Effect of added salt on ring-closing metathesis catalyzed by a water-soluble hoveyda-grubbs type complex to form N-containing heterocycles in aqueous media

Article abstract of DOI:10.1021/om4005302

The efficiency of ring-closing metathesis catalyzed by a Hoveyda-Grubbs type catalyst in water can be enhanced by addition of a chloride salt under neutral conditions. UV-vis spectroscopic study showed that a characteristic band of the catalyst around 380 nm remained over 16 h in the presence of KCl, whereas the band distinctly decreased in the absence of KCl. The disappearance of the band is ascribed to a displacement of a chloride ligand by a water molecule or a hydroxide anion. The spectral changes can be related to the metathesis activity. The experimental results indicate that avoidance of the chloride ligand loss is important to maintain the metathesis activity in water.

Full text of DOI:10.1021/om4005302

Article
pubs.acs.org/Organometallics
Effect of Added Salt on Ring-Closing Metathesis Catalyzed by a
Water-Soluble Hoveyda−Grubbs Type Complex To Form
N‑Containing Heterocycles in Aqueous Media
Takashi Matsuo,* Takefumi Yoshida, Akira Fujii, Keiya Kawahara, and Shun Hirota
Graduate School of Materials Science, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192,
Japan
S
* Supporting Information
ABSTRACT: The efficiency of ring-closing metathesis catalyzed by a
Hoveyda−Grubbs type catalyst in water can be enhanced by addition of a
chloride salt under neutral conditions. UV−vis spectroscopic study showed
that a characteristic band of the catalyst around 380 nm remained over 16 h in
the presence of KCl, whereas the band distinctly decreased in the absence of
KCl. The disappearance of the band is ascribed to a displacement of a chloride
ligand by a water molecule or a hydroxide anion. The spectral changes can be
related to the metathesis activity. The experimental results indicate that
avoidance of the chloride ligand loss is important to maintain the metathesis
activity in water.
One factor to decrease the catalytic activity of metathesis-
mediating ruthenium complexes in aqueous media is the water-
induced dissociation of a chloride ligand from the complex. The
process is believed to be the principal deactivation pathway for
these complexes in protic solvents.9 It has been known that the
chloride ligand significantly affects the metathesis reactivity of
ruthenium complexes,10 and some research examples have
demonstrated that replacement of the chloride ligand with
other anionic ligands can enhance or reduce the catalytic
performance of the ruthenium complexes.11,12 It has also been
reported that the ligand exchange sometimes causes the
formation of a dimerized complex, which can work as a
precatalyst in organic solvents13 or result in an inactive form.14
Accordingly, the avoidance of chloride ligand loss will be
another strategy to enhance the metathesis activity of
ruthenium complexes in aqueous media.
In this paper, we demonstrate the effects of chloride salt on
the catalytic activity of water-soluble ruthenium complex 1
(Chart 1).5d The ROMP activity of 1 increases in the presence
of 1 equiv of hydrochloric acid.5d Furthermore, the loss of a
chloride ligand in protic solvent has been suggested.15 In this
context, we propose that addition of chloride salt is useful for
enhancing the catalytic activity of 1-mediating RCM under
neutral conditions in water. Concerning the application to
biochemical experiments, the effect of buffer reagents that are
often used for biochemical research on the catalytic activity was
also investigated.
INTRODUCTION
■
Olefin metathesis catalyzed by ruthenium complexes, known as
an effective method for constructing new carbon−carbon
bonds,1 is often conducted in nonpolar solvents such as
dichloromethane. However, the recent development of
ruthenium complexes with an N-heterocyclic carbene (NHC)
ligand and a 2-alkoxybenzylidene ligand (so-called Hoveyda−
Grubbs type catalyst) and its diverted catalysts2 has prompted
us to conduct olefin metathesis in protic organic solvents or
water,3 because these complexes are rather stable toward air
and/or moisture. Olefin metathesis in water is useful for polar
substrates and attractive from the viewpoint of development of
eco-friendly chemical processes. In order to increase the
solubility of the catalysts in protic media, ruthenium complexes
with a polyethylene glycol moiety4 or tertiary ammonium
groups2e,f,5 in ligands have been prepared. Furthermore, some
of the Hoveyda−Grubbs type complexes have been applied as a
biochemical research tool.6 Preparation of artificial biocatalysts
with olefin metathesis activity has also been attempted, where
the ruthenium complexes were attached to proteins.7
However, the activity of metathesis-mediating ruthenium
complexes in aqueous media is often decreased from that in
organic solvents.5c,8 Grubbs and co-workers successfully
enhanced the catalytic activity for the ring-opening metathesis
polymerization (ROMP) of norbornadiene derivatives in
aqueous media under acidic conditions.4b,5a A similar strategy
has also been employed for ring-closing metathesis (RCM)
mediated by ruthenium complex conjugated proteins.7a,b
However, other strategies to enhance the metathesis efficiency
under milder conditions are desirable for acid-sensitive
substrates and biomolecules.
Received: June 9, 2013
© XXXX American Chemical Society
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Chart 1. Structure of Water-Soluble Catalyst 1
Table 1. Ring-Closing Metathesis (RCM) To Form N-
a
Containing Heterocycles in D2O
RESULTS AND DISCUSSION
■
Table 1 summarizes the effects of salt and buffer reagent on
RCM to produce N-containing heterocycles in water. At first,
we investigated the RCM of substrates 2 and 3, the compounds
employed in our previous work (entries 1−12).7c 1H NMR
spectra of the reaction mixtures for 2 and 3 are shown in
Figures S1 and S2 (Supporting Information), respectively.
