First vilsmeier-haack synthesis of flavones using bis-(trichloromethyl) carbonate/dimethylformamide

Full text of DOI:10.1080/00304940802710947

Organic Preparations and Procedures International, 41:69–75, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304940802710947
First Vilsmeier-Haack Synthesis of Flavones
using bis-(Trichloromethyl)
Carbonate/Dimethylformamide
W. K. Su, X. Y. Zhu, and Z. H. Li
College of Pharmaceutical Sciences, Zhejiang University of Technology,
Zhejiang Key Laboratory of Pharmaceutical Engineering, Hangzhou, P. R. China
Flavones are a class of naturally occurring compounds with various biological activities.1–4
One of the most commonly used methods for the synthesis of flavones is the cy-
clodehydration of 1-(2-hydroxyphenyl)-3-aryl-1,3-propanediones. Many of these pro-
cedures use strong acids such as H2SO4,5-6 HCl,7 HBr or HI,8 catalysts such
as NaHSO4/SiO2,9 H3PMo12O40·nH2O/SiO2,10 H3PW12O40·nH2O/SiO2,10 non-aqueous
cation-exchange resin,11 or supported trifluoromethanesulfonic acid.12 All of these agents
require high temperatures to complete the reaction. Other methods include the use of Br2 or
I2 under irradiation conditions,13 ionic liquid [EtNH3]NO3,14 CuCl2,15 or montmorillonite
K-10 clay16 as the catalyst by microwave-assisted synthesis have been reported in various
yields.
The Vilsmeier-Haack reaction was initially used for the formylation of activated aro-
matic substrates and carbonyl compounds.17 It is now used as a powerful synthetic tool for
the construction of many heterocyclic compounds such as quinolines, indoles, pyridines,
and quinazoline derivatives.18–23 However, its application to cyclodehydration reactions
has not been reported. Following our recent work,24–29 we carried out an investigation on
the feasibility of cyclodehydration of 1-(2-hydroxyphenyl)-3-aryl-1,3-propanediones un-
der Vilsmeier-Haack conditions with bis-(trichloromethyl) carbonate/dime-thylformamide
(BTC/DMF) to synthesize flavones (Scheme 1).
Firstly, the ratio of reactants was investigated. It was shown that using 1,2-
dichloroethane as the solvent, BTC/DMF/1-(2-hydroxyphenyl)-3-aryl-1,3-propanedione =
1:3:1.5 was optimum to obtain the desired product in good yields. If the ratio was decreased,
the yield was reduced dramati-cally. Several conventional organic solvents such as DMF,
diethyl ether, THF, toluene, and halohydro-carbons were used to optimize the reaction
conditions. 1,2-dichloroethane and DMF were found to be more suitable solvents for the
reaction under similar conditions because of their excellent solvating properties. When
Received February 21, 2008; in final form September 26, 2008
Address correspondence to W.K. Su, Zhejiang University of Technology, College of Phar-
maceutical Sciences, Zhejiang Key Laboratory of Pharmaceutical Engineering Hangzhou 310014,
P. R. China. E-mail: suweike@zjut.edu.cn
69

