CH EM. R ES. CH I ESE U.

2004, 20 ( 5) , 668 670 N

Syn theses of Novel Flavones Con ta in ing Sch iff Ba se M o iety

TAN G L i2jun
1, 2

In troduction

F lavones and their deriva t ives ex ist ing in na tu 2 rae a re comm on ly con ta ined in p lan t s. T he m em 2 bers of the flavone cla ss show a w ide va riety of b io 2 [1 ] log ica l act ivit ies, such a s an t i2inflamm a to ry , an 2 [2 ] [3 ] t im icrob ia l and an t itum o r act ivit ies . Sch iff ba ses have been in ten sively invest iga ted due to their an t ibacteria l act ivity and an t itum o r p rop er2 [ 4, 5 ] ty . T he au tho rs of th is p ap er believe tha t in terest 2 ing resu lt s m ay be ob ta ined by p rep a ring the com 2

Results and D iscuss ion

3 Suppo rted by the N a tiona l N a tu ra l Science Founda tion of Ch ina (N o. 20076006 ) and T ran s2cen tu ry T ra in ing P ro 2 gramm e Founda tion fo r the T a len ts by the N in istry of Educa tion in Ch ina. 3 3 To w hom co rrespondence shou ld be addressed. E 2 a il: zhangshf@ chem. dlu t. edu. cn m

Cu rren t ly there a re a num ber of m ethod s ava ilab le fo r syn thesizing flavones, includ ing A l2

, ZHAN G Shu 2fen 1, 3 3 , GAO W en 2tao 2 and YAN G J in 2zong 1 1. S ta te K ey L abora tory of F ine C hem ica ls, D a lian U n iv ersity of T echnology , D a lian 116012, P. R . C h ina; 2. I nstitu te of S up erf ine C hem ica ls , B oha i U n iv ersity , J inz hou , 121003, P. R . C h ina
R eceived A ug. 26, 2003
Ke yw o rds F lavone, Sch iff ba se, Syn thesis
R eagen ts and cond ition s: ( ) (CH 3CO ) 2O , H 3PO 4 , 90% ; ( ) A lC l3 , n itrobenzene, 60% ; ( ) p 2n itrobenzoyl ch lo ride p yrid ine, 91% ; ( ) KO H p yrid ine, 80% ; ( ) V ( E tO H ) V (H 2SO 4 ) = 9 1, 90% ; ( ) N a 2S 2O 4 , V ( E tO H ) V (H 2O ) = 2 1, 90 % ; ( ) ( sub stitu ted ) benzaldehyde d ry benzene.

A rtic le I 100529040 ( 2004) 2052668203 D

8a. R 1 = R 2 = H; 8b. R 1 = H , R 2 = N (CH 3 ) 2; 8c. R 1 = O CH 3 , R 2 = O H

. Schem e 1 Syn thesis of Sch iff ba se - con ta in ing f lavones

pound s w h ich con ta in bo th flavone and Sch iff ba se m o iet ies. T hu s the p resen t w o rk is a im ed a t the syn theses of a few such novel com pound s. W e re2 po rt herein tha t 42am ino 262 ethylflavone ( 7 ) w a s m syn thesized from p 2creso l v ia six step s, and th ree Sch iff ba se 2con ta in ing flavones w ere p rep a red v ia the conden sa t ion of com pound 7 w ith benza lde2 hyde, p 2 , N 2d im ethylbenza ldehyde and van illin, N resp ect ively. T he p rocedu re adop ted in th is w o rk is show n in Schem e 1.
[6 ] lan 2 Rob in son syn thesis , syn thesis from cha l2 [7 ] cones , and the B aker 2 enka ta ram an m eth 2 V [ 8, 9 ] od s . T he la t ter app roach w a s adop ted in ou r

