Functional ionic liquid [bmim][Sac] mediated synthesis of ferrocenyl thiopropanones via the dual activation of the substrate by the ionic liquid

Article abstract of DOI:10.1039/c3ra22543g

An artificial sweetener saccharin based functional ionic liquid [bmim][Sac] mediated synthesis has been explored for the first time in the organometallic field. The ionic liquid plays a critical role as the catalyst for substrate activation by directly facilitating the solvent-free Michael addition of thiol to ferrocenyl enone. The key to the present methodology is the dual hydrogen bonding of the saccharinate anion that is believed to play a crucial role in thiol activation. All the synthesized ferrocene thiopropanones were examined for their in vitro anti-proliferative activity.

Full text of DOI:10.1039/c3ra22543g

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COMMUNICATION
Functional ionic liquid [bmim][Sac] mediated synthesis
of ferrocenyl thiopropanones via the ‘‘dual activation of
the substrate by the ionic liquid’’3
Atul Kumar,*a Suman Srivastava,a Garima Gupta,a Promod Kumara
and Jayanta Sarkarb
Cite this: RSC Advances, 2013, 3, 3548
Received 17th October 2012,
Accepted 14th January 2013
DOI: 10.1039/c3ra22543g
www.rsc.org/advances
An artificial sweetener saccharin based functional ionic liquid
[bmim][Sac] mediated synthesis has been explored for the first
time in the organometallic field. The ionic liquid plays a critical
role as the catalyst for substrate activation by directly facilitating
the ‘‘solvent-free’’ Michael addition of thiol to ferrocenyl enone.
The key to the present methodology is the dual hydrogen
bonding of the saccharinate anion that is believed to play a
crucial role in thiol activation. All the synthesized ferrocene
thiopropanones were examined for their in vitro anti-proliferative
activity.
due to the diverse applications of these compounds in various
fields, such as pharmaceuticals, material sciences, biosensors, as
well as molecular receptors.8,9 Recently, Jaouen’s research group
has been actively involved with the synthesis of organometallic
compounds with the ferrocenyl entity and have also explained
their biological activity.10 Due to their above mentioned properties,
ferrocene derivatives have acquired a growing significance in
applications which necessitate a more economical and efficient
synthesis. It is interesting to apply the anion–cation cooperative
interaction of functional ionic liquids for the greener synthesis of
bioactive organometallics.
Carbon–sulfur bond formation by the conjugate addition of
thiols to a,b-unsaturated carbonyl compounds is currently
attracting a multifaceted interest in many areas due to their
advantageous applications in chemistry and biology.11 Owing to
their biological relevance, several methods have been developed
for the facile access to such compounds. Although there are
various reports on the Michael reaction of conjugated enones,
Michael addition to ferrocenyl enones has been less explored.12 In
addition, several reports have shown the catalyst-free, solvent free
addition of thiol to an enone.13 These protocols are either not or
less effective for the addition of thiol to ferrocenyl enones. Herein,
as a continuation of the drive towards the greener synthesis of a
bioactive compounds14a,b and the functional ionic liquid mediated
synthesis of dihydrothiophene and tacrine derivatives,14c we report
the conjugate addition of thiol to a ferrocenyl enone mediated by
the artificial sweetener saccharin based functional ionic liquid
[bmim][Sac] (Scheme 2). The synthesis approach for [bmim][Sac] is
shown in Scheme 1.15
The saccharin group was chosen as it is less toxic, it has been
approved for human consumption and is used as a non-nutritive
sweetener.16 To optimize the best reaction conditions, 1-ferroce-
nyl-3-phenyl-2-propen-1-one (1a) was treated with thiophenol/4-
chlorothiophenol (2a/2b) in the presence of catalytic amounts of
various [bmim] based ILs (ionic liquids) (Table 1, Scheme 2).