70
Su, Zhu, and Li
Scheme 1
other solvents were used, the reaction proceeded slowly and gave low yields. In addition,
we used N, N-diethyl-4-methylbenzamide instead of DMF to accomplish the reaction and
also obtained good yields.
On the basis of the above results, to extend the scope and generality of the reaction,
this procedure was applied to other structurally diverse 1-(2-hydroxyphenyl)-3-aryl-1,3-
propanediones under similar conditions. The results are listed in Table 1. It could be seen
that all the substrates easily underwent cyclodehydration to give flavones with short reaction
times and good yields. It is worthwhile noting that electron-withdrawing and electron-
donating groups on the aromatic ring did not seem to affect the reaction significantly, either
in the yield of product or the rate of the reaction.
In conclusion, the present version of the Vilsmeier-Haack reaction with BTC/DMF
provides an efficient and rapid synthesis of flavones by the cyclodehydration of the corre-
sponding 1-(2-hydroxyphenyl)-3-aryl-1,3-propanediones. High yields, mild reaction con-
ditions, and short reaction times are the notable advantages of this procedure. We believe
that this procedure will provide a better scope and a more practical alternative to the existing
methods for the synthesis of flavones.
Experimental Section
1-(2-Hydroxyphenyl)-3-aryl-1,3-propanediones were prepared by procedures reported
previously.30-31 Other reagents were from commercial sources. Melting points (mps) were
determined on a WRS-1B digital melting point apparatus and are uncorrected. Infrared
1
spectra were recorded on a Thermo Nicolet Avatar 370 spectrophotometer. H NMR and
13C NMR spectra were obtained on a Varian Mercury plus-400 spectrometer using CDCl3
as the solvent with TMS as the internal standard. Mass spectra were measured with a Finni-
gan Trace DSQ spectrometer. Elemental analyses were measured on a Thermo Finnigan
Flash EA 1112 elemental analyzer.
Typical Procedure
A solution of BTC (0.4 g, 1.33 mmol) in ClCH2CH2Cl (10 mL) was added dropwise
to a solution of DMF (4 mL, 4 mmol) in ClCH2CH2Cl (10 mL) in an ice-water bath,

Vilsmeier-Haack Synthesis of Flavones
71
Table 1
Preparation of Flavones with BTC/DMF in 1,2-Dichloroethanea
Time Yieldb
mp (◦C)
(lit. mp)
Entry Product (h)
(%)
IR (cm−1
)
1H NMR (δ)
1
2a
2
94
96–97
(96–9732)
1646, 1605, 1568, 8.24 (d, J = 8.0 Hz, 1 H,
1128, 768
ArH), 7.94 (d, J = 8.0
Hz, 2 H, ArH), 7.71
(t, J = 8.0 Hz, 1 H, ArH),
7.53–7.60 (m, 4 H, ArH),
7.43 (t, J = 8.0 Hz, 1 H,
ArH), 6.86 (s, 1 H, CH)
2
2b
2
93
185–187
(185–18833)
1641, 1466, 1090, 8.21 (d, J = 8.0 Hz, 1 H,
828, 772
ArH), 7.84 (d, J = 8.0
Hz, 2 H, ArH), 7.70
(t, J = 8.0 Hz, 1 H, ArH),
7.54 (d, J = 8.0 Hz, 1 H,
ArH), 7.48 (d, J = 8.0
Hz, 2 H, ArH), 7.42
(t, J = 8.0 Hz, 1 H,
ArH), 6.78 (s, 1 H, CH)
3
4
2c
2.5
2.5
90
91
193–195
(192–19334)
1651, 1368, 1153, 8.26 (d, J = 8.0 Hz, 1 H,
1066, 909, 767
ArH), 7.62–7.71 (m, 2 H,
ArH), 7.39 -7.53 (m, 5 H,
ArH), 6.67 (s, 1 H, CH)
2d
172–175
(172–17435)
1650, 1467, 1381, 8.25 (d, J = 8.0 Hz, 1 H,
1365, 823, 775,
753
ArH), 7.70–7.74 (m, 1 H,
ArH), 7.60 -7.61 (m, 2 H,
ArH), 7.51 (d, J = 8.0
Hz, 1 H, ArH), 7.40–7.46
(m, 2 H, ArH), 6.66 (s, 1
H, CH)
5
6
7
2e
2f
3
3
92
91
94
226–227
(226–22736)
1658, 1492, 1438, 8.19 (s, 1 H, ArH), 7.85 (d,
1092, 906, 831,
664
J = 8.0 Hz, 2 H, ArH),
7.64–7.67 (m, 1 H, ArH),
7.51–7.54 (m, 3 H, ArH),
6.79 (s, 1 H, CH)
248–251
(249–25037)
1649, 1612, 1492, 8.29 (s, 1H, ArH), 8.04 (s,
1092, 839, 699
1H, ArH), 7.93 (d, J =
8.0 Hz, 2H, ArH), 7.53
(d, J = 8.0 Hz, 2H,
ArH), 6.84 (s, 1H, CH)
2gc
2.5
179–180
1638, 1490, 1410, 8.05 (d, J = 8.0 Hz, 1 H,
1092, 906, 827,
813, 477
ArH), 7.77–7.80 (m, 2 H,
ArH), 7.43 -7.46 (m, 2 H,
ArH), 7.29 (s, 1 H, ArH),
7.19 (d, J = 8.0Hz, 1 H,
ArH), 6.70 (s, 1 H, CH),
2.47 (s, 3 H, CH3)
(Continued on next page)

