A Study of 2' : 5'-Hydroxy-Flavonols. (From the Department ( f Chemi.s'try, Delhi University, Delhi) (Received September 22, 1952)

Transcription

1 NUCLEAR AND OXDATON N FLAVONES RELATED MPOUNDS Part XL. A Study f 2' : 5'-Hydrxy-Flavnls BY J. M. SEHGAL AND T. R. SESHADR, F.A.Sc. (Frm the Department ( f Chemi.s'try, Delhi University, Delhi) (Received September 22, 1952) N Part XXXV: the first example invlving para-nuclear xidatin in the side phenyl nucleus f the flavne structure was described. 3'-Hydrxy3 : 5 : 7 : 4' : 5'-pentamethxy flavne ([) btained frm the glucside cammbiscitrin was xidised with persulphate t the Y:6'-dihydrxy cmpund () and by subsequent demethylatin the crrespnding heptahydrxy flavne was secured (H). t was nticed that in regard t the alkali clur reactins the intrductin f the para-dihydrxy gruping did nt prduce any marked difference as in similar cases invlving the cndensed benzene ring. n rder t get mre infrmatin n the influence f the dihydrxyl grups in the side phenyl nucleus simpler examples have nw been prepared. These are 3: 7: 2': 5'-tetra-hydrxy flavne (Via) and 3 : 5: 7: 2' : 5'-penta-hydrxy flavne (V b). They have been btained by flavne synthesis in which a,-methxy resacetphenne (V a) and Jmethxy-phlracetphenne (V b) are cndensed with the anhydride and the sdium salt f gentisic acid dimethyl ether. OH ' - t i J 1cH", \ / \ / - Hs : tc~: \/\/ H3 (:) U ~ c - OH OH ~\ c - O C H - OH OCH 3 ---> (:) /- J t.,.,. \/\/ c HO (n:) 355

2 356 J. M. SEHGAL AND T. R. SESHADR H0--1/~--0H k/--ch,och ~ -.-+ i R (iv) li;j\ Oft H-/\/\--/~\,z " / N / x / -.-/\/\--/~\ ~ OCH O[CH R 0 t J ] \ / R c (vn) The resrcinl derivative (V a) has als been independently prepared using the methd f nuclear xidatin. The stages are as fllws.: J-Methxy resacetphenne (V a) is cndensed with the anhydride f 2-benzylxy benzic acid and its sdium salt. The resulting 7-hydrxy-3-, methxy-2'-benzylxy flavne (V) is methylated and subsequently deb~rlzylated using acetic acid and hydrchlric acid. 3:7-Dimethxy-2'- hydrxy flavne (X) btained thereby underges para-nuclear xidatin with ptassium persulphate yielding the quinl (X) which, n methylatin, yields 2: 7" 2': 5'-tetramethxy flavne identical with the sample btained by the direct flavne synthesis. A study f the clur reactins f the new cmpunds is f interest. Cmpund (X) is the first example btained s far having a free hydrxyl grup nly in the T-psitin. t des nt give the ferric chlride clur thus ruling ut the existence f chelatin between the hydrxyl and the pyrne xygen. A lne hydrxyl in the 8-psi,tin gives a prminent c/ur with alchlic ferric chlride. 2 That given by a 5-hydrxyl which is che~d with the grup is well knwn. Even the quinl (X) is very unimpressive in its clur reactins as cmpared with primetin 3 (X- a)r 3-methxy tarimetin 4 (X b). t::gives n clur with ferric chlride and wi~h

