A convenient one-pot synthesis of 7-hydroxy-isoflavones from resorcinol with substituted phenylacetic acids

Article abstract of DOI:10.1016/j.tetlet.2006.09.034

A mild and highly efficient one-pot synthesis of 7-hydroxy-isoflavones is reported. The acylation of resorcinol with various phenyl acetic acids in molten zinc chloride affords an intermediate deoxybenzoin which without isolation is subjected to cyclization with N,N-dimethylformamide in the presence of boron trifluoride diethyl etherate and methanesulfonyl chloride to afford the 7-hydroxy-isoflavone without the formation of any by-product.

Full text of DOI:10.1016/j.tetlet.2006.09.034

Tetrahedron Letters 47 (2006) 8161–8163
A convenient one-pot synthesis of 7-hydroxy-isoflavones
from resorcinol with substituted phenylacetic acidsq
Himanshu Singh and Ram Pratap*
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
Received 22 June 2006; revised 30 August 2006; accepted 7 September 2006
Available online 29 September 2006
Abstract—A mild and highly efficient one-pot synthesis of 7-hydroxy-isoflavones is reported. The acylation of resorcinol with
various phenyl acetic acids in molten zinc chloride affords an intermediate deoxybenzoin which without isolation is subjected to
cyclization with N,N-dimethylformamide in the presence of boron trifluoride diethyl etherate and methanesulfonyl chloride to afford
the 7-hydroxy-isoflavone without the formation of any by-product.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
an intermediate deoxybenzoin 2,4 which is then cyclized
with a one carbon electrophile. A convenient approach
is that of Baker et al.5 who used oxalyl chloride and pyr-
idine as the cyclizing agent, whereas others have used
ethyl formate,6 triethyl orthoformate,7 or carbon disul-
fide.8 Deoxybenzoins have been utilized as starting
materials in some reported methods but need to be pre-
pared prior to the cyclization.9 Long cyclization periods
are another disadvantage, for example, with POCl3 and
DMF.10 Also, additional hydroxy groups have to be
protected.8
Flavonoids and isoflavonoids are a diverse group of
phenolic compounds produced by various higher plants1
to protect themselves from environmental stress and are
present in foods such as beans, cabbage, soya beans,
grains and hops.
They are structurally similar to mammalian oestrogen
and oestradiol, and have oestrogenic properties. Com-
pounds in this class show a wide variety of biological
activities such as anti-viral, anti-inflammatory, anti-
bacterial, anti-fungal and anti-cancer.2 Other potential
areas of benefit include diabetes, osteoporosis, heart
disease and cognitive function.
During the synthesis of 7-hydroxy-isoflavone via the
two-step procedure where we utilized the crude deoxy-
benzoin, obtained by electrophilic substitution of resor-
4
cinol with phenylacetic acid using ZnCl2 followed by
The antioxidant properties3 of these molecules have
been implicated as a reason for the above activities.
We therefore became interested in these molecules to
design drugs for antidiabetic activity. This encouraged
us to investigate a simple synthesis of 4H-1-benzopyran-
4-one derivatives.
cyclization with DMF and MeSO2Cl in BF3OEt2,11
a
by-product was isolated in an appreciable yield
(ꢀ35%). The structure of by-product 4 was established
by spectral analysis. Elemental analysis13 and the mole-
cular ion peak (M+1) at 357 suggested a molecular for-
mula C23H16O4. In the IR spectrum, there was a band at
1627 cmÀ1 corresponding to an a,b-unsaturated car-
bonyl. In the proton NMR spectrum, the proton peri
to the carbonyl at C-5 appeared as an ortho coupled
doublet at d 8.30. The proton at C-2 appeared as a sin-
glet at d 7.98. The presence of these two protons sug-
gested an isoflavone skeleton. However, in comparison
with an isoflavone structure, the by-product had no
meta coupled doublet at d 6.79 for the C-8 proton,
which suggested the attachment of a benzyl ketone at
C-8. A two- proton singlet at d 3.91 suggested the
The literature synthesis for isoflavones in general in-
volves two steps wherein a phenol is reacted in the pres-
ence of a Lewis acid with phenylacetic acid to generate
Keywords: 7-Hydroxy-isoflavones; Deoxybenzoin.
q CDRI Communicaion No 6997.
Corresponding author. Fax: +91 522 2623405; e-mail: rpcdri@
*
yahoo.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.034

