A medium fluorous Grubbs-Hoveyda 2nd generation catalyst for phase transfer catalysis of ring closing metathesis reactions

Article abstract of DOI:10.1016/j.tetlet.2015.01.097

A fluorous Grubbs-Hoveyda metathesis catalyst supported on Teflon powder, that readily moves between the solid phase (Teflon) and the liquid phase (DMF) was prepared. By modulating the hydrophobicity of the reaction medium at the end of the reaction, the supported catalyst could be recovered by simple filtration even though the catalyst existed in a homogeneous state during the reaction. In RCM reactions, the catalyst could be reused up to three times with only a slight loss in reactivity with each subsequent cycle.

Full text of DOI:10.1016/j.tetlet.2015.01.097

Accepted Manuscript
nd
A medium fluorous Grubbs-Hoveyda 2 generation catalyst for phase transfer
catalysis of ring closing metathesis reactions
Yuki Kobayashi, Sae Inukai, Natsuki Kondo, Tomoko Watanabe, Yuya
Sugiyama, Hiromi Hamamoto, Takayuki Shioiri, Masato Matsugi
PII:
S0040-4039(15)00124-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.01.097
TETL 45767
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
8 December 2014
9 January 2015
14 January 2015
Please cite this article as: Kobayashi, Y., Inukai, S., Kondo, N., Watanabe, T., Sugiyama, Y., Hamamoto, H., Shioiri,
nd
T., Matsugi, M., A medium fluorous Grubbs-Hoveyda 2 generation catalyst for phase transfer catalysis of ring
closing metathesis reactions, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.01.097
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A medium fluorous Grubbs-Hoveyda 2 generation
catalyst for phase transfer catalysis of ring closing
metathesis reactions
Leave this area blank for abstract info.
Yuki Kobayashi, Sae Inukai, Natsuki Kondo, Tomoko Watanabe, Yuya Sugiyama, Hiromi Hamamoto,
Takayuki Shioiri, Masato Matsugi∗

1
Tetrahedron Letters
journal homepage: www.els evier.com
nd
A medium fluorous Grubbs-Hoveyda 2 generation catalyst for phase transfer
catalysis of ring closing metathesis reactions
Yuki Kobayashi, Sae Inukai, Natsuki Kondo, Tomoko Watanabe, Yuya Sugiyama, Hiromi Hamamoto,
Takayuki Shioiri, Masato Matsugi∗
Faculty of Agriculture, Meijo University, 1-501 Shiogamaguchi, Tempaku, Nagoya 468-8502, Japan
ARTICLE INFO
ABSTRACT
®
A fluorous Grubbs-Hoveyda metathesis catalyst supported on Teflon powder, that readily
®
moves between the solid phase (Teflon ) and the liquid phase (DMF) was prepared. By
Article history:
Received
Received in revised form
Accepted
modulating the hydrophobicity of the reaction medium at the end of the reaction, the supported
catalyst could be recovered by simple filtration even though the catalyst existed in a
homogeneous state during the reaction. In RCM reactions, the catalyst could be reused up to
three times with only a slight loss in reactivity with each subsequent cycle.
Available online
Keywords:
2
014 Elsevier Ltd. All rights reserved.
Medium fluolous strategy
Phase transfer catalyst
Hydrophobicity
nd
Grubbs-Hoveyda 2 generation
Ring closing metathesis
Perfluorocarbons generally exhibit an extremely low affinity
1
for water due to the fact that the C-F bonds of perfluorocarbons
don’t form hydrogen bonds. By being so hard and non-
polarizable, perfluorocarbons "exclude" water and organic
compounds and thereby prefer to interact with each other in their
2
own phase rather than with an organic or aqueous phase. We
wanted to exploit this remarkable feature of the perfluorocarbons
by exploring their ability to control a fluorous compound’s
physical properties simply by tuning the reaction medium in
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Figure 2. Fluorous catalyst 1a supported on Teflon .
3
which it is present. More specifically, we planned to achieve an
effective catalytic reaction manifold wherein the catalyst can be
recovered easily in a solid state after the reaction even though the
catalyst exists in the homogeneous state during the reaction. This
allows us to take advantage of solution phase reaction kinetics
with the benefits of solid phase purification techniques. We
reasoned that such a catalytic system could be possible by
carefully controlling both the amount of water in the reaction
medium and the degree of fluorophilicity of the fluorous catalyst.
Herein, we would like to report the first example of a phase
4
transferable Grubbs-Hoveyda type metathesis catalyst where the
catalyst moves between the solid phase and the liquid phase in
5
ring closing metathesis (RCM) reactions.
6
We prepared a novel medium fluorous catalyst 1a (Figure 1)
bearing a C10
phase transfer catalysis hypothesis as described above. We chose
F21 tag, and used it for the purposes of exploring our
®
7
Teflon powder as the fluorous solid support used to recover the
catalyst at the end of the reaction as a manageable solid because
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Teflon is significantly cheaper than other available fluorous
8
solid supports such as fluorous silica gel. As shown in Figure 2,
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Figure 1. Fluorous metathesiscatalysts and GH2 generation
catalyst.
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we were able to prepare a fluorous supported catalyst on Teflon
by evaporating the solvent of a dichloromethane solution of
—
——
∗
Corresponding author. Tel.: +81-52-832-1151; fax: +81-52-835-7450; e-mail: matsugi@meijo-u.ac.jp

