Acid-mediated activation of modified ring-closing metathesis catalysts

Article abstract of DOI:10.1016/j.tetlet.2009.11.112

To improve the reactivity of Grubbs catalyst, novel ligands were designed and synthesized which possess nitrogen-containing heterocycles such as imidazole and pyridine. The modified catalysts were treated with a range of acids and the acid salt forms were

Full text of DOI:10.1016/j.tetlet.2009.11.112

Tetrahedron Letters 51 (2010) 709–713
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Acid-mediated activation of modified ring-closing metathesis catalysts
a,
Seyoung Kim a, Wonmi Hwang a, In Seon Lim a, Sung Hye Kim a, Sang-gi Lee b, , B. Moon Kim
*
*
a Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, South Korea
b Division of NanoScience, Ewha Womans University, Seoul 120-750, South Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 June 2009
Revised 24 November 2009
Accepted 26 November 2009
Available online 29 November 2009
To improve the reactivity of Grubbs catalyst, novel ligands were designed and synthesized which possess
nitrogen-containing heterocycles such as imidazole and pyridine. The modified catalysts were treated
with a range of acids and the acid salt forms were used as catalysts for ring-closing metathesis (RCM)
reactions. As a result, reactions employing the acid-modified catalysts showed considerable reactivity
enhancement in RCM.
Ó 2009 Elsevier Ltd. All rights reserved.
In regard to the construction of five- to seven-membered and
macrocyclic rings, ring-closing metathesis (RCM) has become an
indispensable tool to organic chemists. The RCM has been widely
utilized as a key step in the synthesis of many natural products
(see Fig. 1).1
In recent years, a large number of metathesis catalysts have
been reported by several research groups. Among several catalysts
for the RCM, ruthenium–benzylidene2 pre-catalysts have been the
most widely used due to their stability and tolerance toward many
functional groups. After the development of Grubbs first genera-
tion catalyst (1) and N-heterocyclic carbene-based second genera-
tion catalyst (2),3 boomerang-type pre-catalysts were reported.4
Among them, Grubbs–Hoveyda catalysts 3a and 3b equipped with
a chelating ether moiety have shown superior stability compared
to prior Grubbs catalysts and are even recoverable by column chro-
matography.2g,5 However, though reactions employing the cata-
new catalysts that exhibit improved reactivity while preserving
stability observed in the Hoveyda-type catalysts (see Fig. 2).
In recent years, a range of Hoveyda-type ruthenium precatalysts
were reported based upon various ligand modifications. These ap-
proaches involve structural modification of N-heterocyclic carbene
moiety7 as well as changes on the benzylidine structure as shown
in catalysts 4a–e.8,9 Among various ligand-modification strategies,
we focused on the tuning of the benzylidine moiety with an elec-
tron-density monitoring group. For example, introduction of elec-
tron-withdrawing nitro or ester group as in 4c and 4d,
respectively, led to enhancement of the leaving group properties
and showed increased catalyst activities.9b,c
In relation with this approach, Grela and co-workers reported a
new Hoveyda-type catalyst containing diethylamine-substitution
on the aromatic ring (4e).9d They utilized the amino group in the
catalyst for both anchoring and activation of the catalyst. In the
reactions employing this catalyst, enhanced reactivity was ob-
served when it was anchored onto sulfonic acid resin.
lysts
3 show great performance, their initial reaction rates
proved to be slower than those employing catalyst 2, probably as
a result of steric and electronic factors caused by isopropoxy
group.6 Therefore, many research groups tried to come up with
Based on the improved results of the RCM employing catalyst
4a–e, one can assume that decreasing the electron density on the
Figure 1. Commonly used ruthenium olefin metathesis catalysts. Cy = cyclohexyl, Mes = mesitylene.
* Corresponding authors. Tel.: +82 2 880 6644; fax: +82 2 872 7505.
E-mail address: kimbm@snu.ac.kr (B.M. Kim).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.112

