CpTiCl2, an Improved Titanocene(III) Catalyst in Organic Synthesis

Article abstract of DOI:10.1002/ejoc.201801120

Preparation, EPR analysis, and advantages in green organic chemistry of CpTiCl₂, an improved single-electron transfer catalyst, are reported. Under mild conditions, this organometallic complex provides excellent yields of homoallylic and homopropargylic alcohols in Barbier-type allylation and propargylation reactions. Moreover, in the presence of a bidentate BOX ligand, Barbier-type cyclization reactions catalyzed by CpTiCl₂ can be carried out in an enantioselective manner.

Full text of DOI:10.1002/ejoc.201801120

A Journal of
Accepted Article
Title: CpTiCl₂, an Improved Titanocene(III) Catalyst in Organic
Synthesis.
Authors: Esther Roldan-Molina, Natalia M Padial, Luis Lezama, and
Juan Enrique Oltra
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801120
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801120
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10.1002/ejoc.201801120
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CpTiCl2, an Improved Titanocene(III) Catalyst in Organic
Synthesis.
Esther Roldan-Molina, [a] Natalia M. Padial, [a] Luis Lezama[b] and J. Enrique Oltra* [a]
Abstract: Preparation, EPR analysis, and advantages in green
organic chemistry of CpTiCl2, an improved single-electron transfer
catalyst, are reported. Under mild conditions, this organometallic
Results and Discussion
Electronic configuration of conventional Ti(III) catalyst Cp2TiCl
has not been characterized so far. Therefore CpTiCl2 was
generated in situ from commercial CpTiCl3 by stirring with Mn
dust in deoxygenated THF under argon atmosphere. Room
temperature EPR spectra of diluted solutions in THF of this
titanocene(III) complex showed the expected pattern for well
magnetically isolated Ti3+ ions (Fig.S1),[9] including the hyperfine
structure resulting from the interaction of the unpaired electron
with 47Ti and 49Ti nuclei, being giso=1.994 and ATi=25 MHz. The
spectra of frozen CpTiCl2/THF solutions at 150 K exhibit a signal
with axial symmetry (Fig.S2).[9] The observed g||=1.997 and
g=1.992 values are typical for a d1 system with the unpaired
electron residing mainly in the dz2 orbital.[10] The spin parameters
g and A are similar to those observed in other titanium
compounds and confirmed the presence of the oxidation state of
Ti(III) in this complex.[11]
Once the electronic configuration of CpTiCl2 was confirmed,
we considered the hypothesis of using stoichiometric proportions
of this SET reagent for organic synthesis. For this purpose, we
chose the coupling of ketone 1 with propargyl chloride as a
model reaction. Conventional Cp2TiCl generally requires about 8
equivalents of Mn dust to be generated from commercial
Cp2TiCl2. In this scenario we decided to determine the minimum
proportion of Mn required for generating CpTiCl2 from
commercial CpTiCl3. The results of this study are summarized in
Table 1.
complex provides
excellent yields of
alcohols in Barbier-type
homoallylic and
allylation and
homopropargylic
propargylation reactions. Moreover, in the presence of a bidentate
BOX ligand, Barbier-type cyclization reactions catalyzed by CpTiCl2
can be carried out in an enantioselective manner.
Introduction
In recent years, inner-sphere single-electron transfer (SET)
reagents, such as t-butyltin hydride, SmI2 (Kagan reagent) and
others, have proven to be really useful tools in organic
synthesis.[1] Among them, the Ti(III) complex, Cp2TiCl (Nugent-
RajanBabu reagent)[2] shows several advantages over others
due to the abundance of titanium in the Earth’s crust,[3] the mild
conditions under which it works, the compatibility with many
functional groups and its safety and environmentally friendly
characters.[4] Nevertheless, Cp2TiCl also has some limitations
derived from the usual requirements of relatively high quantities
of reductive metals, Mn or Zn, (generally 8 equivalents) to be
generated from commercial Cp2TiCl2, high proportions of
titanocene-regenerating agents needed to behave as
a
catalyst,[5] and the absence of enough valence-shell vacancies to
co-ordinate with bidentate chiral ligands. Here we present an
improved Ti(III) SET catalyst, CpTiCl2, which overcomes many
of these drawbacks. CpTiCl2 has been previously used as a
stoichiometric reagent for aldol additions of titanium and boron
enolates.[6] It has been also used as a catalyst for deprotection of
allyl- and propargyl-carbamates to amines.[7] More recently, a
closely related complex, Cp*TiCl2, demonstrated to be effective
to catalyze [3+2] cycloadditions of N-Acylaziridines and
alkenes.[8] In this paper we present the in situ preparation, EPR
analysis not previously described, new applications for Barbier-
type allylation and propargylation reactions and the use in
enantioselective reactions of CpTiCl2.
