Synthesis of stable functional titanocene enolates

Article abstract of DOI:10.1021/om100245r

A modular approach to bench-stable titanocene enolates is described. The reaction of titanocenes containing pendent acid chlorides with activated methylene compounds in the presence of excess base results in the formation of the pivotal enolates. In all cases, the enolates are coordinated to the titanocene, which acts as a stabilizing template in an intramolecular manner, as demonstrated by NMR spectroscopy and X-ray crystallography. Upon protonation with strong acids, the C-C bond formed during the acylation is cleaved. Hence, the template effect can be reversed by adjusting the acidity of the reaction medium.

Full text of DOI:10.1021/om100245r

Organometallics 2010, 29, 3227–3230 3227
DOI: 10.1021/om100245r
Synthesis of Stable Functional Titanocene Enolates§
,†
Andreas Gansauer,* Andreas Okkel, Dennis Worgull, and Gregor Schnakenburg
†
†
‡
€
†
ꢀ
€
€
Kekule-Institut fur Organische Chemie und Biochemie der Universitat Bonn, Gerhard Domagk Strasse 1,
53121 Bonn, Germany, and ‡Institut fu€r Anorganische Chemie der Universita€t Bonn, Gerhard Domagk
Strasse 2, 53121 Bonn, Germany
Received March 30, 2010
Summary: A modular approach to bench-stable titanocene
enolates is described. The reaction of titanocenes containing
pendent acid chlorides with activated methylene compounds in
the presence of excess base results in the formation of the pivotal
enolates. In all cases, the enolates are coordinated to the titanocene,
which acts as a stabilizing template in an intramolecular manner,
as demonstrated by NMR spectroscopy and X-ray crystallo-
graphy. Upon protonation with strong acids, the C-C bond
formed during the acylation is cleaved. Hence, the template effect
can be reversed by adjusting the acidity of the reaction medium.
aggregates and nanostructures by organometallic gelators.2
Moreover, cationic amide-substituted titanocenes have emerged
as novel reagents in catalytic3 electron transfer reactions4 with
epoxides. In this manner, thermodynamically and kinetically
difficult radical 4-exo cyclizations5 that are impossible to realize
with traditional alkyl-substituted titanocenes6 that operate via a
passive occupation of space7 could be accomplished. These
particular catalysts are also highly attractive for other purposes
in reagent-controlled radical chemistry, such as stereoselective
radical generation8 and the control of diastereoselectivity
of C-C bond forming processes such as intermolecular addi-
tions7,8c to activated olefins or radical cyclizations.9
Introduction
The common feature of the use of the functionalized
titanocenes is the proper adjusting of the intermolecular
interactions between the titanocene’s functional groups, its
metal center, and its binding partners, such as enzymes or
receptors in medicinal chemistry,1 the solvent and other
molecules of the gelator in the formation of gels,2 and
organic substrates in catalysis.5 Another interesting aspect
of the chemistry of the functionalized titanocenes, which has,
as yet, not been exploited, is constituted by the intramole-
cular stabilization of reaction products or reactive inter-
mediates by intramolecular coordination of these species to
Due to their ability to bind and recognize other molecular
entities, cationic and neutral titanocenes with pendent polar
functional groups have attracted attention in a number of
topical fields. These include the treatment of cancer in medicinal
chemistry by titanocenes1 and the assembly of supramolecular
§ Dedicated to Prof. Uwe Rosenthal on the occasion of his 60th birthday.
*To whom correspondence should be addressed. E-mail: andreas.
gansaeuer@uni-bonn.de.
€
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2010 American Chemical Society
Published on Web 06/24/2010
pubs.acs.org/Organometallics

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Gansauer et al.
3228 Organometallics, Vol. 29, No. 14, 2010
Scheme 1. Synthetic Approach to the Synthesis of Enolates Templated by Titanocenes
the titanium in a template manner. To this end, enolates
constitute an attractive class of intermediates because of
their undisputed utility in synthetic applications and because
of the well-documented influence of the counterion on their
stability and reactivity. In this note, we describe our first
results in this area.
Second, the two ester and the two nitrile groups can in
principle be utilized for further functionalization such as
complexation of other metal complexes. Third, upon in situ
deprotonation of the acidic tricarbonyl compounds formed
as intermediates, the desired titanocene-templated enolates
can be obtained directly.
Gratifyingly, with 1a and di-tert-butyl malonate as enolate
precursor, the desired product 3 could be obtained in 66% yield.
