Thiamine hydrochloride as a promoter for the efficient and green synthesis of 12-aryl-8,9,10,12 tetrahydrobenzoxanthene-11-one derivatives in aqueous micellar medium

Article abstract of DOI:10.1016/j.tetlet.2013.09.125

An environmentally benign, three-component, one-pot integrated chemical process has been developed for the synthesis of 12-aryl-8,9,10,12- tetrahydrobenzoxanthene-11-one by nucleophilic addition reaction between aldehyde and β-naphthol followed by Michael

Full text of DOI:10.1016/j.tetlet.2013.09.125

Accepted Manuscript
Thiamine hydrochloride as a promoter for the efficient and green synthesis of
12-aryl-8,9,10,12 tetrahydrobenzoxanthene-11-one derivatives in aqueous mi-
cellar medium
Shahin Fatma, Pravin K. Singh, Preyas Ankit, Shireen, Mandavi Singh, J. Singh
PII:
S0040-4039(13)01700-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.09.125
TETL 43625
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 June 2013
26 September 2013
28 September 2013
Please cite this article as: Fatma, S., Singh, P.K., Ankit, P., Shireen, Singh, M., Singh, J., Thiamine hydrochloride
as a promoter for the efficient and green synthesis of 12-aryl-8,9,10,12 tetrahydrobenzoxanthene-11-one derivatives
in aqueous micellar medium, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.09.125
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Thiamine hydrochloride as a promoter for the efficient and green synthesis of
12-aryl-8,9,10,12 tetrahydrobenzoxanthene-11-one derivatives in aqueous
micellar medium
Shahin Fatma1, Pravin K. Singh2, Preyas Ankit1, Shireen1, Mandavi Singh1 &
J. Singh1*
1Department of Chemistry, University of Allahabad, Allahabad – 211002, India
2Food Analysis and Research Lab, Centre of Food Technology, University of Allahabad, Allahabad-21002,
India
Email : dr.jds@rediffmail.com
Abstract:
Environmentally benign, three-component, one-pot integrated chemical process has been developed for the
synthesis of 12-aryl-8,9,10,12-tetrahydrobenzoxanthene-11-one by nucleophilic addition reaction between
aldehyde and β-naphthol followed by Michael addition of dimedone, catalyzed by thiamine hydrochloride in
aqueous micellar medium with excellent yield. Simple reaction conditions, no requirement of chromatographic
separation, short reaction time, ease of isolation, use of inexpensive, easily recoverable and reusable catalyst
makes this protocol very interesting from an economic and environmental perspective.
Keywords: Benzoxanthenone, Michael addition, nucleophilic addition, Environmentally
benign, aqueous micellar medium.
The rapid assembly of molecular diversity is an important aim of synthetic organic
chemistry and one of the key paradigms of modern drug discovery. One of the way to cope
with this challenge, involves the development of multicomponent reactions (MCRs),1 in
which three or more reactants are combined together in a single reaction flask, incorporating
most of the atoms contained in the starting materials, to generate a product. In addition to the
intrinsic atom-economy and selectivity underlying such reactions, simpler procedures and
equipment, time and energy savings, as well as environmental friendliness2 have all led to a
sizable effort to design and implement MCRs in both academia and industry.3 As a one-pot
reaction, MCRs generally afford good yields and are fundamentally different from two-
component reactions in several aspects4 and permitted rapid access to combinatorial libraries

of organic molecules for efficient structure-identification and optimization, in drug
discovery.5
Xanthenes and benzoxanthenes exhibit various pharmacological activities and are
useful as antibacterial6 anti-inflammatory7 and antiviral agents.8 They are useful antagonists
for the paralyzing action of zoxazolamine9 and also in photodynamic therapy.10 These
compounds were discovered to be pH-sensitive fluorescent materials for visualization of
biomolecular assemblies. They can also be utilized as dyes11 and in laser technologies.12 The
well known dyes having xanthene nucleus are Rhodamine B and Rhodamine 6G.Therefore
synthesis of xanthenes has gained prominence in synthetic organic as well as medicinal
chemistry.
On the past decade, various methods have been developed for the synthesis of
tetrahydrobenzo(a)xanthenes-11-ones. Generally they are synthesized by the three-
component condensation of cyclic 1,3-diketone with an aldehyde and β-naphthol, which
entails the use of PTSA in ionic liquid,13 perchloric acid adsorbed on silica gel,14 tetrabutyl
ammonium fluoride,15 dodecatungstophosphoric acid,16 indium chloride and phosphorus
pentaoxide,17 strontium triflate,18 NaHSO4.SiO2 cyanuric chloride,20 iodine,21 Zr(HSO4),22
,19
silica sulfuric acid,23 proline triflate24 in water and TTAB24b in water. Although, a number of
modified methods, under improved conditions have been reported, many of them suffer from
one or more drawbacks, such as unsatisfactory yields, very high temperature, long reaction
time and use of toxic organic solvents and catalysts. Hence, it is necessary to develop, an
efficient and convenient method to construct these important biologically active heterocyclic
compounds. It is well known that thiamine hydrochloride (VB1) is a cheap non-flammable
and non-toxic reagent, containing a pyrimidine ring and a thiazole ring linked by a methylene
bridge (Fig 1).
VB1 analogs a powerful catalysts have been applied in various organic
transformations for carbon-carbon and carbon-heteroatom bond formation reactions.25
Recently several VB1 catalyzed reactions for the synthesis of heterocyclic compounds such

