A rapid and efficient CsF catalyzed tandem Knoevenagel-Michael reaction

Article abstract of DOI:10.1016/j.jfluchem.2013.11.010

A simple, experimentally rapid and efficient CsF catalyzed tandem Knoevenagel-Michael reaction protocol is developed for the synthesis of a series of functionalized 9-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)-3,3-dimethyl- 2,3,4,9-tetrahydro-1H-xanthe

Full text of DOI:10.1016/j.jfluchem.2013.11.010

Journal of Fluorine Chemistry 158 (2014) 1–5
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
A rapid and efficient CsF catalyzed tandem Knoevenagel–Michael
reaction
a
b
a
Khalid Mohammed Khan a, , Imran Khan , Shahnaz Perveen , Muhammad Imran Malik
*
a H.E.J. Research Institute of Chemistry, International Centre for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
b PCSIR Laboratories Complex, Karachi, Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi 75280, Pakistan
A R T I C L E I N F O
A B S T R A C T
Article history:
A simple, experimentally rapid and efficient CsF catalyzed tandem Knoevenagel–Michael reaction
protocol is developed for the synthesis of a series of functionalized 9-(2-hydroxy-4,4-dimethyl-6-
oxocyclohex-1-enyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one (1–7) by reacting dimedone
with substituted salicylaldehydes. The use of CsF as a catalyst allowed reactions under moderate
conditions and resulted in better yields.
Received 1 August 2013
Received in revised form 13 November 2013
Accepted 15 November 2013
Available online 23 November 2013
ß 2013 Elsevier B.V. All rights reserved.
Keywords:
Tandem Knoevenagel–Michael reaction
Xanthenes
Salicylaldehydes
CsF
1. Introduction
and reaction protocols has been reported for synthesis of this
fascinating class of compounds [17]. The synthesis of 1-
Heterocyclic compounds are very important materials due to
their biological and pharmacological activities [1]. Facile and
robust synthesis of these materials is a major topic of organic
chemistry, both in academia and industry. The exploration of new,
facile, high yield and eco-friendly methods are very crucial even for
classical compounds. The Knoevenagel condensation followed by
the Michael addition reaction is one of the simplest methods for
carbon–carbon double bond formation [2]. In tandem Knoevena-
gel–Michael reaction on different substrates with variety of
catalysts opened a horizon of new and facile synthesis methods
with improved yields.
One of the important classes of oxygen containing tricyclic
organic compounds is xanthenes. The biological and pharmaco-
logical activities of xanthenes are well documented in literature,
such as antiviral [3], antibacterial [4], antioxidants, antineoplastic,
vasodilators and anti-inflammatory [5–15]. Blennolide C and
diversonol (Fig. 1) are xanthene carrying natural compounds that
showed anti-cell growth activity measured by National Cancer
Institute [16].
oxohexahydroxanthene analogs have been reported by react-
ing substituted salicylaldehyde with dimedone using variety of
catalysts such as TEBA in aqueous medium [18], 2,4,6-trichloro-
1,3,5-triazine [19], CeCl3Á7H2O [20], p-TSA/H2O [16].
The sole use of ionic salts for tandem Knoevenagel–Michael
reaction is a relatively new idea. The use of ionic salts as catalyst in
organic synthetic chemistry is very important because it leads to
mild reaction conditions and simpler work-up.
The use of cesium fluoride as a catalyst has been reported by
Jeanne et al. in which reported the enhancement of the reactivity of
carboxylic ester toward trifluoromethylation under room temper-
ature that afford silyl ether intermediate that on hydrolysis gives
ketone [21]. Another group of scientist Dong et al. reported the use
of cesium fluoride as a nucleophile in polar solvents (tert-alcohol)
that significantly enhanced reactivity of the fluoride as
a
nucleophile [22]. Baldwin and co-workers targeted the Stille
coupling reaction in the presence of cesium fluoride and copper
salt [23]. Do et al. reported a facile method for deboronation of o-
carboranes using cesium fluoride [24]. Murashima et al. reported
synthesis of crown ether-annulated porphyrin in the presence of
cesium fluoride [25]. Some other uses of cesium fluoride as a
catalyst has been reported for the polymerizations [26] and
cyclization reactions [27]. Fluoride ion increases the nucleophilic
character of compounds that have acidic protons [28]. Some other
reported examples of ionic salts as a catalyst are aromatic
There are myriad of research articles reporting synthesis of
functionalized xanthenes. A wide range of starting materials
*
Corresponding author. Tel.: +92 2134824910; fax: +92 2134819018.
E-mail addresses: hassaan2@super.net.pk, khalid.khan@iccs.edu (K.M. Khan).
0022-1139/$ – see front matter ß 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2013.11.010