N o. 5

T he H NM R sp ect ra w ere reco rded on a V a ri2 an I NOVA 400 NM R Sp ect rom eter (V a rian I 2 NO VA L td. Co. , U SA ) w ith TM S a s the in terna l standa rd in CDC l3. T he m a ss sp ect ra w ere deter2 m ined on an H P 1100 system of H PL C M S (H ew let t Packa rd L td. Co. , U SA ) by u sing the a tm o sp heric p ressu re chem ica l ion iza t ion (A PC I)
1

w o rk and show n to be effect ive. 22hyd roxy 252 ethylace2 In th is p rocess, m top henone ( 3 ) w a s p rep a red from p 2creso laceta te ( 2) by m ean s of the F ries rea rrangem en t and con 2 sequen t ly converted in to a benzoyl ester ( 4 ). T h is sp ecies w a s then iso la ted and t rea ted w ith po ta ssi2 um hyd rox ide in p yrid ine to cau se an in t ram o lecu 2 la r C la isen conden sa t ion, fo rm ing 1, 32d iketone ( 5 ). T he acid t rea tm en t of com pound 5 induced a dehyd ra t ive cycliza t ion to fo rm flavone 6, then flavone 6 w a s reduced by sod ium d ith ion ite to g ive desired flavone 7. Com pound s 8a _ 8c exh ib it in their IR sp ect ra the typ ica l band s of O in the C= - 1 1 vicin ity of 1640 cm and in the H NM R sp ect ra the signa ls in the range of 61797 61814 fo r C 3 2 H and 81330 81464 fo r hyd rogen in the N CH g roup.

Exper i en ta l m

techn ique. T he h igh reso lu t ion m a ss sp ect ra w ere reco rded on M a riner System 5303 (A pp lied B io sys2 tem s L td. Co. , U SA ). T he IR sp ect ra w ere m ea 2 su red ( KB r p ellet s ) w ith an FT IR 2430 infra red sp ect rop ho tom eter (JA SCO L td. Co. , J ap an ). T he U V sp ect ra w ere reco rded on a U V 3100 sp ec2 t rop ho tom eter ( Sh im adzu L td. Co. , J ap an ) in m m ethano l ( ax in nm ). T he m elt ing po in t s w ere m ea su red on a M el2T em p cap illa ry m elt ing po in t app a ra tu s (B eijing T ech In st rum en t L td. Co. , Ch i2 na ) and w ere unco rrected. p 2 reso l aceta te ( 2 ) and 22hyd roxy 252 ethy 2 C m lacetop henone ( 3 ) w ere syn thesized acco rd ing to [ 10 ] the litera tu re m ethod . 52 ethyl222( p 2n it robenzoyloxy ) acetop henone M ( 4) w a s p rep a red acco rd ing to W adodka rs [ 11 ] p ro 2 cedu re. [ 12 ] 42 it ro 222hyd roxy 252 e 2 Com pound ( 5 ) N m thyld ibenzoylm ethane w a s syn thesized a s fo llow s. Com pound 4 ( 612 g, 2414 mm o l) w a s d isso lved in d ry p yrid ine ( 50 mL ) , then d ry and cru shed po ta s2 sium hyd ro 2x ide ( 2173 g, 4818 mm o l) w a s added to the so lu t ion. T he m ix tu re w a s st irred under anhy 2 d rou s cond it ion s fo r 3 h a t 45 . T he m ix tu re w a s then pou red on to ice 2 l and the yellow p recip i2 HC

TAN G L i2jun et a l.

