Starting from ε-methoxy-resacetophenone and adopting the procedure described in Part 1, 6:7-dihydroxy flavonols with 0,1 and 3 hydroxyls in the side-phenyl nucleus have been prepared. The characteristic properties of the group with reference to the hydroxy-compounds and their partial and complete methyl ethers are described. An alternative method starting with hydroxy-quinol has also been investigated and the simplest member of the group prepared by this method also.

Izalpinin (7-methyl ether of galangin) has been obtained by the demethylation of galangin di- and trimethyl ethers using both aluminium chloride and aluminium bromide. The synthetic sample has all the properties recorded for the naturally occurring substance. The condensation of ω:4:6-trimethoxy-phloroacetophenone with benzoic anhydride and sodium benzoate yields mainly 3:7-dimethyl ether of galangin.

Kanugin C₁₉H₁₆O₇ yields myristicic acid andp-methoxy salicylic acid when decomposed with aqueous alcoholic potash and myristicic acid ω: 4-dimethoxy-2-hydroxy-acetophenone when decomposed with absolute alcoholic potash. Nor-kanugin has been identified as robinetin by a comparison of the flavonols and their derivatives. It is, therefore, concluded that kanugin is 3∶7∶5′-trimethoxy-3′∶4′-methylenedioxy-flavone. The crystalline components of the seeds, flowers and root bark ofPongamia glabra are compared.

The synthesis of 3-methoxy-7-hydroxy-3′∶4′-methylenedioxyflavone, kanugin andiso-kanugin has been effected. Myristicic acid required for the synthesis of kanugin is prepared from oil of nutmeg by a simplified procedure and an improved method for its synthetic preparation worked out. There is marked difference in properties between kanugin andiso-kanugin (3∶5∶7-trimethoxy-3′∶4′-methylene-dioxyflavone).

The colouring matter of the flower petals ofHibiscus vitifolius consists almost entirely of gossypin along with very small amounts of quercetin. These petals form a very good source of this new and interesting glycoside and eventually of gossypetin also.

The analytical data indicate that gossypin is a monoglucoside. As a result of complete methylation and hydrolysis it yields an O-pentamethyl gossypetin. From a study of its decomposition with alcoholic potash whereby veratric acid is obtained and from a comparison of its properties with those of isomeric compounds, it is concluded that it has a free hydroxyl in the 8-position. Consequently gossypin should be 8-monoglucoside of gossypetin. The synthesis of O-pentamethyl gossypetin with a hydroxyl in the 3-position has been described.

The constitution of gossypin as the 8-monoglucoside of gossypetin is confirmed by a detailed study of the pentamethoxy monohydroxy-flavone obtained by the complete methylation and subsequent hydrolysis of the glucoside. It is different from gossypetin-pentamethyl ether containing a free hydroxyl group in the 5-position but both give on oxidation the same quinone which is transformed into a quinol. Further its ethyl ether is shown to have the ethoxyl in the 8-position by unambiguous synthesis.

Nuclear oxidation leading to the preparation of 8-hydroxy-galangin and gossypetin has been carried out. 3∶7-dimethyl-ether of galangin and 3∶7∶ 3′∶4′-tetramethyl-ether of quercetin have been oxidised by means of potassium persulphate to the corresponding 5∶8-dihydroxy-compounds (quinols). Even the 5∶7-dihydroxy-compounds, 3-O-methyl-galangin and 3∶3′∶4′-O-trimethyl-quercetin could be oxidised to the corresponding 5∶7∶8-trihydroxy-derivatives in good yields. Subsequent methylation yields the fully methylated ethers of 8-hydroxy-galangin and gossypetin and demethylation the free hydroxy-flavonols. These experiments not only illustrate facile nuclear oxidation in the flavone series in support of the theory of biogenesis, but also constitute simple and elegant methods for the synthesis of 5∶7∶8-hydroxy-flavonols.

The nuclear oxidation of chrysin and tectochrysin has been successfully effected using potassium persulphate. The first yields norwogonin and the second the 7-methyl-ether now named isowogonin. The method of oxidative demethylation of the 5- and 8-positions has also been employed for the preparation of isowogonin from 5∶7∶8-trimethoxy-flavone.

The difficulty of the demethylation of synthetic primetin dimethyl ether into primetin has been solved by the use of anhydrous aluminium chloride in benzene medium. The possibility of the formation of primetin in the Primula through the intermediate stage of 5-hydroxy-flavone is suggested. This is supported by a new synthesis of primetin in which the nuclear oxidation of 5-hydroxy-flavone is effected by means of persulphate. 5-Hydroxy-flavone required for these experiments has been prepared by independent methods.

