A simple procedure for the synthesis of benzoxanthene derivatives under microwave irradiation conditions

Article abstract of DOI:10.1002/jhet.5570450345

(Chemical Equation Presented) A rapid and efficient method is developed to synthesize a series of benzoxanthene derivatives by the reaction of aldehydes and 2-hydroxynaphthalene-1,4-dione in mixed solvent of acetic acid and ethylene glycol under microwave irradiation. The method has the advantages of short synthetic route, operational simplicity and higher yields (70%～85%).

Full text of DOI:10.1002/jhet.5570450345

May-Jun 2008
931
A Simple Procedure for the Synthesis of Benzoxanthene Derivatives
Under Microwave Irradiation Conditions
Yan Chen a, Shanshan Wu b, Shujiang Tu b *, Chunmei Lib, Feng Shib
a School of Chemistry and Chemical Engineering, Xuzhou Institute of Technology College, Xuzhou, Jiangsu
221008, PR China; - chenyan681110@126.com
bSchool of Chemistry and Chemical Engineering, Xuzhou Normal University, Key Laboratory of
Biotechnology on Medical Plant, Xuzhou, Jiangsu 221009, PR China;
Received July 27, 2007
- laotu2001@263.net
O
acetic acid / ethylene glycol
140oC MW
+
ArCHO
2
OH
O
1
2
O
Ar
O
O
O
O
3
A rapid and efficient method is developed to synthesize a series of benzoxanthene derivatives by the
reaction of aldehydes and 2-hydroxynaphthalene-1,4-dione in mixed solvent of acetic acid and ethylene
glycol under microwave irradiation. The method has the advantages of short synthetic route, operational
simplicity and higher yields (70%~85%).
J. Heterocyclic Chem., 45, 931 (2008).
2-hydroxynaphthalene-1,4-dione
2
under microwave
INTRODUCTION
irradiation to afford a series of new heterocyclic
compounds, the aryl-substituted dibenzo[b,i]xanthene
derivatives (Scheme 1).
Much attention has been paid to the development of new
methods for the synthesis of heterocyclic compounds due
to their potential importance in the fields of
pharmaceutical and agricultural drugs. 4H-Benzo[b]-
pyrans and their derivatives have shown wide range of
biological properties [1,2], such as spasmolytic, diuretic,
anti-coagulant, anti-cancer and anti-ancaphylactia
activities [3-5]. With 4H-Benzo[b]pyrans as structural
unit, xanthenes and benzoxanthenes [6] are interesting
compounds not only because of their pharmaceutical
properties examplified by anti-bacterial [7], antiviral [8]
and anti-inflammatory activities [9], but also for their
useful applications in dyes [10] and fluorescent materials
[11]. As a result, the synthesis of new heterocyclic
compounds containing xanthene and benzoxanthene
scaffolds as well as the development of more rapid and
efficient entry to these heterocycles have attracted
considerable attention [12,13].
Scheme 1
O
O
O
Ar
O
O
acetic acid / ethylene glycol
140oC MW
+
2
ArCHO
OH
O
O
1
2
3
RESULTS AND DISCUSSION
To explore the scope and versatility of this method,
various reaction conditions were investigated. Choosing
an appropriate solvent is of crucial importance for the
successful microwave-assisted synthesis. To search for
the optimal solvent, the reaction of 3,4-dimethoxyphenyl
aldehyde (1i) with 2-hydroxynaphthalene-1,4-dione 2 was
examined using solvents of DMF, ethylene glycol, acetic
acid and mixed solvent of acetic acid with ethylene glycol
in different ratio, respectively. All the reactions were
carried out at 140 °C with the maximum power of
300W and the results are summarized in Table 1.
Microwave irradiation (MW) is
a very useful
technique in organic synthesis [14-17] since it is a simple,
timesaving, high yielding, and environmentally friendly
process. We have already reported the synthesis of
heterocyclic compounds under microwave irradiation
[18-20]. In continuation of our recent interest in the
construction of heterocyclic scaffolds, we have developed
a facile two-component reaction between aldehydes 1 and
As can be seen in Table 1, the reaction in mixed solvent
of acetic acid with ethylene glycol (HOAc/ Ethylene
glycol=2:1 V/V) gave the highest yield (Table 1, Entry 6).

932
Y. Chen, S. W, S. Tu, C. Li, F. Shi
Vol 45
This kind of mixed solvent was thus chosen as the solvent
for all further reactions.
conditions. The yield of 3i is 78% and the reaction time
is 8 h. Therefore, microwave irradiation exhibited
obvious advantages over conventional heating by greatly
reducing the reaction time and improving the reaction
yield.
