An efficient synthesis of 4,6 dimethoxyaurones

Article abstract of DOI:10.3987/com-01-9182

4,6-Dimethoxybenzofuran-3(2H)-one was synthesized in two steps starting from phloroglucinol and used as a useful starting block for the synthesis of aurones by condensation with benzaldehyde derivatives.

Full text of DOI:10.3987/com-01-9182

HETEROCYCLES, Vol. 55, No.5, 2001, pp. 967 - 972, Received, 19th February, 2001
AN EFFICIENT SYNTHESIS OF 4,6 DIMETHOXYAURONES
Chantal Beney, Anne-Marie Mariotte, and Ahcène Boumendjel*
Laboratoire de Pharmacognosie. Département de Pharmacochimie Moléculaire,
UMR-CNRS 5063. UFR de Pharmacie de Grenoble, 38706 La Tronche – France
Abstract 4,6-Dimethoxybenzofuran-3(2H)-one was synthesized in two steps
Starting from phloroglucinol and used as a useful starting block for the synthesis
of aurones by condensation with benzaldehyde derivatives.
INTRODUCTION
Aurones are secondary metabolite pigments widely present in fruits and vegetables. These highly colored
flavonoids derivatives are mostly found as their hydroxylated, methoxylated or glycosylated forms (Figure
1). Beside their contribution to plants color, aurones possess a wide range of biological activities.1 Especially,
they have been described as antifungal agents and as phytoalexins. Aureusidin (4,6,3’,4’-
tetrahydroxyaurone) was found to be a potent inhibitor of iodothyronine-deiodinase in rat liver microsomal
membrane.2 Recently, Kayser et al. reported the drug-potential of aurones for Leishmania infections.3
Literature surveys have disclosed the frequent presence of a 4,6-dihydroxyl groups in these compounds
(Figure 1).4 In the flavone series, these hydroxyl groups (positions 5 and 7) are often required for the
biological activities.5,6 Our interest in the biological properties of variably substituted aurones prompted us
to investigate the synthesis of 4,6-oxygenated aurones.
Aurones are synthesized by the oxidative cyclization of 2’-hydroxychalcones.7 Joshi et al. have synthesized
aurones by condensation of 2-bromo-2’-hydroxyacetophenone with salicylaldehyde.8 Flavones are also
oxidized to aurones using strong oxidizing agents.9-11 Some sensitive substituents, like glycosyl and
isoprenyl groups which are frequently present on flavones and aurones,4 are incompatible with such reagents.
In this Note, we describe the synthesis of 4,6-dimethoxybenzofuran-3(2H)-one as a convenient starting block
and its use for the synthesis of aurones.
4'
1
1
O
O
7
1'
6
1'
3
4
5
4
O
O
Flavone
Aurone
Figure 1.

RESULTS AND DISCUSSION
The key intermediate, 4,6-dimethoxybenzofuran-3(2H)-one (4) was obtained in three steps starting from
phloroglucinol.
HO
2'
HO
OH
1
4'
O
HO
OH
i
ii
2
+
NC
Cl
Cl
87%
1'
OH
86%
O
OH
R
O
OH
3
2
MeO
MeO
O
O
iii
75%
R-C6H4-CHO
iv
O
O
62 - 95%
OMe
OMe
4
1
Scheme 1. (i) a. ZnCl2, HCl, Et2O, 0°C ; b. 1N HCl, 100°C. (ii). MeONa, MeOH, reflux, 2 h. (iii). MeI,
K2CO3, DMF, 80°C, 1 h. (iv). KOH, MeOH/H2O, rt, 1 h.
Condensation of phloroglucinol with chloroacetonitrile catalyzed by ZnCl2 gave the imine intermediate
which was hydrolyzed in situ with aqueous 1N HCl to provide the corresponding ketone (2) in 87 %
yield.12,13 Using chloroacetyl choride as the acylating agent furnished 2 in very low yield. Treatment of 2
with sodium methoxide in MeOH gave benzofuranone (3) in 86% yield. The overall yield for this process
was about 74 % and we have found it can be easily accomplished on multigram scale.
The acidic 6-hydroxyl group and the chelated 4-hydroxyl group were protected with MeI using K2CO3 in
DMF to give (4) in 75 % yield. Condensation of (4) with benzaldehyde derivatives in the presence of an
excess of KOH in H2O/MeOH gave the expected aurone (1) in high yields. The configuration of the double
bond is exclusively Z as can be assigned on the basis of the chemical shift of the olefinic proton δ 6.70
(δ 7.01 for the E isomer) as previously reported.7
Table 1. 4,6-Dimethoxyaurones (1) prepared according
to Scheme 1.
Entry
R
Yield (%) of 1 from 4
H
62
77
94
80
95
71
1a
4’-F
1b
4’-Cl
1c
4’-Br
1d
2’,4’,5’-(OMe)3
4’-N(Me)2
1e
1f

