Cp2TiX Complexes for Sustainable Catalysis in Single-Electron Steps

Article abstract of DOI:10.1002/chem.201705707

We present a combined electrochemical, kinetic, and synthetic study with a novel and easily accessible class of titanocene catalysts for catalysis in single-electron steps. The tailoring of the electronic properties of our Cp₂TiX-catalysts that

Full text of DOI:10.1002/chem.201705707

A Journal of
Accepted Article
Title: Cp2TiX Complexes for Sustainable Catalysis in Single Electron
Steps
Authors: Andreas Gansäuer, Ruben Benedikt Richrath, Theresa
Olyschläger, Sven Hildebrandt, Daniel G Enny, Godfred D
Fianu, and Robert A Flowers II
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Cp2TiX Complexes for Sustainable Catalysis in Single Electron
Steps
Ruben B. Richrath,[a] Theresa Olyschläger,[a] Sven Hildebrandt,[a] Daniel G. Enny,[b] Godfred D. Fianu,[b]
Robert A. Flowers II,*[b] and Andreas Gansäuer*[a]
Abstract: We present a combined electrochemical, kinetic, and
synthetic study with a novel and easily accessible class of titanocene
catalysts for catalysis in single electron steps. The tailoring of the
electronic properties of our Cp2TiX-catalysts that are prepared in situ
from readily available Cp2TiX2 is achieved by varying the anionic
ligand X. Of the complexes investigated, Cp2TiOMs proved to be
either equal or substantially superior to the best catalysts developed
earlier. The kinetic and thermodynamic properties pertinent to
‘catalysis in single electron steps’[6] and ‘metalloradical catalysis’
in cobalt(II) catalyzed transformations.
In the latter case, Co(II) porphyrin complexes react with diazo
compounds or azides to give Co(III) metalloradicals that are either
carbon or nitrogen centered. These intermediates have been
used in many reactions including cyclopropanations,
aziridinations, and C-H bond aminations.[7] The use of
enantiomerically pure porphyrin ligands has led to highly
enantioselective reactions.[8]
catalysis have been determined. They allow
a mechanistic
understanding of the subtle interplay of properties required for an
efficient oxidative addition and reduction. Therefore, our study
highlights that efficient catalysts do not require the elaborate covalent
modification of the cyclopentadienyl ligands.
With titanocene(III) complexes, epoxides were used as radical
precursors in oxidative additions to generate β–titanoxy
radicals.[9] These intermediates have been used in atom-
economical syntheses of polycyclic tetrahydrofurans[3,6a,6b] and in
atom-economical radical arylations[10] via catalysis in single
electron steps. In both cases, the reductive elimination is critical
for catalytic turn-over (Scheme 1).
Introduction
Chemical reactions involving carbon-centered radicals are highly
attractive due to the mildness of their conditions, their high
chemoselectivity, the ease of radical generation, and the ease of
C-C bond formation.[1,2] Traditionally, radical reactions are
conducted as chain processes that proceed under substrate
control. The alternative process of carrying out radical reactions
via a transition metal catalyzed process under reagent control is
less well established.[3] However, it is highly appealing because
the metal and its ligands can control radical generation, radical
trapping, and radical translocation because the metal remains
bound to the radical.
In order to be able to catalyze radical reactions, the metal complex
must be able to shuttle between neighboring transition states
efficiently. This implies that oxidative additions and reductive
eliminations occur in single electron steps.[4] The realization of this
concept in titanocene(III) catalyzed reactions[5] has been called
[a]
[b]
R. B. Richrath, T. Olyschläger, S. Hildebrandt, Prof. Dr. A. Gansäuer
Kekulé-Institut für Organische Chemie und Biochemie
Universität Bonn
Gerhard Domagk-Str. 1, D-53121 Bonn (Germany)
E-mail: andreas.gansaeuer@uni-bonn.de
D. G. Enny, G. D. Fianu, Prof. Dr. R. A. Flowers II
Department of Chemistry
Scheme 1. Single electron reductive elimination as key-step in the titanocene
catalyzed tetrahydrofuran synthesis and radical arylation.