Table 1. Optimization of reaction conditions: reductive metal Mn proportions.[a]
Entry
Mn (equiv)
CpTiCl3 (equiv)
Yield [%][b]
1
2
3
4
5
8
4
1
1
1
1
1
95
92
94
70
62
[a]
[b]
E. Roldan-Molina, Dr. N.M. Padial, Prof. Dr. J. E. Oltra. Department
of Organic Chemistry. University of Granada
Campus Fuentenueva s/n, E-18071, Granada, Spain.
E-mail: joltra@ugr.es
2
1.5
1
http://organicsynthesis.ugr.es/
Prof. Dr. L. Lezama. Department of Inorganic Chemistry and
BCMaterials. University of the Basque Country. UPV/EHU, 48080,
Bilbao, Spain
[a] Reactions were performed under argon atmosphere at room temperature
for 6h, using THF as solvent. [b] Determined by 1H NMR.
As can be seen in Table 1, the lower proportion of Mn
required for the adequate behavior of CpTiCl2 was only 2
Supporting information for this article is given via a link at the end of
the document.
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equivalents (Table 1, entry 3). Minor quantities of Mn (1.5 or less
equivalents) gave lower yields of the desired product 2 (Table 1,
entry 4-5). In any case, the excess of Mn can be recovered by
simple filtration at the end of the reaction and reused.
regenerated. These results suggest the hypothetic catalytic
cycle depicted in Scheme 1.
Commercial CpTiIVCl3 is reduced in situ to CpTiIIICl2 by
reductive metal Mn. CpTiIIICl2 abstracts the chlorine atom from
propargyl chloride giving allenyl titanium complex I. This
complex coordinates with the ketone generating II, which
evolves to alkynyl derivative III by the electronic rearrangement
depicted in Scheme 1. Subsequently, Me3SiBr regenerates
CpTiIVBrCl2, giving trimethylsilyl derivative IV. Eventually, the
final acidic quenching gives the desired homopropargylic alcohol
V.
At this point, we deemed that CpTiCl2 could be used not only
as a SET stoichiometric reagent but also, more importantly, as a
catalyst for organic synthesis. For this purpose, it was relevant
to develop an adequate titanocene-regenerating system (TRS).
We checked different potential TRS candidates. The results are
summarized in Table 2.
Table 2. Relative percentages of substrate (1) and product (2) obtained using
CpTiCl2 (20 mol%) and different titanocene-regenerating systems.[a]
Entry
TRS[b] (equiv)
1 [%][c]
2 [%][c]
1
2
3
4
5
Collidine (7)/Me3SiCl (4)
Collidine (7)/Me3SiBr (4)
Et3N·HCl (2)/Me3SiCl (3)
Me2NH•HCl (2)/Me3SiCl(3)
Me3SiBr(3)
80
75
70
100
4
20
25
30
0
96
[a] Unless otherwise noted, reactions were performed under argon atmosphere
at room temperature for 6h, using THF as solvent, 0.2 equiv (20 mol%) of
CpTiCl3 and 2 equiv of reductive metal Mn. [b] TRS: titanocene-regenerating
system. [c] Determined by 1H NMR
Unexpectedly, the combination of 2,4,6-collidine and
[5c, 12]
Me3SiCl, which gave such good results with Cp2TiCl,
did
not work with CpTiCl2 (Table 2, entry 1), which supports the
differences between the chemical behaviors of both catalysts.
Neither did a slight modification of this combination (Table 2,
entry 2). The potential titanocene-regenerating system
summarized in Table 2 entry 3, [13] was not capable of providing
more than 30% yield of the desired homopropargylic alcohol 2.
After assaying the combination reported in Table 2 entry 4, only
the starting material (1) was obtained, suggesting that it
decomposes the CpTiCl2 catalyst. Finally (Table 2 entry 5), and
Scheme 1. Hypothetical catalytic cycle for CpTiCl2-catalyzed coupling
between ketones and alkynes.
fortunately, not
a
reagents combination
but simple
bromotrimethylsilane (Me3SiBr), not previously described as
titanocene-regenerating agent, gave the best yield of the desired
homopropargylic alcohol 2 (96%).