710
S. Kim et al. / Tetrahedron Letters 51 (2010) 709–713
Synthesis of the heterocycle-containing ligands is depicted in
Scheme 1. From commercially available 3-bromosalicylaldehyde
5, compound 7a was obtained through etherification followed by
Ullmann-type coupling. For the preparation of pyridine-containing
ligand 7b, Suzuki–Miyaura coupling of 5 with 4-pyridylboronic
acid was carried out. Resulting aldehyde 7 was converted to vinyl
derivative 8 through Wittig reaction. To generate ruthenium–car-
bene complex, 8 was treated with Grubbs catalyst in the presence
of copper(I) chloride. Detailed reagents and yield of each step are
described in Scheme 1.
Table 1
Results of RCM with various acid-activated catalystsa
Entry
Catalyst
Acid
Conversionb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
9
None
45
99
95
89
77
60
55
48
97
99
99
96
24
Figure 2. Benzylidine-modified olefin metathesis catalysts.
HClc
TFA
PTSA
oxygen atom of the isopropyl fragment and increasing the steric
bulk of the Hoveyda-type ruthenium carbene complex result in
an increase in catalytic activity. Therefore, we envisioned that elec-
tron-withdrawing imidazolium or pyridinium salts attached to the
benzylidine part of the catalyst would weaken ruthenium–oxygen
chelation and facilitate the initiation of the catalytic cycle. Though
pyridine and imidazole moieties were embedded in a few modified
Grubbs catalysts10 and in derivatives for ionic liquid application,11
there was no report on the acid-mediated activation of the cata-
lysts using the imidazole or pyridine moieties to the best of our
knowledge. Herein, we report on the synthesis of modified Grubbs
catalyst and results of RCM with such acid-activated catalysts.
Perfluoropropanoic acid
Triflic acid
CSA
10a
10b
None
HClc
TFA
None
HClc
TFA
a
Catalyst activation with acids was performed through stirring the catalyst with
an acid for 30 min prior to RCM reaction.
b
Conversions were determined from GC analysis.
A 4 N solution in 1,4-dioxane was used.
c
Scheme 1. Reagents and conditions: (a) 2-iodopropane, Cs2CO3, K2CO3, DMF, rt, 12 h, 99%; (b) imidazole, CuI, Cs2CO3, N,N0-dimethylethylene-diamine, 170 °C, 48 h, 87%; (c)
4-pyridylboronic acid, Pd(dppf)Cl2, Na2CO3, DME/H2O = 3:1, reflux, 3 h, 80%; (d) methyltriphenyl-phosphonium bromide, LHMDS, THF, 0 °C?rt, 12 h, 86%; (e) Grubbs catalyst,
CuCl, CH2Cl2, reflux, 2 h, 55–60%.

S. Kim et al. / Tetrahedron Letters 51 (2010) 709–713
711
With the new catalysts in hand, RCM reactions using various
acids were carried out for 2 h with 1 mol % of catalyst and equiva-
lent amount of acids. The results are summarized in Table 1 and
Figure 3. When catalyst 9 was tested with various acids, the cata-
lyst bearing electron-donating imidazole group showed low activ-
ity in RCM (entry 1), which bodes well with our assumption.
However, the in situ-formed imidazolium salts obtained by treat-
ment with acids showed enhanced activity to the same reaction.
It is of particular note that, when HCl or trifluoroacetic acid (TFA)
was used as additives, the reaction reached over 95% conversion
within 2 h (entries 2 and 3). Moreover, the initial rate of the reac-
tion using HCl salt was faster than that of the reaction using pris-
tine Grubbs–Hoveyda first generation catalyst. In cases of other
acid salts, relatively lower levels of activation were observed.
In the case of pyridine-containing catalyst 10a, it was observed
that the propagation rate of the reaction is almost same as that of
imidazole-containing catalyst system (less than 60% of conversion
after 150 min, Fig. 4). However, reactions using acid-activated cat-
alyst such as HCl or TFA salt proceeded very rapidly (entries 9 and
10 of Table 1 and Fig. 4). It is interesting to note that, in case of
pyridine-substituted catalyst 10a, reaction using TFA salt pro-
ceeded faster than that of an HCl salt (Fig. 4).
We also prepared a pyridine-containing carbene complex 10b
because it was expected to lead to a more reactive catalytic system.
The reaction was completed within 30 min even without HCl treat-
ment. Though initiation rate was found to be greatly enhanced in
the case of HCl treated 10b, the conversions were almost same
after 20 min in either HCl activated or non-activated case. How-
ever, when TFA was used instead of HCl, the reaction stopped at
around 25% conversion (Fig. 5). In the case of pyridine catalyst
10b, the acid-activation process may render the catalyst too active
and thus it may decompose during the activation and reaction. This
was verified in part from the fact that the reaction using the acid-
Figure 5. RCM with activated catalyst 10b.
Table 2
Results of RCM with pyridine ligands 10a and 10ba
Entry Substrate
Product
Yieldb (%)
10aꢀTFA
10bꢀHCl
10b
Figure 3. RCM using various acid-activated catalysts 9 compared with parent
Hoveyda catalyst.
1
2
99
60 (69)d 84
99
84
90
3
4
99
99
78
66
99
99
5
46 (80)c n.r.
n.r.
a
All the reactions were carried out with 1 mol % catalyst and 1 mol % acid in
dichloromethane at room temperature for 2 h.
b
Isolated yields.
Value in parentheses is yield after 20 h.
The acid and the catalyst were added together without prior stirring for 30 min.
c
d
Figure 4. RCM with activated pyridine catalyst 10a.

