Ferrocenyl derivatives are currently under investigation by our group and several series containing both amidothienyl and amidothiazolyl systems have been synthesised and characterised.  The incorporation of thienyl/thiazolyl groups into a ferrocenyl- or ferrocenylphenyl system greatly enhances the number of potential donor atoms for coordination with metal fragments e.g. PtII, PdII with a view to platinum anti-cancer studies and/or interaction with guest molecules through suitable hydrogen bonding interactions.



In nature, thiazole has been found to be vital in certain natural products:  examples include the antibiotic bacitracin and the siderophore yersiniabactin.  In therapeutic studies the antitumour compound epothilone A and myxothiazole (inhibitor) have been extensively studied

Alley, Steven

Gallagher, John F.

Hooper, Vincent M.

Kenny, Peter T.M.

Lough, Alan J.

English

DCU Online Research Access Service

National Institute for Cellular BiotechnologySynthesis and characterisation of novel ferrocenyl thienyl & thiazolyl systemsSteven Alley,a,b John F. Gallagher,a,b Vincent M. Hooper,a Peter T.M. Kennya,b and Alan J. Loughca School of Chemical Sciences, Dublin City University, Glasnevin, Dublin 9, Irelandb National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Irelandc Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada M5S 3H6IntroductionFerrocenyl derivatives are currently under investigation by our group and several series containing both amidothienyl and amidothiazolyl systems have been synthesised and characterised. The incorporation of thienyl/thiazolyl groups into a ferrocenyl- or ferrocenylphenyl system greatly enhances the number of potential donor atoms for coordination with metal fragments e.g. PtII, PdII with a view to platinum anti-cancer studies and/or interaction with guest molecules through suitable hydrogen bonding interactions.In nature, thiazole has been found to be vital in certain natural products:  examples include the antibiotic bacitracin and the siderophore yersiniabactin.  In therapeutic studies the antitumour compound epothilone A and myxothiazole (inhibitor) have been extensively studied.1Synthesis of compounds 1 - 6The ferrocenylphenylamido thienyl and thiazolyl esters 1-6 have been prepared via a Schotten-Baumann reaction of the relevant acid chloride with thienyl or thiazolyl amines. These systems have been characterised by a range of spectroscopic techniques including 1H, 13C (top right), infra-red (solution/KBr), UV-vis, electrochemistry and mass spectrometry.Yields in a range from 20 – 65% were typically recorded. The structures of 1 - 6 were unambiguously assigned from NMR (Table 2, middle right) and mass spectrometric data.1: C23H19NO3SFe, monoclinic, space group P21/n, a = 10.1428(3), b = 8.0965(2), c = 23.0557(7) Å, β = 95.4912(14)°, V = 1884.67(9) Å3, Z = 4, T = 150(1) K, density = 1.569 g.cm-3 (calc.), F(000) = 920, µ = 0.937 mm-1, 16090 reflections from 2-27.5°, 4313 unique, 3441 > 2σ(I), 268 parameters, R factor = 0.036, wR2= 0.088.References1 R.S. Roy, A.M. Gehring, J.C. Milne, P.J. Belshaw and C.T. Walsh, Nat. Prod. Rep. 1999, 16, 249-263.2  F.H. Allen, Acta Crystallographica Section B58, 2002, 380-388.3 S. Alley, J.F. Gallagher, V.M. Hooper, P.T.M. Kenny and A.J. Lough, Dalton Trans., 2004, submitted.In perspective, related CSD searches for the five-membered heteroaromatic ringspyrrole, C4NH and imidazole, C3N2H groupsyield 1269 and 1667 structures, respectively, and comparable to thiophene/thiazole in abundance, whereas pyridine as C5N is present in 34519 structures (ca. 10% of the CSD). To date no structures are available on the CSD (Jan. 2004) containing any η5-C5based transition metal metallocenyl(sandwich) type compound with a C3NSthiazolyl fragment. The vast majority ofmetallothiazolyl derivatives are therefore in the general area of coordination chemistry.Structural studies of 1 and 3 - 5The single crystal X-ray structures of 1 (below) and 3 to 5 have been determined and selected crystallographic and structural details are listed for the para-derivatives 1 (below) and 4 (top right). Of interest is the fact that there are no crystal structures currently on the Cambridge Structural Database (version 5.25, April 2004) that contain both a ferrocenyl and thiazole moiety thus highlighting the novel nature of these structural systems.2,3Figure 2 ORTEP diagram of 4 (top) and hydrogen bonding interactions in the crystal structure of 4 (bottom)Figure 1 ORTEP diagram of the para-ferrocenylphenylamidothienyl ester 1 at the 30% probability level.Table 1 Comparison of the hydrogen bonding interactions in the para- 4 and meta- 5 systems:  the differences (Å,°) in molecular aggregation is easily discerned.  † - repeated across an inversion centre.Database analysesComparisons of 1 and 3 to 5 with the Cambridge Structural Database (January 2004, release v5.25) reveals several interesting features.  Firstly, the thienyl group is a well studied system and 2001 structures are available as C4S moiety (no restrictions and no H atoms, as in Scheme 3).  Other searches are detailed by the fragments depicted in the scheme.  However, a search for compounds containing both the ferrocenyl and C3NSthiazolyl groups yields 0 ‘hits’.  This is unusual given the widespread application of both systems in organometallic/organic compounds.  Conclusions and further researchTo date we have synthesized several series of organometallic thienyl and thiazolyl derivatives encompassing a range of potential biological and materials applications.  Further studies, in combination with high-level ab initio calculations are on-going and include formation of metal complexes and incorporation into larger peptide strands.AcknowledgementsWe wish to thank the National Institute for Cellular Biotechnology and Dublin City University for grants in aid of research and particularly under the Irish Government PRTLI cycle 3 initiative (2001-2008).Molecular and Crystal structure of 4Compound 4 crystallises with two molecules in the asymmetric unit in the space group P1 (No. 2). The A and B molecules aggregate through intermolecular N-H…O=Cester interactions generating a hydrogen bonded chain as (A…B..)n.  These are augmented by flanking C-H…O=C and C-H…N interactions as depicted for the A/B* pair in the diagram (bottom left).  Crystallographic details for 4 are summarized below.4: C24H22N2O3SFe, triclinic, space group P1 (No. 2), a = 12.7466(4), b = 12.8752(8), c = 13.5661(7) Å, α = 91.811(3)°, β = 106.096(3)°, γ = 92.735(3)°, V = 2134.35(18) Å3, Z = 4, T = 150(1) K, density = 1.476 g.cm-3 (calc.), F(000) = 984, µ = 0.834 mm-1, 22426 reflections from 2.6-27.5°, 9714 unique, 5617 > 2σ(I), 582 parameters, R factor = 0.050, wR2= 0.126.  Comparisons of the interactions in 4 and 5 are listed below.SSNCOHSCOO00Fe andSNSNSNCOHNSCO200FeNSFragments used and 'hits' found in the CSD searches20014202568420NSCO223/120and00000000SCO2EtiFeFeCOCl+o-/m-/p-H2NC6H4CO2EtFeii1- 3, (p-/m-/o-)FeOC-N    HCO2Meiii00NS4 - 6, (p-/m-/o-)FeOC-N    HCH2CO2EtivSNCOH YXNCOHR RMMMMX=S/N, Y=N/SCO2Me 4A 4B 5† N-H…O=Cester (Å) 2.980(4) 2.977(4) 3.055(3) H…O/N-H…O° 2.35(4) / 164(5)° 2.28(3) / 158(4)° 2.15(3) / 169(3)° C-H…O=Cester (Å) 3.186(5) 3.394(4) 3.304(3) H…O/C-H…O° 2.24 / 173° 2.46 / 167° 2.58 / 135° C-H…Nthiazole (Å) 3.642(7) 3.536(5) 3.375(3) H…N/C-H…N° 2.67 / 168° 2.56 / 169° 2.41 / 166°   Compound 1H, NH 1H, H12/15 / H13/14 13C, CC=Oamide/ester 1 11.97 4.89 / 4.56 163.44 / 166.46 2 12.06 4.76 / 4.40 163.78 / 166.40 3 10.70 4.49 / 4.22 166.96 / 165.11 4 10.15 4.74 / 4.43 164.35 / 170.22 5 10.32 4.68 / 4.38 164.79 / 170.17 6 11.14 4.32 / 4.21 167.57 / 169.95  Schemes 1 and 2.  Synthesis of compounds 1 to 6:  The donor atoms present in 1 to 3, 4 to 6. NMR spectroscopyThe NMR data confirm the functional groups in the chemical structures in 1 to 6.  Two sets of N-H resonances are present with δ 11.97/12.06/10.70 and 10.15/10.32/11.14 (the former due to the intramolecular N-H…O=Cester interaction with the ortho-thienyl carboxylate group in 1 to 3).  Other trends e.g. the ortho-ferrocenyl H12/15 signals derive from the twisted C6 ring from co-planarity with the (η5-C5H4) group.  The C=Oamide signal for 3 at δ 166.96 is different from 1 and 2 at δ 163.44 and 163.78, respectively, and likewise for 4 to 6 indicating the distortion and change in electronic environment for the amide group with respect to the twisted ortho-(ferrocenyl)benzoyl group.Table 2 Selected 1H and 13C NMR (ppm) data for compounds 1 – 6

