4 NIERENSTEIN THE SYNTHESIS OF HYDROXYQUERCETIN. 1 I. - The Synthesis of Hydwxyquercetin. By MAXIMILIAN NIERENSTEIN. BY the oxidation of quercetin (I) with chromic acid Nierenstein and Wheldale (Ber. 1911 44 3487) obt,ained quercetone (11), which yields hydroxyquercetin (111) on simult'aneous acetylation and reduction and subsequent saponification NIERENSTEfN THE SYNTHESIS O F HYDROXYQUERCETIN. 5 Hydroxyquercetin is isomeric with gossypetin quercetagetin, and myricetin b u t not identical with either of them (compare Nierenstein T. 1915 187 869). The synthesis of hydroxy-qucrcetin which was undertaken with the view of establishing the correctness of the above formula was carried out on the same lines as that of quercetin (Kostanecki Lampe and Tambor Ber., 1904 37 1402) and is based on the following scheme of reactions, which are fully described in the experimental p a r t : Me0 Me0 0 OMe (VI.) (VII.) The demethylation of this pentamethoxy-compound yielded liydroxyquercetin with the properties previously described (Zoc.cit.). E X P E R I M E N T A L . The 1 2 3 5-tetrahydroxybenzens (phentetrol) required for this investigation was prepared according to Oettinger's method (Monatsh. 1895 16 248) who seems to have met with difficulties in preparing it from picric acid on a large scale. These difficulties can apparently be overcome by using the following slight modifi-cation of his method. It' consists in adding hydrochloric acid during the transformation of trihydroxyaniline into tetrahydroxy-benzene and subsequently maintaining the solution strongly acid.This modification rendered possible also the preparation of the following substances : 2 3 4 6-Tetrahydroxybenzoic acid C,H(OH),*CO,H is prepared by the actisn of potassium hydrogen carbonate on tetrahydroxy-benzene a stcream of carbon dioxide being constantly passed through the liquid (compare Clibbens and Nierenstein T. 1915 107 1493). The acid crystallises from water when slightly acidified with dilute sulphuric acid in needles which melt and evolve carbon dioxide a t 308-310°. A t 130-135O the acid loses 1 molecule of water. (Found H,O = 9.42. C7H,0,,H,0 requires H,O = 9.11 per cent.) The acid gives all the colour reactions described by Oettinger for tetrahydroxybenzene and also the violet coloration with concen 6 NIERENSTEIN THE SYNTHESIS OF HYDROXYQUERCETIN.trated nitric acid described by Kostanecki (BeT. 1885 18 3206; compare also Dean and Nierenstein Ber. 1913 46 3871) for pyrogallolcarboxylic acid : 0.1753 gave 0.2907 CO and 0.0572 H20. The tetra-acetyl derivative C7H202(OA~)4 crystallises from 0.1512 gave 0.2782 CO and 0.0652 H,O. C,,H1401 requires C=50*55 ; H =4*49 per cent. The tetrabenzoyl derivative C,H202(OB~)4 which is prepared in the usual way using pyridine as a solvent crystallises from alcohol in long prismatic needles melting a t 248-249O: Cz45.23; H=3*66. C,H606 requires C = 45-17 ; H = 3-28 per cent. alcohol in needles melting a t 274-276O: C=50*17; H=4.83. 0.1508 gave 0.3926 CO and 0.0458 H20. Methyl 2 3 4 6-tetramethoxybenzoate C,H(OMe),*CO,Me is It C=70*99; H=3-40.C35H22010 requires C = 69.77 ; H = 3-66 per cent. obtained by the action of diazomethane in ethereal solution. crystallises from benzene in silky needles melting a t 134-136O : C=56*44; H=6'20. 0.1214 gave 0.2512 CO and 0.0672 H20. 2 3 4 6-Tetramethoxybenzoic acid C,H,O,(OMe), is obtained by hydrolysing the above-mentioned methyl ester. It crystallises from a mixture of alcohol and benzene in needles melting a t Cl2HI6O6 requires C =56*25 ; H = 6.25 per cent. 184-186' : 0.1462 gave 0.2918 CO and 0.0722 H20. CI1Hl4O6 requires C = 54.55 ; H = 5.79 per cent. 2 3 4 6-Tetramethoxybenzoyl chloride C6H(OMe)4*COC1 is prepared by warming 2 grams of the acid with a slight molecular excess of phosphorus pentachloride and removing the phosphoryl chloride formed at 35-400/10-12 mm.The residue is dissolved in light petroleum and filtered when the product separates in hair-like needles which melt a t 104O: C =54.44 ; H= 5.53. 