FeCl3·6H2O as a green and readily available catalyst for the synthesis of 1-oxo-hexahydroxanthenes by the condensation of salicylaldehydes with 1,3-diketones in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2015.11.088

A facile and efficient method for the synthesis of 1-oxo-hexahydroxanthenes catalyzed by FeCl₃·6H₂O is described. The iron-catalyzed condensation of salicylaldehydes with cyclic 1,3-diketones afforded 1-oxo-hexahydroxanthene derivati

Full text of DOI:10.1016/j.tetlet.2015.11.088

Accepted Manuscript
FeCl3·6H2O as a green and readily available catalyst for the synthesis of 1-oxo-
hexahydroxanthenes by the condensation of salicylaldehydes with 1,3-diketones
in aqueous media
Mahmood Tajbakhsh, Marzieh Heidary, Rahman Hosseinzadeh,
Mohammadreza Azizi Amiri
PII:
S0040-4039(15)30396-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.11.088
TETL 47028
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 July 2015
10 November 2015
26 November 2015
Please cite this article as: Tajbakhsh, M., Heidary, M., Hosseinzadeh, R., Amiri, M.A., FeCl3·6H2O as a green and
readily available catalyst for the synthesis of 1-oxo-hexahydroxanthenes by the condensation of salicylaldehydes
with 1,3-diketones in aqueous media, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.
2015.11.088
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FeCl3·6H2O as a green and readily available catalyst for the synthesis of 1-oxo-hexahydroxanthenes by the
condensation of salicylaldehydes with 1,3-diketones in aqueous media
Mahmood Tajbakhsh,* a Marzieh Heidary,a Rahman Hosseinzadeh,a Mohammadreza Azizi Amiri a
a Faculty of Chemistry, University of Mazandaran, Babolsar, 47416-95447
* Corresponding Author: Tel.: +981135302351
E-mail address: tajbaksh@umz.ac.ir
Abstract:
A facile and efficient method for the synthesis of 1-oxo-hexahydroxanthenes catalyzed by FeCl3•6H2O is
described. The iron-catalyzed condensation of salicylaldehydes with cyclic 1,3-diketones afforded 1-oxo-
hexahydroxanthene derivatives in a good to excellent yields at room temperature. The use of water as a green
solvent, purification of the products by non-chromatographic methods, catalyst reusability and high yields are some
of the advantages of this protocol.
Keywords: Catalytic reactions, FeCl3•6H2O, Green chemistry, 1-Oxo-hexahydroxanthenes, Organic synthesis
Introduction:
A prominent goal of modern organic chemistry is to maximize the efficiency of reactions using readily
available starting materials and minimize the generation of waste, which are prime principles of green chemistry.1 In
recent years, green chemistry has attracted considerable attention from organic and medicinal chemists. One of the
most important roles of green chemistry is the design and application of chemical reactions that reduce or eliminate
the use of toxic solvents and reagents.2 Water as a reaction medium has numerous advantages including ease of
product isolation, nontoxicity, nonflamability, high specific heat capacity, low cost, large surface tension and high
polarity which make it both economical and environmentally friendly, and thus suitable as a green solvent.3, 4
Heterocyclic compounds, especially oxygen-containing heterocycles, are ubiquitous in natural products and
pharmaceuticals and represent the most important class of key structural units in a large number of bioactive
molecules.5 In particular, xanthenes and their derivatives play an important role in the fields of natural products,
medicinal and materials chemistry.6 Xanthenes are used as leuco-dyes in laser technology7 and as pH-sensitive
fluorescent materials for the visualization of biomolecules.8 Octahydroxanthene derivatives containing the
benzopyran moiety have been used as antispasm,9 antiviral,10 antibacterial,11 antioxidant, antineoplastic, vasodilators
and anti-inflammatory agents12-20 as well as fluorescent fuels.21 The many applications of xanthenediones have
stimulated the development of environmentally benign methods for their synthesis. There are a myriad of research
articles reporting the synthesis of functionalized xanthenes and a wide range of starting materials and reaction
protocols have been applied for the synthesis of this fascinating class of compounds.22, 23
Although there have been many reports related to the synthesis of xanthene derivatives, there are few
regarding the synthesis of 1-oxo-hexahydroxanthenes. Synthetic routes to these compounds generally involve the
condensation of salicylaldehydes with 1,3-diketones under various conditions. Although the reaction has been
accomplished under catalyst free conditions in solvents such as water, glycerol and dimethylformamide, high
temperatures (80-90 °C) and long reaction times (3-12 h) were needed to furnish the corresponding 1-oxo-
hexahydroxanthenes in reasonable yields.24-26 Various homogeneous catalysts such as CeCl3•7H2O,27 acetic acid,28
triethyl-benzylammonium chloride (TEBA) as a cationic surfactant,20 2,4,6-trichloro-1,3,5-triazine,29 CsF,30 L-
proline,31 and PTSA32 have been used. However, some of these catalysts contain halogens20, 30 and require high
temperatures28, 29, 32 or long reaction times.27 Heterogeneous systems such as cellulose sulfuric acid and nano-
ZnAl2O4 have also been developed for the synthesis of 1-oxo-hexahydroxanthenes. Despite showing efficient
catalytic activity, these methods suffer from drawbacks such as the requirement of catalyst preparation and the use
of expensive and/or moisture sensitive reagents.33, 34
Significant interest has been focused on the development of new protocols for environmentally benign
processes that are both economically and technologically practical. In particular is the use of nonhazardous and
inexpensive metals has attracted continued interest in organic synthesis. In this regard iron salts which efficiently
catalyze organic reactions have attracted considerable attention since iron is inexpensive, sustainably produced,
1

