7903
J. Org. Chem. 1993,68, 7903-7905 Scheme I
A Convenient Large-Scale Synthesis of 5-Methoxyflavone and Its Application to Analog Preparation
0
Jeffrey J. Ares;J. Pamela E. Outt,l. Sunil V. Kakodkar,lb Robert C. Bus,lb and Jeffrey C. Geigerlb Procter & Gamble Pharmaceuticals, Miami Valley Laboratories, P.O. Box 398707, Cincinnati, Ohio 45239-8707, and J. T. Baker, Inc., A Procter & Gamble Company, Research and Development Department, 222 Redschool Lane, Phillipsburg, New Jersey 08865-2219
m- s;$ Acid
Received July 27, 1993
0
0
0
Introduction Flavonoids are a group of naturally occurring, low molecular weight compounds that are widely distributed in the plant kingdom and represent a significant part of the average Western dailydiet.2 Many types of compounds comprise the flavonoids, one of the moat abundant being the flavones. Members of the flavone class have been associated with a wide variety of biological activities3and may be useful in the treatment of certain diseases.' Our interest in the biological properties of the compound bmethoxyflavone (3) prompted us to pursue a synthesis of this material which could be readily executed on a several hundred-gram scale. Currently there are a number of methods available to synthesize flavones: including the Wan-Robinson synthesis! the Baker-Venkataramanmethod? synthesisfrom chalcones?*@ and synthesis via an intramolecular Wittig strategy.l0 At the outset, it appeared the Baker-Venkataraman approach, shown generically in Scheme I, would be the most convenientroute to the synthesis of 3. In this process, a 2-hydroxyacetophenone is first converted into a benzoyl ester. This species is then isolated and treated with base (usually potassium hydroxide or potassium carbonate) to effect an intramolecular Claisen condensation, forming a 1,3-diketone. Acid treatment induces a dehydrative cyclization to the desired flavone. VUnfortunately, we found that the conventional Baker-Venkataraman approachll was not suitable for synthesizing large amounta of 3 since low yields and product isolation (1) (a) Procter and Gamble Pharmaceuticals. (b) J. T. Baker, Inc. (2) Middleton, E., Jr. Ann. Allergy 1988,61, 63. (3) (a) Welton, A. F.; Tobias, L. D.; Fiedler-Nagy, C.; Andereon, W.; Hope, W.; Me ern, K.; Coffey, J. W. In Plant Flavonoids in Biology and Medicine;Cdy, V.,Middleton, E., Jr.,Harborne,J. B., Eda.;Alan R. Lisa Inc.: New York, l9W, p 231. (b)Selway, J. W. T. In Plant Flauonoida in Biology and Medicine; Cody, V.,Middleton, E., Jr., Harborne, J. B., Eda.; Alan R. Lm,Inc.: New York, 1986; p 621. (c) Brandi, M. L. Bone Miner. 1992, 19 (suppl.),53. (d) Hagiwara, M.; Inoue, S., T d a , T.; Nunoki, K.; Ito, M.; Hidaka, H. Biochem. Pharmacol. 1988,37,2987. (4) Haveteen, B. Biochem. Pharmacol. 198S,32,1141. (5) For reviews, see (a) Gripenberg,J. In The Chemistry of Flavonoid Compounds; Geiieman, T. A., Ed.;MacMiuan: New York, 1962; p 409. (b) Wagner,H.; F a r b , L. In The Flavonoids; Harborne, J. B., Mabry, T.J.,Mabry, H., Eds.;Academic Preen: New York, 1975;p127. (c) Wmg, L. Zhonggw Y i y m Gongye Zazhi 1990,21, 423. (6) Allan, J.; R o b m n , R. J. Chem. SOC.1924, 2192. (7) (a) Baker, W. J. Chem. SOC.1993, 1381. (b) Mahal, H. 5.; Venkataraman,K. J. Chem. SOC.1994,1767. (8) (a) Iinuma, M.; Iwashia, K.; Matauura, S. Chem. P h r m . Bull. 1984,32,4936. (b) Hoshino, Y.;Oohinnta, T.; Takeno, N. Bull. Chem. SOC. Jpn. 1986,69,2361. (9) (a)Iinuma, M.;Tan&, T.;Matauura, S. Chem.Pharm. Bull. 1984, 32,3364. (b)Matauura, S.:Iiiuma, M.; Ishikawa. K. Chem. Pharm.Bull. 1978,26,306. (10) (a) Hercouet, A.; LeCorre, M.;LeFloc'h, Y. Synthesis 1982,697. (b) LeFloc'h, Y.; LeFeuvre, M. Tetrahedron Lett. 1986, 27, 2761. (c) hFloc'h, Y.; LeFeuvre, M. Tetrahedron Lett. 1986, 6603.