3 Nuclear Oxidatin in Flavnes and Related C;npunds--XL 357 alkali nly a fight yellw. ts xidatin with p-benzquinne t give a red clured prduct is very slw. The tetra-and penta-hydrxy flavnes (V a, V b) d nt give prminent clurs in alkaline slutin as is cmmn with flavnls having the quinl unit in the cndensed benzene ring (e.g., 3-hydrxy primetin),4 but they give red clur with excess f ferric chlride and benzquinne. t is remarkable that these cmpunds and their derivatives d nt give any detectable flurescence. The 2': 5' cmbinatin f hydrxyl and methxyl grups seems t inhibit flurescence emissin. OCTH~ H _" /\ /\ \ / \ - /" ~ \ " 11 \ \/\/_~., OH. t / \ / N _ / N - 1t " \/\/-~.. (x). -+ /\/\-/~\ HO \/\/-, \ {0 / (X) O i - \/,v~-o~.. 1 \ /\ / 0~ _ / - - \ ii \ ix / x /t - ~ ~ *_ -~. ~ 1 (V) /- OC~H=.-+ ~v,,) (x) / 2: 5-Dimethxy benzic acid (X) (tl) R = H (b) R=OCH:: EXPERMENTAL 2: 5-Dihydrxy benzic acid required fr this purpse was prepared in abut 4 0 ~ yield by the nuclear xidatin f salicylic acid with ptassium persulphate in alkaline medium. f sdium persulphate is used in excess and the vlume f the slutin kept dwn as lw as pssible the yield f gentisic acid can be raised cnsiderably (60 ~). t crystallised frm water as clurle~ needles melting at t gives a deep blue clur with alchlic ferric chlride. ts me~hylatin t dimethyl ether was carried ut earlier by Mauthner? The fllwing methd is mre cnvenient and p v ~ a gd yield f a pure prduct.

4 358 J.M. SEHGAL AND T. R. SESHADR Gentisic acid (5 g.) was refluxed in dry acetne (250 c.c.) slutin with ignited ptassium carbnate (25 g.) and freshly distilled dimethyl sulphate (17 c.c.) fr a perid f 50 hurs. The acetne slutin was filtered and the ptassium salts washed with a small quantity f ht acetne. On distilling ff the slvent frm the filtrate a brwnish yellw viscus il was left which was taken in ether and washed twice with 2~/ cld aqueus sdium hydrxide t free it frm any mnmethyl ether. The ily mass btained after the evapratin f ether was hydrlysed by refluxing it with 10~ aqueus sdium hydrxide fr 2 hurs. The brwnish red slutin was filtered and acidified when the dimethyl ether f gentisic acid separated ut as a pale brwn slid. t crystallized frm ht water as clurless needles melting at 76 ; yield 5-1 g. t did nt give any clur with alchlic ferric chlride. Anhydride f 2 : 5-Dimetkxy benzic acid Dry 2 : 5-Dimethxy benzic acid (20 g.) was taken in anhydrus ether (75 c.c.) in a 500 ml. cnical flask and dry pyridine (8-6 c.c.) added t it. The cntents were cled t 0 C. and a slutin f thinyl chlride (4 g.) in dry ether was slwly added in small lts with frequent shaking during-the curse f 30 minutes maintaining the temperature belw zer during the additin. The flask was left in the refrigeratr vernight, the slid mass filtered and triturated successively with ice-cld dilute hydrchlric acid, icecld 5~ sdium bicarbnate slutin and cld water. t was finally washed thrughly with water t remve traces f sdium bicarbnate. The slid anhydride was dried by pressing between flds f filter-paper and keeping in a vacuum desiccatr fr a few days. The dry anhydride was crystallized frm dry ethyl acetate and petrleum ether mixture when it appeared as clurless needles and rectangular prisms melting at 97-8 (Fund: C, 62-9; H, 5-4. C1~H1807 requires C, 62-4; H, 5-2~). 7-Hydrxy-3 : 2' : 5'-trimethxy flavne (V a) ~-Methxy resacetphenne (2 g.) was intimately mixed with gentisic anhydride (16 g.) and sdium gentisate (4 g.) and heated in an il-bath at fr 4 hurs under reduced pressure. The dark viscus mass thus btained was left vernight and refluxed fr 30 minutes with 7~ alchlic ptash (5-3 g. in 80 c.c.). Mst f the alchl was remved by heating ver a steam-bath under vacuum, the residue disslved in water and the dark brwn slutin was filtered and saturated with carbn dixide. t was extracted with ether, the ether extract dried ver anhydrus sdium sulphate and the slvent distilled ff. The reddish yellw mass thus btained was crystallized frm ethyl acetate-petrleum ether mixture. The cmpund came ut in the frm f pale yellw wedge-shaped crystals melting

