Microwave-assisted clean synthesis of xanthenes and chromenes in [bmim][PF6] and their antioxidant studies

Article abstract of DOI:10.1007/s11164-014-1821-4

An efficient one-pot synthesis of xanthene and chromene derivatives by three-component6 reactions of aryl aldehydes, cyclic 1,3-diketones, and 2-naphthol/4-hydroxy coumarin catalyzed by ionic liquid (IL) [bmim][PF₆] under microwave irradiation

Full text of DOI:10.1007/s11164-014-1821-4

Res Chem Intermed
DOI 10.1007/s11164-014-1821-4
Microwave-assisted clean synthesis of xanthenes and
chromenes in [bmim][PF6] and their antioxidant studies
•
P. Iniyavan S. Sarveswari V. Vijayakumar
•
Received: 5 August 2014 / Accepted: 20 September 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract An efficient one-pot synthesis of xanthene and chromene derivatives by
three-component reactions of aryl aldehydes, cyclic 1,3-diketones, and 2-naphthol/
4-hydroxy coumarin catalyzed by ionic liquid (IL) [bmim][PF6] under microwave
irradiation is described. The present scheme provides several advantages such as
short reaction time, mild reaction conditions, good yields, convenient operation, and
reuse of IL. In vitro antioxidant activity was evaluated for the synthesized com-
pounds by DPPH method. Compounds 6a, 6h, 6c, 6b, 4k, and 4a showed the highest
antioxidant potency.
Keywords Xanthenes ꢀ Chromenes ꢀ Ionic liquid ꢀ Antioxidant activity
Introduction
Multicomponent reactions (MCRs) are chemical transformations in which several
reactions are mixed into one synthetic operation to form several bonds to construct a
final complex product in a time- and cost-effective way [1–3]. The primary goal of
MCRs research is to synthesize heterocyclic compounds, which make up the
majority of pharmaceuticals, agrochemicals, natural products, and drug-like
molecules [4, 5]. In a true sense, these reactions are environmentally friendly
processes by reducing the number of steps, energy consumption, and waste output
[6, 7]. In recent times, microwave-assisted chemistry has been demonstrated to be
Electronic supplementary material The online version of this article (doi:10.1007/s11164-014-1821-4)
contains supplementary material, which is available to authorized users.
P. Iniyavan ꢀ S. Sarveswari ꢀ V. Vijayakumar (&)
Centre for Organic and Medicinal Chemistry, VIT University, Vellore 632014, Tamil Nadu, India
e-mail: kvpsvijayakumar@gmail.com
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P. Iniyavan et al.
effective at increasing the rate of MCR procedures [8, 9]. Microwave irradiation
offers several unique advantages like enhanced yields, reproducibility, cleaner
reactions, and being used as an alternative thermal energy source to conventional
heating [10, 11]. It has been applied to a wide range of reactions like cycloaddition,
organometallic reactions, and nanoparticle synthesis [12–14].
Xanthenes and chromenes are cited as active oxygen heterocycles possessing a
broad spectrum of biological activity [15]. Xanthene derivatives have been found to
exhibit as pH-sensitive fluorescent materials for visualization of biomolecules [16].
These compounds have also been used as dyes [17], antagonists [18], and in laser
technologies [19].
On the other hand, chromenes are used as potent anti-tuberculosis agents and
often appear as an important structural element in many biologically active natural
compounds [20, 21]. Though various procedures were described for the preparation
of xanthenes and chromenes, they have been hampered by several disadvantages
like prolonged reaction time, unsatisfactory yields, harsh reaction conditions, and
the requirement of excess catalysts [22].
Recently, the use of ionic liquids (ILs) earned recognition as environmentally
benign green media in organic synthesis, especially those based on the 1,3-
dialkylimidazolium cation have significant intrinsic characteristics over common
organic solvents such as non-inflammable, reusability, low toxicity, wide liquid range,
and acidic catalytic activity and so on [23, 24]. The organic reactions using ILs can be
carried out in a homogeneous phase and it can be recycled in a green procedure [25].
With all of this in mind, and as part of our ongoing research devoted to the
development of novel synthetic methods in heterocyclic chemistry [26–30], here we
describe the microwave-assisted synthesis of xanthene and chromene derivatives by
the reactions of arylaldehydes, 2-naphthol or 4-hydroxycoumarin and 1,3-cyclod-
iones in 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim][PF6]).
Results and discussion
For the synthesis of xanthenes, 4-chlorobenzaldehyde, 2-naphthol and 1, 3-cyclohex-
anedione were selected as model reactants in [bmim][PF6] under conventional way in
different conditions. Although the reactions were successful with moderate yield, it
required prolonged reaction times. Because of the advantage of using microwave
irradiation, the microwave method was applied to this reaction under solvent-free
conditions. The use of microwaves afforded high yield and the reaction time fell to
15 min. In search of an optimization of reaction conditions, the model reaction was
performed with different catalysts and solvents and the results are summarized in Table 1.
Apart from [bmim][PF6], all solvents and catalysts afforded the product with a
moderate yield in longer reaction times. We next investigated the amount of IL
required for this reaction and the results showed that 10 mol % of [bmim][PF6] was
sufficient to catalyze the reaction. Excess or \10 mol % concentration of
[bmim][PF6] has no obvious difference in the reaction yield (Table 1).
To explore the scope and limitations of this reaction, the optimized reaction
conditions (IL, MW 340 W, 40 % power, 15 min) were used for the construction of
123

