synthesis of ferrocene derivatives functionalized with α-methylene-γ-butyrolactone rings

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Journal of Organometallic Chemistry 760 (2014) 19e23

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Journal of Organometallic Chemistry

journal homepage: www.elsevier .com/locate/ jorganchem

Synthesis of ferrocene derivatives functionalized with a-methylene-g-butyrolactone rings

Carlos Anjo a, J. Albertino Figueiredo a,**, M. Isabel Ismael a, Ivânia Cabrita b,Ana C. Fernandes b,*

a Textile and Paper Materials Unity, University of Beira Interior, Rua Marquês d’Ávila e Bolama, 6201-001 Covilhã, PortugalbCentro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal

a r t i c l e i n f o

Article history:Received 3 October 2013Received in revised form27 January 2014Accepted 28 January 2014

Dedicated to Professor Maria José Calhordaon the occasion of her 65th birthday.

Keywords:Ferrocene derivativesa-Methylene-g-butyrolactoneReformatsky-type reaction

* Corresponding author. Tel.: þ351 218419264; fax:** Corresponding author. Tel.: þ351 275319778; fax

E-mail addresses: albfig@ubi.pt (J. Albertino Figueitecnico.ulisboa.pt (A.C. Fernandes).

0022-328X/$ e see front matter � 2014 Elsevier B.V.http://dx.doi.org/10.1016/j.jorganchem.2014.01.032

a b s t r a c t

This work reports the synthesis and characterization of new ferrocene derivatives functionalized withone or two a-methylene-g-butyrolactone rings. These compounds were prepared via Reformatsky-typereaction between carbonyl ferrocene derivatives and ethyl 2-bromomethylacrylate in 33e85% yields.

� 2014 Elsevier B.V. All rights reserved.

1. Introduction

In last past years there has been an increasing interest in thedesign of new compounds incorporating the ferrocene skeleton [1e12], due to its easy chemical modification, small size, relative lip-ophilicity, and stability in aqueous and aerobic media. Several ex-amples of ferrocene derivatives incorporated a drug moiety such asantibiotics (penicillin or cephalosporins) [13] and cancer drugs(tamoxifen) [14] have also been synthesized.

a-Methylene-g-butyrolactones are versatile structural unitspresent in various important natural products which exhibitinteresting biological activities such as antimicrobial [15] andantitumoral [16]. Several method have been developed for thepreparation of a-methylene-g-lactones [17e20], among which theReformatsky-type reaction. In our group, this structural unity wasintroduced in different positions of sugar derivatives, using theReformatsky-type reaction [21].

In continuation of our work about the synthesis of moleculescontaining a-methylene-g-lactone rings [21,22], in this

þ351 218464457.: þ351 275319730.redo), anacristinafernandes@

All rights reserved.

communication we explored the preparation of ferrocene de-rivatives functionalized with a-methylene-g-butyrolactone rings.

2. Results and discussion

The synthesis of ferrocene derivatives functionalized with a-methylene-g-butyrolactone rings was carried out by Reformatsky-type reaction between a carbonyl ferrocene derivative and ethyl2-bromomethylacrylate with zinc as catalyst (Scheme 1).

2.1. Synthesis of starting materials

The Reformatsky-type reaction was initially explored from thecommercial available substrates ferrocenecarboxaldehyde 1, ace-tylferrocene 2, and 1,10-diacetylferrocene 3. The substrates 4 and 5were prepared by FriedeleCrafts acylation reacting ferrocene with(4-chlorophenyl)acetyl chloride or with octanoyl chloride, usingthe method described by Wang et al. [23] (Scheme 2).

The structure of compounds 4 and 5 was confirmed by NMRspectroscopy, where new signals from the carbon chain attached tothe Cp ring of ferrocene were detected. In the 1H NMR spectrum of4 were observed two doublets at d 7.26 and 7.07 ppm, corre-sponding to the aromatic ring of the chlorobenzyl group and asinglet at d 3.96 ppm belonging to the CH2. Formation of 4was alsoconfirmed by the analysis of its 13C NMR spectrum, which showed

Scheme 1. Synthesis of ferrocene derivatives functionalized with a-methylene-g-butyrolactone rings.

