Synthesis of new enantiomerically pure 1 , 3-bis-( 2 ’-oxazolinyl ) ferrocenes as potential pincer ligands

New enantiomerically pure 1,3-bis(2’-oxazolinyl)ferrocenes have been synthesized in good yields starting from 1,3-ferrocene dicarboxylic acid. Moreover, the possibility of performing a regioselective lithiation in position 2 of the disubstituted cyclopentadienyl ring of these compounds has been demonstrated.


Introduction
Since the first reports in the late 1970s on transition metal complexes containing pincer-type ligands, so called because of their particular coordination mode, these systems have attracted increasing interest owing to the unusual properties imparted to the metal centers by the pincer ligand. 1 The control of the properties of metal centers by a well defined ligand system is an ultimate goal of inorganic and organometallic chemistry.In organometallic complexes containing a direct (transition) metal-carbon bond, chelation leads to the formation of metallacycles, which provide additional stabilization of the M−C bond.Typically, these so-called pincer ligands have a general formula [2,6-(ECH 2 ) 2 C 6 H 3 ] − and comprise an anionic aryl ring which is ortho, ortho-disubstituted with heteroatom based substituents, for example, CH 2 NR 2 , CH 2 PR 2 or CH 2 SR.These generally coordinate to the metal center, and therefore support the formation of M−C σ bond.Metal complexation with pincer ligands usually occurs with formation of two five-membered metallacycles which share the M−C bond.Pincer-based metal complexes possess an unique balance of stability vs. reactivity which can be controlled by systematic ligand modifications and /or variation of the metal center, allowing enhancement of metal complex reactivity, stability, reaction selectivity and simultaneously provide a flurry of new fundamental insights.
Various homogeneous catalytic processes with pincer complexes have been reported, 2 including Kharasch addition, 3 Heck olefin arylation, 4 Suzuki biaryl coupling, 5 dehydrogenation of alkanes, 6 transfer hydrogenation 7 and stannyl and silyl transfer to propargylic substrates. 8hiral variants of pincer ligands have been less studied.The stereochemical information can be introduced, for example, at the benzylic carbons or by the donor atom substituents, creating potential stereoselective catalysts.Proline-derived NCN-pincer complexes have been applied as catalysts for Kharasch addition 9 with modest enantioselectivity whereas PCP-containing complexes 10 have been used for the asymmetric aldol reaction between aldehydes and methyl isocyanoacetate obtaining e.e. up to 65%.Richards and co-authors have investigated anionic terdentate ligands derived from 1,3-bis(2'-oxazolinyl)benzenes readily obtained from optically pure β-amino alcohols. 11These pincer ligands provide a series of palladium and platinum pincer complexes that have found application as catalysts for Michael reaction, Diels−Alder reaction and aldehyde and imine silylcyanation.Chiral bis(oxazolinyl)phenyl platinum complexes have also been used in asymmetric alkylation of aldimine with organolithium reagents affording enantiomeric excess up to 82%, 12 whereas the corresponding rhodium complexes act as asymmetric catalysts for enantioselective allylation of aldehydes in up to 80% ee. 13 It is rather remarkable that there have been only few reports until now on attempts to design pincer complexes based on aromatic homocyclic systems other than benzene: viz.cyclopentadienyl ring of metallocenes.Koridze, Poli and co-workers 14 and simultaneously van Koten, Brown and co-workers 15 reported on the synthesis of the first representative ferrocene PCP pincer complexes of rhodium and palladium.Togni reported in 2004 16 the preparation of a new chiral tridentate PCP N-heterocyclic carbene ligand based on a ferrocene backbone and of the corresponding palladium and ruthenium complexes.
Ferrocene derivatives have found widespread application in various fields such as asymmetric catalysis, 17 electrochemistry 18 and development of new pharmaceuticals against malaria. 19Furthermore, the sandwich structure of the ferrocene and the planar chirality, present in derivatives with at least two different substituents in the same ring, 17b,c render these derivatives completely different from conventional aromatic molecules and increase their interest as chiral ligands.Among the plethora of chiral ferrocene derivatives that have been synthesized in the last century, only few examples have been reported so far concerning the synthesis of 1,3disubstituted derivatives. 20s a part of our ongoing interest in ferrocene containing molecules, we have recently synthesized enantiomerically pure ferrocenoylsilanes and thioferrocenoylsilanes, 21 4-ferrocenylβ-lactams, 22 β-hydroxyalkyl, β-aminoalkyl and β-iminoalkyl ferrocenyl sulfides, 23 alcohols, imines, cyanohydrins, amino alcohols, oxazolines and thiazolines bearing the ferrocene moiety. 24ome of these derivatives were successfully employed as ligands in asymmetric catalysis affording high level of enantioselectivity in palladium-catalyzed allylic substitution, 23a,24a in diethylzinc addition to aldehydes 24a and in asymmetric transformation of aldehydes into epoxides.23b Herein we report the synthesis of unprecedented reported enantiomerically pure 1,3bis(2'-oxazolinyl)ferrocenes 1 as possible precursor of pincer complexes.