5 Nuclear Oxidatin in Flavnes and Related Cmpunds--](L 359 at ; yield 1-8 g. (Fund : C, 66-1, H, 5-1. C18H160~ requires C, 65.9; H, 4-9~). t did nt develp any clur with alchlic ferric chlride, gave a pale yellw slutin with 5~ sdium hydrxide and n reductin with magnesium and hydrchlric acid develped a red clur. With cncentrated sulphuric acid it shwed n flurescence. 3: 7: 2': 5'-Tetramethxv.flavne (Vll a) The abve 7-hydrxy cmpund (0-5 g.) was disslved in anhydrus acetne (75 c.c.) and biled with dimethyl sulphate (0-6 c.e.) and anhydrus ptassium carbnate (6 g.) fr 8 hurs. The tetramethxy flavne initially came ut as a viscus il which gradually slidified n cling and scratching with a glass rd. t crystallized frm ethyl acetate and petrleum ether mixture as clurless flat needles and rectangular rds melting at ; yield, 0-41 g. (Fund: C, 66-9; H, 5-3. C19H1806 requires C, 66.7; H, 5.3~). t was insluble in cld dilute sdium hydrxide, gave n clur with aqueus ferric chlride and n reductin with magnesium and hydrchlric acid develped a deep red clur. With cncentrated sulphuric acid it exhibited n flurescence. 3: 7: 2': 5'-Tetrahydrxy flavne (Via) 7-Hydrxy-3: 2': 5'-trimethxy flavne (1 g.) was disslved in acetic anhydride (20 c.c.) and t the slutin was added hydridic acid (10 c.c. ; d, 1.7) cautiusly with cling. The slutin was refluxed fr 2 hurs at 140, diluted with sulphur dixide water (100 c.c.) and left in the refrigeratr vernight. The precipitated hydrxy-flavne was filtered ff, washed thrughly with sulphur dixide water and finally with water. t was first crystallized frm dilute alchl and then frm ethyl acetate-petrleum ether mixture when it came ut as yellw tiny prismsmeltingat ; yield 0.4 g. (Fund: C, 62-6; H, 3-9. Ci~-tl00~ requires C, 62-9; H, 3-6~). The tetrahydrxy flavne gave an live-green clur with aqueus ferric chlride changing t red with excess f the reagent. With p-benzquinne slutin in alchl it develped a dark red clur and it was sluble in aqueus bicarbnate and carbnate giving yellw slutins. With sdium hydrxide slutin an range-yellw clur was given and with cncentrated sulphuric acid it exhibited n flurescence. 5 : 7-Dihydrxy-3 : 2' : 5'-trimethxy flavne (V b) A mixture f J-methxy phlracetphenne (2 g.), 2: 5-dimethxy benzic anhydride (18 g.) and sdium gentisate (4 g.) was maintained at fr 4 hurs under reduced pressure and the prduct wrked up as usual. The flavnl was first crystallized frm alchl and finally frm

