Preparation of Di-, Tri-, and tetra-substituted functionalized ferrocenes via magnesium organometallics

Article abstract of DOI:10.1021/om701046c

Ferrocenyl carboxylic acid derivatives were metalated with TMPMgCl·LiCl, leading after reaction with electrophiles to 1,2-disubstituted ferrocenes. Further metalation of these disubstituted ferrocenes with TMPMgCl·LiCl afforded trisubstituted ferrocenes. A 1,2,3,4-tetrasubstituted ferrocene derivative could also be prepared in this way.

Full text of DOI:10.1021/om701046c

6694
Organometallics 2007, 26, 6694–6697
Preparation of Di-, Tri-, and Tetra-Substituted Functionalized
Ferrocenes via Magnesium Organometallics
Armin H. Stoll, P. Mayer, and Paul Knochel*
Department of Chemistry and Biochemistry, Ludwig-Maximilians-UniVersity Munich,
Butenandtstrasse 5-13, D-81377 Munich, Germany
ReceiVed October 18, 2007
ferrocenes bearing an ester, a nitrile, or a carboxylic acid by
using TMPMgCl · LiCl13 (magnesium 2,2,6,6-tetramethylpip-
eridide-lithium chloride) as a mixed Mg/Li amide. Thus, we
have prepared several readily available ferrocenyl carbonyl
compounds, 1a-d, via lithiation reactions10a,14 or esterification
of the corresponding ferrocenecarbonyl chloride15 (see Sup-
porting Information). We have now found that treatment of
ferrocenes of type 1 with TMPMgCl · LiCl (1.3 equiv, 0–10 °C)
furnishes after a reaction time of 2.5–67 h regioselectively
2-magnesiated ferrocenes 2a-d (Scheme 1). Their reactions
with various electrophiles lead to 1,2-disubstituted ferrocenes.
Thus, the magnesiated esters 2a,b provide after trapping with
iodide (Table 1, entry 1) allyl bromide (entry 2), benzoyl chloride
(entries 3 and 7), pivaldehyde (entries 4 and 6), ethyl chloroformate
(entry 5), di-tert-butyl dicarbonate (entry 8), and the expected 1,2-
disubstituted ferrocenes 3a (60%), 3b (72%), 3c (70%), 3d (60%),
3e (67%), 3f (82%), 3g (80%), and 3h (78%). The benzoylation
reactions (entries 3 and 7) were performed by first transmetalation
of 2a or 2b to the corresponding copper intermediates using
CuCN · 2LiCl16 (1.3 equiv, -30 °C, 30 min). For the preparation
of the 1,2-diester 3e, the magnesiated ferrocene 2a was transmeta-
lated with ZnCl2 (1.3 equiv, -30 °C, 30 min) before a carboxy-
lation with ClCO2Et (1.5 equiv, 25 °C, 2.5 h) in the presence of
Pd(PPh3)4 (1 mol %). A ferrocene bearing a cyano group such as
2c was also smoothly magnesiated with TMPMgCl · LiCl (1.3
equiv, 0 °C, 67 h) and converted to the 1,2-disubstituted products
3i (62%) and 3j (75%) after the reaction with pivaldehyde (entry
9) and allyl bromide (entry 10). Interestingly, the magnesiation of
the carboxylic acid 2d was also successful by performing first a
deprotonation with MeMgCl17 (1.0 equiv, 10 °C, then room
temperature, 30 min) followed by the addition of TMPMgCl · LiCl
(1.3 equiv, 10 °C, 2.5 h). After trapping with allyl bromide the
allylated carboxylic acid 3k was obtained in 76% yield (entry 11).
Summary: Ferrocenyl carboxylic acid deriVatiVes were meta-
lated with TMPMgCl · LiCl, leading after reaction with elec-
trophiles to 1,2-disubstituted ferrocenes. Further metalation of
these disubstituted ferrocenes with TMPMgCl · LiCl afforded
trisubstituted ferrocenes. A 1,2,3,4-tetrasubstituted ferrocene
deriVatiVe could also be prepared in this way.
Since the discovery of ferrocene1,2 in 1951, the preparation
of functionalized ferrocene derivatives has been extensively
studied,3 especially with respect to applications in organic
synthesis, asymmetric catalysis,4,5 materials for nonlinear op-
tics,6 or bioorganometallic chemistry.7 Various lithiation
reactions8,9 have been used for their preparation. Strong
alkyllithium bases as well as sterically hindered lithium amides
provide access to a number of polysubstituted ferrocene
derivatives.10 However, the high reactivity of lithioferrocenes
usually precludes the presence of sensitive functional groups.11
The magnesiation of unsubstituted ferrocene using TMP bases
has also been described.12 Herein, we wish to report the
regioselective preparation of 1,2-, 1,2,3-, and 1,2,3,4-substituted
* Corresponding author. E-mail: paul.knochel@cup.uni-muenchen.de.
(1) Kealy, T. J.; Pauson, P. L. Nature 1951, 168, 1039.
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(3) For a recent overview see: Togni, A.; Hayashi, T. Ferrocenes; VCH:
Weinheim, Germany, 1995.
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(5) For a recent review see: Arrayás, R. G.; Adrio, J.; Carretero, J. C.
Angew. Chem., Int. Ed. 2006, 45, 7674.
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anov, A. N.; Perevalova, E. G.; Golovnya, R. V.; Shiovtseva, L. S. Dokl.
Akad. Nauk SSSR 1955, 102, 535.
This magnesiation procedure could also be extended to the
preparation of new 1,2,3-trisubstituted and 1,2,3,4-tetrasubsti-
tuted ferrocenes. Thus, the treatment of the 1,2-diethyl ferrocenyl
ester 3e and the 1,2-di-tert-butyl ester 3h with TMPMgCl · LiCl
(1.1 equiv, 0 °C, 2 h, Scheme 2) afforded the magnesiated
ferrocenes 4a and 4b. The quenching with various electrophiles
such as chlorotrimethylstannane (Table 2, entry 1), allyl bromide
(10) (a) Rebiere, F.; Samuel, O.; Kagan, H. B. Tetrahedron Lett. 1990,
31, 3121. (b) Enders, D.; Peters, R.; Lochtman, R.; Runsink, J. Synlett 1997,
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Moreau-Bossuet, C. J. Organomet. Chem. 1998, 567, 191. (d) Miao, B.;
Trinkl, M.; Snieckus, V. Tetrahedron Lett. 1999, 40, 2449. (e) Metallinos,
C.; Snieckus, V. Org. Lett. 2002, 4, 1935. (f) Chiffre, J.; Coppel, Y.;
Balavoine, G. G. A.; Daran, J.-C.; Manoury, E. Organometallics 2002, 21,
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Xin, Z-q.; Fischer, D. F.; Schweizer, W. B. Organometallics 2006, 25, 2917.
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(13) (a) Krasovskiy, A; Krasovskaya, V.; Knochel, P. Angew. Chem.,
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2006, 8, 5673. (c) Clososki, G. C.; Rohbogner, C. J.; Knochel, P. Angew.
Chem., Int. Ed. 2007, 46, 7681.
(11) Yus, M.; Foubelo, F. Handbook of Functionalized Organometallics;
Knochel, P., Ed.; Wiley-VCH: Weinheim, Germany, 2005; Vol. 1, p 7.
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T.; Rowlings, R. B. Chem. Commun. 2001, 1678. (b) Clegg, W.; Henderson,
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10.1021/om701046c CCC: $37.00
2007 American Chemical Society
Publication on Web 12/04/2007