as
pyrimidinones26
and
1,2-dihydro-naphth-(1,2-e)(1,3)-oxazine-3-one,27
1,4-
dihydropyridines,28a benzo[4,5]imidazo [1,2-a]pyrimidine and [1,2,4]triazolo[1,5-a]
pyrimidine28b have been reported. We had the opportunity to explore for the first time its
catalytic activity towards the synthesis of 12-aryl-8,9,10,12-tetrahydrobenzo(a)xanthenes-11-
one derivatives.
Scheme 1
From the ecofriendly-point of view, it is of considerable interest to perform organic
reactions in water because it is abundant in nature, has virtually no cost, and is safest among
available solvents, thus leading to environmentally benign chemical processes.29 But the
basic problem in performing reaction in aqueous medium is that many organic compounds
are hydrophobic and are insoluble in water. To overcome this problem is the introduction of
aqueous surfactant solutions in the form of micelles30 as the reaction medium. Considering
the significance of surfactants31-36 and in continuation of our research work37-39 to develop
new and convenient synthetic protocols for the construction of bioactive heterocycles, we
targeted to synthesize 12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-ones using
hexadecyltrimethylammonium bromide (CTAB) in aqueous micellar form. The solubilization
of water-insoluble reactants and products inside the micelles results not only in high
concentration within the small volume, but also in different orientations of the soluble
molecules that influence the reaction mechanism, resulting in remarkable differences in
reaction rate and selectivity that would be observed in a homogeneous system.
In our initial study, reaction of 4-chlorobenzaldehyde, β-naphthol and dimedone in
water was considered as a standard model reaction40 (Scheme 1). During this investigation,
efforts were mainly focused on a variety of surfactants as well as catalyst molar
concentration. In this regard, different cationic surfactants such as cetyltrimethylammonium
bromide (CTAB), methyltriphenylphosphonium bromide (MTPPB) and cetylpyridinium
chloride (CPC) as well as ananionic surfactant, sodium dodecyl sulfate (SDS), were utilized

at ambient temperature. From these preliminary studies, it was observed that the anionic
surfactant SDS and cationic surfactants CPC and MTPPB gave the desired product found in
low yields, i.e., 57%, 32% and 59% respectively (Table 1, entries 1–3). In contrast, the
cationic surfactant CTAB accelerated the model reaction to afford the desired product in
good yield (Table 1, entry 4). From this, it was concluded that cationic surfactants,
particularly quaternaryammonium bromide (CTAB) where the counter ion is bromide are far
superior to other surfactants for efficient catalysis.
Table 1 Screening of surfactantsa:
Temperature (°C)
Entry Surfactant
Time(hour)
yieldb(%)
SDS
RTc
RTc
RTc
RTc
RTc
4.30
4.0
4.0
4.0
3.30
52
30
53
40
76
1
2
3
4
5
CPC
MTPPB
TEAB
CTAB
areaction conditions: β-naphthol 1 (1 mmol), 4-chlorobenzaldehyde 2 (1 mmol), dimedone
3 (1mmol), surfactant (10 mol %), in water (10 ml).
bisolated yields; croom temperature (RT) was 45 °C.
Encouraged by these results we further investigated the effect of catalyst on the
reaction. We found that there is significant reduction in time along with excellent increment
in yield on using thiamine hydrochloride as a catalyst in aqueous micellar system. We
performed the reaction using different molar concentration of catalyst (Table 2) carefully
studied its effect on isolated yield (Fig.2) and found that on using 3, 5, 10 mol% of VB1,
the isolated yield were 88%, 92%, 92% respectively . Further increase in catalyst
concentration did not lead to significant enhancement in the reaction yield, therefore we
decided to use only 5 mol% of the catalyst for the best result.
Table 2 Optimization of catalyst
Entry Catalyst (mol%)
Time(min) yield of Productb(%)
0
3
5
210
46
25
76
1
88
92, 90, 87, 83
92
2
3c
4
10
25
Conditions: 4-Cl-Benzaldehyde (1 mmol), dimedone (1mmol) and β- naphthol(1 mmol),
water(10ml)-CTAB(10mol%), 45°C.
aisolated yields.
bcatalyst was used three times.