Microwave-assisted clean synthesis of xanthenes
Table 1 Synthesis of 12-
Entry
Catalyst
Mol %
Solvent
Time
Yield (%)
(4-chlorophenyl)-9,10-dihydro-
8H-benzo[a]xanthen-11(12H)-
one (4b) in different conditions
1
[bmim][PF6]
[bmim][PF6]
[bmim][PF6]
[bmim][PF6]
[bmim][PF6]
[bmim][PF6]
[bmim][PF6]
[bmim][BF4]
L-Proline
15
10
5
–
15
15
20
15
15
15
15
20
15
15
15
15
30
90
91
88
71
75
83
54
88
75
60
57
31
–
2
–
3
–
4
10
10
10
10
5
EtOH
5
DMF
6
CH2Cl2
7
CH3CN
8
–
–
–
–
–
–
9
5
10
11
12
13
CF3CO2H
AlCl3
5
Experimental conditions:
cyclohexane-1,3-dione (1 mmol),
2-naphthol (1 mmol),
5
CuCl2
5
4-chlorobenzaldehyde (1 mmol)
under microwave irradiation
–
–
a library from various aldehydes (Scheme 1). The reaction went along well with
both electron-withdrawing and electron-donating substituted aromatic aldehydes
(Table 2).
With the encouraging results from the above reaction, it was thought worthwhile
to replace the 2-naphthol with 4-hydroxy coumarin in order to get some novel
chromene derivatives (Scheme 2).
Moreover, compounds with the coumarin scaffold also exhibit a wide range of
biological activities [31–33]. Interestingly all the substrates afford the desired
chromene derivatives in good yields as shown in Table 3.
It was observed that in the absence of 2-naphthol, the [bmim][PF6] catalyzed
reaction of 1,3-cyclodione and aldehyde under the same conditions resulted to the
formation of compounds 7a–i in good yields (Scheme 3; Table 4).
With the above-mentioned results in hand, a plausible sequence of reaction
pathway is depicted in Fig. 1. The interaction of 1,3-cyclodiones and aromatic
aldehydes lead to the intermediate 8 catalyzed with [bmim][PF6]. The resulting
intermediate leads to 10 and 12 by ortho C-alkylation of 2-naphthol/4-hydroxy
coumarin. Subsequently, 10 and 12 intermediate losses a molecule of H2O by
cyclodehydrogenation afforded the products 4a–k and 6a–h. In the absence of 1, the
second molecules of 1,3-dicarbonyl compounds attacks intermediate 8 leading to
the compounds 7a–i.
The catalytic activity of the recycled IL was also studied. To our delight, IL was
recycled for five runs without an apparent loss of activity under the above-
investigated conditions (Fig. 2).
DPPH radical scavenging assay
The antioxidant activities of the synthesized compounds was investigated using
DPPH (2,2-diphenyl-1-picrylhydrazyl) free radical scavenging assay with respect to
123

P. Iniyavan et al.
O
3
R2
O
OH
O
2
[bmim][PF6]
mw
R1
R1
R2
H
R1
O
R1
O
4
1
Scheme 1 [bmim][PF6] catalyzed synthesis of benzoxanthene derivatives under microwave irradiation
(4a–k)
Table 2 Physical data of the synthesised compounds 4a–k
Entry
R2
R1
Product
Time
(min)
Yield
(%)
m.p (°C)
Found
Lit
1
3,4,5-(OCH3)C6H2
4-ClC6H5
H
4a
4b
4c
4d
4e
4f
12
15
15
12
17
15
16
17
17
16
15
92
91
90
90
85
91
87
83
82
87
92
180–182
205–207
182–184
189–191
194–196
225–227
231–233
270–272
205–207
190–192
205–207
–
2
H
208–209 [34]
–[43]a
3
3,4-(OCH3)C6H3
3,5-OCH3-4-OHC6H2
2-OCH2CH3C6H4
4-C6H5C6H4
H
4
H
–
5
H
–
6
H
–
7
3-NO2C6H4
H
4g
4h
4i
235–236 [35]
8
2-FC6H4
H
–
9
3-OHC6H4
H
–
10
11
C6H5
CH3
CH3
4j
189–190 [35]
–
3,5-OCH3-4-OHC6H2
4k
The reaction was carried out with 1 (1 mmol), 2 (1 mmol), 3 (1 mmol), ionic liquid (10 mol %) under
microwave irradiation for the given time in the table
a
Reported, but m.p is unavailable
O
3
O
R2
O
OH
O
O
2
[bmim][PF6]
mw
O
R1
R1
R2
H
R1
O
O
6
O
R1
5
Scheme 2 [bmim][PF6] catalyzed synthesis of benzo chromene derivatives under microwave irradiation
(6a–h)
the standard BHT (butylated hydroxy toluene). Percentage activity of the compounds
was calculated using the following equation
Â
sample is the absorbance of the compounds. The percentage of inhibition was given
À
ÁÃ
Inhibition ð%Þ ¼ 1 ꢁ Asample=Acontrol ꢂ 100
where Acontrol is the absorbance of the control (blank, without compound) and
A
123

Microwave-assisted clean synthesis of xanthenes
Table 3 Physical data of the synthesised compounds 6a–h
Entry
R2
R1
Product
Time
(min)
Yield
(%)
m.p (°C)
Found
Lit
1
2
3
4
5
6
7
8
3,4,5-(OCH3)C6H2
3,4-(OCH3)C6H3
3,5-OCH3-4-OHC6H2
4-C6H5C6H4
H
6a
6b
6c
6d
6e
6f
12
15
12
15
17
17
17
15
92
91
92
89
86
90
88
89
179–181
192–194
176–178
235–237
238–240
178–180
209–211
178–180
–
H
–
H
–
H
–
3-FC6H4
H
–
4-OHC6H4
H
180 [36]
3-OHC6H4
H
6g
6h
–
–
3,5-OCH3-4-OHC6H2
CH3
The reaction was carried out with 5 (1 mmol), 2 (1 mmol), 3 (1 mmol), ionic liquid (10 mol %) under
microwave irradiation for the given time in the table
O
R2
O
O
O
O
[bmim][PF6]
mw
R1
R1
R1
R1
R2
H
R1
O
R1
7
2
3
Scheme 3 [bmim][PF6] catalyzed synthesis of xanthene derivatives under microwave irradiation (7a–i)
Table 4 Physical data of the synthesised compounds 7a–i
Entry
R2
R1
Product
Time
(min)
Yield
(%)
m.p (°C)
Found
Lit
a
1
2
3
4
5
6
7
8
9
3,4,5-(OCH3)C6H4
3,4-(OCH3)C6H4
3,5-OCH3-4-OHC6H2
4-C6H5C6H4
H
7a
7b
7c
7d
7e
7f
10
10
10
12
15
10
10
15
15
93
91
91
92
87
92
90
89
88
182–184
215–217
224–226
196–198
170–172
186–188
173–175
205–207
230–232
–
H
216 [37]
–
H
H
196–198 [38]
a
–
4-OC2H5C6H4
3,4,5-(OCH3)C6H4
3,4-(OCH3)C6H4
C6H5C6H4
H
CH3
CH3
CH3
CH3
187–189 [39]
170 [40]
7g
7h
7i
204–207 [41]
223–225 [42]
3-OHC6H4
The reaction was carried out with 2 (1 mmol), 3 (2 mmol), ionic liquid (10 mol %) under microwave
irradiation for the given time in the table
a
Reported, but m.p is unavailable
123

