Modular synthesis of functional titanocenes

Article abstract of DOI:10.1021/om800700c

A modular approach to carbonyl-functionalized titanocenes is described. Through the introduction of highly electrophilic acid chlorides to the complexes, reactions with nucleophiles can be realized that are incompatible with classical methods of titanocene synthesis. The first amino acid functionalized titanocenes were synthesized. The amide- and ketone- functionalized titanocenes are cationic, due to the complexation of the carbonyl groups that results in the formation of unstrained rings.

Full text of DOI:10.1021/om800700c

Organometallics 2008, 27, 5699–5707
5699
Modular Synthesis of Functional Titanocenes
Andreas Gansa¨uer,*,† Iris Winkler,† Dennis Worgull,† Dieter Franke,† Thorsten Lauterbach,†
Andreas Okkel,† and Martin Nieger‡
Kekule´-Institut fu¨r Organische Chemie und Biochemie der UniVersita¨t Bonn, Gerhard Domagk Strasse 1,
53121 Bonn, Germany, and Laboratory of Inorganic Chemistry, Department of Chemistry, UniVersity of
Helsinki, P.O. Box 55, FIN-00014 UniVersity of Helsinki, Finland
ReceiVed July 23, 2008
A modular approach to carbonyl-functionalized titanocenes is described. Through the introduction of
highly electrophilic acid chlorides to the complexes, reactions with nucleophiles can be realized that are
incompatible with classical methods of titanocene synthesis. The first amino acid functionalized titanocenes
were synthesized. The amide- and ketone-functionalized titanocenes are cationic, due to the complexation
of the carbonyl groups that results in the formation of unstrained rings.
potent donor solvents,5 the redox potential and Lewis acidity
of titanocene(III) complexes can be tailored by interactions with
appended donor ligands. In this way, the lifetime of the epoxide
-derived radicals can be increased to enable kinetically and
thermodynamically unfavorable transformations.6,7 Second, the
regioselectivity of epoxide opening, e.g. in enantioselective
reactions,8 can be controlled by fine tuning of the catalyst’s steric
demand.9 This constitutes an approach more general and flexible
than the introduction of bulky alkyl groups.10
Unfortunately, access to these functional complexes has, until
recently, been rather difficult.11 Because the [TiCl2] fragment
is rather electrophilic, titanocenes have been considered to be
incompatible with most of the nucleophilic reagents typically
used in organic synthesis. Introduction of functional groups is
thus usually carried out early in the synthetic sequence before
the metalation with titanium. In this manner a large variety of
ether-, amine-, and thiol-substituted cyclopentadienes and the
corresponding metallocenes have been prepared.11
Introduction
Organometallic complexes, and in particular metallocenes
containing additional organic groups, have recently attracted
considerable interest.1 This has been especially so when both
the metal and the organic fragment are able to bind and
recognize other molecular entities or to mediate reactivity. Such
bifunctional molecules are highly attractive as catalysts, for the
generation of supramolecular aggregates, and for the selective
binding of biological targets in medicinal chemistry.
Due to the Lewis acidity of their metals, group 4 metallocenes
are of special interest in this respect. With appropriate substitu-
tion they can interact with both (Lewis) acidic and basic sites.
Therefore, they have been employed successfully in the topical
and interdisciplinary fields of organometallic antitumor agents2
and organometallic gelators.3
Additionally, such complexes are also very interesting as
electron transfer catalysts in reductive epoxide openings4 for
two reasons. First, in the same manner as for the addition of
However, this straightforward approach employing function-
alized cyclopentadienyl anions has distinct disadvantages.12
* To whom correspondence should be addressed. E-mail:
andreas.gansaeuer@uni-bonn.de.
(5) Larsen, J.; Enemærke, R. J.; Skrydstrup, T.; Daasbjerg, K. Orga-
nometallics 2006, 25, 2031–2036.
† Universita¨t Bonn.
‡ University of Helsinki.
(1) (a) Butenscho¨n, H. Chem. ReV. 2000, 100, 1527–1564. (b) Bareille,
L.; Le Gendre, P.; Richard, P.; Mo¨ıse, C. Eur. J. Inorg. Chem. 2005, 2451–
2456.
(6) (a) Gansa¨uer, A.; Lauterbach, T.; Geich-Gimbel, D. Chem. Eur. J.
2004, 10, 4983–4990. (b) Friedrich, J.; Dolg, M.; Gansa¨uer, A.; Geich-
Gimbel, D.; Lauterbach, T. J. Am. Chem. Soc. 2005, 127, 7071–7077.
(7) (a) Gansa¨uer, A.; Rinker, B.; Pierobon, M.; Grimme, S.; Gerenkamp,
M.; Mu¨ck-Lichtenfeld, C. Angew. Chem. 2003, 115, 3815-3818; Angew.
Chem., Int. Ed. 2003, 42, 3687-3690. (b) Gansa¨uer, A.; Rinker, B.; Ndene-
Schiffer, N.; Pierobon, M.; S.; Grimme, S.; Gerenkamp, M.; Mu¨ck-
Lichtenfeld, C. Eur. J. Org. Chem. 2004, 2337–2351.
(8) (a) Gansa¨uer, A.; Lauterbach, T.; Bluhm, H.; Noltemeyer, M. Angew.
Chem. 1999, 111, 3112-3114; Angew. Chem., Int. Ed. 1999, 38, 2909-
2910. (b) Gansa¨uer, A.; Bluhm, H.; Lauterbach, T. AdV. Synth. Cat. 2001,
343, 785–787. (c) Gansa¨uer, A.; Bluhm, H.; Rinker, B.; Narayan, S.; Schick,
M.; Lauterbach, T.; Pierobon, M. Chem. Eur. J. 2003, 9, 531–542. (d)
Gansa¨uer, A.; Fan, C.-A.; Keller, F.; Keil, J. J. Am. Chem. Soc. 2007, 129,
3484–3485. Gansa¨uer, A.; Fan, C.-A.; Keller, F.; Karbaum, P. Chem. Eur.
