Regioselective synthesis of 3,4,6,7-tetrahydro-3,3-dimethyl-9-phenyl-2H-xanthene-1,8(5H,9H)-diones through ascorbic acid catalyzed three-component domino reaction

Article abstract of DOI:10.1016/j.tetlet.2014.08.040

An efficient, three-component domino reaction of dimedone 1, aromatic aldehydes (2a-o), and 1,3-cyclohexanedione 1a in the regio-selective synthesis of 3,3-dimethyl-9-phenyl-2H-xanthene-1,8(5H,9H)-diones (3a-o) is reported. The desired product, 3 is effic

Full text of DOI:10.1016/j.tetlet.2014.08.040

Accepted Manuscript
Regioselective synthesis of 3,4,6,7-tetrahydro-3,3-dimethyl-9-phenyl-2H-xan-
thene-1,8(5H,9H)-diones through ascorbic acid catalyzed three-component
domino reaction
Ayyakannu Arumugam Napoleon, Fazlur-Rahman Nawaz Khan, Euh Duck
Jeong, Eun Hyuk Chung
PII:
S0040-4039(14)01361-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.08.040
TETL 45007
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 June 2014
7 August 2014
9 August 2014
Please cite this article as: Napoleon, A.A., Khan, F.N., Jeong, E.D., Chung, E.H., Regioselective synthesis of 3,4,6,7-
tetrahydro-3,3-dimethyl-9-phenyl-2H-xanthene-1,8(5H,9H)-diones through ascorbic acid catalyzed three-
component domino reaction, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.08.040
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Regioselective synthesis of 3,4,6,7-tetrahydro-3,3-dimethyl-9-phenyl-2H-xanthene-
1,8(5H,9H)-diones through ascorbic acid catalyzed three-component domino
reaction
Ayyakannu Arumugam Napoleona, Fazlur-Rahman Nawaz Khana b
*, *
b
Euh Duck Jeong Eun Hyuk Chung
b
*
aOrganic and Medicinal Chemistry Research Laboratory, Organic Chemistry Division, School of Advanced
Sciences, VIT-University, Vellore 632 014, Tamil Nadu, India.
bKorea Basic Science Institute, Busan Center, Busan 618 230, South Korea.
*Correspondence: E-mail; Prof. F. Nawaz Khan: nawaz_f@yahoo.co.in; fnkn@kbsi.re.kr; Dr. E.D Jeong,
edjeong@kbsi.re.kr
Abstract
An efficient, three-component domino reaction of dimedone 1, aromatic aldehydes (2a-o) and 1,3-cyclohexanedione 1a in the
regio-selective synthesis of 3,3-dimethyl-9-phenyl-2H-xanthene-1,8(5H, 9H)-diones (3a-o) is reported. The desired product, 3 is
efficiently promoted by ascorbic acid as an organo catalyst.
Keywords: Regioselective synthesis, xanthene-1,8(5H, 9H)-diones, ascorbic acid, three-component domino reaction.
Xanthenes and benzoxanthenes have attracted substantial
researchers due to their pharmaceutical activities such as
(without the need of isolation of intermediates). To the best of
our knowledge there are no reports on organo-catalyzed
synthesis of unsymmetrical xanthenediones in a one- pot reaction.
Based on our research interests,25-35 herein we report an efficient
regioselective synthesis of 3,4,6,7-tetrahydro-3,3-dimethyl-9-
phenyl-2H-xanthene-1,8(5H,9H)diones 3a-o through three-
component domino reaction in presence of ascorbic acid under
reflux conditions in ethanol. (Fig. 1)
antibacterial,1 antiviral,2
anticancer,3 anti-inflammatory
activities,4 their use in photodynamic therapy and as dyes.5 There
are numerous reports on the synthesis of 1,8-dioxo octahydro
xanthene involving p-dodecyl benzene sulfonic acid in an
aqueous media,6 glycerol as a promoting medium in catalyst-free
synthesis,7 InCl3.4H2O in ionic liquid,8 zinc oxide nanoparticles,9
cesium fluoride in ethanol,10 Fe3O4 nanoparticles,11 β-cyclo-
dextrin in water,12 molecular iodine using isopropanol,3 alumina-
Preliminary reaction was attempted using benzaldehyde 2 (2a, 1
mmol), dimedone 1 (1 mmol), 1,3-cyclohexanedione 1a (1 mmol)
in refluxing ethanol in the presence of ascorbic acid. The desired
sulfuric
acid
in
alcohol,13 silica
sulfuric
acid,14
Montmorillonite,15
polyaniline-p-toluene sulfonate salt in
unsymmetrical
3,4,6,7-tetrahydro-3,3-dimethyl-9-phenyl-2H-
aqueous media,16 SmCl3 in acetic acid under solvent-free
thermal condition.18 There are also reports on the synthesis of
benzoxanthenones catalyzed by proline triflate in water,19
strontium triflate,20 pTSA in ionic liquid and neat conditions,21
and molecular iodine under solvent-free conditions.22 There are
also reports on the synthesis of 14-aryl-14H-dibenzoxanthene-
8,13-diones catalyzed by silica chloride.23,24 Most of the above
reported methods involved the condensation of aldehyde with
dimedone or 1,3-cyclohexanedione towards symmetrical
xanthenediones synthesis and however not in the presence of both
of them to afford the unsymmetrical derivatives. Therefore, the
synthesis of unsymmetrical xanthenediones derivatives is of
enormous importance.
xanthene-1,8(5H,9H)-dione, 3a was obtained in moderate yield
along with trace amounts of other symmetrical xanthenediones 4a
and 5a. With the intention of obtaining regioselectivity in the
three-component reaction, optimization of molar fraction of two
cyclohexanedione reactants, catalysts, catalyst loading and
solvent were investigated and the results are discussed in tables
(Table 1 and 2).
17
From the experimental results it is observed that 1,3-
cyclohexanedione (1,3-CHD) has higher reactivity in comparison
to dimedone (DMD). i.e., equimolar substrates when reacted
afforded unsymmetric xanthenedione 3a as the major product
(entry 7, Table 1) along with other xanthenediones 4a and 5a.
However the later compound 5a was obtained in higher yield
compared to 4a. In order to ascertain the selectivity and to
increase the desired product (3a) yield the different molar ratio of
the DMD, 1 and 1,3-CHD, 1a was been investigated. With an
increase of DMD, 1 the yield of the desired product also
Domino or cascade reactions form a versatile organic synthetic
method for the polycyclic compounds of biological interest. The
main advantages of a cascade reaction are their rapid reactivity
(due to intramolecular reactions), one pot reaction approach
1