/
Scheme I1 1. KOtBu(leq),THF 2. C&.C(O)CI
CH3 HO
0
acetone
CH3
0
CH30
3. KOtBu (1 eq) . * 4. reflux
(64-68% yield) 1
3
2
complications were encountered in the benzoylation and Claisen condensation steps, respectively. In addition, newer methods for directly converting hydroxyacetophenones into the required diketones, such as potassium carbonate,l2 organolithium reagents,13J4or phase-transfer to be ineffective or impractical for largecataly~is,~6proved wale use. In this Note, we describe a simple and convenient large-scale synthesis of 5-methoxyflavone (31, which employs potassium tert-butoxide (KOtBu) in a modified Baker-Venkataraman process. Results and Discussion The synthesis of 3 is shown on Scheme 11. The starting material, 2-hydroxy-6-methoxyacetophenone (l),was readily prepared, several moles at a time, from commercially available 2,6-dihydroxyacetophenoneusing methyl iodide w d potassium carbonate in acetone according to established procedures.ls Transformation of 1 into ita potassium phenoxide anion with 1.1 equiv of KOtBu was followed by treatment with benzoyl chloride to form the benzoyl ester. To this reaction mixture was directly added a second 1.1 equiv of KOtBu which, after refluxing overnight, provided crystalline diketone 2 in 6448% isolated yield. Treatment of 2 with sulfuric acid in refluxing acetic acid afforded 5-methoxyflavone (3)in 70(11) Wheeler,T.S.OrganicSyntheses;Wiley New York,1963;Collect. Vol. N, 418. (12) Wu, E.5.C.; Cole, T. E.; Davideon, T. A.; Dailey, M. A.; Doring, K. G.;Fedorchuk, M.; Loch, J. T.; Tho-, T. L.; Bloaeer, J. C.; Borrelli, A. R.; Kinsolving,C. R.;Parker, R. B.; Strand, J. C.; Watkine, B. E. J.
Med. Chem. 1989,32,183. (13) Baneji, A.; Ooomer, N. C. Synthesis 1980,874. (14) Cuehman,M.;Nagarathnam,D.TetrahedronLett.1990,31,6497. (16) (a) Jain, P.K.; Makrandi,J. K.; Grover,S. K. Synthesis 1982,221. (b) Saxena, 5.; Makrandi, J. K.; Grover, S. K. Synthesis 1985,697. (16) Lau, C. K.;Belanger, P. C.; Defreene, C.; Scheigetz, J. J. Org. Chem. 1987,62, 1670.
0022-3263/93/1958-7903$04.00/0(d 1993 American Chemical Society
7904 J. Org. Chem., Vol. 58, No. 27, 1993
Notes
Table I. Flavones Synthesized
Scheme I11
3’
1. KOtBu (1 eq),THF 2. C&l&(O)Cf 3. KOtBu (1 ea)
R
K
R
HO
0
comDound
R
4
7-OMe 7-OMe 5-OMe
5 6 7 8 9 10 11
5-F
R’ 3’-CF3
2’-C1 4‘-CF3 H
method’ A A A A A A A A B B B B B
yield ( % ) b 30 23 41 18 49 45 40 25 33 20 38 42 37
2’-Me H H 4’-Me H 2’-F 7-OMe 4’-F 12 5-OMe 3’,5’-diF 13 5-OMe 3’,5’-diCFs 14 5-OMe 4’-F 16 5-OMe 4‘-Me 16 5-OMe 4’-C1 0 In Method A, the hydroxyacetophenoneis treated with 2.2 equiv of KOtBu, followed by addition of the benzoyl chloride and heating. In method B, the hydroxyacetophenoneis treated sequentially with 1.1equivof KOtBu, the benzoyl chloride,asecond 1.1equiv of KOtBu and heating. See text for more details. b Yield of purified flavone from the starting acetophenone. 75% yield. The overall yield for this process from 1 was about 46 % , and we have found it can be easily accomplished on a several hundred-gram scale. The simple and convenient nature of this 5-methoxyflavone synthesis prompted us to examine its generalutility for the synthesis of substituted flavones. Our results are collected in Table I. Two variations of the method could be employed. In method A, the hydroxyacetophenone was treated with 2.2 equiv of KOtBu. The benzoyl chloride was then added, and after heating, the diketone was obtained. Method B more closely parallels the 5-methoxyflavone synthesis. In this method, the hydroxyacetophenone was instead treated sequentially with 1.1equiv of KOtBu, the benzoyl chloride, and then a second 1.1 equiv of KOtBu. After heating, the diketone was isolated. By either method, the diketones were generally obtained as crude oils that were directly cyclized without purification, although on occasion, the diketones were crystallized from ethanol. The methods are well suited for the synthesis of monosubstituted