Byproducts such as cycloisomerized compounds4a,5d were not
detected. On the whole, compound 3 gave a higher product
yield than 2. This is due to the lack of electrostatic repulsion
between 3 and catalyst 1. The product yield was increased by
potassium chloride (KCl) for both the substrates (entry 1 vs 2,
entry 8 vs 9). In other words, the RCM activity in water can be
enhanced under neutral conditions when a chloride salt is
added to the reaction medium. Other inorganic salts such as
KNO3 were ineffective for enhancing RCM efficiency (entry
12).16
In contrast, the reactions in MES buffer (pD 6.4; MES = 2-
morpholinoethanesulfonic acid) showed a decrease in product
yield (entry 1 vs 3 and entry 8 vs 10). MES is one of the
popular buffer reagents in biochemical reactions under weakly
acidic conditions. A possible reason for the decrease in yield is
that coordination of sulfonyl groups in a buffer molecule could
occur, leading to the inhibition of the catalytic cycle. The
addition of KCl brought out the slight recovery of the yield
even in buffer solutions (entry 3 vs 4/5 and entry 10 vs 11),
suggesting that the inhibition by the buffer reagent is caused by
a reversible process (vide infra). However, the employment of
HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), a
buffer reagent for experiments under weakly basic conditions,
brought about the inhibition of RCM even in the presence of
KCl (entry 7). This is attributable to the increase in the
concentration of hydroxide anion at the pH and may be
associated with the ligand exchange between a chloride ligand
and a hydroxide anion.
a
Conditions: [substrate] = 8.4 mM; [1] = 5 mol %; reaction time 24
b
h; at 25 °C under N2 in a tube with a J. Young valve. Determined by
c
1H NMR. The acidity was calculated by using the relationship pD =
d
e
f
pH + 0.4. pD 6.4. pD 7.4. Not determined due to the appearance of
several unidentified peaks in H NMR. Reaction time 48 h.
g
1
On the other hand, the tertiary ammonium species 4 gave no
distinct RCM product in spite of KCl addition and showed a
small amount of several unidentified peaks in the H NMR
1
Next, the time dependence of the RCM reactions were
investigated using compounds 2 and 3 (Figure 1). In reactions
of both 2 and 3, the initial reaction velocities increased in the
presence of KCl. This tendency agrees with an increase in the
overall yield by KCl. Furthermore, the effect on the reaction
rates is dependent on KCl and buffer concentrations (see traces
b−f in Figure 1A). It has been reported that the replacement of
chloride ligand with another coordinating ligand affects the
velocity of metathesis in organic solvents.11a,12 In aqueous
reaction media, a huge excess of water molecules and/or
strongly coordinating hydroxide anions can replace a chloride
ligand. Consequently, the observed effects of KCl and the
buffer reagent on the RCM reaction rates can be related to the
spectrum (Figure S3 (Supporting Information) and entry 13 vs
14 (Table 1)). The quaternary ammonium species 5 did not
produce a detectable amount of the RCM product (Figure S4
(Supporting Information) and entry 15 vs 16 (Table 1)).
Compound 5 is basically poor in reactivity toward RCM
catalyzed by various water-soluble ruthenium catalysts.2f,4a,5d
These findings indicate that the RCM efficiency is not
improved by the addition of KCl for intrinsically unreactive
substrates. The utility of chloride salt addition was confirmed
for the unsymmetrical ammonium species 6, giving a six-
membered-ring compound in RCM (Figure S5 (Supporting
Information) and entry 17 vs 18 (Table 1)).
B
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As described above, the lability of the chloride ligand in
aqueous media is one of the probable factors affecting the RCM
activity in water. In order to investigate this matter in detail, the
stability of catalysis 1 in aqueous media was evaluated using
UV−vis spectroscopy. Figure 2 shows typical UV−vis spectral
Figure 2. UV−vis spectral changes of 1 (89 μM) in aqueous solution
at 25 °C under N2: (A) in solution without KCl; (B) in aqueous KCl
(100 mM). The solutions contain a small amount of MeOH (0.1% (v/
v)). The spectra drawn as red and light blue lines in spectra A and B
were taken at the start of measurements and after 16 h, respectively.
The measurements were started on addition of a stock solution of 1 in
MeOH to the aqueous solutions.
changes in the absence and the presence of KCl (100 mM). On
dissolution of 1 in water without KCl, an MLCT absorption
band appeared at 373 nm18 and decreased over 16 h (Figure
2A). No RCM activity was observed even if substrate 2 or 3 was
added further to the solution after 16 h. In other words, the
chemical species finally formed was inactive with respect to
RCM. In an aqueous solution of KCl (100 mM), the MLCT
band appeared at 381 nm on addition of 1 to the aqueous
solution, which is at a longer wavelength than that observed in
the absence of KCl (Figure 2B). In contrast to the spectral
change in the medium without KCl, the band at 381 nm
remained even after 16 h. The band in a NaCl-containing
solution appeared at the same wavelength as that in a KCl-
containing solution (Figure S6, Supporting Information).
