Ferrocenoyl benzotriazole, IV: Microwave-assisted synthesis of novel 1,1′-Bis-ferrocenamides

Article abstract of DOI:10.1080/00397911.2013.797998

An easily applicable microwave-assisted novel 1,1′-bis- ferrocenoylbenzotriazole-mediated synthesis of novel derivatives for 1,1′-bis-ferrocenamides was applied. This is a cheap, easy, and green method because of microwave irradiation and recovery of benzotriazole. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]

Full text of DOI:10.1080/00397911.2013.797998

This article was downloaded by: [Universitaets und Landesbibliothek]
On: 19 October 2013, At: 06:41
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Ferrocenoyl Benzotriazole IV: Microwave Assisted
Synthesis of Novel 1,1′-bis Ferrocenamides
Büşra Köroğlu a & Deniz Hür a b
a Department of Chemistry , Anadolu University, Faculty of Science , Eskişehir , Turkey
b Anadolu University Plant, Drug and Scientific Researches Center (AUBİBAM) , Eskişehir ,
Turkey
Accepted author version posted online: 27 Aug 2013.
To cite this article: Synthetic Communications (2013): Ferrocenoyl Benzotriazole IV: Microwave Assisted Synthesis of Novel
1,1′-bis Ferrocenamides, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, DOI: 10.1080/00397911.2013.797998
To link to this article: http://dx.doi.org/10.1080/00397911.2013.797998
Disclaimer: This is a version of an unedited manuscript that has been accepted for publication. As a service
to authors and researchers we are providing this version of the accepted manuscript (AM). Copyediting,
typesetting, and review of the resulting proof will be undertaken on this manuscript before final publication of
the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the
content, and all legal disclaimers that apply to the journal relate to this version also.
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

ACCEPTED MANUSCRIPT
FERROCENOYL BENZOTRIAZOLE IV: MICROWAVE ASSISTED
SYNTHESIS OF NOVEL 1,1’-BIS FERROCENAMIDES
Büşra Köroğlu1, Deniz Hür1,2,
1Department of Chemistry, Anadolu University, Faculty of Science, Eskişehir, Turkey
2Anadolu University Plant, Drug and Scientific Researches Center (AUBİBAM),
Eskişehir, Turkey
Corresponding author: Dr. Deniz Hür: Anadolu University Plant, Drug and Scientific
Researches Center (AUBİBAM), 26470 Eskişehir, Turkey Tel: +90 222 3350580 / ext:
3661 Fax: +90 222 3204910 E-mail: dhur@anadolu.edu.tr
Abstract
An easily applicable microwave assisted novel 1,1’-Bis ferrocenoylbenzotriazole
mediated synthesis of novel derivatives for 1,1’-Bis-ferrocenamides was applied. This is
cheap and easy as well as a green method because of microwave irradiation and recovery
of benzotriazole.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications® for the following free supplemental resource(s):
Full experimental and spectral details.]
KEYWORDS: bisferrocenamides, benzotriazole, ferrocenoylbenzotriazole, microwave
INTRODUCTION
Ferrocene amides and 1,1’-bisferrocene amides are readily available ferrocene derivatives
by us and other workers in literature. These amide functionalized ferrocene moieties have
been generally prepared via a) reaction of acyl halide derivatives of ferrocenes with
amines [1–3] b) in-situ functionalization of ferrocene carboxylic acids with TBTU/DIEA [4]
ACCEPTED MANUSCRIPT
1