Lehigh University
Bethlehem, PA 18015 USA
E-mail: rof2@lehigh.edu
In tetrahydrofuran synthesis, the reductive elimination can be
regarded as an organometallic oxygen rebound.In the arylation,
this step is composed of the ‘back electron transfer’ from the
radical σ–complex followed by the protonation of the Ti-O bond or
a proton coupled electron transfer (PCET).[11] It is clear that for the
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201705707
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tetrahydrofuran synthesis and the radical arylation, the reductive
elimination will be thermodynamically more favorable if the Ti(IV)
is a stronger oxidant and, correspondingly, Ti(III) a weaker
reductant. Quantitatively, these effects can be easily determined
by measuring the redox potentials of the corresponding species
by cyclic voltammetry (CV).
have synthesized complexes 2 – 6 by this strategy from Cp2TiMe2
and the corresponding acids in the indicated yields (Scheme 2).
For applications in catalysis in single electron steps an easy in
situ reduction of Cp2Ti(IV)X2 to the active Cp2Ti(III)X is essential.
Gratifyingly, complexes 4, 5, and 6 can be conveniently reduced
at room temperature to Cp2TiX in THF with Zn dust in less than
30 min.[16] However, for 3an extended time of about 90 min is
required. The convenient and operationally simple Zn-reduction is
inadequate for 2 because it requires more than 10h. The exact
reasons for these differences remain unclear. We suggest that
differences in the solubility of ZnX2 are involved. Instead, for
Cp2Ti(OTf)2 the reduction has to be carried out with NaBH4.[14b]
Care has to be taken to avoid the formation of catalytically
inactiveCp2TiBH4.
There are two ways of manipulating the redox properties of
titanocene(III) and titanocene(IV) complexes. First, the
introduction of substituents to cyclopentadienyl ligands
significantly affects the redox potential of the titanocene
complexes.[12] The drawback of this powerful approach is that
particular ligands have to be prepared for each complex and that
the complexes require hydrochloride additives, such as Coll*HCl.
Therefore, an efficient screening of a large variety of potential
catalysts can be difficult. Second, the electronic properties can be
altered by variation of the inorganic ligand. This approach has
remained largely unexplored and has the potential advantage of
using a single titanocene precursor for the preparation of a large
variety of complexes. In this way, the properties of many potential
catalysts can be screened in a fast and efficient manner. A first
step in this direction has been the use of Cp2TiOTf as catalyst in
radical arylation reactions.[13] The modification of the inorganic
ligand from chloride to iodide or phenoxide has been shown to
substantially improve the yields in titanocene catalyzed reductive
umpolung reactions with nitriles as radical trap.[5i,j]
Here, we give a full account of our investigation of the synthesis,
electronic properties and catalytic performance of Cp2TiX2 and
Cp2TiX complexes (X = sulfonates and O2C2F3). Thereby, we
provide a toolbox for the development of efficient reaction
conditions for catalysis in single electron steps. As a result, we
identified new catalysts that are easily prepared and that display
high activity, stability, and functional group tolerance in the
absence of additives. They are therefore superior to and more
sustainable than our earlier complexes.
complex
HX
pKa (H2O)
yield/[%]
2[14a,b]
3[14c]
4[14d]
5[14e]
6
HOTf
HOTs
HOMs
TFA
-20[15a]
-2.8[15b]
-1.9[15c]
-0.2[15d]
2.2[15e]
80
88
97
67
77
CSA
OTf = triflate, OTs = tosylate, OMs = mesylate, TFA = trifluoroacetate, CSA =
camphorsulfonate.
Scheme 2. Modular two-step synthesis of Cp2TiX2 (2) - (6) from Cp2TiCl2 (1).
Results and Discussion
For an efficient catalytic turn-over in radical arylations with
Cp2TiX2-derived systems, it is essential to understand the
composition of the catalytic system and the redox potentials of its
components. Since no information is available on our
Cp2TiX2/Cp2TiX redox couples, we studied their redox properties
and compositions in THF by cyclic voltammetry to provide the
necessary information for the efficient design of reactions
catalyzed by Cp2TiX complexes.
Synthesis and Reduction of Cp2TiX2
For providing a general and high yielding approach to the desired
Cp2TiX2 catalyst precursors, an efficient and flexible synthesis of
these complexes from a readily available titanocene building
block is important (Scheme 2).
The use of operationally simple and high yielding transformations
and of easily accessible and cheap reagents is mandatory. The
syntheses of Cp2Ti(OTf)2 highlight these issues.[14a,b] Originally,
the complex has been synthesized from Cp2TiCl2 and AgOTf via
a chloride exchange.[14a] This approach uses commercially
available Cp2TiCl2 as the most attractive titanocene building block.
