A modular and efficient synthesis of functional titanocenes

Article abstract of DOI:10.1021/ja054185r

A modular synthesis of functional titanocenes featuring building blocks is described. The approach allows straightforward access to large numbers of structurally diverse titanocenes that are pertinent for catalysis, structural studies, and bioinorganic chemistry. Among the functional groups introduced are amino acids, sugars, and fluorescence labels that are attached to the cyclopentadienyl ligand as esters and amides. Copyright

Full text of DOI:10.1021/ja054185r

Published on Web 07/30/2005
A Modular and Efficient Synthesis of Functional Titanocenes
Andreas Gansa¨uer,* Dieter Franke, Thorsten Lauterbach, and Martin Nieger
Kekule´-Institut fu¨r Organische Chemie und Biochemie und Institut fu¨r Anorganische Chemie der UniVersita¨t Bonn,
Gerhard Domagk Strasse 1, 53121 Bonn, Germany
Received June 24, 2005; E-mail: andreas.gansaeuer@uni-bonn.de
Group 4 metallocenes and titanocenes, in particular, continue to
be of substantial importance in their own right1 as efficient reagents
and catalysts2 and as a promising class of antitumor agents.3
Currently, synthetic interest in these compounds concentrates on
the incorporation of polar functional groups into the cyclopenta-
dienyl ligands, especially for cytotoxicity studies.4
However, access to these functional complexes that are also
important as catalysts is noticeably limited by the linear synthetic
Figure 2. Optimized conditions for the synthesis of 4a.
sequences employed for their preparation.5 Because the TiCl2
fragment is rather electrophilic, polar nucleophilic groups have to
be introduced at the ligand preparation stage before metalation.6
This can be disadvantageous as the presence of protic functional
groups is excluded, for example.
Table 1. Acylation Reactions of Titanocene Building Blocks 3a-c
with Amines (see Supporting Information for experimental and
structural details)
Modular routes offer more general synthetic perspectives. This
is especially so for approaches featuring building blocks containing
a [TiCl2] moiety for the rapid preparation of large numbers of
complexes. However, such sequences have remained elusive, as
yet.5
Here, we address exactly these issues by reporting such a
titanocene synthesis. To employ the planned building blocks, it is
mandatory that they contain functional groups more reactive toward
nucleophiles than the TiCl2 fragment. To this end, we decided to
attach highly electrophilic carboxylic acid chlorides to the titanocene
framework for the first time. Our concept for the synthesis of the
novel titanocene building blocks is outlined in Figure 1.
Figure 1. Synthesis of the titanocene building blocks 3a-3c: a, RdCH3,
Cp′ ) Cp; b, R)(CH2)5, Cp′ ) Cp; c, RdCH3, Cp′ ) Me5Cp). For the
preparation of 1a,b, see Supporting Information.
We exploited the high stability of titanocenes toward acidic
reaction conditions by treating 2a with SOCl2. Acid chloride 3a
was formed quantitatively and used without further purification.
Similar yields were obtained for the other building blocks, 3b and
3c, investigated in this study. Complex 2a was obtained from 1a
in 64% yield over two steps by metalation and ester cleavage in
20 g batches. Thus, our strategy allows the straightforward
preparation of structurally diverse and highly reactive titanocene
building blocks on a large scale.
NaH constituted the best base as the byproducts are either volatile
(H2) or removed by filtration (NaCl). Amines were inadequate. The
hydrochlorides could not be removed from 4.
As summarized in Table 1, our optimized conditions proved to
be general in the preparation of amides from primary, secondary,
benzylic, and aromatic amines in high yields, amply demonstrating
the power of our modular approach.6 These compounds are cationic
through complexation of titanium by the carbonyl group in solution.
At present, the mechanistic details of the cation formation remain
unresolved. Compounds 4a, 4b, 5, and 8 have been characterized
by X-ray crystallography and display this behavior in the solid state
also, as shown for 8 in Figure 3.
We then turned our attention to the introduction of the pivotal
functional groups. The optimized conditions for the acylation of
3a with benzylamine to yield 4a are shown in Figure 2.
9
11622
J. AM. CHEM. SOC. 2005, 127, 11622-11623
10.1021/ja054185r CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
DNA intercalation studies. The high yielding preparation of
dinuclear 9 also highlights the potential of our strategy. This
otherwise difficult to prepare compound is pertinent for linking
biomolecules and as a catalyst in reductive epoxide openings.10
Gratifyingly, 3b and 3c gave similar yields in the preparation of
4b and 4c from benzylamine as 3a. This amply demonstrates the