J. 2007, 13, 8084–8090.
(9) (a) Daasbjerg, K.; Svith, H.; Grimme, S.; Gerenkamp, M.; Mu¨ck-
Lichtenfeld, C.; Gansa¨uer, A.; Barchuk, A.; Keller, F. Angew. Chem. 2006,
118, 2095–2098. Angew. Chem. Int. Ed. 2006, 45, 2041-2044. (b) Gansa¨uer,
A.; Barchuk, A.; Keller, F.; Schmitt, M.; Grimme, S.; Gerenkamp, M.;
Mu¨ck-Lichtenfeld, C.; Daasbjerg, K.; Svith, H. J. Am. Chem. Soc. 2007,
129, 1359–1371.
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2004, 23, 1168–1171.
(11) Qian, Y.; Huang, J.; Bala, M. D.; Lian, B.; Zhang, H.; Zhang, H.
Chem. ReV. 2003, 103, 2633–2690.
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McGowan, P. C. Organometallics 2004, 23, 288–292. (g) Tacke, M.; Allen,
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W. G.; Tacke, M. Organometallics 2007, 26, 2501–2506. (j) Gansa¨uer, A.;
Winkler, I.; Worgull, D.; Lauterbach, T.; Franke, D.; Selig, A.; Wagner,
L.; Prokop, A. Chem. Eur. J. 2008, 14, 4160–4163.
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Chem. Commun. 2007, 1894–1895.
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986–997. (b) Gansa¨uer, A.; Bluhm, H.; Pierobon, M. J. Am. Chem. Soc.
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100, 2771–2788. (d) Gansa¨uer, A.; Narayan, S. AdV. Synth. Catal. 2002,
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10.1021/om800700c CCC: $40.75
2008 American Chemical Society
Publication on Web 09/30/2008

5700 Organometallics, Vol. 27, No. 21, 2008
Gansäuer et al.
Scheme 1. Modular Synthesis of Functionalized Titanocenes
Scheme 2. Synthetic Approach to the Titanocene
Carboxylates 4
Table 1. Synthesis of the Titanocene Carboxylates 4a-k
compd
R, R
R′, R′
R′′
2a/%
4b/%
a
b
c
d
e
CH3, CH3
H, H
H
CH3
C(CH3)3
5 CH3
H
H
H
C(CH3)3
H
C(CH3)3
H
81
81
81
81
16
57
50
50
61
61
76
66
40
50
47
67
58
61
52
63
35
52
CH3, CH3
CH3, CH3
CH3, CH3
CH3, CH3
(CH2)4
(CH2)5
(CH2)5
(CH2CH2)2CHtBu
(CH2CH2)2CHtBu
nBu, nBu
H, H
H, H
H, H
CH3, CH3
H, H
H, H
H, H
H, H
H, H
H, H
c
f
g
h
id
j
First, both the generation and use of these basic and strongly
nucleophilic anions precludes the simple introduction of protic
functional groups and synthetically useful carbonyl groups such
as aldehydes and ketones. To the best of our knowledge, only
unreactive alkyl-substituted amide groups have been successfully
attached to titanocenes in this manner.13 Second, the linear
sequences usually employed do not allow the rapid preparation
of large numbers of structurally and functionally diverse
complexes due to the absence of synthetic branching points.
Such an efficient approach is, however, essential for investiga-
tions in catalysis or medicinal chemistry, where screening of
large parts of chemical space14 is mandatory.
A modular route employing functional building blocks already
containing the [TiCl2] fragment would circumvent these prob-
lems and, moreover, allow rapid and efficient access to
titanocene complexes with novel properties. Here, we report
exactly such a modular titanocene synthesis.15
k
a From 1. b From 2. c Cp* as ligand. d See Figure2 for the structure of
4i.
Preparation of the Carboxylates. For the flexibility of the
synthesis, it is essential that the carboxylates themselves can
be prepared in a general and modular manner. To realize this
goal, we chose the synthetic sequence shown in Scheme 2.
It features two key steps. First, the introduction of the pivotal
ester group is realized through an enolate addition to the fulvene
117 to generate the functionalized cyclopentadienyl ligand 2.
This demonstrates that tert-butyl esters are compatible with the
nucleophilic cyclopentadienyl anion. Second, after metalation
with the (substituted) half-titanocenes, 3 is generated. The tert-
butyl ester in 3 was chosen with the intention of an acid-induced
ester cleavage that could even be promoted by the [TiCl2]
fragment. Indeed, in most cases it turned out to be impossible
to isolate 3 and in many cases pure 4 was obtained directly.
When mixtures of 3 and 4 were obtained, the formation of 4
could be completed either by simple heating in toluene or by
reaction with ZnCl2. These results are summarized in Table 1.
The yields of cyclopentadiene formation are good to high,
with the exception of 2e, and are typically in the range of
40-70% for the metalation and ester cleavage that leads to the
preparation of 4. The molecular structures of 4a,e, which
demonstrate the intramolecular carboxylate formation, are shown
in Figure 1. The Ti-O bond lengths of 1.95 and 1.91 Å are
close to the value observed for the titanocene bis(benzoate) (1.92
Å).18 The almost perfect staggering of the substituents of the
C(sp3)-C(sp3) bond of the tether in 4a,e suggests strongly that
the titanium-containing ring formed during ester cleavage is
unstrained.