250
200
150
100
50
catalyst concentration (mol%)
time(min)
yield(%)
0
1
2
3
4
Fig. 2 Graphical presentation of effect of catalyst concentration on reaction
From the comparable study of the previously reported work on the synthesis of 12-
aryl-8,9,10,12-tetrahydrobenzo(a)xanthenes-11-one derivatives and our work (Table 3), we
can say that thiamine hydrochloride in aqueous micellar system is an excellent catalyst for
reducing the time and enhancing the yield.
To extend the scope of the reaction and to generalize this method, a variety of
structurally diverse non-aromatic/ aromatic aldehydes, 5,5-dimethyl-1,3-cyclohexanedione /
5,5-dimethylcyclopentane-1,3-dione, and β-naphthol were examined, and the results are
summarized in Table 1. Various non aromatic and aromatic aldehydes containing electron-
withdrawing and electron-donating substituent at ortho, meta or para-positions were smoothly
converted to their corresponding tetrahydroxanthenones in high to excellent yields. To further
expand the scope of the present method, the replacement of 5,5-dimethyl-1,3-
cyclohexanedione with 5,5-dimethylcyclopentane-1,3-dione was examined. To our delight,
under the same optimized conditions, the reactions proceeded steadily to afford a series of
xanthene-based compounds in good yields. We have also tried to make benzoxanthen-11-
ones using α-naphthol or other phenols instead of β-naphthol, it was found that under the
same conditions, when β-naphthol was replaced by other phenols/ α-naphthol, either no
product was obtained or product formation took place with very poor yield. Identity of the
1
synthesized products was confirmed by comparing the physical and spectral data (IR & H
NMR) with those of the reported compounds.14-24

Table 3: Comparison of previously reported work with our work for the synthesis of 12-aryl-
8,9,10,12-tetrahydrobenzo(a)xanthenes-11-one derivatives
Entry
1
Catalyst
Conditions
Time
(min)
70
Yield
(%)
86
Ref.
dodecatungsto
phosphoric acid
HClO4-SiO2
PTSAa
60°C/heat
16
80° C/heat
[bmim]BF4/heat
120°C /heat
120°C /heat
H2O/rt
72
180
30
89
90
84
14
-
2
3
4
5
6
7
InCl3
17
21
-
I2
TTABb
180
300
87
85
Sr(OTf)2
1,2-dichloroethane
/80°C
18
TCT
TBAFc
80 °C /neat
H2O/reflux
CH2Cl2/reflux
100°C
50
540
300
30
90
99
91
95
93
20
15
19
22
-
8
9
NaHSO4/SiO2
10
11
12
Silica sulfuric acid
Thiamine hydrochloride
rt /aqueous
micellar system
25
apara-Toluene sulphonic acid
btetradecyltrimethylammonium bromide
ctetra(n-butyl)ammonium fluoride
Entry 12 : our work.

Table 4: Thiamine hydrochloride catalyzed condensation of aldehydes, 1,3-dicarbonyl
compounds and β-naphthol
Entry
R
n
product Time Yield (%)
(min)
Colour of product
Mp (
)
1
2
C6H5-
p-MeO.C6H4-
o-MeO.C6H4-
p-Me.C6H4-
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0
0
4A
4B
4C
4D
4E
4F
25
32
30
32
25
30
20
33
35
30
32
20
35
40
30
40
36
37
38
35
92
86
87
86
92
83
90
78
76
84
84
92
86
85
88
87
89
90
90
91
147-149
208-210
164-166
172-174
179-181
177-179
176-179
223-125
237-239
221-223
166-168
175-177
209-211
188-190
262-264
146-148
116-117
110-111
233-234
223-224
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
Pale yellow solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
3
4
5
p-Cl.C6H4-
6
o-Cl.C6H4-
7
o,p-Cl2.C6H3-
p-HO.C6H4
4G
4H
4I
8
9
m-HO.C6H4
10
11
12
13
14
15
16
17
18
19
20
o-NO2.C6H4-
m-NO2.C6H4-
p-NO2.C6H4-
2-HO-3-MeO.C6H3-
2-HO-3-EtO.C6H3-
2-HO-5-NO2.C6H3-
-CH=CH-C6H5
-CH(CH3)2
4K
4L
4M
4N
4O
4P
4Q
4R
4S
-C.(CH3)3
p-Cl.C6H4-
4T
4U
3,4-(CH3)2.C6H3-