easily accessible, non-toxic, air and moisture stable and easy to store for long periods under normal laboratory
conditions. It is also an environmentally benign metal.35, 36 These factors have led chemists to pay more attention to
iron-based catalysis for mild and green reactions.37-39
FeCl3•6H2O as a Lewis acid catalyst has been increasingly utilized in a wide variety of organic reactions such
as the preparation of xanthenediones,2 and Hantzsch 1,4-dihydropyridines,40 Biginelli condensations41 and
Beckmann rearrangements.42 The synthesis of 1-oxo-hexahydroxanthene derivatives is still highly desirable in terms
of developing more practical procedures and mild reaction conditions. As a consequence of our interest in
developing new and efficient synthetic methodologies for the synthesis of organic compounds,43-47 we report herein
a convenient, mild and environmentally benign method for the preparation of 1-oxo-hexahydroxanthenes by the
condensation of salicylaldehydes with cyclic 1,3-diketones using catalytic FeCl3•6H2O at room temperature in
aqueous media. To the best of our knowledge, the synthesis of 1-oxo-hexahydroxanthenes catalyzed by FeCl3•6H2O
has not been reported.
Results and discussion
The reaction of salicylaldehyde (1.0 mmol) with dimedone (2.0 mmol) using FeCl3•6H2O was chosen as a
model reaction to determine the optimal reaction condition. When the model reaction was performed under solvent-
free conditions in the absence of catalyst, only 10% yield of the desired product 3a was obtained after 9 h (Table 1,
entry 1). The use of water as solvent, significantly improved the yield from 10% to 80% however the reaction time
was still long (Table 1, entries 1-2). The reaction conducted in the presence of FeCl3•6H2O (10 mol %) in water for
30 minutes gave 3a in 97% yield (Table 1, entry 3). In subsequent optimization, use of 15 mol% FeCl3•6H2O did not
improve the reaction rate and furnished 3a in 97% yield (Table 1, entry 4). Lowering the catalyst loading to 5 mol%
decreased the yield to 90% (Table 1, entry 5).We also examined different Lewis acids using the same model
compounds and reaction conditions. It was found that FeCl3•6H2O exhibited higher efficiency than other Lewis
acids examined (entries 6-9) or reported (entry 10). The model reaction was also carried out under solvent free
conditions and in different solvents such as EtOH, CH2Cl2, CH3CN, THF and EtOH/H2O (1:1), however this
resulted in lower yields of 3a (Table 1, entries 11-17). Therefore, the best results were obtained from the reaction of
salicylaldehyde (1 mmol) with dimedone (2 mmol) in water (3 mL) in the presence of FeCl3•6H2O (10 mol%) at
room temperature (Table 1, entry 3).
2

Table 1. Optimization for the reaction of 1 with 2.
Time
(min)
Yield
(%)a
Entry
Catalyst (mol %)
Solvent
1
720
10
80
-
-
-
H2O
360
2
3
FeCl3•6H2O (10)
FeCl3•6H2O (15)
FeCl3•6H2O (5)
CrCl3•6H2O (10)
CoCl2•6H2O (10)
Co(NO3)2•6H2O (10)
ZnCl2 (10)
H2O
H2O
H2O
H2O
H2O
H2O
H2O
30
30
30
30
30
30
30
97
97
90
50
60
85
80
4
5
6
7
8
9
10
11
12
13
CeCl3•7H2O b
FeCl3•6H2O (10)
FeCl3•6H2O (10)
FeCl3•6H2O (10)
H2O
Solvent Free
Solvent Free (60 C)
EtOH
180
30
30
9227
30
60
30
50
14
15
FeCl3•6H2O (10)
FeCl3•6H2O (10)
CH2Cl2
THF
30
30
30
10
16
17
FeCl3•6H2O (10)
FeCl3•6H2O (10)
CH3CN
30
30
40
80
EtOH/H2O (1:1)
Reaction conditions: salicylaldehyde (1.0 mmol), dimedone (2.0 mmol), solvent
a
b
(3mL), catalyst, room temperature. Yields refer to isolated products. Reflux,
catalyst amount not given.
Encouraged by these results, and in order to show the generality and scope of this new protocol, the
optimized reaction conditions were applied to a variety of salicylaldehydes and cyclic 1,3-diketones (Table 2). The
1-oxo-hexahydroxanthenes were generally obtained by filtration of the reaction mixture, avoiding solvent extraction
or tedious chromatographic purification steps, and where necessary the crude products were further purified by
crystallization. This simple workup procedure illustrates the attractiveness of this protocol and afforded the target 1-
oxo-hexahydroxanthene derivatives in good to excellent yields.
3

