An environmentally benign and cost-effective synthesis of aminoferrocene and aminoruthenocene

Article abstract of DOI:10.1021/om400009g

An improved synthesis of aminoferrocene has been carried out that adheres with the basic green chemistry guidelines. Amination from aqueous NH₃ as the nitrogen source, with the inexpensive CuI/Fe₂O₃ couple as cocatalyst in ethanolic solution, makes the process environmentally attractive as well as a viable alternative for all practical purposes. This procedure has also been applied to prepare aminoruthenocene, being reported for the first time.

Full text of DOI:10.1021/om400009g

Note
pubs.acs.org/Organometallics
An Environmentally Benign and Cost-Effective Synthesis of
Aminoferrocene and Aminoruthenocene
Anna Leonidova,† Tanmaya Joshi,† David Nipkow,† Angelo Frei,† Johanna-Elena Penner,
Sandro Konatschnig, Malay Patra, and Gilles Gasser*
Institute of Inorganic Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
S
* Supporting Information
ABSTRACT: An improved synthesis of aminoferrocene has
been carried out that adheres with the basic green chemistry
guidelines. Amination from aqueous NH3 as the nitrogen
source, with the inexpensive CuI/Fe2O3 couple as cocatalyst in
ethanolic solution, makes the process environmentally
attractive as well as a viable alternative for all practical
purposes. This procedure has also been applied to prepare
aminoruthenocene, being reported for the first time.
s surprising as it may be, very simple and routinely used
work from Sato, Nesmeyanov, and co-workers.6−8 This
Aaminocyclopentadienyl organometallic derivatives are procedure was later slightly modified by Heinze et al.9 More
specifically, in this method, iodoferrocene, which can be
obtained from readily available ferrocene, is used as the starting
material. Coupling of iodoferrocene with copper phthalimide
gave ferrocenyl phthalimide, which was converted to amino-
ferrocene via a Gabriel synthesis (reaction D in Scheme 1).
Another widely utilized method for making aminoferrocene
involves the preparation of azidoferrocene from bromoferro-
either not commercially available or extremely expensive. For
example, 1 g of aminoferrocene, which can be considered as the
simplest amino-containing organometallic complex, costs more
than 330 Euro!1 This, we believe, is due to a dearth of
industrially scalable procedures that meet the demands for
producing such a compound in a cost-effective manner. As
such, over the last 60 years, several synthetic routes have been
developed for the laboratory preparation of aminoferrocene. To
highlight a few relevant methods, historically, the first synthesis
of aminoferrocene was reported by Arimoto et al. in 1955.2 In
this procedure, ferrocenecarboxylic acid was first reacted with
PCl5 in benzene and then with NaN3 in acetone to form
ferrocenoyl azide (reaction A in Scheme 1). The desired
aminoferrocene was finally obtained via a Curtius rearrange-
ment and subsequent removal of the benzyl formate group. In
2002, Butler et al. reported a further improvement to this
synthesis, where use of milder conditions afforded a better
yield.3 Earlier to this, in 1983, Herberhold et al. proposed a
slightly modified strategy involving the preparation of N-
ferrocenylamide, which can be transformed to aminoferrocene
under basic conditions (reaction B in Scheme 1).4 Another
approach was proposed by Knox et al. in 1990. It first involved
n-butyllithium-mediated lithiation of ferrocene and then the
reaction of the monolithiated ferrocene with O-benzylhydroxyl-
amine (reaction C in Scheme 1). However, the post acid
treatment yielded only a relatively small amount of the desired
aminoferrocene.5 Bildstein et al. reported in 1999 another
optimized and high-yielding synthetic pathway involving the
sequence ferrocene−monolithioferrocene−iodoferrocene−fer-
rocenyl phthalimide−aminoferrocene on the basis of the initial
10
cene and its subsequent reduction with LiAlH4 or by
hydrogenation (reaction E in Scheme 1).11 Even though this
hydrogenation approach has only been used to synthesize 1,1′-
diaminoferrocene from 1,1′-dibromoferrocene via 1,1′-diazidi-
ferrocene,11 it can be anticipated that it would also work for the
monosubstituted ferrocene. However, the procedure presents a
major drawback, as azidoferrocene can potentially be
explosive1,1′-diazidoferrocene is prone to explosion if heated
rapidly above 56 °C.11 In 2001, van Leusen et al. proposed a
two-step strategy involving first the deprotonation of ferrocene
and then the use of α-azidostyrene (reaction F in Scheme 1).12
However, the latter is not commercially available and the
preparation requires a three-step synthetic route.