Results and Discussion
General methods for the preparation of 1,3-disubstituted ferrocenes are severely lacking.In order to synthesize a suitable precursor for 1,3-bis(oxazolinyl)ferrocenes 1, we prepared 1,3ferrocenedicarboxylic acid 2 following two different synthetic strategy according to published procedures 25a,b as depicted in scheme 1.The first methodology consists in a two steps procedure involving the photochemical displacement of p-xylene from CpFe[p-xylene] + PF 6 − 3 26  The second route to 1,3-ferrocenedicarboxylic acid 2 involves a lengthy set of sequential reactions 27a-d from ethylferrocene, namely (i) the Friedel Crafts acetylation that furnished the desired 1,3-disubstituted derivative 7 in 30% yield besides 1-acetyl-2-ethylferrocene and 1-acetyl-1'-ethylferrocene, (ii) the oxidation of compound 7 to the diacyl derivative 8 with MnO 2 in refluxing chloroform for 17 days, and the final haloform reaction.The first methodology has been preferred to the second one due to possibility of preparing the desired diacid 2 in a higher yield and quicker manner.
The dicarboxylic acid 2 was then transformed in quantitative yields into the corresponding ferrocene-1,3-diacid chloride 9 by reaction with oxalyl chloride in toluene (Scheme 2).Among the available procedures described in the literature for the synthesis of oxazolines starting from β-amino alcohols, the most common are (i) single step methodologies 28 or (ii) cyclic dehydration reactions of a β-hydroxy amide (by converting the hydroxyl group into a good leaving group using different reagents). 29The bis-β-hydroxy amides 10a-c were successfully prepared in very good yield by reaction of 1,3-ferrocenoyl dichloride 9 with three different enantiomerically pure β-amino alcohols in CH 2 Cl 2 in the presence of Et 3 N at 30 °C (Scheme 3).Bis-amides 10a-c were then cyclodehydrated using TsCl/DMAP/Et 3 N affording the corresponding 1.3-bis-oxazolines 1a-c in good isolated yield.
Various methods such as direct cyclometalation, oxidative addition, transmetalation and transcyclometalation have been developed for metalation of aryl pincer ligands and the creation of a new transition metal-carbon σ bond.1a The application of each of these methods is strongly dependent on the metal and the donor site of the pincer ligand.Lithiation of the NC(H)N ligand precursors has been applied extensively to the preparation of suitable substrates for transmetalation (Scheme 4).

Scheme 4
Accordingly, we have started an investigation on the possibility of performing lithiation of 1,3-bis(2'-oxazolinyl)ferrocenes 1 in position 2 of the disubstituted cyclopentadienyl ring using product 1a as model compound.The use of LDA in the presence of TMEDA, 30 n-BuLi or t-BuLi at room temperature failed and the 1,3-bis oxazoline 1a was recovered unchanged.The use of 1.5 equivalents of t-BuLi in Et 2 O at reflux afforded the desired lithium derivative as demonstrated by quenching the reaction mixture with p-tolyl disulfide which leads to product 11 in 60% yield (Scheme 5).The structure of 11 was verified by the absence from the 1 H-NMR spectrum of the proton ortho to both the oxazoline rings.It is interesting to remark that the lithiation of 1a occurs in a regioselective fashion and no trace of lithiation at C 4 or C 5 of the disubstituted cyclopentadienyl ring was found.This fact is extremely important in view of the preparation of pincer complexes since these latter kind of lithium derivatives would lead to simple cyclopalladated products decreasing the selectivity in the pincer complex formation.
In conclusion new enantiomerically pure 1,3-bis(2'-oxazolinyl)ferrocenes 1 have been synthesized starting from 1,3-ferrocene dicarboxylic acid and the possibility of performing a regioselective lithiation in position 2 of the disubstituted cyclopentadienyl ring of these compounds has been demonstrated.Further studies are in progress in our laboratories in order to obtain pincer complexes via transmetalation of the lithium species.