The mixture was stirred at room temperature in neat
conditions, and the reaction reached completion in 15 min. The
reaction mixture became turbid and the excess (unreacted) thiol
settled as liquid droplets. The crude product, 3a, was isolated after
The recently growing awareness about the synthesis and applica-
tions of novel functional ionic liquids has attracted the attention
of chemists.1 The functional ionic liquid approach has the
capability of designing novel media with defined properties that
make them accurate working systems rather than simply media
and can be transformed according to the requirements of the
application.2 Functional ionic liquids have many applications in
various areas of organic synthesis.3 In spite of this advancement,
the application of functional ionic liquids in the organometallic
field has been less explored.
Recently, studies have focused on discovering efficient catalytic
processes which benefit from the synergistic effect of the cations
and anions of ionic liquids.4 The intramolecular and intermole-
cular hydrogen bonding in functional ionic liquids indicate that
they are excellent assemblies constituted by hydrogen bond
donors and hydrogen bond acceptors.5 A review of ionic liquids
reveals that the cations activate electrophiles, as the hydrogen
bond donors, and the anions of the ionic liquids activate
nucleophiles, as the hydrogen bond acceptors.6,7
The coupling of biomolecules and biologically active molecules
with ferrocene has become more and more a centre of attraction
aMedicinal and Process Chemistry Division, Central Drug Research Institute, CSIR,
Lucknow, 226001, India
bDrug Target Discovery and Development Division, Central Drug Research Institute,
CSIR, Lucknow, 226001, India. E-mail: dratulsax@gmail.com;
Fax: +91-522-2623405/2623938
Electronic supplementary information (ESI) available: Experimental procedures
3
and spectral data for all the compounds. See DOI: 10.1039/c3ra22543g
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Table 1 Reaction of 1-ferrocenyl-3-phenyl-2-propen-1-one (1a) with thiophe-
nol/4-chlorothiophenol in the presence of various ILsa
Entry
ILs
Mol %b
3a yield (%)c
3b (yield)%d
20
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
[bmim][Br]
[bmim][Br]
[bmim][BF4]
[bmim][BF4]
[bmim][PF6]
[bmim][PF6]
[bmim][Cl]
[bmim][Cl]
[bmim][NTf2]
[bmim][OAc]
[bmim][N(CN)2]
[bmim][N3]
Imidazole
10
20
10
20
10
20
10
20
20
20
20
20
20
20
20
5
20
30
10
25
10
20
30
50
10
50
10
10
0
Scheme 1 Synthesis of [bmim][Sac].
35
12
27
11
22
35
50
10
59
10
5
0
0
0
55
80
95
workup in good yields. The catalytic activity of imidazolium-based
ionic liquids7 for the addition of thiols to ferrocenyl enones
follows the order Sac . OAc . Cl . Br . BF4 . PF6 . NTf2 .
N(CN)2 . N3 and [bmim][Sac] is the most effective amongst all the
[bmim] based ILs. Subsequently, we examined the reaction with
[bmim][Sac] in the presence of a protic solvent such as ethanol or
methanol but in these cases the product was not obtained
Saccharin
Na[Sac]
[bmim][Sac]
[bmim][Sac]
[bmim][Sac]
0
0
50
78
90
(Table 2, ESI ).
3
The reaction of enone with thiophenol in the presence of
imidazole, saccharin and Na[Sac] did not afford any product
(Table 1, entries 13–15) indicating the significant catalytic role of
[bmim][Sac].
It has been recognized that hydrogen bonding plays an
important role in the behaviour and activity of an ionic liquid.5
The catalytic efficiency of most ionic liquids is strongly influenced
by the C-2 hydrogen of [bmim] and the counter anion of the ionic
liquid.4,6
The catalytic efficiency of [bmim][Sac] is due to the sacchar-
inate anion which plays an important role in the activation of the
thiol nucleophile along with the C-2 hydrogen of the [bmim]
cation (Fig. 1).
10
20
a
1-Ferrocenyl-3-phenyl-2-propen-1-one (1a) (1 mmol) was reacted
with thiophenol/4-chlorothiophenol (2a/2b) (1.2 mmol) in the
b
presence of the ILs (20 mol %) for 15 min at rt. Amount of IL used
with respect to 1a. Isolated yield of 3a. Isolated yield of 3b. The
product was characterized by NMR and MS.
c
d
atom of the enone by the sulfur atom of the thiol followed by
proton transfer forms thia-Michael adducts.
