Synthesis of Neoflavonoids: 4-(4’-methoxyphenyl)- 3,4-dihydrocoumarins

Os neoflavonóides 7-hidroxi-5-metil-4-(4’-metoxifenil)-3,4-diidrocumarina (1), 5-hidroxi-7-metil-4-(4’-metoxifenil)-3,4-diidrocumarina (2), 5-metil-7-O-cumaroil-4(4’-metoxifenil)-3,4-diidrocumarina (3), 5-hidroxi-4-(4’-metoxifenil)-α-pirano -(6”,5”:7,8)-3,4diidrocumarina (7) e 7-pentadecil-4-(4’-metoxifenil)-3,4-diidrocumarina (8) foram sintetizados por condensação, catalisada pelo tricloreto de alumínio, en tre o cloreto do ácido 4-metoxicinâmico com orcinol, 5,7-dihidroxicumarina e cardanol hidrogenado. Os produtos das reações foram caracterizados com base nos da dos espectrais de RMN H e C, usando-se principalmente a técnica de espectroscopia nOe diferencial.

Neoflavonoids 1 in clude the im por tant de riv a tives 3,4-dihydro-4-aryl-coumarins.Some of these dis play pharma co log i cal prop er ties, such as those of bactericide 2 , molluscicide 3 , and in sec ti cide 4 .The 4-aryl-3,4-dihydro coumarins have mainly been pre pared by two meth ods: Pechmann con den sa tion of an acetophenone and benzoylacetic acid (ArCOCH 2 COOH) 3,5 , and β-ad di tion of a phe no lic com pound to a cinnamic acid 6 .
The con den sa tion of cinnamic ac ids with phe nols to yield 4-phenyl-and 4-aryl-dihydrocoumarins is well known, and has been re ported by Simpson and Ste phen 6 , who pointed out that good yields are gen er ally ob tained when the re ac tion be tween cinnamic acid and phe nols is car ried out by boil ing with con cen trated hy dro chlo ric acid.Krajnak et al. 7 found that 72% vv sul fu ric acid at 160 °C was very ef fec tive for con dens ing cinnamic acid with p-cresol and p-methoxy-phenol.The con den sa tion of phenols with cinnamic acid in the pres ence of polyphosphoric Ar ti cle acid led to the for ma tion of chalcones and flavanones, and with 4-methoxycinnamic acid the prod ucts were 4-(4-methoxyphenyl)-3,4-dihydrocoumarins and 7-methoxycoumarin which was formed through an intramolecular con ver sion of 4-methoxycinnamic acid 8 .This pa per re ports the syn the sis of new 4-(4-methoxyphenyl)-3,4-dihydro-coumarins via the conden sa tion of 4-methoxycinnamic acid with nat u ral and syn thetic phe nols in the pres ence of alu minium trichloride.

