Deprotonative metallation of ferrocenes using mixed lithium-zinc and lithium-cadmium combinations

Article abstract of DOI:10.1039/b924939g

A mixed lithium-cadmium amide and a combination of lithium and zinc amides were reacted with a range of ferrocenes; deprotonative mono- or dimetallation in general occurred chemoselectively at room temperature, as evidenced by subsequent quenching with iodine.

Full text of DOI:10.1039/b924939g

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Deprotonative metallation of ferrocenes using mixed lithium–zinc
and lithium–cadmium combinationsw
Gandrath Dayaker,ab Aare Sreeshailam,ab Floris Chevallier,a Thierry Roisnel,c
Palakodety Radha Krishna*b and Florence Mongin*a
Received (in Cambridge, UK) 26th November 2009, Accepted 12th February 2010
First published as an Advance Article on the web 4th March 2010
DOI: 10.1039/b924939g
A mixed lithium–cadmium amide and a combination of lithium
and zinc amides were reacted with a range of ferrocenes;
deprotonative mono- or dimetallation in general occurred
chemoselectively at room temperature, as evidenced by sub-
sequent quenching with iodine.
bearing reactive functions and sensitive heterocycles. Hence
we decided to attempt their use in the ferrocene series.
It is known9 that ferrocene can be lithiated using 2 equiv. of
tert-butyllithium in the presence of 0.1 equiv. of potassium
tert-butoxide in THF (tetrahydrofuran) at ꢁ75 1C. The
lithium–cadmium base, which can be considered as
(TMP)3CdLi,8 was first chosen to attempt the metallation of
ferrocene (1). When treated with 0.5 or 1 equiv. (with respect
to Cd) of (TMP)3CdLi in THF at room temperature for 2 h,
ferrocene (1) remained unchanged, as demonstrated by
subsequent quenching with iodine. In contrast, when the
deprotonation step was carried out using 1 equiv. of base at
the reflux temperature of pentane for 3 h, the iodide 2a was
isolated in 86% yield (Scheme 1).
Metallocenes have met an important development. Ferrocene
has notably been extensively used to synthesize a variety
of derivatives with applications ranging from catalysis1 to
materials science2 and bioorganometallic chemistry.3
Among the methods used to functionalize ferrocene
compounds, deprotonative metallation plays an important role.4
The presence of a substituent containing heteroatoms on ferro-
cene usually directs deprotonation to the adjacent position,
giving after subsequent quenching 1,2-unsymmetrical ferrocenes.
The reagents classically used for this purpose are lithium bases,
which are highly polar reagents, hardly tolerating the presence
of reactive functional groups. For these reasons, restricted
conditions such as low temperatures or solvents of low polarity
have to be used in order to ensure good results, when attained.
In recent studies, ferrocene was mono- or polymetallated
using mixed alkali metal–magnesium, –zinc, and –manganese
bases, and the species isolated were studied by X-ray
diffraction.5 Another mixed lithium–magnesium base,
In the presence of a chelating group, the same reaction is
favoured. Thus, the similar functionalization of the acetal 3
can be performed either at the reflux temperature of pentane
to afford the acetal-protected iodide 4a in 76% yield, or
at room temperature in THF to give, after subsequent
deprotection of the aldehyde, the derivative 5a in 51% overall
yield. When THF was the solvent, the 2,5-diiodo derivative 4b
was also formed in 10% yield (Scheme 2). It is pertinent to
mention that lithium bases were previously used to deproto-
nate the acetal 3, albeit at lower temperatures in order to
prevent substantial cleavage of the dioxane ring.10
TMPMgClꢀLiCl (TMP
= 2,2,6,6-tetramethylpiperidino),
In order to check the chemoselectivity of reactions using
(TMP)3CdLi, the metallation of ferrocene ketones was
attempted. Starting from acetylferrocene (6) logically resulted
in THF or pentane in a complex mixture presumably due to
the presence of acidic a-protons. From benzoylferrocene (7), it
proved possible using 0.5 equiv. of base in THF at room
temperature for 2 h to isolate the mono- and diiodide 8a,b in
36 and 2% yield, respectively (Scheme 3).
allowed chemoselective deprotonation reactions of ferrocenes
bearing an ester, a nitrile and a carboxylic acid function, when
used in a polar solvent at temperatures around 0 1C.6
Among recently documented non cryogenic alternatives for
the deprotonative metallation of aromatics,5 in situ prepared
mixtures of ZnCl2ꢀTMEDA7 (TMEDA = N,N,N0,N0-tetra-
methylethylenediamine), or CdCl2ꢀTMEDA,8 and 3 equi-
valents of LiTMP proved efficient for the functionalization
of a large range of ferrocene substrates including aromatics
We then turned to methyl ferrocenecarboxylate (9), which
should be less sensitive than ketones 6,7. Indeed, employing
only 0.5 equiv. of base resulted in the formation of the mono-
and diiodide 10a,b in 73 and 10% yield, respectively. Reaction
times of 0.5 and 4 h did not modify significantly the yields. The
dimetallation could be favoured using 1 equiv. of base, to
furnish the diiodide 10b in 82% yield (Scheme 4). The
a
´
Chimie et Photonique Moleculaires, UMR 6510 CNRS,
Universite de Rennes 1, Batiment 10A,
´
ˆ
Case 1003, Campus Scientifique de Beaulieu, 35042 Rennes, France.
E-mail: florence.mongin@univ-rennes1.fr; Fax: +33-2-2323-6955
b D-211, Discovery Laboratory, Organic Chemistry Division-III,
Indian Institute of Chemical Technology, Hyderabad-500 607, India.
E-mail: prkgenius@iict.res.in; Fax: +91-40-27160387
c Centre de Diffractome´trie X, Universite´ de Rennes 1, Baˆtiment 10B,
Campus Scientifique de Beaulieu, F-35042 Rennes Cedex, France
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization of compounds, CIF files of 10b
(CCDC 755178), 15c (CCDC 755179) and 20a (CCDC 755180). For
ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/b924939g
Scheme 1 Deprotonative cadmiation of ferrocene.
ꢂc
This journal is The Royal Society of Chemistry 2010
2862 | Chem. Commun., 2010, 46, 2862–2864