P. Iniyavan et al.
R2
O
[bmim][PF6]
O
H
R2
O
R2
[bmim][PF6]
H
O
1
2
H
OH
O
H
R1
OH
R1
R1
O
R1
R1
O
R1
7
8
3
[bmim][PF6
]
O
R2
O
R
2
R2
O
H
R1
R1
H2O
R1
O
4a-k
R1
R1
O
OH
OH
OH
R1
9
10
[bmim][PF
6]
[bmim][PF6]
O
O
O
R2
O
R2
O
O
R2
O
O
R2
O
H
5
O
O
O
H
O
O
H
2O
O
8
OH
OH
O
[bmim][PF
6]
OH
6a-h
[bmim][PF6]
[bmim][PF
6]
11
12
O
O
R2
O
O
R2
O
R2
O
O
R2
O
H
O
H
H2O
R
1
3
R1
R1
R1
R1
R1
R1
R1
R1
R1
R1
O
HO
OH
R1
O
O
R1
HO
R1
8
[b mi m][PF6]
[bmim][PF6]
14
13
7a-i
[bmim][PF6]
F
N
F
P
F
F
F
F
N
[bmim][PF6]
Fig. 1 Proposed mechanism for the synthesis of xanthenes and chromenes
in Table 5. The results revealed that the radical scavenging activities of benzo-
chromenes were found more active in comparison to benzoxanthenes. Compounds
6a, 6h, 6c, 6b, 4k, and 4a have showed better activity at their higher concentrations.
Experimental
Solvents and reagents were commercially sourced and used without further
purification. Melting points were recorded on an Elchem microprocessor-based DT
apparatus in open capillary tubes and are uncorrected. IR spectra were obtained on
an Avatar-330 FT-IR spectrophotometer (Thermo Nicolet) using KBr pellets. NMR
spectra were recorded on a Bruker 400-MHz spectrometer with TMS as internal
standard using CDCl3 and DMSO-d6. Mass analysis was performed using a Waters
Micromass ZQ mass spectrometer. The microwave oven used was a synthetic
microwave, CATA R catalyst microwave synthesizer with the maximum power of
850 W at 100 % power level. All reactions were carried at 40 % power level, which
123

Microwave-assisted clean synthesis of xanthenes
Fig. 2 Reusability of ionic liquid
Table 5 Antioxidant activity of synthesized compounds by DPPH method
Product Inhibition (%)
100 lg/ml 500 lg/ml 1,000 lg/ml
Product Inhibition (%)
100 lg/ml 500 lg/ml 1,000 lg/ml
BHT
4a
4b
4c
94
21
8
96
54
15
52
40
35
21
17
16
51
31
98
78
33
76
67
61
36
22
25
65
51
4k
6a
6b
6c
6d
6e
6f
25
35
31
30
8
58
62
55
53
22
33
46
42
56
53
50
81
87
80
81
35
41
76
77
86
76
75
17
14
11
8
4d
4e
9
4f
25
21
34
18
15
4g
4h
4i
5
6g
6h
7a
7c
5
20
9
4j
produces power of 340 W. TLC was performed on silica gel preparative plates (S.D.
Fine-Chem) and spots were visualized in an iodine chamber.
General procedure for the synthesis of xanthene and chromene derivatives
For the synthesis of 4a–k and 6a–h, 2-naphthol/4-hydroxy coumarin (1 mmol),
cyclic1,3-diketones(1 mmol), aromaticaldehydes(1 mmol), [bmim][PF6](10 mol %)
was taken and microwave irradiation at 40 % power was applied for the reaction
mixture and the progress of the reaction was followed by TLC. For the synthesis of
compounds 7a–i, 1,3-diketones (2 mmol) and aromatic aldehydes (1 mmol) have
taken in the same conditions. After the reaction completion, the mixture was
123