Scheme 3. Preparation of compound 6 using Wittig reaction conditions.

C. Anjo et al. / Journal of Organometallic Chemistry 760 (2014) 19e2320

the signal of the carbonyl group at d 201.6 ppm, the signals of thearomatic ring at d 133.4, 132.6, 130.7, 128.6 ppm and the CH2 groupat d 45.8 ppm.

The carbon chain of compound 5 appears in the 1H NMR spec-trum as two multiplets at d 1.72e1.65 ppm and 1.34e1.29 ppm andas two triplets at d 2.68 and 0.87 ppm. The carbonyl group wasvisible in the 13C NMR spectrum at d 204.8 ppm, which confirms theintroduction of the carbon chain.

We have also prepared the ferrocene derivative 6 via Wittigreaction between ferrocenecarboxaldehyde 1 and 1-(triphenyl-phosphoranylidene)-2-propanone in CH3Cl at reflux temperaturein 80% yield (Scheme 3). In the 1H NMR spectrum of 6 weredetected two doublets at d 7.42 and 6.34 ppm, with a couplingconstant of J ¼ 16 Hz, confirming the (E)-configuration of thedouble bond, and a singlet at d 2.30 ppm corresponding to themethyl group. In the 13C NMR spectrum were identified thecarbonyl group at d 197.7 ppm, two signals belonging to the doublebond at d 145.0 and 124.1 ppm and the methyl group at d 27.1 ppm.

2.2. Synthesis of ferrocene derivatives functionalized with a-methylene-g-butyrolactone rings

The synthesis of ferrocene derivatives functionalized with a-methylene-g-butyrolactones was carried out from the carbonylferrocene derivatives 1e6 via Reformatsky-type reactionwith ethyl2-bromomethylacrylate in the presence of activated granulatedzinc (20 mesh). These reactions were performed in dry THF underinert atmosphere at 50 �C (Scheme 4). The products 7e12 wereobtained in 33e85% yields after purification by chromatography.The formation of the lactone derivative in compounds 7e12 wasconfirmed by the analysis of their 1H and 13C NMR spectra. Thesignals corresponding to the a-methylene-g-butyrolactones arereported in Tables 1and 2. Lactones present in 1H NMR spectracharacteristic values for CH2 of ring, assigned as H-4a and H-4b(Scheme 5), at d 2.83e3.34 ppm. The CH2 from double bond appearsat d 6.18e6.33 ppm (H-1’a) and at d 5.57e5.71 ppm (H-10b). In the13C NMR spectra, the signal of the carbonyl group of lactone isdetected at d 169.7e170.1 ppm. The quaternary carbon (C-3) of thedouble bond appears at d 134.9e136.1 ppm and CH2 (C-10) atd 121.9e122.5 ppm. C-5 presents signals for compounds 8e12 at

Scheme 2. Synthesis of ferrocene derivatives 4 and 5 by FriedeleCrafts acylation.

d 81.4e84.4 ppm as quaternary carbons, whereas for compound 7,C-5 appears at d 75.6 ppm (CH). Finally, the CH2 group (C-4) oflactone rings is observed at 34.5e41.9 ppm. Compound 9 has somesignals duplicated in 13C NMR spectrum due to the presence of twolactone rings. Mass spectrometry studies are concordant with thestructures of the ferrocene derivatives 7e12.

3. Conclusion

In conclusion, we have synthesized and characterized six novelferrocene derivatives functionalized with a-methylene-g-butyr-olactone by Reformatsky-type reaction in 33e85% yields. Thesekinds of ferrocene derivatives can serve as potential candidates forbiological screening. The synthesis of a variety of other ferrocenederivatives containing a a-methylene-g-butyrolactone ring and acarbohydrate moiety is currently in progress in our laboratory.

