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Several letters to the editor are presented in response to articles in previous issues including an article by Greg May on the mysterious inhabitant of Loch Ness in Scotland, "The Enchanted Isle" by Roger Clarke and "Blast from the Past" by Theo Paijmans.

Epimerization and solvolysis of the benzylic 4-hydroxyl group is shown to be a general property of flavan-3,4-diols, and the diols give 4- ethoxyflavan-3-ols with ethanolic hydrochloric acid (1%). The diols are first converted into epimeric mixtures of 3,4-cis- and 3,4-trans-diols and in aqueous media cis-cis-flavan-3,4-diols yield mainly 2,3-cis-3,4- trans-diols. These 2,3-cis-3,4-diols undergo solvolysis to yield 2,3- cis-3,4-trans-4-ethoxyflavan-3-ols in which the 3,4-trans- stereochemistry is controlled by participation of the neighbouring 3ax- hydroxyl group. 2,3-trans-Flavan-3,4-diols give mixtures of trans- trans-diols and 2,3-trans-3,4-cis-diols and solvolysis first yields 2.3-trans-3,4-cis-4-ethoxyflavan-3-ols and then mixtures of the 3,4- cis- and 3,4-trans-ethers; the final proportion of these two ethers is controlled by thermodynamic factors. Solvolysis under mild conditions gives minor products considered to be 3-oxoflavans (or their enols) because of their immediate conversion into antho-cyanidins by cold acids in the presence of air, and from the formation of an enol-ether on prolonged solvolysis under more vigorous conditions. The relevance of these observations to the mechanism of formation of anthocyanidins from flavan-3,4-diols is discussed. Other by-products of solvolysis reactions include a dimeric cyclic ether (dioxan derivative) of 2,3- trans-3,4-cis-7,8,4?-trimethoxyflavan-3,4-diol. The structure and stereochemistry of solvolysis products were established by N.M.R. data; the 4-ethoxyl group in the ethers generally gave rise to an ABX3 multiplet.

Condensation of 2-acetoxymethylbenzaldehyde with 2-hydroxy-4- methoxyacetophenone gave a low yield of the phthalan named in the title instead of the desired 2-hydroxymethylchalcone. The 1,3- dihydroisobenzofuran, presumably formed by cyclization of the chalcone, showed long-range coupling between the 1- and 3-protons as part of an ABM2X system.

Flav-3-ene epoxides cannot be prepared by the reaction of peracetic acid with a flavene, which leads mainly to the 2,3-trans-3,4-cis-4-acetoxyflavan-3-ols. The epoxides of flav-3-enes lacking electron releasing substituents in ring A may be prepared under weakly basic conditions, and on reduction give 2,3-trans-flavan-3-ols. Flavenes with electron-releasing substituents in conjugated positions in the A ring do not give epoxides under acidic or basic conditions, but the 2,3-trans-flavan-3-ols can be prepared by hydrogenolysis of the products obtained by interaction with peracetic acid. Mechanisms are proposed to account for the products obtained in the peroxidation reactions, and N.M.R. was used to establish the configurations of all the products. Migration of the acetyl group from the 4- to the 3-oxygen atom was observed in two cases, and the resultant 2,3-trans-3,4-cis-3-acetoxyflavan-4-ols showed virtual coupling of the 2- and 4-protons because of the accidental coincidence in chemical shift of the 2- and 3-protons. 2,3-cis-3,4-trans-3-Bromo-4,4'-dimethoxyflavan showed similar virtual coupling owing to near equivalence in the chemical shift of the 3- and the 4-protons.

X-ray crystallographic determination of structure has shown that the even-electron product obtained thermally from 5-(10-phenyl-5,10-dihydro-5-phenazinioyl)-1,3-dimethyl-4-barbiturate (1) (e.g. by heating in benzene) has the structure 1,3-dimethy1-5-(10-pheny1-2,10-dihydrophenazin-2-y1idene)- hexahydropyrimidine-2,4,6-trione (3) instead of the previously supposed dehydro dimer structure (2). Crystals of compound (3) are triclinic, Pī, a 11014(3), b 9343(3), c 10927(3) , α 11047(4), β 6499(4), γ 10147(4), Z = 2. Full-matrix least-squares refinement gave R 009. The rearrangement that occurs in the conversion of the free-radical betaine (1) into the trione (3) is a novel type of N to p-aromatic rearrangement which presumably entails dissociation followed by recombination and oxidation.