value of our approach for a modular synthesis as steric effects do
not markedly affect the performance of the acylation reaction.
As shown in Table 2, alcohols also proved to be excellent
nucleophiles in acylation reactions. The examples demonstrate that
a galactose derivative and cholesterol can be attached to the
metallocene fragments in high to excellent yields to deliver the
desired 11 and 12a-12c. As before, varying the titanocene building
block 3a, 3b, and 3c did not result in a substantial variation of the
yields in the acylation reaction. In CH2Cl2, 3a constitutes one of
the rare examples of an organometallic gelator.11 Complex 14
containing a fluorescence label and a DNA intercalating group was
obtained in good yield and the dimeric 13 in almost quantitative
yield. In contrast to the amides, all ester-substituted titanocenes
were not cationic, as judged by their NMR spectra, and distinctly
more soluble in organic solvents.
Figure 3. Molecular structure of 8 in the solid state.
Table 2. Acylation Reactions of Titanocene Building Blocks 3a-c
with Alcohols (for experimental details and compound
characterization, see Supporting Information)
In summary, we have demonstrated that functional titanocene
complexes, relevant to applications in catalysis, bioinorganic, and
medicinal chemistry, can be accessed quickly and in large numbers
by a modular approach featuring novel titanocene building blocks.
It has become clear that titanocenes are quite tolerant to polar
functional groups that can additionally promote the formation of
cationic intermediates and even stabilize them.
Acknowledgment. We are indebted to the SFB 624 Template-
Vom Design chemischer Schablonen zur Reaktionssteuerung for
generous financial support.
Supporting Information Available: Experimental procedures,
spectral, and crystal structure details. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
(1) Metallocenes; Togni, A., Halterman, R. L., Eds.; Wiley-VCH: Weinheim,
Germany, 1998; Vols. 1-2.
(2) Titanium and Zirconium in Organic Synthesis; Marek, I., Ed.; Wiley-
VCH: Weinheim, Germany, 2002.
(3) (a) Ko¨pf-Maier, P.; Ko¨pf, H. Chem. ReV. 1987, 87, 1137-1152. (b) Clarke,
M. J.; Zhu, F.; Frasca, D. R. Chem. ReV. 1999, 99, 2511-2534. (c)
Harding, M. M.; Moksdi, G. Curr. Med. Chem. 2000, 7, 1289-1303.
(4) For some recent examples, see: (a) Alle, O. R.; Croll, L.; Gott, A. L.;
Knox, R. J.; McGowan, P. C. Organometallics 2004, 23, 288-292. (b)
Tacke, M.; Allen, L. T.; Cuffe, L.; Gallagher, W. M.; Lou, Y.; Mendoza,
O.; Mu¨ller-Bunz, H.; Rehmann, F.-J. K.; Sweeney, N. J. Organomet.
Chem. 2004, 689, 2242-2249. (c) Causey, P. W.; Baird, M. C.; Cole, S.
P. C. Organometallics 2004, 23, 4486-4494.
These results are in sharp contrast to the only other cationic
titanocene complex that contains an amide, albeit without an N-H
bond. This complex had to be prepared by the action of a Lewis
acid or a Meerwein salt to replace chloride by noncoordinating
anions, such as tetrafluoroborate.7 In our case, the presence of the
strong hydrogen bond between the amide proton and chloride (Cl2)
provides extra stabilization of chloride lacking in the case above.8
Such stabilization of cationic intermediates has been postulated to
be essential for biological activity.4
Our approach proved powerful in the preparation of functional
titanocenes with groups that have not been attached covalently to
the metallocene before. Complex 8 constitutes the first example of
a titanocene containing a covalently attached natural amino acid
and opens the field for peptide-modified titanocenes. Metallocenes
of this type have recently attracted considerable interest in bio-
organometallic and medicinal chemistry.9 Compound 10 with the
fluorescence label 1-aminopyrene is valuable for identifying the
binding sites of titanocenes to biomolecules in cytotoxicity and
(5) Such strategies are absent in the most recent review on the synthesis of
titanocenes: Qian, Y.; Huang, J.; Bala, M. D.; Lian, B.; Zhang, H.; Zhang,
H. Chem. ReV. 2003, 103, 2633-2690.
(6) (a) Siemeling, U. Chem. ReV. 2000, 100, 1495-1526. (b) Butenscho¨n,
H. Chem. ReV. 2000, 100, 1527-1564. (c) Jutzi, P.; Redeker, T. Eur. J.
Inorg. Chem. 1998, 663-674.
(7) Oberhoff, M.; Duda, L.; Karl, J.; Mohr, R.; Erker, G.; Fro¨hlich, R.; Grehl,
M. Organometallics 1996, 15, 4005-4011.
(8) Steiner, T. Angew. Chem., Int. Ed. 2002, 41, 48-76.
(9) (a) van Staveren, D. R.; Metzler-Nolte, N. Chem. ReV. 2004, 104, 5931-
5985. (b) Dialer, H.; Polborn, K.; Ponikwar, W.; Su¨nkel, K.; Beck, W.
Chem.sEur. J. 2002, 8, 691-699.
(10) (a) Gansa¨uer, A.; Bluhm, H. Chem. ReV. 2000, 100, 2771-2788. (b)
Gansa¨uer, A.; Lauterbach, T.; Narayan, S. Angew. Chem., Int. Ed. 2003,
42, 5556-5573.
(11) Bu¨hler, G.; Feiters, M. C.; Nolte, R. J. M.; Do¨tz, K.-H. Angew. Chem.,
Int. Ed. 2003, 42, 2494-2497.
JA054185R
9
J. AM. CHEM. SOC. VOL. 127, NO. 33, 2005 11623