4. Experimental

4.1. General consideration

Melting points were determined with a melting point apparatus(Leitz-Biomed) with platinum plate and are uncorrected. IR spectrawere recorded in a Nicolet iS10 with smart iTR spec-trophotometer.1H NMR spectra were run with a Bruker AC-250Pand Bruker Avance III (400 MHz) spectrometer. Chemical shiftsare expressed in parts per million (ppm) downfield from TMS. The13C NMR spectra were run at 62.90 and 100.6 MHz in the samespectrometers. The experiments were performed in chloroform-d.The progress of all reactions was monitored by thin layer chro-matography (TLC) using aluminium sheets precoated with silica gel60 F254 to a thickness of 0.2 mm (Merck). Compounds weredetected with UV light (254 nm) and/or by spraying the sheets witha 3% vanillin in ethanol/sulfuric acid (100 mL/1.5 mL) followed byheating. Column chromatography (CC) was conducted under lowpressure by elution of the columns filled with silica gel (0.040e0.063 mm, Merck). The synthesis of ethyl 2-bromomethylacrylate[24] and the activation of zinc granules (20 mesh) [25] were car-ried out according to the techniques reported in the literature. Allother chemicals and solvents used were obtained from commercialsources and used as received or dried using standard procedures.

4.2. Synthesis of compounds 4e6

Compounds 4 and 5 were prepared according with the methodreported by Wangs [23] by reaction between ferrocene (5 mmol)and (4-chlorophenyl)acetyl chloride (15mmol) or octanoyl chloride(15 mmol) catalyzed by ZnO (6 mmol).

4.2.1. 2-(4-Chlorophenyl)-1-ferrocenylethanone (4)

Scheme 4. Synthesis of ferrocene derivatives functionalized with a-methylene-g-butyrolactones.

C. Anjo et al. / Journal of Organometallic Chemistry 760 (2014) 19e23 21

Dark orange solid in yield 85%; m.p. 118e119 �C; 1H NMR (dppm, J Hz, CDCl3): 7.26 (d, 2H, J ¼ 7.9 Hz, H-Ph), 7.07 (d, 2H,J ¼ 7.9 Hz, H-Ph), 4.82 (s, 2H, H ferrocene), 4.54 (s, 2H, H ferrocene)4.13 (s, 5H, H ferrocene), 3.96 (s, 2H CH2); 13C NMR (d ppm, J Hz,CDCl3): 201.6 (C]O), 133.4 (C of Ph), 132.6 (C of Ph), 130.7 (2 CH ofPh), 128.6 (2CH of Ph), 74.2 (C-1 ferrocene), 72.6-69.7 (CH ferro-cene), 45.8 (CH2-Ph).

4.2.2. 1-Ferrocenyloctan-1-one (5)

Orange oil, yield 83%; IR (ATR, cm�1): 1669 cm�1; 1H NMR (dppm, JHz, CDCl3): 4.77 (s, 2H,H ferrocene), 4.47 (s, 2H,H ferrocene),4.18 (s, 5H, H ferrocene), 2.68 (t, 2H, J¼ 7.5 Hz, CH2-2),1.72e1.65 (m,2H, CH2-3), 1.34e1.29 (m, 8H, CH2-4-7), 0.87 (t, 3H, CH3-8,J ¼ 6.6 Hz); 13C NMR (d ppm, CDCl3): 204.8 (C]O), 72.2 (C-1ferrocene), 69.8e69.4 (CH ferrocene), 39.8 (CH2-2), 31.8, 29.6, 29.3,24.7, 22.7 (CH2-3-7), 14.2 (CH3-8).

4.2.3. 4-Ferrocenylbut-3-en-2-one (6)

A solution of ferrocenecarboxaldehyde 1 (1.54 g, 7.2 mmol) inchloroform (35 mL) was added to a solution of 1-(triphenylphos-phoranylidene)-2-propanone (4.64 g, 14.6 mmol) in chloroform(35 mL). The mixture was stirred at reflux during 1 h. After

Table 1Lactone rings signals of compounds 7e12 in the 1H NMR spectra.