P. Iniyavan et al.
extracted with chloroform and the combined organic phase was evaporated and the
residue was recrystallized with ethanol to afford the product. The remaining IL was
dried in vacuum at 90 °C, which was used for further subsequent runs without
further purification.
Spectral data of compounds 4a–k, 6a–h, and 7a–i
12-(3,4,5-Trimethoxyphenyl)-9,10-dihydro-8H-benzo[a]xanthen-11(12H)-one (4a):
1
white solid, mp 180–182 °C; H NMR (400 MHz, CDCl3): d 2.05 (m, 2H, CH2),
2.46 (m, 2H, CH2), 2.72 (m, 2H, CH2), 3.72 (s, 9H, OCH3), 5.7 (s, 1H, CH), 6.53 (s,
2H, ArH), 7.34 (d, J = 8.8 Hz, 1H, ArH), 7.4 (d, J = 8, 2H, ArH), 7.78 (t,
J = 7.6 Hz, 2H, ArH), 7.97 (d, J = 8 Hz, 1H, ArH) ppm; 13C NMR (100 MHz,
CDCl3): d 20.32, 27.82, 34.65, 37.14, 56.1, 60.75, 105.68, 115.56, 116.97, 117.53,
123.78, 125.05, 127.09, 128.46, 129.01, 131.53, 136.35, 140.77, 147.97, 152.99,
165.82, 197.31 ppm; DEPT-135 (100 MHz, CDCl3): d 20.27 (CH2, C-9), 27.77
(CH2, C-8), 34.6 (CH, C-12) 37.08 (CH2, C-10), 56.05 (OCH3, C-17 170), 60.7
(OCH3, C-18), 105.62 (CH, C-14,140), 116.73 (CH, C-6), 123.73 (CH, C-1), 125
(CH, C-5), 127.04 (CH, C-4), 128.41 (CH, C-3), 128.95 (CH, C-2) ppm; LC–MS:
m/z 416.95 (M ? 1); Anal. calcd. for C26H24O5 C, 74.98; H, 5.81, Found C, 74.28;
H, 5.86.
12-(4-Chlorophenyl)-9,10-dihydro-8H-benzo[a]xanthen-11(12H)-one (4b): white
solid, mp 205–207 °C; 1H NMR (400 MHz, CDCl3): d 2.05 (m, 2H, CH2), 2.39 (m,
2H, CH2), 2.69 (m, 2H, CH2), 5.71 (s, 1H, CH), 7.12 (d, J = 6.8 Hz, 2H, ArH), 7.25 (d,
J = 6.4 Hz, 2H, ArH), 7.34 (d, J = 8.8 Hz, 1H, ArH), 7.4 (d, 2H, J = 7.6 Hz, ArH),
7.78 (t, 2H, J = 7.6 Hz, ArH), 7.87 (d, 2H, J = 8 Hz, ArH) ppm; 13C NMR
(100 MHz, CDCl3): d 20.41, 27.87, 34.26, 37.16, 115.26, 117.12, 117.20, 123.63,
125.16, 127.26, 128.62, 129.24, 131.33, 131.65, 132.09, 143.65, 147.88, 165.9,
197.22 ppm; Anal. calcd. for C23H17ClO2 C, 76.56; H, 4.75, Found C, 75.98; H, 4.25.
12-(3,4-Dimethoxyphenyl)-9,10-dihydro-8H-benzo[a]xanthen-11(12H)-one (4c):
1
white solid, mp 182–184 °C; H NMR (400 MHz, CDCl3) d: 2.03 (m, 2H, CH2),
2.45 (m, 2H, CH2), 2.75 (m, 2H, CH2), 3.74 (s, 3H, OCH3), 3.81 (s, 3H, OCH3) 5.7
(s, 1H, CH), 6.64 (d, J = 8, 2H, ArH), 7.01 (s, 1H, ArH), 7.42 (m, 3H, ArH), 7.77 (t,
J = 7.6 Hz, 2H, ArH), 7.95 (d, J = 8 Hz, 1H, ArH) ppm; 13C NMR (100 MHz,
CDCl3): d 20.41, 27.86, 34.14, 37.19, 55.81, 55.99, 111.04, 112.25, 115.8, 117.02,
117.83, 120.5, 123.85, 125.02, 127.08, 128.48, 128.9, 131.56, 131.6, 137.99,
147.41, 147.95, 148.7, 165.6, 197.34 ppm; Anal. calcd. for C25H22O4 C, 77.70; H,
5.74, Found C, 78.20; H, 5.71.
12-(4-Hydroxy-3,5-dimethoxyphenyl)-9,10-dihydro-8H-benzo[a]xanthen-
1
11(12H)-one (4d): white solid, mp 189–191 °C; H NMR (400 MHz, CDCl3)
d: 2.03 (m, 2H, CH2), 2.46 (m, 2H, CH2), 2.71 (m, 2H, CH2), 3.75 (s, 6H,
OCH3), 5.32 (s, 1H, OH) 5.68 (s, 1H, CH), 6.53 (s, 2H, ArH), 7.33 (m, 3H,
ArH), 7.78 (m, 2H, ArH), 7.95 (m, 1H, ArH) ppm; 13C NMR (100 MHz,
CDCl3) d: 20.31, 27.15, 32.7, 36.94, 55.86, 56.05, 106.88, 111.15, 113.01,
113.72, 116.41, 116.85, 120.02, 122.43, 124.31, 132.19, 135.6, 148.13,
148.71, 152.56, 153.78, 160.76, 163.58, 196.23 ppm; Anal. calcd. for
C
25H22O5 C, 74.61; H, 5.51, Found C, 73.91; H, 5.43.
123