Experimental Section
General Procedures.Reactions were conducted in oven-dried (120 °C) glassware under a positive pressure of argon.The transfer of anhydrous solvents or mixtures was accomplished with oven-dried syringes/septum techniques.THF was distilled from sodium/benzophenone prior to use and stored under argon.CH 2 Cl 2 was passed through basic alumina and distilled from CaH 2 prior to use.Other solvents were purified by standard procedures.Light petroleum ether refers to the fraction with a boiling range of 40-60 °C.Unless otherwise noted, all reagents were obtained from commercial suppliers and used without further purification.Thin-layer chromatography (TLC) was performed with plastic plates coated with (0.20 mm) silica gel 60 F 254 or aluminum oxide 60 F 254 neutral.Column chromatography was carried out with 70-230 mesh silica gel or 70-230 mesh aluminum oxide 90 active neutral.Preparative thick-layer chromatography was carried out with glass plates using a 1 mm layer of silica gel 60 PF 254 .Melting points are uncorrected.IR spectra were recorded on a Perkin-Elmer model 257 grating spectrometer. 1H and 13 C NMR spectra were recorded at 400 and 100 MHz, respectively, in CDCl 3 as solvent.Chemical shifts are reported on the δ scale and measured in ppm relative to residual CHCl 3 (δ=7.26ppm) for 1 H NMR and to the central line of CDCl 3 (δ=77.0ppm) for 13 C NMR spectra.J values are given in Hz. 13 C NMR spectral assignments were based on the results of DEPT experiments.The manufacturer's software was used for DEPT, gradient-enhanced COSY, as well as for the inversed-detected gradient selected heteronuclear correlations gHMBC and gHSQC data analysis.Mass spectra (MS) were obtained using an electrospray ionization source (ESIMS).All the ESIMS spectra were performed by using MeOH as the solvent.[α] D values are given in 10 -1 deg cm 2 g -1 .Elemental analyses were performed using Flash EA1112 Automatic Elemental Analyzer CE instruments.The originality of all compounds was checked by a CAS on-line structure search.

Compound characterization
Ferrocene-1,3-diacid chloride (9).Oxalyl chloride (3.5 mmol, 0.3 mL) and a drop of DMF were added to a suspension of 1,3-ferrocene dicarboxylic acid (1.1 mmol, 300 mg) in toluene (25 mL).The mixture was reacted for 1h a 60°C and then the solvent was evaporated under vacuum.The obtained dichloride was dissolved with a mixture of dry Et 2 O/pentane 1:5 and filtered.The filtrate was concentrated under vacuum affording the title compound in quantitative yield (335 mg).The dichloride was used immediately without further purification, owing to its low stability.

General procedure for the synthesis of the bis-β-hydroxy amides (10a-c).
To a solution of amino alcohol (1.42 mmol) in CH 2 Cl 2 (5 mL), Et 3 N (1.9 mmol, 0.27 mL) and the dichloride (0.64 mmol, 200 mg) were added.The mixture was reacted overnight at 30 °C, then quenched with saturated NaHCO 3 solution.The organic layer was extracted with CH 2 Cl 2 /MeOH 10:1 and then dried over magnesium sulfate and concentrated under reduced pressure.The reaction mixture was purified by column chromatography on silica gel (CH 2 Cl 2 /MeOH 20:1 as the eluent) affording the title compound as a yellow solid.Protons and carbons assignments were made by gCOSY, gHSQC and gHMBC.