These findings indicate that the added salt contributes to the
stability in aqueous media, which is independent of a
countercation. The wavelength of the band observed in the
initial UV−vis spectrum is dependent on the concentration of
KCl (381 nm in 100 mM KCl, 378 nm in 1 mM KCl (Figure
S7, Supporting Information), and 373 nm in solutions without
KCl). This indicates that rapid ligand exchange between a
chloride ligand and a water molecule occurs during the mixing
of a stock solution of 1 with an aqueous solution without KCl.
In other words, the chemical species with the absorption band
at 373 nm would be the state that a chloride ligand is partially
lost from the metal center. The decrease in the absorption band
around the wavelengths also depends on the concentration of
KCl (Figure S8, Supporting Information). The effect of KCl on
the spectral changes coincides with the catalytic activity of 1
(Table 1). After incubation of catalyst 1 in a non-KCl aqueous
solution for 1 h, addition of KCl to the solution showed the
shift of the absorption band from 373 to 381 nm (Figure S9,
Supporting Information), which is similar to the spectrum
initially observed in an aqueous KCl solution. Consequently, it
can be concluded that a KCl-involving equilibrium step exists
during the conversion into the catalytically inactive form over
the period of the spectral change.
Figure 1. Time courses of RCM of 2 (A) and of 3 (B) catalyzed by 1
at 25 °C under N2 ([substrate] = 8.2 mM, [catalyst 1] = 0.42 mM).
Black, red, and blue indicate data taken in nonbuffered solutions, 1
mM MES (pH 6.0), and 10 mM MES (pH 6.0), respectively. Filled
circles and triangles denote data obtained in the presence and absence
of KCl, respectively.
ligand exchange of a chloride ligand with solvent molecules
(vide infra).
The reactions of 2 reached the maximum yield around 15 h
in all medium conditions employed, although no compound
other than the starting material and the RCM product was
detected in all reactions with 2. This suggests that the catalysis
deactivation occurred in parallel with the RCM reactions. One
of the possible factors causing the catalysis deactivation is the
ligand exchange at the metal center led by solvent molecules.
However, other factors affecting the catalytic activity should
also be taken into consideration, because the reaction of 3 is
terminated at an earlier stage than that of 2 (around 4 h) in
spite of the presence of KCl. On the basis of the fact that more
rapid reactions are terminated at an earlier stage, the catalysis
deactivation caused by the catalytic cycle also leads to the
termination of the reaction as well as the catalysis deactivation
in the absence of a substrate. One of the possible mechanisms
of the substrate-inducing deactivation is inhibition by ethylene
(5.41 ppm) produced as a coproduct. Another mechanism is
the formation of a ruthenium hydride species via isomerization
of a ruthenacycle intermediate.17
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On the basis of the result of the UV−vis spectroscopic study,
EXPERIMENTAL SECTION
■
a plausible mechanism is depicted in Scheme 1. Additive
General Comments. All manipulations were carried out in an N2-
filled glovebox or using conventional Schlenk techniques unless noted.
All solvents were degassed by freeze−pump−thaw methods before
RCM reactions. The 1H NMR spectra were recorded on a JEOL ECP
400 MHz NMR spectrophotometer. The chemical shifts were
referenced to TMS (in CDCl3) or sodium 4,4-dimethyl-4-
silapentane-1-sulfonate (DSS) (in D2O). The UV−vis spectra were
measured using a Shimadzu UV-2550 spectrophotometer with a
thermostated cell holder. ESI-MS analysis was carried out using a
JEOL JMS-T100LC mass spectrometer.
Scheme 1. Plausible Mechanism for the Effect of the
a
Chloride Ligand
Catalyst 15d was synthesized in the same manner as given in a
previous report, and the NMR data agreed with the reported data.5d,7c
Compound 5 was purchased from Tokyo Chemical Industry Co., Ltd.
a
1
The numbers in right-corner of complexes indicate the overall
(TCI) as a 60% aqueous solution and used as received. In the H
charges of the complexes considering the charges on the metal center
and on the ligands.
NMR measurements for the reaction of 5, a presaturation technique
for the peak derived from H2O was employed to increase the spectral
resolution and sensitivity. An authentic sample of the RCM product
from 6 (6-RCM) was purchased from Wako Pure Chemical Industries
Ltd. (Wako). The spectroscopic data of these compounds are
indicated below. Other substrates and authentic products were
obtained by neutralization of commercially available amines or by
syntheses as described below. A buffer solution dissolved in D2O was
prepared from the corresponding H2O solution. After the H2O
solution was concentrated by using an evaporator, the same volume of
D2O was added to the residue. This procedure was repeated three
times.
chloride salt contributes to the equilibrium shifting to the Cl-
bound form, whereas a chloride ligand may be easily replaced
by a water molecule or a hydroxide anion in the absence of a
chloride ion source. This species may have reduced catalytic
activity because of the more strongly coordinating character of
water or hydroxide anion. A similar mechanism has been
reported using a pyridine-substituted Ru complex in organic
solvents.11c The intermediate will be gradually converted into
the completely inactive form. The final form of the catalysts has
not been identified at present. Although the ESI-TOF-MS
spectrum (Figure S10, Supporting Information) obtained in the
final stage suggested the formation of a Cl-bridged dimer, the
structure is not clear at present because such chemical species
in organic solvents can work as a precatalyst. Another
possibility is an oxo-bridged form because of dissolution in
water, although more experimental investigation is required to
identify the catalytically inactive form in the future.
