoflavone (R = Ph) Scheme 5.10 relies upon a Claisen-Hke condensation between the enolate of a 2-hydroxyphenyl ketone and ethyl formate (methanoate) (Scheme 5.11). 

There are few cases in which free /3-aldehydo esters have been condensed successfully with ureas. Commonly, alkoxymethylene esters are used. The initial reaction leads to an acyclic intermediate that may require a separate treatment to induce ring closure. The reaction of a /3-keto ester with urea may be a two-step process in which case acid catalysis can be used in the formation of an acyclic intermediate, with ring closure effected by strong alkali. When the ester component is a lactone or chromone, the product contains a hydroxyalkyl <2000JME3837> or 2-hydroxyphenyl substituent <2004S942>, as shown by the synthesis of the 5-(2-hydroxyethyl)-4-pyrimidinone 657 and the 6-(2-hydroxyphenyl)-pyrimidine 659. 

The problems of configurational assignment are principally the same for the cases discussed in Sections 4.3.3.2.2. (Formation of Chiral, Racemic Products) and 4.3.3.2.3.1. [Formation of Nonracemic Products with Known Configuration at (at least) One Chiral Unit]. This can be illustrated by the example of the conjugate addition of a methyl group to a chromone (9 on p 411) which has been performed both with racemic and with enantiomerically pure material. Thus the (relative) configuration of the reaction products was determined making use of both the racemic and the nonracemic series (see pp 472 and 480)108. 

The formation of such chromones as 3,8-dihydroxy-2-methyl-chromone by treating uronic acids or pentoses with dilute acid was reported by Aso,119 and studied by Popoff and Theander,120 who obtained a number of these compounds in 3.5% yield, as well as some catechols. Although nothing is yet known about the mechanism of formation of these compounds, the fact that the chromones contain 10 carbon atoms and are produced both from pentoses and uronic acids suggests that they may be derived from 2-furaldehyde or re-ductic acid, or produced from a decarboxylated intermediate. 

While treatment in HBr + AcOH by the Tarbell method424 leads directly from allylphenols 168 to compounds 169, other methods involve the formation of the brominated derivative obtained by adding HBr (in the presence of diphenylamine) to the allylphenol.432 Ring closure is effected by sodium ethoxide. Thus, the ll//-furo[3,2-a]xanthone derivative (177) can be obtained either directly from the allyl derivative (175) or via the bromo derivative (176).432 433 Similarly, 179 has been obtained from the chromone 178.434... 

A mass spectral study of 2-methyl-, 3-methyl- and 2,3-dimethyl-chromone (136), (137) and (138) has been reported (790MS345). In each case the molecular ion appears as the base peak, together with ions which correspond to [M-CO]-, [M-CHO]t, [RDA]t, [RDA + H]+ and [RDA-CO]t. Metastable peaks confirmed that the formation of [M-CHO]- occurs in two steps from [M]t. The reaction pathway for (136) and (138) is given in equation (2). In compound (137), [M-CHO]t is an abundant fragment ion (60%, cf. 35% for 136). That its generation occurs by more than one route is suggested not only by its high abundance, but also by the appearance of appropriate metastable ion peaks two pathways are operative (Scheme 17). 

Breakdown via RDA cleavage with the formation of [RDA] ions constitutes an important pathway for chromones (20) and (136). Interestingly in (137) and (138), the intensities of the [RDA] ion peaks decrease, whilst those of the [RDA+H]+ ion increase. The latter arise by a hydrogen transfer reaction prior to ring cleavage. Relative peak intensities of... 

Carbanions generated in situ by strong bases cleave pyran-2-one rings but acidification may result in the formation of a new ring, as, for example, by reaction of 4-methoxycoumarin with the methanesulfinylmethide ion (272), which results in the formation of a chromone (273) (78S208). 

Chromones are readily oxidized by permanganate or dichromate with opening of the pyran ring and the formation of a salicylic acid (402). Flavones and isoflavones are also degradatively oxidized for example oxidation of munetone (403) with alkaline hydrogen peroxide yields 2-methoxybenzoic acid and 4-hydroxy-2-isopropylbenzofuran-5-carboxylic (isotubaic) acid. 

Chromone-2-carbonyl chloride (496) reacts readily with a Grignard reagent to yield a ketone (497) without the need to add iron (III) chloride or to maintain the temperature at -70 °C (81JCS(P1)2552> as is customary in order to suppress the formation of f-alcohol. 

One of the rare nucleophilic displacements on the chromone ring is the formation of 2-amino-3-chlorochromone (518) or its tautomer by the action of ammonia on the nitrile (517) at low temperature (74JCS(P1)2570). 

When a homoisoflavanone, for example 3-benzylidenechromanone (649), is heated with a base in DMF, two products are obtained. The main reaction is the migration of the exocyclic double bond to form 3-(3 -hydroxy-4 -methoxybenzyl)chromone (650) a skeletal rearrangement through a ring opening reaction accounts for the formation of the other minor product, 3 -hydroxy-4 -methoxy-3-methylflavone (651). Labelling with 14C showed... 

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