Microwave-assisted clean synthesis of xanthenes
12-(2-Ethoxyphenyl)-9,10-dihydro-8H-benzo[a]xanthen-11(12H)-one (4e): white
solid, mp 194–196 °C; 1H NMR (400 MHz, CDCl3): d 1.46 (t, 3H, OCH2CH3), 2.03
(m, 2H, CH2), 2.38 (m, 2H, CH2), 2.72 (m, 2H, CH2), 3.97,4.08(q, 2H, J = 7.6 Hz,
OCH2CH3), 5.93 (s, 1H, CH), 6.74 (d, J = 8 Hz, 1H, ArH), 6.8 (t, J = 7.2 Hz, 1H,
ArH), 7.02 (t, J = 7.6 Hz, 1H, ArH), 7.24 (d, J = 7.2 Hz, 1H, ArH), 7.33 (t,
J = 7.6 Hz 1H, ArH), 7.41 (d, J = 7.6 Hz, 2H, ArH), 7.72 (t, J = 8 Hz, 2H, ArH),
8.29 (d, J = 8.4 Hz, 1H, ArH) ppm; 13C NMR (100 MHz, CDCl3): d 15.00, 20.64,
27.95, 30.91, 37.29, 63.87, 112.12, 114.7, 118.28, 120.44, 124.22, 126.72, 127.78,
128.41, 131.40, 132.04, 132.99, 147.88, 156.31, 165.96, 197.15 ppm; Anal. calcd. for
C25H22O3 C, 81.06; H, 5.99, Found C, 80.37; H, 5.13.
12-(Biphenyl-4-yl)-9,10-dihydro-8H-benzo[a]xanthen-11(12H)-one (4f): white
1
solid, mp 225–227 °C; H NMR (400 MHz, CDCl3): d 2.04 (m, 2H, CH2), 2.46
(m, 2H, CH2), 2.72 (m, 2H, CH2), 5.77 (s, 1H, CH), 6.53 (d, J = 6.4 Hz, 8H, ArH),
7.47 (t, J = 7.6 Hz, 3H, ArH), 7.78 (t, J = 6.0 Hz, 2H, ArH), 7.9 (d, J = 8.4 Hz,
1H, ArH) ppm; 13C NMR (100 MHz, CDCl3): d 20.43, 27.91, 34.45, 37.22, 115.62,
117.16, 117.75, 123.85, 125.08, 127.09, 127.12, 127.18, 128.55, 128.74, 128.99,
129.03, 131.52, 131.64, 139.16, 141.03, 144.26, 147.94, 165.86, 197.33 ppm; Anal.
calcd. for C29H22O2 C, 86.54; H, 5.51, Found C, 86.91; H, 5.39.
12-(3-Nitrophenyl)-9,10-dihydro-8H-benzo[a]xanthen-11(12H)-one (4g): white
solid, mp 231–233 °C; 1H NMR (400 MHz, CDCl3): d 2.07 (m, 2H, CH2), 2.44 (m,
2H, CH2), 2.77 (m, 2H, CH2), 5.84 (s, 1H, CH), 7.42 (d, 4H, ArH), 7.82 (t,
J = 8.4 Hz, 4H, ArH), 7.95 (d, J = 7.2 Hz, 1H, ArH), 8.08 (s, 1H, ArH) ppm; 13
C
NMR (100 MHz, CDCl3): d 20.39, 27.88, 34.85, 37.06, 114.54, 116.15, 117.30,
121.75, 123.29, 123.46, 125.33, 127.49, 128.83, 129.21, 129.81, 131.08, 131.74,
135.09, 147.13, 147.97, 148.60, 166.39, 197.15 Anal. calcd. for C23H17NO4 C,
74.38; H, 4.61; N, 3.77, Found C, 74.18; H, 4.22; N, 4.12.
12-(2-Fluorophenyl)-9,10-dihydro-8H-benzo[a]xanthen-11(12H)-one (4h): red
1
solid, mp 270–272 °C; H NMR (400 MHz, CDCl3): d 2.17 (m, 2H, CH2), 2.55
(m, 2H, CH2), 2.72 (m, 2H, CH2), 5.75 (s, 1H, CH), 6.61 (m, 2H, ArH), 7.01 (m, 2H,
ArH), 7.34 (m, 1H, ArH), 7.37 (m, 3H, ArH), 7.64 (d, J = 8.0 Hz, 1H, ArH), 7.79
(m, 1H, ArH), ppm; 13C NMR (100 MHz, CDCl3): d 20.08, 28.05, 28.28, 31.08,
36.52, 76.85, 77.16, 77.48, 115.29, 116.65, 117.65, 118.85, 121.56, 123.57, 125.41,
127.67, 128.13, 128.39, 129.07, 129.27, 131.19, 131.67, 132.83, 147.95, 153.15,
168.81, 201.21 ppm; Anal. calcd. for C23H17FO2 C, 80.22; H, 4.98, Found C, 79.01;
H, 5.13.
12-(3-Hydroxyphenyl)-9,10-dihydro-8H-benzo[a]xanthen-11(12H)-one (4i): white
solid, mp 205–207 °C; 1H NMR (400 MHz, DMSO-d6): d 1.86 (s, 2H, CH2), 2.35 (s,
2H, CH2), 2.73 (s, 2H, CH2), 5.52 (s, 1H, CH), 6.45 (m, 1H, ArH), 6.64 (m, 1H, ArH),
6.75 (m, 1H, ArH), 6.97 (m, 1H, ArH), 7.43 (m, 3H, ArH), 7.92 (m, 3H, ArH), 9.26 (s,
1H, OH) ppm; 13C NMR (100 MHz, DMSO-d6): d 18.52, 19.90, 26.42, 26.92, 30.49,
33.81, 36.45, 56.03, 113.13, 113.26, 114.47, 115.04, 115.59, 117.07, 117.33, 118.46,
118.98, 123.17, 124.94, 127.09, 128.51, 128.95, 129.04, 130.67, 131.02, 146.46, 147.22,
156.93, 157.13, 164.75, 165.62, 196.15 ppm; Anal. calcd. for C23H18O3 C, 80.68; H,
5.30, Found C, 79.98; H, 5.23.
9,9-Dimethyl-12-phenyl-9,10-dihydro-8H-benzo[a]xanthen-11(12H)-one (4j):
1
white solid, mp 205–207 °C; H NMR (400 MHz, CDCl3): d 0.98 (s, 3H, CH3),
123