If appropriately substituted benzaldehydes are selected, our synthetic approach constitutes a simple and high
yield procedure for the synthesis of diverse aurones. The 4,6-methoxy groups can be partialy or totally
hydrolyzed to yield 4-hydroxy-6-methoxy aurones or 4,6-dihydroxyaurones respectively.14 This
methodology may aid in studying the structure-activity relationship of aurones.
EXPERIMENTAL
General : Melting points were measured on a Fisher micromelting point apparatus and are uncorrected. MS
1
spectra were determined on a JEOL HX-110 spectrometer. H and 13C NMR spectra were measured on
Bruker AC-200 spectrometer and were referenced to internal standards, TMS (δH = 0.00, δC = 0.0); CDCl3
(δH = 7.27, δC = 77.0); CD3OD (δH = 4.87, δC = 49.2), or DMSO-d6 (δH = 2.49, δC = 39.4).
2’,4’,6’-Trihydroxy-2-chloroacetophenone (2). To a mixture of phloroglucinol (5 g, 39.7 mmol) and
chloroacetonitrile (2.5 mL, 39.7 mmol) in ether (100 mL) was added anhydrous ZnCl2 (0.54 g, 3.96 mmol).
The solution was cooled to 0°C and HCl was bubbled through the reaction for 15 min. The solution was left
in the cold-room overnight and HCl was bubbled again for 15 min. The precipitated imine was filtered off
and washed three times with ether. The imine was dissolved in 100 mL of 1N HCl and heated at 100°C for 1
h. The solid was filtered off, washed three times with water and dried under vacum to yield pure
acetophenone (2) as a pale white solid which was used without further purification. Yield 6.97 g (87%) ; mp
185-187 °C (Et2O); 1H NMR (DMSO-d6, 200 MHz) δ 4.20 (2H, s), 6.15 (2H, s), 11.23 (1H, br s), 12.76 (2H,
br s); 13C NMR (DMSO-d6, 50 MHz) δ 50.8 (C-2), 94.8 (C-3’, C-5’), 102.6 (C-1’), 164.0 (C-2’, C-6’), 165.6
(C-4’), 194.7 (C-1); HRMS calcd for C8H7O4Cl: 202.1951; found: 202.1948. Anal. Calcd for C8H7O4Cl: C,
47.43; H, 3.48; Cl, 17.50. Found: C, 47.36; H, 3.47; Cl, 17.41.
4,6-Dihydroxybenzofuran-3(2H)-one (3). To a solution of (2) (4.3 g, 21.2 mmol) in methanol (50 mL) was
added sodium methoxide (4.19 g, 77.6 mmol) and the mixture was refluxed for 2 h. After cooling, the
solution was acidified with 1N HCl and evaporated. The residue was extracted with ethyl acetate and the
extract was washed with water, brine, dried over Na2SO4 and evaporated. Column chromatography using
1
CH2Cl2 as eluent gave 3.02 g (86%) of 3 as a brown solid. mp 210-212 °C (CH2Cl2); H NMR (CD3OD,
13
200 MHz) δ 4.56 (2H, s), 5.88 (1H, d, J = 1.8 Hz), 5.94 (1H, d, J = 1.8 Hz); C NMR (CDCl3, 50 MHz) δ
76.48 (C-2), 91.6 (C-7), 95.5 (C-5), 104.1 (C-9), 159.2 (C-8), 170.4 (C-6), 177.8 (C-4), 198.1 (C-3); HRMS
calcd for C8H6O4: 165.7342; found: 165.7342. Anal. Calcd for C8H6O4: C, 57.84; H, 3.64. Found: C, 57.80;
H, 3.61.