The electronic effect of aryl group on this reaction was
also investigated. Under optimized reaction conditions,
both electron-withdrawing and electron-donating
substituents readily provided dibenzo[b,i]xanthene
derivatives in higher yields (Table 3). Therefore, the
electronic nature of the substrate has no significant
effect on this reaction.
The formation of 3 is likely to proceed via initial
condensation of aldehydes 1 with 2-hydroxynaphthalene-
1,4-dione 2 to afford 3-arylidenenaphthalene-1,2,4(3H)-
trione 4 which further undergoes Michael addition with
2-hydroxynaphthalene-1,4-dione 2 to furnish 5, which
upon intermolecular cyclization and dehydration gives
rise to 3 (Scheme 2).
To optimize the reaction temperature, the same reaction
of 1i with 2 was carried out in above mixed solvent at
temperature ranging from 100 °C to 150 °C, with the
increment of 10 °C each time. The results are shown in
Table 2.
Table 1
Solvent optimization for the synthesis of 3i
Entry
Solvent
DMF
HOAc
Volume ratio Time(min) Yield(%)
1
2
3
4
5
6
—
—
6
6
6
6
6
6
trace
46
Ethylene glycol
Mixed solventa
Mixed solventa
Mixed solventa
—
35
62
1:2 (V/V)
1:1(V/V)
2:1(V/V)
70
85
aThe mixed solvent of HOAc and Ethylene glycol
Table 2
The structures of all the synthesized compounds were
characterized by IR, 1H NMR and elemental analysis. The
IR spectrum of compound 3i showed strong absorptions at
Temperature optimization for the synthesis of 3i
Entry
Power(W)
T (°C)
Time(min) Yield (%)
1
1697 and 1662 cm-1 due to C=O groups. The H NMR
1
2
3
4
5
6
300
300
300
300
300
300
100
110
120
130
140
150
9
8
7
6
6
6
62
68
71
73
85
85
spectrum of 3i showed a singlet at δ 5.07 due to CH.
Scheme 2
O
O
O
O
Ar
O
ArCHO
+
The yield of product 3i was increased with the
increasement of temperature from 100 °C to 140 °C
(Table 2, Entry 1-5). However, the yield leveled off
when the temperatures was further increased to 150 °C
(Table 2, Entry 6). So, the temperature of 140 °C was
considered to be the most suitable for the reaction.
Under these optimized reaction conditions [140 °C,
mixed solvent of acetic acid and ethylene glycol (HOAc/
Ethylene glycol=2:1 V/V)], a series of products 3 were
synthesized with this simple reaction procedure. The
results are summarized in Table 3.
OH
O
HO
O
2
1
O
O
4
Ar
O
O
O
Ar
O
O
OH
OH
O
O
O
5
6
O
Ar
O
H2O
O
Moreover, we performed the synthesis of 3i in the
same mixed solvent at 140 °C under classical heating
O
O
3
Table 3
Synthesis of Compounds 3
entry
1
2
3
4
5
6
Compd
Ar
Time
Temp.
(°C)
140
140
140
140
140
140
Yield
(%)
Mp
(°C)
(min)
>300
3a
4-NO2C6H4
76%
7
8
6
7
6
>300
>300
>300
>300
>300
3b
3c
3d
3e
3f
3-NO2C6H4
4-OH-3-NO2C6H3
4-ClC6H4
70%
72%
72%
81%
78%
2-ClC6H4
3-BrC6H4
7
>300
>300
>300
7
8
9
3g
3h
3i
4-BrC6H4
4-OCH3C6H4
3,4-(OCH3)2C6H3
6
7
6
140
140
140
83%
80%
85%

May-Jun 2008
A Simple Procedure for the Synthesis of Benzoxanthene Derivatives
933
general procedure; ir (potassium bromide): CO 1682, 1665 cm-1;
1H nmr: δ 8.10-8.14 (m, 2H, ArH), 8.03 (d, 1H, ArH, J = 7.6
Hz), 7.96-7.99 (m, 2H, ArH), 7.88-7.92 (m, 2H, ArH), 7.76 (d,
1H, ArH, J = 7.6 Hz), 7.50 (d, 2H, ArH, J = 8.4 Hz), 7.32 (d,
2H, ArH, J = 8.4 Hz), 5.12 (s, 1H, CH). Anal calcd. for
C27H13ClO5: C, 71.61; H, 2.89. found C, 71.82; H, 2.73.