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Organometallics, Vol. 26, No. 27, 2007 6695
Table 1. Double Functionalized Ferrocene Derivatives of Type 3
Prepared by the Reaction of Magnesiated Ferrocene Derivatives of
Type 2 and Various Electrophiles
Scheme 1. Regioselective Preparation of 1,2-Disubstituted
Functionalized Ferrocene Derivatives Using TMPMgCl · LiCl
(entries 2 and 6), N,N-diethyl(methylene)immonium trifluoro-
acetate (entry 3), and ethyl cyanoformate (entries 4 and 7)
provided the corresponding 1,2,3-trifunctionalized ferrocene
derivatives 5a-f in 34–50% yields.
Interestingly, the trisubstituted ferrocene 5d could be mag-
nesiated again with TMPMgCl · LiCl (1.1 equiv, -10 °C, 1 h),
leading to the magnesium species 4c. By the reaction with ethyl
cyanoformate (0.9 equiv, -20 to 5 °C, 2 h) the ester 6 was
obtained in 60% yield. The formation of the intermediate
magnesiated reagents 4a-c (Table 2, entries 1–7) was monitored
by GC analysis of reaction aliquots quenched with a solution
of iodide in THF, or alternatively with allyl bromide in the
presence of CuCN · 2LiCl.
Although the magnesiation of ferrocenes of type 3 proceeded
well using TMPMgCl · LiCl, the resulting tri- and tetra-
substituted ferrocenes were found to be sensitive toward
chromatographic purification (silica gel or Al2O3), leading to
extensive decomposition. Furthermore, most of the polyfunc-
tionalized ferrocenes proved also to be light sensitive. In order
to get some structural information that would explain the
instability of these ferrocenes, we have performed an X-ray
structure analysis of the trisubstituted ferrocene 5d (Figure 1)
and the tetrasubstituted ferrocene 6 (Figure 2). The average
a Isolated yield of analytically pure compound. b Reaction performed
after the addition of catalytic or stoichiometric amounts of CuCN · 2LiCl
(0.1–1.3 equiv). c Reaction performed after the addition of ZnCl2 (1.3
equiv, solution in THF) and Pd(PPh3)4 (1 mol %).
Figure 1. Molecular view of 5d with atom-labeling scheme.
Ellipsoids represent 30% probability.
Scheme 2. Ester-Directed Magnesiation of 1,2- and
1,2,3-Substituted Ferrocenes 3e, 3h, and 5d Followed by
Trapping with Electrophiles
Fe-C bond distances for the ferrocenes 5d and 6 are very
similar (2.03–2.04 Å), showing no especially weak η5-binding.
However, the corresponding cyclopentadienyl anions
(EtO2C)3C5H2- and (EtO2C)4C5H- should be highly stabilized
anions.18 Their formation may be the driving force of the
ferrocene decomposition.
Figure 2. Molecular view of 6 with atom-labeling scheme.
Ellipsoids represent 30% probability.