Choosing appropriate conditions for the purification are crucial.
Results and Discussion
Our synthetic approach to the synthesis of the titanocene-
templated enolates is highlighted in Scheme 1. It is based on
the use of the titanocene-containing acid chlorides 2 that are
readily accessible in gram quantities from the titanocene
carboxylates 1 via our recently developed modular titano-
cene synthesis.10 Our approach of functionalizing the cyclo-
pentadienyl ligands after metalation is especially attractive
here because the ester and especially the ketone groups of the
desired products are not stable to the strongly nucleophilic
cyclopentadienyl anion. Therefore, they cannot be intro-
duced to the ligand before metalation because of the high
nucleophilicity of cyclopentadienyl anions.11
Our synthesis relies critically on the reactions of acid
chlorides with C-nucleophiles to yield ketones. As enolate
precursors, activated methylene compounds, such as mal-
onates or malonodinitriles, are especially attractive for three
reasons. First, enolate generation can simply be carried out
with NaH as base. Thus, the only byproduct of the acylation
will be NaCl, which is easy to remove by a simple filtration.
Gel permeation chromatography on BioBeads, as introduced
ꢀ
1l
for the purification of cationic titanocenes by Melendez, with
CH2Cl2 as eluent proved to be the method of choice for the
removal of residual 1a. Crystallization of the crude reaction also
provides clean 3, albeit in substantially reduced yields. The 1H
and 13C NMR spectra prove the complexation of the enolate
oxygen to titanium. The CH3 groups of the gem-dimethyl group
are observed as two signals in the 1H and13C NMR spectra. The
two protons of the methylene group attached to the gem-
dimethyl group are diastereotopic and hence appear as an AB
1
system in the H NMR spectrum. Further examples for the
preparation of these enolates are summarized in Table 1.
The desired products were obtained in 54% to almost quan-
titative yields as red solids that are stable under ambient condi-
tions for several days. The coordination of titanium by the eno-
late oxygen results in spectra similar to 3 for all titanocene
enolates prepared here. For 9 this complexation was addition-
ally confirmed by an X-ray structural analysis (Figure 1).
˚
The Ti-O bond length (1.91 A) is in the typical range of
Ti-O bonds.12 The length of the enolate double bond (1.35 A) is
˚
also typical for a C-C double bond. It should be noted that only
the ester group (E) to the enolate oxygen is in conjugation with
the enolate (dihedral angle = 179°), whereas the second ester
group is oriented almost perpendicular (97°) to the olefin and
hence does not participate in the stabilization of the enolate. The
almost perfect staggering of the substituents of the C(sp3)-
C(sp3) bond of the tether in 9 and the dihedral angle (C13-
C12-C6-C7) of 172.65°, which is close to 180°, suggest
strongly that the titanium-containing ring is unstrained.
In principle, the two ester groups and especially the two
nitrile groups are ideally positioned to interact with other
metals or metal complexes to form bi- or even polymetallic
complexes. This issue will be further pursued.
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(11) (a) Butenschon, H. Chem. Rev. 2000, 100, 1527–1564. (b) Qian, Y.;
(12) (a) Benzoates: Hoffman, D. M.; Chester, N. D.; Fay, R. C.
Organometallics 1983, 2, 48–52. (b) Alkoxides: Berno, P.; Floriani, C.;
Chiesi-Villa, A.; Guastini, C. Organometallics 1990, 9, 1995–1997. (c)
Enolates: Hortmann, K.; Diebold, J.; Brintzinger, H. H. J. Organomet.
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Note
Table 1. Synthesis of the Enolates 4-13 (yield over two steps)
Organometallics, Vol. 29, No. 14, 2010 3229
Figure 1. Molecular structure of 9. Displacement parameters
are drawn at the 50% probability level. Hydrogen atoms are
omitted for reasons of clarity.
Scheme 2. Activation of 7 by the Titanocene Template under
Protic Conditions
This changes upon addition of concentrated HCl to the NMR
solvent. After 48 h the enolate 7was consumed and the carboxy-
late 1b had formed quantitatively. We attribute this C-C bond
cleavage to a template activation of the ketone 14 formed upon
protonation (Scheme 2). Complexation of the carbonyl group
by the Lewis acidic cationic titanocene leads to a strong activa-
tion toward addition of the weakly nucleophilic H2O. After
formation of the hydrate 15, di-tert-butyl malonate and car-
boxylate 1b are formed by C-C bond cleavage and proton
transfer. Thus, depending on the acidity or basicity of the
reaction medium, the titanocene template can either activate
the carbonyl group toward nucleophilic addition or stabilize its
corresponding enolate by complexation.
