Cite this: RSC Advances, 2013, 3, 3548

Received 17th October 2012,Accepted 14th January 2013

Functional ionic liquid [bmim][Sac] mediated synthesisof ferrocenyl thiopropanones via the ‘‘dual activation ofthe substrate by the ionic liquid’’3

DOI: 10.1039/c3ra22543g

www.rsc.org/advances

Atul Kumar,*a Suman Srivastava,a Garima Gupta,a Promod Kumara

and Jayanta Sarkarb

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.

The recently growing awareness about the synthesis and applica-tions of novel functional ionic liquids has attracted the attentionof chemists.1 The functional ionic liquid approach has thecapability of designing novel media with defined properties thatmake them accurate working systems rather than simply mediaand can be transformed according to the requirements of theapplication.2 Functional ionic liquids have many applications invarious areas of organic synthesis.3 In spite of this advancement,the application of functional ionic liquids in the organometallicfield has been less explored.

Recently, studies have focused on discovering efficient catalyticprocesses which benefit from the synergistic effect of the cationsand anions of ionic liquids.4 The intramolecular and intermole-cular hydrogen bonding in functional ionic liquids indicate thatthey are excellent assemblies constituted by hydrogen bonddonors and hydrogen bond acceptors.5 A review of ionic liquidsreveals that the cations activate electrophiles, as the hydrogenbond donors, and the anions of the ionic liquids activatenucleophiles, as the hydrogen bond acceptors.6,7

The coupling of biomolecules and biologically active moleculeswith ferrocene has become more and more a centre of attraction

due to the diverse applications of these compounds in variousfields, such as pharmaceuticals, material sciences, biosensors, aswell as molecular receptors.8,9 Recently, Jaouen’s research grouphas been actively involved with the synthesis of organometalliccompounds with the ferrocenyl entity and have also explainedtheir biological activity.10 Due to their above mentioned properties,ferrocene derivatives have acquired a growing significance inapplications which necessitate a more economical and efficientsynthesis. It is interesting to apply the anion–cation cooperativeinteraction of functional ionic liquids for the greener synthesis ofbioactive organometallics.

Carbon–sulfur bond formation by the conjugate addition ofthiols to a,b-unsaturated carbonyl compounds is currentlyattracting a multifaceted interest in many areas due to theiradvantageous applications in chemistry and biology.11 Owing totheir biological relevance, several methods have been developedfor the facile access to such compounds. Although there arevarious reports on the Michael reaction of conjugated enones,Michael addition to ferrocenyl enones has been less explored.12 Inaddition, several reports have shown the catalyst-free, solvent freeaddition of thiol to an enone.13 These protocols are either not orless effective for the addition of thiol to ferrocenyl enones. Herein,as a continuation of the drive towards the greener synthesis of abioactive compounds14a,b and the functional ionic liquid mediatedsynthesis of dihydrothiophene and tacrine derivatives,14c we reportthe conjugate addition of thiol to a ferrocenyl enone mediated bythe artificial sweetener saccharin based functional ionic liquid[bmim][Sac] (Scheme 2). The synthesis approach for [bmim][Sac] isshown in Scheme 1.15

The saccharin group was chosen as it is less toxic, it has beenapproved for human consumption and is used as a non-nutritivesweetener.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 ofvarious [bmim] based ILs (ionic liquids) (Table 1, Scheme 2).

The mixture was stirred at room temperature in neatconditions, and the reaction reached completion in 15 min. Thereaction mixture became turbid and the excess (unreacted) thiolsettled as liquid droplets. The crude product, 3a, was isolated after

aMedicinal and Process Chemistry Division, Central Drug Research Institute, CSIR,

Lucknow, 226001, IndiabDrug Target Discovery and Development Division, Central Drug Research Institute,

CSIR, Lucknow, 226001, India. E-mail: dratulsax@gmail.com;

Fax: +91-522-2623405/2623938

3 Electronic supplementary information (ESI) available: Experimental proceduresand spectral data for all the compounds. See DOI: 10.1039/c3ra22543g

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3548 | RSC Adv., 2013, 3, 3548–3552 This journal is � The Royal Society of Chemistry 2013

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workup in good yields. The catalytic activity of imidazolium-basedionic liquids7 for the addition of thiols to ferrocenyl enonesfollows 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 ormethanol but in these cases the product was not obtained(Table 2, ESI3).

The reaction of enone with thiophenol in the presence ofimidazole, 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 animportant role in the behaviour and activity of an ionic liquid.5

The catalytic efficiency of most ionic liquids is strongly influencedby the C-2 hydrogen of [bmim] and the counter anion of the ionicliquid.4,6

The catalytic efficiency of [bmim][Sac] is due to the sacchar-inate anion which plays an important role in the activation of thethiol nucleophile along with the C-2 hydrogen of the [bmim]cation (Fig. 1).

Herein we proposed a ‘‘electrophile–nucleophile dual activa-tion’’ role for [bmim][Sac] (Fig. 1).