H-10a H-10b H-4a H-4b H-5

7 6.28 (dd) 5.70 (dd) 3.34e3.26 (m) 3.06e2.99 (m) 5.36e5.31 (m)8 6.29 (dd) 5.67 (dd) 3.23 (dt) 2.96 (dt) 1.70 (s, CH3-5)9 6.31 (s) 5.71 (s) 3.24 (d) 2.97 (d) 1.69 (s, CH3-5)10 6.18 (dd) 5.57 (dd) 3.25 (dt) 3.07 (dt) e

11 6.33 (s) 5.71 (s) 3.27 (d) 3.04 (d) e

12 6.23 (dd) 5.64 (dd) 2.95 (dt) 2.83 (dt) 1.57 (s, CH3-5)

concentration under reduced pressure, the residue was purified bychromatography eluting with ethyl acetate/cyclohexane (1:4) togive 6 as dark orange solid in 80% yield (1.85 g). m. p. 84e85 �C; IR(ATR, cm�1): 1662,1637 cm�1; 1H NMR (d ppm, JHz, CDCl3): 7.42 (d,1H, J ¼ 16 Hz, H-3), 6.34 (d, 1H, J ¼ 16 Hz, H-4), 4.51, 4.45 (2s, 4H, Hferrocene), 4.16 (s, 5H, H ferrocene), 2.30 (s, 3H, CH3CO); 13C NMR (dppm, CDCl3): 197.7 (C-2), 145.0 (C-3), 124.1 (C-4), 78.1 (C-1 ferro-cene), 70.0e69.6 (CH ferrocene), 27.1 (CH3CO).

4.3. General procedure for the synthesis of ferrocene derivativesfunctionalized with a-methylene-g-butyrolactone 7e12 [21]

A solution of ethyl 2-bromomethylacrylate (5 mmol) inanhydrous THF (2.5 mL) was added to a mixture containing thecarbonyl compound (3 mmol) in anhydrous THF (1.2 mL) andactivated granulated zinc 20 mesh (1.23 mmol) at room temper-ature under inert atmosphere. The reaction mixture was heated at50 �C during 3e5 h. After cooling to room temperature, a hy-drochloric acid solution (10%, 25 mL), cooled at 0 �C, was added.Then, the reaction mixture was extracted with dichloromethane(3 � 15 mL), the organic phase was neutralized with a solution ofsodium hydrogen carbonate (2.5%, 25 mL) and dried with anhy-drous sodium sulphate. After evaporation of the solvent, theresidue was purified by chromatography (ethyl acetate/cyclo-hexane 1:10).

4.3.1. 5-Ferrocenyl-3-methylene-1,4-lactone (7)

Table 2Lactone rings signals of compounds 7e12 in the 13C NMR spectra.

C-2 C-3 C-10 C-5 C-4

7 170.1 134.9 121.9 75.6 (CH) 34.58 169.7 136.0 122.0 82.2 41.99 169.7 135.8, 135.7 122.5, 122.4 82.2 41.810 169.7 135.3 122.2 83.7 38.311 170.0 136.1 122.1 84.4 39.312 169.8 135.3 122.2 81.4 40.8

Scheme 5. Assignment of proton and carbon of synthesized lactones (Fc ¼ ferrocenyl).

C. Anjo et al. / Journal of Organometallic Chemistry 760 (2014) 19e2322

Yellow solid, yield 59% (0.50 g); m.p.135e139 �C; IR (ATR, cm�1):1746, 1660 cm�1; 1H NMR (d ppm, J Hz, CDCl3): 6.28 (dd, 1H, JH-10a,H-4a ¼ 2.5 Hz, JH-10a,H-4b ¼ 5.5 Hz, H-10a), 5.70 (dd, 1H, JH-10b,H-4a ¼ 2.3 Hz, JH-10b,H-4b ¼ 4.7 Hz, H-10b), 5.36e5.31 (m, 1H, H-5), 4.26(s, 3H, H ferrocene), 4.23 (s, 6H, H ferrocene), 3.34e3.26 (m, 1H, H-4a), 3.06e2.99 (m, 1H, H-4b); 13C NMR (d ppm, CDCl3): 170.1 (C-2),134.9 (C-3), 121.9 (C-10), 86.5 (C-1 ferrocene), 75.6 (C-5), 68.8e66.1(CH ferrocene), 34.5 (C-4); ESI(þ)-HRMS: found 282.03450(282.03377 calcd for C15H14O2Fe).