6696 Organometallics, Vol. 26, No. 27, 2007
Communications
Table 2. Polyfunctionalized Ferrocene Derivatives of Type 5 and 6
by Successive Magnesiation and Trapping with Various
Electrophiles
room temperature. The reaction mixture was stirred at room
temperature until gas evolution was completed (24-48 h).
General Procedure GP(A) for the Metalation of
Monosubstituted Ferrocenes 1a,b. A dry and argon-flushed Schlenk
flask, equipped with a magnetic stirring bar and a septum, was charged
with the ferrocene derivative 1a or 1b and dissolved in THF/dioxane
(9:1). The reaction mixture was cooled to 10 °C, and TMPMgCl · LiCl
(1.3 equiv, ca. 1.35 mol/L, solution in THF) was added dropwise. The
completion of the metalation was checked by GC analysis of reaction
aliquots quenched with a solution of I2 in THF, or alternatively with
allyl bromide in the presence of CuCN · 2LiCl. After 2.5 h at 10 °C
the neat electrophile (liquids) or its solution in THF (solids) was added
at -30 °C. After 30 min, the cooling device was switched off, allowing
the reaction mixture to warm slowly for 1-1.5 h. The completion of
the reaction was checked by GC analysis of reaction aliquots quenched
with saturated aqueous NH4Cl solution.
General Procedure GP(B) for the Metalation of
Monosubstituted Ferrocene 1c. A dry and argon-flushed Schlenk
flask, equipped with a magnetic stirring bar and a septum, was
charged with the ferrocene derivative 1c and dissolved in THF/
dioxane (9:1). The reaction mixture was cooled to 0 °C, and
TMPMgCl · LiCl (1.3 equiv, ca. 1.35 mol/L, solution in THF) was
added dropwise. The completion of the metalation was checked
by GC analysis of reaction aliquots quenched with a solution of I2
in THF, or alternatively with allyl bromide in the presence of
CuCN · 2LiCl. After 67 h at 0 °C the neat electrophile (liquids) or
its solution in THF (solids) was added at -30 °C. After 30 min,
the cooling device was removed, allowing the reaction mixture to
warm to room temperature for 1 h. The completion of the reaction
was checked by GC analysis of reaction aliquots quenched with
saturated aqueous NH4Cl solution.
a Isolated yield of analytically pure compound. b Reaction performed
after the addition of catalytic amounts of CuCN · 2LiCl (0.1 equiv).
General Procedure GP(C) for the Metalation of
1,2-Disubtituted Ferrocenes 3e and 3h. A dry and argon-flushed
Schlenk flask, equipped with a magnetic stirring bar and a septum,
was charged with the ferrocene derivative 3e or 3h and dissolved
in THF/dioxane (9:1). The reaction mixture was cooled to 0 °C,
and TMPMgCl · LiCl (1.1 equiv, ca. 1.35 mol/L, solution in THF)
was added dropwise. The completion of the metalation was checked
by GC analysis of reaction aliquots quenched with a solution of I2
in THF, or alternatively with allyl bromide in the presence of
CuCN · 2LiCl. After 2 h at 0 °C, the neat electrophile (liquids) or
its solution in THF (solids) was added at -30 °C. The completion
of the reaction was checked by GC analysis of reaction aliquots
quenched with saturated aqueous NH4Cl solution.
Ethyl 2-Iodoferrocenecarboxylate (3a). According to GP(A), a
solution of 1a (258 mg, 1.0 mmol) in THF (0.9 mL) and dioxane (0.1
mL) was reacted with TMPMgCl · LiCl (0.95 mL, c ) 1.37 mol/L)
and iodide (0.33 g, 1.3 mmol). The reaction mixture was quenched
with NH4Clsat. (25 mL) and H2O (25 mL) and then extracted with
CH2Cl2 (3 × 40 mL). The combined organic extracts were dried with
Na2SO4 and concentrated in Vacuo. The crude residue was purified
by column chromatography (eluant: pentane/CH2Cl2, 2:1) and gave
3a (229 mg, 60%) as a viscous, red-brown oil.
2-(1-Hydroxy-2,2-dimethylpropyl)ferrocenylnitrile (3i). Ac-
cording to GP(B), a solution of 1c (211 mg, 1.0 mmol) in THF