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Tetrahedron Letters
®
catalyst 1a that had Teflon powder added to it. Catalyst
deposition on the solid supported is evidenced by the isolated
circumstances. This result suggests that the slightly larger
fluorine content of the medium fluorous catalyst is required to
achieve the effective phase transfer phenomenon.
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solid being green in color where the Teflon powder itself is
Since it was found that a combination of catalyst 1a and
methanol or DMF was suitable for the phase transfer strategy, we
next turned our attention to the RCM reaction that gives
1
3
cyclopentene 3 from N,N-diallyl-p-toluenesulfonamide 2 in
order to verify catalytic activity in these solvents initially in the
®
absence of the Teflon powder. Gratifyingly, by using 1a (5
mol%) at a concentration of 0.05M conditions, the RCM product
was obtained in quantitative yield in 30 min at room temperature
in DMF. Unfortunately, the RCM reaction did not go to
completion under the same conditions when using methanol as a
solvent. Although we could drive the reaction to completion by
raising the reaction temperature to 40 °C, we observed the
Figure 3. A phase-transfer strategy of fluorous catalyst.
1
white. The supported catalyst was air-stable over several days, so
special handling wasn't required. A similar strategy for catalyst
recovery has been employed by the Gladysz group in their
disappearance of the characteristic H NMR resonance at ꢀ 16.4
ppm assigned to the carbene proton of the catalyst which was
verified by comparison to a fresh sample of catalyst (see the
4
a
9
®
10
1
Supplemental Data for H NMR spectrum). This suggests that at
pioneering work where they use Teflon tape as a way to
remove a heavy fluorous ruthenium catalyst from reaction
mixtures. In this work they relied on temperature to move the
catalyst from one phase to another in a thermomorphic catalytic
slightly elevated temperatures, the catalyst decomposes.
Therefore for simplicity, we decided to use DMF as the solvent
for further investigations of the phase transfer catalytic system.
Interestingly, the use of the commercially available catalyst 1c
9
b
system for hydrosilylation. We however, planned to effect
recovery of the fluourous metathesis catalyst by changing the
hydrophobicity of the reaction medium with the addition of water
after the reaction as detailed in Figure 3. At first, the behavior of
the fluorous catalyst 1a in various organic reaction media was
nd
(Grubbs-Hoveyda 2 generation, Figure 1) in the RCM reaction
when DMF was used as the solvent resulted in lower catalytic
activity, when compared to the medium fluorous catalyst 1a. In
other words for this type of catalytic system to be efficient, the
use of the fluorous catalyst 1a is required to achieve the
necessary reactivity. Figure 5 shows the difference in catalytic
activity between 1a and 1c in a RCM reaction using 4 as a
®
examined in the presence of Teflon powder. To confirm the
phase transfer capability of 1a between the organic liquid phase
®
and the Teflon powder solid phase, 30 times, by weight, the
®
amount of catalyst to Teflon powder was used for the catalyst
1
substrate, and measured with H NMR in DMF-d7.
mixture. Interestingly we could readily confirm that the catalyst
was transferring phases visually: as shown above, the color of the
1
1
solid catalyst 1a was green, and so we could observe the
transfer of the catalyst by the trace of the green color present in
the organic solvent phase. We found that the optimum solvent
for the phase transfer phenomenon was either methanol or N,N-
dimethylformamide (DMF) when medium fluorous catalyst 1a
was employed. Figure 4 shows the phase transfer activity of the
®
fluorous catalyst 1a between methanol and the Teflon powder
and how it varies based on the amount of water present in the