0-2004 gave 0-1114 AgCl. C1= 13.76. C,,H,,O,Cl requires C1= 13.63 per cent. 2 3 4 6 Tetrahydroxyacetophenone C6H(OH),*COMe. Ten grams of 1 2 3 5 tetrahydroxybenzene are dissolved in freshly distilled glacial acetic acid and heated for fifteen t o twenty minutes with granulated zinc chloride which is prepared by pour-ing molten zinc chloride into s-tetrachloroethane. After cooling, the solution is diluted with water and the precipitate crystallised from alcohol. Faintly yellow needles melting a t 204-205O ar NIERENSTEIN THE SYNTHESI3 OF HYDROXYQUERCETIN.7 obtained from alcohol and also from dilute acetic acid. is 84-85 per cent. of the t,heoretical: The yield 0*1568* gave 0.2989 CO and 0.0637 H,O. C8H80 requires C = 52.17 ; H = 4.35 per cent. The phenylhydrazone C,H(OH),*CMe:N2Ph crystallises from s-tet,rachloroethane in deep red prismatic needles melting and decomposing a t 248-251O : C=51.98; H=4*54. 0.1039 gave 9.5 C.C. N (moist) a t 22O and 760 mm. CI4Hl4O4N2 requires N = 10.26 per cent. N=10*35. 2 6-Bih ydroxy-3 4-dimethoxyacetopheno?~e, C,H(OMe),(OH),*COMe. To a boiling alcoholic solution of 10 grams of tetrahydroxyaceto-phenone saturated for some time with hydrogen 15 grams of methyl sulphate and 8.6 grams of sodium hydroxide dissolved in alcohol are slowly added and the mixture is kept boiling for three to four hours hydrogen being passed through all the time.After evaporation of the alcohol steam and hydrogen are passed through, when a small quantity of tetramethoxywetophenone, CGH (0 Me),. co Me, passes 0ver.t (This crystallises from dilute alcohol in colourless, silky needles melting a t 92-93O. It is best obtained by the action of diazomethane on tetrahydroxyacetophenone in ethereal suspension. Found C= 59-63 ; H = 6.94. C12Hl,0 requires C=59.96; H=6*67 per cent.) On acidification with dilute sulphuric acid a precipitate is formed which crystallises from dilute alcohol in colourless silky needles melting a t 166-168O. The yield is 94 per cent. of the theoretical: 0.1798 gave 0.3746 CO and 0.0919 H,O. C=56*73; H=5.72.Cl0H,2O5 requires C = 56.56 ; H = 5-65 per cent. 2-Hydroxy-3 4 ; 6-trimethoxyacetophenone, CGH (OMe)3(0H)*COMe. The reaction is carried out on the same lines as t h a t used by Waliaschko (Ber. 1909 42 727) for the methylation of quercetin. Ten grams of the dry disodium salt of 2 6-dihydroxy-3 4-dimeth-oxyacetophenone are triturated in a mortar with 13.7 grams of methyl sulphate. After some time evolution of heat occurs and * Dried at 150". t Mr. H. F. Dean when working in this laboratory found that a modification on similar lines of Perkin and Weizmmn's method (T. 1906 89, 1649) for the preparation of trimethoxygdlic acid gives better yields than bhose obtained by them the increase amounting to about 16 per cent 8 NIERENSTEIN THE SYNTHESIS OF HYDROXYQUERCETIN.the product is then allowed to remain in a desiccator for two to three days. On acidification 2-hydroxy-3 4 6-trimethoxyaceto-phenone and 6-hydroxy-2 3 4-trimethoxyacet~phenone are obtained which can be separated by fractional crystallisation the former being less readily soluble in alcohol than the latter. 2-Hydroxy-3 4 6-trimethoxyacetophenone crystallises from alcohol in large cubes which melt a t 125-126O. The yield is 95 per cent. of the theoretical : C=58*01; H = 6.95. 0.1826 gave 0.3884 CO and 0.1054 H,O. CtllH140 requires C = 58.41 ; H = 6.19 per cent. The constitution of this compound can be regarded as proved, since it forms on oxidation with chromic acid in acetic acid solu-tion 3 4 6-trimethoxy-2 5-quinoacetophenone, This crystallises from glacial acetic acid in red cubes which melt and decompose a t about 235-238O: 0.1794 gave 0.3627 CO and 0.0654 H20.I n order to convert the quinone into the corresponding C=55*10; H=4-06. C1,H120 requires C = 55.00 ; H = 4.88 per cent. 2 5-dihydroxy-3 4 6-trimethoxyucetophenoneJ C,(OMe),(OH),-COMe, it is heated with zinc dust and acetic anhydride the resulting white precipitate being hydrolysed with dilute sulphuric acid. The product crystallises from alcohol and water in microscopic, faintly yellow plates which melt a t 174-176O : 0.2100 gave 0.4218 CO and 0.1088 H20. 6-Hydroxy-2 3 4-trimet?