Results and Discussion
Synthetic Strategy. The key to using the building blocks as
synthetic branching points is the incorporation of functional
groups that are more electrophilic than the [TiCl2] moiety. We
chose carboxylic acid chlorides as our target because they are
highly reactive, can be prepared from carboxylic acid deriva-
tives, and are among the most useful functional groups for the
preparation of a wide variety of compounds by classical organic
reactions. These transformations include the acylation of hetero
nucleophiles and Friedel-Crafts acylation.16 Thus, from a single
building block large numbers of structurally and functionally
diverse complexes become readily available (Scheme 1). All
complexes described in this paper with a carbonyl group
coordinated by titanium are chiral and have been obtained in
racemic form.
It should be noted that in the preparation of 4i the issue of
diastereoselectivity of the enolate addition to 1i arises. We have
(13) Hu¨erla¨nder, D.; Fro¨hlich, R.; Erker, G. Dalton Trans. 2002, 1513–
1520.
(14) Burke, M. D.; Schreiber, S. L. Angew. Chem. 2004, 116; 48-60;
(17) (a) Pauson, P. L. J. Am. Chem. Soc. 1954, 76, 2187–2191. (b) Knox,
G. R.; Munro, J. D.; Pauson, P. L.; Smith, G. H.; Watts, W. E. J. Chem.
Soc. 1961, 4619–4624. (c) Dialer, H.; Polborn, K.; Ponikwar, W.; Su¨nkel,
K.; Beck, W. Chem. Eur. J. 2002, 8, 691–699.
Angew. Chem., Int. Ed. 2004, 43, 46-58.
(15) Gansa¨uer, A.; Franke, D.; Lauterbach, T.; Nieger, M. J. Am. Chem.
Soc. 2005, 127, 11622–11623.
(16) Gerecs, A.; Olah, G. A. Friedel-Crafts and Related Reactions;
Wiley: London, 1964; Vol. 3, pp 499ff.
(18) Hoffman, D. M.; Chester, N. D.; Fay, R. C. Organometallics 1983,
2, 48–52.

Modular Synthesis of Functional Titanocenes
Organometallics, Vol. 27, No. 21, 2008 5701
Figure 2. Proposed Structure of 4i and molecular structure of 5.
Displacement parameters are drawn at the 50% probability level.
Scheme 3. Preparation of the Acid Chlorides 6
can be easily varied. Thus, our highly modular synthesis allows
a straightforward access to large numbers of derivatives of 4.
Synthesis of Carbonyl-Substituted Titanocenes. We turned
our attention toward the use of the carboxylates as building
blocks in acylation reactions of heteronucleophiles and
Friedel-Crafts acylations. To this end, the corresponding acid
chlorides 6 had to be prepared. We exploited the high stability
of titanocenes toward acidic reaction conditions by treating the
complexes 4 with SOCl2, as shown in Scheme 3.
We assumed that the acid chlorides 6 were obtained in
quantitative yield and used them without further purification.
For the success of the ensuing reactions, it is essential that excess
SOCl2 is completely removed. This was routinely achieved by
heating of the samples of 6 to 50 °C under vacuum for 2-3 h.
Preparation of the Amide-Functionalized Titanocenes.
With the acid chlorides in hand, we investigated the prepara-
tion of the amides via acylation of amines. The optimized
conditions for the reaction of benzylamine with 6a are
depicted in Scheme 4.
The use of NaH as base is essential for the success of the
transformation. The byproducts of the reaction are either volatile
(H2) or can be removed by simple filtration (NaCl). It is
indispensable that high-quality NaH be used. In the presence
of NaOH, which is present in old or not properly handled
samples of NaH, extensive decomposition of the titanocenes
occurs, presumably through attack of the oxygen nucleophile
at the titanium center. This is readily apparent from the color
change from dark red (titanocenes intact) to light yellow. Amine
Figure 1. Molecular structures of 4a,e. Displacement parameters
are drawn at the 50% probability level. In 4a the solvent toluene is
not shown for reasons of clarity.
not yet been able to grow single crystals suitable for analysis
by X-ray crystallography. The substitution pattern of the
cyclohexane shown in Figure 2 is, however, strongly supported
by the structure of the closely related 5. It was prepared as a
single isomer by addition of MeLi to 1i followed by metalation
with TiCl4 and subsequent reaction of the half-titanocene
obtained in this way with NaCp. The titanocene moiety is
positioned axially and the tert-butyl equatorially. The Supporting
Information gives details of the synthesis and characterization.
The mechanistically analogous equatorial addition of nucleo-
philes to 4-tert-butylcyclohexanone lends further support to our
assignment.19
Because all reactions employed are general with respect to
substitution of the substrates, the carboxylate substitution pattern
(19) (a) Mengel, A.; Reiser, O. Chem. ReV. 1999, 99, 1191–1223. (b)
Reetz, M. T.; Stanchev, S. J. Chem. Soc., Chem. Commun. 1993, 328–330.
(c) Maruoka, K.; Itoh, T.; Sakurai, M.; Nonoshita, K.; Yamamoto, H. J. Am.
Chem. Soc. 1988, 110, 3588–3597. (d) Maruoka, K.; Itoh, T.; Yamamoto,
H. J. Am. Chem. Soc. 1985, 107, 4573–4576.

5702 Organometallics, Vol. 27, No. 21, 2008
Gansäuer et al.
Table 2. Synthesis of Amide-Functionalized Titanocenes
Scheme 4. Optimized Preparation of 7 by Acylation of
Benzylamine with 6a
bases can be used to obtain the desired amides. However, we
found it very hard to remove the amine hydrochlorides formed
from the highly polar 7. Polymer-bound pyridines also gave no
satisfactory results.