4,6-Dimethoxybenzofuran-3(2H)-one (4). To a solution of 3 (1 g, 6.02 mmol) in DMF (15 mL) was added
K2CO3 (1.66 g, 12.04 mmol) and MeI (1.12 mL, 18.06 mmol). The solution was heated at 80°C for 1 h,
poured into water and extracted with EtOAc. The EtOAc was dried with anhydrous Na2SO4, filtered and
removed by rotary evaporation to yield a brown, viscous oil. The oil was subjected to column
chromatography using 1:1 hexane:EtOAc to yield 876 mg (75%) of pure 4 as a yellow solid. mp 132-
133 °C (EtOAc); 1H NMR (CDCl3, 200 MHz) δ 3.74 (3H, s), 3.78 (3H, s), 4.45 (2H, s), 5.88 (1H, d, J = 1.7
Hz), 6.02 (1H, d, J = 1.7 Hz); 13C NMR (CDCl3, 50 MHz) δ 56.03 (OCH3), 56.05 (OCH3), 75.5 (C-2), 88.9
(C-7), 93.0 (C-5), 104.8 (C-9), 158.9 (C-8), 169.8 (C-6), 177.2 (C-4), 194.9 (C-3), HRMS calcd for
C10H10O4: 193.7883; found: 193.7883. Anal. Calcd for C10H10O4: C, 61.85; H, 5.19. Found: C, 61.78; H,
5.15.
Aurones 1(a-f), general procedure: To a solution of 4 (100 mg, 0.51 mmol) in MeOH (5 mL) was added
benzaldehyde (0.76 mmol) followed by the addition of KOH (500 mg, 8.92 mmol in 1 mL of H2O). The
solution was stirred at rt for 30 min, hydrolyzed by adding water and extracted three times with EtOAc. The
EtOAc was dried with anhydrous Na2SO4, filtered and removed by evaporation to yield crude 1 which was
purified by column chromatography using hexane:ethyl acetate 3:1.
(Z)-Benzylidene-4,6-dimethoxybenzofuran-3(2H)-one (1a): Yellow powder; mp 154-156 °C (EtOAc); 1H
NMR (CDCl3, 200 MHz) δ 3.90 (3H, s), 3.94 (3H, s), 6.12 (1H, d, J = 1.8 Hz), 6.37 (1H, d, J = 1.7 Hz), 6.76
(1H, s), 7.40-7.37 (3H, m), 7.85 (2H, dd, J1 = 1.7 Hz, J2 = 8.1 Hz); 13C NMR (CDCl3, 50 MHz) δ 56.1
(OCH3), 56.2 (OCH3), 89.3 (C-7), 94.1 (C-5), 106.6 (C-9), 110.7 (Ph-CH=), 128.7 (C-2’, C-6’), 129.3 (C-4’),
131.1 (C-3’, C-5’), 132.6 (C-1’), 147.9 (C-2), 159.5 (C-8), 169.0 (C-4’, C-6’), 180.6 (C-3) ; HRMS calcd for
C17H14O4: 281.8978; found: 281.8978. Anal. Calcd for C17H14O4: C, 72.33; H, 5.00. Found: C, 72.26; H :
4.98.
(Z)-4,6-Dimethoxy-(4’-fluorobenzylidene)benzofuran-3(2H)-one (1b): White powder; mp 173-174 °C
(EtOAc); 1H NMR (CDCl3, 200 MHz) δ 3.92 (3H, s), 3.96 (3H, s), 6.14 (1H, d, J = 1.7 Hz), 6.38 (1H, d, J =
1.7 Hz), 6.73 (1H, s), 7.16 (2H, t, J = 8.7 Hz), 7.85 (2H, dd, J1 = 5.5 Hz, J2 = 8.7 Hz); 13C NMR (CDCl3, 50
MHz) δ 56.2 (OCH3), 56.3 (OCH3), 89.4 (C-7), 94.2 (C-5), 105.0 (C-9), 109.7 (Ph-CH=), 116.1 (d, J = 22.4
Hz, C-3’, C-5’), 129.0 (C-1’), 133.1 (d, J = 8.5 Hz, C-2’, C-6’), 147.6 (C-2), 159.6 (C-8), 163.2 (d, J = 250
Hz, C-4’), 169.1 (C-4, C-6), 180.7 (C-3) ; HRMS calcd for C17H13O4F: 299.8883; found: 299.8880. Anal.
Calcd for C17H13O4F: C, 68.00; H, 4.36; F, 6.33. Found: C, 67.95; H, 4.35; F, 6.02.