Mass spectrum after 15 min of treatment/mixing of 1j and 2a
with [bmim][Sac]
Herein we proposed a ‘‘electrophile–nucleophile dual activa-
tion’’ role for [bmim][Sac] (Fig. 1).
In order to prove the supramolecular assembly concept, we
planned to identify and characterize the two supramolecular
structures A/B (Fig. 1). Electrospray ionization mass spectrometry
(ESIMS)18 is an analytical technique for the study of noncovalent
adducts in the gas phase. We performed (+ve) ESIMS studies of
samples withdrawn after 15 min from the [bmim][Sac] catalyzed
reaction of 1j with 2a. The total ion chromatogram (TIC) revealed
the presence of ions at m/z 788.1 (m1), 766.2 (m2), 709.1 (m3),
583.2 (m4), 467.1 (m5) and 445.1 (m6), corresponding to [A/B +
Na+], [A/B + H+], [A/B + 2 Bu], [A/B + 2 Sac], [Product + Na+],
[Product + H+], respectively (Fig. 2), which supports the formation
of supramolecular assemblies A/B.
Encouraged by this result, we planned to determine the
generality of these reaction conditions. Two enones, 3-ferrocenyl-
1-phenyl-2-propen-1-one and 1,3-bisferrocenyl-2- propen-1-one,
were treated with aryl thiols (e.g. thiophenol and 4-chlorothiophe-
nol) in (bmim)[Sac] at room temperature and the corresponding
The hydrogen bond between the C-2 of the imidazole ring and
the carbonyl group improves the electrophilicity of the b-carbon.
Then the charge–charge interaction between the quaternary
nitrogen atom of [bmim] and the amidic site of the saccharinate
anion arises. In case of the saccharinate, the delocalization of the
negative charge occurs and thus both the nitrogen and the
carbonyl oxygen bear a partial negative charge.17 Both the amidic
nitrogen and the amidic oxygen form a hydrogen bond to activate
the thiol (Fig. 1, A and B, respectively).17 The charge–charge
interaction of the lone pair of electrons of the sulfur atom of the
thiol with the quaternary nitrogen atom of [bmim] and the
electrostatic interaction of the carbonyl b-carbon with the sulfur
atom of the thiol form a six membered chair like transition state.
This sequence of hydrogen bonds and charge–charge interactions
forms two types of supramolecular assemblies (A/B) as catalytic
intermediates (Fig. 1). The nucleophilic attack at the b-carbon
Scheme 2 Addition of thiol to 1-ferrocenyl-3-phenyl-2-propen-1-one.
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Fig. 1 Dual activation of the saccharinate anion.
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Table 2 Michael addition via the [bmim][Sac] catalysis of thiol to the ferrocenyl
enonea
Entry
Comp.
R1
R2
R3
Yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
H
H
-
-
-
-
-
-
-
-
-
-
-
-
H
90
95
87
80
85
79
85
89
87
88
89
83
86
76
87
67
4-Cl
4-Cl
H
4-Cl
4-Cl
4-NO2
2-Br
4-OCH3
4-F
4-OCH3
4-F
2-CH3
2-CH3
-
H
4-Cl
4-Cl
4-Cl
H
H
H
4-Cl
H
H
4-Cl
H
Fig. 2 TIC of the (+ve) ESIMS of the sample withdrawn after 15 min of the reaction
of 1j with 2a catalyzed by [bmim][Sac].