solvent. Although catalyst 1a is completely soluble in methanol
Figure 4, left image), it is not soluble in 75% aqueous methanol,
(
®
and is rapidly re-adsorbed onto the Teflon powder (Figure 4,
right image). Similar results could be obtained when DMF was
used as the solvent with the catalyst being in solution but then
®
being readily adsorbed onto the Teflon when the aqueous
1
2
content of the solvent reached 60%. The use of other solvents
such as THF, acetonitrile, and acetone failed to result in an
effective phase transfer of catalyst 1a. When light fluorous
11b
catalyst 1b (Figure 1) was used instead of the medium fluorous
catalyst 1a, effective phase transfer was not observed under any
nd
Figure 5. Catalytic activity of fluorous catalyst 1a and GH 2
generation 1c for the RCM reaction of 4 in DMF-d7.
Figure 4. Catalyst 1a in a methanol solution (left) and
adsorbed onto the Teflon in aqueous methanol (right).
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3
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Table 1. RCM reactions using fluorous Grubbs-Hoveyda metathesis catalyst 1a supported on Teflon powder.
a
Isolated yield.
The recovered solid phase catalyst in entry 1 was used.
b
c
The recovered solid phase catalyst in entry 2 was used.
Conversion yield determined by H NMR of the crude product.
d
1
Next, we tried the full phase transfer catalytic RCM reaction
almost clean and resonances corresponding to the free ligand
(fluorous 1-isopropoxy-2-vinylbenzene) could not be observed
®
of 2 using the supported fluorous catalyst 1a on Teflon powder
in DMF. Additionally the purification of the supported catalyst
by filtration and recycling features of the catalyst were also
examined. In these reactions, we used 90 times Teflon®
1
by either H or F NMR analysis. Spiking the RCM product 3
19
with 0.3 mol% of benzotrifluoride (an amount equivalent to 6%
of the original amount of fluorous catalyst) showed that the CF
3
(
diallyl-p-toluenesulfonamide 2 (439 mg, 1.74 mmol) and
weight/weight) of the catalyst for effective recovery. N,N-
group of the spike was readily detected, so the fluorine content of
the original cyclopentene sample must be well below this. The
yield of the RCM products we obtained ranged from 63% to
94%, while the supported catalyst was recovered almost
®
supported catalyst on Teflon (100 mg: 1a, 0.087mmol; 9.0g:
®
Teflon 90-fold by mass in comparison to the amount of 1a) were
1
4
added to DMF (35 mL, 0.05 M), and the mixture was stirred for 1
h at room temperature. After addition of water to the reaction
mixture to a concentration of 60% aqueous DMF, the mixture
was stirred for 5 min at 5 °C, and then the green supported
catalyst was removed by filtration. After dilution of the filtrate
with water, extraction with ether gave the RCM product 3 in 94%
yield (364 mg) and the supported catalyst in 100% recovery yield
quantitatively in each cycle. At the third cycle, the RCM
reaction was slower, and the starting material alkene 2 was not
completely consumed. As such, the catalytic activity of the
1
supported catalyst was inactivated after the third cycle. The H
NMR spectrum of the recovered non-supported catalyst 1a
obtained by washing the supported catalyst with chloroform
wasn't exactly the same as the original catalyst. Thus,
unfortunately, the third cycle appears to be the limit of this
catalytic system.
(
9.09g), respectively (Table 1, Entry 1). After drying in vacuo,
the recovered supported catalyst was used directly in the second
cycle with appropriate adjustments of all other components to
maintain the same 5 mol% catalyst ratio and the same reaction
time. This process was repeated for three cycles (Entry 2-3). The
Other RCM reactions using the phase transfer catalytic system
were examined, and the results are shown in Table 1 (Entries 4-
11). Except for trisubstituted substrates, all reactions proceeded
1
H NMR spectrum of product 3, through the second cycle, was