3-Oxochroman was prepared by a known route from chrom-3-en-3-carboxylic acid, and 3-ethoxy-carbonyliminochroman and other intermediates were characterized. 3-Formyl-4?-methoxyflav-2-eneand 3-cyano-4?-methoxyflav- 2-ene were prepared in an attempt to obtain 4?-methoxyflav-2-en-3- carboxylic acid for conversion into 4?-methoxy-3-oxoflavan. However, the aldehyde proved resistant to oxidation, and the nitrile resisted hydrolysis, so that this route to 3-oxoflavans appeared unpromising. Reduction of 3-formyl-4?-methoxyflav-2-ene gave the acid-sensitive allylic alcohol, and 3-formyl-4?-methoxyflav-2-ene itself underwent acid-catalysed rearrangement to a mixture of cis- and trans-2-hydroxy- 3-(4-methoxybenzoyl)chroman.

3-Oxoflavan and 4?-methoxy-3-oxoflavan were prepared by Pfitzner- Moffatt oxidation of the corresponding trans-flavan-3-ols, but similar oxidation of 2,3-trans-7,8,3?,4?-tetramethoxyflavan-3-led to an inseparable mixture of 7,8,3?,4?-tetramethoxy-3-oxoflavan and 7,8,3?,4?-tetramethoxy-3-methylthiomethoxyflav-3-ene. Pyrolysis of 2,3- trans-3,4-cis-acetoxy-7,4?-dimethoxyflavan-3-ol led to formation of 7,4?-dimethoxy-3-oxoflavan and 2,3-tuans-3,4-cis-3-acetoxy-7,4?- dimethoxyflavan-4-ol(by migration of the acetyl group). N.m.r. data are recorded for the compounds obtained.

The previously proposed structure (2) for the compound named in the title is confirmed by spectroscopic methods and by synthesis of related compounds. The barbituric acid undergoes a very facile thermal fragmentation in the mass spectrometer into 1,3-dimethyl-5-(4-ethylamino-3-nitrobenzy1)-barbituric acid (3) (which was also prepared by unambiguous synthesis) and 1,3-dimethyl-5-methylenebarbituric acid (4). The electron-impact, chemical-ionization, and negative-ion mass spectrometric behaviour of the barbituric acid (2) was examined.

Treating 2'-(4-methoxybenzyl)-4,4'-dimethoxychalcone epoxide with hydrochloric acid in acetic acid gave trans-3-hydroxy-7,4'-dimethoxyflavanone (18%), the first dihydroflavonol with a 4'-methoxylsubstituent obtained by this route. This observation indicates the possibility that replacing the 2'-(4-methoxybenzyl) protecting group in the chalcone by one with more powerful electron-releasing substituents could lead to an acceptable synthesis of dihydroflavonols.

Preparation of a number of intermediates for the synthesis of ()-mopanol trimethyl ether is described, together with exploratory reactions with model compounds, and especially with 7-methoxyflavanone-2'-carboxylic acid. 7-Methoxyflavan-4-ol, the initial product from reduction of 7-methoxyflavanone-2'-carboxylic acid with complex metal hydrides, was found to undergo facile dehydration to a novel intramolecular dibenzyl ether [the cyclic ether (19)*]. It was noted that the methoxymethyl group, which may be used as a protecting group for phenols, did not survive the conditions of methylation with dimethyl sulphate and potassium carbonate in acetone.

Sodium borohydride reduction of 3-hydroxy-7-benzyloxy-2,3,4'-trimethoxy-flavanone and of 3-hydroxy-2,3,7,4'-tetramethoxyflavanone is shown to yield mainly trans-trans-2-methoxyflavan-3,4-dials, a novel class of flavan derivatives. The 7-benzyloxy hemiacetal also gave a minor quantity of the cis-cis-2-methoxyflavan-3,4-dial and less of the corresponding 2,3-cis-flavan-3,4-trans-dial. Catalytic hydrogenation over palladium, or reduction with complex metal hydrides at room temperature or above, converted the hemiacetals into the flavonols from which they were originally prepared by oxidation with periodic acid in methanol.