69 6

ta te w a s filtered, w a shed w ith w a ter and d ried. T he ob ta ined p roduct is so lub le in d ilu te a lka li and can g ive po sit ive ferric react ion. T he ob ta ined crude p roduct w a s recrysta lized from ethano l to af2 fo rd com pound 5 ( 518 g ) a s a go lden yellow p la te w ith a yield 80% , m. p. 180- 182 . IR ( KB r ) , - 1 1 cm : 1619, 1577. H NM R ( 400 M H z, CDC l3 ) , : 151440 ( s, 1H , O H ) , 111647 ( s, 1H , O H ) , 81433 ( d, 2H , J = 814 H z, A r_ H ) , 81205 ( d, 2H , J = 814 H z, A r _ H ) , 71653 ( s, 1H , A r _ H ) , 71434 ( d, 1H , J = 716 H z, A r_ H ) , 71052 ( d, 1H , 716 H z, 61979[ s, 1H , J= A r_ H ) , CO CH C (O H ) ], 41771 ( a sm a ll sing le p eak, CO CH 2CO ) , 21478 ( s, 3H , CH 3 ) ( T he m o la r ra t io of eno l to ketone fo rm w a s found to be 92 8 ). M S (A PC I, nega t ive m ode ) , m z : 298 ( [M H ] ). 42 it ro 262 ethylflavone ( 6 ) w a s p rep a red a s N m fo llow s. Com pound 5 ( 410 g, 1314 mm o l) w a s p u t in 180 mL of a so lu t ion of ethano l in su lfu ric acid [V ( E tO H ) V (H 2 SO 4 ) = 9 1 ] and hea ted st rong 2 ly under reflux fo r 5 h un t il com pound 6 w a s sep er2 a ted ou t. T he so lu t ion w a s coo led and the filtered p recip ita te w a s w a shed successively w ith w a ter, co ld sod ium hyd rox ide ( 2 m o l L ) and w a ter aga in. T hen it w a s d ried. T he ob ta ined com pound ( 6 ) w a s crysta llized from g lacia l acet ic acid to g ive 314 g of p a le p ink need le 2like crysta ls, m. p. 230- 232 . IR ( KB r ) , cm - 1: 1637, 1521, 1344. U V , 1 ax nm : 276, 308. H NM R ( 400 M H z, CDC l3 ) , m : 81344 ( d, 2H , J = 814 H z, 3, 52H ) , 81105 ( d, 2H , J = 814 H z, 2, 62 ) , 71983 ( s, 1H , 52 ) , H H ( d, 1H , J = 810 H z, 72 ) , 71489 ( d, 1H , 71546 H J = 810 H z, 82 ) , 61862 ( s, 1H , 32 ) , 21475 ( s, H H ). HRM S (A PC I, po sit ive m ode ) , ca lcd. 3H , CH 3 ( % ) fo r C 16H 12NO 4 ( [M + H ] + ) : 28210766, found ( % ) : 28210762. 42 Am ino 262 ethylflavone ( 7) w a s syn thesized m a s fo llow s. Com pound 6 ( 1183 g, 615 mm o l) w a s p u t in 120 mL of a so lu sion of ethano l in w a ter [V ( E tO H ) V (H 2O ) = 2 1 ] and hea ted under re2 flux. Sod ium d ith ion ite ( 114 g, 810 mm o l ) w a s g radua lly added to the fla sk t ill the com pound w a s d isso lved com p letely to g ive a yellow so lu t ion. A n excess of app rox im a te 014 g of sod ium d ith ion ite w a s then added to the so lu t ion and the so lu t ion w a s refluxed fo r ano ther 2 h. T he ethano l w a s d is2 t illed a t a reduced p ressu re and the rem a ined so lu 2 t ion w a s pou red to 80 mL of ho t concen t ra ted HC l and hea ted fu rther un t il the sm ell of SO 2 d isap 2

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CH EM. R ES. CH I ESE U. N

. V o l 20

p ea red. T he so lu t ion w a s filtered ho t and then coo led, then neu t ra lized w ith amm on ia to g ive com pound 7, w h ich w a s crysta llized from xylene to g ive a yellow need le 2like p roduct w ith a yield 90% , m. p. 210 211 . IR ( KB r ) , cm - 1: 3334, 3222, 1631 . U V , ax nm : 235, 319, 369. m 1 H NM R ( 400 M H z, CDC l3 ) , : 71988 ( s, 1H , 52 H ) , 71725 ( d, 2H , J = 814 H z, 2, 62 ) , 71397 H - 71448 (m , 2H , 7, 82H ) , 61738 ( d, 2H , J = 814 H z, 3, 52H ) , 61666 ( s, 1H , 32 ) , 41168 ( s, b r, H 2H , N H 2 ) , 21441 ( s, 3H , CH 3 ) , HRM S (A PC I, po sit ive m ode ) , ca lcd. ( % ) fo r C 16 H 14 NO 2 ( [M + H ] + ) : 25211025, found ( % ) : 25210900. P rep a ra t ion of Com pound 8a ( genera l p roce2 du re ) w a s ca rried ou t a s fo llow s. Com pound 7 ( 110 mm o l ) and benza ldehyde ( 110 mm o l ) w ere d is2 so lved in 40 mL of d ry benzene, the resu lted m ix 2 tu re w a s refluxed fo r 5 h w ith the a id of azeo t rop ic d ist illa t ion to get rid of the w a ter fo rm ed. T hen benzene w a s evapo ra ted a t a reduced p ressu re and the residue ob ta ined w a s recrysta llized from ethano l to affo rd o range p la te ( yield 44% ) , m. p. 181 - 182 . IR ( KB r ) , cm - 1: 1643. U V , 1 ax nm : 276, 355. H NM R ( 400 M H z, CDC l3 ) , m : 81464 ( s, 1H , N CH ) , 81004 ( s, 1H , flavone 52H ) , 71911 - 71950 (m , 4H , A r _ H ) , 71444 71520 (m , 5H , A r _ H ) , 71300 ( d, 2H , J = 818 H z, A r_ H ) , 61797 ( s, 1H , flavone 32 ) , 21452 H ( s, 3H , CH 3 ). HRM S (A PC I, po sit ive m ode ) , + ca lcd. ( % ) fo r C 23H 18NO 2 ( [M + H ] ) : 34011338, found ( % ) : 34011317. Sch iff ba ses 8b and 8c w ere ob ta ined by fo l2 low ing the sim ila r m ethod a s described above. 8b: yield 41% , go lden yellow p la te, m. p. 228- 230 . IR ( KB r ) , cm - 1: 1644. U V , 1 m ax nm : 254, 317, 391. H NM R ( 400 M H z, CD 2 C l3 ) , : 81330 ( s, 1H , N CH ) , 81011 ( s, 1H , flavone 52 ) , 71923 ( d, 2H , J = 814 H z, A r_ H ) , H 71782 ( d, 2H , J = 818 H z, A r_ H ) , 71448 71481