The cationic structure of 7 in the solid state is shown in Figure
3 and was proven by X-ray crystallography. The Ti-O distance
(1.98 Å) is only slightly longer than in the carboxylate 4a (1.95
Å). This indicates a rather strong interaction between the amide
and the metal center. The almost perfect staggering of the
substituents of the C(sp3)-C(sp3) bond of the tether suggests
an unstrained complexation for the amides, also. This is in sharp
contrast to Erker’s cationic complex13 containing an additional
CH2 group in the tether that leads to 1,3-diaxial interactions.
The shortened amide C-N bond (1.31 Å) reflects the mesomeric
stabilization of the positive charge by the +M effect of N.
The higher stability of our cationic complexes is also reflected
by their spontaneous formation. No activation by chloride
abstraction with Meerwein’s salt is necessary, as in Erker’s
case.13 The ease of generation of our cationic titanocenes may
well be essential for applications in catalysis.
In solution complexation is apparent from the NMR spectra.
The protons of the methylene group R to the amide are
diastereotopic and appear as an AB system. The same pattern
is observed for the signal of the benzylic protons. Moreover,
1
the methyl groups are diastereotopic in the H NMR spectrum
and the 13C NMR spectrum. Without coordination of the amide
by titanium, this could not be the case.
Our reaction conditions are quite general with respect to the
alkyl groups derived from the pentafulvene, as summarized in
Table 2. Only in the case of the highly substituted 9 was a
relatively low yield of the amide observed.
Recently, organometallic compounds that contain amino acids
and peptides have attracted considerable interest as potential
drugs and for the specific labeling of functional groups.17c,20
However, titanocene-labeled amino acids and esters have
remained elusive as of yet. To the best of our knowledge, the
only related compound has been obtained by Beck via addition
of the lithiated Scho¨llkopf auxiliary to dimethylfulvene and
ensuing metalation of the cyclopentadienyllithium with
Cp*TiCl3. However, no attempts for demasking the amino acid
have been reported.17c
We therefore employed the titanocene-modified acid chlorides
5 in acylation reactions of amino acid esters. It turned out that
using the amino ester hydrochlorides with NaH directly did not
yield satisfactory results. Instead, the hydrochlorides were first
treated with a suspension of K2CO3 in CH2Cl2 to yield the free
amines. These relatively unstable compounds were readily
acylated by 6a in the presence of NaH. For the success of these
reactions, it is essential to ensure that the amino acid hydro-
chlorides are dry. Otherwise, lower yields and extensive
decomposition are observed. The conditions for the preparation
of 15-18 are shown in Scheme 5.
(20) (a) Severin, K.; Bergs, R.; Beck, W. Angew. Chem. 1998, 110,
1722-1743; Angew. Chem., Int. Ed. 1998, 37, 1635-1654. (b) van Staveren,
D. R.; Metzler-Nolte, N. Chem. ReV. 2004, 104, 5931–5985.
Figure 3. Structure of 7 in the solid state. Displacement parameters
are drawn at the 50% probability level.

Modular Synthesis of Functional Titanocenes
Organometallics, Vol. 27, No. 21, 2008 5703
Scheme 5. Conditions for the Acylation of Amino Acid Ester
Hydrochlorides
Table 3. Synthesis of Amino Acid Functionalized Titanocenes
Figure 4. Molecular structures of 15 and 17. Displacement
parameters are drawn at the 50% probability level for 15 and the
30% level for 17. In 17 the solvent CH2Cl2 is not shown for reasons
of clarity.
Under these conditions we have been able to obtain the first
examples of titanocene-functionalized amino acids, as sum-
marized in Table 3.
spectroscopic data also suggest that in the ester-functionalized
titanocene complexes the carbonyl group is not complexed by
titanium, as opposed to the case for the amides. For the
The molecular structure of 15 in the solid state is depicted in
Figure 4. As for the other amides, the carbonyl oxygen is
coordinated by titanium, resulting in the formation of a cationic
complex. The Ti-O distance (2.01 Å) and the staggering of
the substituents are very similar to the situation observed for 7.
As with 13, the diastereoselectivity of the complexation of
titanium is low for amino acids other than glycine.
Preparation of the Ester-Functionalized Titanocenes. The
optimized conditions for the preparation of the amides also
worked well for the acylation of alcohols. Some of the examples
of the synthesis of ester-substituted titanocenes are summarized
in Table 4.
As before, functional nucleophiles can be readily employed
and varying the titanocene building block did not significantly
affect the isolated yields of the products in most cases. In this
manner, the cholesterol-substituted titanocenes 22 and 23,
complex 24 (containing a fluorescence label), and the dinuclear
25 could be obtained in high yields.
1
complexes 19, 24, and 25 without asymmetric carbon, the H
NMR signal of the CH2 group R to the ester is a singlet and in
1
both the H NMR and 13C NMR spectra only one signal for
the CH3 groups is observed at the substituents on the “upper”
Cp ligand. This is not possible with a chelation of the ester. In
this case both the methylene protons and the methyl groups are
diastereotopic and, hence, two signals should be detected, as is
indeed observed for the amides. Moreover, for 20-23 and 26
with enantiomerically pure substituents only one set of signals
is obtained in both 1H NMR and 13C NMR spectra. In the case
of the cationic amide complexes 12, 13, 16, and 17 two sets of
signals were recorded, due to the relatively unselective chelation
of the carbonyl group.
Preparation of the Ketone-Functionalized Titanocenes.
Due to the high nucleophilicity of cyclopentadienyl anions,
ketone-substituted titanocenes could not be prepared by the usual
linear sequences for ligand preparation prior to metalation.