increased (entries 8-12, Table 1) and vice versa with the increase
of 1,3-CHD, 1a (entries 1-6, Table 1). The best result was
obtained when optimized molar quantities of 1.2:0.8 (DMD and
All the prepared compounds gave good yield (80-88%). The
spectral data and their interpretation are provided in SI.
Table 1 Optimization of molar ratio of reactantsa.
1,3-CHD) was utilized.
With these available results in hand,
Entry Reactants (mmol)
Product
Yield (%)b
further investigation on effect of catalyst, catalyst loading was
attempted. The results are reported in Table 2. Among the
various acidic catalysts employed viz., L-ascorbic acid, L-tartaric
acid, L-glycine, L-lysine, L-aspartic acid, L-proline, PTSA and
molecular iodine, the best result was obtained when the reaction
was performed with an optimized amount of 10mg (0.056 mmol)
of ascorbic acid (entry 12, Table 2)
Molar
ratio
DMD,
1,3-CHD
3
4
5
1
1a
1: 1a
0.400
0.416
0.428
0.444
0.454
0.473
0.5
0.525
0.545
0.555
0.583
0.600
1
2
3
4
5
6
7
8
0.8
1.2
1.4
1.4
1.0
1.2
1.0
1.0
0.9
1.0
0.8
1.0
0.8
30
42
47
50
52
54
58
62
64
70
78
88
4
8
60
40
39
37
35
28
24
23
20
15
12
8
1.0
0.6
0.8
1.0
0.9
1.0
1.0
1.2
1.0
1.4
1.2
11
13
13
14
12
10
9
6
5
2
O
O
R
R
R
O
O
O
O
O
O
1
1a
CHO
9
2
O
O
5
4
10
11
12
Many reports
This work
Ascorbic acid
Many reports
O
O
+
6- 8 hrs, Ethanol
Reflux
O
O
R
R
R
aReaction conditions: Benzaldehyde 2a (1mmol), ethanol (5 ml),
ascorbic acid 10mg (0.056 mmol), reflux 8h., bisolated yields (the
spectral data of -dimedone products and unsymmetrical products
are given in supporting information, SI.)
O
O
O
O
O
O
+
+
O
O
O
3
Major (80-88%)
5
4
O
Cl
Cl
Cl
Cl
F
Br
f
h
g
c
d
e
a
b
The possible mechanism is depicted in Scheme 1.
NO2
OH
O
O
O
S
O
The cyclohexane-1,3-dione, 1a and dimedone, 1 offered the
corresponding alkylidene intermediates, I1a and I1 repectively
in the first step. In the second step, intermediate I1a can react
with 1,3-CHD or the intermediate I1 reacting with DMD to
afford the corresponding symmetrical xanthenediones, 4 and 5.
Similarly, the intermediate I1a can react with DMD or the
intermediate, I1 reacting with 1,3-CHD to afford the same
unsymmetrical xanthenediones, 3 through the same intermediate
I1c.
o
j
n
k
l
m
i
Fig.1 Multicomponent domino reactions of dimedone,
benzaldehyde and cyclohaxane 1,3-dione
Further, among the investigated solvents viz., water, absolute
ethanol, methanol, isopropanol, isobutanol, glycerol, acetonitrile,
dichloromethane and1, 4-dioxane, absolute ethanol appears to be
the best solvent in the reaction of dimedone (1.2 mmol) 1,3-
cyclohexanedione (0.8 mmol) and benzaldehyde (1 mmol) in the
presence of ascorbic acid as catalyst. The acetonitrile reaction
was comparable with that of the ethanol reaction as reported in
Table 2.
Having optimized the regioselective reaction36, we further
explored the scope of the reaction to afford a series of 3,4,6,7-
tetrahydro-3,
3-dimethyl-9-phenyl-2H-xanthene-
1,8(5H,9H)diones (3a-o) as presented in Fig 1.
2