Once we were confident about the possibilities of CpTiCl2 as
a catalyst, we tried to lower the required quantities of this
complex. We checked 0.15 and 0.1 equivalents and observed
that with only 0.1 the reactions work as well as with 0.2 which is
the habitual proportion with conventional Cp2TiCl. Therefore, a
substantial lowering of the catalyst amount was achieved. It
should be noted that the process took place at rt, under mild
conditions compatible with a relatively reactive trisubstituted
double bond. Moreover, when the assay was repeated in the
absence of titanocene, the starting material 1 was recovered
unchanged, confirming the crucial role played by the CpTiCl2
catalyst. Additionally, when the reaction was assayed in the
absence of Me3SiBr, only a 10% yield of product 1 was obtained,
indicating that under these conditions titanocene(III) is not
Scheme 2. CpTiCl2-catalyzed Barbier-type propargylation of ketone 1.
Under the experimental conditions summarized in Scheme 2,
CpTiCl2 was also able to catalyze the Barbier-type
propargylation of ketones 3-11, giving homopropargylic alcohols
12-19 in yields ranging from 63% to 96% (Table 3, entries 1-8)
and γ-lactone 20 (62%) (Table 3, entry 9).
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[a]
Table 3. Barbier-type propargylation of ketones 3-11 catalyzed by CpTiCl2.
catalyzed by CpTiCl2 under the experimental conditions
summarized in Scheme 3.
Scheme 3. CpTiCl2-catalyzed Barbier-type allylation of ketones 1, 3-11
Thus, couplings between allyl chloride and ketones 1, 3-10,
catalyzed by CpTiCl2, gave homoallylic alcohols 21-29 in yields
ranging from 75% to 96% (Table 4 entries 1-9). When allyl
bromide was used instead of allyl chloride, poorer yields were
obtained, in a similar way that occurs with the above described
propargylation reactions. Moreover, the reaction between 11 and
allyl chloride gave a good 80% yield of lactone 30, probably by
Ti-catalyzed cyclization of the homoallylic alcohol precursor.
Table 4. Barbier-type allylation of ketones 1, 3-11 catalyzed by CpTiCl2.[a]
[a] Experimental conditions: Under argon atmosphere at room temperature.
CpTiCl3 (10 mol%), Mn dust (2 equiv), Me3SiBr (3 equiv) and THF as
solvent.[b] Rt: reaction time (hours) [c] Yield determined by 1H-NMR.
As can be seen in Table 3, the SET catalyst CpTiCl2, was
capable of promoting propargylation reactions of ketones at rt
under mild conditions compatible with alkenes, aromatic
derivatives, alkyl chlorides, and esters. It should be noted that
propargylation of keto ester 11 produced lactone 20, possibly by
lactonization of the corresponding homopropargylic alcohol
precursor. When propargyl bromide was used instead of
propargyl chloride the obtained yields of products 12-20 were
lower.
The good yields obtained in the above propargylation
reactions prompted us to also check allylation reactions
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Table
5.
CpTiCl2/BOX-catalyzed
enantioselective
intramolecular
propargylation (cyclization) of ketones 35 and 36.[a]
[a] Experimental conditions: Under argon atmosphere at room temperature.
CpTiCl3 (10 mol%), Mn dust (2 equiv), Me3SiBr (3 equiv) and THF as
solvent.[b] Rt: reaction time (hours) [c] Yield determined by 1H-NMR.
Once we were confident about the power of this catalyst for
intermolecular reactions, we decided to check it in intramolecular
reactions (cyclizations). We assayed the cyclization of substrate
31 catalyzed by CpTiCl2 thus obtaining a mixture (3:2) of
diastereomers 32 and 33 with an overall yield of 90% (Scheme
4).The relative stereochemistry of both isomers were determined
with the aid of NOE experiments.[9]
[a] Experimental conditions: Under argon atmosphere at room temperature for
6h. CpTiCl3 (10 mol%), Mn dust (2 equiv), Me3SiBr (3 equiv), (-)-34 (0.2 equiv)
and THF as solvent. [b] Determined by 1H-NMR.[c] Determined by chiral HPLC
analysis.
As can be seen in Table 5, both yields and enantiomeric
excesses (ee) are similar to those previously obtained with a
chiral Brintzinger-type catalyst.[14] Despite of the enantiomeric
excesses are relatively low, these results are promising in the
way of assaying new chiral ligands to improve the asymmetric
catalytic power of CpTiCl2.
Scheme 4. CpTiCl2-catalyzed intramolecular allylation (cyclization) of ketone
31.