8162
H. Singh, R. Pratap / Tetrahedron Letters 47 (2006) 8161–8163
heating at about 120–130 °C followed by the slow addi-
HO
OH
HO
OH
O
tion of resorcinol (90 mmol). After completion (TLC),
the reaction mixture was cooled to room temperature,
followed by the addition of DMF (60 mL), and
BF3OEt2 (363 mmol) at 0 °C. To this mixture was added
a solution of MeSO2Cl (272 mmol) in DMF (10 mL) at
50 °C and the temperature was raised to ꢀ110 °C for
90 min. The reaction mixture was cooled and poured
into ice water. The separated oil was extracted with
ethyl acetate, the organic layer washed with water, dried
and the solvent removed. The residue was purified by
column chromatography on silica gel using ethyl
acetate/hexane (50:50) or chloroform/methanol (98:2)
(Table 1).14
a
R
1
2
b
O
R
O
HO
O
HO
R
R
O
O
3
(R= Ph)
4
In conclusion, our procedure provides an easy access to
7-hydroxy-isoflavones in 56–78% yields in one-pot from
resorcinol and substituted phenylacetic acids without
the isolation of the deoxybenzoin intermediate. Using
the combination of two Lewis acids avoids the forma-
tion of any by-product.
Scheme 1. Reagents and conditions: (a) ZnCl2, RCH2CO2H, 120 °C
and (b) DMF, BF3OEt2, 0 °C, MeSO2Cl, 50–110 °C, 3 h.
Table 1. One-pot synthesis of 7-hydroxy-isoflavone derivatives 3a–e
Product
R
Yield (%)
Mp (°C)
Acknowledgements
3a
3b
3c
3d
3e
C6H5
78
56
72
65
68
207–208
220–223
198–200
210–213
215–217
o-NO2C6H4
m-ClC6H4
p-MeOC6H4
C10H7
We are thankful to the Sophisticated Analytical
Instrumentation Facility (SAIF) group for providing
spectral data and also to CSIR, New Delhi, for provid-
ing a Diamond Jubilee Year Fellowship to H.S.
presence of a benzylic methylene, which thus confirmed
the structure of the by-product as 7-hydroxy-8-phenyl-
acetyl-isoflavone (4, R = Ph). The isolation of 4
suggested the possibility of an acylation reaction of
phenylacetic acid with activated phenols. Boron trifluo-
ride is known to suppress the activity of phenols towards
electrophilic substitution,9 we therefore envisaged that
the addition of BF3OEt2 during the course of the reac-
tion would suppress the side reaction and also, on the
other hand, would facilitate ring closure as the combina-
tion of two Lewis acids might enhance the activity.12
This led us to study the reaction in a one-pot regime.
References and notes
1. Dixon, R. A.; Steele, C. L. Trends Plants Sci. 1999, 4, 394–
400.
2. (a) Vrijsen, R.; Everaert, L.; Boeye, A. J. Gen. Virol. 1988,
69, 1749–1751; (b) Ito, M.; Ishmoto, S.; Nishida, Y.;
Shiramizu, T.; Yumoki, H. Agric. Biol. Chem. 1986, 50,
1073–1074; (c) Miski, M.; Ulubelen, A.; Johansson, C.;
Mabry, T. J. J. Nat. Prod. 1983, 46, 874–875.
3. (a) Ruiz-Larrea, M. B.; Mohan, A. R.; Paganga, G.;
Miller, N. J.; Bolwell, G. P.; Rice-Evans, C. A. Free
Radical Res. 1997, 26, 63–70; (b) Wagner, J. D.; Cefalu,
W. T.; Anthony, M. S.; Litwak, K. N.; Zhang, L.;
Clarkson, T. B. Metabolism 1997, 46, 698–705.
4. Dohme, A. R. L.; Cox, E. H.; Miller, E. J. Am. Chem. Soc.
1926, 48, 1688–1693.
5. Baker, W.; Chadderton, J.; Harborne, J.; Ollis, W. D. J.
Chem. Soc. 1953, 1852–1864.
6. Mahal, H. S.; Rai, H. S.; Venkataraman, K. J. Chem. Soc.
1934, 1120–1122.
7. Sathe, V. R.; Venkataraman, K. Curr. Sci. India 1949, 18,
373.
8. Kim, Y. W.; Brueggemeier, R. W. Tetrahedron Lett. 2002,
43, 6113–6115.
The one-pot procedure began with the reaction of an
appropriately substituted phenylacetic acid with resor-
cinol in the presence of zinc chloride4 via the formation
of an intermediate deoxybenzoin 2 followed by cycliza-
tion to the corresponding isoflavone 3 on treatment with
BF3OEt2, DMF and MeSO2Cl (Scheme 1). BF3OEt2 is
believed to form a complex with the ortho-hydroxy-
aryl-ketones, which deactivates the aromatic ring,
preventing ring acylation and consequent polymeriza-
tion.11 The use of two Lewis acids, namely, zinc chloride
and boron trifluoride diethyl etherate, proved beneficial
in this procedure, as by-product 4 was not formed. A
series of 7-hydroxy-isoflavones 3 was prepared in good
yields using this procedure (Table 1).14
9. Wahala, K.; Hase, T. A. J. Chem. Soc., Perkin Trans. 1,
1991, 3005–3008.
10. Kagal, S. A.; Nair, P. M.; Venkataraman, K. Tetrahedron
Lett. 1962, 14, 593–597.
11. Bass, R. J. J. Chem. Soc., Chem. Commun. 1976, 78–79.
12. Jung, M. E.; Ho, D.; Chu, V. H. Org. Lett. 2005, 7, 1649–
1651.
2. General experimental procedure
13. Elemental analysis and physical data of 4: Found: C,
77.14; H, 4.88; O, 17.98% C23H16O4 requires: C, 77.31; H,
4.48; O, 17.92%; IR (KBr): 3206, 2363, 1627, 1581, 1470,
To molten anhydrous ZnCl2 (99 mmol), phenylacetic
acid (108 mmol) was added with vigorous stirring and
1384, 1267, 1099, 858, 703 cmÀ1 1H NMR (300 MHz,
;