P. Iniyavan et al.
1.12 (s, 3H, CH3), 2.3 (q, J = 8.8 Hz, 2H, CH2), 2.59 (s, 2H, CH2), 5.74 (s, 1H,
CH), 7.33 (m, 2H, ArH), 7.35 (m, 4H, ArH), 7.4 (m, 2H, ArH), 7.78 (m, 2H, ArH),
8.04 (d, J = 6.8 Hz, 1H, ArH) ppm; 13C NMR (100 MHz, CDCl3): d 27.39, 29.43,
32.47, 34.53, 41.57, 51.06, 114.3, 117.23, 117.73, 123.82, 125.08, 127.06, 127.13,
128.56, 128.74, 128.92, 129.02, 131.53, 131.64, 139.07, 141, 143.98, 147.88,
164.16, 197.19 ppm; Anal. calcd. for C25H22O2 C, 84.72; H, 6.26, Found C, 85.12;
H, 6.39.
12-(4-Hydroxy-3,5-dimethoxyphenyl)-9,9-dimethyl-9,10-dihydro-8H-benzo[a]
xanthen-11(12H)-one (4k): white solid, mp 205–207 °C; 1H NMR (400 MHz,
CDCl3): d 0.99 (s, 3H, CH3), 1.12 (s, 3H, CH3), 2.29 (s, 2H, CH2), 2.56 (s, 2H,
CH2), 3.75 (s, 6H, OCH3), 5.32 (s, 1H, OH) 5.64 (s, 1H, CH), 6.54 (s, 2H, ArH),
7.32 (m, 4H, ArH), 7.77 (m, 2H, ArH), 8 (m, 1H, ArH) ppm; 13C NMR (100 MHz,
CDCl3): d 27.06, 27.13, 29.37, 29.44, 31.62, 32.20, 32.28, 34.50, 40.92, 41.45,
50.76, 50.93, 56.27, 56.35, 105.38, 105.53, 114.38, 115.73, 116.98, 117.63,
123.70, 124.97, 126.99, 128.41, 128.86, 131.50, 133.12, 133.47, 135.43, 136.14,
146.64, 146.73, 147.80, 162.18, 163.81, 197.07. ppm; Anal. calcd. for C27H26O5.
C, 75.33; H, 6.09, Found C, 74.37; H, 6.29.
7-(3,4,5-Trimethoxyphenyl)-10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-
dione (6a): white solid, mp 179–181 °C; 1H NMR (400 MHz, CDCl3): d 2.14 (m, 2H,
CH2), 2.44 (m, 2H, CH2), 2.77 (m, 2H, CH2), 3.76 (s, 3H, OCH3), 3.8 (s, 6H, OCH3),
4.95(s, 1H, CH), 6.59(s, 2H, ArH), 7.32(t, J = 8 Hz, 2H, ArH), 7.56(d, 1H, ArH), 7.88
(d, J = 8.0, 2H, ArH) ppm; 13C NMR (100 MHz, CDCl3): d 20.44, 27.27, 33.33, 37.03,
56.38, 60.79, 106.20, 106.73, 113.72, 116.26, 117, 122.55, 124.44, 132.41, 137.4,
138.24, 153.14, 160.85, 163.91, 196.28 ppm; Anal. calcd. for C25H22O7 C, 69.12; H,
5.10, Found C, 69.19; H, 5.65.
7-(3,4-Dimethoxyphenyl)-10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-
1
dione (6b): white solid, mp 192–194 °C; H NMR (400 MHz, CDCl3): d 1.96 (m,
2H, CH2), 2.29 (m, 2H, CH2), 2.95 (m, 2H, CH2), 3.95 (s, 3H, OCH3), 4.05 (s, 3H,
OCH3), 5.10 (s, 1H, CH), 6.61 (s, 2H, ArH), 7.32 (t, J = 8.0 Hz, 2H, ArH), 7.56 (d,
1H, ArH), 7.86 (d, J = 8.0, 2H, ArH) ppm; 13C NMR (100 MHz, CDCl3): d 20.34,
27.20, 32.72, 36.98, 55.87, 56.06, 76.84, 77.16, 77.48, 106.89, 111.03, 112.91,
113.73, 116.42, 116.91, 120.01, 122.48, 132.26, 135.58, 148.08, 148.65, 152.57,
153.83, 160.86, 163.66, 196.38 ppm; Anal. calcd. for C24H20O6 C, 71.28; H, 4.98,
Found C, 71.39; H, 5.06.
7-(4-Hydroxy-3,5-dimethoxyphenyl)-10,11-dihydrochromeno[4,3-b]chro-
1
mene-6,8(7H,9H)-dione (6c): white solid, mp 176–178 °C; H NMR (400 MHz,
CDCl3): d 2.14 (m, 2H, CH2), 2.45 (m, 2H, CH2), 2.79 (m, 2H, CH2), 3.83 (s, 6H,
OCH3), 4.93 (s, 1H, OH), 5.47 (s, 1H, CH), 6.61 (s, 2H, ArH), 7.32 (t, J = 8.0 Hz, 2H,
ArH), 7.56 (d, 1H, ArH), 7.86 (d, J = 8.0, 2H, ArH) ppm; 13C NMR (100 MHz,
CDCl3): d 20.39, 27.20, 33.12, 36.98, 56.54, 105.93, 106.78, 113.68, 116.32,
116.91, 122.5, 124.39, 132.31, 133.86, 134.24, 146.87, 152.57, 153.83, 160.82,
163.71, 196.32 ppm; Anal. calcd. for C24H20O7 C, 68.57; H, 4.80, Found C, 69.21;
H, 5.09.
7-(Biphenyl-4-yl)-10,11-dihydrochromeno[4,3-b]chromene-6,8(7H, 9H)-dione
1
(6d): white solid, mp 235–237 °C; H NMR (400 MHz, CDCl3): d 2.13 (m, 2H,
CH2), 2.42 (m, 2H, CH2), 2.88 (m, 2H, CH2), 5.03 (s, 1H, CH), 7.29 (d, J = 7.6 Hz,
123