4.3.2. 5-Ferrocenyl-5-methyl-3-methylene-1,4-lactone (8)

Light orange solid, yield 70% (0.67 g); m.p. 73e75 �C; IR (ATR,cm�1): 1743, 1661 cm�1; 1H NMR (d ppm, J Hz, CDCl3): 6.29 (dd, 1H,JH-10a,H-4a ¼ 2.8 Hz, JH-10a,H-4b ¼ 5.6 Hz, H-10a), 5.67 (dd, 1H, JH-10b,H-4b ¼ 2.5 Hz, JH-10b,H-4a ¼ 5.0 Hz, H-10b), 4.19 (s, 2H, H ferrocene), 4.17(s, 2H, H ferrocene), 4.09 (s, 5H, H ferrocene), 3.23 (dt, 1H, JH-10a,H-4a ¼ 2.8 Hz, JH-10b,H-4a ¼ 5.0 Hz, H-4a), 2.96 (dt, 1H, JH-10a,H-4b ¼ 5.6 Hz, JH-10b,H-4b ¼ 2.5 Hz, H-4b), 1.70 (s, 3H, CH3-5); 13C NMR(d ppm, CDCl3): 169.7 (C-2), 136.0 (C-3), 122.0 (C-10), 93.3 (C-1ferrocene), 82.2 (C-5), 68.8e65.3 (CH ferrocene), 41.9 (C-4), 29.0 (C-50); ESI(þ)-HRMS: found 296.04977 (296.04942 calcd forC16H16O2Fe).

4.3.3. 5,50-(Ferrocenyl-1, 10-diyl)bis(5-methyl-3-methylene-1,4-lactone) (9)

Yellow solid, yield 35% (0.43 g);m.p.122e125 �C; IR (ATR, cm�1):1750, 1665 cm�1; 1H NMR (d ppm, J Hz, CDCl3): 6.31 (s, 2H, H-10a),5.71 (s, 2H, H-10b), 4.23 (s, 4H,H ferrocene), 4.10 (s, 4H,H ferrocene),3.24 (d, 2H, J¼ 6.8Hz, H-4a), 2.97 (d, 2H, J¼ 6.8Hz, H-4b),1.69 (s, 6H,CH3-5); 13CNMR (dppm, CDCl3): 169.7 (C-2),135.8,135.7 (C-3),122.5

(C-10), 122.4 (C-10), 94.6 (C-1 ferrocene), 94.5 (C-1 ferrocene), 82.2(C-5), 69.4e66.0 (CH ferrocene), 41.8 (C-4), 29.2 (C-50); ESI(þ)-HRMS: found 406.08563 (406.08622 calcd for C22H22O4Fe).

4.3.4. 5-Ferrocenyl-5-(4-chlorobenzyl)-3-methylene-1,4-lactone(10)

Light green solid, yield 85% (1.03 g); m.p. 149e151 �C; IR (ATR,cm�1): 1743, 1665 cm�1; 1H NMR (d ppm, J Hz, CDCl3): 7.18 (d, 2H,J¼8.30Hz,H-Ph), 6.93 (d, 2H, J¼8.30Hz,H-Ph), 6.18 (dd,1H, JH-10a,H-4a¼2.9Hz, JH-10a,H-4b¼5.8Hz,H-10a), 5.57 (dd,1H, JH-10b,H-4b¼2.6Hz,JH-10b,H-4a ¼ 5.1 Hz, H-10b), 4.21e3.90 (m, 9H, H ferrocene), 3.25 (dt,1H, JH-10a,H-4a¼ 2.9 Hz, JH-10b,H-4a¼ 5.1 Hz, H-4a), 3.13 (d,1H, J¼ 13.8,CH2

00), 3.07 (dt,1H, JH-10a,H-4b¼ 5.8 Hz, JH-10b,H-4b¼ 2.6 Hz, H-4b), 2.95(d,1H, J¼ 13.8, CH2

00); 13C NMR (d ppm, CDCl3): 169.7 (C-2),135.3 (C-3),133.3 (Cof Ph),133.0 (Cof Ph),132.2 (2CHof Ph),128.3 (2CHof Ph),122.2 (C-10), 93.7 (C-1 ferrocene), 83.7 (C-5), 68.8e66.1 (CH ferro-cene), 48.3 (CH2-Ph), 38.3 (C-4); ESI(þ)-HRMS: found 406.04229(406.04181 calcd for C22H19O2ClFe).

