Easily removable olefin metathesis catalysts

Article abstract of DOI:10.1039/c2gc36015b

A small family of olefin metathesis catalysts bearing a polar quaternary ammonium group is described. The presence of this group allows for efficient separation of ruthenium impurities after the reaction. Application of catalysts 9 and 11 leads to organic

Full text of DOI:10.1039/c2gc36015b

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Easily removable olefin metathesis catalysts
Krzysztof Skowerski,*a Celina Wierzbicka,a Grzegorz Szczepaniakb, Łukasz Gułajaski,a Michał Bieniek,a
and Karol Grela*b
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A small family of olefin metathesis catalysts bearing a polar
quaternary ammonium group is described. The presence of
this group allows for efficient separation of ruthenium
impurities after the reaction. Application of catalysts 9 and 11
10 leads to organic products of high purity, which exhibit
surprisingly low ruthenium contamination levels (usually
below 5 ppm) after simple and inexpensive purification step.
Alternative solution to these problems can be tailored catalysts
that allow for easier purification.11 For example, catalysts bearing
polar ammonium group in the benzylidene fragment were
40 reported (Fig. 1).12,13,14 It was shown that simple filtration of the
reaction mixture through silica gel results in lowering the amount
of catalyst impurities in the crude products, however in the most
cases the residual Ru level was still too high for pharmaceutical
applications.12 This problem is probably related to placing of the
45 quaternary ammonium group in the benzylidene part which
dissociates during metathesis act. Ru-complexes containing
quaternary ammonium groups in the NHC ligand should be
better solution for removal of Ru-containing impurities after the
reaction. A related approach was reported by Grubbs, who
50 removed ruthenium from crude product by extraction with water.
Poly-(ethylene glycol) (PEG) supported N-heterocyclic carbene-
based ruthenium complex 6 migrates to water fraction, giving the
product with low residual ruthenium (42 ppm).11c
The development of modern Ru metathesis catalysts, such as
15 Grubbs and Hoveyda–Grubbs carbenes combining high activity
with an excellent tolerance to a variety of functional groups has
been the key to widespread applications of olefin metathesis in
synthesis of a large number of compounds.1
N
N
N
N
PCy3
Cl
Ru
N
N
Cl
Mes
Mes
Mes
Mes
Mes
Mes
Ph
Cl
Cl
Ph
Ru
Ru
O
Ru
Ph
PCy3
Cl
Cl
Cl
Cl
PCy3
PCy3
Recently, we elaborated
a simple synthetic protocol for
Gru-II
Ind-I
Ind-II
Hov-II
55 preparation of water soluble, quaternary ammonium chloride
tagged catalysts.15 Quaternization of the preformed metal
complexes allows for very simple preparation of highly polar
catalysts. This method allows to obtain various Ru-complexes
containing quaternary ammonium groups in the NHC ligand.
60 Using this methodology we synthesized new complexes 9-11
(Scheme 1), according to pathway presented on Scheme 2.
O-PEG-Me
Mes
N
N
Mes
Mes
N
N
Mes
Cl
Mes
Cl
N
N
Cl
Ru
Mes
Ru
O
Cl
Cl
Ru
X
O
Cl
(
)
n
N
R
N
O
PF6
Et
Et
1
2
: X = I, R = CH3
: X = TsO, R = H
3
4
5
: n = 0
: n = 1
: n = 3
6
N
N
Figure 1. Standard catalysts (Gru-II
designed for simple removal of Ru from metathesis products
(Mes = 2,4,6-tri-methylphenyl, Cy = cyclohexyl, TsO = p-toluenosulfonate)
,
Ind-I
,
Ind-II
,
Hov-II) and selected complexes
1
-6
N
Mes
N
N
N
Mes
Mes
Mes
Cl
Cl
Ru
Ru
Cl
Cl
O
O
NO2
20 Despite general superiority offered by this family of catalysts,
they share some disadvantages. Removing of heavy-metal
impurities from the reaction products becomes one of the major
problems in introduction of olefin metathesis in pharmaceutical
industry. The development of an efficient, economical and
25 practical method to remove metal containing by-products might
be crucial for further application of metathesis methodology in
8
7
CH3I
CH3I
CH3Cl
N
N
N
N
N
I
Cl
I
N
N
N
N
Mes
Mes
Mes
Mes
Mes
Mes
Cl
Cl
Cl
industry.2 Several protocols to solve the problems associated with
Ru contamination arising during pharmaceutical or fine chemical
processing have been proposed.3 Use of biphasic aqueous
30 extraction,4 various scavengers, such as lead tetraacetate,5
DMSO,6 triphenylphosphine oxide, isocyanide,7 functionalized
mesoporous silicates,8 (DMSO) and supported phosphines9 were
reported to reduce the ruthenium content to 10–1200 ppm.
