3- chromone 1,3-diketones

A modification of the K-R reaction was introduced by Mozingo. This method involved reacting an o-hydroxyacetophenone with an ester in the presence of metallic sodium to form a 1,3-diketone. Treatment of the diketone with an acid then delivered the chromone via an intramolecular cyclization reaction. This method was applied to the preparation of 2-ethylchromone (21). 0-hydroxyarylketone 22 was allowed to react with ethyl propionate (23) in the presence of sodium metal.The resulting sodium enolate was then quenched with acetic acid to deliver the 1,3-diketone 24. Upon heating 24 in glacial acetic acid and hydrochloric acid, 2-ethylchromone (21) was delivered in 70-75% overall yield. 

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... 

A carbonyl group can also be effective in the cyclization step following the rearrangement. Thus, para-methoxyphenyl 3-oxobutanoate (244) is rearranged to the p-diketone 245, which is, in turn, cyclized to chromone 246 in high yield (Scheme 64) [184]. 

These 3-diketones are useful intermediates for the synthesis of flavones and chromones f—R = Ph Flavone R = Me Chromone... 

The synthesis of chromones by the Kostanecki-Robinson method frequently yields a 3-acetylchromone. This acetyl group forms a 1,3-diketone with the pyran carbonyl group and is therefore labile in an alkaline medium. Treatment with aqueous carbonate or other base removes such groups but has no effect on other acyl substituents, for example the 6-acetyl of 3,6-diacetyl-2-methylnaphtho[l,2- ]pyran-4-one (516). 

Upon treatment with a base, the activated methyl group in 2-hydroxyacetophenone is converted into a carbanion. Claisen condensation with an ester gives rise to a 1,3-diketone, the sodium salt of which may be isolated although this process is usually unnecessary. Cyclization to the chromone occurs readily in acid solution (Scheme 147). 

Not unexpectedly, a substituent on the acetyl group of the 2-hydroxyacetophenone has an effect on the condensation, though successful preparations of 3-substituted chromones have been achieved. A neat alternative approach to such chromones involves alkylation of the intermediate diketone and subsequent cyclization (34JCS1311). 

When deuterated acetic anhydride and sodium acetate are used to cyclize the 1,3-diketone, the deuterated chromone is formed with >95% incorporation of the isotope (Scheme 158) <75JCS(Pl)1845>. 

The Kostanecki-Robinson reaction proceeds through O-acylation followed by a Baker-Venkataraman rearrangement to the 1,3-diketone. Cyclization then yields the chromone. Early evidence was based on the observation that both of the 1,3-diketones (448) and (449) yielded the same chromone on reaction with the appropriate acid anhydride (33JCS1381). Thus, the reactions were considered to proceed through the common intermediate (450 Scheme 159). 

Salicylic acid derivatives serve a similar purpose to 2-hydroxyacetophenones in a number of chromone syntheses, acting as a precursor of the 1,3-diketone fragment. For instance, a Claisen reaction between methyl 2-methoxybenzoate and acetone takes place in the presence of sodium to give the diketone. Demethylation occurs on reaction with hydriodic acid with concomitant ring closure to the chromone (00CB1998). The corresponding naphthol derivatives are a source of benzochromones (52JOC1419). 

The requisite 1,3-diketones have been prepared by the condensation of acid chlorides with lithium enolates at -70 °C. The technique has proved of value in the synthesis of cycloalkyl fused chromones (456) (78JCS(P1)726). 

However, the 1,3-diketone (470) has been isolated from the high temperature reaction between 3-dimethylaminophenol and ethyl benzoylacetate (64CR(259)1645>. Subsequent cyclization with acid yielded the chromone. It is likely that the hydroxydiphenylketone arises... 

In practice, the Konstanecki-Robinson synthesis of chromones commences with O-benzoylation not C-benzoylation, to afford ester 9.24. Base-catalysed rearrangement produces the required 1,3-diketone 9.21, via intramolecular benzoylation of the intermediate enolate. Acid-catalysed dehydration then affords flavone 9.19. 