As pointed out by Luinstra, the choice of solvent and the control
of stoichiometry is critical. Therefore, the reaction of Cp2TiMe2
with TfOH was introduced as a more robust and simple alternative
for the preparation of Cp2Ti(OTf)2.[14b] Moreover, no Ag-salts have
to be employed. Solutions of Cp2TiMe2 are commercially available
or can be easily prepared from Cp2TiCl2 and 2 eq. of MeLi. We
Cyclic Voltammetry of Cp2TiX2 and Zn-Cp2TiX2
Cyclic voltammetry is ideally suited to identify compounds in
mixtures of redox-active compounds, the study of their properties,
and the kinetics of their reactions.[17] The seminal studies of
Daasbjerg have demonstrated that this is also the case for
titanocene halides.[18] Therefore, we decided to examine the
Cp2TiX2-derived systems using this technique. Our investigation
is divided into two parts. First, we determined the properties of
electrochemically reduced Cp2TiX2. In this manner, the redox
properties of [Cp2TiX2]- and Cp2TiX can be measured and it can
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be established how easily X- dissociates from [Cp2TiX2]-. Second,
Zn-reduced Cp2TiX2 (Zn-Cp2TiX2) was analyzed. In this fashion, it
can be shown if Cp2TiX dimerizes in solution and how easily
Cp2Ti+, an attractive catalyst in its own right especially for those
substrates which suffer from a slow ‘electron-back transfer’
(Scheme 1, lower image), can be formed from Cp2TiX in THF.
The relevant peak potentials of the species observable in the
voltammograms are summarized in Table 1. We found that under
our conditions the potentials are reproducible within a margin of
0.02 V. Curiously, the highest potential (Ep,c) for the reduction of
Cp2TiX2 is that of Cp2Ti(OTs)2 (3) and not that of Cp2Ti(OTf)2 (2).
Complex 5 is most difficult to reduce. Since 4 and 6 have
essentially the same potentials, the steric demand of the ligand
has no appreciable effect on the redox properties.
Electrochemically reduced Cp2TiX2
The electrochemically reduced complexes allow the investigation
of the EqCr scheme shown in Scheme 3 as a function of X.[19]In
this way, the peak potentials of [Cp2TiX2]- and Cp2TiX that are
both pertinent to catalysis can be measured. Moreover,
information about the position of the equilibrium can be obtained.
In the case of Cp2TiCl-based systems, this equilibrium is essential
for the stability of the catalytic system by providing the anionic
titanocene(III) complex as a resting state for the catalyst.[12]
For Cp2TiOTf a peak potential of -0.31 V was measured on the
oxidative sweep (Figure 1, pink voltammogram) that is generally
associated with the generation of Cp2Ti+.[12,13,20] Therefore, OTf-
can dissociate from Ti even in THF without the aid of a Lewis acid.
It is noteworthy, that the cationic species Cp2Ti+ is not generated
during the sweep by a so called parent-child reaction since the
oxidation current of Cp2Ti+ does not decrease significantly upon
increasing the sweep rate, which is otherwise indicative for this
reaction. The other peak potentials (Ep,a1) corresponding to the
oxidation of [Cp2TiX2]- follow the expected trend. The least
coordinating anion OTs- results in the most difficult oxidation,
whereas the trifluoroacetate complex with the most nucleophilic
anion has the most negative potential. As for the Ep,a1 the Ep,c
value is, within experimental error, not affected by the steric bulk
of the ligand.
Scheme 3. EqCr-scheme for the electrochemical reduction of Cp2TiX2,
(Eq = quasi-reversible electrochemical reduction, Cr = reversible chemical
reaction).