ACCEPTED MANUSCRIPT
and c) HOBt/EDC or DCC [5–7]. Recently we have prepared several ferrocene amides and
ferrocene amidoamino acid derivatives by functionalization of ferrocene carboxylic acid
via BtH/SOCl2 methodology [8–10] which is cheaper, atom ecomomic and has easier
reaction procedure and work-up.
Ferrocene amides have wide application areas in material science and chemistry. These
sandwich type compounds generally used to use as ion selective redox sensors and
especially ferrocenamidopeptides used in biosensor applications. There are hundreds of
publications about redox and biosensor applications of ferrocene amides in literature.
Heinz-Bernhard Kraatz had summarized works on ferrocene amino acids, peptides and
nucleic acids which are contains ferrocene amide function [11]. A review was published in
2011 which summarized biological and non-biological application of ferrocene amides
[12]. 1,1’-bisferrocene amide containing polysiloxanes were prepared in 2011 [13]
.
Ferrocene amide linkers were used in order to construct heterobimetallic architectures [14]
.
Additionally, electropolymerization of bisferrocene amide derivatives has been done for
investigation of electrochemical sensory devices [15]. Following our previous works [8–10]
we now disclose preparation of some 1,1’-bis-ferrocenamides as precursor of ferrocene
containing ionic liquids. In this work, we have used benzotriazole chemistry [16,17] and
microwave irradiation for the syntheses.
,
RESULTS AND DISCUSSION
The novel starting material 1,1’-Bis ferrocene di-(N-benzotriazolyl)carboxamide, 1, was
prepared [7] by reaction of 1,1-Bisferrocenedicarboxylic acid with 1H-benzotriazole
ACCEPTED MANUSCRIPT
2

ACCEPTED MANUSCRIPT
(BtH) in presence of thionylchloride in dichloromethane (Scheme 1). The advantages of
this method for functionalization of ferrocene were discussed before in our previous
publications [7–9]
.
Only after addition of title carboxylic acid in one portion to mixture of Bt-H / SOCl2
reaction mixture was became dark red and white hydrochloride salt of 1H-benzotriazole
(BtH.HCl) was started to precipitate. After reaction was finished in ambient temperature,
precipitates were filtered and washed with dichloromethane. After removing solvent,
starting material 1 was collected as red peels. Filtrated by product BtH.HCl was dissolve
in water, acid was neutralized by 1N NaOH solution and this solution was extracted with
ethylacetate to recover BtH in 83% yield. Reaction was easily monitored by TLC under
UV, since both BtH and ferrocene are UV active compounds. The structure of 1 was
elicited using both 1H and 13C NMR analyses. In 1H spectrum, broad peak around 12.00
ppm, which was depicted to hydroxyl group of ferrocenedicarboxylic acid, was
disappeared. Instead of this signal, doublet peaks between 8.02 - 8.12 ppm and triplet
signals at 7.49 and 7.59 ppm were recorded and these signals are clue for N-substituted
benzotriazole. Additionally, singlet signals at 4.78 and 5.65 ppm supports bis-substitution
of both cyclopentadienyl (Cp) rings of ferrocene. Since benzotriazole group has high
electron withdrawing property unexpected 5.65 ppm chemical shift was observed for
cyclopentadienyl protons which are in α-position to amide group. On the other hand, in
13C NMR spectrum characteristic signals for N-substituted benzotriazole were recorded
between 100 - 148 ppm. Bis-substituted ferrocene signals were recorded between 69 - 74
ppm. Signal at 168.46 ppm was depicted to carbonyl signal of product.
ACCEPTED MANUSCRIPT
3

ACCEPTED MANUSCRIPT
Starting material, 1, was reacted with different amines under microwave irradiation to
give title compound, 1,1’-bisferrocenamides, 2a-h, in good yield (Scheme 2, Table 1).
Structures of 2a-h were testified using NMR. 1H-NMR analyses does not give
characteristic signals depicted to N-substituted benzotriazoles. This supports the idea of
nucleophilic substitution of benzotriazole with amines. Instead of benzotriazole signals,
1H NMR of products includes proton signals belongs to amine moiety. Similarly, 13C
NMR spectra have showed no signals for N-substituted benzotriazole and gave signals
for amine moiety. The synthesis of 2f was conducted both under microwave irradiation
and conventional methods to put forth advantage of microwave for consideration. In
conventional method, reaction mixture was refluxed with heating mantle for 6 hours to
give 2f in 18% yield. According to this result one can say that microwave irradiation has
advantageous over conventional methods for the synthesis of 2a-h using benzotriazole
chemistry. During the workup procedure of reaction of starting material 1 and amines,
leaving group benzotriazole was recovered in 87% almost pure form.
The preparation of 1,1’-bisferrocenamides by microwave irradiation using benzotriazole
chemistry is promising and encourages us to prepare “cage ferrocene” (Scheme 3)
compounds similar to prepared by other groups [18,19] and 1,1’-bisferrocene esters for
future works.
EXPERIMENTAL
ACCEPTED MANUSCRIPT
4