flavonessubstituted in either aromatic ring, as well as flavones substituted in both rings. Although the overallyields of purified products are slightly lower than that of the conventional Baker-Venkataraman sequence,” it should be noted that this new method takes far less time to execute, is operationally simple and, as noted with 5-methoxyflavone, is amenable to scaleup procedures. This method can also be adapted to the synthesis of certain A-ring alkoxyflavones from dihydroxyacetophenones, an example of which is illustrated in Scheme 111. Acylation of 2,6-dihydroxyacetophenone with benzoyl choride was followed by alkylation a t the second phenolic oxygen with tert-butyl bromoacetate and KOtBu-induced acyl migration to provide diketone 17. Acid-catalyzed cyclization of 17 was accompanied by ester hydrolysis to afford the desired 5-(carboxymethoxy)flavone (18). This demonstrates the feasibility of converting a dihydroxyacetophenone into an A-ring alkoxyflavone using only two reaction vessels and without the need for rigorous purification of intermediates. It is reasonable to assume that
C
H
0
.
-
4. BrCH2CO@U 5. KOtBu (1 eq) 6. reflux
(95% crude yield)
qp 17
____) H 2 m 4
HOAC
0
(60% yield)
H02CCH20
0
if one began with a nonsymmetrical dihydroxyacetophenone (such as 2,4-dihydroxyacetophenone),the same goal could be accompbhed by simply reversing the order of the alkylation and benzoylation steps. Conclusions In summary, a convenient large-scale preparation of 5-methoxyflavone has been developed using a KOtBumediated diketone synthesis as the key step. Thismethod has been successfully applied to the convenient synthesis of a number of flavone analogs. It has also been combined with a phenolic alkylation step, thereby providing a short and efficient means of transforming dihydroxyacetophenones into A-ring alkoxyflavones.
Experimental Section Liquid chromatography was performed by (a) using flash chromatography conditions (silica gel, 60 X 60 pm, purchased from Amicon of Beverly, MA), or (b) filtering through a fritted glass funnel packed with a layer each of sand/flash silica gel/ sand using a dater aspirator vacuum (hereafter this method will be referred to as a vacuum column). Thin-layerchromatography (TLC) w q accomplished using silica gel GHLF (260 pm) on prescored plates (10 X 20 cm) obtained from Analtech Inc., Newark, DE. TWF was dried over sodium/benzophenone. lH and nuclear magneticresonance (NMR) spectrawere recorded wing CDC13 as a solvent except where noted. Melting points were uncorrected. Elemental analyses were obtained from Galbraith Laboratories, Inc., Knoxville, TN or Oneida Research Services, Whitesboro, NY. Synthesis of 6-Methoxyflavone (3). KOtBu (157.6 g, 1.4 mol) was placed in a 6-L, three-necked round-bottom flask equipped with an agitator, immersion thermometer, addition funnel, and nitrogen inlet. Dry THF (700 mL) was added, and the mixture was cooled to 0-6 O C with stirring. 2-Hydroxy-6methoxyacetophenone (1)Ie (200 g, 1.2 mol) in dry THF (700 mL) was added slowly to the reaction flask over 30 min while keeping the reaction temperature below 6 OC. The ice bath was
removed, and the mixture was stirred at room temperature for 36 min. The mixture was recooled to 0-5 O C and benzoyl chloride (181.6 g, 150 mL, 1.29 mol) was added dropwise over 16 min while keeping the reaction temperature below 5 O C . After this addition was complete, the mixture was stirred at room temperature for 2 h, at which point TLC (20% EtOAc in hexane) revealed only a trace of starting acetophenone. The mixture was recooled to 5 “C and KOtBu (157.5g, 1.4 mol) was added,resulting in an increase in the reaction temperature to 23 O C . A reflux condenser was attached. The mixture was heated at reflux overnight, cooled to room temperature, and 3N HCl was added until the pH of the mixture was 3. The mixture was concentrated to afford a reddish brown oil (372 9). The oil was dissolved in CHzClz (450 mL), and the organic mixture was washed succes-