Table 1. CV data for the reduction of Cp2TiX2 (1–6) in THF in terms of peak
potentials for the cathodic wave (Ep,c) and the two anodic waves (Ep,a1 and
Ep,a2) recorded at a glassy carbon disk electrode in 0.2 M Bu4NPF6/THF at a
sweep rate of 0.2 Vs-1.[a]
Changing the anionic ligands in our readily accessible Cp2TiX2
complexes 2 – 6 should allow a straightforward modification of the
redox properties of titanocene complexes and the dissociation of
the anionic ligands from the metal center.
complex
Ep,c/V
Ep,a1/V
Ep,a2/V
[b]
1, X = Cl
2, X = OTf
3, X = OTs
4, X = OMs
5, X = TFA
6, X = CSA
-1.37[b]
-1.05
-0.96
-1.03
-1.08
-1.05
-1.23[b]
-0.31
-0.81
-0.92
-0.98
-0.93
-
-
-0.70
-0.62[c]
-0.58
-0.64
[a] All potentials are given in units of V vs. Fc+/Fc and can be converted to
V vs. SCE by adding 0.52 V. [b] not visible at the sweep rates used here[12]
[c] Recorded at a sweep rate of 0.5 Vs-1
.
The second oxidation wave (Ep,a2) pertains to the oxidation of
Cp2TiX. We did not observe the formation of any dimers (Cp2TiX)2.
Since the decomposition of Cp2TiCl has been suggested to occur
via its dimer[10d] our catalysts should be stable without additives.
Curiously, of all measured complexes Cp2Ti(OTs) (-0.70 V) is the
strongest and Cp2Ti(O2C2F3) (-0.58 V) the weakest reductant. To
understand this difference quantitatively, an analysis of the
solvation of Cp2TiX and Cp2TiX+ is necessary. This is beyond the
scope of this study. From these values, it is clear that just by
varying the anionic ligand the values for Ep,c, Ep,a1, and
Ep,a2(except for Ep,a1 of 2 that pertains to Cp2Ti+) changes by at
least 400 mV for electrochemically reduced Cp2TiX2. Thus, it can
be expected that these complexes show distinctly differing
Figure 1. Cyclic voltammograms of 2 mM Cp2TiX2 (legend) recorded at a glassy
carbon disk electrode with  = 0.2 V s-1 in 0.2 M Bu4NPF6/THF.
The formation of Cp2TiX is more favorable for the less nucleophilic
tosylate than for mesylate. However, steric effects are also very
important for the formation of Cp2TiX. With the bulky
camphorsulfonate the loss of the anionic ligand is even more
advantageous than for OTs-. Interestingly, even for the bidentate
trifluoroacetate that should also be the most nucleophilic anion
investigated some Cp2TiX is formed.
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reactivity in oxidative additions and reductive eliminations in
single electron steps.
In the lower images of Figure 2, three segments of the oxidation
wave of Zn-3 at sweep rates of 0.2, 1.0, and 2.0 Vs-1 are shown.
At the lowest sweep rate of 0.2 Vs-1 no Cp2Ti+ was observed. At
the higher sweep rates of 1.0 and 2.0 Vs-1 the oxidation wave of
Cp2Ti+ at -0.19 V is detectable. Its intensity increases with higher
sweep rate. Moreover, the oxidation wave pertinent to
Cp2TiOTs*Zn(OTs)2 is present in all voltammograms but loses
intensity at higher sweep rates. Based on the fact, that cyclic
voltammetry is a dynamic technique, at low sweep rates the
component that is easier to oxidize is detected with an oxidation
wave of higher intensity. In our case, the relevant equilibrium for
Zn-3 is that between Cp2TiOTs*Zn(OTs)2 and Cp2Ti+ together
with the solvent separated anion [Zn(OTs)3]-. At higher sweep
rates, the complexation is outrun and the detection of Cp2Ti+
becomes possible. The precise composition of the solution
content could be determined if sufficiently high sweep rates are
employed to decrease the time scale of the experiment and hence
to outrun follow-up reactions. Unfortunately, this is not possible
with the ordinary microelectrodes used here.