712
S. Kim et al. / Tetrahedron Letters 51 (2010) 709–713
activated catalyst without 30 min prior activation gave slightly
better yield after 2 h (Table 2, entry 1, number in parentheses).
Since the rates of reactions employing the pyridine catalyst 10a
is slightly faster than those of the imidazole-containing catalyst 9,
the scope of substrates in the reactions employing the pyridine cat-
alyst 10a was explored using various substrates under the acid-
activated conditions. The results are summarized in Table 2. To a
1 mol % of pyridine catalyst 10a and 10b, the same amount of
hydrochloric acid (for 10a) or trifluoroacetic acid (for 10b) was
added and the mixture was stirred for 30 min. With the pyridini-
um–TFA salt from 10a, all the di-substituted substrates were cy-
clized smoothly within 2 h at room temperature. When the TFA–
10a salt was employed in an enyne metathesis, only 46% cycliza-
tion was observed in 2 h, but longer reaction time increased the
yield to 80% (Table 2, entry 5).
Meanwhile, reactions involving catalyst 10b showed relatively
low yields compared to 10a. Most of the reactions showed high
conversion at early stage. However, as in the case of TFA-activated
catalyst 10b in Figure 5, the reactions did not proceed further after
2 h and the starting materials remained. We assumed that activa-
tion of the pyridine catalyst 10b with HCl renders the catalyst too
unstable to proceed within the given reaction time. To confirm this
hypothesis, we carried out same series of reactions with non-acti-
vated catalyst 10b and obtained much higher yields of the products
as shown in Table 2.
To see if the pyridine-containing catalyst 10a is stable toward
the acid, it was treated with an equiv of TFA in an nmr tube for
one day and RCM was carried out using this acid-treated catalyst.
As shown in Figure 6, the RCM of N,N-diallyl p-toluenesulfonamide
using this TFA-treated catalyst proceeded at the same rate as the
one using the catalyst treated with TFA for 0.5 h, both of which
are much faster than the reaction using unactivated catalyst 10a.
That the activation of the catalyst 10a was truly due to the acti-
vation of the pyridine ring rather than other parts of the catalyst
was confirmed by the following experiments: RCMs using catalyst
3a were carried out after activation with an acid for 0.5 or 24 h. As
shown in Figure 7, RCMs using 3a activated with HCl for 0.5 h pro-
ceeded slightly faster, but the reaction using 3a activated with TFA
for 0.5 h was somewhat slower than the one using untreated 3a.
When the reactions were carried out using 3a treated with an acid
for a day, they were considerably slower presumably due to the
decomposition of the catalyst by the acids.
Figure 7. Results of RCM using acid-treated Grubbs–Hoveyda catalyst (3a).
the catalyst with an acid was shown to be an efficient way to en-
hance activity of the catalytic system. Compared to classical Hov-
eyda-type catalyst, some of our acid-activated catalysts showed
enhanced activity toward RCM while retaining stability Figure 7.
RCM with acid-treated Grubbs–Hoveyda first catalyst.
Acknowledgment
Generous financial support from the Korea Research Fund
(2006-312-C00229) is gratefully acknowledged.
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Figure 6. RCM with TFA-activated catalyst 10a.

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