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Tetrahedron Letters
at room temperature and were complete within 1 h to give the
reaction media thereby allowing for easy reaction purification as
well as optimal solution phase catalyst kinetics. The fluorous
Grubbs-Hoveyda metathesis catalyst could be reused up to three
times although a slight loss in reactivity with each subsequent
cycle was observed. We believe that this phase transfer strategy
should also be applicable to the various other kinds of fluorous
tagged catalysts that are known.
1
5
corresponding RCM products in good yields, and the supported
catalyst was recovered in approximately 98-100% yield in each
case.
In summary, we prepared a fluorous solid supported Grubbs-
®
Hoveyda metathesis catalyst using Teflon powder, where the
®
catalyst could be shuttled between the solid Teflon phase and
the liquid DMF phase by simple control of water content of the
5
.
For reviews, see: (a) Majumdar, K. C.; Nandi, R. K.; Ray, K. Adv. in
Org. Synth. 2013, 6, 355-435. (b) Perez de Vega, M. J.; Garcia-Aranda,
M. I.; Gonzalez-Muniz, R. Medicinal Research Reviews, 2011, 31, 677-
715. (c) Hassan, H. M. A. Chem. Commun. 2010, 46, 9100-9106.
Matsugi, M.; Suganuma, M.; Yoshida, S.; Hasebe, S.; Kunda, Y.;
Hagihara, K.; Oka, S. Tetrahedron Lett. 2008, 49, 6573-6574.
Acknowledgments
6
7
.
.
This research was partially supported by JSPS KAKENHI
Grant Number (C) 26450145. We thank Prof. Dennis P. Curran,
University of Pittsburgh, for useful suggestions of the fluorous
catalyst synthesis. We also thank Meiji Seika Pharma Co., Ltd.
for funding this work.
The material is commercially available from SANPRATEC corp.
(
Average particle size: 25 ; largest particle size: 120 ).
8. (a) Zhang, W.; Curran, D. P. Tetrahedron 2006, 62, 11837-11865; (b)
Curran, D. P. “Separations with Fluorous Silica Gel and Related
Materials”, in The Handbook of Fluorous Chemistry, Gladysz, J.;
Horváth, I.; Curran, D. P. Wiley-VCH: Wienheim, 2004, pp101-127.
9
.
(a) Gladysz, J. A. Science, 1994, 266, 55-56. (b) Dinh, L. V.; Gladysz, J.
A. Angew. Chem., Int. Ed. 2005, 44, 4095-4097. (c) Seidel, F. O.;
Gladysz, J. A. Adv. Synth. Catal. 2008, 350, 2443-2449.
Supplementary data
1
1
0. Pels, K.; Dragojlovic, V. Beilstein J. Org. Chem. 2009, 5, No75.
nd
1. A green light fluorous GH 2 variant, see: (a) Matsugi, M.; Curran, D.
Supplementary data associated with this article can be found, in
the online version, at http://xxxxx.
P.; J. Org. Chem. 2005, 70, 1636-1642. (b) Matsugi, M.; Kobayashi, Y.;
Suzumura, N.; Tsuchiya, Y.; Shioiri. T. J. Org. Chem. 2010, 75, 7905-
7
908.
References and notes
1
2. In the case of DMF instead of methanol, a similar complete movement of
the catalyst can be confirmed; however we could not take a suitable
®
photo due to the floating phenomenon of the Teflon .
1
.
Horváth, I. T.; Curran, D. P.; Gladysz, A. J. Fluorous Chemistry: Scope
Definition. In Handbook of Fluorous Chemistry, Horváth, I. T.;
Curran, D. P.; Gladysz, A. J., Eds.; WILEY-VCH: Weinheim, 2004; pp1-
.Goering, B. K. Ph.D. Dissertation, Cornell University, 1995.
&
1
1
3. Terada, Y.; Arisawa, M.; Nishida, A. Angew. Chem. Int. Ed. 2004, 43,
063-4067.
4
4
4. The RCM sample of the first cycle (Entry 1 in Table 1) was analyzed by
EPMA (Electron Probe Micro Analysis) using ZAF-correction method.
An average of two determinations indicated the leaching amount of Ru
was 0.42At% (See, Supplementary data).
2
3
.
.
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