There is much interest in anthrapyran antibiotics. Synthesis of S-indomycinone indicates that a revision is required <07CEJ9939>. A total synthesis of racemic y-indomycinone 49 based on a Baker-Venkataraman rearrangement of the anthraquinone ester 47 and cyclisation of the resulting diketone to the chromone 48 has been reported <07EJ01905>. A total synthesis of the structurally simpler topopyrone C involves similar methodology <07TL1049>. In an alternative approach which is readily adaptable to the synthesis of other anthrapyrans, the... 

IS),125 has been obtained by the Baker-Venkataraman rearrangement of the o-acetophenyl ester of selenophene-2-carboxylic acid by the action of alkali in pyridine. This diketone, however, is unstable and turns easily into 2-(selenien-2-yl)chromone (19). 

The base-catalyzed rearrangement of aromatic ort/70-acyloxyketones to the corresponding aromatic (3-diketones is known as the Baker-Venkataraman rearrangement. 3-Diketones are important synthetic intermediates, and they are widely used for the synthesis of chromones, flavones, isoflavones, and coumarins. The most commonly used bases are the following KOH, potassium fert-butoxide in DMSO, Na metal in toluene, sodium or potassium hydride, pyridine, and triphenylmethylsodium. 

The reaction between the acid chloride of chromone-2-carboxylic acid and ethyl ethoxymagnesioacetoacetate probably leads to the expected fi-diketone which enolizes and cyclizes spontaneously to spirofuranone(52).127 A different approach was made by Hungarian workers in their synthesis of tachrosin (53), an unusual kind of flavone isolated from Tephrosia poly-stachyoides and one of the earliest natural furanones to be isolated. They subjected an unsaturated ketone (Scheme 32) to oxidative rearrangement by thallium(III) salts, a reaction well known in chalcone chemistry, and eliminated methanol from the product to obtain the necessary starting material.128... 

Most syntheses of chromones require the prior construction of a l-(orf/to-hydroxyaryl)-l,3-diketone, or equivalent, and it is in the manner by which this intermediate is generated that the methods differ. 

An elegant and flexible strategy for the assembly of a synthon for the ort/to-hydroxyaryl-1,3-diketone required for a chromone synthesis depends on the use of an isoxazole as surrogate for the 1,3-diketone unit (25.7). An isoxazole was produced by the cycloaddition (25.12.1.2) of an aryl nitrile oxide to tri-n-butylstannylacetylene, the product coupled with 2,4,6-trihydroxyiodobenzene and then the N-0 bond hydrogenolytically cleaved. ... 

The initial compound (9) was prepared by stirring 1,3,5 trimethoxybenzene with 1 -methyl-4-piperidone in glacial acetic acid. The tram alcohol (10) was obtained by hydration of the double bond and the corresponding cis compound (11) then made via the ketone by oxidation then reduction. Treatment with acetic anhydride and an acid catalyst such as boron trifluoride etherate gave (12). Treatment of this compound at room temperature with ethyl benzoate in the presence of sodium metal produced the diketone (13) which was cyclised to (14) by the addition of mineral acid. Final demethoxylation of the chromone hydroxy groups with pyridine hydrochloride was carried out for several hours at 180°. 

The chromone system behaves as a Michael acceptor towards nucleophiles. Normally, attack occurs at C-2, but is less likely on C-4, and after addition leads frequently to ring transformations. For instance, the 4//-pyran-4-one ring is opened by aqueous alkali, owing to H2O addition to 1, to form o-hydroxyphenyl-1,3-diketones 2. Subsequent acid cleavage produces either o-hydroxyphenyl ketones and carboxylic acids or salicyclic acid and ketones ... 

The reversible ring-opening of the chromone system giving o-hydroxyphenyl-1,3-diketones 2 (see above) can also occur by acid catalysis. If a fiirther OH function is present in position 5, it also takes part in the recyclization. Chromones and especially flavones with an unsymmetrically substituted benzene ring undergo isomerization by this route when treated with strong acids (Wesseley-Moser rearrangement) e.g. 7 8 ... 

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