Chromones rearrangements

The discovery of the utility of the bis-chromone carboxylic acid derivative cromolyn sodium in the treatment of asthma and related allergies has led to an intensive, and thus far not very fruitful, effort to discover analogues which would show oral activity in contrast to the lead which must be administered by inhalation. Preparation of a typical analogue, proxicromil (63), starts with the O-allylated phenol 57. Claisen rearrangement leads to the corresponding C-allylated product 58. 

Cyclobuta[fc]chroman-4-ols, derived from chromones by a [2+2] photocycloaddition to ethylene, are prone to acid-catalysed rearrangements. Elaboration of the parent system prior to rearrangement has enabled the marine sesquiterpene filiformin <96JOC4391>, the henzo-1,3-dioxan nucleus of averufin <96JOC9164> and cyclobuta[h][l]benzoxepin-8,9-diones <96CC1965> to be synthesised. 

An interesting annelation reaction of allene-derived 13-dipoles with 3-(IV-aryliminomethyl)chromones 38 affords, in fair yields, after [4 +3] cycloaddition and a subsequent cascade of rearrangements, derivatives of the novel iV-aryl-2,3-dihydro-4-ethoxycarbonylchromano[2,3-h]azepin-6-one system 39 (for example, R = Me, R1 = Cl) (Scheme 9). In the initial cycloaddition, the substituted chromone acts as an azadiene moiety <00OL2023>... 

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]. 

The photo-Fries rearrangement of aryl hydrogen (or methyl) succinates 267 leads to 4-(2-hydroxyaryl)-4-oxobutanoic acids (or methyl esters 268), which are readily cyclized to 5-(2-acetoxyaryl)-2(3//)-furanones (269) (Scheme 68). [189-191] Photolysis of 269 [191] or the analogous open-chain enol acetates [192,193] leads to chromones. 

Another problem for the synthetic use of PFR is that the ortho-rearranged products may act as internal light filters, stopping the reaction. In synthetic routes leading to chromanones, chromones, and related compounds, this is of vital importance because the overall yield is limited by the photochemical step. Improved yields can be obtained if the a, 3-unsamrated orr/io-hydroxyphenones resulting from PFR are removed and cyclized to chromanones. This can be acomplished in one pot by irradiation in a two-phase system benzene/10% aqueous NaOH, whereby chromanones are directly obtained from phenyl crotonates in 80-90% yields [210]. 

Novel a,/ -unsaturated amide derivatives at C(4) of chromones 335 were synthe-sized (equation 124). Oximes 332 and 333 rearranged in the presence of PCI5 into the same amides 335 in high yields. Spiroisoxazolines 334, formed from oxime 332 by acid treatment, also produce 335 under Beckmann rearrangement conditions. 

The preparation of chromone-2-carbonyl chlorides from the acid and thionyl chloride often leads to the trichloride (498) as a byproduct (61JGU523) but this is suppressed when a few drops of DMF are added (72JMC865) or phosphorus pentachloride and cyclohexane are used (73BSF2392). When the trichloride is treated with water, an amine or acid, it rearranges to 4-chlorocoumarin (499) (63JGU1806). 

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... 

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). 

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). 

Although there is evidence that chromone syntheses which proceed by the cyclization of phenyl esters under Friedel-Crafts conditions may involve a Fries rearrangement and hence require the formation of one bond adjacent to the heteroatom, syntheses of chromones from phenols will be considered together in this section. The Simonis reaction (530R(7)l)... 

There has been some controversy about the mechanisms of the Simonis and Pechmann reactions, which still remain in doubt. It has been suggested (50BSF1132) that the condensations proceed through a common oxonium ion (467). Dehydration to the phenoxyacrylic ester (468) is followed by cyclization to the chromone whilst a rearrangement to the substituted phenol (469) subsequently affords the coumarin (Scheme 171). 

It is pertinent to note that the ester (472) yields a chromone on treatment with hydrogen fluoride (54LA(587)16), suggesting the intervention of a Fries rearrangement once again. The same applies in the formation of 2-chlorochromone from phenyl 3,3-dichloropropenoate <60CR(250)2819). 

The O-tosyl derivative of 2-acetylbenzofuran oxime is converted into the chromone (480) on reaction with an alcohol (49JA2652). It is accompanied by 2-coumaranone (480a) and what is thought to be an acetal (480b). The chromone was thought to arise through a rearrangement of the o-quinonoid acetal (479 Scheme 173). 

Treatment of the chroman-4-one 1 with benzyl chloride in DMF at 100°C gave the corresponding benzyl ether 2. When the reaction temperature was raised to 153°C, however, the products obtained were the chromone 3 and the flavone 4. It was subsequently shown that the same type of rearrangement could be effected simply by heating 1 with benzyl chloride in DMF containing potassium carbonate. 

Similar studies of the relationship between bond structures and the Claisen rearrangement have been made with allyloxy derivatives of other aromatic compounds, among them anthracene,60 phenanthrene,61 hy-drindene,62 fluorene,68 chromone,64 flavone,64 fluorenone,66 and 2-methylbenzothiazole.660... 

The photo-cycloaddition of ethylene to 3-alkoxy chromones such as 315 has been applied to the synthesis of marine sesquiterpene filiformin and congeners (Scheme 43) <1996JOC4391>. Tandem [2+2] 7i-photo-cycloaddi-tion and y-hydrogen abstraction provided tetracyclic intermediate 316 which was converted to terpene 317 by subsequent oxetane ring reduction and acid-catalyzed rearrangement. 

Dimethylamino)vinyl)chromones 813 undergo a [2+2] cycloaddition reaction with DMAD to form the intermediate 814, which rearrange to afford xanthones in modest yield (Scheme 229) <1997J(P1)2167, 1999J(P1)3005>. ( )-2-(2-(Dimethylamino)vinyl)chromones 813 can also react with iV-phenylmaleimide 815 and chromone-3-carboxylic acid 816 to afford xanthones in modest yield (Scheme 230) <1997J(P1)2167, 1999J(P1)3005>. 

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. 

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