Summary
The intramolecular binding of the enolate by the titanium
thus provides a unique stabilization of the reactive inter-
mediate that even allows a chromatographic purification.
We decided to probe the relevance of this template effect
by exposing the enolates to water and acid. Compound 6 was
dissolved in D8-THF and H2O (0.5 -1.0 equiv) and com-
pound 7 in CD2Cl2 and H2O. The 1H NMR spectra revealed
no decomposition of 6 and 7 to 1b over 72 h in these solvents.
In summary, we have devised a synthetic approach to
bench-stable functionalized titanocene enolates that criti-
cally relies on a modification of the titanocenes after meta-
lation. The enolate oxygen is complexed by a titanium
template to achieve an arrangement of the substituents of
the cyclopentadienyl ligands that displays minimal steric
interactions. Upon protonation of the enolate to the ketone,
the titanocene template strongly activates the carbonyl

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Gansauer et al.
3230 Organometallics, Vol. 29, No. 14, 2010
group toward addition of H2O, which results in the cleavage
of the C-C bond formed under basic conditions.
for 2 h at 50 °C. The acid chloride was dissolved in THF (10 mL)
and transferred via syringe to a suspension of NaH (100 mg, 2.5
mmol, 60% dispersion in mineral oil) and malononitrile (37.0 mg,
0.550 mmol, 1.10 equiv) in THF (10 mL). Stirring was continued
for 16 h at rt. After filtration through Celite the solvent was
removed under reduced pressure. The residue was chromato-
graphed on Bio Beads S-X3 to yield enolate 5 (108 mg, 60%) as a
red solid: mp 66-70 °C; 1H NMR (400 MHz, CDCl3) δ 6.93 (ddd,
3JHH =3.0Hz, 3JHH =3.0Hz, 4JHH = 2.1 Hz, 1H), 6.66-6.63 (m,
1H), 6.62 (s, 5H), 5.93-5.88 (m, 2H), 2.83 (d, 2JH,H = 14.9 Hz,
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 distilled from sodium. Cyclopentadiene was freshly
distilled before use.
1H), 2.77 (d, 2JH,H = 14.9 Hz, 1H), 1.36 (s, 3H), 1.16 (s, 3H); 13
C
1
Physical Measurements and Instrumentation. H NMR and
13C NMR spectra were recorded on a DPX 300 and a DPX 400
Bruker spectrometer; chemical shifts (in ppm) are reported
relative to nondeuterated solvent residual as reference. EI mass
spectra were recorded on a MS 50 spectrometer from Kratos as
well as on a MAT 95 spectrometer from Thermoquest. IR
spectra were recorded on a MAT 95 XL spectrometer from
Thermo Finnigan, and ESI mass spectra were recorded on a
micrOTOF-Q spectrometer from Bruker Daltonik. IR spectra
were recorded on an ATR Nicolet 380 spectrometer from
NMR (75 MHz, CDCl3) δ 191.3, 146.7, 126.6, 120.7, 116.2, 116.2,
115.4, 114.2, 107.4, 62.3, 46.4, 34.3, 29.8, 27.0; HRMS (ESI, 10 eV)
m/z calcd for C18H17N2O48Tiþ 325.0816, found 325.0807 [M -
Cl]þ; IR ATR, ν [cm-1] 2920, 2850, 2220, 2205, 1505, 1430, 1385,
1235, 1025, 1015, 820, 615.
Synthesis of 9: 1c (177 mg, 0.500 mmol) was reacted with
SOCl2 (0.2 mL) in CH2Cl2 (5 mL) for 2.5 h at rt. Excess SOCl2
was removed in vacuo for 2 h at 70 °C. The acid chloride was
dissolved in THF (10 mL) and transferred via syringe to a
suspension of NaH (50 mg, 1.25 mmol, 60% dispersion in
mineral oil) and diethyl malonate (110 mg, 0.688 mmol, 1.38
equiv) in THF (10 mL). Stirring was continued for 16 h at rt.