The hydrogen bond between the C-2 of the imidazole ring andthe carbonyl group improves the electrophilicity of the b-carbon.Then the charge–charge interaction between the quaternarynitrogen atom of [bmim] and the amidic site of the saccharinateanion arises. In case of the saccharinate, the delocalization of thenegative charge occurs and thus both the nitrogen and thecarbonyl oxygen bear a partial negative charge.17 Both the amidicnitrogen and the amidic oxygen form a hydrogen bond to activatethe thiol (Fig. 1, A and B, respectively).17 The charge–chargeinteraction of the lone pair of electrons of the sulfur atom of thethiol with the quaternary nitrogen atom of [bmim] and theelectrostatic interaction of the carbonyl b-carbon with the sulfuratom of the thiol form a six membered chair like transition state.This sequence of hydrogen bonds and charge–charge interactionsforms two types of supramolecular assemblies (A/B) as catalyticintermediates (Fig. 1). The nucleophilic attack at the b-carbon

atom of the enone by the sulfur atom of the thiol followed byproton transfer forms thia-Michael adducts.

Mass spectrum after 15 min of treatment/mixing of 1j and 2awith [bmim][Sac]

In order to prove the supramolecular assembly concept, weplanned to identify and characterize the two supramolecularstructures A/B (Fig. 1). Electrospray ionization mass spectrometry(ESIMS)18 is an analytical technique for the study of noncovalentadducts in the gas phase. We performed (+ve) ESIMS studies ofsamples withdrawn after 15 min from the [bmim][Sac] catalyzedreaction of 1j with 2a. The total ion chromatogram (TIC) revealedthe 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 formationof supramolecular assemblies A/B.

Encouraged by this result, we planned to determine thegenerality 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

Scheme 1 Synthesis of [bmim][Sac].

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

1 [bmim][Br] 10 20 202 [bmim][Br] 20 30 353 [bmim][BF4] 10 10 124 [bmim][BF4] 20 25 275 [bmim][PF6] 10 10 116 [bmim][PF6] 20 20 227 [bmim][Cl] 10 30 358 [bmim][Cl] 20 50 509 [bmim][NTf2] 20 10 10

10 [bmim][OAc] 20 50 5911 [bmim][N(CN)2] 20 10 1012 [bmim][N3] 20 10 513 Imidazole 20 0 014 Saccharin 20 0 015 Na[Sac] 20 0 016 [bmim][Sac] 5 50 5517 [bmim][Sac] 10 78 8018 [bmim][Sac] 20 90 95

a 1-Ferrocenyl-3-phenyl-2-propen-1-one (1a) (1 mmol) was reactedwith thiophenol/4-chlorothiophenol (2a/2b) (1.2 mmol) in thepresence of the ILs (20 mol %) for 15 min at rt. b Amount of IL usedwith respect to 1a. c Isolated yield of 3a. d Isolated yield of 3b. Theproduct was characterized by NMR and MS.

Fig. 1 Dual activation of the saccharinate anion.Scheme 2 Addition of thiol to 1-ferrocenyl-3-phenyl-2-propen-1-one.

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thia-Michael adducts were obtained in 80–95% yields (Scheme 3and 4).

Excellent results were obtained on each occasion irrespective ofthe electronic and steric factors. Ferrocenyl enones carryingelectron donating groups, 2-methyl and 4-methoxy, or electron-withdrawing groups, 4-chloro and 4-nitro, on the phenyl ringefficiently produced the final products (Table 2). The progress ofthe reactions was monitored by TLC after intervals of 5, 10, and 15min. However, it was also possible to monitor the reactionsvisually. A purple colour solution of ferrocenyl enone was obtainedafter the addition of the thiol to the ferrocene grafted enone in theIL, and a yellow precipitate was formed after the completeconsumption of the ferrocene grafted enone (TLC).

The recyclability of [bmim][Sac] was examined. For the recoveryof the ionic liquid, the extraction was performed using diethylether. After completion of the reaction, diethyl ether was added tothe reaction mixture followed by stirring. Then, the two liquidlayers were separated by decantation, the ionic liquid was driedand the reactants were added to start the next run. It is interestingto note that the ionic liquid could be reused without a detectablereduction of product yield for at least 5 cycles.

Electrochemistry

The electrochemical behaviour of compound 3a was examined(Fig. 3). At all scan rates, the compound gave rise to a reversibleFeCp2

0/+ couple and an irreversible oxidation wave. For compound3a the first wave was observed due to the oxidation of theferrocene moiety and is a reversible process. Since it has beenreported that the cytotoxic activity of ferrocenyl derivatives mayoriginate from their oxidized forms.19

Anti-proliferative activity

In bioorganometallic chemistry, derivatives of ferrocene exhibit avariety of medicinal properties due to their antitumor activity.10

OH–ferrocifen, with n = 3, is highly cytotoxic to both hormonedependent and hormone independent breast cancer cells (IC50

values in the range of 0.5 mM) (Fig. 4). It has been hypothesizedthat the novel mechanism of action of this OH–ferrocifen complexcould involve the generation of quinone methide due to aconjugated redox ferrocenyl moiety.20 The unusual redox activityof the ferrocenyl compound depends on the oxidation state of theiron in the ferrocene moiety and is the key to the high activity offerrocene compounds as anticancer agents. Therefore, theincorporation of one or more ferrocene moieties has been

Fig. 2 TIC of the (+ve) ESIMS of the sample withdrawn after 15 min of the reactionof 1j with 2a catalyzed by [bmim][Sac].