H
4-F
4-F
-
-
-
-
thia-Michael adducts were obtained in 80–95% yields (Scheme 3
and 4).
a
Ferrocenyl enone (1a–p) (1 mmol) was reacted with thiophenol/4-
chlorothiophenol (2a/2b) (1.2 mmol) in the presence of the ionic
Excellent results were obtained on each occasion irrespective of
the electronic and steric factors. Ferrocenyl enones carrying
electron donating groups, 2-methyl and 4-methoxy, or electron-
withdrawing groups, 4-chloro and 4-nitro, on the phenyl ring
efficiently produced the final products (Table 2). The progress of
the reactions was monitored by TLC after intervals of 5, 10, and 15
min. However, it was also possible to monitor the reactions
visually. A purple colour solution of ferrocenyl enone was obtained
after the addition of the thiol to the ferrocene grafted enone in the
IL, and a yellow precipitate was formed after the complete
consumption of the ferrocene grafted enone (TLC).
The recyclability of [bmim][Sac] was examined. For the recovery
of the ionic liquid, the extraction was performed using diethyl
ether. After completion of the reaction, diethyl ether was added to
the reaction mixture followed by stirring. Then, the two liquid
layers were separated by decantation, the ionic liquid was dried
and the reactants were added to start the next run. It is interesting
to note that the ionic liquid could be reused without a detectable
reduction of product yield for at least 5 cycles.
b
liquid (20 mol %) for 15 min at rt. Yield was obtained after
crystallization.
Electrochemistry
The electrochemical behaviour of compound 3a was examined
(Fig. 3). At all scan rates, the compound gave rise to a reversible
FeCp20/+ couple and an irreversible oxidation wave. For compound
3a the first wave was observed due to the oxidation of the
ferrocene moiety and is a reversible process. Since it has been
reported that the cytotoxic activity of ferrocenyl derivatives may
originate from their oxidized forms.19
Anti-proliferative activity
In bioorganometallic chemistry, derivatives of ferrocene exhibit a
variety of medicinal properties due to their antitumor activity.10
OH–ferrocifen, with n = 3, is highly cytotoxic to both hormone
dependent and hormone independent breast cancer cells (IC50
values in the range of 0.5 mM) (Fig. 4). It has been hypothesized
that the novel mechanism of action of this OH–ferrocifen complex
could involve the generation of quinone methide due to a
conjugated redox ferrocenyl moiety.20 The unusual redox activity
of the ferrocenyl compound depends on the oxidation state of the
iron in the ferrocene moiety and is the key to the high activity of
ferrocene compounds as anticancer agents. Therefore, the
incorporation of one or more ferrocene moieties has been
Scheme 3 Addition of thiol to 3-ferrocenyl-1-phenyl-2-propen-1-one.
Fig. 3 Cyclic voltammogram of 3a in CH2Cl2–0.1 M Bu4NPF6 at 100 mV s21
.
Scheme 4 Addition of thiol to 1,3-bisferrocenyl-2- propen-1-one.
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Table 3 Results of the in vitro antiproliferative activity assayb of selected
and the electrophilic activation of the enone, due to the C-2
hydrogen of the [bmim] cation, play an indispensable role in the
formation of the non-covalent adducts of an IL, thiol and enone as
discrete catalytic species due to its supramolecular assemblies
through hydrogen bonds and charge–charge interaction. All the
synthesized ferrocene thiopropanones were examined for their in
vitro anti-proliferative activity.
compounds from Scheme 1–3
IC50 (mg ml21 a
)
Entry
Comp.
KB
C-33A
MCF-7
A549
NIH3T3
1
2
3
4
5
6
3a
3i
3k
3p
5.82
5.18
5.22
6.22
0.199
-
13.7
14.95
3.77
7.77
0.28
-
28.59
10.89
8.59
5.59
0.456
13.7
26.77
8.77
12.77
8.77
0.33
-
28.98
9.73
9.98
8.98
-
Doxorubicinc
Tamoxifen
Acknowledgements
-
Authors S.S., G.G. and P.K. thank the CSIR-UGC New Delhi for
the award of a senior research fellowship. The authors also
acknowledge the SAIF-CDRI for providing the spectral and
analytical data. CDRI communication no. 8390.
a
IC50 = compound concentration required to inhibit tumor cell
b
proliferation by 50%. The in vitro antiproliferative activity of all the
synthesized compounds is given in Table 3 of the ESI. Doxorubicin
was used as a positive control.
c
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