Recycling titanocene dichloride from the petasis methylenation reaction

Article abstract of DOI:10.1021/om0508381

A simple method for recycling the titanium species used in the Petasis methylenation reaction is described. Treatment of the titanocene oxide byproduct with chlorotrimethylsilane and pyridine allows regeneration, recovery, and successful reuse of titanocene dichloride in amounts corresponding to nearly 90% of the dimethyltitanocene reagent initially employed.

Full text of DOI:10.1021/om0508381

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52
Organometallics 2006, 25, 552-553
Recycling Titanocene Dichloride from the Petasis Methylenation
Reaction
Patrick E. Berget and Neil E. Schore*
Department of Chemistry, UniVersity of California, DaVis, One Shields AVenue, DaVis, California 95616
ReceiVed September 29, 2005
Summary: A simple method for recycling the titanium species
used in the Petasis methylenation reaction is described. Treat-
ment of the titanocene oxide byproduct with chlorotrimethyl-
silane and pyridine allows regeneration, recoVery, and suc-
cessful reuse of titanocene dichloride in amounts corresponding
to nearly 90% of the dimethyltitanocene reagent initially
employed.
for its recycling would presumably be applicable to much more
costly and comparably useful reagents such as Cp ZrCl . There
2
2
have been scattered reports of the regeneration of Ti-Cl species
(but not Cp complexes) from the corresponding oxo compounds.
Hupperts and F u¨ rstner demonstrated the use of chlorosilanes
to convert titanium oxides into chlorides, effectively rendering
7
the McMurry coupling catalytic. We chose a similar approach
to regenerate titanocene dichloride from the oxide formed during
Petasis methylenation. Given the reduced oxophilicity of the
bis(cyclopentadienyl)titanium moiety compared with that of
simple inorganic Ti(IV), we reasoned that a moderately oxo-
philic chlorosilane should be effective in this case as well.
Herein we describe conversion of the crude Ti-containing
product of a Petasis transformation first into titanocene dichlo-
ride and then back into an active methylenating species:
effectively a recycling of the Petasis reagent.
Introduction
Dimethyltitanocene, introduced by Petasis for the methyl-
enation of heteroatom-substituted carbonyl compounds, has
proven to be a valuable alternative to the Tebbe reagent. Unlike
the latter, the Petasis reagent, which is easily prepared from
1
methylmagnesium chloride and titanocene dichloride, is rela-
tively air- and water-stable. The two species afford somewhat
complementary chemoselectivity: the Tebbe system, which
requires a Lewis base to release the Ti carbene from its
precursor, shows selective reactivity toward more basic sub-
strates (e.g., amides), while the Petasis system selects for the
more electrophilic carbonyl (e.g., esters). When it is heated to
0-75 °C, dimethyltitanocene efficiently methylenates a wide
variety of carbonyl compounds, nitriles, and even alkynes. A
useful feature of the Petasis system is that similar reactivity
can be obtained from a number of other dialkyltitanocenes,
including dibenzyl and bis(trimethylsilylmethyl) derivatives.
Petasis reagents are also tolerant of numerous functional groups,
Results and Discussion
Typical Petasis-type methylenations use an excess of titanium
reagent to achieve the desired outcome, even though the
mechanism suggests that only 1 equiv should be necessary.8