Hence, to summarize, the best available procedures for
aminoferrocene synthesis require several synthetically challeng-
ing steps, are low-yielding, or involve the preparation of
potentially explosive intermediates. Considering the potential
of ferrocene in a multitude of research areas,13 there is a
definitive need for a simple and efficient synthetic pathway for
preparing aminoferrocene and, more generally, for organo-
Received: January 7, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/om400009g | Organometallics XXXX, XXX, XXX−XXX

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Note
a
Scheme 1. Nonexhaustive List of Synthetic Procedures To Prepare Aminoferrocene
a
(A) Synthesis proposed by Arimoto et al.:2 (i) (1) PCl5, benzene, (2) NaN3, acetone; (ii) phenylmethanol; (iii) NaOH (10%). (B) Synthesis
proposed by Herberhold et al.:4 (i) (1) PCl5, benzene, (2) NaN3, acetone; (ii) acetic anhydride; (iii) KOH (10%). (C) Synthesis proposed by Knox
et al.:5 (i) (1) n-BuLi, Et2O, (2) benzylhydroxylamine, (3) HCl/H2O. (D) Synthesis proposed by Heinze et al.:9 (i) copper phthalimide; (ii)
N2H4·H2O. (E) Synthesis proposed by Arnold et al.:11 (i) NaN3, CuCl, EtOH/H2O; (ii) H2, Pd/C (5% Pd), MeOH. (F) Synthesis proposed by van
Leusen et al.:12 (i) t-BuLi, THF; (ii) (1) α-azidostyrene, (2) HCl/H2O.
metallic aminocyclopentadienyl derivatives. To emphasize the
importance of such small amino-functionalized ferrocenyl
compounds, it has to be reminded that they have already
been used, for example, as building blocks for the preparation
of ferrocenyl peptide bioconjugates as well as aminoferrocene-
based prodrug candidates.14−20 One such peptide conjugate
showed potential for the electrochemical sensing of chemical
warfare agent mimics.19,20 Over recent years, such small
organometallic constructs have also been used as inserts for
parent organic drugs to prepare novel organometallic-based
antiparasitic and anticancer drug candidates.21,22
Scheme 2. Aminoferrocene and Aminoruthenocene
Synthesis Proposed by Our Group
a
a
Conditions: (i) t-BuLi, I2, THF;23,26 (ii) NH3(aq), CuI (10 mol %),
Fe2O3 (10 mol %), NaOH, EtOH, 90 °C.
Herein, we report, to the best of our knowledge, the most
environmentally friendly and economically attractive synthesis
of aminoferrocene and aminoruthenocene from the corre-
sponding monosubstituted iodo precursors using aqueous
ammonia and an iron/copper cocatalyst system (Scheme 2).