Zn reduced Cp2TiX2 (Zn-Cp2TiX2):
Typically, the Cp2TiX complexes employed in catalytic radical
arylations or tetrahydrofuran synthesis are prepared by reduction
of Cp2TiX2 with Zn powder (Zn-Cp2TiX2).[16] The presence of Zn2+
has a profound influence on the composition of Cp2TiCl2 based
systems as they are able to abstract Cl- from [Cp2TiCl2]- to
generate the catalytically active Cp2TiCl. For our complexes 3 –
6, Cp2TiX and no [Cp2TiX2]- could be detected. Their
voltammograms are shown in the upper part of Figure 2. In case
of 5 only one oxidation peak is observable at -0.48 V that can be
assigned to the neutral Cp2Ti(O2C2F3). For 4 a second oxidation
wave at -0.19 V was observed that is owing to Cp2Ti+. The
difference of the oxidation potential pertaining to Cp2Ti+ derived
from Cp2Ti(OTf)2 is due to the lower sweep rate which effects the
peak potential of the wave (Table 1, entry 2). Also, the different
reaction conditions for the preparation of (Zn-Cp2Ti(OTs)2) and
the in situ electrochemical reduction of the catalyst (Cp2Ti(OTf)2)
might have a minor effect on the peak potential. The situation is
less clear-cut for 3 and 6. The second oxidation waves cannot
originate from Cp2Ti+. We suggest that they are due to
Cp2TiX*ZnX2 because of their potentials of -0.40 V (for 3) and -
0.37 V (for 6) that demonstrate that they are less electron deficient
than Cp2Ti+ but more electron deficient than Cp2TiX.
Kinetic Investigation of Zn-2 – Zn-6
Table 2. Rate constant for epoxide opening with Cp2TiX2.
2 mM Zn-[Cp2Ti(OTs)2] 3
2 mM Zn-[Cp2Ti(OMs)2] 4
2 mM Zn-[Cp2Ti(TFA)2] 5
2 mM Zn-[Cp2Ti(CSA)2] 6
5
4
Rate Constant,
M-1s-1
Epoxide
order
Entry
Cp2TiX2
3
1
2
3
4
5
6
1[a], X = Cl
2[b], X = OTf
3, X = OTs
4, X = OMs
5, X = TFA
6, X = CSA
1.1 ± 0.1
1.0 ± 0.1
1.1 ± 0.1
1.1 ± 0.2
1.3 ± 0.2
0.9 ± 0.2
1.0 ± 0.3
0.0035 ± 0.0003
0.022 ± 0.005
0.013 ± 0.003
0.019 ± 0.005
0.019 ± 0.005
2
1
0
-1
[Cp2TiX2] = 2 mM; [Zn] = 16 mM; THF = 3 mL; λmax for [Ti(III)] is 675 nm; [Ti(III)]
solutions were filtered before commencing runs;[a] 4 mM Coll*HCl added; [Mn] =
8 mM; λmax for [Ti(III)] is 800 nm [b] [NaBH4] = 2 mM; 4-10 mM CHD added; λmax
for [Ti(III)] is 800 nm.
-2
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
E / V vs. Fc+/Fc
The impact of ligands on the activity of titanocene(III) complexes
was further investigated by measuring the rate constants for
opening epoxide 7 (Table 2). The epoxide opening experiment
was performed under pseudo-first order conditions and the rate
constants were obtained by monitoring the decay of the active
titanocene(III) band via UV-vis spectroscopy (See Supporting
Information for details). The order for epoxide 7 was also
determined to ensure the mechanism for the epoxide opening
reactions with the different titanocene(III) complexes were similar.
All experiments were repeated twice to ensure reproducibility of
results. The rate constant for opening 7 was highest with the
traditional Cp2TiCl, which had to be performed in the presence of
Coll*HCl to obtain a stable catalyst. Conversely, the rate constant
for opening 7 was the lowest with Cp2TiOTf, the most Lewis acidic
and least reducing titanocene(III) complex in this study (Table 1,
entry 2).
Figure 2. [a] CVs of Zn-2 to Zn-6 recorded at a sweep rate of 0.2 Vs-1 in 0.2 M
Bu4NPF6/THF (upper image) and [b] segments of the oxidation wave of Zn-3 at
sweep rates of 0.2, 1.0 and 2.0 Vs-1.
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obtained from the catalyst stability tests (Figure 3). The reaction
progress was monitored via in situ IR spectroscopy. Thus, catalyst
generation by mixing of Cp2TiX2 and Zn is both straightforward to
carry out and more sustainable than for the earlier systems.
0,05
0,045
0,04
0,035
0,03
0,025
0,02
0,015
0,01
0,005
0
0,05
Cp2Ti(OTs) stability test
Cp2Ti(O2C2F3) stability test
0,04
Performance of Zn-2 – Zn-6 in Catalysis in Single Electron
Steps
0,03
100% Run
100% Run
50% Run (Time adjusted)
0,02
50% Run (Time-adjusted)
Radical arylation of epoxides
0,01
0
0
20
40
60
80
0
20
40
60
80
We have previously shown that in the arylation of epoxide derived
radicals, the ‘back-electron transfer’ or the proton coupled
electron transfer and, therefore, the reductive elimination is the
turn-over limiting step.[10d] It is crucial to employ a catalyst with
electronic properties facilitating the electron transfer from the
arene to the Ti(IV)-center in order to regenerate the active catalyst
and furnish the desired product (Scheme 1). If the catalyst’s
electronic properties are not adequately adjusted, this may lead
to catalyst decomposition and even to the failure of the arylation.
