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Journal of Organometallic Chemistry 718 (2012) 105e107
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Journal of Organometallic Chemistry
journal homepage: www.elsevier .com/locate/ jorganchem
Communication
Synthesis of ferrocene-labelled steroid derivatives via homogeneous catalyticmethods
Eszter Szánti-Pintér a, Zsolt Csók b,c, László Kollár b,c, Károly Vékey d, Rita Skoda-Földes a,*
aUniversity of Veszprém, Institute of Chemistry, Department of Organic Chemistry, Egyetem u. 10, P.O. Box 158, H-8200 Veszprém, HungarybUniversity of Pécs, Department of Inorganic Chemistry, Ifjúság u. 6, P.O. Box 266, H-7624 Pécs, Hungaryc János Szentágothai Research Center, University of Pécs, H-7624 Pécs, Hungaryd Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Pusztaszeri út 59-67, H-1025 Budapest II., Hungary
a r t i c l e i n f o
Article history:Received 27 June 2012Received in revised form30 July 2012Accepted 7 August 2012
Keywords:FerroceneSteroidsPalladiumCarbonylationCopperCycloaddition
* Corresponding author. Tel.: þ36 88 624719; fax: þE-mail address: [email protected] (R
0022-328X/$ e see front matter � 2012 Elsevier B.V.http://dx.doi.org/10.1016/j.jorganchem.2012.08.013
a b s t r a c t
Carbonylative Sonogashira coupling and copper catalyzed azideealkyne cycloaddition were used effec-tively in the synthesis of ferrocene-labelled steroids. Steroidal alkynyl ketones were obtained inmoderate yield from 17-ethynyl steroids without the necessity for the protection of the 17b-OH group ofvarious compounds. Unfortunately, the alkynyl ketone derivatives could not be converted to steroidswith heterocyclic groups at C-17 using methylhydrazine cyclocondensation agent. At the same time, 17-triazolyl steroids with ferrocene labels were synthesized in excellent yields starting from the samesubstrates by a copper-catalyzed azide alkyne cycloaddition. The new compounds were characterized by1H and 13C NMR, MS and IR.
� 2012 Elsevier B.V. All rights reserved.
1. Introduction
Ferrocene labelled steroids have many interesting propertiesand several literature examples prove the significance of thesecompounds. Some ferroceneesteroid conjugates show liquid crys-talline properties and they can be used for the controlledconstruction of macromolecular aggregates, e.g. membranes [1]. Inanother example, the oxidation of the ferrocenyl group to ferro-cenium led to a phase transition from gel to solution state [2]. Thepresence of the ferrocenyl moiety may enable the electrochemicaldetection of steroids. 17a-(Ferrocenylethynyl)-estradiol was shownto be recognized by the natural estrogen receptors, in spite of theattachment of the bulky substituent to the steroidal core [3].Ferrocene-labelling increases the sensitivity of detection of steroidsin liquid chromatography-mass spectrometry [4]. Coupling ofsteroids with ferrocene could also be important in medicine.Antibacterial and antitumour behaviour of some of thesecompounds have been proved [5e7].
At the same time, several steroid derivatives with variousheterocyclic rings in the side chain show interesting biologicalactivity. Androstenes with imidazolyl [8], pyrazolyl [8], isoxazolyl
36 88 624469.. Skoda-Földes).
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[8], oxazolyl [9], thiazolyl [9] and triazolyl [10,11] groups, as well assteroidal benzoazole and pyrazine derivatives [12] were found to bevery potent inhibitors of 17a-hydroxylase-C17,20-lyase and to haveconsiderable antitumour activity. Estra-1,3,5(10)-triene derivatives,bearing heterocyclic substituents (oxazole, tetrazole, triazole)tethered to C-17, showed high anti-proliferative effect in breast andprostate cancer cell lines [13]. Some estradiol 17a-triazolinesshowed the same catabolic properties exhibited by estrone [14].
Based on these findings, as part of our ongoing interest in thesynthesis of ferrocene-labelled steroid derivatives [15e18], wedecided to explore possible synthetic routes to obtain ferrocene-functionalized C-17 heterocyclic steroid derivatives.
2. Results and discussion
2.1. Carbonylative Sonogashira coupling of steroids 1ae3a
Three steroid derivatives with a 17a-ethynyl substituent (Fig. 1,1ae3a) were chosen as model compounds to obtain newferroceneesteroid conjugates.