J. Org. Chem., Vol. 58, No. 27,1993 7905
Notes sively with 5% sodium bicarbonate solution (2x 200 mL), brine (2 x 200 mL), and water (1 X 200 mL). The organic layer was dried (Na&Od and evaporated to an oil (317g). The oil was crystallized from ethanol to yield yellow needles of diketone 2 (209.7g, 64.5%). This material was dissolved in glacial acetic acid (525mL),and concentrated sulfuric acid (24mL) was added. The mixture was refluxed for 2.5 h, and the hot solution was poured carefully into 3-4 L of crushed ice containing 1 L of water. Vigorous stirring was continued for 45 min, and the mixture was then placed in the refrigerator overnight. The resulting solid was filtered and washed with water (4-5 L). This material was oven-dried at 60 OC to provide 3 as a light green solid (186g, 95% yield): mp 127-128OC,lit.mp 130°C.17Thisproductwasfurther purified by recrystallization from 2-propanol (75% yield for the recrystallization) to afford a yellow crystalline material: mp 128129 OC. The overall yield from 1 was 46%. Representative Procedure for Method A Synthesis of 7-Methoxy-3'-(trifluoromethyl)flavone (4). To a suspension of KOtBu (1.92g, 17.1 mmol) in THF (5mL) in an ice bath was added 2-hydroxy-4-methoxyacetophenone(1.30g, 7.8 mmol) in THF (4mL). The reaction was stirred for 20 min at 0 "C. After 20 min, 3-(trifluoromethyl)benzoylchloride (1.62g, 7.8mmol) in THF (4mL) was added and the reaction was stirred for 15 min at 0 OC and then 10min at room temperature and finally refluxed for 3 h. The reaction was cooled to room temperature, acidified to pH 1 with 1 N HC1, and extracted with CHZClz (3 X 80 mL). The combined organic layers were washed with water (1 X 50 mL) and dried (NazSO,). Filtration and rotary evaporation yielded the diketone which was used without purification in the next step. A solution of the diketone and 12drops of Concentrated sulfuric acid in glacial acetic acid (20mL) was refluxed overnight. The reaction was cooled and poured into an ice/water solution. This mixture was stirred until it became an unstirrable mass, then extracted with CHzClz (3 X 70 mL). The combined organic layers were washed with water (1 X 50 mL) and half-saturated NaHCOa (1 X 50 mL) and dried over Na2SO1. (In some cases with other compounds, the extraction step was unnecessary because the material was filterable from the aqueous layer). Filtration and rotary evaporation provided a dark brown solid which was purified by flash chromatography (eluting with 25% EtOAc in hexane; material loaded on column in CHzCls) yielding 4 (0.755g, 30% overall yield): mp 142-144 O C ; lH NMR (300 MHz) 6 3.93 (8, 3 H, OCHa), 6.77 (8, 1 H), 7.01 (m, 2 H), 7.65 (m, 1 H), 7.78 (m, 1 H), 8.05 (m, 1 HI, 8.13 (m, 2H); '% NMR (75 MHz)S55.92,100.36,108.35,114.84,117.76,122.94,125.48,127.11, 127.84, 129.25, 129.66,131.68, 132.09, 132.79, 157.95, 161.16, 164.43,177.51;MS (CI) mlz 321 [M + HI+. Anal. Calcd for C17HllF808: C, 63.75;H, 3.46. Found C, 63.41;H, 3.43. Representative Procedure for Method B Synthesis of 3',6'-Difluoro-6-methoxyflavone (12). To a suspension of KOtBu (1.35g, 12.08 mmol) and THF (6mL) at 0 OC was added 2-hydroxy-6-methoxyacetophenone (1,1.72 g, 10.42 mmol)16 in THF (7 mL). The reaction was stirred for 0.5 h at room temperature, cooled to 0 OC, and then treated with 3,5difluorobenzoyl chloride (1.98 g, 11.25 mmol). The reaction mixture was then stirred at room temperature for 1 h, cooled to 0 OC, treated with KOtBu (1.35 g, 12.08 mmol), and heated at reflux overnight. The reaction mixture was adjusted to a pH of 2using a 50/50mixture of concentrated HCVwater. This aqueous material was extracted with CHzClZ (3X 80 mL). The combined organic layers were washed with water (2X 50 mL), dried over NaZSOd, filtered, and rotary evaporated to yield the diketone (17) Donnelly,J. A,;Dorm, H. J.; Murphy,J. J. Tetrahedron 1973,29,
1037.