As exemplified for 26, the ester group is not nucleophilic
enough to coordinate to titanium, as shown in Figure 5. The

5704 Organometallics, Vol. 27, No. 21, 2008
Gansäuer et al.
Table 4. Synthesis of Ester-Functionalized Titanocenes
Figure 5. Molecular structure of 26. Displacement parameters are
drawn at the 50% probability level.
Scheme 6. Conditions for the Friedel-Crafts Acylation of 6
CH2Cl2, as demonstrated by the molecular structure of 29 that
is shown in Figure 6. The Ti-O distance (1.98 Å) is very similar
to those of the carboxylates and amides. Also, the same
staggering of the substituents of the tether was observed. This
suggests a complexation of the ketone that is unstrained, as in
the case of the carboxylates and amides.
The coordination of the keto group was proven spectroscopi-
cally for all complexes. The two protons of the CH2 group R to
the ketone are diastereotopic and hence appear as an AB system
1
in the H NMR spectrum. The same holds true for the CH3 or
CH2 groups at the substituents on the “upper” Cp ligand.
Our reaction conditions are relatively insensitive to the
substitution pattern of both the upper and the lower cyclopen-
tadienyl ligand. The ketones were obtained in good to high
yields.
Therefore, such compounds have as yet not been described in
the literature.12
We decided to exploit the stability of titanocenes under acidic
conditions by employing the classical Friedel-Crafts acylation
for the preparation of the desired ketones.16
The acidic reaction medium offers perspectives not available
under the basic acylation conditions used above. The Lewis acid
can abstract a chloride ligand from titanium and enforce the
formation of a cationic complex, even in the presence of poor
ketone donor ligands.
After screening of a number of reagents, it turned out that
ZnCl2 consistently gave the best yields of the desired ketone-
functionalized titanocenes. The optimized conditions for the
reactions of the acid chlorides 6 with methoxy-substituted arenes
are shown in Scheme 6, and some examples are summarized in
Table 5.
Conclusion
In summary, we have developed a highly modular approach
to the synthesis of carbonyl-substituted titanocenes that allows
the rapid preparation of large numbers of structurally and
functionally diverse complexes. The key intermediates of our
sequences are titanocenes with appended acid chlorides. The
high electrophilicity of the organic group allows reactions with
nucleophiles that are incompatible with traditional methods of
titanocene synthesis. In this manner the first examples of amino
acid functionalized titanocenes were prepared.
The amide- and ketone-functionalized titanocenes spontane-
ously form cationic complexes that are highly attractive for
applications in catalysis. The ease of this process is explained
by our crystallographic investigations, which demonstrate that
the coordination of the carbonyl groups results in the formation
of an unstrained ring without diaxial interactions.
The ketone complexes were obtained in good to high yields
as the cationic tetrachlorozincates containing one molecule of

Modular Synthesis of Functional Titanocenes
Organometallics, Vol. 27, No. 21, 2008 5705
Table 5. Synthesis of Ketone-Functionalized Titanocenes
Figure 6. Structure of one cationic titanocene unit of 29. The second
titanocene unit, [ZnCl4]2-, and CH2Cl2 are not shown for purposes
of clarity. See the Supporting Information for a complete picture.
Displacement parameters are drawn at the 50% probability level.
melting point apparatus and are uncorrected. Elemental analysis
(EA) was performed on an Elmer Vario EL instrument from Vario.
Crystal Structure Studies for 4a (GA20) and 17 (GA23).
Single-crystal X-ray diffraction studies were carried out an a Nonius
KappaCCD diffractometer at 123(2) K using Mo KR radiation (λ
) 0.710 73 Å). The structures were solved by Patterson methods
(4a) and direct methods (17) (SHELXS-9721), respectively, and
refinement were carried out using SHELXL-9721 (full-matrix least-
squares refinement on F2). The hydrogen atoms were localized by
difference electron density determination and refined using a
“riding” model (in 17 H(N) free). The absolute structure of 17 was
determined by refinement of Flack’s x parameter (x ) -0.02(5)22).
Important details of the data collection and structure solution and
refinement are given in Table 6. Crystallographic data (excluding
structure factors) for the structures reported in this work have been
deposited with the Cambridge Crystallographic Data Centre as
Supplementary Publication Nos. CCDC 690363 (4a), CCDC
691963 (4e), CCDC 691965 (5), CCDC 690364 (17), CCDC
691964 (26), and CCDC 691962 (29). Copies of the data can be
obtained free of charge on application to The Director, CCDC, 12
Union Road, Cambridge DB2 1EZ, U.K. (fax, int.code+(1223)336-
033; e-mail, deposit@ccdc.cam.ac.uk).
General Procedures for the Preparation of Titanocene Car-
boxylates (GP1). Synthesis of Fulvene 1h. Pyrrolidine (5.33 g,
75 mmol) was slowly added to a cooled solution (0 °C) of 4-tert-
butylcyclohexanone (7.71 g, 50 mmol) and cyclopentadiene (6.61
g 100 mmol) in methanol (100 mL). The solution was stirred for
4 h and then neutralized with glacial acetic acid (5 mL), poured
into brine (50 mL), extracted with cyclohexane (3 × 50 mL), and
dried over MgSO4. Removal of the solvent yielded 1h (9.91 g (49
mmol; 98%) as a yellow solid. Mp: 83-84 °C. 1H NMR (400 MHz,
CDCl3): δ 6.56-6.59 (m, 2 H), 6.30-6.34 (m, 2 H), 3.08-3.16
Experimental Section
General Procedures. All starting materials were purchased from
commercial sources and used as received unless stated otherwise.
Dichloromethane was dried prior to use over CaH2; THF was
destilled from sodium. Cyclopentadiene was freshly distilled before
use.