Table 2. Synthesis of 1-oxo-hexahydroxanthenes (3a-o) using FeCl3•6H2Oa, b, c
3a48
3b31
60 min, 90%
3c48
60 min, 95%
3d48
120 min, 90%
3e20
90 min, 90%
30 min, 97%c
3f27, 32
3g27
3h29
3i32
3j31
60 min, 95%
30 min, 95%
75 min, 95%
45 min, 95%
90 min, 90%
3k32
3l20
3m20, 32
3n34
3o20, 49
60 min, 97%
150 min, 95%
75 min, 95%
45 min, 98%
90 min, 97%
a Reaction conditions: dimedone or 1,3-cyclohexanedione (2 mmol), substituted salicylaldehyde (1 mmol), FeCl3•6H2O (10
mol%), water (3 mL), room temperature. b All compounds are known and their structures were established from comparison of
their spectral data and melting points with literature values. c Yields refer to isolated products.
FeCl3•6H2O showed remarkable reactivity and considerably accelerated the reaction. On the basis of our
experimental results and literature reports,34, 49, 50 we propose a plausible mechanism for the formation of 1-oxo-
hexahydroxanthene derivatives 3a-o in the presence of FeCl3•6H2O (Scheme 1). FeCl3•6H2O facilitates a
Knoevenagel type coupling through Lewis acid sites (Fe3+) coordinated to the oxygen of the carbonyl group of 2-
hydroxybenzaldehyde, thus generating intermediate (I). Subsequently, during the Michael addition step,
nucleophilic attack of intermediate (I) by the carbon nucleophile afforded intermediate (II). The phenol oxygen first
attacks the enone in an 'oxy-Michael' reaction to give intermediate (III) (possibly with iron acting as a Lewis acid on
the enone oxygen), forming an enolate, which then undergoes elimination of water to afford product 3. The
1
structures of all synthesized compounds (3a–o) were ascertained on the basis of IR, H NMR and 13C NMR spectra
(see ESI).
In order to show the advantage of the present method, we compared the model reaction with previously reported
catalysts for the preparation of 1-oxo-hexahydroxanthene 3a (Table 3).
Table 3. Comparison of the catalytic activity of FeCl3·6H2O with selected reported catalysts
for the synthesis of 3a (Table 2, entry 1)
Yield b
Time
Entry
Catalyst/ Reference
(min)
4

(%)
1
2
para-Toluenesulfonic acid (H2O, 90 °C, 10 mol%)32
2,4,6-Trichloro-1,3,5-triazine (Solvent free, 120 °C, 10 mol%)29
30
83
92
105
3
4
5
L-proline (EtOH, 60 °C, 35 mol%)31
30
95
92
92
CeCl3•7H2O (H2O, 90°C, small amount)27
180
240
Triethylbenzylammonium chloride (H2O, 90 °C, 44 mol%)20
Cellulose sulfuric acid (ground, r.t, 0.08gr)33
Nano ZnAl2O4 (EtOH, 80 °C, 50 mol%)34
20
15
90
92
6
7
8
FeCl3•6H2O (H2O, r.t, 10 mol%)a
30
97
a This work, b Yields refer to isolated products, c Amount not given.
It was clear from Table 3 that FeCl3·6H2O was good candidate for the synthesis of 1-oxo-
hexahydroxanthenes.
Scheme 1. Plausible mechanism for the synthesis of 1-oxo-hexahydroxanthene derivatives.
To investigate the recovery and reusibility of FeCl3⋅6H2O, after filtration of the reaction mixture, the filtrate
was charged with the same substrates and reused for four cycles. This afforded the desired product in high yields
that were similar to that obtained in the first run, although an increase was observed in the reaction time (Table 4).
Table 4. Reusability of the catalyst for the synthesis of compound 3a (Table 2, entry 1)a.
Run No
1
Isolated yield (%)
97
Reaction time (min)
30
5

2
3
4
95
94
93
40
45
50
a Reaction conditions: salicylaldehyde (1 mmol), dimedone (2 mmol), FeCl3•6H2O (10
mol%), water, room temperature.
Conclusion
In conclusion, a convenient one-pot procedure for the synthesis of 1-oxo-hexahydroxanthenes derivatives by
condensation of salicylaldehydes with cyclic 1,3-diketones in the presence of catalytic of FeCl3•6H2O as a reusable
homogenous catalyst has been developed. The main advantages of this methodology include; (i) a simple procedure,
using a catalyst that does not require inert or anhydrous conditions; (ii) simple work-up without chromatographic
purification; (iii) high atom economy by avoiding the use of organic solvents; (iv) catalyst reusability, and (vi) mild
reaction conditions, giving the products in excellent yields using an environmentally benign procedure. These
advantages render this protocol facile and suitable to create a diversified library of derivatives of 1-oxo-
hexahydroxanthenes.
Acknowledgments
We are grateful to the University of Mazandaran for supporting our research.
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Graphical abstract
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