ACCEPTED MANUSCRIPT
All chemicals were of reagent-grade purity or better, and used as obtained from the
commercial suppliers. Column chromatography was conducted with silica gel 200-425
mesh. Melting points were determined on a hot-stage apparatus and are uncorrected.
Reactions under microwave irradiation were conducted in round bottom flask by reflux.
Microwave heating was carried out with a single-mode cavity Discover Microwave
Synthesizer (CEM Corporation, NC), producing continuous irradiation at 2450 MHz.
NMR spectra were recorded in CDCl3 with TMS as the internal standard for 1H (500
MHz) or a solvent as the internal standard for 13C (125 MHz) using Bruker NMR
equipment.
General Preparation Of 1,1'-Bis-(N-Benzotriazolyl) Ferrocenecarboxamide, 1
Thionylchloride (1 eq.) was added dropwise to solution of 1H-benzotriazole (8 eq.) in
dichloromethane under nitrogen atmosphere at 25 °C. The reaction mixture was stirred
for 30 min. Then ferrocenedicarboxylic acid (1 eq.) was poured into the reaction flask.
The reaction mixture was stirred for 2h at ambient temperature. Precipitated white solid
was filtered off. Filtrate was extracted with 6N HCl (3x50mL) to remove excess of Bt-H.
The collected organic layers were dried over magnesium sulphate, the solvent was
evaporated via vacuum to obtain 1,1’-Bis ferrocene di-(N-benzotriazolyl)carboxamide as
dark-red peels in 82% yield.
1,1'-Bis-(N-Benzotriazolyl) Ferrocenecarboxamide, 1
(novel, dark-red peels, yield 82%). ¹H NMR (500 MHz, CDCl3, 25˚C) δ = 8.12 (d, ³Jʜ,ʜ =
8,22 Hz, 2 H), 8.02 (d, ³Jʜ,ʜ = 8.21 Hz, 2 H), 7.59 (t, ³Jʜ,ʜ = 7.57 Hz, 2 H), 7.49 (t, ³Jʜ,ʜ =
ACCEPTED MANUSCRIPT
5