(0.9 mL) and dioxane (0.1 mL) was reacted with TMPMgCl · LiCl
(0.96 mL, c ) 1.35 mol/L) and pivaldehyde (78 mg, 0.9 mmol).
The reaction mixture was quenched with NH4Clsat. (25 mL) and
H2O (25 mL) and then extracted with CH2Cl2 (3 × 40 mL). The
combined organic extracts were dried with Na2SO4 and concentrated
in Vacuo. The crude residue was purified by column chromatog-
raphy (eluant: pentane/diethyl ether, 4:1) and gave 3i (165 mg, 62%
based on used electrophile) as an orange solid.
Triethyl ferrocene-1,2,3-tricarboxylate (5d). According to
GP(C), a solution of 3e (165 mg, 0.5 mmol) in THF (0.45 mL)
and dioxane (0.05 mL) was reacted with TMPMgCl · LiCl (0.41
mL, c ) 1.34 mol/L) and ethyl cyanoformate (45 mg, 0.9 mmol).
In summary, we have shown that the magnesiation of
monosubstituted ferrocene derivatives with TMPMgCl · LiCl
allows the regioselective preparation of various new polyfunc-
tionalized ferrocenes bearing functional groups such as an ester,
a nitrile, or a carboxylic acid. The mild reaction conditions and
the versatile functional group tolerance of this method provide
a useful complement to the well-known directed lithiation
reaction,10 opening a new way to the preparation of tri- and
tetra-substituted ferrocenes.
Experimental Section
General Procedures. All reactions were carried out under an argon
atmosphere in dried glassware. All starting materials were purchased
from commercial sources and used without further purification. Due
to the light sensitivity of ferrocene derivatives, all reaction flasks were
properly protected from light sources. Column chromatographies were
also performed properly protected from light under a flow of nitrogen.
THF was continuously refluxed and freshly distilled from sodium
benzophenone ketyl under nitrogen before use. Yields refer to isolated
yields of compounds estimated to be >95% pure as determined by
1H NMR and capillary GC.
Preparation of the Reagent TMPMgCl · LiCl. A dry and argon-
flushed 250 mL Schlenk flask, equipped with a magnetic stirrer
and a septum, was charged with freshly titrated iPrMgCl · LiCl19
(100 mL, 1.2 M in THF, 120 mmol). 2,2,6,6-Tetramethylpiperidine
(TMPH, 19.8 g, 126 mmol, 1.05 equiv) was added dropwise at
(18) (a) Chambers, R. D.; Gray, W K; Vaughan, J. F. S.; Korn, S. R.;
Medebielle, M.; Batsanov, A. S.; Lehmann, C. W.; Howard, J. A. K.
J. Chem. Soc., Perkin Trans. 1 1997, 135. (b) Laganis, E. D.; Lemal, D. M.
J. Am. Chem. Soc. 1980, 102, 6633.
(19) iPrMgCl · LiCl is commercially available from Chemetall GmbH
(Frankfurt am Main) and can be efficiently titrated by using I2 in THF
Procedure described in: Krasovskiy, A.; Knochel, P. Synthesis 2006, 890.

Communications
Organometallics, Vol. 26, No. 27, 2007 6697
The reaction mixture was stirred for 1 h warming slowly from -30
to -20 °C. After removing the cooling device the mixture was
stirred for 1 h at room temperature. Quenching with NH4Clsat. (25
mL) and H2O (25 mL), extraction with Et2O (3 × 40 mL), drying
with Na2SO4, and concentration in Vacuo afforded after purification
by column chromatography (eluant: pentane/CH2Cl2, 2:1) 5d (90
mg, 50%) as a dark brown solid.
Note Added after ASAP Publication. In the version of this
paper that was published on the Web December 4, 2007, refs 10b
and 10i were incorrect. The versions of these references that now
appear are correct.
Supporting Information Available: Experimental procedures
and analytical data. This material is available free of charge via
the Internet at http://pubs.acs.org.
Acknowledgment. We thank the Fonds der Chemischen
Industrie, the Deutsche Forschungsgemeinschaft (DFG), and
Merck Research Laboratories (MSD) for financial support.
We also thank Chemetall (Frankfurt) and BASF AG (Lud-
wigshafen) for the generous gift of chemicals.
OM701046C