A method of complete synthesis of 5∶6∶7∶8-hydroxy flavonols is described. It starts from ω∶3∶6-trimethoxy-2∶4-dihydroxy-acetophenone which is subjected to partial methylation (of the 4-hydroxyl group) and subsequently to persulphate oxidation. The product, 2∶5-dihydroxy-ω∶3∶4∶6-tetramethoxy-acetophenone is condensed with the anhydride and sodium salt of anisic acid and also of benzoic acid. The resulting 6-hydroxy-flavones yield on further methylation the fully methylated ethers of calycopteretin and 6∶8-dihydroxy-galangin and on demethylation, the free hydroxy-flavonols.

The simpler methoxy flavones and some of the corresponding hydroxy compounds are markedly toxic to fish. This definitely establishes that the pyrone ring containing the atom grouping II is a toxophore.

The simpler coumarins are considerably less toxic as compared with the simpler flavones. This could be attributed to the lack of a side-phenyl nucleus in the former. 3-Phenyl and 4-phenyl umbelliferones and their methyl ethers are found to be highly toxic and compare favourably with 7-hydroxy and 7-methoxy-flavones. A large number of related coumarin derivatives have been studied for their toxicity towards fish.

Nuclear oxidation of baicalein and scutellarein takes place readily in the 8-position, the partial methyl ethers being employed. Further methylation yields fully methylated ethers of the nobiletin series and demethylation the corresponding nor-compounds. For purposes of comparison these substances have also been prepared from 2∶5-dihydroxy-3∶4∶6-trimethoxy acetophenone by the Allan-Robinson method. The characteristic properties and reactions of these compounds are described.

The simpler chromones having no side phenyl ring have poor toxic properties and resemble the simpler coumarins. Hydroxy isoflavones are more toxic than the corresponding flavones and the methoxy derivatives less toxic. In this there is resemblance to the hydroxy- and methoxy-phenyl coumarins. Among allyl-derivatives of chromones, flavones and isoflavones, ethers have high toxicity.

A more detailed study of scandenin is made and its important properties compared with those of lonchocarpic and robustic acids. The three non-rotenoids show marked resemblance. They do not give the Durham test, and are definitely acids owing this property not to carboxyl groups but to specially active hydroxyl groups. They are quite stable to aqueous and alcoholic alkali. The fully methylated ethers have three methoxy groups in all the three cases and these ethers undergo decomposition readily in alcoholic alkali in the presence of zinc, the main products being neutral in nature. The three compounds do not give chemical tests for the presence of carbonyl groups, exhibit definite toxicity to fish and have very similar ultra-violet absorption spectra. The toxicity and the spectra indicate the presence of carbonyl groups in conjugation with ethylenic bonds.

Oxidation with alkaline hydrogen peroxide yieldsp-hydroxy-benzoic acid with all the three compounds. In acetic acid solution scandenin and lonchocarpic acid add on two atoms of bromine; whereas robustic acid takes up 4 bromine atoms.

Nobiletin has been synthesised by adopting the method of nuclear oxidation of the flavone skeleton. For this purpose 6-hydroxyluteolin has been prepared for the first time and subjected to partial methylation, oxidation and final methylation successively whereby nobiletin is obtained. Demethylation of this yields nornobiletin having all the propertics described in the literature. Nobiletin has also been prepared independently from 2: 5-dihydroxy-3: 4: 6-trimethoxy-acetophenone by condensation with sodium veratrate and veratric anhydride and subsequent methylation.

Gossypitrin is fully methylated by means of dimethyl sulphate and potassium carbonate in acetone medium. The pentamethyl gossypetin obtained by hydrolysis has been directly compared with a synthetic sample and mixed melting point taken. Its ethyl ether has also been made.

Phloroacetophenone-2 ∶ 4-dibenzyl ether is prepared; it does not undergo persulphate oxidation satisfactorily. Monobenzylation of phloroacetophenone yields the 4-benzyl ether readily; it is partially methylated to the 2-methyl-4-benzyl ether. Starting with this compound, persulphate oxidation, Allan-Robinson condensation using benzoic anhydride and sodium benzoate and methylation produce 5 ∶ 6-dimethoxy-7-benzyloxyflavone Hydrobromic acid causes besides debenzylation, demethylation in the 5-position. The final product is the 6-methyl ether of baicalein which is identical with oroxylin-A isolated from the root and stem barks ofOroxylum indicum.

The two stage process of ortho-oxidation is applied to partial methyl ethers of gossypetin in order to introduce a new hydroxyl in the 6 position. The pentamethyl ether with a free hydroxyl in the 7- position does not react with hexamine. On the other hand, its isomer with a free 5-hydroxyl yields a mixture of products, one of which is the 6-aldehyde which could be oxidised by means of hydrogen peroxide. A more satisfactory procedure is to use the tetramethyl ether having the 5 and 8 hydroxyls free. It yields only the 6-aldehyde and subsequent oxidation with hydrogen peroxide leads to the formation of 5∶6∶8-trihydroxy compound. The products are useful partial methyl ethers and yield 6∶8-dihydroxy-quercetin on demethylation and its heptamethyl ether on methylation.

A new synthesis of nobilein has been achieved employing the two stage process of ortho-oxidation. 5∶8-Dihydroxy-7∶3′∶4′-trimethoxy flavone (III) is condensed with hexamine to yield the 6-aldehyde (IV) which undergoes smooth oxidation with hydrogen peroxide to 7∶3′∶4′-trimethyl ether (V) of nornobiletin. Final methylation of (V) produces nobiletin (VI).

Kellin (I) has been synthesised starting from 2-methyl-5 ∶ 7-dihydroxychromone (VII). The stages are as follows: (1) treatment with bromacetic ester (VIII); (2) oxidation with alkaline persulphate in which the ester group sets hydrolysed (IX); (3) partial methylation with 2 moles of dimethyl sulphate (X); (4) condensation with hexamine to introduce an aldehyde group in the 6-position (XI); (5) complete methylation (XII); (6) gentle alkali hydrolysis to aldehydo-acid (XIII); and (7) final boiling with acetic anhydride and sodium acetate. Kellin-quinone and nor-kellin have been prepared as convenient derivatives.