we could successfully optimize the reaction conditions to
isolate aminoferrocene in 65% yield after purification. To the
best of our knowledge, this is the simplest route reported so far
for preparing aminoferrocene. Furthermore, the use of cheap
cocatalysts (iron and copper salts), ethanol as solvent, and
aqueous ammonia for the nitrogen source makes the procedure
environmentally friendly as well as economically attractive, even
for industrial purposes.24 Of note, we also assessed the
possibility of employing similar copper(I) iodide mediated
Ullmann-type coupling as reported by Bolm and co-workers for
the preparation of nitrogen-substituted ferrocenes.25 While
aminoferrocene could still be obtained following this approach,
addition of the cocatalyst iron(III) oxide, however, results in a
2-fold increase in the reaction yield. A similar improvement in
RESULTS AND DISCUSSION
■
As described in Scheme 2, the synthetic strategy that we report
herein for aminoferrocene synthesis involves the preparation of
iodoferrocene from ferrocene and its corresponding amination
using aqueous ammonia. For this, the iodoferrocene precursor
was easily prepared following the recently reported procedure
from Goeltz and Kubiak.23 Inspired by the recent report by Wu
and Darcel, which describes a ligand-free iron/copper-
cocatalyzed amination of aryl iodides with aqueous ammonia,24
B
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Organometallics
Note
Perkin-Elmer FTIR spectrometer fitted with an ATR platform. Peak
intensities are given as broad (b), very strong (vs), strong (s), medium
(m), and weak (w).
reaction yields was also observed by Wu and Darcel for
amination of aryl iodides.24 The iron/copper cocatalyst system
allowed us to use ethanol/water as solvent instead of dimethyl
sulfoxide (DMSO), hence avoiding the use of Schlenk
techniques (quite frequently employed in synthetic organo-
metallic chemistry) and shortening the reaction time from 16 to
6 h in comparison with the conditions originally reported by
Bolm and co-workers. Furthermore, in the absence of any
sodium hydroxide, only a slight decrease in reaction yield (ca.
10%) was observed for a 100-fold excess of ammonia solution
being used.
Synthesis. Aminoferrocene (3a). Iodoferrocene (0.10 g, 0.32
mmol) was dissolved in EtOH (3 mL). Copper iodide (6.0 mg, 0.032
mmol), Fe2O3 (5.0 mg, 0.032 mmol), and NaOH (30 mg, 0.75 mmol)
were added to the solution. Aqueous ammonia (13.5 M, 1.5 mL) was
added to the resulting red suspension, and the reaction mixture was
heated to 90 °C for 6 h in a pressure-proof vessel. The reaction
mixture was cooled to room temperature, and diethyl ether (50 mL)
was added. The organic phase was then washed with 1 M aqueous
NaOH (3 × 50 mL), dried over anhydrous MgSO4, filtered, and
evaporated to dryness to obtain the crude product, which was purified
by silica gel column chromatography (SiO2, eluent gradient gradually
changed from hexane/EtOAc 1/1 to hexane/EtOAc 1/4) to obtain 3a
as a yellow-orange solid. Yield: 42 mg (65%). Rf = 0.38 in hexane/
EtOAc 1/4. The analytical data for 3a matched those previously
reported.3
Aminoruthenocene (3b). Compound 3b was prepared following a
procedure similar to that described for 3a, using iodoruthenocene
(0.17 g, 0.47 mmol), copper iodide (8.9 mg, 0.047 mmol), Fe2O3 (7.5
mg, 0.047 mmol), NaOH (47 mg, 1.18 mmol), and aqueous ammonia
(13.5 M, 2.1 mL) in EtOH (8 mL). The reaction mixture was cooled
to room temperature, diethyl ether (70 mL) was added, and the
ethereal solution was washed with 10 mM phosphate buffer (pH 7.01)
(2 × 25 mL). The organic phase was extracted with water (2 × 15 mL,
acidified to pH 3.0 using 1 M HCl) and freeze-dried to obtain the
hydrochloride salt of 3b as an off-white solid. The hydrochloride salt
was dissolved in water (10 mL), and the pH of the aqueous solution
was adjusted between 7 and 8 using 1 M NaOH. After extraction with
dichloromethane (3 × 35 mL), the organic phase was dried over
Na2SO4 and filtered. The filtrate was concentrated under reduced
pressure to obtain an analytically pure sample of aminoruthenocene as
a yellowish black solid.30 Yield: 69 mg (60%). Anal. Calcd for
C10H12ClNRu: C, 42.48; H, 4.28; N, 4.95. Found: C, 42.66; H, 4.52;
N, 4.86. IR (ATR): ν 3405 w (N−H), 3281 w, 3087 s (C−H), 2925 w
(C−H), 1494 vs, 1408 m, 1255 s, 1099 s, 995 s, 799 vs cm−1. 1H NMR
(400 MHz, THF-d8): δ 4.41−4.40 (m, 2H, C5H4), 4.38 (s, 5H, C5H5),
4.11−4.10 (m, 2H, C5H4), 3.07 (br s, 2H, -NH2) ppm. 13C NMR (100
MHz, THF-d8): δ 112.2, 70.9, 65.9, 62.1 ppm. MS (ESI+): m/z 248.0
[M + H]+. HR-ESI mass spectrum (methanol + NaI): found, m/z
248.00045; calcd for [C10H12NRu], m/z 248.00077.