Table 2 Effect of Solvent and catalyst influence in the synthesis of 3, 4, 6, 7-tetrahydro-3, 3-dimethyl- 9-arylxanthene-1, 8-dione
Entry
Catalysta
Solvent
Time (h)
Product Yield (%)c
3a
5a
4a
1
Ascorbic acid
Ascorbic acid
Ascorbic acid
Ascorbic acid
Ascorbic acid
Ascorbic acid
Ascorbic acid
Ascorbic acid
Ascorbic acid
Ascorbic acid
Ethanol
6
72
25
2
2
Acetonitrile
Dichloromethane
Methanol
Water
6.5
6
70
62
50
50
38
40
52
56
44
22
20
22
30
25
22
35
30
25
4
6
3
4
7
10
10
2
5.
6.
7.
8.
9.
10
7
Glycerol
7.5
9
1,4-Dioxane
Isopropanol
Isobutanol
THF
4
6
6
7
10
10
7.5
11
12b.
Ascorbic acid
Ascorbic acid
Toluene
Ethanol
9
6
30
88
30
2
20
8 (traces)
(60,67, 75)
(traces)
11.
12.
13.
14.
15.
16.
17.
L-Tartaric acid
Citric acid
L-Glycine
L-Lysine
Ethanol/
Acetonitrile
7.0
7.5
8
66/60
70/65
54/52
23/20
15/10
10/12
15/12
13/13
10/12
10/12
5/5
7/5
Ethanol/
Acetonitrile
Ethanol/
Acetonitrile
8/8
Ethanol/
Acetonitrile
5
7/5
65/6
L-Aspartic acid
pTSA
Ethanol/
Acetonitrile
6
60/62
8/8
Ethanol/
Acetonitrile
7
35/30
40/33
40/38
15/15
L-Proline
Ethanol/
Acetonirtile
6.5
aReaction conditions: DMD, 1 (1.2 mmol), benzaldehyde (1 mmol), 1,3-CHD, 1a (0.8 mmol), solvent (5 ml) reflux 8h, catalyst loading
20mg (0.113 mmol) unless otherwise stated, bascorbic acid 10mg (0.56 mmol) in parathesis 1mg (0.0056 mmol), 5 mg (0.0284), 15 mg
(0.0852 mmol), cisolated yields (the spectral data of dimedone products and unsymmetrical products isolated by column chromatography
are given in SI. Few reactions were monitored through GCMS and their reports are also attached with SI.)
3