~oxyacetopheno.lze, C=54*75; H=5-75. C11H1406 requires C= 54.54 ; H = 5-78 per cent. C,H(OMe),(OH)*COMe, crystallises from alcohol in needles melting a t 164-65O.It does not yield a quinone on oxidation with chromic acid: 0.1788 gave 0.3824 CO and 0.1046 H20. C =58*33 ; H = 6-55. CI1Hl4O5 requires C =58*41; H = 6.19 per cent,. 2-Hydroxy-3 4 6-trimethoxypheilzyl 3 4-Dim.ethoxystyry1 Ketone (IV). To 10 grams of 2-hydroxy-3 4 6-trimethoxyacetophenone and 7 grams of veratraldehyde dissolved in 50 C.C. of alcohol are added 20 grams of a 50 per cent. solution of sodium hydroxide in water. Themixture is left for about three to four days during which tim NIERENSTEIN THE SYNTHESIS OF HYDROXYQUERCETIN. 9 i t solidifies. After acidification with dilute hydrochloric acid and drying on a porous plate it crystallises from alcohol in yellow needles which melt a t 143O. The yield corresponds with 84 per cent.of the theoretical : 0.1206 gave 0.2839 CO and 0.0646 H,O. The acetyl derivative crystallises from alcohol in colourless 0.1696 gave 0.3943 CO and 0.1026 H20. C=64*21; H=5*99. C2,HE07 requires C = 64.17 ; H =5*89 per cent. needles melting a t 168-169O : C =63*41; H = 6.77. C,,H,,O requires C = 63.48 ; H = 5-82 per cent. 5 7 8 31 4~-Pentamethoxyflavanone (V). Five grams of the above ketone are dissolved in 750 C.C. of alcohol containing 25 C.C. of concentrated hydrochloric acid and 75 C.C. of water. The solution is heated under reflux for thirty hours and is then left to remain in an open dish for about a week when at first yellow crystals of the unchanged ketone (0.84-1-26 grams) separate. 'The filtrate gives after longer keeping (about three to four days) the flavanone which is nearly colourless.It is purified by dissolving it in a little s-tetrachloroethane from which it separates as a colourless powder. It crystallises from alcohol in long colourless needles which melt a t 186-187O. The yield of the crystallised flavanone is about 64 per cent. of the theoretical : 0.1334 gave 0.3129 CO and 0.0712 H,O. C=63*97; H=5*97. C,,H2207 requires C = 64-17 ; H =5*89 per cent. 3-isoiVitroso-5 7 8 3' 4r-pe?ztamethoxyflavanone (VI). Five grams of the flavanone dissolved in alcohol are boiled with 15 grams of amyl nitrite and 150 C.C. of concentrated hydrochloric acid. The isonitroso-derivative is purified after the evaporation of the alcohol by dissolving in a 10 per cent. solution of sodium hydroxide in water and precipitation with acetic acid.It crystal-lises from alcohol in faintly yellow needles which melt and decorn-pose a t about 218-220°: 0.1829 gave 5.8 C.C. N (moist) a t 22O and 758 mm. N=3*66 CvlHelOsN requires N = 3.47 per cent. 5 7 8 ; 31 4~-Perctamethoxyflavonol (VII). Five grams of the isonit,roso-derivative are dissolved in glacial acetic acid and heated with dilute sulphuric acid under reflux for about five hours when the flavonol separates 011 keeping. It crystallises from alcohol in small needles which melt a t 147-149O, B 10 COPISAROW THE FRIEDEL-CRAFTS’ REACTlON. PART I. as found by Nierenstein and Wheldale (Zoc. cit.) for this product, with t,he exception that it does not sinter a t 136-138O as previously observed. (Found C = 61.92 ; H = 5-14. C,,H,,O, requires C= 61-85 ; H = 5-10 per cent.) Hydroxy quer ce tin (111). The free hydroxyquercetin is obtained on heating the penta-methoxy-derivative for several hours with concentrated hydriodic acid (Zeisel). It crystallises from dilute alcohol in small yellow needles melting a t 354-355O (Nierenstein and Wheldale give 352-355O). The melting point is not depressed when mixed with hydroxyquercetin from quercetone (Nierenstein and Wheldale Zoc. c i t . ) or isoquercetone (Nierenstein T. 1915 107 869). (Found * : C=56.42; H=3*38. C,,H,,08 requires C=56*63; H=3.17 per cent.) It yields on treatment with diazomethane in ethereal suspension the hexamethoxy-derivative previously described by Nierenstein (Zoc. cit. p. 872) which crystallises from alcohol in colourless needles melting a t 142-143O as previously observed. The product was not analysed. BIOCHEMICAL LAB ORATORY, CHEMICAL DEPARTMENT, UNIVERSITY OF BRISTOL. [Received October 18th 1916.