Encouraged by the excellent results obtained for amino-
ferrocene, taking a step further, we also attempted the
preparation of its heavier homologue, aminoruthenocene, via
a similar pathway. As expected, the desired product was
successfully isolated, in 60% yield, with no further chromato-
graphic purification. The identity of the product was established
1
by H and 13C NMR spectroscopy, IR spectroscopy, ESI-MS,
high-resolution mass spectrometry (HRMS) and elemental
analysis. The 1H NMR spectra showed multiplets between 4.10
and 4.40 ppm, characteristically assigned to the monosub-
stituted ruthenocene, a broad signal at 3.07 ppm ascribable to
the −NH2 group, and signals for the corresponding carbons in
the 13C NMR spectra. The signal at m/z 248.0 for the
corresponding [M + H]+ ion observed in ESI-MS further
confirmed the formation of the desired aminoruthenocene
product.
CONCLUSION
■
In summary, in this work, we present a remarkable improve-
ment over the methodologies available for the preparation of
aminoferrocene. The applied synthetic route is, to the best of
our knowledge, the most direct pathway reported thus far in the
literature. Importantly, the use of inexpensive CuI/Fe2O3
couple as cocatalysts and of NH3(aq)/EtOH as reaction
medium make this procedure an environmentally friendly and
cost-effective route. Moreover, using aminoruthenocene as an
example, we could successfully show that the scope of this
amination strategy can potentially be extended to prepare other
small organometallic building blocks, further adding to its
advantage over existing protocols.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra (Figures S1 and S2) and ESI-MS of
3b (Figure S3). This material is available free of charge via the
Internet at http://pubs.acs.org.
EXPERIMENTAL SECTION
■
Materials. All chemicals were of reagent grade quality or better,
obtained from commercial suppliers, and used without further
purification. Solvents were used as received or distilled using standard
procedures.27 Thin-layer chromatography (TLC) was performed using
silica gel 60 F-254 (Merck) plates, with detection of spots being
achieved by exposure to UV light. Column chromatography was done
using silica gel 60 (0.040−0.063 mm mesh, Merck). Eluent mixtures
are expressed as volume to volume (v/v) ratios. Iodoferrocene (2a)23
and iodoruthenocene (2b)26 were synthesized according to literature
procedures.
AUTHOR INFORMATION
Corresponding Author
*G.G.: e-mail, gilles.gasser@aci.uzh.ch; fax, +41 44 635 6803;
tel, +41 44 635 4630; web, www.gassergroup.com.
■
Author Contributions
†These authors contributed equally.