which was cyclized as described above for 4 without purification. Crystallization of the crude product from 2-propanol,and further purification by a vacuum column (eluting with 100% CH2C12) afforded 12 (1.0g, 33% overall yield): mp 206-207 OC; 1H NMR (300MHz) 6 3.98 (8,3H, OCHa), 6.65 (s,lH), 6.82 (d, 1 H), 6.95 (m, 1 H), 7.10 (d, 1 H), 7.37 (m, 2 H), 7.58 (m, 1 H); 1% NMR (75MHz) 6 56.47,106.19,106.52,106.75,108.93,109.05,109.17, 109.29, 110.00, 114.47, 134.16, 134.69, 157.98, 158.28, 159.77, 161.48,161.65, 164.79, 164.96, 177.77;MS (CI) mlz 289 [M + HI+. Anal. Calcd for CI,&,FZOS:C, 66.67;H, 3.50. Found C, 66.62;H, 3.39. Synthesis of 6-(Carboxymethoxy)flavone (18)from 2,6Dihydroxyacetophenone. KOtBu (22.4g, 0.2mol) was added to dry THF (250mL) in a 1-L, three-necked round-bottom flask equipped with an agitator, immersion thermometer, addition funnel, and nitrogen inlet. The mixture was cooled to 0-5 OC. 2,6-Dihydroxyacetophenone(30.4g, 0.2 mol) in THF (150mL) was added dropwise over 15 rnin while maintaining the temperature below 5 OC. The ice bath was removed, and the mixture was allowed to warm to room temperature and stir for an additional 50 min. The mixture was subsequently cooled to 0-5 OC and benzoyl chloride (28.1 g, 0.2 mol, 23.2 mL) was added dropwise over 15 min while maintaining the temperature below 5 "C. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then recooled to 6 "C, and KOtBu (22.4g, 0.2 mol) was added. This resulted in a strong exothermic reaction, and the reaction temperature rose to 20 OC. THF (100mL) was added, and the mixture was cooled to 0-5 OC. tertButy1 bromoacetate (39g, 0.2 mol, 32.3mL) was added dropwisewhile maintaining the reaction temperature below 5 OC. The ice bath was removed, and the mixture was stirred at room temperature for 2 h and recooled to 0-5 OC. KOtBu (24.3g, 0.21 mol) was then added, resulting in an exothermic reaction. A reflux condenser was attached, and the mixture was heated overnight at reflux. The mixture was then diluted with water (100 mL) and acidified to pH 2 with 1 N HCl. The mixture was concentrated on the rotary evaporator to a syrup which was taken up in CHZClz (300mL) and washed successivelywith 5% sodium bicarbonate solution (2X 100 mL), water (1X 100 mL), and brine (1X 300 mL). The organic layer was dried (NaZSO,) and evaporated to provide diketone 17 as an oil (70 g, 95% yield). A small portion of this material was crystallid from ethanoltoaffordyellow needles. Thiscrystalline diketone 17 (2.8g, 7 mmol) was dissolved in glacial acetic acid (15mL), and concentrated sulfuric acid (1 mL) was added. The solution was refluxed for 30 min, and the hot solution was poured into a beaker containing crushed ice (250-300mL). The beaker was kept in a refrigerator for 1.5 h, and the resulting solid was filtered and washed well with cold water. The product was dried overnight at 50 OC and recrystallized from glacial acetic acid, providing pure flavone 18 (1.35g, 60% yield): mp 208-210 OC; 'H NMR (300MHz, drDMSO) 6 4.86 (8, 2 H, CH2),6.93 (m, 2 H), 7.35 (d, 1 H), 7.58 (m, 3 H), 7.69 (apparent t, 1 H), 8.06 (m, 2 H), 13.05 (br 8, 1 H); lBC NMR (75 MHz, &DMSO) 6 66.12, 108.56,109.34, 111.21, 114.33, 126.41, 129.38, 131.03, 131.96, 134.45,157.71,157.77,160.68, 170.09,176.94;MS (CI) mlz 297 [M HI+. Anal. Calcd for Cl,H120&.25H20: C, 67.88;H, 4.19. Found C, 67.80;H, 4.28.
+
Supplementary Material Available: Physical and spectroscopic data for compounda till and 13-16, as well as the synthesis of any precursors (7pages). This material is contained in libraries on microfiche, immediately follow this article in the microfilm version of the journal, and can be ordered from the ACS; see any current masthead page for ordering information.