ACCEPTED MANUSCRIPT
7.63 Hz, 2 H), 5.65 (s, 4 H), 4.78 (s, 4 H) ppm. ¹³C NMR (125 MHz, CDCl3, 25˚C) δ =
168.5, 145.3, 131.8, 130.2, 126.0, 119.9, 114.9, 75.2, 74.7, 7.4 ppm. Elemental analysis:
C24H16FeN6O2, calculated: C, 60.52; H, 3.39; N, 17.65. Found: C, 60.32; H, 3.43; N,
17.63.
General Procedure For Preparation Of 1,1’-Bis Ferrocenamides 2a-H
An appropriate amine (2 eq) and 1,1’-Bis ferrocene di-(N-benzotriazolyl)carboxamide 1
(1 eq.) were dissolved in freshly distilled toluene in a round bottom flask. The flask was
placed into the single cavity microwave equipment and reflux condenser was connected
on flask. The reaction mixture was exposed to 100W MW for 60 min. After reaction was
completed, the mixture was extracted with 2N NaOH (3x50 mL). The collected organic
layers were dried with magnesium sulphate, solvent was removed via vacuum. Reaction
mixture was purified by column chromatography using EtOAc : Hexane mixture as
eluent to get 2a-h in 52-96% yield.
1,1'-Bis-(N-Piperidinyl) Ferrocenecarboxamide, 2a
(novel, dark-brown microcrystals, yield 58%). M.p: 169-170 ⁰C. ¹H NMR (500 MHz,
CDCl3, 25˚C) δ = 4.59 (t, ³Jʜ,ʜ =1.75, 2.05 Hz, 4H), 4.39 (t, ³Jʜ,ʜ = 1.75, 205 Hz, 4H),
3.60 (t, ³Jʜ,ʜ = 5.26 Hz, 8H), 1,52-1,72 (m, 12H) ppm. ¹³C NMR (125 MHz, CDCl3,
25˚C) δ = 168.6, 81.0, 71.9, 71.2, 47.9, 44.2, 26.5, 25.2, 24.8 ppm. Elemental analysis:
C22H28FeN2O2, calculated: C, 64.71; H, 6.91; N, 6.86. Found: C, 64.32; H, 7.22; N, 6.61.
CONCLUSION
ACCEPTED MANUSCRIPT
6

ACCEPTED MANUSCRIPT
An easier, cheaper and atom economic preparation of 1,1’-bisferrocene amides were
prepared and characterized using BtH/SOCl2 methodology under microwave irradiation.
SUPPORTING INFORMATION
Full experimental details, 1H and 13C NMR spectra, characterization data of the prepared
compounds can be find Supplementary Content section of this article’s webpage.
ACKNOWLEDGEMENTS
This project has been supported by Anadolu University Scientific Research Foundation,
Project Number: 1004F136. Authors would like to thank Anadolu University Plant, Drug
and Research Center for NMR analyses.
REFERENCES
[1] Gang, L.; Yinglin, S.; Hongwei, H.; Linke, L.; Yoating, F.; Yu, Z.; Xiangru, M.;
Liwei, M. Synthesis, Crystal Structures, and Third-Order Nonlinear Optical Properties of
a Series of Ferrocenoyl Organometallics. Inorg. Chem. 2003, 42, 939-944.
[2] Moriuchi, T.; Ikeda I.; Hirao T. Synthesis and Molecular Structure of the Novel
Imıde-Bridged [3]Ferrocenophane. Organometallics 1995, 14, 3578-3580.
[3] Hartinger, C. G.; Nazarov, A. A.; Arion, V. B.; Giester, G.; Kuznetsov, M. L.;
Galanski, M.; Keppler, B. K. 1,1’-Bis(oxazolin-2-yl)ferrocenes: An investigation of Their
Complexation Behavior toward [Pb(η3-allyl)Cl]2. Eur. J. Inorg. Chem. 2005, 1589-1600.
ACCEPTED MANUSCRIPT
7