H. Singh, R. Pratap / Tetrahedron Letters 47 (2006) 8161–8163
8163
CDCl3): d 10.15 (s, 1H, Ar–OH), 8.30 (d, 1H, ArH,
J = 8.9 Hz), 7.98 (s, 1H, @CH), 7.56–7.55 (m, 2H, ArH),
7.46–7.25 (m, 8H, ArH), 7.13 (dd, 1H, ArH, J = 8.7,
2.1 Hz), 3.91 (s, 2H, –CH2C6H5); 13C NMR (75.47 MHz,
CDCl3): d 167.8, 153.6, 151.8, 130.2, 128.0, 127.6, 127.0,
126.5, 126.3, 121.1, 118.1, 109.5, 40.1; ESMS m/z (%): 357
(100, [M+H]+).
6.81 (m, 2H, ArH); ESMS m/z (%): 284 (100, [M+H]+);
Compound 3c: IR (KBr): 3232, 2365, 1626, 1588, 1351,
1258, 1096, 783 cmÀ1 1H NMR (200 MHz, CDCl3 +
;
DMSO/d6): d 10.39 (s, 1H, Ar–OH), 8.03 (d, 1H, ArH,
J = 8.7 Hz), 7.87 (s, 1H, @CH), 7.50 (s, 1H, ArH), 7.35–
7.29 (m, 3H, ArH), 6.91–6.81 (m, 2H, ArH); ESMS m/z
(%): 273 (100, [M+H]+), 275 (33, [M+2+H]+), 237 (15,
[M-Cl]+); Compound 3d: IR (KBr): 3136, 2369, 1602,
14. Physical and spectral data of compounds (3a–e): Com-
pound 3a: IR (KBr): 3258, 2366, 1625, 1454, 1385, 1266,
1512, 1453, 1249, 1178, 1024, 886, 811, 777 cmÀ1 1H
;
697 cmÀ1
;
1H NMR (200 MHz, CDCl3 + DMSO/d6): d
NMR (200 MHz, CDCl3 + DMSO/d6): 10.10 (s, 1H, Ar–
OH), 8.11 (d, 1H, ArH, J = 8.6 Hz), 7.89 (s, 1H, @CH),
7.48 (d, 2H, ArH, J = 8.6 Hz), 6.98–6.86 (m, 4H, ArH),
3.84 (s, 3H, –OCH3); ESMS m/z (%): 269 (100, [M+H]+),
238 (30, [MÀOCH3]+); Compound 3e: IR (KBr): 3444,
10.17 (s, 1H, Ar–OH), 8.01 (d, 1H, ArH, J = 8.7 Hz), 7.89
(s, 1H, @CH), 7.46 (d, 2H, ArH, J = 6.6 Hz), 7.37–7.28
(m, 2H, ArH), 7.23–7.18 (m, 1H, ArH), 6.86 (d, 1H, ArH,
J = 8.7 Hz), 6.79 (d, 1H, ArH, J = 1.4 Hz); ESMS m/z
(%): 239 (100, [M+H]+), 238 (30, [M]+); Compound 3b: IR
2930, 2367, 1730, 1640, 1398, 1261, 1138, 777 cmÀ1 1H
;
(KBr): 3251, 2364, 1627, 1580, 1356, 1227, 850, 785 cmÀ1
;
NMR (300 MHz, CDCl3 + DMSO/d6): d 7.97 (d, 2H,
ArH, J = 7.9 Hz), 7.86 (d, 2H, ArH, J = 7.2 Hz), 7.77 (d,
2H, ArH, J = 8.1 Hz), 7.55–7.30 (m, 4H, ArH), 7.25 (s,
1H, @CH); FABMS m/z (%): 288 (30, [M]+).
1H NMR (200 MHz, CDCl3 + DMSO/d6): d 10.04 (s, 1H,
ArOH), 8.01–7.94 (m, 2H, ArH), 7.90 (s, 1H, @CH), 7.63–
7.52 (m, 2H, ArH), 7.30 (d, 1H, ArH, J = 7.9 Hz), 6.88–