6 360 J. M. SEHGAL AND T. R. SESHADR ethyl acetate-petrleum ether mixture when it appeared as yellw sft needles melting at ; yield, 1.9 g. (Fund : C, 62.9 ; H, 5-1. C18H1,O7 requires C, 62-8; H, 4.7~). t gave a red clur with magnesium and hydrchlric acid and a brwnish red clur with aqueus ferric chlride and did nt emit any flurescence with cncentrated sulphuric acid. 3: 5: 7: 2': 5'-pentamethxy flavne (Vllc) The abve trimethyl ether (0-5 g.) was methylated using anhydrus acetne (75 c.c.), dimethyl sulphate (1-5 c.c.) and ptassium carbnate (5 g.) and refluxing n a water-bath fr a perid f 40 hurs. The pentamethxy flavne crystallized frm acetne as clurless aggregates f rectangular plates melting at ; yield, 0-47 g. (Fund: C, 64-1; H, 5-5. C20H~007 requires C, 64-5; H, 5-4~). t did nt give any clur with aqueus ferric chlride, was insluble in cld dilute sdium hydrxide and develped a red clur n treatment with magnesium and hydrchlric acid. With cncentrated sulphuric acid it gave n flurescence. 3 : 5 : 7 : 2' : 5'-Pentahydrxy flavne (V b) The trimethxy cmpund (V b) (1 g.) was refluxed with acetic anhydride (20c.c.) and hydridic acid (10c.c., d, 1-7) fr 2 hurs at 140 and the prduct wrked up as usual. The flavne was first crystallized frm dilute alchl and finally frm ethyl acetate-petrleum ether mixture when beautiful yellw tiny prisms were btained decmpsing at ; yield 0-45 g. (Fund: C, 59" 8 ; H, 3-6. ClsHx007 requires C, 59-6 ; H, 3-3~0). t gave an live-green clur with aqueus ferric chlride changing t cherry red n the additin f excess f the reagent. With p-benzquinne slutin in alchl it develped a deep red clur. t was sluble in aqueus sdium bicarbnate, carbnate and sdium hydrxide giving in each case a yellw slutin and did nt give any flurescence with cncentrated sulphuric acid. 2-Benzylxy-benzic anhydride 2-Benzylxy benzic acid required fr this preparatin was made accrding t the prcedure adpted by Chen and Dudley." T a suspensin f the dry acid (22-8 g.) in anhydrus ether (100c.c.) cntaining anhydrus pyridine (4 c.c.) was added thinyl chlride (3-6 c.c.) little by little with shaking at 0 ver a perid f 45 minutes. After the additin f thinyl chlride, the flask was left in the refrigeratr vernight, the semislid mass was taken up in ether and the ether extract was washed respectively with cld dilute hydrchlric acid, cld aqueus sdium bicarbnate and finally with cld water. t was then dried and the slvent distilled ff when the anhydride was left as a dark viscus mass. Further

7 Nuclear Oxidatin in Flavnes and Related Cmpunds--XL 361 drying was dne by leaving it in a vacuum ver sulphuric acid fr tw days; yield 16 g. The crude prduct had a biling range f /10mm. and was directly emplyed fr the cndensatin as such withut purificatin by distillatin. t was mst cnvenient t use it as a slutin in dry chlrfrm and distil ff the slvent befre the cndensatin. 7-Hydrxy-3-methxy-2'-benzylxy flavne (V) An intimate mixture f J-methxy resacetphenne (3 g.) 2-benzylxybenzic anhydride (20 g.) and sdium 2-benzylxy benzate (6 g.) was heated under reduced pressure at fr 4 hurs. The prduct was wrked up as in similar cases. The crude prduct was btained as a viscus il which did nt slidify n keeping in the refrigeratr fr several days. t was then taken up in ether, dried ver magnesium sulphate and the slvent distilled ff. Nw the viscus mass partially slidified n leaving it fr abut ten days in the refrigeratr. The slid was cllected and crystallized frm a mixture f ether and acetne when it appeared as clurless aggregates f beautiful tiny plates and fiat needles melting at ; yield 1-2 g. (Fund: C, 74-0; H, 4.5. C,3H1805 requires C, 73-8; H, 4-8~). The substance gave n clur with aqueus ferric chlride, was sluble in aqueus sdium carbnate and sdium hydrxide and with cncentrated sulphuric acid it gave a lemn yellw slutin withut any flurescence. 3 : 7-Dimethxy-2'-benzylxy flavne (X) The abve cmpund (V) (0-9 g.) was methylated in dry acetne (100c.c.) by refluxing fr 8 hurs with anhydrus ptassium carbnate (5 g.) and dimethyl sulphate (0.4 c.c.). The dimethxy ftavne crystallized frm dry ether in the frm f clurless rectangular prisms melting at ; yield,. 0.8g. (Fund: C, 74-3; H, 5.3. C2~H2005 requires C, 74-2; H, 5"2~). t was insluble in aqueus sdium carbnate and sdium hydrxide and gave n clur with ferric chlride. With cncentrated sulphuric acid it exhibited n flurescence. 3 : 7-Dimethxy-2'-hydrxy flavne (X) 3:7-Dimethxy-2'-benzylxy flavne (0-8 g.) was disslved in glacial acetic acid (18 c.c.) and cncentrated hydrchlric acid (12 c.c.) added. The cntents were heated ver a water-bath fr ninety minutes, diluted with water (150 c.c.) and left in the refrigeratr fr 4 hurs. The slid was cllected, dried and crystallized frm ethyl acetate when it appeared as clurless rectangular plates melting at ; yield, 0.35 g. (Fund: C, 68-6; H, 4-8. C17H1405 requires C, 68-4; H, 4-7%). t was sluble in aqueus sdium carbnate and sdium hydrxide giving in each case lemn yellw slutins and exhibited n flurescence in cncentrated sulphuric acid slutin,