2-Amino-N-alkydiphenylamines and 2-aminotriphenylamines react with alloxan at room temperature to give green, intensely coloured, stable, free-radical betaines (dihydrophenazinioylbarbiturates). Heating the free-radical betaines alone or in a solvent gives rise to blue dimers. 3,7-Disubstitution of the phenazinioyl nucleus by methyl groups prevents formation of the blue dimers, which are therefore considered to arise by dimerization at the 3-position, followed by dehydrogenation. Dimerization of 3,7- dimethyldihydrophenazinioylbarbi- turates gives deep green 3,3?-dimers in which the 3,3?-methyl substituents prevent the dehydrogenation step entailed in the formation of the blue dehydro dimers. A violent explosion occurred in two instances during preparation of phenazine by oxidative sublimation of crude dihydrophenazine by Morley's method (J. chem. Soc., 1952, 4008).

Some reduction products (chromens, chroman-4-ols, and flavonols) obtained from isochromeno(4?,3?:2,3)chromone and its 7-methoxy derivative with lithium aluminium hydride, sodium di(2- methoxyethoxy)aluminium hydride, and catalytic hydrogenation are described. Allylic coupling is evident in isochromano(4?,3?:2,3)- chrom-3-ens, and the absence of allylic coupling in 3-alkoxyflav-3-enes is therefore attributed to the latter occurring in the conformation with the 2-aryl group axial (cf.1).

Synthesis of ()-peltogynol trimethyl ether [()-trans-trans-7,6?,7?- tri-methoxyisochromano(4?,3?:2,3)chroman-4-ol and its (&)-cis-cis- stereoisomer are described. (+)-Peltogynol tetramethyl ether is shown to be the trans-trans-4,7,6?,7?-tetramethyl ether, and acid-catalysed etherification of the ()-cis-cis-stereoisomer of peltogynol trimethyl ether with methanol is shown to yield the ()-2,3-cis-3,4-trans- 4,7,6?,7?-tetramethyl ether. Oxidation of cis-cis-2?-hydroxymethyl- 7,4?,5?-trimethoxyflavan-3,4-diol with manganese dioxide gave 3(3?)- hydroxy-7,6?,7?-trimethoxyisochromano(4?,3?:2,3)chroman-4-one (a hemiacetal) and 2?-formyl-7,4?,5?-trimethoxyflavonol. Similar oxidation of trans-trans-2?-hydroxymethyl-7,4?,5?-trimethoxyflavan-3,4-diol gave minor quantities of the hemiacetal and 2?-formyl-7,4?,5?- trimethoxyflavonol, and yielded mainly the 2,3-trans-3-hydroxy- flavanone. N.m.r. data are presented for the compounds described.

(-)-Teracacidin (7,8,4'-trihydroxy-2,3-cis-flavan-3,4-cis-diol) has been isolated from Acacia sparsiflora, and obtained crystalline for the first time. The leucoanthocyanidin was accompanied by melacacidin and 7,8,4'-trihydroxyflavonol.

The dihydroflavonol previously isolated from Acacia excelsa is shown to be ()-7,8,3',4'-tetrahydroxydihydroflavonol. A. salicina wood is found to contain (-)-7,8,3',4'-tetrahydroxyflavanone, 7,8,3',4'-tetrahydroxydihydroflavonol, and 7,8,3',4'-tetrahydroxyflavonol. The wood of A. cambagei contains the same flavonoids, principally the flavonol, and traces of melacacidin.

Condensation of alloxan and o-dimethylaminoaniline gives 1,2,3,4.tetrahydro-4-methylquinoxaline-2-spiro-5-(hexahydro-2,4,6-trioxopyrimidine) (I) formed as a result of a unique ring-closure involving a methyl group of the o-dimethylamino substituent. The structure of the closely related compound previously formulated as its 3-hydroxy derivative (a carbinolamine) (II) is now revised to the corresponding betaine, a dihydroquinoxalinium barbiturate (III; R = H). The 6-methyl, 7-methyl, and 6,7-dimethyl analogues of the spiran (I), like the parent compound, were regarded as anils by Rudy and Cramer. Betaine structures (cf. III) may be assigned to the 6,7-dimethyl and 6,7-dichloro analogue of the barbiturate (III; R = H). o-Diethylaminoaniline reacts differently from o-dimethylaminoaniline with alloxan in giving a benzimidazolium barbiturate (VIII; R = H). We propose a similar benzimidazolium barbiturate structure for the analogous product from 4,5-dimethyl-2-dipropylaminoaniline. Mass spectra of the lowly volatile betaines and some of their deuterated derivatives were obtained and rationalized in terms of the assigned structures. Several dihydrobenzimidazoles have been prepared, and their N.M.R. and light absorption spectra recorded.