After filtration through Celite the solvent was removed under
reduced pressure. Recrystallization (CH2Cl2/cyclohexane)
yielded enolate 9 (192 mg, 78%) as a red solid: mp 220 °C
(dec); 1H NMR (400 MHz, CDCl3) δ 6.66 (td, 3JH,H = 3.0 Hz,
4JH,H = 2.1 Hz, 1H), 6.54-6.50 (m, 1H), 6.41 (s, 5H), 5.94 (td,
3JH,H = 3.1 Hz, 4JH,H = 2.3 Hz, 1H), 5.89 (dt, 3JH,H = 2.8 Hz,
4JH,H = 2.5 Hz, 1H), 4.32-4.09 (m, 4H), 3.16 (d, 2JH,H = 13.7
€
Thermo Electron. Melting points were measured on a Buchi
530 melting point apparatus and are uncorrected.
Synthesis of Titanocene Enolates 3, 5, and 9. Synthesis of 3: 1a
(156 mg, 0.500 mmol) was reacted with SOCl2 (1.5 mL) for 2 h at
rt. Excess SOCl2 was removed in vacuo for 2 h at 50 °C. The acid
chloride was dissolved in THF (10 mL) and transferred via syringe
to a suspension of NaH (60 mg, 1.5 mmol, 60% dispersion in
mineral oil) and di-tert-butyl malonate (151.4 mg, 0.70 mmol, 1.40
equiv) in THF (10 mL). Stirring was continued for 16 h at rt. After
filtration through Celite the solvent was removed under reduced
pressure. The residue was chromatographed on Bio Beads S-X3 to
yield enolate 3 (168.6 mg, 66%) as a red solid: mp 77-78 °C (dec);
2
Hz, 1H), 3.07 (d, JH,H = 13.6 Hz, 1H), 1.97-1.36 (m, 10H),
1.33 (t, 3JH,H = 7.1 Hz, 3H), 1.25 (t, 3JH,H = 7.2 Hz, 3H); 13
C
1H NMR (400 MHz, CDCl3) δ 6.56 (ddd, 3JHH=3.1 Hz, 3JHH
=
NMR (75 MHz, CDCl3) δ 177.3, 167.6, 166.0, 145.5, 125.7,
118.7, 115.5, 114.7, 108.1, 103.9, 60.6, 59.8, 43.9, 38.1, 36.7,
26.9, 25.8, 22.1, 22.0, 14.3, 14.3; HRMS (ESI, 10 eV) m/z
calcd. for C25H31O548Tiþ 459.1648, found 459.1646 [M - HCl
- C2H5]þ; IR ATR, ν [cm-1] 3105, 2930, 2855, 1650, 1555, 1445,
1315, 1270, 1200, 1170, 1090, 1045, 955, 825, 470. Anal.
Calcd for C25H31ClO5Ti (494.83) C, 60.68; H, 6.31. Found: C,
60.60; H, 6.68.
3.0 Hz, 4JHH = 2.3 Hz, 1H), 6.45 (s, 5H), 6.38 (ddd, 3JHH = 3.0 Hz,
4JHH=2.3 Hz, 4JHH=2.3 Hz, 1H), 5.98 (ddd, 3JHH=3.1 Hz, 3JHH
3.1 Hz, 4JHH=2.5 Hz, 1H), 5.94 (ddd, 3JHH=2.5 Hz, 4JHH=2.5 Hz,
4JHH=2.5 Hz, 1H), 3.22 (d, 2JHH=15.0 Hz, 1H), 2.87 (d, 2JHH
15.0Hz, 1H), 1.54(s, 9H), 1.47(s, 9H), 1.30(s, 3H), 1.16(s, 3H);13
=
=
C
NMR (100 MHz, CDCl3) δ 175.3, 166.9, 166.1, 146.3, 122.5, 118.7,
117.9, 114.4, 106.0, 105.9 80.3, 80.0, 44.7, 33.9, 29.1, 28.5, 28.5, 28.4;
HRMS (ESI, 10 eV) m/z calcd for C26H35ClNaO548Tiþ 531.1592,
found 531.1601 [M þ Na]þ; IR ATR, ν [cm-1] 2970, 1690, 1570,
1365, 1340, 1230, 1160, 1080, 1000, 820, 540.
Acknowledgment. We are indebted to the SFB 624
(“Template-Vom Design Chemischer Schablonen zur
Reaktionssteuerung” for continuing financial support.
Synthesis of 5: 1a (156 mg, 0.500 mmol) was reacted with
SOCl2 (2.5 mL) for 2 h at rt. Excess SOCl2 was removed in vacuo
Supporting Information Available: This material is available
free of charge via the Internet at http://pubs.acs.org.
(13) Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112–122.
(14) Flack, H. D. Acta Crystallogr. 1983, A39, 876–881.