Scheme 4 Addition of thiol to 1,3-bisferrocenyl-2- propen-1-one.

Scheme 3 Addition of thiol to 3-ferrocenyl-1-phenyl-2-propen-1-one.

Table 2 Michael addition via the [bmim][Sac] catalysis of thiol to the ferrocenylenonea

Entry Comp. R1 R2 R3 Yield (%)b

1 3a H - H 902 3b H - 4-Cl 953 3c 4-Cl - 4-Cl 874 3d 4-Cl - H 805 3e 4-NO2 - H 856 3f 2-Br - 4-Cl 797 3g 4-OCH3 - 4-Cl 858 3h 4-F - 4-Cl 899 3i 4-OCH3 - H 87

10 3j 4-F - H 8811 3k 2-CH3 - H 8912 3l 2-CH3 - 4-Cl 8313 3m - H H 8614 3n - 4-F H 7615 3o - 4-F 4-Cl 8716 3p - - H 67

a Ferrocenyl enone (1a–p) (1 mmol) was reacted with thiophenol/4-chlorothiophenol (2a/2b) (1.2 mmol) in the presence of the ionicliquid (20 mol %) for 15 min at rt. b Yield was obtained aftercrystallization.

Fig. 3 Cyclic voltammogram of 3a in CH2Cl2–0.1 M Bu4NPF6 at 100 mV s21.

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recognized as an attractive way to functionally endow a novelmolecule.

A total of 16 ferrocenyl thiopropanones (Scheme 2–4) weregenerated during the present work and all of them were subjectedto an in vitro antiproliferative activity assay against five humancancer cell lines: KB (oral epidermal carcinoma), C33A (cervicalcarcinoma), MCF-7 (breast adenocarcinoma), A-549 (lung carci-noma) and NIH3T3 (mouse fibroblast). In order to generate ameaningful structure activity relationship in all schemes, varia-tions were made by phenyl ring functionalization of theacetophenone moiety, which included H and 4-F, while 6 changes,represented by H, 4-F, 4-Cl, 4-Br, 4-OCH3, 4-NO2 and 2-CH3, weremade in the phenyl group of the aldehyde subunit. Among thecompounds belonging to Scheme 2, those where the phenyl ringof the aldehyde moiety did not carry any substitution or carry4-OCH3 or 2-CH3 groups displayed a good antiproliferative effect,whereas 4-F, 4-Cl and 4-Br substitutions on the aryl ring of thealdehyde or acetophenone subunit showed a lower antiprolifera-tive effect. The introduction of a ferrocene ring on both phenylrings resulted in compounds belonging to 3p, which exhibited asignificant antiproliferative activity (Table 3).

Conclusion

In conclusion, the functional ionic liquid, which has not beenused before in ferrocene chemistry, appears to be a simple but veryeffective catalyst as well as a medium to prepare ferrocenylthiopropanone derivatives. A mechanism has been proposedinvolving an ambiphilic dual activation role of the saccharinateanion through the dual hydrogen bond formation with thiol. Thedual hydrogen bond by the saccharinate anion to activate the thiol

and the electrophilic activation of the enone, due to the C-2hydrogen of the [bmim] cation, play an indispensable role in theformation of the non-covalent adducts of an IL, thiol and enone asdiscrete catalytic species due to its supramolecular assembliesthrough hydrogen bonds and charge–charge interaction. All thesynthesized ferrocene thiopropanones were examined for their invitro anti-proliferative activity.

Acknowledgements

Authors S.S., G.G. and P.K. thank the CSIR-UGC New Delhi forthe award of a senior research fellowship. The authors alsoacknowledge the SAIF-CDRI for providing the spectral andanalytical data. CDRI communication no. 8390.

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Table 3 Results of the in vitro antiproliferative activity assayb of selectedcompounds from Scheme 1–3

Entry Comp.

IC50 (mg ml21)a

KB C-33A MCF-7 A549 NIH3T3

1 3a 5.82 13.7 28.59 26.77 28.982 3i 5.18 14.95 10.89 8.77 9.733 3k 5.22 3.77 8.59 12.77 9.984 3p 6.22 7.77 5.59 8.77 8.985 Doxorubicinc 0.199 0.28 0.456 0.33 -6 Tamoxifen - - 13.7 - -

a IC50 = compound concentration required to inhibit tumor cellproliferation by 50%. b The in vitro antiproliferative activity of all thesynthesized compounds is given in Table 3 of the ESI. c Doxorubicinwas used as a positive control.

Fig. 4 Tamoxifen, ferrocifen and the designed molecule.

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