The reactions of 9S highlight this point (Scheme 4).
Time, min
Time, min
0,05
Cp2Ti(CSA) stability test
0,05
0,04
0,03
0,02
0,01
0
Cp2Ti(OMs) stability test
0,045
0,04
0,035
0,03
0,025
0,02
0,015
0,01
0,005
0
100% Run
50% Run (Time- adjusted)
100% Run
50% Run (Time-adjusted)
0
50
100
150
200
250
0
10
20
30
40
50
60
70
80
90
Time, min
Time, min
Figure 3. Time-adjusted decay plots for 100% and 50% runs with Zn-Cp2TiX2
as catalyst. Reaction conditions: 100% Runs; [Epoxide] = 56 mM; [Cp2TiX2] =
5.5 mM; [Zn] = 11 mM; THF = 15 mL; T = 60 °C; 50% Runs; [Epoxide] = 28 mM;
[Cp2TiX2] = 5.5 mM; [Zn] = 11 mM; THF = 15 mL; T = 60°C.
With the newly generated titanocene(III) complexes (3 – 6), the
reactions were done in the absence of salt additives and the rate
constants for opening 7 where within the same order of
magnitude. The rate constant for opening 7 with Zn-3 as the
catalyst was slightly higher, followed by Zn-5 and Zn-6, whose
rate constants were identical. Zn-4 recorded the lowest rate
constant for the newly synthesized titanocene complexes. It could
however be argued that the rate constants for opening epoxide 7
are within error uncertainty for the newly generated titanocene
complexes. Moreover, these titanocene catalysts are faster than
Cp2TiOTf at opening 7.
Scheme 4. Performance of Zn-Cp2TiX2 in the radical arylation of 9S.
The two electron-withdrawing substituents render the ‘back-
electron transfer’ too unfavorable to allow good results with
Cp2TiCl2 as precatalyst. Our catalysts 3 – 6 give very good results
with 7S when the Zn-reduction and arylation are carried out in
refluxing THF for 2 h. Complexes 4 and 6 give similar yields than
our ‘best’ catalysts (C5H4Cl)2TiCl2and 2.[10a,10d] However, our new
catalysts are easier to prepare by Zn-reduction and do not require
an additive (Coll*HCl for (C5H4Cl)2TiCl2).To check if shorter
reaction times are possible, we investigated the reactions
of8Sthat is a very good substrate for the radical arylation next
(Scheme 5). Only with 5 we obtained a very good yield (90%) of
8P. Complex 4 was less active but still gave a good yield of 77%.
However, 3 and 6 gave only a low conversion to the product.
Because of their satisfying performance in the reactions of 7S and
8S, we decided to use 4 and 5 for a set of substrates to define
their scope (Scheme 6).
To demonstrate the stability of the newly generated catalysts (Zn-
3 to Zn-6) in the absence of a salt additive predicted by CV we
studied the unimolecular arylation of 8S to 8P (Figure 3). To this
end, two separate reactions were carried out with the same
catalyst under identical conditions, with the only difference being
that one reaction starts with 50% of the reactant concentration.
The principle behind this technique is that if the stoichiometry of
the reactants during the reaction is known and there is no
substrate or product inhibition, the catalyst concentration should
remain constant throughout the reaction. Under ideal conditions,
8S is consumed, 8P is formed and [titanocene] is constant. A
second reaction that was started under conditions that
correspond to 50% conversion of the first reaction should follow
the reaction profile of the first reaction as long as [titanocene] is
constant. In other words, a graphical overlay will be observed for
a time-resolved plot of the reactant decay over time for both
experiments if the catalyst is stable.[21] The titanocene(III)
complexes 3 – 6 efficiently catalyzed the radical arylation of 8S to
8P, and were stable without a salt additive as shown in the results
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by a strong binding of the catalyst to the polar carbamate that
inhibits binding of the epoxide and, therefore, leads to a slower
epoxide opening.