Alternatively, two cycles of chromatography, followed by 12 h
35 incubation with activated charcoal, resulted in <100 ppm of
residual ruthenium.10
Ru
O
Ru
Ru
Cl
Cl
Cl
O
NO2
O
NO2
9
10
poorly defined complex
11
Scheme 1. New route to ammonium tagged Ru-complexes
Compound 13 was synthesized from commercially available N,N-
dimethyl allylamine and was used in its crude form. Purification
of 14 involved only removal of excess of 2,4,6-trimethylaniline
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and filtration of crude product through a short pad of silica gel. 35 complexes 9–11 outweigh the adverse effects of the use of
Salt 15 was purified by crystallization and was finally obtained in
30 % overall yield. Upon action of potassium tert-amylate, a free
NHC was generated, which was reacted in situ with Ind-I to yield
16. This complex was then reacted with benzylidene ligand
precursors 17 and 18, to give free amine-containing catalysts 7
and 8, respectively. Quaternization of these neutral complexes
with methyl iodide or methyl chloride afforded catalysts 9–11 in
high yields (Scheme 2). Some interesting differences in solubility
10 of complexes 9–11 were observed. Catalyst 9 is soluble only in
organic solvents (such as dichloromethane) and is not soluble in
water. Complex 10 showed negligible solubility in both organic
solvents and water, therefore its structure was confirmed only by
IR and MS analysis. However, solubility of 10 in refluxing DCM
15 is sufficient to perform homogeneous metathesis reactions. On
the other hand, catalyst 11 showed good solubility in organic
solvents as well as in water.
dichloromethane.
Table 1. Model metathesis reactions
Conv.a
(%)
Ru
(ppm)
Yield
(%)
Time
(h)
Entry
Substrate
Product
Cat.
5
>99
>99
1
2
9
10
2
0.25
98
99
4.6b
1.5b
NTs
NTs
19
20
3
4
9
10
5.5
0.5
98
>99
96
99
4.8b
2.0b
NTs
NTs
21
22
CO2Et
3.8b
2.6b
9
5
6
7
8
4
97
98
93
89
98
>99
>99
>99
CO2Et
10
11
11
0.5
0.3
0.3
0.8b
CO2Et
CO2Et
<0.004c
23
24
0.9b
ND
CO2Et
CO2Et
CO2Et
CO2Et
9
9
10
2
5
95
95
99
>99
91
NI
97
89
10
11
12
10
10
11
1.0b
0.9c
25
26
2
3.8b
ND
13
14
15
16
9
1.3
98
97
99
>99
96
NI
99
86
10
10
11
0.15
0.5
0.15
O
O
2.6b
8.4c
Ph
Ph
Ph
28
Ph
27
H
Cl
N
O
1) Br H O
MesNH
70 %
2,
2
2
N
O
(
)
OTBS
O
2) HCl
17
18
19
9
10
11
1.3
0.5
0.3
98
>99
>99
97
98
90
Br
3
1.7b
0.8b
29
66 %
13
12
( )
3
Br
31
<0.004c
O
OTBS
30
N
Conditions: catalyst 1 mol%, DCM, 40 oC, C = 0.05 M,a - determined by GC,
b - filtration; c - extraction, NI - not isolated, ND - not determined
N
TEOF, NH BF
4
1) t-AmOK
4
2) Ind-I
N
N
Mes
Mes
BF
62 %
MesHN
14
83 %
NHMes
H
We checked that the optimal purification protocol for reactions in
which 9–11 were applied consists of filtration of the reaction
mixture through a short pad of silica gel (Figure 2A, 2B) (silica
40 gel/substrate mass ratio = 7) and product elution with additional
portion of DCM (Figure 2C, 2D).
15
4
N
CH I
3
17
9
7
CuCl
68 %
98 %
N
N
Mes
Mes
CH I
3
Ph
Cl
10
11
86 %
Ru
, CuCl
18
Cl
8
69 %
CH Cl
3
PCy
16
3
64 %
OPr-i
OPr-i
O N
2
18
17
TEOF - triethyl orthoformate
Scheme 2. Synthesis of complexes
9-11
The catalytic activity of complexes 9–11 was determined by
conducting a standard set of RCM, CM and enyne reactions in
20 refluxing dichloromethane (results are summarized in Table 1).
Catalyst 9 shows good overall efficiency, however RCM of more
challenging trisubstituted dienes were accomplished only after
prolonged reaction time. Although poorly defined, complex 10
proved to be more active and efficient than 9. However, due to
25 the above mentioned difficulties in its characterization, we think
that this complex is of limited usefulness in practical applications.