As indicated in Table 1, the RCM activity of 1 in buffer
solutions dramatically decreased, even if KCl is present in the
reaction media (e.g. entry 2 vs 4−7). Accordingly, the intrinsic
stability of catalysis of 1 in buffer solutions was evaluated by the
UV−vis spectral changes (Figures S11 and S12, Supporting
Information). The absorption band of the initial spectrum in
buffer solution appeared in the higher energy region, in
comparison with that in nonbuffered solutions (λmax 368 nm in
10 mM MES buffer and 360 nm in 10 mM HEPES buffer). The
absorption bands distinctly decreased over 6 h. Recovery of the
catalytic activity by addition of KCl was moderate in the buffer
solutions. The experimental observations suggest that the
decreased RCM yields in the buffer solutions are dominantly
caused by the inhibition of the substrate binding process.
Evaluation of RCM Activity. A reaction mixture was prepared in a
glovebox and charged into an NMR tube with a J. Young stopcock at
25 °C, and the RCM reaction was followed by 1H NMR spectroscopy.
The product yields were calculated on the basis of the peak intensities
originating from the starting materials and products.
Compound 2.3b The corresponding free amine purchased from
TCI was neutralized by HCl in ether. The precipitated white solid was
quickly collected by suction and dried in vacuo. This compound is
1
highly hygroscopic. H NMR (D2O, 400 MHz): δ 5.96−5.86 (m, 2H,
−CHCH2 × 2), 5.53−5.47 (m, 4H, −CHCH2 × 2), 3.66 (d, J =
6.8 Hz, 4H, −NCH2CHCH2 × 2). 13C NMR (D2O, 100 MHz): δ
130.6, 126.3, 51.4.
Authentic Sample of RCM Product from 2 (2-RCM).3b 3-
Pyrroline (free amine form of 2-RCM) purchased from Wako was
neutralized by HCl in ether. After the solvent was evaporated, the oily
residue was dried in vacuo. 1H NMR (D2O, 400 MHz): δ 5.92 (s, 2H,
olefinic protons), 4.08 (s, 4H, methylene protons). 13C NMR (D2O,
100 MHz): δ 127.4, 54.7.
Compound 3. The compound was synthesized according to the
method reported in a previous report.7c 1H NMR (D2O, 400 MHz): δ
5.92−5.74 (m, 2H, −CHCH2 × 2), 5.26−4.81 (m, 4H, −CHCH2
× 2), 4.45 (d, J = 8.0 Hz, 1H, sugar-1′ H), 4.15 (m, 1H,
−OCHαCH2(OC)N−), 4.05 (br, 2H, −(OC)NCH2CH
CH2), 3.97 (br, 2H, −(OC)NCH2CHCH2), 3.90 (m, 2H,
OCHβCH2(OC)N− and sugar-6′Hα), 3.70 (dd, J = 5.8, 9.6 Hz, 1H,
sugar-6′Hβ), 3.47 (dd, 1H, J = 9.3 Hz, 9.3 Hz, 1H, sugar-3′H), 3.43
(m, 1H, sugar-5′H), 3.36 (dd, J = 9.3 Hz, 9.6 Hz, 2H, sugar-4′H), 3.24
(dd, J = 8.0 Hz, 9.3 Hz, 1H, sugar-2′H), 2.79 (t, J = 6.2 Hz, 2H,
−OCH2CH2(OC)N−). 13C NMR (D2O, 100 MHz): δ 176.5,
135.1, 134.8, 119.1, 119.0, 105.3, 78.6, 78.4, 75.8, 72.3, 68.7, 63.4, 53.1,
51.3, 35.7.
CONCLUSION
■
In order to conduct RCM mediated by a water-soluble
Hoveyda−Grubbs type complex in water effectively, addition
of chloride salt is both practical and useful. The method is
applicable to secondary ammonium and amide substrates.
Added chloride salt contributes to maintenance of the chloride-
bound form of the Hoveyda−Grubbs catalyst in aqueous
media. Furthermore, buffer solutions which are often used in
biochemical experiments may cause a decrease in the
metathesis activity, although the presence of chloride salt
gives rise to recovery of yield. This knowledge will be useful for
developing protocols of synthetic routes based on olefin
metathesis in aqueous media and application of olefin
metathesis in the field of biochemical research.
Authentic Sample of RCM Product from 3 (3-RCM). The
authentic sample of 3-RCM was obtained by the following synthesis:
In a 50 mL two-neck flask equipped with a condenser,
compound 77c (90 mg, 0.18 mmol) was dissolved in dry
D
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−NCHαCHCH2), 3.92 (d, J = 13 Hz, 2H, −NCHβCHCH2), 3.02
(s, 3H, methyl protons). 13C NMR (D2O, 100 MHz): δ 127.2, 64.5,
44.6. EI-MS (positive mode): m/z 84 ([M − Cl]+), 69 ([M − Cl −
CH3]+), 57 ([M − Cl − NCH3]+).