Notes
Instrumentation and Methods. H and 13C NMR spectra were
1
The authors declare no competing financial interest.
recorded in deuterated solvents on an AV2-401 spectrometer, at room
temperature. The chemical shifts, δ, are reported in ppm (parts per
million). The signals from the residual protons of deuterated solvent
have been used as an internal reference.28,29 The abbreviations for the
peak multiplicities are as follows: s (singlet), d (doublet), dd (doublet
of doublets), t (triplet), q (quartet), m (multiplet), and br (broad). ESI
mass spectrometry was performed using a Bruker Esquire 6000
spectrometer. In the assignment of the mass spectra, the most intense
peak is listed. High-resolution accurate mass spectra were recorded with
Bruker maXis QTOF high-resolution mass spectrometer (Bruker
Daltonics, Bremen, Germany). Infrared spectra were recorded on a
ACKNOWLEDGMENTS
■
This work was financially supported by the Swiss National
Science Foundation (SNSF Professorship PP00P2_133568 and
Research Grant No. 200021_129910 to G.G.) and the
University of Zurich (G.G.).
REFERENCES
(1) Price from TCI Europe on Dec 18, 2012.
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Organometallics
Note
(2) Arimoto, S.; Haven, A. C., Jr. Derivatives of Dicyclopentadieny-
liron. J. Am. Chem. Soc. 1955, 77, 6295−6297.
(25) Oezcubukcu, S.; Schmitt, E.; Leifert, A.; Bolm, C. A General and
Efficient Synthesis of Nitrogen-Substituted Ferrocenes. Synthesis 2007,
3, 0389−0392.
(3) Butler, D. C. D.; Richards, C. J. Synthesis of 1′-Substituted
Derivatives of 1,2,3,4,5-Pentaphenylferrocene. Organometallics 2002,
21, 5433−5436.
(26) Bednarik, L.; Neuse, E. Lithiierung und iodierung von
ruthenocen. J. Organomet. Chem. 1979, 168, C8−C12.
(27) Armarego, W. L. F.; Perrin, D. D. Purification of Laboratory
Chemicals, 4th ed.; Butterworth-Heinemann: Oxford, U.K., 1996.
(28) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. NMR Chemical
Shifts of Common Laboratory Solvents as Trace Impurities. J. Org.
Chem. 1997, 62, 7512−7515.
(4) Herberhold, M.; Ellinger, M.; Kremnitz, W. Ferrocenylamine. J.
Organomet. Chem. 1983, 241, 227−240.
(5) Knox, G. R.; Pauson, P. L.; Willison, D.; Solcaniova, E.; Toma, S.
Ferrocene Derivatives. 23. Isocyanoferrocene and Isothiocyanatoferro-
cene. Organometallics 1990, 9, 301−306.
(29) Fulmer, G. R.; Miller, A. J. M.; Sherden, N. H.; Gottlieb, H. E.;
Nudelman, A.; Stoltz, B. M.; Bercaw, J. E.; Goldberg, K. I. NMR
Chemical Shifts of Trace Impurities: Common Laboratory Solvents,
Organics, and Gases in Deuterated Solvents Relevant to the
Organometallic Chemist. Organometallics 2010, 29, 2176−2179.
(30) Note: slow decomposition of aminoruthenocene in halogenated
solvents was observed in the presence of light. Therefore, as much as
possible, the workup procedure should be carried out in absence of
light and prolonged suspension of aminoruthenocene in halogenated
solvents should also be avoided. To increase the lifetime of
aminoruthenocene, storage as the hydrochloride salt below −20 °C
is recommended.
(6) Bildstein, B.; Malaun, M.; Kopacka, H.; Wurst, K.; Mitterboeck,
M.; Ongania, K.-H.; Opromolla, G.; Zanello, P. N,N′-Diferrocenyl-N-
heterocyclic Carbenes and Their Derivatives. Organometallics 1999, 18,
4325−4336.
(7) Sato, M.; Ebine, S.; Akabori, S. Condensation of Halobenzenes
and Haloferrocenes with Phthalimide in the Presence of Copper(I)
Oxide; A Simplified Gabriel Reaction. Synthesis 1981, 472−473.
(8) Nesmeyanow, A. N.; Ssazonowa, W. A.; Drosd, V. N. Synthese
von Ferrocenderivaten mittels bor- und halogensubstituierter
Ferrocene. Chem. Ber. 1960, 83, 2717−2729.