The synthesis of herbacetin and hibiscetin from kæmpferol and myricetin is described. As before, the partial methyl ethers of the latter have been subjected to nuclear oxidation with alkaline persulphate. The oxidation proceeds smoothly and gives rise to good yields of the products.

Using the new discovery of facile nuclear oxidation in hydroxy-flavones, (1) wogonin and (2) its 5-methyl ether have been synthesised. Starting with 7-O-benzyl-chrysin, oxidation followed by partial methylation and debenzylation yields (1) and by complete methylation and debenzylation hields (2).

It is shown that 5:6:7:8-hydroxy-flavonols (Calycopterein series) can be made from 5:6:7-hydroxy-flavonols (quercetagetin series) by the nuclear oxidation of the 8-position. Quercetagetin and nor-tangeretin have thus been converted into 6:8-dihydroxy-quercetin and calycopteretin in good yields.

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 6-methyl ether of euxanthone has been oxidised to 6-methoxy-1∶4-dihydroxy-xanthone by means of alkaline persulphate. By demethylation with hydriodic acid 1∶4∶6-trihydroxy-xanthone has been obtained. This compound and its derivatives differ from those obtained by Nierenstein by the oxidation of euxanthone itself with chromic acid and subsequent reduction.

Gossypin has been ethylated and hydrolysed. The resulting pentaethyl ether of gossypetin is further methylated and the product converted into tetra-ethyl tambuletin by alkali fission and condensation of the ketonic product with the anhydride and sodium salt ofp-ethoxy benzoic acid. This confirms the relationship between gossypin and tambuletin.

Using typical examples, some of which are new, oxidative demethylation of methoxy benzenes, ketones, chalkones and flavones with nitric acid is discussed. The flavones without exception undergo simple conversion into para quinones. The others fall into two categories: (a) 1∶2∶4∶5-Tetramethoxy benzene and its derivatives suffer only oxidative demethylation like the flavones to yield the corresponding para quinones: (b) 1∶2∶3∶5-Tetramethoxy benzene and its derivatives, either ketones or chalkones, on the other hand undergo further change involving demethylation of another methoxyl group yielding hydroxy quinones. In the case of ketones and chalkones this second stage demethylation involves the methoxyl which is situated ortho to the ketonic carbonyl and which is subjected to the combined influence of this carbonyl and the one in the quinone group. These results are of importance in the study of pedicellin-pedicinin conversion.

Under favourable conditions hydroxy quinones can be methylated by means of dimethyl sulphate and potassium carbonate to the corresponding methyl ethers,e.g. lawsone. In some cases fully methylated ethers of the corresponding quinols could be obtainede.g. gossypetone. This is obviously due to the preliminary dismutation of the quinone into the corresponding quinol and complex products. The action of alkali on benzoquinone and tetramethyl gossypetone has been studied using different conditions.

Pedicin is considered to be apara-dihydroxy chalkone and this constitution is confirmed by its synthesis from 2-hydroxy-3: 4: 6-trimethoxy chalkone using the method of nuclear oxidation with persulphate. The synthetic pedicin could be readily converted into pedicellin and pedicinin. Under the ordinary conditions of chalkone-flavanone conversion it yields isopedicin which is therefore given the constitution of 6-hydroxy-5: 7: 8-trimethoxy flavanone. The constitutions of pedicinin and methyl pedicinin are discussed on the basis of the analogies presented in an earlier paper on oxidative demethylation using nitric acid and fresh data derived from the conversion of 2: 5-dihydroxy-3: 4: 6-trimethoxy acetophenone and pentamethoxy acetophenone into hydroxy-quinone-ketone analogous to pedicinin. It is concluded that pedicinin and methyl pedicinin have the hydroxy-quinone-chalkone structure. Methyl pedicinin which is an intermediate stage in the formation of pedicinin is now found to occur in the leaves ofD. pedicellata. A scheme of biogenesis of pedicin and its allies is given. The most conclusive evidence for this scheme as well as for the mechanism of the pedicin-pedicinin change and incidentally for the pedicellin-pedicinin change also, is the gentle oxidation of pedicin to the trimethoxy-quino-chalkone and further stepwise hydrolysis to methyl pedicinin and pedicinin. Using diazomethane for partial methylation it is possible to methylate pedicinin to methyl pedicinin.

Resokæmpferol, its tri-acetate and tri-methyl ether are prepared and described.