14-(2-chlorophenyl)-14H-dibenzo[b,i]xanthene-1,6,8,13-
tetraone (3e). This compound was obtained according to above
general procedure; ir (potassium bromide): CO 1701, 1665 cm-1;
1H nmr: δ 8.13 (d, 2H, ArH, J = 8.0 Hz), 8.02 (d, 1H, ArH, J =
7.6 Hz), 7.99(d, 1H, ArH, J = 7.6 Hz), 7.92-7.94 (m, 1H, ArH),
7.88-7.91 (m, 2H, ArH), 7.73-7.77 (m, 1H, ArH), 7.46-7.48 (m,
1H, ArH), 7.37-7.40 (m, 1H, ArH), 7.19-7.22 (m, 2H, ArH),
5.51 (s, 1H, CH). Anal calcd. for C27H13ClO5: C, 71.61; H, 2.89.
found C, 71.79; H, 2.71.
14-(3-bromophenyl)-14H-dibenzo[b,i]xanthene-1,6,8,13-
tetraone (3f). This compound was obtained according to above
general procedure; ir (potassium bromide): CO 1681, 1663 cm-1;
1H nmr: δ 8.12 (t, 2H, ArH, J = 8.00 Hz), 8.03 (d, 1H, ArH, J =
7.6 Hz), 7.95-7.99 (m, 2H, ArH), 7.89-7.91 (m, 2H, ArH), 7.75
(t, 1H, ArH, J = 7.6 Hz), 7.65 (s, 1H, ArH) 7.50 (d, 1H, ArH, J =
8.0 Hz), 7.38 (d, 1H, ArH, J = 8.0 Hz), 7.23 (t, 1H, ArH, J = 8.0
Hz),5.11 (s, 1H, CH). Anal calcd. for C27H13BrO5: C, 65.21; H,
2.63. found C, 65.03; H, 2.81.
14-(4-bromophenyl)-14H-dibenzo[b,i]xanthene-1,6,8,13-
tetraone (3g). This compound was obtained according to above
general procedure; ir (potassium bromide): CO 1681, 1663 cm-1;
1H nmr: 8.14−8.16 (m, 2H, ArH), 8.11 (d, 1H, ArH, J = 8.0Hz),
8.03 (d, 1H, ArH, J = 7.6 Hz), 7.94-7.98 (d, 2H, ArH), 7.90-7.92
(m, 2H, ArH), 7.75 -7.77(m, 1H, ArH), 7.45 (s, 3H, ArH ) 5.09
(s, 1H, CH). Anal calcd. for C27H13BrO5: C, 65.21; H, 2.63.
found C, 65.42; H, 2.49
In summary, we have demonstrated a rapid and direct
method that offers a simple and efficient route for the
synthesis of biologically important benzoxanthene
derivatives in excellent yields. Particularly valuable
features of this method included operational simplicity,
increased safety for small-scale as well as short reaction
time. Most importantly, the series of benzoxanthene
derivatives may be interesting new lead compounds for
biological activity evaluation.
EXPERIMENTAL
Microwave irradiation was carried out with microwave oven
EmrysTM Creator from Personal Chemistry, Uppsala, Sweden.
Melting points were determined in open capillaries and were
uncorrected. IR spectra were taken on
a TENSOR 27
spectrometer in KBr and reported in cm-1. 1H NMR spectra
were measured on a Bruke DPX 400 MHz spectrometer in
DMSO-d6 with chemical shift (δ) given in ppm relative to TMS
as internal standard. Elemental analyses were determined by
using a Perkin-Elmer 240c elemental analysis instrument.
General Procedure for the synthesis of 14-Aryl-14H-
dibenzo[b,i]xanthene-1,6,8,13–tetraone. The reactions were
performed in a monomodal EmrysTM Creator from Personal
Chemistry, Uppsala, Sweden. In a 10 mL EmrysTM reaction
vial, an aldehyde 1 (1 mmol), 2-hydroxynaphthalene-1,4-dione 2
(1 mmol), acetic acid (1.0 mL) and ethylene glycol (0.5 mL)
were mixed and then capped. The mixture was irradiated for 6−8
min at 300 W power and 140 °C. Upon completion, monitored
by TLC, the reaction mixture was cooled to room temperature
and then poured into cold water. The solid product was filtered
to give the crude product, which was further purified by
recrystallization from EtOH (95%) (3a-3i). All the products
were characterized by IR, 1H NMR and elemental analysis.