CH2Cl2 (5 mL) under a N2 atmosphere. To the solution was
added catalyst 8 (5.6 mg, 4 μmol, 5 mol %). The reaction
mixture was stirred at 40 °C for 4.5 h. After the solvent was
evaporated, the residue was subjected to silica gel column
chromatography (elution: hexane/AcOEt = 4/1 → 1/1). The
fractions with Rf = 0.45 on TLC (elution: hexane/AcOEt = 1/
1) were collected, and the solvent was evaporated to yield a
colorless oil. The material was dissolved in MeOH, and
NaOMe (9.7 mg) was added. The solution was stirred at room
temperature for 12 h. After addition of Dowex-50 WX8 cationic
exchange resin (5.0 g), the solution was filtered. The solvent
was evaporated to afford the compound 3-RCM as a colorless
Spectroscopic Data of Compound 5. 1H NMR (D2O, 400
MHz): δ 6.04 (m, 2H, −CHCH2 × 2), 5.71(m, 4H, −CHCH2 ×
2), 3.89 (d, 4H, J = 7.4 Hz, −NCH2CHCH2−), 3.01 (s, 6H, -NCH3
× 2). 13C NMR (D2O, 100 MHz): δ 131.8, 127.0, 68.8, 52.1. EI-HR-
MS (positive mode): calcd 98.0964 for C6H12N ([M − Cl]+), found
98.0970.
Authentic Sample of RCM Product from 5 (5-RCM).4 An
authentic sample of 5-RCM was obtained by the following synthesis:
1
oil (42 mg, 77% yield). H NMR (D2O, 400 MHz): δ 5.92−
5.86 (m, 2H, olefinic protons), 4.65 (d, J = 8.2 Hz, 1H, sugar-
1′H), 4.38 (br, 2H, −(OC)NCH2−), 4.19 (br, 3H, −(O
C)NCH2− and −OCHαCH2(OC)N−), 3.99 (m, 1H,
−OCHβCH2(OC)N−), 3.88 (dd, J = 2.1 Hz, 12.2 Hz, 1H,
sugar-6′Hα), 3.71 (dd, J = 5.6, 12.2 Hz, 1H, sugar-6′Hβ), 3.48−
3.43 (m, 2H, sugar-3′ and 5′), 3.36 (dd, 1H, J = 8.2 Hz, 8.2 Hz,
2H, sugar-4′), 3.23 (dd, J = 8.0 Hz, 8.0 Hz, 1H, sugar-2′), 2.73
(t, J = 6.2 Hz, 2H, −OCH2CH2(OC)N−). 13C NMR (D2O,
100 MHz): δ 176.5, 135.1, 134.8, 119.1, 119.0, 105.0, 78.6,
78.4, 75.8, 72.4, 63.5, 53.1, 51.9, 35.7. FAB-HR-MS (positive
mode): calcd 304.1396 for C13H22NO7 ([M + H]+), found
304.1398.
In a 100 mL flask, K2CO3 (4.0 g, 29 mmol) was suspended in
20 mL of EtOH. To the suspension were added 3-pyrroline
(0.201 g, 2.9 mmol) and MeI (0.803 g, 5.8 mmol). The
solution was stirred at room temperature for 2 h, and the
insoluble materials were removed by filtration. After the solvent
was evaporated, the residue was dissolved in 60 mL of EtOH.
To the solution was added Dowex 1X2 (Cl−) ion-exchange
resin (5 g). The suspension was stirred for 10 min and filtered.
After the solvent was evaporated, the compound 5-RCM was
1
Compound 4. The corresponding free amine purchased from
Wako was neutralized by HCl in ether. After the solvent was
obtained as a white solid (0.281 g, 73%). H NMR (D2O, 400
MHz): δ 5.96 (m, 2H, olefinic protons), 4.33 (s, 4H, methylene
protons), 3.28 (s, 6H, methyl protons). 13C NMR (D2O, 100
MHz): δ 127.1, 74.9, 56.1 EI-HR-MS (positive mode): calcd
98.0964 for C6H12N ([M − Cl]+), found 98.0970. Anal. Calcd
for C6H12NCl: C, 53.93; H, 9.05; N, 10.48. Found: C, 53.71; H,
9.07; N, 10.30.
1
evaporated, the oily residue was dried in vacuo. H NMR (D2O, 400
MHz): δ 5.92 (s, 2H, −CHCH2 × 2), 4.08 (s, 4H, −CHCH2 ×
2), 3.83 (dd, 2H, J = 13.2 Hz, 7.6 Hz, −NCHαCHCH2), 3.69 (dd,
2H, J = 13.2 Hz, 7.6 Hz, −NCHβCHCH2), 2.81 (s, 3H, −NCH3).
13C NMR (D2O, 100 MHz): δ 129.2, 128.4, 60.2, 41.4. Anal. Calcd for
C7H14NCl: C, 56.94; H, 9.56; N, 9.49. Found: C, 56.70; H, 9.53; N,
9.29.
Compound 6.4 The compound was synthesized by the following
method:
Authentic Sample of RCM Product from 4 (4-RCM).19 The
authentic sample of 4-RCM was obtained by the following synthesis:
In a 100 mL two-neck flask with a dropping funnel, a 40%
solution of methylamine in methanol (8 mL) was dissolved in
THF (20 mL) and cooled with an ice bath. From the dropping
funnel, cis-1,4,dichloro-2-betene (2.48 g, 20 mmol) in THF (10
mL) was slowly added to the methylamine solution. The
solution was stirred at room temperature for 16 h. The reaction
solution was poured into ice and acidified by concentrated HCl.
The solution was washed with ether twice. The water phase was
separated and was adjusted to pH ∼11 with 2 M aqueous
NaOH. The solution was subjected to distillation. A fraction at
65−72 °C was collected to yield the free amine of 4-RCM
In a 200 mL flask, allylamine (0.566 g, 9.92 mmol) and
triethylamine (1.00 g, 9.92 mmol) were dissolved in CH2Cl2
(20 mL) and cooled with an ice bath. 2-Nitrobenzenesulfonyl
chloride (2.00 g, 9.02 mmol)20 was added dropwise over 5 min,
and the solution was stirred at room temperature for 30 min.