(Z)-(4’-Chlorobenzylidene)-4,6-dimethoxybenzofuran-3(2H)-one (1c): White powder; mp 173-174 °C
(EtOAc); 1H NMR (CDCl3, 200 MHz) δ 3.92 (3H, s), 3.96 (3H, s), 6.14 (1H, d, J = 1.7 Hz), 6.38 (1H, d, J =
1.7 Hz), 6.70 (1H, s), 7.39 (2H, d, J = 8.6 Hz), 7.79 (2H, d, J = 8.6 Hz); 13C NMR (CDCl3, 50 MHz)
δ 56.1 (ΟCH3), 56.2 (OCH3), 89.3 (C-7), 94.2 (C-5), 105.0 (C-9), 109.3 (Ph-CH=), 129.0 (C-3’, C-5’), 131.1
(C-1’), 132.2 (C-2’, C-6’), 135.2 (C-4’), 148.0 (C-2), 159.5 (C-8), 169.0, 169.1 (C-4, C-6), 180.4 (C-3) ;
HRMS calcd for C17H13O4Cl: 316.3427; found: 316.3418. Anal. Calcd for C17H13O4Cl: C, 64.46; H, 4.14; Cl,
11.19. Found: C, 64.42; H. 4.11; Cl, 11.08.
(Z)-4’-Bromobenzylidene-4,6-dimethoxybenzofuran-3(2H)-one (1d): Yellow powder; mp 171-172 °C
(EtOAc); 1H NMR (CDCl3, 200 MHz) δ 3.92 (3H, s), 3.96 (3H, s), 6.14 (1H, d, J = 1.7 Hz), 6.38 (1H, d, J =
1.7 Hz), 6.68 (1H, s), 7.54 (2H, d, J = 8.6 Hz), 7.72 (2H, d, J = 8.6 Hz); 13C NMR (CDCl3, 50 MHz)
δ 56.1 (ΟCH3), 56.2 (ΟCH3); 89.3 (C-7), 94.1 (C-5), 105.1 (C-9), 109.2 (Ph-CH=), 123.5 (C-4’), 131.5 (C-
1’), 131.9 (C-2’, C-6’), 132.3 (C-3’, C-5’), 148.1 (C-2), 159.5 (C-8), 169.0, 169.1 (C-4, C-6), 180.4 (C-3) ;
HRMS calcd for C17H13O4Br: 360.7935; found: 360.7930. Anal. Calcd for C17H13O4Br: C, 56.53; H, 3.63;
Br, 22.12. Found: C, 56,49; H, 3.60; Br, 22.00.
(Z)-Benzylidene-4,6,2’,4’,5’-pentamethoxybenzylidenebenzofuran-3(2H)-one (1e): Yellow powder ; mp
> 260 °C (CH2Cl2); 1H NMR (CDCl3, 200 MHz) δ 3.84 (3H, s), 3.85 (3H, s), 3.80 (3H, s), 3.91 (3H, s), 3.95
(3H, s), 6.12 (1H, d, J = 1.7 Hz), 6.32 (1H, d, J = 1.7 Hz), 6.51 (1H, s), 7.29 (1H, s), 7.83 (1H, s); 13C NMR
(CDCl3, 50 MHz) δ 55.2 (OCH3), 55.3 (OCH3), 55.4 (OCH3), 55.6 (OCH3), 55.9 (OCH3), 88.3 (C-7), 93.1
(C-5), 95.7 (C-3’), 104.6 (C-9), 112.6 (Ph-CH=), 113.9 (C-6’), 142.3 (C-5’), 145.8 (C-2), 151 (C-4’), 153.9
(C-2’), 158.5 (C-8), 167.6 (C-4, C-6), 179.6 (C-3); HRMS calcd for C20H20O7: 371.6772 ; found: 371.6772.
Anal. Calcd for C20H20O7: C, 64.51; H, 5.41. Found : 64.45; H, 5.37.
(Z)-4,6-Dimethoxy-(4’-dimethylaminobenzylidene)benzofuran-3(2H)-one 1f: Orange powder; mp 188-
189 °C (CH2Cl2); 1H NMR (CDCl3, 200 MHz) δ 3.04 (6H, s), 3.89 (3H, s), 3.94 (3H, s), 6.11 (1H, d, J = 1.7
13
Hz), 6.36 (1H, d, J = 1.7 Hz), 6.70 (1H, s), 6.75 (2H, d, J = 8.8 Hz), 7.77 (2H, d, J = 8.8 Hz); C NMR
(CDCl3, 50 MHz) δ 40.2 (Ν-(Me)2), 56.1 (Ο CH3), 56.3 (OCH3), 89.2 (C-7), 93.8 (C-5), 105 (C-9), 112.1
(C-3’, C-5’), 112.7 (Ph-CH=), 120.5 (C-1’), 133.1 (C2’, C-6’), 146.0 (C-2), 151.1 (C-4’), 159.3 (C-8), 168.3,
168.5 (C-4, C-6), 180 (C-3) ; HRMS calcd for C19H19NO4: 324.9666; found: 324.9661. Anal. Calcd for
C19H19NO4: C, 70.14; H, 5.89; N, 4.31. Found: C, 69.64; H, 5.90; N, 4.33.