14-(4-nitrophenyl)-14H-dibenzo[b,i]xanthene-1,6,8,13-
tetraone (3a). This compound was obtained according to above
general procedure; ir (potassium bromide): CO 1681, 1667 cm-1;
1H nmr: δ 8.13-8.16 (m, 2H, ArH), 8.10-8,12 (m, 2H, ArH), 8.03
(d, 2H, ArH, J = 8.4 Hz), 7.95-7.97 (m, 2H, ArH,), 7.88-7.92 (m,
2H, ArH), 7.80 (d, 2H, J = 8.4 Hz), 5.25 (s, 1H, CH). Anal calcd.
for C27H13NO7: C, 69.98; H, 2.83; N, 3.02. found C, 69.77; H,
2.98; N, 3.22.
14-(4-methoxyphenyl)-14H-dibenzo[b,i]xanthene-1,6,8,13-
tetraone (3h). This compound was obtained according to above
general procedure; ir (potassium bromide): CO 1701, 1662 cm-1;
1H nmr: δ 8.09-8.13 (m, 2H), 8.02 (d, 1H, ArH, J = 7.6 Hz),
7.94-7.97 (m, 2H, ArH), 7.88-7.91 (m, 2H, ArH), 7.74(t, 1H,
ArH, J = 7.6 Hz), 7.36 (t, 2H, J = 8.4 Hz ), 6.81 (d, 2H, J = 8.4
Hz ) 5.07 (s, 1H, CH), 3.67 (s, 3H, OCH3). Anal calcd. for
C28H16O6: C, 75.00; H, 3.60. found C, 75.23; H, 3.45.
14-(3,4-dimethoxyphenyl)-14H-dibenzo[b,i]xanthene-1,6,8,
13-tetraone (3i). This compound was obtained according to
above general procedure; ir (potassium bromide): CO 1697, 1681
1
14-(3-nitrophenyl)-14H-dibenzo[b,i]xanthene-1,6,8,13-tetra-
one (3b). This compound was obtained according to above general
procedure; ir (potassium bromide): CO 1680, 1663 cm-1; 1H nmr: δ
8.26-8.28 (m, 1H, ArH), 8.21-8.23 (m, 1H, ArH), 8.14 (d, 2H,
ArH, J = 8.4 Hz), 8.03-8.05 (m, 2H, ArH), 7.96-8.01 (m, 2H, ArH),
7.88-7.90 (m, 2H, ArH), 7.77 (d, 1H, ArH, J = 8.0 Hz), 7.58-7.60
(m, 1H, ArH),5.26 (s, 1H, CH). Anal calcd. for C27H13NO7: C,
69.98; H, 2.83; N, 3.02. found C, 69.72; H, 2.67; N, 3.19.
cm-1; H nmr: δ 8.10-8.14 (m, 2H, ArH), 8.03 (d, 1H, ArH, J =
8.0 Hz), 7.97-7.99 (m, 2H, ArH), 7.88-7.91 (m, 2H, ArH), 7.74
(t, 1H, ArH, J = 8.0 Hz), 6.99 (d, 1H, J = 8.0 Hz), 6.94 (d, 1H, J
= 8.0 Hz), 6.81 (d, 1H, J = 8.0 Hz), 5.07 (s, 1H, CH), 3.67 (s,
3H, OCH3), 3.73 (s, 3H, OCH3). Anal calcd. for C29H18O7: C,
72.80; H, 3.79. found C, 72.99; H, 3.52.
Acknowledgments. We thank for the National Natural
Science Foundation of China (No. 20672090), the Nature
Science Foundation of the Jiangsu Province (No. BK2006033),
Six Kinds of Professional Elite Foundation of the Jiangsu
Province(No. 06-A-039), the Foundation of Qinglan Project
(No. QL200512) the financial support.
14-(4-hydroxy-3-nitrophenyl)-14H-dibenzo[b,i]xanthene-
1,6,8,13–tetraone (3c). This compound was obtained according
to above general procedure; ir (potassium bromide): CO 1681,
1
1667 cm-1; H nmr: δ 10.90 (s , 1H, OH), 8.11 (d, 2H, ArH, J =
8.0 Hz), 8.03 (d, 1H, ArH, J = 8.0 Hz), 7.95-7.98 (m, 2H, ArH),
7.88-7.91 (m, 3H, ArH), 7.76 (d, 1H, ArH, J = 8.0 Hz), 7.66 (d,
1H, ArH, J = 8.0 Hz), 7.02(d, 1H, ArH, J = 8.4 Hz), 5.10 (s, 1H,
CH). Anal calcd. for C27H13NO8: C, 67.65; H, 2.73; N, 2.92.
found C, 67.91; H, 2.83; N, 2.76.
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