As alkynones are versatile starting materials for the synthesis ofa great variety of heterocycles [19,20], at first a possible route,involving a palladium-catalyzed carbonylative Sonogashira couplingfollowed byan additionecyclocondensation reaction in the presence
Fig. 1. Ethynyl-steroids 1ae3a, used as substrates.
Scheme 1. Palladium-catalyzed carbonylative Sonogashira coupling of steroids 1ae3a with iodoferrocene (4).
Table 1Carbonylative Sonogashira coupling of ethynylsteroids 1ae3a with iodoferrocene(4).a
Entry Steroid CO pressure[bar]
Steroid/4 molarratio
Reactiontime
Product Isolatedyield [%]b
1 1a 15 1/1 12 1b 452 1a 15 1.25/1 12 1b 633c 1a 15 1.25/1 12 1b 504 1a 25 1.25/1 12 1b 275 1a 15 1.25/1 20 1b 666 2a 15 1.25/1 12 2b 507 3a 1 1.25/1 12 3b 51
a Reaction conditions: 4/Pd/Cu/Et3N ¼ 1/0.1/0.04/1, 60 �C in THF.b mmol product/mmol iodoferrocene � 100.c Without CuI.
E. Szánti-Pintér et al. / Journal of Organometallic Chemistry 718 (2012) 105e107106
of compounds with two nucleophilic moieties (e.g. hydrazines), wasenvisioned.
Several ferrocene derivatives have been synthesized in ourgroup, via a palladium-catalyzed carbonylative Sonogashiracoupling of iodoferrocene and terminal alkynes [21]. Moreover,according to the literature, there are some examples for thecoupling of steroids and ferrocene via the Sonogashira reaction[22], but the carbonylative version had not been used for thesynthesis of steroideferrocene conjugates.
In the catalytic cycle of the Sonogashira coupling, the activePd(0) species is formed from a Pd(II) pre-catalyst via reductiveelimination of a symmetric diyne from a Pdediacetylide complex[23]. The Pdediacetylide complex is generated from PdCl2(PPh3)2and the terminal alkyne or coppereacetylide. The oxidative addi-tion of the aryl-halide to the Pd(0) complex, formed in situ,produces a Pd(II) intermediate which is supposed to react witha coppereacetylide species in a transmetallation step. The nextsteps involve the reductive elimination of the product and theregeneration of the catalytically active Pd(0) species. Under COatmosphere the reaction may follow similar steps, except that theoxidative addition of an aryl halide is followed by CO insertion,leading to the formation of an acyl complex.
In the present study, the carbonylative coupling of ethynyl-steroids and iodoferrocene was carried out in the presence of themost widely used PdCl2(PPh3)2/CuI catalytic system (Scheme 1).Our previous results concerning carbonylative Sonogashiracoupling of iodoferrocene showed that a moderate CO pressure hadto be used in order to convert iodoferrocene into alkynyl ketonesand to avoid homo-coupling of the terminal acetylene reactionpartner. Also, optimal conversion of iodoferrocene was obtainedwhen at least a twofold excess of simple alkynes was used. In orderto optimize reaction conditions for the steroidal reaction partners,steroid 1a was reacted with iodoferrocene (4) using different 1a/4ratios, catalyst system and CO pressure (Table 1). When iodo-ferrocene and 1a were reacted in equimolar amounts, the product(1b) could be isolated in 45% yield (entry 1). (It should bementioned that 1a was used as a non-separable mixture of D5 andD4 isomers (1ab) in a ratio of 8/2. According to the 1H NMR spec-trum of the product 1b, this ratio did not change during the reac-tion.) The use of a slight excess of steroid 1a led to an increase in theyield of 1b (entry 2). The absence of the CuI cocatalyst (entry 3), aswell as the use of a higher CO pressure resulted in lower yields(entry 4). As an increase in the reaction time did not lead toa considerable improvement in the yield of 1b (entry 5), the other
two substrates, 2a and 3a, were reacted with iodoferrocene (4)under conditions corresponding to entry 2. The products (2b and3b) were obtained in 50% and 51% yields, respectively (entries 6, 7).