(9) Heinze, K.; Schlenker, M. Main Chain Ferrocenyl Amides from 1-
Aminoferrocene-1-carboxylic Acid. Eur. J. Inorg. Chem. 2004, 2974−
2988.
(10) Nesmeyanov, A. N.; Drozd, V. N.; Sazonova, V. A. Ferrocene
azides. Dokl. Akad. Nauk SSSR 1963, 150, 321−324.
(11) Shafir, A.; Power, M. P.; Whitener, G. D.; Arnold, J. Synthesis,
Structure and Properties of 1,1′-Diamino- and 1,1′-Diazidoferrocene.
Organometallics 2000, 19, 3978−3982.
(12) van Leusen, D.; Hessen, B. 1,1′-Diisocyanoferrocene and a
Convenient Synthesis of Ferrocenylamine. Organometallics 2001, 20,
224−226.
(13) Stepnicka, P., Ferrocenes: Ligands, Materials and Biomolecules;
Wiley: Chichester, U.K., 2008.
(14) Heinze, K.; Beckmann, M.; Hempel, K. Solid-Phase Synthesis of
Transition Metal Complexes. Chem. Eur. J. 2008, 14, 9468−9480.
(15) Kirin, S. I.; Kraatz, H.-B.; Metzler-Nolte, N. Systematizing
structural motifs and nomenclature in 1,n′-disubstituted ferrocene
peptides. Chem. Soc. Rev. 2006, 35, 348−354.
(16) Siebler, D.; Forster, C.; Heinze, K. Redox-responsive organo-
metallic foldamers from ferrocene amino acid: Solid-phase synthesis,
secondary structure and mixed-valence properties. Dalton Trans. 2011,
40, 3558−3575.
̌
̌ ́ ́
(17) Semencic, M. C.; Heinze, K.; Forster, C.; Rapic, V.
̈
Bioconjugates of 1′-Aminoferrocene-1-carboxylic Acid with (S)-3-
Amino-2-methylpropanoic Acid and L-Alanine. Eur. J. Inorg. Chem.
2010, 2010, 1089−1097.
(18) Barisic, L.; Dropucic, M.; Rapic, V.; Pritzkow, H.; Kirin, S. I.;
Metzler-Nolte, N. The first oligopeptide derivative of 1′-amino-
ferrocene-1-carboxylic acid shows helical chirality with antiparallel
strands. Chem. Commun. 2004, 2004−2005.
(19) Khan, M. A. K.; Kerman, K.; Petryk, M.; Kraatz, H.-B.
Noncovalent Modification of Carbon Nanotubes with Ferrocene-
Amino Acid Conjugates for Electrochemical Sensing of Chemical
Warfare Agent Mimics. Anal. Chem. 2008, 80, 2574−2582.
(20) Hagen, H.; Marzenell, P.; Jentzsch, E.; Wenz, F.; Veldwijk, M.
R.; Mokhir, A. Aminoferrocene-Based Prodrugs Activated by Reactive
Oxygen Species. J. Med. Chem. 2011, 55, 924−934.
(21) Dive, D.; Biot, C. Ferrocene Conjugates of Chloroquine and
other Antimalarials: the Development of Ferroquine, a New
Antimalarial. ChemMedChem 2008, 3, 383−391.
̀
(22) Hillard, E. A.; Vessieres, A.; Jaouen, G., Ferrocene Function-
alized Endocrine Modulators as Anticancer Agents. In Medicinal
Organometallic Chemistry; Jaouen, G., Metzler-Nolte, N., Eds.;
Springer-Verlag: Heidelberg, Germany, 2010; Vol. 32, pp 81−117.
(23) Goetz, J. C.; Kubiak, C. P. Facile Purification of Iodoferrocene.
Organometallics 2011, 30, 3908−3910.
(24) Wu, X.-F.; Darcel, M. Ligand Free Iron-Copper Co-catalyzed
Amination of Aryl Iodides. Eur. J. Org. Chem. 2009, 4753−4756.
D
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