Fortunately, the well defined complex 11, showed a very similar
application profile as 10. Therefore, complex 10 can be treated as
Figure 2. Filtration of the reaction mixture through silica gel
All products obtained using complexes 9 and 10 have very low
45 ruthenium contamination (below 5 ppm) as determined by ICP
MS. Water solubility of 11 (2 mg/ml) gives even more interesting
opportunity for ruthenium removal from crude reaction mixtures
by extraction with water. In order to compare efficiency of
various Ru-removal techniques, we performed two separate RCM
50 reactions of diethyl diallylmalonate (23) promoted by the same
amount of catalyst 11. One of these reaction mixtures was filtered
as described above, leading to the product with very low residual
ruthenium level (Table 1, entry 7). To the second reaction mixture
(Fig. 3A) water was added and the two phase mixture formed
a
staging post in synthesis of catalyst 11. Although
30 dichloromethane is not an environmentally and user friendly
solvent, we find it most suitable, since our catalysts are not
soluble in toluene – the second most commonly used solvent in
olefin metathesis. Nonetheless, we believe that simplicity and
efficiency of ruthenium residues removal with the use of
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(Figure 3B) was vigorously shaken for 10 minutes.
30 Boc-N',N'-diallylprolinamide (32) was accomplished with very
good isolated yield, however the residual ruthenium level was
slightly higher than that observed for standard RCM products.
Also, CM of steroid derivative 34 resulted in isolation of product
with good yield. Ruthenium contamination was very low in this
35 case.
Water solubility of complex 11 makes it quite universal. After
proving its usefullness in metathesis in organic solvent we
decided to test 11 with selected model water soluble substrates.
Table 3. Metathesis in water
Conversiona (%)
Catalyst (mol%) Time (h)
Entry
Substrate
N
Product
N
Cl
Cl
1
11 (2.5)
2.5
>99
Figure 3. Extraction of reaction mixture with water
36
37
Almost all ruthenium migrated to water phase and organic
fraction was only slightly coloured (Figure 3C). After fifth
extraction (Figure 3D) both organic and water phases were
colourless. As we checked, ruthenium level in the crude product
was below detection limit of ICP MS method. Removal of
residual ruthenium by extraction should be especially suitable in
OD
DO
5
2
11 (0.5)
1
94
OD
DO
E-38
Z-38
Conditions: D2O, 25 oC, C = 0.2 M, a - determined by 1H NMR
40 Although 11 is only sparingly soluble in neat water, it effectively
promoted metathesis reactions carried out in this medium. RCM
of 36 and isomerisation of 38 were accomplished with very good
results (Table 3).
In conclusion, we are reporting the homogenous Hoveyda-Grubbs
45 type catalysts containing a quaternary ammonium group in the
NHC ligand. Products of olefin metathesis reactions promoted by
complexes 9–11, have been readily and efficiently purified from
Ru-residues. Filtration of the reaction mixture through a small
amount of silica gel or its extraction with water can be applied for
50 removal of Ru-containing catalyst's remains. These results may
be especially interesting for pharmaceutical industry.
10 industrial applications, however discharging relatively large
amounts of impure water that contains heavy metal might also be
problematic. Disposal of small quantities of contaminated silica
gel should be much more convenient. Therefore, we decided to
check if we can remove ruthenium impurities from the combined
15 water fractions (Figure 3E). To do so, we added a small amount
of silica gel to the contaminated water and resulted suspension
was stirred at room temperature for 10 minutes. After the black
coloured solid sedimented, the water phase became colourless
(Figure 3G) and ruthenium level was determined to be only 0.11
20 ppm. It shall be noted that according to our knowledge such
simple method for purification of Ru-contaminated water was
never reported before. Removal of ruthenium impurities by
extraction with water was previously reported by Grubbs and
Hong.11c However, that protocol was less efficient, and required
25 prior evaporation of dichloromethane, dissolving of the product
in diethyl ether and finally the extraction of this etheral solution
with water.
Apeiron Synthesis acknowledges the National Centre for
Research and Development for financial support within “IniTech”
55 programme. MB acknowledges the Foundation for Polish Science
for financial support within “INNOWATOR” programme.
KG and GS acknowledge the Foundation for Polish Science for
‘TEAM’ Programme co-financed by the European Regional
Development Fund, Operational Program Innovative Economy
60 2007-2013.
Next, we decided to check the performance of 10 and 11 in
metathesis of selected bio-like compounds (Table 2). RCM of N-
Table 2. Metathesis with bio-like substrates
Notes and references
Ru
(ppm)
Time Yield
Entry
Substrate
Product
Cat.
a Apeiron Synthesis Sp. z o.o., Klecińska 125, 54-413 Wrocław, Poland.
Fax: +48 71 7985622; Phone: +48 71 7985621; E-mail:
krzysztof.skowerski@apeiron-syntheis.com
(h)
(%)
29a
24b
2.5
2
96
84
1
2
N
10
11
65 b Department of Chemistry, Warsaw University, Pasteura 1, 02-093
Warsaw. Phone: +48-22-822-28-92 , E-mail: klgrela@gmail.com
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
N
N
t-BuO2C
N
O
O
Boc
33
32
O
O
70 ‡ Footnotes should appear here. These might include comments relevant
to but not central to the matter under discussion, limited experimental and
spectral data, and crystallographic data.
O
O
O
O
5.3a
1.6b
1
1
88
84
3
4
10
11
O
O
O
O
35
34
Condition: catalyst 1 mol%, DCM, 40 oC, C = 0.05 M, a - filtration, b - extraction
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