After the reaction mixture was quenched with aqueous HCl (1
M, 20 mL), the organic phase was separated. The solvent was
evaporated, and the residue was dissolved in AcOEt and washed
with water. The organic phase was dried over Na2SO4, and the
solvent was evaporated. The evaporation of the solvent gave
1
(1.10 g, 68% yield). H NMR (CDCl3, 400 MHz): δ 5.76 (m,
2H, olefinic protons), 3.46 (m, 4H, methylene protons), 2.48
(s, 3H, methyl protons).
The free amine obtained above was dissolved in ether containing
acetic acid and the solution evaporated. The residue was dissolved in
MeOH. To the solution was added Dowex 1X2 (Cl−) ion-exchange
resin (3 g). The suspension was stirred for 10 min and filtered. After
the solution was evaporated, the resultant residue was dissolved in a
minimum amount of MeOH and ether was added to form a white
solid. The white solid was quickly collected, rinsed with ether, and
dried in vacuo to give 4-RCM as a highly hygroscopic solid. Due to its
1
compound 10 as a colorless oil (1.65 g, 76% yield). H NMR
(CDCl3, 400 MHz): δ 8.14−8.12 (m, 1H, 3-Ph), 7.88−7.85
(m, 1H, 4-Ph), 7.77−7.73 (m, 2H, 5-Ph and 6-Ph), 5.73 (m,
1H, −CHCH2), 5.43 (br, 1H, −SO2NH−), 5.23−5.18 (m,
1H, −CHCHα), 5.13−5.09 (m, 1H, −CHCHβ), 3.77 (m,
2H, −NCH2CHCH2).
1
Compound 10 (1.65 g, 6.80 mmol) obtained above was dissolved in
DMF (10 mL) in a 100 mL flask equipped with a condenser. After
hygroscopicity, the yield was not precisely evaluated. H NMR (D2O,
400 MHz): δ 5.92 (m, 2H, olefinic protons), 4.39 (d, J = 13 Hz, 2H,
E
dx.doi.org/10.1021/om4005302 | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
K2CO3 (2.80 g, 20.4 mmol) and 4-bromo-1-butene (1.00 g, 7.50
mmol) were added, the solution was stirred at 60 °C under a N2
atmosphere. After 1 h, 4-bromo-1-butene was further added (0.50 g,
3.75 mmol) and the solution was stirred at 60 °C for 30 min. The
solution was cooled to room temperature, and water (50 mL) was
added before extraction with ether (three times). The ether phases
were combined and dried over Na2SO4. The solvent was evaporated,
and the red residue was subjected to silica gel column chromatography
with hexane/AcOEt = 2/1 as eluent to give compound 11 as a pale
ACKNOWLEDGMENTS
■
This work was supported by a Grant-in-Aid for Science
Research on Innovative Areas (Molecular Activation Directed
toward Straightforward Synthesis, MEXT Japan) and “The
Green Photonics Project” (NAIST, Japan). We thank Ms.
Yuriko Nishiyama and Ms. Yoshiko Nishikawa for mass
analyses and Mr. Leigh McDowell for kind advice in the
preparation of the manuscript.
1
yellow oil (1.74 g, 87% yield). H NMR (CDCl3, 400 MHz): δ 8.05
(d, J = 6.8 Hz, 1H, 3-Ph), 7.72−7.62 (m, 3H, 4-Ph, 5-Ph, and 6-Ph),
5.70 (m, 2H, −CHCH2 × 2), 5.21 (m, 2H, −NCH2CHCH2),
5.02 (m, 2H, −NCH2CH2CHCH2), 3.96 (d, 2H, J = 7.0 Hz,
−-NCH2CHCH2), 3.36 (dd, J = 7.5 Hz, 7.5 Hz, 2H,
−NCH2CH2CHCH2), 2.29 (dd, J = 7.5 Hz, 7.5 Hz, 2H,
−NCH2CH2CHCH2). 13C NMR (D2O, 100 MHz): δ 135.6,
130.0, 126.4, 121.6, 52.1, 48.5, 32.7. EI-HR-MS (positive mode): calcd
112.1121 for C7H14N ([M − Cl]+), found 112.1133.
REFERENCES
■
(1) (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18−29.
(b) Handbook of Metathesis; Wiley-VCH: Weinheim, Germany, 2003.
(c) Hoveyda, A. H.; Zhugralin, A. R. Nature 2007, 450, 243−251.
(d) Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012−3043.
̈
(2) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J.
Am. Chem. Soc. 2000, 122, 8168−8179. (b) Connon, S. J.; Rivard, M.;
Zaja, M.; Blechert, S. Adv. Synth. Catal. 2003, 345, 572−575.
(c) Vehlow, K.; Gessler, S.; Blechert, S. Angew. Chem., Int. Ed. 2007,
46, 8082−8085. (d) Grela, K.; Harutyunyan, S.; Michrowska, A.
Angew. Chem., Int. Ed. 2002, 41, 4038−4040. (e) Michrowska, A.;
Gułajski, Ł.; Kaczmarska, Z.; Mennecke, K.; Kirschning, A.; Grela, K.
