Synthesis of Benzopyran-4-one and Phloroglucinol Monomethyl Ether Derivatives from the Naturally Occurring Compound (Visnagin) A. H. ABDEL-RAHMAN, A. M. KHALIL, S. I. EL-DESOKY, and E. M. KESHK Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, Egypt Received 4 May 1998 The reaction of 6-formyl-7-hydroxy-5-methoxy-2-methylbenzopyran-4-one with dimethyl acetyl- enedicarboxylate and benzil gave the respective 4Я,6Я-ругапо[3,2-р]сЬготепе and imidazolylben- zopyran derivatives. Treatment of the imidazolylbenzopyran with hydrazine hydrate or hydroxyl- ammonium chloride yielded imidazolylpyrazolyl- or imidazolylisoxazolylbenzenes, while the alka­ line hydrolysis of imidazolylbenzopyran afforded imidazolylacetophenone that reacted with some aromatic aldehydes to give the corresponding chalcones. Oxidation of the chalcone with hy­ drogen peroxide led to the formation of 6-hydroxy-4-methoxy-5-[4,5-diphenylimidazol-2-yl]-2-(4- methoxybenzylidene)coumaran-3-one, while the reaction with hydrazine hydrate gave the corre­ sponding imidazolylpyrazolinylbenzene. Also, the imidazolylacetophenone was reacted with phenyl- hydrazine and hydroxylammonium chloride to give the respective hydrazone and oxime products. Fischer indolization of the above hydrazone yielded the corresponding indole derivative. Numerous imidazole derivatives have been pre­ NMR spectrum showed the presence of 10 aromatic pared and investigated for therapeutic and prophy­ protons at 6 = 7.5—8.0 of imidazole moiety, and the lactic application [1—3]. IR spectrum revealed the presence of NH group at v Also benzopyran derivatives possess coronary va­ = 3250 cm"1. sodilating [4], spasmolytic [5], and antiatherogenic and Treatment of IV with hydrazine hydrate or hy­ antiatherosclerotic activity [6]. In the light of this re­ droxylammonium chloride led to the formation of the port, compounds having a combination of benzopy­ only regioisomers: l,3-dihydroxy-5-methoxy-6-[4,5-di- ran and imidazole moieties can be expected to ex­ phenylimidazol-2-yl]-4-[5-methyl-3-pyrazolyl or isox- hibit marked biological activity. Thus this investiga­ azolyl]benzene (V) and (VI), respectively, via the tion deals with the synthesis of such type of com­ opening of the chromone ring followed by reaction pounds. with the above reagents. The naturally occurring furobenzopyran "visna­ The mass spectrum of V revealed molecular ion gin" (/) yields 6-formyl-7-hydroxy-5-methoxy-2-me- peak [M+] at m/z = 439 as* the base peak, which was thylbenzopyran-4-one (II) upon oxidation with potas­ in agreement with its molecular mass, also two daugh­ sium dichromate and sulfuric acid by rupture of furan ter peaks at m/z = 220 and 140 from the rupture of ring [7]. The reaction of Я with dimethyl acetylenedi- the diphenylimidazole and methylpyrazole rings, re­ carboxylate (DMAD) in the presence of anhydrous spectively. potassium carbonate gave 7,8-bis(methoxycarbonyl)- Bromination of IV using an excess of bromine led 6-hydroxy-5-methoxy-2-methyl-4#,6#-pyrano[3,2-#]- to the formation of 8-bromo-5,7-dihydroxy-2-methyl- chromen-4-one (III). The 1H NMR spectrum of com­ 6-[4,5-diphenylimidazol-2-yl]benzopyran-4-one (VII). pound III showed the presence of two singlets for two Demethylation of 5-methoxy group was accomplished methyl ester groups at S = 3.90 and 3.99, the IR spec­ from the effect of the hydrogen bromide formed dur­ trum showed the absence of aldehyde absorption (v — ing the reaction as reported in the case of khellin and 1710 cm-1), also the mass spectrum revealed a molec­ visnagin with several reagents such as dilute hydrogen ular ion [M+] at m/z — 376, which was in agreement halides [8, 9]. with its molecular mass. On the other hand, nitration of compound /Vgave When the aldehyde II was refluxed with benzil in 8-nitrobenzopyranone derivative VIII. IR spectrum -1 the presence of ammonium acetate in glacial acetic revealed the vibrations z>as(N02) = 1350 cm and -1 acid, it gave 7-hydroxy-5-methoxy-2-methyl-6-[4,5- i/s(N02) = 1530 cm . The mass spectrum of VIII diphenylimidazol-2-yl]benzopyran-4-one (IV). The XH revealed molecular ion [M+] at m/z = 470 which cor- Chem. Papers 53 (5) 323—327 (1999) 323 A. H. ABDEL-RAHMAN, A. M. KHALIL, S. I. EL-DESOKY, E. M. KESHK ОСНз СНз СбН4С1-4 ЬсНСбН4ОСНз-4 XVII XVIII Scheme 1 responded with its molecular mass. Alkaline hydrolysis of IV gave a quantitative yield The Vilsmeier—Haack formylation of IV failed to of imidazolylacetophenone derivative XI which was re­ give the corresponding 8-formyl derivative IX