From the mechanistic point of view it is proposed that the mechanism of formation of
the target compounds may follow either route I or route II (Scheme 2). In route I, first step
proceeds via the nucleophilic addition of β-naphthol to aldehyde, catalyzed by VB1, to give an
intermediate orthoquinone methide (o-QM) Ib via Ia. Subsequent Michael addition of the o-
QM with dimedone followed by intramolecular cyclization and dehydration affords the
desired product 4. In second possible route (route II), first step proceeds via Knoevenagel
condensation between diketone and aldehyde and second step is a Michael type conjugate
addition followed by intramolecular cyclization and dehydration affords the desired product
4. To confirm the reaction mechanism pathway, we performed the reaction via both the
proposed routes of mechanism (route I and route II) by adding reagent sequentially. From
route I we have isolated intermediate, orthoquinone methide (o-QM) Ib, which upon
entrapment with active methylene compound via Michael addition followed by ring closure
and dehydration gave the desired product. But when the reaction was performed according to
route II, we have not got the intermediate. Since no intermediate could be observed or
isolated via route II, the former mechanism (route I) fit for this reaction.
O
OH
VB1
O
R O
H
O
H
VB1
O
n
O
R
H
Hydrophobic interior
Hydrophilic exterior
:CTAB

Sc
heme 2: Proposed mechanism for the benzoxanthen-11-ones

In summary we have developed an efficient one pot synthesis of 14-aryl-14H-
dibenzo[a,j]xanthene and 12-aryl-8,9,10,12-tetrahydrobenzo[a]-xanthen-11-one derivatives
by condensation of various substituted benzaldehydes, β-naphthol and dimedone using
thiamine hydrochloride as a green catalyst under aqueous micellar system. This methodology
is endowed with several advantages such as inexpensive as well as non-toxic catalyst, easy
work-up procedure, use of non-hazardous solvent, low temperature. Only 5 mol% of thiamine
hydrochloride gives the products in excellent yield within very short.

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40. General method for synthesis of compound 4: To a mixture of β-naphthol 1 (1 mmol),
aromatic/ non-aromatic aldehyde 2 (1mmol) and cyclic 1,3 dicarbonyl 3 (1mmol) in
water/CTAB micellar system (10 mol% CTAB in 10 ml water), Thiamine
hydrochloride (5 mol %) was added. This reaction mixture was allowed to stir
vigorously at room temperature (45°C). Progress of the reaction was monitored by
TLC (ethyl acetate: n-hexane; 2:8 v/v). After completion of the reaction, the solid
obtained was collected by filtration and washed successively with warm water and
cool aqueous ethanol. The crude product was recrystallized from ethanol to afford
analytically pure desired product 4. 12-(4-Chlorophenyl)-9,9-dimethyl-
8,9,10,12-tetrahydrobenzo[a]xanthen-11-one (4E): White solid; Rf = 0.50
(1:9 EtOAc /Hexane), IR (KBr, cm-1): 3078, 2915, 1637, 1367, 1219,
1
1164, 1081. H NMR (300 MHz, CDCl3): δ 7.97 (d, J = 8.1 Hz, 1H),
7.83–7.79 (m, 2H), 7.48–7.14 (m, 7H), 5.70 (s, 1H), 2.60 (s, 2H), 2.37 (d,
J = 16.2 Hz, 1H), 2.31 (d, J = 16.2 Hz, 1H), 1.14 (s, 3H), 0.94 (s, 3H). 13C
NMR (75 MHz, CDCl3): δ 196.1, 164.7, 150.6, 148.7, 145.5, 132.9,
131.9, 129.9, 130.2, 128.9, 127.8, 125.9, 123.9, 122.6, 115.9, 115.1,
111.5, 50.1, 40.3, 33.8, 31.7, 28.9, 27.9. MS (FAB): m/z = 389.89
[M+H]+. Anal. Calcd for C25H21ClO2: C, 77.21%; H, 5.44. Found: C,
77.29; H, 5.36%.
.

Graphical Abstract
Environmentally benign, three-component, one-pot integrated
chemical process has been developed for synthesis of 12-aryl-
8,9,10,12-tetrahydrobenzoxanthene-11-one by nucleophilic addition
reaction between aldehyde and β-naphthol followed by Michael
addition of dimedone, catalyzed by thiamine hydrochloride in aqueous
micellar medium with excellent yield. Simple reaction conditions, no
requirement of chromatographic separation, short reaction time, ease of
isolation, use of inexpensive, easily recoverable and reusable catalyst
makes this protocol very interesting from an economic and
environmental perspective.
Thiamine hydrochloride as a
promoter for the efficient and
green synthesis of 12-aryl-
8,9,10,12
tetrahydrobenzoxanthene-11-
one derivatives in aqueous
micellar medium
Shahin Fatma1, Pravin K. Singh2, Preyas Ankit1, Shireen1, Mandavi Singh1 & J. Singh1*