Scheme 5. Performance of Zn-Cp2TiX2 in the radical arylation of 8S.
For the indolines and tetrahydroquinoline products 10P – 13P
yields in the range of 90% were obtained with both 4 and 5. For
these substrates 2 gave similar yields and, therefore, our new
catalysts 4 and 5 are at least as active and stable as the formerly
best catalyst.
Compared to 8Pand 10P– 13P, the pyrrole 14P was obtained in
a lower yield of 71% with 4. Presumably, this is due to the
sensitivity of 14S to Lewis-acids. However, 4 is superior to 2 that
resulted in a 67% yield of 14P.[22]
Scheme 7. Performance of Zn-Cp2TiX2 in the radical arylation of 15S and 16S.
Thus, Zn-Cp2Ti(OMs)2 (Zn-4) is to date the best catalytic system
for the radical arylation of epoxides. It is as active as the
Cp2Ti(OTf)2-derived systems but does not lead to Lewis-acid
induced side reactions and is more active than Zn-(C5H4Cl)2TiCl2
without inducing undesired side-reactions.
Scheme 6. Performance of Zn-Cp2Ti(OMs)2 4 and Zn-Cp2Ti(TFA)2 5 in the
radical arylation with various substrates. Conditions: THF, reflux, 2 h – 5 h.
Epoxides 15S and 16S are substrates that are more critical. The
tricyclic core of 15P is fairly strained and therefore an efficient
back electron transfer is mandatory to a high yield of 15P.
Moreover, 15P is somewhat sensitive to Lewis-acids and,
therefore, a too Lewis-acidic catalyst will result in product
decomposition. Complex 4 is the best compromise between both
requirements and results in higher yields of 15P than 2 (77%) or
(C5H4Cl)2TiCl2 (70%).[10a,10d]
The issue of the Lewis-acidity of the catalyst is even more
important for carbamate substrates. The FMOC-protected 16S is
not suitable for reactions with Cp2Ti(OTf)2 (2) because of Lewis-
acid induced intramolecular epoxide opening reactions by the
carbamate. However, 4 gave a satisfactory yield of 16P with 10 or
20 mol% of the catalyst. The higher loading can be rationalized
Synthesis of polycyclic tetrahydrofurans
The titanocene catalyzed synthesis of polycyclic tetrahydrofurans
is another reaction that proceeds via catalysis in single electron
steps.[3]As in the radical arylation, the reductive elimination
(Scheme 1) that proceeds via a homolytic substitution is the
critical step of the catalytic cycle. The reductive elimination that
may be regarded as an organometallic oxygen rebound will be
favored when using more electron deficient titanocenes. We have
previously shown that Zn-(C5H4CO2Et)CpTiCl2 is higher yielding
catalytic system than Zn-Cp2TiCl2 (1) because the reductive
elimination proceeds more efficiently with a catalyst containing
the electron withdrawing ester substituted cyclopentadienyl
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ligand.[3]It should be noted that (C5H4CO2Et)CpTiCl2 has to be
synthesized from the somewhat sensitive precursor CpTiCl3 and
the ester substituted cyclopentadiene.
Our Cp2TiX2derived systems are ideally suited for probing the
influence of the electronic properties of the catalyst on the
reductive elimination and on the overall performance of the
reaction. The investigations with 17Sand the catalysts 2 – 6are
summarized in Scheme 8.
Scheme 9. Performance of Zn-Cp2TiX2 in the synthesis of the benzylic
tetrahydrofuran synthesis 18P.
Conclusions
In summary, with Zn-Cp2Ti(OMs)2 (Zn-4)we have discovered a
highly active and stable catalytic system with a high functional
group tolerance for the atom-economical arylation of epoxide-
derived radicals and for the atom-economical synthesis of
polycyclic tetrahydrofurans. The straightforward synthesis of
Cp2Ti(OMs)2from Cp2TiCl2 in two steps and the easy generation
of Zn-4that requires no additives add to the sustainability of the
catalytic reactions. By our approach of tailoring the electronic
properties of titanocene complexes Cp2TiX2 by varying the
anionic ligand X renders the more tedious method of covalently
modifying the cyclopentadienyl ligands superfluous.
Scheme 8. Zn-Cp2TiX2catalyzed tetrahydrofuran synthesis from 17S.