but acted with some aromatic aldehydes, namely benz- demethylation of 5-methoxy group occurred afford­ aldehyde, p-anisaldehyde, p-chloro- and p-nitrobenz- ing 5,7-dihydroxy-2-methyl-6-[4,5-diphenylimidazol-2- aldehyde to give the corresponding chalcones Xlla— yl]benzopyran-4-one (X). Xlld. The IR spectra of Xlla—XIId showed a charac- 324 Chem. Papers 53(5)323—327 (1999) DERIVATIVES FROM VISNAGIN teristic a,/3-unsaturated ketone band at v — 1630— C, 4.28 % H. IR spectrum: i>(C=0 chromone)/cm_1: 1640 cm-1, also гЯ NMR spectra of ХПа showed a 1658, i>(C=0 esterj/cm"1: 1723, 1750, 9(011)/cm'1: X doublet signal of —CH=CH—Ar at S = 5.67 (J = 10 3450. H NMR spectrum (CDC13), S: 2.3 (s, 3H, CH3), Hz). 3.8 (s, 3H, OCH3), 3.9 (s, 3H, COOCH3), 3.99 (s, 3H, Oxidation of the chalcone Xllb with hydrogen COOCH3), 5.3 (s, IH, H-4), 6.1 (s, IH, H-7), 6.7 (s, peroxide in sodium hydroxide led to the forma­ IH, OH), 8.1 (s, IH, H-10). EI mass spectrum, m/z tion of 6-hydroxy-4-methoxy-5-[4,5-diphenylimidazol- (Ir/%): 376 (3, [M+]). 2-yl]-2-(4-methoxybenzylidene)coumaran-3-one(XI/7). The assigned structure of XIII was established on the 7-Hydroxy-5-methoxy-2-methyl-6-[4,5-di- basis of the correct analytical and spectral data. Mass phenylimidazol-2-yl]benzopyran-4-one (IV) spectrum showed a molecular ion peak [M+] at m/z = 516 as the base peak which corresponded to its A mixture of aldehyde II (1.0 g; 4 mmol), ben- molecular mass. Also, when the chalcone XIIc was re­ zil (0.9 g; 4 mmol), and ammonium acetate (3 g; acted with hydrazine hydrate, it gave the correspond­ 4 mmol) in glacial acetic acid (20 cm3) was re- ing imidazolylpyrazolinylbenzene derivative XIV. The fluxed for 2 h. The precipitate that formed was fil­ oxime derivative XV which was obtained from con­ tered off and washed several times with hot ace­ densation of compound XI with hydroxylammonium tone to give IV, m.p. = 256—257<C; yield = 70 %. chloride failed to give the isoxazole derivative XVII on For C26H2o04N2 (Mr = 424.45) «4(found): 73.80 % treatment with acetic anhydride/pyridine mixture. On C, 5.00 % H, 6.6 % N; Wi(calc): 73.57 % C, 4.75 the other hand, on boiling phenyl hydrazone deriva­ % H, 6.6 % N. IR spectrum, />(C=N)/cm-1: 1620, tive X VTthat was obtained from condensation of com­ />(C=0 chromone)/cm-1: 1658, //(NH^cm"1: 3250, pound XI with phenyl hydrazine with polyphosphoric i/ÍOHJ/cm-1: 3500. XH NMR spectrum (DMSO-cfe), acid gave according to Fischer indole synthesis the cor­ S: 2.4 (s, 3H, CH3), 3.9 (s, 3H, OCH3), 6.1 (s, IH, H-3), responding indole product XVIII 7.1 (s, IH, H-8), 7.5—8.0 (m, 12H, lOAr—H, OH and NH). EI mass spectrum, m/z (IT/%): 424 (74.4, [M+]). EXPERIMENTAL l,3-Dihydroxy-5-methoxy-6-[4,5-diphenylimid- Melting points were uncorrected. Elemental analy­ azol-2-yl]-4-[5-methylpyrazol-3-yl]benzene (V) sis was carried out in the Microanalytical Unit at the Faculty of Science, Mansoura and Cairo Universities. A mixture of IV (1.0 g; 4 mmol) and hydrazine IR spectra were recorded on Mattson 5000 FTIR spec­ hydrate (0.4 cm3, 8 mmol) in absolute ethanol (30 trometer using KBr wafer technique. 1H NMR spec­ cm3) was refluxed for 8 h. The solid so obtained was tra were determined on Varian-Gemini 200 MHz and filtered off, then washed several times with hot acetone Jeol-Ex-270 MHz NMR spectrometers using TMS as to give compound V, m.p. = 299—300X1; yield = 97 an internal standard with S = 0. Electron impact (EI) %. For C26H22O3N4 (Mr = 438.5) ti*(found): 71.50 % mass spectra were determined on a GC-MS QP-100 C, 5.00 % H, 12.5 % N; u*(cala): 71.22 % C, 5.05 % H, EX spectrometer Shimadzu (Japan). The purity of the 12.78 % N. IR spectrum: i/(C=N)/cm-1: 1630, P(NH, -1 synthesized compounds was tested by TLC. OH)/cm : 3200—3450. EI mass spectrum, m/z (Ir Compound //was prepared adopting the published /%): 439 (100, [M+]). [7] procedure with the same m.p. = 189°C. l,3-Dihydroxy-5-methoxy-6-[4,5-diphenylimid- 7,8-Bis(methoxycarbonyl)-6-hydroxy-5- azol-2-yl]-4-[5-methylisoxazol-3-yl]benzene (VI) methoxy-2-methyl-4ii,6#-pyrano[3,2-0]- chromen-4-one (III) A solution of hydroxylammonium chloride (0.8 g) in water (5 cm3) was added to a solution of IV (1.0 A mixture of aldehyde II (1.0 g; 4 mmol), dimethyl g) in pyridine (10 cm3) and refluxed for 4 h, the mix­ acetylenedicarboxylate (0.6 g; 4 mmol), and anhy­ ture was cooled, then acidified with diluted acetic acid. drous potassium carbonate (0.5 g; 4 mmol) in dry The precipitate that formed was filtered off and crys­ benzene (50 cm3) was refluxed for 6 h.