3
2
(m, 2 H), 2.24 (td, J(H,H) ) 13.0 Hz, J(H,H) ) 4.2 Hz, 2 H),
2.00-2.10 (m, 2 H), 1.21-1.41 (m, 3 H), 0.87 (s, 9 H). 13C NMR
(100 MHz, CDCl3): δ 158.5, 139.2, 130.9, 120.1, 48.2, 33.7, 32.7,
+
29.5, 27.7. HRMS (EI/70 eV): m/z calcd for C15H22 202.1721,
Physical Measurements and Instrumentation. 1H NMR (400
MHz) and 13C NMR (100 MHz) spectra were recorded on Bruker
DPX 300 and DPX 400 spectrometers; the chemical shifts (in ppm)
are reported relative to residual nondeuterated solvent as reference.
EI mass spectra were recorded on an MS 50 spectrometer from
Kratos as well as on a MAT 95 spectrometer from Thermoquest.
IR spectra were recorded on an ATR Nicolet 380 spectrometer from
Thermo Electron. Melting points were measured on a Bu¨chi 530
found 202.1722 [M]+. IR (KBr): ν 3070, 2950, 2860, 1640, 1620,
1465, 1440, 1360, 1085, 855, 690 cm-1. Anal. Calcd for C15H22
(202.2): C, 89.04; H, 10.96. Found: C, 88.83; H, 11.02.
Synthesis of Ligand 2h. To diisopropylamine (4.63 g, 46 mmol)
in THF (13 mL) was added at -60 °C n-BuLi (15.2 mL, 38 mmol,
(21) Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112–122.
(22) Flack, H. D. Acta Crystallogr. 1983, A39, 876–881.

5706 Organometallics, Vol. 27, No. 21, 2008
Gansäuer et al.
Table 6. Crystallographic Data and Structure Solution and Refinement Details for 4a and 17
4a
17
empirical formula
formula wt
temp (K)
cryst syst
space group
a (Å)
C15H17ClO2Ti · 0.5(toluene)
[C21H29ClNO3Ti]+[Cl]- · CH2Cl2
358.70
547.18
123(2)
monoclinic
P21/n (No. 14)
6.3068(1)
123(2)
orthorhombic
P212121 (No. 19)
11.1976(3)
b (Å)
14.3906(2)
11.3228(3)
c (Å)
18.1641(4)
21.4285(7)
R (deg)
90
90.662(1)
90
90
90
90
ꢀ (deg)
γ (deg)
V (Å3)
1648.44(5)
2716.88(14)
Z
4
4
Dcalcd (g cm-3
)
1.445
0.69
748
1.338
0.73
1136
abs coeff (mm-1
F(000)
)
cryst size (mm)
2θmax (deg)
limiting indices
0.35 × 0.25 × 0.20
0.40 × 0.25 × 0.10
55
50
-6 e h e 8, -18 e k e 18, -23 e l e 23
-10 e h e 13, -13 e k e 11, -25 e l e 24
no. of rflns collected
unique reflections
Rint
16 446
3687
0.044
12 377
4736
0.025
no. of data/restraints/params
3687/27/189
1.05
4736/1/284
1.08
GOF on F2
R1 (I > 2σ(I))
0.040
0.106
1.03/-0.60
0.062
0.185
1.19/-0.57
wR2 (all data)
largest diff map peak/hole (e Å-3
)
2.5 M in hexane). After the mixture was stirred for 1 h, tert-butyl
acetate (5.32 g, 46 mmol) was added and the mixture was stirred
for 1 h. After addition of 1h (9.26 g, 46 mmol) the mixture was
stirred at -60 °C for 16 h. The solution was washed with saturated
NH4Cl solution (2 × 10 mL) and brine (3 mL). It was dried over
MgSO4 and purified by flash chromatography (SiO2) to yield 2h
(8.94 g, 28 mmol; 61%) as a mixture of isomers forming a yellow
solid. Rf ) 0.20 (cyclohexane). Mp: 48-50 °C. 1H NMR (400 MHz,
C22H2948TiO2Cl 408.1336, found 408.1345 [M+] IR (KBr pellet):
ν 3100, 2940, 2860, 1650, 1445, 1320, 1280, 1165, 1115, 820, 690
cm-1
.