Conclusions
We then assayed the enantioselective version of this
CpTiCl2-catalyzed cyclization using bidentate BOX chiral ligand
(-)-34 (Scheme 5). This levogyre ligand provided dextrogyre
cyclization product (+)-33 (αD=+9) with a moderate enantiomeric
excess (ee) of 14%. The absolute configuration of (+)-33 could
be that depicted in Scheme 5 or the contrary. Despite of this,
this preliminary result suggests that, in line with our initial
hypothesis, CpTiCl2, in the presence of a bidentade chiral ligand,
is capable of achieving asymmetric catalysis in organic
synthesis.
To sum up, preparation and EPR analysis of the improved SET
reagent CpTiCl2 are described. This reagent can be used as a
catalyst with the new titanocene-regenerating agent Me3SiBr.
CpTiCl2 has proven to be a useful tool for catalyzing Barbier-type
allylations and propargylations of ketones. Moreover, CpTiCl2
has also proved to be capable of catalyzing intramolecular
reactions (cyclizations) between alkenes or alkynes and ketones.
These reactions can be carried out in an enantioselective
manner with the aid of chiral BOX bidentate ligands.
At the moment, we are assaying other bidentate ligands in order
to improve the enantioselectivity of CpTiCl2 in C-C bond forming
reactions.
There are no conflicts of interest to declare.
Experimental Section
General procedure for propargylations of ketones catalyzed by
CpTiCl2: Freshly distilled deoxygenated THF (8 mL) was added to a 25
mL round-bottom flask charged with a mixture of commercial CpTiCl3 (22
mg, 0.1 mmol) and Mn dust (110 mg, 2 mmol) under argon atmosphere
at room temperature. The suspension was stirred until it turned green
(around a couple of minutes) and subsequently, bromotrimethylsilane
(0.40 ml, 3 mmol) was added. Then, a solution of the corresponding
ketone (1 mmol) and propargyl chloride (0.14 ml, 2 mmol) in THF (2 mL)
was slowly added over a period of 1 h. The mixture was stirred for 2-8 h
(see Table 2). The reaction was filtered and the organic solvent was
removed under reduced pressure. The residue was diluted in AcOEt,
Scheme 5. CpTiCl2/BOX-catalyzed enantioselective intramolecular allylation
(cyclization) of ketone 31. [a] Determined by chiral HPLC analysis.
The above result prompted us to compare the CpTiCl2/BOX-
catalyzed enantioselective cyclization with previously described
reactions using a chiral Brintzinger-type catalyst.[14] These
results are summarized in Table 5.
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[1] a) H. B. Kagan, Tetrahedron, 2003, 59, 1035-10372; b) R. S. Miller, J.
M. Sealy, M. Shabangi, M. L. Kuhlman, J. R. Fuchs, R. A. Flowers, II. J.
Am. Chem. Soc., 2000, 122, 7718-7722; c) G. A. Molander, C. R. Harris,
Chem. Rev., 1996, 96, 307-338; d) D. P. Curran, T. L. Fewig, C. P.
Jasperse, M. J. Totleben, Synlett, 1992, 943-961.
quenched with 3% HCl, washed with brine, dried over anhydrous Na2SO4
and the solvent was removed. Products were purified by flash
chromatography (hexane/AcOEt mixtures).
General procedure for allylations of ketones catalyzed by CpTiCl2:
Freshly distilled deoxygenated THF (8 mL) was added to a 25 mL round-
bottom flask charged with a mixture of commercial CpTiCl3 (22 mg, 0.1
mmol) and Mn dust (110 mg, 2 mmol) under argon atmosphere at room
temperature. The suspension was stirred until it turned green (around a
couple of minutes) and subsequently, bromotrimethylsilane (0.40 ml, 3
mmol) was added. Then, a solution of the corresponding ketone (1 mmol)
and allyl chloride (0.16 ml, 2 mmol) in THF (2 mL) was quickly added.
The mixture was stirred for 2-5 h (see Table 3). The reaction was filtered
and the organic solvent was removed under reduced pressure. The
residue was diluted in AcOEt, quenched with 3% HCl, washed with brine,
dried over anhydrous Na2SO4 and the solvent was removed. Products
were purified by flash chromatography (hexane/AcOEt mixtures).
[2] T. V. RajanBabu, W. A. Nugent, J. Am. Chem. Soc., 1994, 116, 986-
997.
[3] D. J. Ramon, M. Yus, Chem. Rev., 2006, 106, 2126-2208.