72
Su, Zhu, and Li
Table 1
Preparation of Flavones with BTC/DMF in 1,2-Dichloroethanea (Continued)
Time Yieldb
mp (◦C)
(lit. mp)
Entry Product (h)
(%)
IR (cm−1
)
1H NMR (δ)
8
2h
2.5
93
198–199
(198–19936)
1643, 1621, 1483, 7.99 (s, 1 H, ArH), 7.83 (d,
1089, 902, 820,
707
J = 8.4 Hz, 2 H, ArH),
7.43–7.51 (m, 4 H, ArH),
6.76 (s, 1 H, CH), 2.46
(s, 3 H, CH3)
9
2i
2.5
90
95
183–184
(183–18436)
1641, 1613, 1465, 8.16 (s, 1 H, ArH), 7.78 (d,
1436, 1358,
816, 670
J = 8.0 Hz, 2 H, ArH),
7.61 (d, J = 8.0 Hz, 1 H,
ArH), 7.50 (d, J = 8.0
Hz, 1 H, ArH), 7.31
(d, J = 8.0 Hz, 2 H,
ArH), 6.79 (s, 1 H, CH),
2.43 (s, 3 H, CH3)
10
2j
2
108–111
(108–11135)
1637, 1465, 1371, 8.21 (d, J = 8.0 Hz, 1 H,
1227, 817, 752,
634
ArH), 7.78 (s, 2 H, ArH),
7.65 (t, J = 4.0 Hz, 1 H,
ArH), 7.52 (s, 1 H, ArH),
7.27 (s, 1 H, ArH), 7.38
(t, J = 8.0 Hz, 2 H,
ArH), 6.76 (s, 1 H, CH),
2.40 (s, 3 H, CH3)
11
12
2k
2l
2
2
94
93
121–122
1638, 1615, 1482, 8.00 (s, 1 H, ArH), 7.90 (d,
(12236)
1359, 1044,
883, 814, 778
J = 8.0 Hz, 2 H, ArH),
7.43–7.52 (m, 5 H, ArH),
6.79 (s, 1 H, CH), 2.45
(s, 3 H, CH3)
129–131
1637, 1606, 1449, 8.14 (s, 1 H, ArH), 7.91 (d,
(128–13034)
1371, 1157,
866, 772
J = 8.0 Hz, 2 H,
ArH),7.51 (s, 3 H, ArH),
7.35 (s, 1 H, ArH), 7.22
(d, J = 8.0 Hz, 1 H,
ArH), 6.81 (s, 1 H, CH),
2.50 (s, 3 H, CH3)
13
14
2m
2n
2.5
1.5
95
97
151–152
1643, 1613, 1483, 8.00 (s, 1 H, ArH), 7.80 (d,
(150–15136)
817
J = 8.0 Hz, 2 H, ArH),
7.44–7.50 (m, 2 H, ArH),
7.31 (d, J = 8.0 Hz, 2 H,
ArH), 6.77 (s, 1 H, CH),
2.46 (s, 3 H, CH3), 2.43
2.46 (s, 3 H, CH3)
157–159
1649, 1608, 1465, 8.21 (d, J = 8.0 Hz, 1 H,
(157–15836)
1380, 1133,
827, 767
ArH), 7.85 (d, J = 8.4
Hz, 2 H, ArH), 7.65–7.69
(m, 1 H, ArH), 7.53
(d, J = 8.0 Hz, 1 H,
ArH), 7.40 (t, J = 7.2 Hz,
1 H, ArH), 6.98–7.01 (m,
2 H, ArH), 6.72 (s, 1 H,
CH), 3.87 (s, 3 H, CH3)