Microwave-assisted clean synthesis of xanthenes
2H, ArH) 7.33 (d, J = 8.0 Hz, 3H, ArH), 7.38 (t, J = 7.6 Hz, 4H, ArH), 7.51 (d,
J = 6.8 Hz, 2H, ArH), 7.56 (t, J = 7.6 Hz, 1H, ArH), 7.88 (d, J = 7.6 Hz, 2H,
ArH) ppm; 13C NMR (100 MHz, CDCl3): d 20.37, 27.29, 33.13, 37.03, 106.82,
113.78, 116.41, 117.03, 122.58, 124.44, 127.20, 127.28, 128.76, 129.14, 132.39,
140.07, 141.06, 141.87, 152.73, 154.08, 160.83, 163.83, 196.35 ppm; Anal. calcd.
for C28H20O4 C, 79.98; H, 4.79, Found C, 80.18; H, 4.27.
7-(3-Fluorophenyl)-10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-
1
dione (6e): white solid, mp 238–240 °C; H NMR (400 MHz, CDCl3): d 2.17
(m, 2H, CH2), 2.49 (m, 2H, CH2), 2.9 (m, 2H, CH2), 5.03 (s, 1H, CH), 7.29 (d,
J = 7.6 Hz, 2H, ArH) 7.33 (d, J = 8.0 Hz, 3H, ArH), 7.38 (t, J = 7.6 Hz,
4H, ArH), 7.51 (d, J = 6.8 Hz, 2H, ArH), 7.56 (t, J = 7.6 Hz, 1H, ArH), 7.88
(d, J = 7.6 Hz, 2H, ArH) ppm; 13C NMR (100 MHz, CDCl3): d 20.32, 27.27,
33.24, 36.96, 106.33, 113.63, 114.08, 114.29, 115.46,115.68, 116.07, 117.06,
122.63, 124.53, 124.67, 124.7, 129.76 129.84, 132.57, 145.15, 145.21,
152.75, 154.23, 160.70, 161.74, 164, 164.19 196.19 ppm; Anal. calcd. for
C
22H15FO4 C, 72.92; H, 4.17, Found C, 71.28; H, 4.29.
7-(4-Hydroxyphenyl)-10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione
1
(6f): white solid, mp 178–180 °C; H NMR (400 MHz, DMSO-d6): d 2.39 (m, 2H,
CH2), 2.53(m, 2H, CH2), 2.75(m, 2H, CH2), 5.55(m, 1H, CH), 6.49(m, 1H, ArH), 6.68
(m, 1H, ArH), 7.02 (m, 1H, ArH), 7.46 (m, 2H, ArH), 7.95 (d, J = 8.0 Hz, 2H, ArH),
8.02 (d, J = 8.0 Hz, 1H, ArH), 9.32 (s, 1H, OH) ppm; 13C NMR (100 MHz, DMSO-
d6): d 19.91, 26.92, 33.82, 36.45, 79.16, 113.26, 114.49, 115.05, 117.06, 118.98,
123.18, 124.92, 127.08, 128.50, 128.94, 129.03, 130.68, 131.02, 146.46, 147.23,
157.16, 165.57, 196.09 ppm; Anal. calcd. for C22H16O5 C, 73.33; H, 4.48, Found C,
72.93; H, 4.56.
7-(3-Hydroxyphenyl)-10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione
(6g): white solid, mp 209–211 °C; 1H NMR (400 MHz, DMSO-d6): d 1.95 (m, 2H,
CH2), 2.4 (m, 2H, CH2), 2.81 (m, 2H, CH2), 4.64 (s, 1H, CH), 6.56 (s, 1H, ArH), 6.67
(m, 2H, ArH), 7.03 (d, J = 7.6 Hz, 1H, ArH), 7.43 (m, 2H, ArH), 7.67 (m, 1H, ArH),
7.95 (d, J = 8.0 Hz, 1H, ArH), 9.32 (s, 1H, OH) ppm; 13C NMR (100 MHz, DMSO-
d6): d 19.80, 21.03, 26.36, 32.57, 36.38, 105.84, 113.06, 113.78, 114.94, 115.37,
116.55, 118.84, 122.55, 124.77, 129.13, 132.77, 144.25, 151.86, 153.58, 157.08,
159.95, 164.45, 172.02, 196.09 ppm; Anal. calcd. for C22H16O5 C, 73.33; H, 4.48,
Found C, 74.02; H, 4.63.
7-(4-Hydroxy-3,5-dimethoxyphenyl)-10,10-dimethyl-10,11-dihydrochromeno[4,3-
b]chromene 6,8(7H,9H)-dione (6h): white solid, mp 178–180 °C; 1H NMR (400 MHz,
CDCl3): d 1.14 (s, 3H, CH3), 1.18 (s, 3H, CH3), 2.31 (m, 2H, CH2), 2.69 (m, 2H, CH2),
3.83(s, 6H, OCH3),4.9(s, 1H, OH),5.4(s, 1H, CH), 6.6(s, 2H, ArH), 7.34(m,2H, ArH),
7.55 (m, 1H, ArH), 7.87 (m, 1H, ArH) ppm; 13C NMR (100 MHz, CDCl3): d 27.30,
29.42, 30.95, 32.32, 33.22, 40.89, 50.71, 56.46, 105.86, 106.91, 113.73, 115.12, 116.96,
122.42, 124.29, 132.24, 133.71, 134.13, 146.82, 152.58, 153.72, 160.75, 162.05,
196.08 ppm; Anal. calcd. for C26H24O7 C, 69.63; H, 5.39, Found C, 69.92; H, 5.79.
9-(3,4,5-Trimethoxyphenyl)-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione
(7a): white solid, mp 182–184 °C; 1H NMR (400 MHz, CDCl3): d 2 (m, 4H, CH2),
2.35 (m, 4H, CH2), 2.64 (m, 4H, CH2), 3.77 (s, 3H, OCH3), 3.82 (s, 6H, OCH3), 4.79 (s,
1H, CH), 6.52 (s, 2H, ArH) ppm; 13C NMR (100 MHz, CDCl3): d 20.45, 27.27, 31.54,
123