ACCEPTED MANUSCRIPT
[4] Hatten, X.; Cournia, Z.; Huc, I.; Smith, J. C. Metzler-Nolte N. Force-Field
Development and Molecular Dynamics Simulations of Ferrocene-Peptide Conjugates as a
Scaffold for Hydrogenase Mimics. Chem. Eur. J. 2007, 13, 8139-8152.
[5] Stepnicka, P.; Cisarova, I. Preparation and hydrogen bonding in
ferrocenecarboxamides substituted with 2-hydroxyethyl group at the amide nitrogen
atoms. CrystEngComm. 2005, 7, 37-43.
[6] Furuta, K.; Akutsu, H.; Yamada, J.; Nakatsuji, S. New Organic Functional Anions:
-
Ferrocenyl-(CONHCH2SO3 )n (n=1-2) and their TTF Salts. Synth Met. 2005, 152, 381-
384.
[7] Drexler, C.; Milne, M.; Morgan, E.; Jennings, M.; and Kraatz, H.-B. Synthesis and
characterization of new ferrocene peptide conjugates. Dalton Trans. 2009, 4370–4378.
[8] Ekti, S. F.; Hur, D. Microwave assisted synthesis of ferrocene amides. Inorg. Chem.
Commun. 2008, 11, 1027–1029.
[9] Hür, D.; Ekti, S. F.; Dal, H. N-ferrocenoyl benzotriazole: A convenient tool for the
synthesis of ferrocenoyl esters. J. Organomet. Chem. 2010, 695, 1031–1034.
[10] Hür, D.; Dal, S. F. E.; Varol, G. A.; Hür, E. N-acylbenzotriazole mediated
microwave assisted synthesis of protected and novel unprotected ferrocenoylamidoamino
acids. J. Organomet. Chem. 2011, 696, 2543-2548.
[11] Kraatz, H-B. Ferrocene-Conjugates of Amino Acids, Peptides and Nucleic Acids. J.
Inorg. Organomet. Polym. 2005, 15, 83-106.
[12] Lal, B.; Badshah, A.; Altaf, A. A.; Khan, N.; Ullah, S. Miscellaneous applications of
ferrocene-based peptides/amides. Appl. Organometal. Chem. 2011, 25, 843-855.
ACCEPTED MANUSCRIPT
8

ACCEPTED MANUSCRIPT
[13] Abd-El-Aziz, A. S.; Winram, D. J.; Shipman, O.; Dalgakıran, S. S.; Shipley, P.;
Bichler, L.; Patrick, B. Micro and nano-sized polysiloxanes containing organoiron
moieties. New J. Chem. 2011, 35, 2341-2348.
[14] Ni, J.; Wei, K-J.; Chen, Y-W.; Liu, Y. Self-assembled hetero-bimetallic sandwich
with Ag-Ag bridging using a flexible two-arm ferrocene amide linker. J. Mol. Struct.
2012, 1011, 76-80.
[15] Moutet, J-C.; Saint-Aman, E.; Ungureanu, M.; Visan, T. Electropolymerization of
ferrocene bis-amide derivatives: a possible route to an electrochemical sensory device. J.
Electroanal. Chem. 1996, 410, 79-85.
[16] Katritzky, A. R.; Lan, X.; Yang, J. Z.; Denisko, O. V. Properties and Synthetic
Utility of N-Substituted Benzotriazoles. Chem. Rev. 1998, 98, 409-548.
[17] Hür, D.; Ekti, S. F.; Say, R. N-Acylbenzotriazole Mediated Synthesis of Some
Methacrylamido Amino Acids. Lett. Org. Chem. 2007, 4, 585-587.
[18] Huang, H.; Mu, L.; He, J.; Cheng, J-P. Ferrocenyl-Bearing Cyclopseudopeptides as
Redox-Switchable Cation Receptors. J. Org. Chem. 2003, 68, 7605-7611.
[19] Evans, N. H.; Serpell, C.J.; Christensen, K. E.; Beer, P. D. Amide and Urea
Ferrocene-Containing Macrocycles Capable of the Electrochemical Sensing of Anions.
Eur. J. Inorg. Chem. 2012, 939–944.
ACCEPTED MANUSCRIPT
9

ACCEPTED MANUSCRIPT
Table 1. Amines used for the preparation of 2a-i and yields of products.
Entry Product Amine
Yield%
58
1
2a
2
2b
65
3
4
2c
2d
61
79
5
6
2e
2f
68
52 (18)a
7
8
2g
2h
89
96
a: Yield obtained from conventional heating
ACCEPTED MANUSCRIPT
10

ACCEPTED MANUSCRIPT
Scheme 1. Preparation of starting material, 1.
ACCEPTED MANUSCRIPT
11

ACCEPTED MANUSCRIPT
Scheme 2. Preparation of 1,1’-bisferrocenamides, 2a-h.
Scheme 3. Sample of cage ferrocene molecules.
ACCEPTED MANUSCRIPT
12