2
K.M. Khan et al. / Journal of Fluorine Chemistry 158 (2014) 1–5
et al. [39]. It is well known that among alkaline metal salts,
cesium salts have the lowest degree of solvation and ion pairing
ability that makes cesium ion naked to coordinate more
effectively with carbonyl oxygen making carbonyl carbon more
electrophilic.
First the coordination of cationic part of the CsF with carbonyl
oxygen of salicylaldehyde. The cationic part of the cesium
fluoride, cesium coordinates with carbonyl carbon of salicylalde-
OH O
O
OH O OH
O
OH OH
OH
Me2OC
OH
hyde. In the process,
p–electrons from carbonyl carbon are
Blennolide C
Diversonol
withdrawn that induces electrophilicity. Secondly, the counter
fluoride consumes the acidic protons of dimedone and generates
an enolized dimedone. This enolized dimedone might attack the
Fig. 1. Xanthene carrying natural compounds.
electrophilic center of salicylaldehyde and consequently
a
carbon–carbon double bond is formed. This condensation leads
to an intermediate. In the next step hydroxyl group on
salicylaldehyde might be attacked on the carbonyl carbon of
the dimedone that results in cyclic 1,4-Michael-type substrate.
This cyclic substrate serves for 1,4-attack by the second enolate of
the dimedone produced by fluoride base. The general chemical
reaction is shown in Scheme 1 and their plausible mechanism is
given in Scheme 2.
Various substituted salicylaldehydes with electron donating
and withdrawing groups have been used. The electron withdraw-
ing group on salicyaldehydes resulted in excellent yields. However,
good yields are obtained for salicylaldehyde with electron
donating groups (Table 1).
polysulfide synthesis [29], conversion of organic acids to organic
esters [30] and promotion of chemo- and regio-selective ring
opening reaction through SN2 mechanism [31].
However, the major disadvantages of most of the methods are
harsh reaction conditions, long reaction time and tedious work-up
procedures.
The literature survey on cesium fluoride unfold a special effect
like ‘‘cesium effect’’. Cesium effect describes the advantages
regarding yield, short time, smaller amount of reagent, milder
reaction conditions and easier work up procedure as compared to
conventional non cesium protocol. While studying the literature
on multidimensional role of cesium fluoride really inspire us to
perform and optimized the tandem Knoevenagel–Micheal reac-
tion. In this study we report an experimentally simple, efficient
and rapid CsF catalyzed tandem Knoevenagel–Michael reaction
for the synthesis of functionalized 9-(2-hydroxy-4,4-dimethyl-6-
oxocyclohex-1-enyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-
xanthen-1-one (1–7) by reacting dimedone with substituted
salicylaldehyd.
The 1H NMR spectrum of 5-bromo-7-chloro-9-(2-hydroxy-
4,4-dimethyl-6-oxocyclohex-1-enyl)-3,3-dimethyl-2,3,4,9-tet-
rahydro-1H-xanthen-1-one (1) were recorded in deuterated
dimethyl sulphoxide at 300 MHz. The spectrum showed two
singlets for a aromatic protons at
benzylic protons resonated at 5.06, and 8 methelene protons as
a multiplet appeared at 1.98–2.54. Two signals for six methyl
protons appeared at 1.01 and 0.92. However, six protons for
other two methyl groups resonated at 0.87 as a singlet. The
d 7.40 and d 6.93 respectively,
d
d
d
d
2. Results and discussion
compounds are stable enough and allowed performing E.I. mass
spectrometry. The results confirm that the newly developed
method provides a facile and robust reaction protocol for the
synthesis of 9-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-
enyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one deri-
vatives. The reactions times were comparatively short under
mild conditions with excellent yields and simple work-up. All
synthesized compounds were characterized by using spectro-
scopic techniques like 1H NMR and EI-MS. The compounds were
also subjected to elemental analyses and the results are in good
agreement with the expected values. Since all the compounds
are known. The physical data of our compounds have been
compared with the earlier literature [40].
According to our previous research involving CsF as a solid
base, fluoride ion has a strong affinity for active hydrogen [32–
38]. This inspired us to explore the multidimensional studies
which may lead us to new possibilities regarding the utility of
utility of CsF for tandem Knoevenagel–Michael reaction. In
current study, dimedone was reacted with functionalized
salicylaldehydes in dichloromethane under mild conditions as
compared to all of the previous reports for tandem Knoevenagel–
Michael reaction.
The function of cesium fluoride in this reaction is very
important due to several reasons. Scheme 2 shows the reaction
mechanism on the basis of previous work reported by Ishikawa
Scheme 1. Synthetic route for tandem Knoevenagel–Michael reaction by CsF. Structure 1–7 with R group, where R group are H, OH OMe, Cl, F and Br on the functionalized
salicylaldehyde given in Table 1.