Chemical-shift and coupling-constant data for protons in 68 flavan derivatives are reported. Coupling-constant data for interactions involving the 2-, 3-, and 4-protons have been used to define the configuration of the 2-, 3-, and 4-substituents and the conformation of the heterocyclic ring. It is shown that chemical-shift data for protons of the heterocyclic ring and of 3- and 4-acetoxyl groups are of little value in stereochemical studies. Analysis of the absorptions of the aromatic protons shows that N.M.R. is useful for determining the oxygenation pattern in rings A and B.

Rates of oxidation with lead tetra-acetate have been used to establish the geometrical configurations of some flavan-3,4-diols. Mollisacacidin trimethyl ether is thereby shown to be a trans-glycol, and it is confirmed that (-)-teracacidin trimethyl ether and (-)-melacacidin tetramethyl ether are cis-glycols.

Lithium aluminium hydride reduces 2,3-trans-3-bromo-4'-methoxy-6-methyl-flavanone to 2,3-trans-3,4-trans-3-bromo-4'-methoxy-methylflvan-4-ol which is converted by acetic anhydride-potassium acetate into 3,4-trans-diacetoxy-4'-methoxy-6-methyl-2,3-cis-flavan. Similar reactions with the 3',4'-dimethoxy analogue give 3,4-trans-diacetoxy-3',4'-dimethoxy-6-methyl-2,3-cis-flavan. The corresponding cis-bromoflavanones are reduced to 2,3-cis-3,4-cis-3-bromoflavan-4-ols.

Mass spectral data are reported for eight 3-hydroxyflavanones, ten flavan-3-ols, and twelve flavan-3,4-diol derivatives. The principal fragmentation of each of these three classes of compound yields ions derived by retro Diels-Alder fission of the heterocyclic nucleus, accompanied in the case of 3-hydroxyflavanones and flavan-3-ols by hydrogen transfer from the 3-hydroxyl group to the A ring fragment. Deuteration experiments with flavan-3-ols confirmed the origin of the hydrogen atom transferred. Flavan-3,4-diols show two characteristic fragmentation patterns depending on the insertion technique. Mass spectra obtained by indirect insertion of flavan-3,4-diols showed a very marked enhancement of the intensities of the M-18 and M-18-28 peaks, and of their fragmentation ions, compared with spectra obtained by direct insertion.

Oxidation of three 2,3-cia-3,4-cis-3-methoxyflavan-4-ols with active manganese dioxide gave the corresponding 2,3-cis-3-methoxyflavanones which were equilibrated in deuterochloroform containing trifluoroacetic acid to mixtures of cis- (c.33%) and trans-3-methoxyflavanones (c.67%). Tominaga's base-catalysed cyclization of 2'-hydroxy-α-methoxycha1cones to 3-methoxyflavanones has been found to yield the 2,3-trans isomers. The higher stability of the 2,3-trans-configuration of 3-hydroxy- flavanones (dihydroflavonols) compared with 3-methoxyflavanones is attributed to hydrogen bonding; no cis-isomer was detected when acid-catalysed epimerization of a trans-3-hydroxyflavanone was attempted. M.m.r. data are reported for the compounds described.