4.3.5. 5-Ferrocenyl-5-heptyl-3-methylene-1,4-lactone (11)

Yellow solid, yield 60% (0.68 g); m.p. 66e67 �C; IR (ATR, cm�1):1755, 1662 cm�1; 1H NMR (d ppm, J Hz, CDCl3): 6.33 (s, 1H, H-10a),5.71 (s, 1H, H-10b), 4.31e4.01 (s, 9H, H ferrocene), 3.27 (d, 1H,J ¼ 10.6 Hz, H-4a), 3.04 (d, 1H, J ¼ 10.6 Hz, H-4b), 1.80-1.70 (m, 2H,CH2-100), 1.21 (brs, 10H, CH2-200-600), 0.85 (t, 3H, J ¼ 4.2 Hz, CH3-700);13C NMR (d ppm, CDCl3): 170.0 (C-2), 136.1 (C-3), 122.1 (C-10), 94.6(C-1 ferrocene), 84.4 (C-5), 69.1e66.1 (CH ferrocene), 43.4 (C-100),39.3 (C-4), 31.8, 29.6, 29.1, 23.7, 22.6 (CH2-200-600), 14.1 (CH3-700);ESI(þ)-HRMS: found 380.14308 (380.14334 calcd for C22H28O2Fe).

4.3.6. 5-(2-Ferrocen-ethenyl)-5-methyl-3-methylene-1,4-lactone(12)

C. Anjo et al. / Journal of Organometallic Chemistry 760 (2014) 19e23 23

Light orange solid, yield 33% (0.32 g); m.p. 84e85 �C; IR (ATR,cm�1): 1754,1669,1653 cm�1; 1H NMR (d ppm, JHz, CDCl3): 6.36 (d,1H, J ¼ 15.6 Hz, H-100), 6.23 (dd, 1H, JH-10a,H-4a ¼ 2.7 Hz, JH-10a,H-4b¼5.4Hz,H-10a), 5.83 (d,1H, J¼15.6Hz,H-200), 5.64 (dd,1H, JH-10b,H-4b¼ 2.4 Hz, JH-10b,H-4a¼ 4.7 Hz, H-10b), 4.32 (s, 9H,H ferrocene), 4.23(s, 9H, H ferrocene), 2.95 (dt, 1H, JH-10a,H-4a ¼ 2.7 Hz, JH-10b,H-4a¼ 4.7 Hz, H-4a), 2.83 (dt,1H, JH-10a,H-4b¼ 5.4Hz, JH-10b,H-4b¼ 2.4Hz,H-4b),1.57 (s, 3H, CH3-5); 13CNMR (d ppm, CDCl3): 169.8 (C-2),135.3(C-3),128.2,127.0 (C-100, C-200),122.2 (C-10), 82.6 (C-1 ferrocene), 81.4(C-5), 69.2e66.8 (CH ferrocene), 40.8 (C-4), 27.1 (C-50); ESI(þ)-HRMS: found 322.06480 (322.06509 calcd for C18H18O2Fe).

Acknowledgement

This research was supported by FCT through projects PTDC/QUI-QUI/102114/2008 and PEst-OE/QUI/UI0100/2013. C. Anjo andI. Cabrita (SFRH/BD/74280/2010) thank to FCT for a grant. Theauthors thank the Portuguese NMR Network (IST-UTL Center) forproviding access to the NMR facilities and the Portuguese NationalMass Spectrometry Network (REDE/1501/REM/2005) for the ESI(þ)-HRMS measurements.

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