We began this study with an attempt to obtain reasonable
conversion using a minimal excess of Ti-containing reagents
prior to investigating the possibility of recycling the titanium.
Part of this effort required defining conditions to keep the
titanium in solution and amenable to later transformation. We
prepared the Petasis reagent following the procedure of Payack
2
6
3
4
5
making them quite useful for natural products synthesis. A
significant drawback to the use of such systems is the formation
1
et al., by addition of CH3MgCl to Cp2TiCl2 in THF/toluene to
6
of the strong oxygen-titanium bond, which, while serving as
give a 76% yield of a solution of Cp2Ti(CH3)2.
the driving force of the reaction, has inhibited the development
of versions that are catalytic in titanium.
Petasis methylenation generally proceeds best in the presence
3a
of a donor solvent that inhibits the formation of µ-oxo species
We are interested in exploring the means to render organo-
metallic catalysts and reagents reusable. Rising costs for both
purchase and, more recently, disposal of such species are
motivations for these efforts, as is a desire from an environ-
mental perspective to maximize their utility before disposal. The
ready availability of titanocene dichloride makes it a convenient
reagent to examine for recyclability. Although Cp2TiCl2 is not
particularly expensive (at least by today’s standards), methods
9
of reduced solubility. For simplicity of quantitation, we used
cyclohexanone as the substrate to test feasibility. Methylenation
of cyclohexanone using 1 equiv of dimethyltitanocene in THF/
1
toluene was carried out at 80-85 °C. After 6 h the H NMR
showed complete disappearance of the signals at δ 6.05 and
-0.16 ppm due to Cp2Ti(CH3)2 and appearance of a new signal
at δ 5.82 ppm, presumably due to Cp2TiO, probably as a THF
complex. The formation of methylenecyclohexane in 60-65%
yield was confirmed by the appearance of the signal for its
alkene hydrogens at δ 4.58 ppm.
*
To whom correspondence should be addressed. E-mail: neschore@
ucdavis.edu.
(
1) Payack, J. F.; Hughes, D. L.; Cai, D.; Cottrell, I. F.; Verhoeven, T.
R. Org. Synth. 2002, 79, 19.
In an initial attempt to regenerate Cp2TiCl2, the reaction
mixture was treated directly with (CH3)3SiCl at reflux overnight.
NMR analysis revealed the presence of a mixture of Cp2TiCl2
(
2) Pine, S. H.; Pettit, R. J.; Geib, G. D.; Cruz, S. G.; Gallego, C. H.;
Tijerina, T.; Pine, R. D. J. Org. Chem. 1985, 50, 1212.
3) (a) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392.
b) Petasis, N. A.; Fu, D. K. Organometallics 1993, 12, 3776. (c) Petasis,
N. A.; Lu, S. P. Tetrahedron Lett. 1995, 36, 2393.
4) (a) Petasis, N. A.; Bzowej, E. I. J. Org. Chem. 1992, 57, 1327. (b)
Petasis, N. A.; Akitopoulou, I. Synlett 1992, 665.
5) Hartley, R. C.; McKiernan, G. J. J. Chem. Soc., Perkin Trans. 1 2002,
763.
6) D o¨ tz, K. H. Angew. Chem., Int. Ed. Engl. 1984, 23, 587. (b) Luo,
L.; Li, L.; Marks, T. J. J. Am. Chem. Soc. 1997, 119, 8574.
(
(
[
6.59 ppm), CpTiCl3 (7.10 ppm), [Cp2TiCl]2O (6.91 ppm), and
(CH3)3Si]2O (0.44 ppm); a black precipitate was also observed.
(
(
(7) F u¨ rstner, A.; Hupperts, A. J. Am. Chem. Soc. 1995, 117, 4468.
(8) Meurer, E. C.; Santos, L. S.; Pilli, R. A.; Eberlin, M. N. Org. Lett.
2003, 5, 1391.
(9) Smith, M. R., III; Matsunaga, P. T.; Andersen, R. A. J. Am. Chem.
Soc. 1993, 115, 7049.
(
2
(
1
0.1021/om0508381 CCC: $33.50 © 2006 American Chemical Society
Publication on Web 12/17/2005