P. Iniyavan et al.
37.09, 56.26, 60.79, 105.73, 116.81, 117.22, 136.71, 140, 152.91, 164.19,
196.83 ppm; Anal. calcd. for C22H24O6 C, 68.74; H, 6.29, Found C, 68.29; H, 6.19.
9-(3,4-Dimethoxyphenyl)-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione
1
(7b): white solid, mp 215–217 °C; H NMR (400 MHz, CDCl3): d 2.01 (m, 4H,
CH2), 2.37 (m, 4H, CH2), 2.67 (m, 4H, CH2), 3.79 (s, 6H, OCH3), 4.77 (s, 1H,
CH), 6.7 (s, 2H, ArH), 7 (s, 1H, ArH) ppm; 13C NMR (100 MHz, CDCl3): d
20.17, 20.34, 27.16, 30.95, 36.99, 55.79, 55.95, 60.41, 110.90, 112.66, 116.95,
119.61, 137.28, 147.53, 148.42, 163.88, 196.72 ppm; Anal. calcd. for C21H22O5
C, 71.17; H, 6.26, Found C, 70.29; H, 6.01.
9-(4-Hydroxy-3,5-dimethoxyphenyl)-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-
dione (7c): white solid, mp 224–226 °C; 1H NMR (400 MHz, CDCl3): d 2.04 (m, 4H,
CH2), 2.35 (m, 4H, CH2), 2.59 (m, 4H, CH2), 3.85 (s, 6H, OCH3), 4.76 (s, 1H, OH), 5.36
(s, 1H, CH)6.54(s, 2H, ArH)ppm; 13C NMR (100 MHz, CDCl3): d 20.39, 27.18, 31.30,
37.02, 56.44, 76.73, 77.05, 77.25, 77.37, 105.55, 116.90, 133.63, 135.56, 146.65,
163.87, 196.70 ppm; Anal. calcd. for C21H22O6 C, 68.10; H, 5.99; Found C, 69.79; H,
6.14.
9-(Biphenyl-4-yl)-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (7d): white
solid, mp 196–198 °C; 1H NMR (400 MHz, CDCl3): d 2.02 (m, 4H, CH2), 2.36 (m,
4H, CH2), 2.65 (m, 4H, CH2), 4.85 (s, 1H, CH), 7.38 (m, 9H, ArH) ppm; 13C NMR
(100 MHz, CDCl3): d 20.32, 27.20, 31.36, 36.99, 116.85, 126.96, 127.08, 128.61,
128.78, 139.28, 141.16, 143.49, 164.04, 196.69. ppm; Anal. calcd. for C25H22O3 C,
81.06; H, 5.99, Found C, 80.85; H, 6.04.
9-(4-Ethoxyphenyl)-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (7e): white
1
solid, mp 170–172 °C; H NMR (400 MHz, CDCl3): d 1.35 (t, J = 6.8 Hz, 3H,
OCH2CH3), 1.98 (m, 4H, CH2), 2.34 (m, 4H, CH2), 2.56 (m, 4H, CH2), 3.94 (m, 2H,
OCH2CH3), 4.74 (s, 1H, CH), 6.74 (d, J = 8.0 Hz, 2H, ArH), 7.19 (d, J = 8.0 Hz, 2H,
ArH) ppm; 13C NMR (100 MHz, CDCl3): d 15.03, 20.45, 27.27, 30.86, 37.11, 63.37,
76.84, 77.16, 77.47, 114.18, 117.22, 129.42, 136.69, 157.57, 163.82, 196.75 ppm;Anal.
calcd. for C21H22O4 C, 74.54; H, 6.55, Found C, 74.91; H, 6.78.
3,3,6,6-Tetramethyl-9-(3,4,5-trimethoxyphenyl)-3,4,5,6,7,9-hexahydro-1H-
1
xanthene-1,8(2H)-dione (7f): mp 186–188 °C; H NMR (400 MHz, CDCl3): d
1 (s, 6H, CH3), 1.11 (s, 6H, CH3), 2.23 (s, 4H, CH2), 2.47 (s, 4H, CH2), 3.8 (s,
9H, OCH3), 4.7 (s, 1H, CH), 6.51 (s, 2H, ArH), ppm; 13C NMR (100 MHz,
CDCl3): d 27.21, 29.39, 32.21, 40.92, 50.75, 56.11, 60.73, 105.70, 115.58,
136.54, 139.75, 152.80, 162.39, 196.57 ppm; Anal. calcd. for C26H32O6 C,
70.89; H, 7.32, Found C, 70.23; H, 7.19.
9-(3,4-Dimethoxyphenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-
1,8(2H)-dione (7g): mp 173–175 °C; 1H NMR (400 MHz, CDCl3): d 0.93 (s, 6H, CH3),
1.03 (s, 6H, CH3), 2.15 (q, J = 8.0 Hz, 4H, CH2), 2.39 (m, 4H, CH2), 3.78 (s, 6H,
OCH3), 4.62 (s, 1H, CH), 6.65 (d, J = 9.6 Hz, 2H, ArH) 6.83 (s, 1H, ArH) ppm; 13
C
NMR (100 MHz, CDCl3): d 27.26, 29.35, 31.23, 32.20, 40.88, 50.75, 55.76, 55.88,
110.83, 112.28, 115.75, 120.11, 136.99, 147.45, 148.43, 162.18, 196.58. ppm; Anal.
calcd. for C25H30O5 C, 73.15; H, 7.37, Found C, 73.29; H, 7.96.
9-(Biphenyl-4-yl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-
dione (7h): white solid, mp 205–207 °C; 1H NMR (400 MHz, CDCl3): d 1(s, 6H, CH3),
1.1 (s, 6H, CH3) 2.23 (q, J = 10.4 Hz, 4H, CH2), 2.48 (s, 4H, CH2), 4.79 (s, 1H, CH),
123

Microwave-assisted clean synthesis of xanthenes
7.27 (d, J = 8.4 Hz, 1H, ArH),), 7.36 (t, J = 7.6 Hz, 4H, ArH), 7.45 (d, J = 8 Hz, 2H,
ArH), 7.51 (d, J = 8 Hz, 2H, ArH) ppm; 13C NMR (100 MHz, CDCl3): d 27.37, 29.29,
32.05, 40.80, 50.66, 113.29, 126.73, 129.87, 132.81, 134.04, 163.24, 196.55 ppm; Anal.
calcd. for C29H30O3 C, 81.66; H, 7.09, Found C, 81.82; H, 7.76.
9-(3-Hydroxyphenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-
1
1,8(2H)-dione (7i): white solid, mp 230–232 °C; H NMR (400 MHz, CDCl3): d
1(s, 6H, CH3), 1.09 (s, 6H, CH3) 2.21 (q, J = 8 Hz, 4H, CH2), 2.46 (s, 4H, CH2),
4.73 (s, 1H, CH), 6.58 (d, J = 8.0 Hz, 1H, ArH),), 6.71 (d, J = 8.0 Hz, 4H, ArH),
7.01 (s, 1H, ArH), 7.04 (t, J = 8.0 Hz, 1H, ArH) ppm; 13C NMR (100 MHz,
CDCl3): d 27.44, 29.19, 31.72, 32.26, 40.88, 50.69, 113.62, 115.61, 116.32, 119.70,
129.16, 145.55, 155.91, 162.59, 196.98 ppm; Anal. calcd. for C23H26O4 C, 75.38;
H, 7.15, Found C, 75.59; H, 7.49.
Conclusions
In summary, a convenient, green, and efficient methodology was developed to
synthesize xanthene and chromene derivatives via a three-component reaction of
aldehydes, 4-hydroxy coumarin/2-naphthol and 1,3-cyclohexanediones. The syn-
thesis of variety of these compounds with better yield in reasonable reaction time is
the main scope of this developed methodology. In addition, the reactions were
carried out in IL, which is considerably safer, nontoxic, and reusable. Antioxidant
studies of the synthesized compounds revealed that the compounds showed good-to-
moderate activity.
Acknowledgments The authors are thankful to the administration of VIT University, Vellore, India,
for providing facilities to conduct research work and are also thankful to SIF-Chemistry, VIT University,
for providing NMR and IR spectral facilities. Author P. Iniyavan is thankful to the VIT University for
providing an Research Associateship.
References
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