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Fig. 1 ORTEP diagram (30% probability) of the diiodide 10b.
Scheme 2 Deprotonative cadmiation of 2-ferrocenyl-1,3-dioxane.
Scheme 5 Deprotonative dicadmiation of ferrocenecarboxylate 11.
Scheme 3 Deprotonative cadmiation of benzoylferrocene.
structure of the latter was determined unequivocally by X-ray
diffraction analysis of crystals obtained by slow evaporation of
a dichloromethane solution (Fig. 1)w.
This possibility was successfully extended to the ferrocene-
carboxylate 11, for which the corresponding diiodide 12b was
isolated in a satisfying yield (Scheme 5).
Scheme 6 Deprotonative zincation of 2-ferrocenyl-1,3-dioxane.
generated mixture of (TMP)2Zn (0.5 equiv.) and LiTMP
(0.5 equiv.). From the ferrocene ester 9, the monoiodide 10a
was selectively obtained, and isolated in 83% yield (the 1H
NMR spectra showed that remaining starting material was the
only impurity present in the crude). The dideprotonation
was similarly not observed when cyanoferrocene (13) and
N,N-diethylferrocenecarboxamide (14) were involved in the
reaction, and the expected iodides 15a and 16a were isolated in
87 and 91% yield, respectively (Scheme 7).
The base in situ prepared from ZnCl2ꢀTMEDA and
3 equivalents of LiTMP, which can be considered as a 1 : 1
mixture of (TMP)2Zn and LiTMP,7 was then chosen to
attempt the metallation of some ferrocene compounds. Bare
ferrocene (1) remained unchanged when treated at room
temperature in THF with the lithium–zinc base. Exchanging
THF for pentane and carrying out the reaction at reflux
resulted in the formation of a mixture of monoiodide 2a,
1,10-diiodide 2b and unreacted ferrocene (1). This contrasts
with what has been obtained using (TMP)3CdLi, and showed
that the lithium–cadmium base is more efficient for the
functionalization of bare ferrocene.
Deprotonative zincation of aromatic compounds followed
by in situ palladium-catalyzed cross-coupling of the lithium
zincate so generated constitutes a straightforward access to
biaryl compounds.7 Using catalytic amounts of PdCl2 as
palladium source and 1,10-diphenylphosphinoferrocene (dppf)
as ligand with 2-chloropyridine allowed the synthesis of the
pyridine derivatives 15c and 16c in satisfying yields (Scheme 8).
The structure of the compound 15c was determined unequi-
vocally by X-ray diffraction analysis (Fig. 2)w.
Monometallation mediated by the lithium–zinc base also
proved possible for methyl ferrocene-1,10-dicarboxylate (17).
Under the same reaction conditions, the iodide 18a was
obtained in 72% yield. Unfortunately, using 1 equiv. of
(TMP)3CdLi with this substrate failed in only giving one
In the case of the acetal 3, as previously observed using
(TMP)3CdLi, a mixture of the mono- and the diiodide 4a,b
(80 : 20 ratio) was obtained using 1 equiv. of ZnCl2ꢀTMEDA
and 3 equiv. of LiTMP in THF at room temperature. Dividing
by two the amount of base made it possible to discard the
diiodide 4b, but to the detriment of the conversion (Scheme 6).
In the presence of electron-withdrawing substituents, the
ferrocene ring can be efficiently deprotonated using the in situ
Scheme 4 Deprotonative mono- and dicadmiation of methyl ferro-
Scheme 7 Deprotonative zincation of methyl ferrocenecarboxylate,
cyanoferrocene and N,N-diethyl ferrocenecarboxamide.
cenecarboxylate.
ꢂc
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Scheme 10 Deprotonative zincation of bromoferrocene.
Scheme
8 Deprotonative zincation of cyanoferrocene and
N,N-diethylferrocenecarboxamide followed by cross-coupling.
Fig. 3 ORTEP diagram (30% probability) of the iodide 20a: main