General Procedure for the Preparation of Amide-Function-
alized Titanocenes (GP2). 4f (339 mg, 1.0 mmol) was reacted
with SOCl2 (1.0 mL) for 1 h at room temperature. Excess SOCl2
was removed in vacuo for 2 h at 50 °C. The residue was dissolved
in CH2Cl2 (5 mL) and the solution transferred via syringe to a
suspension of NaH (192 mg, 8.0 mmol) and aniline (186 mg, 2.0
mmol) in CH2Cl2 (5 mL). Stirring was continued for 16 h at room
temperature. Filtration through Celite and crystallization from
CH2Cl2/pentane afforded 12 (343 mg, 76%) as red crystals. Mp:
3
3
CDCl3): δ 6.52 (dd, J(H,H) ) 5.3 Hz, J(H,H) ) 1.5 Hz, 1 H),
3
3
3
6.41 (ddd, J(H,H) ) 5.2 Hz, J(H,H) ) 1.8 Hz, J(H,H) ) 1.8
3
3
Hz, 1 H), 6.29 (dd, J(H,H) ) 5.4 Hz, J(H,H) ) 1.3 Hz, 1 H),
6.22 (dd, 3J(H,H) ) 2.0 Hz, 3J(H,H) ) 1.1 Hz, 1H), 6.08 (dd,
3J(H,H) ) 1.8 Hz, 3J(H,H) ) 1.8 Hz, 1H), 2.97 (d, 3J(H,H) ) 1.5
1
221 °C. H NMR (500 MHz, DMSO-d6): δ 13.15 (m, 1 H), 7.56
3
3
3
3
Hz, 2 H), 2.88 (d, J(H,H) ) 1.4 Hz, 2H), 2.19-2.28 (m, 2 H),
(d, J(H,H) ) 7.9 Hz, 2 H), 7.47 (dd, J(H,H) ) 7.9 Hz, J(H,H)
3
2.22 (s, 2 H), 2.21 (s, 2H), 1.52-1.58 (m, 2 H), 1.37-1.48 (m, 2
H), 1.31 (s, 9 H), 1.29 (s, 9H), 1.03-1.16 (m, 2H), 1.00 (t, 3J(H,H)
) 2.8 Hz, 1 H), 0.97 (t, 3J(H,H) ) 2.7 Hz, 1H), 0.77 (s, 9H), 0.76
(s, 9 H). 13C NMR (100 MHz, CDCl3): δ 171.0, 170.9, 151.6, 149.7,
133.2, 132.0, 132.9, 131.2, 129.1, 127.8, 79.8, 52.3, 50.7, 48.5,
48.4, 40.2, 38.9, 37.5, 36.6, 32.5, 28.1, 27.7, 23.6. HRMS (EI/70
eV): m/z calcd for C21H34O2 318.2559, found 318.2557 [M]+. IR
(KBr): ν 2965, 1715, 1475, 1390, 1360, 1250, 1110, 985, 860, 680
cm-1. Anal. Calcd for C21H34O2 (318.5): C, 79.19; H, 10.76. Found:
C, 78.80; H, 10.52.
) 7.9 Hz, 2 H), 7.45 (m, 1 H), 7.33 (t, J(H,H) ) 7.4 Hz, 1 H),
7.13 (m, 1 H), 6.78 (s, 5 H), 6.73 (m, 1 H), 6.20 (m, 1 H), 3.34 (d,
2J(H,H) ) 14.2 Hz, 1 H), 2.63 (d, 2J(H,H) ) 14.2 Hz, 1 H),
1.49-1.92 (m, 8 H). 13C NMR (125 MHz, DMSO-d6): δ 175.1,
149.5, 135.2, 129.2, 127.1, 123.6, 123.5, 121.7, 121.6, 116.8, 111.0,
45.4, 45.2, 35.3, 22.8. HRMS (EI, 70 eV): m/z calcd for
C23H24ClNO46Ti 411.1067, found 411.1066 [M - HCl]+. IR
(ATR): ν 2725, 1625, 1605, 1570, 1495, 1440, 1375, 990, 825,
765, 690 cm-1
.
General Procedure for the Preparation of Amino Acid
Functionalized Titanocenes (GP3). A suspension of glycine
methyl ester hydrochloride (315 mg, 2.5 mmol) and K2CO3 (483
mg, 3.5 mmol) in CH2Cl2 (10 mL) was stirred for 16 h at room
temperature. NaH (300 mg, 12.5 mmol) was added, and stirring
was continued at room temperature for 1 h. 4g (883 mg, 2.5 mmol)
was reacted with SOCl2 (3 mL) for 1 h at room temperature. Excess
of SOCl2 was removed in vacuo for 2 h at 50 °C. The residue was
dissolved in CH2Cl2 (10 mL) and transferred via syringe to the
reaction mixture. Stirring was continued for 16 h at room temper-
ature. Filtration through Celite and recyrstallization from CH2Cl2/
toluene afforded 16 (779 mg, 68%) as red crystals. Mp: 228 °C
dec. 1H NMR (400 MHz, CDCl3): δ 12.42 (dd, 3J(H,H) ) 5.1 Hz,
1 H), 7.21 7.17 (m, 1 H), 7.08 (br s, 1 H), 6.66 (s, 5 H), 6.57 (br
s, 1 H), 6.10 (br s, 1 H), 3.96 (d, 3J(H,H) ) 5.7 Hz, 2 H), 3.72 (s,
Synthesis of Carboxylate 4h. To a solution of 2h (4.37 g, 15
mmol) in THF (24 mL) was added at -78 °C n-BuLi (8.8 mL, 13
mmol, 2.5 M in hexane), and the mixture was stirred for 2 h. Then
CpTiCl3 (2.75 g, 13 mmol) in THF (62 mL) at -40 °C was added
and the mixture was stirred 16 h at room temperature. Washing
with MTBE yields 4h (3.85 g, 9 mmol) as a red solid. Mp: >235
1
3
°C. H NMR (400 MHz, CDCl3): δ 6.74 (dd, J(H,H) ) 5.0 Hz,
3
3
3J(H,H) ) 3.1 Hz, 1 H), 6.66 (dd, J(H,H) ) 5.0 Hz, J(H,H) )
3
3
2.6 Hz, 1 H), 6.51 (s, 5 H), 6.05 (dd, J(H,H) ) 3.0 Hz, J(H,H)
3
) 2.8 Hz, 2H, H-4), 2.65 (d, J(H,H) ) 12.2 Hz, 1H), 2.26 (ddd,
3J(H,H) ) 13.8 Hz, J(H,H) ) 5.6 Hz, J(H,H) ) 2.8 Hz, 1H),
3
3
2.12 (d, J(H,H) ) 12.2 Hz, 1 H), 2.02 (ddd,3J(H,H) ) 13.8 Hz,
3
3J(H,H) ) 6.1 Hz, J(H,H) ) 2.9 Hz, 1 H), 1.44-1.66 (m, 3 H),
3
0.87-1.05 (m, 4 H), 0.75 (s, 9 H). 13C NMR (100 MHz, CDCl3):
δ 175.6, 145.0, 127.8, 119.5, 116.8, 114.5, 109.5, 53.2, 47.6, 38.7,
38.4, 37.4, 32.4, 27.5, 23.4, 23.3. HRMS (EI/70 eV): m/z calcd for
2
2
3 H), 3.39 (d, J(H,H) ) 13.5 Hz, 1 H), 2.82 (d, J(H,H) ) 13.5
Hz, 1 H), 1.98-1.85 (m, 2 H), 1.80-1.63 (m, 3 H), 1.60-1.49

Modular Synthesis of Functional Titanocenes
Organometallics, Vol. 27, No. 21, 2008 5707
(m, 1 H), 1.44-1.31 (br s, 3 H), 1.20-1.07 (br s, 1 H). 13C NMR
(100 MHz, CDCl3): δ 178.3, 167.9, 150.3, 125.6, 121.9, 121.4,
115.8, 111.4, 52.8, 46.6, 42.4, 38.7, 38.5, 34.1, 25.3, 22.2, 21.8.