Green. Chem. 2006, 8, 685−688. (f) Gułajski, Ł.; Michrowska, A.;
In a 100 mL two-neck flask equipped with a condenser, p-
toluenethiol (1.83 g, 14.8 mmol) was dissolved in MeCN (5 mL) and
cooled with an ice bath. To the solution was added 11 M aqueous
KOH (1.4 mL) over 10 min, and the solution was stirred for 5 min.
Compound 11 (1.74 g, 5.9 mmol) in MeCN (5 mL) was slowly added
to the aforementioned solution over 20 min before the solution was
stirred at 50 °C for 1 h. After the disappearance of 11 was confirmed
by TLC, aqueous HCl (1 M) was added to extract the deprotected
amine. The water phase was brought out to pH 12 by adding aqueous
KOH. The amine was extracted with CH2Cl2 three times to remove
excess p-toluenethiol, and the organic phase was dried over Na2SO4.
After filtration, the solution was cooled with an ice bath. To the
solution was added di-tert-butyl dicarbonate (1.54 g, 7.10 mmol). The
reaction mixture was stirred at room temperature for 1 h, washed with
water, and dried over Na2SO4. The solvent was evaporated to yield a
colorless oil. The oil was dissolved in 4 M HCl in dioxane, and the
solution was stirred at room temperature for 18 h. After the solvent
was evaporated, the residue was triturated with ether to yield a white
solid. The solid was collected by suction, rinsed with ether, and dried
in vacuo. Compound 6 (0.540 g) was obtained in a yield of 62% in
Naroznik, J.; Kaczmarska, Z.; Rupnicki, L.; Grela, K. ChemSusChem
̇
2008, 1, 103−109. (g) Binder, J. B.; Guzei, I. A.; Raines, R. T. Adv.
Synth. Catal. 2007, 349, 395−404.
(3) (a) Grela, K.; Gułajski, Ł.; Skowerski, K. Alkene Metathesis in
Water. In Metal-Catalyzed Reactions in Water; Dixneuf, P. H.,
Cadierno, V., Eds.; Wiley-VCH: Weinheim, Germany, 2013; pp
291−336. (b) Binder, J. B.; Blank, J. J.; Raines, R. T. Org. Lett. 2007, 9,
4885−4888.
(4) (a) Hong, S.-H.; Grubbs, R. H. J. Am. Chem. Soc. 2006, 128,
3508−3509. (b) Gallivan, J. P.; Jordan, J. P.; Grubbs, R. H.
Tetrahedron Lett. 2005, 46, 2577−2580.
(5) (a) Lynn, D. M.; Kanaoka, S.; Grubbs, R. H. J. Am. Chem. Soc.
1996, 118, 784−790. (b) Lynn, D. M.; Mohr, B.; Grubbs, R. H. J. Am.
Chem. Soc. 1998, 120, 1627−1628. (c) Kirkland, T. A.; Lynn, D. M.;
Grubbs, R. H. J. Org. Chem. 1998, 63, 9904−9909. (d) Jordan, J. P.;
Grubbs, R. H. Angew. Chem., Int. Ed. 2007, 46, 5152−5155.
(e) Connon, S. J.; Blechert, S. Bioorg. Med. Chem. Lett. 2002, 12,
1873−1876.
(6) (a) Lin, Y. A.; Chalker, J. M.; Davis, B. G. J. Am. Chem. Soc. 2010,
132, 16805−16811. (b) Lin, Y. A.; Chalker, J. M.; Floyd, N.;
Bernardes, G. J. L.; Davis, B. G. J. Am. Chem. Soc. 2008, 130, 9642−
9643. (c) Chalker, J. M.; Lin, Y. A.; Boutureira, O.; Davis, B. G. Chem.
Commun. 2009, 3714−3716. (d) Cochrane, S. A.; Huang, Z.; Vederas,
J. C. Org. Biomol. Chem. 2013, 11, 630−639. (e) Binder, J. B.; Raines,
R. T. Curr. Opin. Chem. Biol. 2008, 12, 767−773.
(7) (a) Mayer, C.; Gillingham, D. G.; Ward, T. R.; Hilvert, D. Chem.
Commun. 2011, 47, 12067−12068. (b) Lo, C.; Ringenberg, M. R.;
Gnandt, D.; Wilson, Y.; Ward, T. R. Chem. Commun. 2011, 47,
12065−12067. (c) Matsuo, T.; Imai, C.; Yoshida, T.; Saito, T.;
Hayashi, T.; Hirota, S. Chem. Commun. 2012, 48, 1662−1664.
(d) Philippart, F.; Arlt, M.; Gotzen, S.; Tenne, S.-J.; Bocola, M.; Chen,
H.-H.; Zhu, L.; Schwaneberg, U.; Okuda, J. Chem. Eur. J. 2013,
DOI: 10.1002/chem.201301515.
(8) Michrowska, A.; Grela, K. Pure Appl. Chem. 2008, 80, 31−43.
(9) (a) Banti, D.; Mol, J. C. J. Organomet. Chem. 2004, 689, 3113−
3116. (b) Dinger, M. B.; Mol, J. C. Eur. J. Inorg. Chem. 2003, 2827−
2833.
(10) (a) Straub, B. F. Adv. Synth. Catal. 2007, 349, 204−214.
(b) Falivene, L.; Poater, A.; Cazin, C. S. J.; Slugovc, C.; Cavallo, L.
DaltonTrans 2013, 42, 7312−7317. (c) Straub, B. F. Angew. Chem., Int.