K.M. Khan et al. / Journal of Fluorine Chemistry 158 (2014) 1–5
3
Table 1
Highly functionalized 9-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one (1–7).
S. No.
1
Functionalized salicylaldehydes
Products
Yield (%)
80
2
70
3
75
4
70
5
78
6
86

4
K.M. Khan et al. / Journal of Fluorine Chemistry 158 (2014) 1–5
Table 1 (Continued )
S. No.
7
Functionalized salicylaldehydes
Products
Yield (%)
80
Scheme 2. Plausible mechanism of CsF catalyzed tandem Knoevenagel–Michael reaction for synthesis of highly functionalized 9-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-
enyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one derivatives (1–7).
3. Conclusions
300 MHz and 500 MHz spectrometers. Mass spectra were recorded
at JEOL JMS-HX110 mass spectrometer using FABMS-H. CHN
analysis was performed on a Carlo Erba Strumentazion-Mod-1106,
Italy.
An expeditious and robust method has been devised for the
synthesis of highly functionalized 9-(2-hydroxy-4,4-dimethyl-6-
oxocyclohex-1-enyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-
xanthen-1-one 1–7. The newly developed method expanded the
scope of the tandem Knoevenagel–Michael reaction. The ionic salts
such as CsF are an excellent base for promoting the tandem
Knoevenagel–Michael reaction. Extensive studies are required to
fully explore the potential of inorganic ionic compounds as
catalysts in synthetic organic chemistry. This will be topic of our
forthcoming publications of this series.
4.1. General procedure for the synthesis of functionalized 9-(2-
hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)-3,3-dimethyl-2,3,4,9-
tetrahydro-1H-xanthen-1-one
In a typical reaction, catalytic amount of CsF (5 Mol%) was
added to the solution of appropriate substituted salicylaldehyde
(1–7) (1.0 equiv) in dichloromethane (10 mL) at room tempera-
ture. Dimedone (2.0 equiv) was added slowly and reaction mixture
was stirred for 30–40 min. The product was precipitated that was
monitored by TLC. The resultant Precipitate was washed with
distilled water to obtain the pure product. The structure of these
compounds was confirmed by different spectroscopic techniques
like 1H NMR, and MS.
4. Experimental
All the salicylaldehyde analogs and other starting material were
reacted together without purification as received from the supplier
Sigma/Aldrich, USA. 1H NMR spectra were recorded on Bruker

K.M. Khan et al. / Journal of Fluorine Chemistry 158 (2014) 1–5
5
4.2. Spectroscopic data
Acknowledgement
4.2.1. 5-Bromo-7-chloro-9-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-
The authors are thankful to the OPCW, The Netherlands, for
their financial support for project No. L/ICA/ICB/173681/12.
1-enyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one
Yield: 80%; 1H NMR; (DMSO-d6)
d ppm: 7.40 (s, 1H), 6.93 (s, 1H),
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78 (55.7), 63.0 (64.9).
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