An essential point which has not been established in a simple manner by the previous study of pedicinin and its synthesis relates to the position of the methoxyl group. This has now been settled in an unambiguous manner by the reduction of pedicinin with stannous chloride to dihydropedicinin and its ethylation. The product is found to be identical with 4-methoxy-2∶3∶5∶6-tetraethoxy chalkone obtained synthetically starting from 2∶6 dimethoxy quinol. This chalkone undergoes oxidative de-ethylation with nitric acid yielding ethyl pedicinin and eventually pedicinin.

The toxic properties of dimethyl pedicinin (2∶4∶5-trimethoxy-quino chalkone) have been studied using fish.

Though despedicellin and dihydropedicinin are prepared from chalkones and were earlier given the chalkone constitution, their properties indicate that they are flavanones. This constitution is also in accordance with the recent discovery of the new effect of hydrogen bonds on the stability of flavanones. It is confirmed by the following experiments. (1) The two compounds undergo partial methylation with diazomethane yielding 5-hydroxy-6: 7∶8-trimethoxy-flavanone which forms with nitric acid 6∶7-dimethoxy-quinoflavanone identical with the sample obtained from 5∶6∶7∶8-tetramethoxy flavanone. (2) Dihydropedicinin undergoes oxidation withp-benzoquinone to form allopedicinin which is different from pedicinin. Methylation of this with diazomethane yields 6∶7-dimethoxyquinoflavanone. (3) The estimation of active hydrogen atoms agrees with the flavanone and not chalkone structure for these two compounds. That isopedicin is also a flavanone is confirmed by its methylation with diazomethane to 5∶6∶7∶8-tetramethoxy flavanone. The constitution of the important reference compound, tetramethoxy flavanone is established by its conversion into the corresponding flavonol.

The most important example of ortho-oxidation from the point of view of the biogenesis of the anthoxanthins is the conversion of quercetin into myricetin.O-3∶5∶7∶3′-Tetramethyl quercetin has now been oxidised toO-tetramethyl-myricetin by the two stage process already explored in Part XV. The intermediate O-tetramethyl quercetin aldehyde and the final myricetin tetramethyl ether are obtained in satisfactory yields. From the latter 5-methoxykanugin, hexamethyl myricetin and myricetin have been obtained. These experiments could be taken as support for the multi-stage mechanism of ortho-oxidation. The appropriateness of the reagents from the point of view of biogenesis is discussed.

The following three partial methyl ethers of flavonols which are derivatives of naturally occurring monoglucosides having only one free hydroxyl group have been conveniently synthesised by using the method of partial benzylation: (1) 3 ∶ 5 ∶ 4′-O-trimethyl-kæmpferol derived from populnin and related glycosides, (2) 3 ∶ 5 ∶ 3′ ∶ 4′-O-tetramethyl quercetin derived from quercimeritrin and (3) 3 ∶ 5 ∶ 7 ∶ 3′ ∶ 4′-O-pentamethyl gossypetin derived from gossypin.

Apigenin does not undergo persulphate oxidation satisfactorily. But acacetin, its monomethyl ether and analogous higher members do so. By the methylation of the products (quinols) the fully methylated ethers of isoscutellarein, 8-hydroxyluteolin and 8-hydroxytricetin could be readily obtained. Demethylation of the quinols or their methyl ethers with aluminium chloride is not successful. Boiling with hydriodic acid produces isomeric change yielding conveniently scutellarein and the higher members. 6-Hydroxy-tricetin and its derivatives are newly described.

A characteristic blue or green colour reaction with concentrated nitric acid is given by the fully alkylated ethers of resorcinol and phloroglucinol and by a number of carbonyl derivatives of them. n the case of these carbonyl compounds one orthohydroxyl could be free. Certain flavanone derivatives of phloroglucinol also give this test whereas chalkones, flavones, diketons and coumaranones do not. It is useful for the differentiation and characterisation of closely related and isomeric compounds belonging to the above categories.

Employing the two stage process of ortho-oxidation eugenol is converted into 5-hydroxy eugenol. Methylation of this yield elemicin and methylenation myristicin. This constitutes the most convenient synthesis of these naturally occurring compounds and is highly significant from the point of view of biogenesis.

In the presence of potassium carbonate or potash, acetone forms an addition product with 2∶6-dimethoxy quinone. Its properties and reactions are described. They give evidence for the presence of an aliphatic hydroxyl group and a ketone carbonyl. The combination is considered to involve addition of the acetone molecule at the C=O group in the 4-position of the quinone. Methyl ethyl ketone also forms a similar addition compound. Other simplep-benzoquinones do not give this type of compounds.