The estradiol derivative (3b) had been synthesized previously bya four-step procedure via the lithiation of MOM-protected ethynyl-estradiol, followed by coupling with the Weinreb-amide derivativeof ferrocene, and deprotection of the OH groups [24]. It is worthnoting that the carbonylative Sonogashira reaction tolerates thetertiary alcohol functionality and therefore, the protection of 17-OHgroups is not necessary. It should be mentioned that a slowdecomposition of ferrocenyl alkynyl ketones 2b and 3b wasobserved in solution.
Next, the additionecyclocondensation reaction of 1b withmethylhydrazine was attempted. Unfortunately, only traces of theexpected pyrazole derivative could be isolated, so we decided tochoose another reaction pathway to synthesize ferrocene-functionalised C-17 heterocyclic steroid derivatives in one step.
2.2. Copper-catalyzed azideealkyne cycloaddition of steroids1ae3a
Copper-catalyzed azideealkyne 1,3-dipolar cycloaddition hasattracted wide attention for its high reaction efficiency, mild reac-tion conditions and stability of the products [25]. The reaction isregiospecific, and leads to 1,4-disubstituted 1,2,3-triazoles. In thecycloaddition reaction, the catalytically active species is a Cu(I)complex. Although various Cu(I) salts and complexes can be effi-ciently used as catalysts, the simplest catalytic system consists ofCuSO4 and sodium ascorbate. In the presence of the ascorbate asthe reducing agent, the catalytically active Cu(I) species is formed in
Scheme 2. Copper-catalyzed azideealkyne cycloaddition of steroids 1ae3a with 1-azido-ethylferrocene (5).
E. Szánti-Pintér et al. / Journal of Organometallic Chemistry 718 (2012) 105e107 107
situ from the Cu(II) salt. In this case, it is not necessary to use inertconditions and the reaction takes place at atmospheric pressure, atroom temperature in an organic solvent/water mixture.
The CuSO4/sodium-ascorbate catalytic system was applied inthe synthesis of steroid-ferrocene derivatives 1ce3c, in a CH2Cl2/water mixture in the presence of ferrocenyl azide 5 as the reactionpartner (Scheme 2). The reactions were followed by thin-layerchromatography. Ethynyl-steroids 1ae3a could be converted tothe triazoles 1ce3c selectively, no formation of side products wasobserved. Steroideferrocene conjugates 1ce3c were obtained ingood yields and they showed good stability even in solution.
As racemic ferrocenyl azide 5 was used as reaction partner andthe products were obtained in nearly quantitative reactions,cycloadditions led undoubtedly to the 1/1 mixture of two epimersof products 1ce3c. However, the epimers gave identical Rf values inthin-layer chromatography, and they could neither be separated bycolumn chromatography. Also, the two epimers gave identicalsignals both in the 1H and 13C NMR spectra. The only sign of thepresence of the two compounds was, that the methine protons ofthe CHeCH3 group of the side chain does not give a quartet, asexpected, but a more complicatedmultiplet. The small difference inthe spectra in the two epimers might be explained by the fact thatthe chiral centre of the side chain is relatively far from those of thesteroid skeleton.
3. Conclusions
New ferrocene labelled steroid derivatives were obtained viaa palladium-catalyzed carbonylative Sonogashira coupling anda copper-catalyzed azideealkyne cycloaddition.
Although ferrocenyl derivatives of 17-ethynyl-steroids can beobtained in one step without protection of OH groups of thesteroids, the yields are moderate and some of the products showlow stability in solution.
The copper-catalyzed azideealkyne cycloadditionwas proved tobe a more efficient methodology for the labelling of 17-ethynylsteroids with ferrocene and for the synthesis of C-17 heterocyclicsteroid derivatives.
Acknowledgements
The authors thank the Hungarian National Science Foundation(OTKA K105632) and project ‘Developing Competitiveness ofUniversities in the South Transdanubian Region’ (SROP-4.2.1.B-10/2/KONV-2010-0002) for financial support. Z. C. thanks the BolyaiGrant of the Hungarian Academy of Sciences. The support of theproject TÁMOP-4.2.2/B-10/1-2010-0025, realized with the support
of the Hungarian Government and the European Union, with theco-funding of the European Social Fund, is also acknowledged.
Appendix A. Supplementary Material
Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.jorganchem.2012.08.013.
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