Vilsmeier-Haack Synthesis of Flavones
73
Table 1
Preparation of Flavones with BTC/DMF in 1,2-Dichloroethanea (Continued)
Time Yieldb
mp (◦C)
(lit. mp)
Entry Product (h)
(%)
IR (cm−1
)
1H NMR (δ)
15
2o
1.5
95
196.1–196.2
1649, 1608, 1515, 7.88 (d, J = 8.0 Hz, 2 H,
(194–19538)
1466, 1382,
1268, 1195,
1026, 827, 768
ArH), 7.61 (d, J = 4.0
Hz, 1 H, ArH), 7.45
(d, J = 8.0 Hz, 1 H,
ArH), 7.29 (d, J = 4.0
Hz, 1 H, ArH), 7.03
(d, J = 8.0 Hz, 2 H,
ArH), 6.76 (s, 1 H, CH),
3.92 (s, 3 H, OCH3), 3.90
(s, 3 H, OCH3)
16
17
2p
2q
3.5
3
90
87
241–243
1659, 1520, 1467, 8.11–8.40 (m, 5 H, ArH),
(242–24434)
1346, 1130,
857, 750, 692
7.48 -7.76 (m, 3 H, ArH),
6.92 (s, 1 H, CH)
194.6–195.1
1646, 1610, 1454, 9.12 (s, 1 H, ArH), 8.52 (d,
(19339)
1340, 1135,
922, 841, 772,
679, 627
J = 8.0 Hz, 1 H, ArH),
7.93–7.95 (m, 2 H, ArH),
7.74 (d, J = 4.0 Hz, 1 H,
ArH), 7.55–7.63 (m, 3 H,
ArH), 6.90 (s, 1 H, CH)
18
19
2r
2s
3.5
89
93
276–278
1639, 1617, 1522, 8.39 (d, J = 8.0 Hz, 2 H,
(275–27736)
1343, 1138,
ArH), 8.11 (d, J = 8.0
Hz, 2 H, ArH), 8.03 (s, 1
H, ArH), 7.50–7.58 (m, 2
H, ArH), 6.90 (s, 1 H,
CH), 2.49 (s, 3 H, CH3)
850, 823, 691
2
200.1–201.8
1642, 1607, 1518, 8.39 (d, J = 8.0 Hz, 2 H,
(198–2009)
1488, 1347,
1020, 853, 826,
697
ArH), 8.11 (t, J = 4.0
Hz, 2 H, ArH), 7.61
(d, J = 4.0 Hz, 1 H,
ArH), 7.55 (d, J = 8.0
Hz, 1 H, ArH), 7.33–7.36
(m, 1 H, ArH), 6.90 (s, 1
H, CH), 3.96 (s, 3 H,
CH3)
aSubstrate 1 (2 mmol), BTC (1.33 mmol) and DMF (4 mL, 4 mmol) was used.
bIsolated yields.
c13C NMR (CDCl3): δ 177.89, 161.60, 156.05, 145.11, 137.55, 130.11, 129.14, 127.24, 126.66,
125.25, 121.46, 117.63, 107.36, 21.69; IR (KBr): 1638, 1490, 1410, 1092, 906, 827, 813, 477 cm−1
;
MS (EI): m/z (%) = 270 (5) [M+], 242 (100), 178 (90), 152 (70), 78 (6); Anal. Calcd for C16H11ClO2:
C, 70.99; H, 4.10; Found: C, 70.92; H, 4.04.
and the mixture was stirred at 0◦C for 10 min and at 20◦C for 30 min. The temperature
was reduced to 0–5◦C and the substituted 1-(2-hydroxyphenyl)-3-aryl-1,3-propanedione
(2 mmol) was added. The reaction proceeded at room temperature and was monitored by
TLC. After completion, the mixture was washed with water (20 mL), and the organic layer
was isolated. The aqueous layer was extracted by CH2Cl2 (20 mL × 2). The combined

74
Su, Zhu, and Li
organic extracts were washed with saturated NaHCO3 solution (20 mL × 2), dried (MgSO4)
and evaporated. The crude product was purified by flash column chromatography to provide
the corresponding product.
Acknowledgment
We are grateful to the Natural Science Foundation of Zhejiang province (No. 202095) and
the Natural Science Foundation of China (No. 20676123) for financial help.
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