Of the catalyst, Zn-3 gave the lowest yield of 17P whereas NaBH4-
reduced 2, Zn-5, and Zn-6 resulted in a similar outcome of the
reaction (71%-75%). However, the use of 2is practically
disadvantageous because it leads in the formation of THF
polymers that are difficult to remove. By far the best result was
obtained with Zn-4. A high yield of 87% of 17P was obtained. No
side-products were detected and the catalyst did not initiate THF
polymerization. Thus, Zn-4 is also the most efficient catalyst for
the formation of 17P.
Catalyst discovery was accomplished by
a
combined
electrochemical, kinetic and synthetic study that delineates the
critical properties of an active and stable catalyst. The
combination of these complementary methods is unique in
providing a mechanism-based platform for efficient catalyst
design that will also be useful in other systems of catalysis in
single electron steps.
Finally, we studied the performance of our catalysts with 18S. This
reaction is challenging for two reasons. First, the reductive
elimination is significantly more difficult because a stabilized
benzylic radical is consumed in tetrahydrofuran formation rather
than an alkyl radical as for 17S.[3,6b] Second, 18P is sensitive to
acidic conditions because a stabilized benzylic cation is formed
after acid-induced ring opening.
As shown in Scheme 9, only Zn-4 and Zn-6 lead to reasonable
conversion and to good yields of 18P. The reaction had to be
carried out at room temperature to avoid decomposition of 18P.
NaBH4-2 and Zn-3lead to extensive decomposition presumably
because of their Lewis-acidity. Zn-5 resulted in a low conversion
to about 40% of 18P. Zn-1 (17% 18P)[6b] and the currently best
catalyst for tetrahydrofuran synthesis Zn-(C5H4CO2Et)CpTiCl2
(40% 18P)[3] give distinctly inferior results and require Coll*HCl
(50 mol%) as additive.
Experimental Section
Representative procedure: Substrate 9S (199 mg, 0.5 mmol, 1 eq.), 5
(10.1 mg, 0.025 mmol, 5.0 mol%), and Zn (6.5 mg, 0.1 mmol, 0.2 eq.) were
placed in an oven-dried Schlenk flask. THF (5 mL) was added, and the
mixture was refluxed under an Ar atmosphere for two hours. The mixture
was cooled to room temperature and filtered through a short pad of
SiO2with ethyl acetate (75 ml). After removal of the solvent under reduced
pressure, the crude product was purified by flash chromatography (SiO2;
cyclohexane/ethyl acetate 80:20) to give 193 mg (97%) of 9P.
Acknowledgements
We thank the Deutsche Forschungsgemeinschaft (SFB 813
‚Chemistry at Spin Centers‘ and Ga 619/12-1), the Konrad-
Adenauer-Stiftung (R. B. R.), the Evangelisches Studienwerk
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10.1002/chem.201705707
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J. I. van der Vlugt, B. de Bruin, Angew. Chem. Int. Ed. 2013, 52, 12510-
12529; Angew. Chem. 2013, 125, 12740-12750; e) N. D. Paul, S. Mandal,
M. Otte, X. Cui, X. P. Zhang, B. de Bruin, J. Am. Chem. Soc. 2014, 136,
1090-1096; f) P. F. Kuijpers, M. J. Tiekink, W.P. Breukelaar, D. L. J
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Chem. Eur. J. 2017, 23, 7945-7952.
Villigst (T. O.), the Jürgen Manchot Stiftung (S. H.) and the
National Science Foundation (CHE-1123815 and CHE-1565741)
for support of this work.
Keywords:arylation • catalysis • cyclic voltammetry • epoxides •
kinetics • radicals
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It’s the inorganic ligand! With the aid of
R. B. Richrath, T Olyschläger, S.
cyclic
voltammetry
and
kinetic
Hildebrandt, D. G. Enny, G. D. Fianu,
R.A. Flowers II,* A. Gansäuer*
investigations Cp2TiX2 complexes with
sulfonate ligands were identified as
attractive catalysts in radical arylations
and tetrahydrofuran synthesis. They do
not require additives for catalyst
stabilization and render the covalent
modification of the cyclopentadienyl
ligands for the tailoring of their
performance in catalysis in single
electron steps superfluous.
Page No. – Page No.
Cp2TiX Complexes for Sustainable
Catalysis in Single Electron Steps
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