enantiomer (left) and racemic mixture (right, X21 = Br, X22 = I and
X22 = Br, X21 = I).
Fig. 2 ORTEP diagram (30% probability) of the compound 15c.
In summary, (TMP)3CdLi efficiently allows the monode-
protonation of weakly activated ferrocenes and the didepro-
tonation of ferrocenes activated by an ester function. The
corresponding Li–Zn base is more suitable for the room
temperature monofunctionalization of activated ferrocenes.
diiodide. Indeed, two diiodides (compounds 18b) and even a
triiodide (18c) were isolated from the complex mixture
obtained (Scheme 9).
Finally, the behaviour of bromoferrocene (19) towards the
lithium–zinc base was considered. Under the conditions
described above, 1-bromo-2-iodoferrocene (20a) was obtained
as the main product (64% yield). 1-Bromo-3-iodoferrocene
(20b) concomitantly formed, and was isolated in 7% yield
(Scheme 10). Such a migration of a heavy halogen has
previously been observed using lithium amides as metallating
agents,11 and could be explained herein by the presence of
LiTMP in the basic mixture.
The authors gratefully acknowledge Rennes Metropole,
´
Region Bretagne for financial support given to G. D. and
´
A. S., University of Rennes 1 and CNRS for financial support
given to G. D. This research has been performed as part of the
Indo-French ‘‘Joint Laboratory for Sustainable Chemistry at
Interfaces’’.
Notes and references
The structure of the iodide 20a was established on the basis
of its NMR spectra, by comparison with previously reported
data.12 By slow evaporation of a dichloromethane solution of
the iodide 20a, it also proved possible to collect suitable
crystals for X-ray diffraction analysis. The presence of bromo
and iodo groups at adjacent positions was confirmed in this
way. However, the analysis of the data was complicated
by a phenomenon which could be interpreted by a partial
enrichment in favour of one enantiomer during the
crystallization (Fig. 3)w.
1 (a) A. Togni, Angew. Chem., Int. Ed. Engl., 1996, 35, 1475–1477;
(b) R. Gomez Arrayas, J. Adrio and J. C. Carretero, Angew.
´ ´
Chem., Int. Ed., 2006, 45, 7674–7715.
2 N. Long, Angew. Chem., Int. Ed. Engl., 1995, 34, 21–38.
3 D. R. van Staveren and N. Metzler-Nolte, Chem. Rev., 2004, 104,
5931–5986.
4 R. C. J. Atkinson, V. C. Gibson and N. J. Long, Chem. Soc. Rev.,
2004, 33, 313–328.
5 (a) R. E. Mulvey, F. Mongin, M. Uchiyama and Y. Kondo,
Angew. Chem., Int. Ed., 2007, 46, 3802–3824, and references cited
therein; (b) R. E. Mulvey, Acc. Chem. Res., 2009, 42, 743–755 and
references cited therein.
6 A. H. Stoll, P. Mayer and P. Knochel, Organometallics, 2007, 26,
6694–6697.
7 J.-M. L’Helgoual’ch, A. Seggio, F. Chevallier, M. Yonehara,
E. Jeanneau, M. Uchiyama and F. Mongin, J. Org. Chem., 2008,
73, 177–183.
8 (a) J.-M. L’Helgoual’ch, G. Bentabed-Ababsa, F. Chevallier,
M. Yonehara, M. Uchiyama, A. Derdour and F. Mongin, Chem.
´
Commun., 2008, 5375–5377; (b) K. Snegaroff, J.-M. L’Helgoual’ch,
G. Bentabed-Ababsa, T. T. Nguyen, F. Chevallier, M. Yonehara,
M. Uchiyama, A. Derdour and F. Mongin, Chem.–Eur. J., 2009,
15, 10280–10290.
9 R. Sanders and U. T. Mueller-Westerhoff, J. Organomet. Chem.,
1996, 512, 219–224.
10 See for example: W. Steffen, M. Laskoski, G. Collins and
U. H. F. Bunz, J. Organomet. Chem., 2001, 630, 132–138.
11 See for example: M. Mallet, G. Branger, F. Marsais and
G. Queguiner, J. Organomet. Chem., 1990, 382, 319–332.
´
12 I. R. Butler, Inorg. Chem. Commun., 2008, 11, 15–19.
Scheme
9
Deprotonative metallation of methyl ferrocene-1,10-
dicarboxylate.
ꢂc
This journal is The Royal Society of Chemistry 2010
2864 | Chem. Commun., 2010, 46, 2862–2864