HRMS (ESI, MeOH, 10 eV): m/z calcd for C22H30NO448Ti
420.1651, found 420.1651 [M - 2Cl + OMe]+. IR (ATR): ν 2925,
in CH2Cl2 (5 mL) and the solution transferred via syringe to a
suspension of ZnCl2 (680 mg, 5 mmol) and 1,2,4-trimethoxybenzene
(840 mg, 5 mmol). After the mixture was stirred overnight, the
solvent was evaporated and 29 (1.44 g, 2.1 mmol) was isolated by
crystallization from CH2Cl2/c-C6H12 as a red solid (49%). Mp: 165
°C dec. 1H NMR (400 MHz, CDCl3): δ 6.89-6.92 (m, 2H),
6.47-6.49 (m, 1H), 6.37 (s, 5H), 6.18-6.21 (m, 1H), 6.15-6.17
(m, 1H), 5.71-5.74 (m, 1H), 4.07-4.09 (m, 1H), 4.04-4.06 (m,
1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.83 (s, 3H), 1.38 (s, 3H), 1.29 (s,
3H). 13C NMR (100 MHz, DMSO): δ 207.6, 162.7, 161.5, 157.9,
150.3, 148.5, 121.9, 119.8, 117.1, 113.0, 111.8, 109.7, 98.1, 57.8,
57.5, 56.3, 55.3, 35.3, 34.1, 33.1. MS (ESI/10 eV/MeOH): m/z (%)
459 (M+ - Cl + OMe, 100), 445 (2), 427 (9), 353 (2). HRMS
(ESI/10 eV/MeOH): m/z calcd for C25H31O548Ti+. 459.1648, found
459.1645 [M+ - Cl- + OMe]. IR (KBr pellet): ν 3080, 2960,
2850, 1740, 1605, 1555, 1440, 1410, 1365, 1200, 825 cm-1
.
General Procedure for the Preparation of Ester-Function-
alized Titanocenes (GP4). 4a (313 mg, 1.0 mmol) was reacted
with SOCl2 (1.0 mL) for 1 h at room temperature. Excess SOCl2
was removed in vacuo for 2 h at 50 °C. The residue was dissolved
in CH2Cl2 (5 mL) and the solution transferred via syringe to a
suspension of NaH (120 mg, 5.0 mmol) and 1-octanol (130 mg,
1.0 mmol) in CH2Cl2 (5 mL). Stirring was continued for 16 h at
room temperature. Filtration through Celite and recrystallization
from CH2Cl2/pentane afforded 19 (382 mg, 83%) as red crystals.
Mp: 119 °C. 1H NMR (500 MHz, CD2Cl2): δ 6.60 (dd, 3J(H,H) )
1620, 1560, 1485, 1380, 1265, 1220, 1015, 840, 730 cm-1
.
4
3
2.7, J(H,H) ) 2.7 Hz, 2 H), 6.56 (s, 5 H), 6.48 (dd, J(H,H) )
2.7, 4J(H,H) ) 2.7 Hz, 2 H), 3.95 (t, 3J(H,H) ) 6.9 Hz, 2 H), 2.59
(s, 2 H), 1.55 (tt, 3J(H,H) ) 6.9, 3J(H,H) ) 6.9 Hz, 2 H), 1.25-1.34
(m, 10 H), 1.46 (s, 6 H), 0.90 (t, 3J(H,H) ) 6.9 Hz, 3 H). 13C
NMR (125 MHz, CD2Cl2): δ 171.5, 147.0, 120.8, 120.7, 117.7,
64.7, 49.1, 37.0, 32.2, 29.6, 29.0, 27.9, 26.3, 23.0, 14.3. HRMS
(EI, 70 eV): m/z calcd for C23H34ClO246Ti 423.1774, found
423.1758 [M - Cl]+. IR (film): ν 3100, 2960, 1710, 1450, 1330,
Acknowledgment. We are indebted to the SFB 624
(”Template-Vom Design chemischer Schablonen zur Reak-
tionssteuerung”) for continuing financial support. We thank
Drs. G. Schnakenburg and J. Daniels for measuring the
structures of 4e, 5, 26, and 29.
Supporting Information Available: Text and figures giving
details of the syntheses and characterization data for all compounds
prepared in this paper. This material is available free of charge via
the Internet at http://pubs.acs.org.
1220, 1110, 860 cm-1
.
General Procedure for the Preparation of Ketone-Function-
alized Titanocenes (GP5). 4a (313 mg, 1.0 mmol) was reacted
with SOCl2 (1.0 mL) for 1 h at room temperature. Excess SOCl2
was removed in vacuo for 2 h at 50 °C. The residue was dissolved
OM800700C