Re sults and Dis cus sion
Some 4-(4-methoxyphenyl)-3,4-dihydrocoumarins were syn the sized by β-ad di tion of dif fer ent phe nols with 4-methoxycinnamic acid un der milder con di tions than those ear lier re ported.Alu minium trichloride was added to the phe nol dis solved in car bon disulfide, fol lowed by the ad di tion of 4-methoxycinnamic acid chlo ride at room temper a ture.4-methoxycinnamic acid was pre pared by the reac tion of anysaldehyde and malonic acid in the pres ence of pyridine 9 .The cor re spond ing 4-methoxycinnamic acid chlo ride was ob tained us ing oxalyl chlo ride dis solved in to -lu ene 10 .The fol low ing phe nols were used: orcinol (4), 5,7-dihydroxycoumarin (5), and hy dro ge nated cardanol (6, 3-pentadecylphenol).
Ethyl propiolate was syn the sized us ing propiolic acid and dry eth a nol in the pres ence of sul fu ric acid 14 .The re ac tion of the coumarin 5 with 4-methoxycinnamic acid chlo ride led to the for ma tion of com pound 7. The com par i son of the NMR spec tral anal y sis of 7 with the cor re spond ing spectro scopic data of its meth yl ated ( 7a ) and acetilated ( 7b ) deriv a tives (Ta ble 2) al lowed the def i ni tion of its chem i cal struc ture as 5-hydroxy-4-(4'-methoxyphenyl)-α-pirano- (6",5":7,8)-3,4-dihydrocoumarin.The pres ence of the hydroxyl group at C-5 of 7 was de duced by downfield shifts ob served for the sig nals of H-6 [ ∆δ H = 6.97 ( 7b ) -Ta ble 1. 1 H (200 MHz) and 13 C (50 MHz) NMR spec tral data for com pounds 1, 2 and 3 [CDCl 3 as sol vent, TMS as in ter nal stan dard, chem i cal shifts in δ (ppm), and cou pling con stants (J) in Hertz]*.Cardanol is a mix ture of 3-pentadecylphenols, dif fer ing in num ber and po si tion of dou ble bonds in the side chain 15 .This mix ture is ob tained from the ca shew nut shell liq uid (CNSL) of Anacardium occidentale .CNSL is a by-product of the ca shew nut pro cess ing in dus tries.A sim i lar con densa tion of hy dro ge nated cardanol ( 6) with 4-methoxycinnamic acid chlo ride af forded 7-pentadecyl-4-(4-methoxyphenyl)-3,4-dihydrocoumarin (8), which was char ac ter ized by the 1 H and 13 C NMR spectra de scribed in Ta ble 3. The com pound 7-hydroxy-5-methyl-4-(4-methoxyphenyl)-3,4-dihydroco umarin ( 1) dis played in vi tro ac tiv ity against Tripanosoma cruzi , and the cor re spond ing cinnamic es ter ( 3) did not show any ac tiv ity against this mi cro or gan ism 16 .

Ex per i men tal
Gen eral ex per i men tal pro ce dures -Melting points were mea sured on a Kofler Hotstage and are un cor rected. 1 Hand 13 C-NMR spec tra were re corded on a Brucker WH-200 Mhz.

Methylation of 7
A so lu tion of CH 2 N 2 in di ethyl ether was added to a solu tion of 7 (4.9 mg, 0.014 mmol) in di ethyl ether, and the mix ture was kept over night.The res i due ob tained was chromatographed on sil ica gel.Upon con cen tra tion, the frac tion eluted with chlo ro form-ethyl ac e tate (95:05), gave a col or less solid ( 7a , 4.9 mg, 95.8 %, m.p.: 228.4-229.6 °C).

8
Hy Ca shew nut shell liq uid was dis tilled un der vacmum after heat ing for 2 h at 130-200 °C (to com plete decarboxilation and de hy dra tion 17 ), giv ing a pale yel low oil that dark ens af ter a few days.This oil was sub mit ted to col umn chro ma tog ra phy.Cardanol was ob tained when the eluent was pure hex ane and cardol.

3-Pentadecylphenol ( 6)
Cardanol (4 g) was dis solved in 10 mL of ab so lute eth anol, and 10% pal la dium on car bon (0.4 g) was added.The mix ture was hy dro ge nated un der pres sure for three days and a solid ma te rial was ob tained (4 g, 98 %, m.p.: 50-53 °C; for NMR spec tral data see Ta ble 3.)

Aknowledgments
The au thors thank UFRRJ for NMR spec tral data, and CNPq, CAPES, and FUNCAP for fi nan cial sup port and fel low ships (CNPq).

1 2 3 O 6 7
r c i n o l 4 5 , 7 -d i h y d r o x y c o u m a r i n 5 H y d r o g e n a t e d c a r d a n o l 13e com par a tive anal y sis of the 1 H and13C NMR of the de riv a tives 7a and 7b in com bi na tion with the homonuclear 1 H{ 1 H}-nOe dif fer ence spec tra per formed with spe cific res o nance of the methoxyl group at C-5 ( δH 3.85) of 7a , which in duced a sig nal en hance ment of H-6 (δ H 6.62, nOe = 11%).