4: C24H22N2O3SFe, triclinic, space group P1(No. 2), a = 12.7466(4), b = 12.8752(8), c = 13.5661(7) Å, α = 91.811(3)°, β = 106.096(3)°, γ = 92.735(3)°,

Acta Crystallographica Section B58,

Fragments used and 'hits' found in the CSD searches

Synthesis and characterisation of novel ferrocenyl thienyl and thiazolyl systems

Ferrocenyl derivatives are currently under investigation by our group and several series containing both amidothienyl and amidothiazolyl systems have been synthesised and characterised.  The incorporation of thienyl/thiazolyl groups into a ferrocenyl- or ferrocenylphenyl system greatly enhances the number of potential donor atoms for coordination with metal fragments e.g. PtII, PdII with a view to platinum anti-cancer studies and/or interaction with guest molecules through suitable hydrogen bonding interactions.\ud
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In nature, thiazole has been found to be vital in certain natural products:  examples include the antibiotic bacitracin and the siderophore yersiniabactin.  In therapeutic studies the antitumour compound epothilone A and myxothiazole (inhibitor) have been extensively studied

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Ferrocenyl derivatives are currently under investigation by our group and several series containing both amidothienyl and amidothiazolyl systems have been synthesised and characterised.  The incorporation of thienyl/thiazolyl groups into a ferrocenyl- or ferrocenylphenyl system greatly enhances the number of potential donor atoms for coordination with metal fragments e.g. PtII, PdII with a view to platinum anti-cancer studies and/or interaction with guest molecules through suitable hydrogen bonding interactions.

In nature, thiazole has been found to be vital in certain natural products:  examples include the antibiotic bacitracin and the siderophore yersiniabactin.  In therapeutic studies the antitumour compound epothilone A and myxothiazole (inhibitor) have been extensively studied

Irish Universities

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Synthesis and characterisation of novel ferrocenyl thienyl and thiazolyl systems

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