O
1
O
OH
OH
H O
2
H O
/ EtOH
/ EtOH
2
O
O
O
O
1a
R
R
R
R
c
i
b
c
i
(AH+)
r
o
i
b
r
c
c
(AH+)
s
a
o
c
A
HC
s
d
A
HC
d
i
c
a
O
HC
O+
O
OH
HC
O+
OH
H
H
Symetrical
xanthenediones, 5
O
O
Symetrical
xanthenediones, 4
OH
slow
R
R
R
R
OH
slow
O
O
O
O
CH
O
CH
O
O+ H2
O+ H2
O
-H2O
I1
-H2O
O
O
I1a
OH
O
OH
faster
faster
1a
O
1
O
R
R
R
R
O
O
O
O
O
O
O
O
H+
O
O
O
H+
HO
O
O
R
O
HO
I1c
I1c
R
R
R
O
O
O
O
O
O
O
O
O+
O
OH
O+ H2
O+
O
OH
O+ H2
H
H
R
-H2O
-H2O
O
O
Unsymetrical
Xanthenediones, 3
O
Scheme 1 Possible mechanism of ascorbic acid catalysed multicomponent reaction
In summary, we have developed a new multicomponent domino
reaction for the synthesis of 3,4,6,7-tetrahydro-3,3-dimethyl-9-
NMR, DST-FIST, GCMS and IR facilities.
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To a solution of dimedone (5,5-dimethylcyclohexane-1,3-
dione) 1 (0.8 mmol), 1,3-cyclohexanedione 1a (1.2 mmol) in 5ml
of ethanol, appropriate aldehyde 2a (1.0 mmol), and ascorbic acid
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3,4,6,7-Tetrahydro-3,3-dimethyl-9-phenyl-2H-xanthene-1,8(5H,
9H)dione 3a
Colorless crystal, yield 88%; mp 174-178 ˚C; FT-IR
(KBr):698.23, 800.46, 1022.27, 1095.57, 1176.58, 1261.45,
1359.82, 1402.25, 1658.78, 2962.66, 3419.79 cm-1; 1H NMR
(400MHz, CDCl3 δ ppm) 1.00 (s, 3H, CH3), 1.10 (s, 3H, CH3),
1.96-2.03 (m, 2H), 2.15-2.25 (d, J = 9.2Hz, 2H), 2.27-2.39 (m2H),
2.47 (s, 2H), 2.51-2.66 (m, 1H), 4.81 (s, CH, 1H), 7.09-7.12 (d, J
= 6.8Hz, 1H, Ar-H), 7.19-7.23 (d, J = 7.2Hz, 2H, Ar-H), 7.26-
7.30 (d, J = 7.2Hz, 2H, Ar-H); 13C NMR (400MHz, CDCl3 δ ppm)
20.35, 27.31, 27.45, 27.52, 29.30, 29.34, 32.20, 32.41, 36.96,
40.95, 50.78, 114.69, 115.93, 121.84, 122.64, 128.92, 135.96,
136.05, 146.51, 148.52, 163.11, 164.79, 196.52, 196.65; GC-MS
(EI) calcd for C21H22O3 322.3; found m/z 322.29
Detailed results of other derivatives have been presented in Fig. 1
and the characterization data and spectral traces are given in SI.
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3,3-dimethyl-9-phenyl substituted xanthene-1,8-diones
5

Regioselective synthesis of 3,4,6,7-tetrahydro-3,3-dimethyl-9-phenyl-2H-
xanthene-1,8(5H,9H)-diones through ascorbic acid catalyzed three-
component domino reaction
Ayyakannu Arumugam Napoleon a, Fazlur-Rahman Nawaz Khana b
*, *
b
b
*
Euh Duck Jeong Eun Hyuk Chung
aOrganic and Medicinal Chemistry Research Laboratory, Organic Chemistry Division, School of
Advanced Sciences, VIT-University, Vellore 632 014, Tamil Nadu, India.
bKorea Basic Science Institute, Busan Center, Busan 618 230, South Korea.
O
O
R
R
R
O
O
O
O
O
O
1
1a
CHO
2
O
O
5
4
Many reports
This work
Ascorbic acid
Many reports
O
O
+
6- 8 hrs, Ethanol
Reflux
O
O
R
R
R
O
O
O
O
O
O
+
+
O
O
O
3
Major (80-88%)
5
4
O
Cl
Cl
Cl
Cl
F
Br
f
h
g
c
d
e
a
b
NO2
OH
O
O
O
S
O
o
j
n
k
l
m
i