Notes
Organometallics, Vol. 25, No. 2, 2006 553
Scheme 1
with respect to the titanium. Note that the volatile mixture
obtained in the vacuum-transfer step containing excess chlo-
rosilane and pyridine may itself be reused in subsequent
regenerations of the titanocene reagent. Thus, proof of the
concept of the strategy has been achieved. The only limit to
the number of recyclings lies in the ability to mechanically
handle the material and minimize loss in the preparation of the
dimethyl derivative. Thus, improving the practicality of the
procedure would depend on the development of improved
conversions of the dichloride into the active methylenating
reagent.
Conclusion
In an attempt to maintain the solubility of Ti-containing material,
pyridine was incorporated into the regeneration procedure.
Pyridine is known to reverse the formation of titanium oxo-
cyclobutanes starting from titanocene oxide by complexing the
We have demonstrated a method for the recycling of the
titanocene-based Petasis reagent based upon conversion of the
oxide byproduct into the dichlorotitanocene starting material
using a chlorosilane. Modifications of the process to improve
its efficiency and to extend recycling to other early-transition-
metal reagents are under study and will be reported in due
course.
1
0
latter. We assumed that pyridine would assist similarly in the
recycling procedure by blocking the empty orbital on the oxide
and diverting it toward O/Cl exchange in the presence of the
chlorosilane. In this case, we repeated the cyclohexanone
methylenation and then added a 10-fold excess of both pyridine
and (CH3)3SiCl. After 8 h of reflux, the major Ti-containing
materials were now the THF and pyridine complexes of Cp2-
TiCl2, appearing in the NMR at δ 6.59 and 6.49 ppm,
respectively. This modification effectively suppressed the
formation of other soluble titanium-containing species, as well
as virtually eliminating the formation of insoluble material.
Vacuum transfer removed all volatiles, including methylene-
cyclohexane, pyridine, (CH3)3SiCl, and [(CH3)3Si]2O, leaving
behind a semisolid residue of Cp2TiCl2 as a mixture of the
pyridine and THF complexes.
Taking up this residue into THF and precipitating with hexane
afforded essentially pure Cp2TiCl2 in 87% yield, based upon
the amount of Cp2Ti(CH3)2 initially used. We then reconverted
the dichloride via the conventional procedure into Cp2Ti(CH3)2.
Despite physical losses associated with an extractive workup
step, the dimethyl derivative could be isolated and used directly
in subsequent methylenation. In this way, from an initial
methylenation employing approximately 0.4 g of Cp2Ti(CH3)2
reagent, four recyclings were achieved, on successively smaller
scales. We reduced the amount of cyclohexanone in each run
to maintain the same ketone-to-reagent ratio. Yields of meth-
ylenecyclohexane remained essentially constant from run to run
at about 60%, and about 65% of usable dimethyltitanocene
reagent was achieved after each recycling, relative to the
previous run. The latter is consistent with an average 87%
efficiency for recycling of titanocene oxide to dichloride,
combined with a 75% yield for the conversion of the dichloride
into dimethyltitanocene. Working on a larger scale (starting with
Experimental Section
General Considerations. Titanocene dichloride (Aldrich, 97%)
and cyclohexanone were used as received. THF was freshly distilled
from Na/benzophenone under N , and toluene and pyridine were
2
dried over 3 Å molecular sieves under Ar for 2 days. Methylmag-
nesium chloride (Acros) was used as a 22% w/w solution in THF.
Reactions were monitored by taking aliquots and assaying by H
NMR. All H NMR spectra were recorded in CDCl
tetramethylsilane as an internal standard on an INOVA 400 MHz
instrument, which was funded in part by a grant from the NSF
1
1
3
using
(
Grant No. CHE-9808183).
Synthesis of Dimethyltitanocene. The literature procedure was
used to prepare this reagent in 76% yield as a standard solution,
1
1
6
-
.63% w/w in 2.1:1 THF/toluene. H NMR: δ 6.058 (s, 10H),
0.152 (s, 6H) ppm.
Petasis Methylenation of Cyclohexanone and Reagent Re-
generation (Representative Procedure). A round-bottom flask was
flushed with Ar and charged with 6.7 mL (0.444 g, 2.13 mmol) of
a standard 6.63% w/w solution of dimethyltitanocene and 0.209 g
2.13 mmol) of cyclohexanone. The mixture was then heated to
0-85 °C for 6 h under Ar. After the mixture was cooled to near
room temperature, 1.688 g (21.3 mmol) of pyridine and 2.318 g
21.3 mmol) of trimethylsilyl chloride were added and the mixture
was heated to 80-85 °C for 8 h. After this mixture was cooled,
the volatiles were removed via vacuum transfer. The nonvolatile
residue, after trituration from THF with hexane, afforded 0.462 g
(87% yield) of titanocene dichloride as a deep purple solid. H
NMR: δ 6.59 (s) ppm. The dichloride was then reconverted to
dimethyltitanocene using the literature procedure.
Methylenecyclohexane. The alkene was obtained as a pale
yellow liquid admixed with THF, chlorotrimethylsilane, pyridine,
(
8
(
1
2
.50 g of Petasis reagent), we found that the yields did not
improve, but the recovered Petasis reagent was of higher purity
after each recycling. Scheme 1 illustrates the process.
The consistent yields of methylenecyclohexane observed from
run to run demonstrate that there is no significant loss in activity
1
toluene, and hexamethyldisiloxane (NMR yield 60-65%).
NMR: δ 4.58 (t, 2H), 2.12 (m, 4H), 1.54 (m, 6H).
H
Acknowledgment. We thank the National Science Founda-
tion for financial support (Grant No. CHE-0313888).
(10) Polse, J. L.; Andersen, R. A.; Bergman, R. G. J. Am. Chem. Soc.
1
995, 117, 5393.
OM0508381