[4] A. Rosales, I. Rodriguez-Garcia, J. Muñoz-Bascon, E. Roldan-Molina, N.
M. Padial, L. Pozo-Morales, M. Garcia-Ocaña, J. E. Oltra, Eur. J. Org.
Chem., 2015, 4567-4591.
[5] a) A. Gansäuer, M. Pierobon, H. Bluhm, Angew. Chem. Int. Ed., 1998,
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[8] W. Hao, X. Wu, J. Z. Sun, J. Siu, S. N. MacMillan, S. Lin, J. Am. Chem.
Soc., 2017,139, 12141-12144.
General procedure for enantioselective intramolecular allylations
and propargylations (cyclizations) of ketones catalyzed by
CpTiCl2/BOX: A mixture of commercial CpTiCl3 (22 mg, 0.1 mmol) and
Mn dust (110 mg, 2 mmol) were introduced in a round-bottom flask under
argon atmosphere at room temperature. Then, freshly distilled
deoxygenated THF (8 mL) was added and the suspension was stirred
until it turned green (around a couple of minutes). Subsequently,
bromotrimethylsilane (0.40 ml, 3 mmol) and BOX ligand (-)-34 (67 mg,
0.2 mmol) were added and a solution of the corresponding ketone (1
mmol) in THF (1 ml) was added over a period of 15 minutes (for racemic
cyclizations, such as that depicted in Scheme 4, no BOX was added).
The mixture was stirred for 6h. Eventually, the reaction was filtered and
the organic solvent was removed under reduced pressure. The residue
was diluted in AcOEt, quenched with 3% HCl, washed with brine, dried
over anhydrous Na2SO4 and the solvent was removed. Products obtained
were purified by flash chromatography (hexane/AcOEt mixtures).
[9] See Supporting Information Available.
[10] G. Labauze, J. B. Raynor, E. Samuel, JCS Dalton, 1980, 2425-2427.
[11] a) S. Van Doorslaer, J. J. Shane, S. Stoll, A. Schweiger, M. Kranenburg,
R. J. Meier, J. Organomet. Chem.,2001, 634, 185-192; b) E. Morra, S.
Maurelli, M. Chiesa, S. Van Doorslaer, Phys. Chem. Chem. Phys., 2015,
17, 20853-20860.
[12] a) J. Muñoz-Bascon, I. Sancho-Sanz, E. Alvarez-Manzaneda, A.
Rosales, J. E. Oltra. Chem., Eur. J., 2012, 18, 14479-14486; b) J.
Muñoz- Bascon, C. Hernandez-Cervantes, N. M. Padial, M. Alvarez-
Corral, A. Rosales, I. Rodriguez-Garcia, J. E. Oltra. Chem. Eur. J., 2014,
20, 801-810.
[13] J. Streuff, M. Feurer, P. Bichovski, G. Frey, U. Gellrich. Angew., Chem.
Int. Ed.2012, 51, 8661-8664.
[14] J. Muñoz-Bascon, C. Hernandez-Cervantes, N. M. Padial, M. Alvarez
Corral, A. Rosales, I. Rodriguez-Garcia, J.E. Oltra, Chem. Eur. J., 2014,
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.
Acknowledgements
.
The authors acknowledge the Spanish MINECO (Project
CTQ2015-70724-R) for financial support. E. R-M thanks the
Spanish Ministry of Education, Culture, and Sport for her FPU
grant (FPU14/01472). Finally, the authors express their
appreciation to Dr. Miguel Paradas, Dr. Miguel Quirós and Dr.
Alegria Carrasco for their collaboration. We also thank Prof.
Spencer C. Bowden (Editorial Board Chairman at Oak-Fortress
Proofreading) and our English colleague Dr. Angela Tate for
revising our English text.
.
Keywords: Allylation
• electron transfer • homogeneous
catalysis • propargylation • titanium
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Improved Titanocene(III) catalyst
Esther Roldan-Molina, Natalia M. Padial,
Luis Lezama and J. Enrique Oltra*
Page No. – Page No.
CpTiCl2, an Improved Titanocene(III)
Catalyst in Organic Synthesis.
CpTiCl2, an improved titanocene(III) single-electron transfer catalyst, under mild
conditions provides excellent yields of homoallylic and homopropargylic alcohols in
Barbier-type allylation and propargylation reactions. Moreover, in the presence of a
BOX ligand, it was capable of catalyzing enantioselective intramolecular allylations
and propargylations (cyclizations) of ketones.
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