8 362 J. M. SEHGAL AND T. R. SESHADR 3: 7-Dimethxy-2'-5'-dihydrxy flavne (X) T a stirred slutin f the abve flavne (X) (0-3 g.) in aqueus sdium hydrxide (0.35 g. in 10c.c.) was added drpwise a saturated slutin f ptassium persulphate (0-8 g.) in the curse f tw hurs, the temperature being kept between After 24 hurs at rm temperature the brwn aqueus slutin was neutralized with dilute hydrchlric acid t cng red, filtered and ether extracted. The aqueus layer was then acidified by the additin f further quantity f hydrchlric acid (10 c.c.) and the cntents heated n a water-bath fr 30 minutes when a brwn slid slwly separated ut. This was filtered, dried and crystallized frm ethyl acetate when it came ut as pale yellw rectangular rds and prisms melting at 237 ; yield 0-08 g. (Fund: C, 64-5; H, 4-7. C17Hl~On requires C, 65.0; H, 4-5%). t develped n clur with alchlic ferric chlride, was sluble in aqueus sdium carbnate and hydrxide giving lemn yellw slutins and with para-benzquinne slutin in alchl it slwly develped a deep cherry red clur n keeping vernight. t did nt exhibit flurescence in cncentrated sulphuric acid slutin. The dihydrxy cmpund (X) was methylated using excess f dimethyl sulphate and anhydrus ptassium carbnate in acetne medium. The tetramethxy flavne (V a) crystallized frm a mixture f ethyl acetate and petrleum ether as clurless rectangular rds and fiat needles melting at t did nt give any clur with aqueus ferric chlride and was insluble in aqueus alkali. The mixed melting pint with the sample btained frm (V a) was nt depressed. SUMMARY 3 : 7 : 2'- 5'-Tetrahydrxy flavne and 3 : 5 : 7 : 2' : 5'-pentahydrxy flavne and their derivatives are prepared and their clur reactins recrded. The flavne with nly 2'-hydrxyl free (X) and als its 5'-hydrxyl derivative (X) d nt give any clur with ferric chlride indicating absence f chela. tin. Alkali clur reactins cnfirm the riginal finding that a quinl ~uping in the side phenyl nucleus des nt prduce marked clur effects. 1. Balakrishna, et al. 2. Baker Ra and Seshadri 3. Rajagpalan, et al. 4. Seshadri, et al. 5. Mauthner 6. Chen and Dudley REFERENCES.. Prc. nd. Acad. Sci., 1951, 33A, 151,.. J.C.S., 1939, 96t... Prc. lnd. Acad. Sci., 1946, 24A, bid., 1947, 25, bid., 1950, 32, J. Prakt. Chem., 1915, 91, J.C.S., 1910, 97, 1745,