REFERENCES AND NOTES
1. J. R. Harborne, The Flavonoids: Advances in Research Since 1986, Chapman and Hall, London, 1994, pp.
399-341.
2. M. Aufmkolk, J. Koerhle, R. D. Hesch, and V. Cody, J. Biol. Chem., 1986, 261, 11623.
3. O. Kayser, A. F. Kiderlen, U. Folkens, and H. Kolodziej, Planta Medica, 1999, 65, 316.
4. J. B. Harborne, H. Baxter, and G. P. Moss, Phytochemical Directory : A Handbook of Bioactive
Compounds from Plants, Taylor & Francis LTD, London, 1999, pp. 362-374.
5. W. F. De Azevedo, H. J. Mueller-Dieckmann, U. Schulze-Gahnem, P. J. Worland, E. Saysville, and S. H.
Kim, Proc. Natl. Acad. Sci. USA, 1996, 93, 2735.
6. F. Sicheri, I. Moarefi, and J. Kuriyan, Nature, 1997, 385, 602.
7. K. Thakkar and M. Cushman, J. Org. Chem., 1995, 60, 6499.
8. U. Kjoshi and M. V. Paradkar, Indian. J. Chem., Sect., 1988, 27B, 378.
9. B. Cummins, D. M. X. Donnely, J. F. Eades, H. Fletcher, F. O’Cinneide, E. M. Philbin, J. Swirski, T. S.
Wheeler, and R. K. Wilson, Tetrahedron, 1963, 19, 499.
10. T. R. Gormley and W. I. O’Sullvian, Tetrahedron, 1973, 29, 369.
11. C. J. Adams and L. Main, Tetrahedron, 1991, 47, 4979.
12. K. Wähälä and T. A. Hase, J. Chem. Soc., Perkin Trans. 1, 1991, 3005.
13. Y. C. Chang, M. G. Nair, R. C. Santell, and W. G. Helferich, J. Agric. Food. Chem., 1994, 42, 1869.
14. In a typical procedure : A solution of aurone (1) in CH2Cl2 was treated with BBr3 (1M in CH2Cl2, 2 eq) at
rt for 24 h to yield 4-hydroxy-6-methoxyaurones and 4,6-dihydroxyaurones which can be separated by
chromatography. In the same conditions, aurone (1e) gave a complex mixture of several compounds.