(m , 2H , A r H ) , 71285 ( d, 2H , J = 814 H z, A r 2 H ) , 61797 ( s, 1H , flavone 32 ) , 61731 ( d, 2H , H J = 818 H z, A r H ) , 31063 ( s, 6H , N (CH 3 ) 2 ) , 21461 ( s, 3H , CH 3 ). HRM S ( A PC I, po sit ive + m ode ) , ca lcd. ( % ) fo r C 25H 23N 2O 2 ( [M + H ] ) : 38311760, found ( % ) : 38311775. 8c: yield 47% , yellow so lid, m. p. 151 153 . IR ( KB r ) , 1 -1 cm : 1632. U V , nm : 251, 320, 364. H NM R ( 400 M H z, CDC l3 ) , : 81358 ( s, 1H , N CH ) , 81013 ( s, 1H , flavone 52 ) , 71940 ( d, 2H , H J = 818 H z, A r_ H ) , 71729 ( d, 1H , J = 818 H z, A r _ H ) , 71625 ( s, 1H , A r_ H ) , 71446 - 71518 (m , 2H , A r_ H ) , 71293 ( d, 2H , J = 818 H z, A r _ H ) , 61814 ( s, 1H , flavone 32 ) , 61739 ( d, 1H , H J = 818 H z, A r _ H ) , 61586 ( s, b r, 1H , O H ) , 31987 ( s, 3H , O CH 3 ) , 21461 ( s, 3H , CH 3 ). HRM S (A PC I, po sit ive m ode ) , ca lcd. ( % ) fo r C 24 + H 20 NO 4 ( [M + H ] ) : 38611392, found ( % ) : 38611395.
Re fe re nce s
[ 1 ] W ang Y. , H am bu rger M. L. , Geceho J. , et a l. , P hy to2 chem istry , 1989, 28 , 2323 [ 2 ] B rasseu r T. , J . P ha rm . B elg. , 1989, 44 , 235 [ 3 ] Sun J. R. , B row n J. M. , Cancer R es. , 1989, 49 , 5664 [ 4 ] Pandeya S. N. , Sriram D. , N ath G. , et a l. , E u rop. J . P ha rm . S ci. , 1999, 9 (1) , 25 [ 5 ] Eh renfreund 2K leinm an T. , A zzam T. , Falk R. , et a l. , J . B iom a teria ls. , 2002, 23 (5) , 1327 [ 6 ] A llan J. , Rob in son R. , J . Chem . S oc. , 1924, 2192 [ 7 ] L inum a M. , I ash im a K. , M atsuu ra S. , Chem . P ha rm . w B u ll. , 1984, 32 , 4935 [ 12 ] Hogale M. B. , D ho re N. P. , Sheler A. R. , et a l. , O rien t. J . Chem . , 1986, 21 (1) , 55 [ 8 ] Baker W. , J . Chem . S oc. , 1933, 1381 [ 9 ] M ahal H. S. , V enkataram an K. , J . Chem . S oc. , 1934, 1767 [ 10 ] L i J ing 2fen, L i B in, Sun Zh i2zhong, Chem ica l W orld , 2002, 10 , 537 [ 11 ] W adodkar P. N. , M arathey, M. G. , Ind ian. J . Chem . , 1972, 10 (2) , 145