2'-Hydroxychalcones and α-alkoxy-2'-hydroxychalcones are converted by sodium borohydride in isopropanol into flav-3-enes and 3-alkoxyflav-3-enes in the convenient new synthesis which makes these flavenes readily available. Catalytic reduction of the flavenes gives the corresponding flavans or 3-alkoxyflavans in high yield, and the latter are obtained mainly in the 2,s-cis-form. The flavenes immediately give flavs lium cations in the cold when treated with acids in air, and oxidation of 5,7,3',4'-tetramethoxyflav-3-ene with benzoquinone in an acidic medium gave the flavylium salt, isolated as the ferrichloride. Reduction of 5,7,3',4'-tetramethoxy-flavylium chloride with lithium aluminium hydride gave 5,7,3',4'-tetramethoxy-flav-2-ene identical with the flavene obtained from (-)-epicatechin tetramethyl ether, and confirms an earlier investigation by Gramshaw, Johnson, and King. In its N.M.R. spectrum the heterocyclic-ring protons of this flav-2-ene give an ABX multiplet which is easily distinguished from the ABX multiplet at much lower field characteristic of flav-3-enes.

Flavanone-2'-carboxylic acid, its methyl ester, and 2'-hydroxymethyl- flavanone were obtained from 3-o-hydroxyphenaoylphthalide. Bromination of the flavanones gave the corresponding cis-3-bromoflavanones which easily underwent base-catalysed dehydrobromination, and flavone-2'-carboxylic acid and its methyl ester were prepared in this way. Bromination of o-tolualdehyde gave o-toluoyl bromide in a known but hitherto neglected reaction which appears to offer a useful route to aroyl bromides.

Nuclear magnetic resonance spectra of 80 compounds belonging to several classes of flavan derivative have been analysed, and chemical shifts and coupling constants of heterocyclic ring protons and aromatic protons are tabulated and discussed. Compounds examined include flav-2-enes, flav-3-enes, 3-substituted flavanones and flavans, 2- and 4-substituted isoflavans, 3,4-disubstituted flavans, and flavan-4-ols. The geometrical configurations of substituents in the heterocyclic ring follow unequivocally from the magnitudes of the vicinal coupling constants.

(-)-Angolensin has been converted into (+)-(2S)-1-(2,4-dimethoxyphenyl)-2-(4-methoxyphenyl)propane, an analogue of (+)-(2S)-1-(2,4,6-trimethoxyphenyl)-2-(3,4-dimethoxyphenyl)propane. The stereochemistry of angolensin is thereby correlated with that of catechin and epicatechin. Oxidation of (+)-(2S)-1-(2-hydroxy-4-methoxyphenyl)-2-(4-methoxyphenyl)propane gave (+)-3-(4-methoxyphenyl)- butyric acid, in agreement with the established absolute configuration of (-)-angolensin. The (+)-butyric acid was also prepared by resolution of the synthetic racemate with quinine, and by homologation of (-)-2-(4-methoxyphenyl)propionic acid.

The conversion of (+)-catechin tetramethyl ether into (-)-2-chloro-5,7,3',4'-tetramethoxyisoflavan is shown to proceed by 1,2-migration of the 2-aryl group with inversion of configuration at the 3-position of the flavan nucleus (the migration terminus). The chloroisoflavan was converted into (+)-cis-2-acetoxy-5,7,3',4'-tetramethoxyisoflavan and reduction of this gave (+)-2-(3,4-dimethoxyphenyl)-3-(2,4,6-trimethoxyphenyl)propan-1-ol. This was converted into the corresponding (+)-propane which gave (-)-methylsuccinic acid on ozonolysis. The (+)-propane therefore possesses the (8)-configuration corresponding to the (S)-configuration of the (+)-2,3-diarylpropan-1-ol and the (3s)-configuration of the (+)-cis-2-acetoxy-isoflavan. (+)-cis-2-Ethoxy- and (+)-cis-2-methoxy-5,7,3',4'-tetramethoxyisoflavan have been converted into the related (+)-1-alkoxy-2,3-diarylpropanes. Chlorination of the phloroglucinol nucleus in (+)-catechin tetramethyl ether may occur during reaction with phosphorus pentachloride and is shown to lead to 2,6-dichloro-5,7,3',4'-tetramethoxyisoflavan. Racemic cis- and laevorotatory and racemic trans-2-acetoxy-5,7,3',4'-tetramethoxyisoflavan have been prepared. Nuclear magnetic resonance and optical rotatory dispersion data for a number of isoflavans are reported. The absolute configurations of pterocarpin, homopterocarpin, and pisatin are inferred.