Ed. 2005, 44, 5974−5978.
(11) (a) Krause, J. O.; Nuyken, O.; Wurst, K.; Buchmeiser, M. R.
Chem. Eur. J. 2004, 10, 777−784. (b) Wappel, J.; Urbina-Blanco, C. A.;
Abbas, M.; Albering, J. H.; Saf, R.; Nolan, S. P.; Slugovc, C. Beilstein J.
Org. Chem. 2010, 6, 1091−1098. (c) Zirngast, M.; Pump, E.; Leitgeb,
A.; Albering, J. H.; Slugovc, C. Chem.Commun. 2011, 47, 2261−2263.
1
three steps from 12. H NMR (D2O, 400 MHz): δ 5.90 (m, 1H,
−NCH2CHCH2), 5.81 (m, 1H, −NCH2CH2CHCH2), 5.49 (m,
2H, −NCH2CHCH2), 5.22 (m, 2H, −NCH2CH2CHCH2), 3.66
(d, 2H, J = 6.8 Hz, −NCH2CHCH2), 3.14 (t, 2H, J = 7.1 Hz,
−NCH2CH2CHCH2), 2.46 (td, 2H, J = 7.1 Hz, 6.9 Hz,
−NCH2CH2CHCH2). 13C NMR (D2O, 100 MHz): δ 135.6,
130.0, 126.4, 121.6, 52.1, 48.5, 32.7. EI-HR-MS (positive mode): calcd
112.1121 for C7H14N ([M − Cl]+), found 112.1133. Anal. Calcd for
C7H14NCl: C, 56.94; H, 9.56; N, 9.49. Found: C, 56.76; H, 9.48; N,
9.52.
Spectroscopic Data of RCM Product from 6 (6-RCM). 1H
NMR (D2O, 400 MHz): δ 5.99 (m, 1H, −NCH2CH2CHCHCH2N-
), 5.77 (m, 1H, −NCH2CH2CHCHCH2N-), 3.68 (dt, 2H, J = 2.6
Hz, 5.5 Hz, −CHCHCH2N−), 3.34 (t, 2H, J = 6.3 Hz,
−NCH2CH2CHCH−), 2.40 (m, 2H, −NCH2CH2CHCH−).
13C NMR (D2O, 100 MHz): δ 128.3, 122.3, 44.4, 43.4, 23.8.
ASSOCIATED CONTENT
* Supporting Information
■
S
Figures giving NMR data of substrates and authentic samples of
products, 1H NMR spectra of reaction mixtures, UV−vis
spectra, and ESI-TOF-MS spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*T.M.: tel, +81-743-72-6112; fax, +81-743-6119; e-mail,
tmatsuo@ms.naist.jp.
■
Notes
The authors declare no competing financial interest.
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(d) Keitz, B. K.; Endo, K.; Patel, P. R.; Herbert, M. B.; Grubbs, R. H. J.
Am. Chem. Soc. 2012, 134, 693−699.
(12) Tanaka, K.; Bohm, V. P. W.; Chadwick, D.; Roeper, M.;
̈
Braddock, D. C. Organometallics 2006, 25, 5696−5698.
(13) (a) Pump, E.; Fischer, R. C.; Slugovc, C. Organometallics 2012,
31, 6972−6979. (b) Macnaughtan, M. L.; Gary, J. B.; Gerlach, D. L.;
Johnson, M. J. A.; Kampf, J. W. Organometallics 2009, 28, 2880−2887.
(c) Leitao, E. M.; van der Eide, E. F.; Romero, P. E.; Piers, W. E.;
McDonald, R. J. Am. Chem. Soc. 2010, 132, 2784−2794. (d) Volland,
M. A. O.; Hansen, S. M.; Rominger, F.; Hofmann, P. Organometallics
2004, 23, 800−816.
(14) Leitao, E. M.; Dubberley, S. R.; Piers, W. E.; Wu, Q.; McDonald,
R. Chem. Eur. J. 2008, 14, 11565−11572.
(15) Lynn, D. M.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 3187−
3193.
(16) Nitrate-bound Ru complexes have been prepared in organic
solvents: Rosebrugh, L. E.; Herbert, M. B.; Marx, V. M.; Keitz, B. K.;
Grubbs, R. H. J. Am. Chem. Soc. 2013, 135, 1276−1279.
(17) (a) Van Rensburg, W. J.; Steynberg, P. J.; Meyer, W. H.; Kirk,
M. M.; Forman, G. S. J. Am. Chem. Soc. 2004, 126, 14332−14333.
(b) Van Rensburg, W. J.; Steynberg, P. J.; Kirk, M. M.; Meyer, W. H.;
Forman, G. S. J. Organomet. Chem. 2006, 691, 5312−5325.
(18) (a) Mingotaud, A.-F.; Mingotaud, C.; Moussa, W. J. Polym. Sci.,
Polym. Chem. 2008, 46, 2833−2844. (b) Thiel, V.; Hendann, M.;
Wannowius, K. J.; Plenio, H. J. Am. Chem. Soc. 2012, 134, 1104−1114.
(19) (a) Mhboobi, S.; Fischer, E. C.; Eibler, E.; Wiegrebe, W. Arch.
Pharm. 1988, 321, 423−424. (b) Bobbitt, J. M.; Amundsen, L. H.;
Steiner, R. I. J. Org. Chem. 1960, 25, 2230−2231.
(20) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995,
36, 6373−6374.
G
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