Synthesis, structure, and catalytic activity of new ruthenium(II) indenylidene complexes bearing unsymmetrical N - heterocyclic carbenes

Article abstract of DOI:10.1021/om4009197

New robust and air-stable ruthenium(II) indenylidene type second-generation precatalysts with unsymmetrical N-heterocyclic carbene (NHC) ligands were synthesized. The reaction profiles of these complexes were studied in commercial-grade solvents in air with model substrates leading to the di-, tri-, and tetrasubstituted olefins. In addition, application of selected precatalysts for olefin metathesis reactions on a broad spectrum of substrates with different functional groups was examined. Studies of solvent effects for the selected precatalysts as well as thermal activation of the corresponding complexes showed significant differences in their activities. Observed relationships in connection with single-crystal X-ray analysis revealed the influence of the unsymmetrical NHC ligands on the initiation rate of precatalysts. Dissociation of the phosphine ligand, the rate-determining step for our most active precatalysts, is accelerated by the steric repulsion of the dangling benzyl arm and the tricyclohexylphosphine ligand. A precatalyst with a hemilabile benzyl arm evinced decreased activity, probably due to coordination of the heteroatom to the ruthenium core taking place after dissociation of the phosphine ligand.

Full text of DOI:10.1021/om4009197

Article
pubs.acs.org/Organometallics
Synthesis, Structure, and Catalytic Activity of New Ruthenium(II)
Indenylidene Complexes Bearing Unsymmetrical N-Heterocyclic
Carbenes
Osman Ablialimov, Mariusz Kędziorek, Maura Malinska, Krzysztof Wozniak, and Karol Grela*
́
́
̇
Department of Chemistry, University of Warsaw, Zwirki i Wigury Street 101, 02-089 Warsaw, Poland
S
* Supporting Information
ABSTRACT: New robust and air-stable ruthenium(II) indenylidene type second-
generation precatalysts with unsymmetrical N-heterocyclic carbene (NHC) ligands
were synthesized. The reaction profiles of these complexes were studied in
commercial-grade solvents in air with model substrates leading to the di-, tri-, and
tetrasubstituted olefins. In addition, application of selected precatalysts for olefin
metathesis reactions on a broad spectrum of substrates with different functional
groups was examined. Studies of solvent effects for the selected precatalysts as well as
thermal activation of the corresponding complexes showed significant differences in
their activities. Observed relationships in connection with single-crystal X-ray analysis
revealed the influence of the unsymmetrical NHC ligands on the initiation rate of
precatalysts. Dissociation of the phosphine ligand, the rate-determining step for our
most active precatalysts, is accelerated by the steric repulsion of the dangling benzyl arm and the tricyclohexylphosphine ligand. A
precatalyst with a hemilabile benzyl arm evinced decreased activity, probably due to coordination of the heteroatom to the
ruthenium core taking place after dissociation of the phosphine ligand.
type ruthenium precatalysts incorporating an unsymmetrical
NHC are known,22,23 those of the indenylidene type remain
unexplored.17 We intended to evaluate the effect of a change in
steric crowding by replacement of one of the traditional mesityl
groups in the NHC ligand with a less constrained benzyl group
on the activity and selectivity of the resulting precatalysts.
Moreover, substituents in the benzyl group can further modify
the electronic and steric properties of this ligand. As an
unsymmetrical NHC ligand alters the steric environment of
catalytically active metathesis intermediates, we were interested
how this would influence E/Z selectivity in cross-metathesis
(CM) reactions and selectivity in diastereoselective ring-
rearrangement metathesis (dRRM) reactions.24
INTRODUCTION
■
Olefin metathesis is a versatile tool for the formation of carbon−
carbon double bonds1 and therefore finds itself very useful in
academia,2 as well as in industry.3−5 Applications include not
only the preparation of small molecules but also the tedious
synthesis of biologically active compounds.6,7 In this respect it
was widely acknowledged by a Nobel Prize to Chauvin,8
Schrock,9 and Grubbs.10
The development of air-stable olefin metathesis precatalysts
which will tolerate the use of commercial-grade purity and
nondegassed solvents is important, because it offers practical
simplicity and as a result extends the scope of olefin metathesis,
especially for industrial applications. Nowadays, there are many
known ruthenium precatalysts with various NHC ligands
designed for olefin metathesis reactions.11 Although this process
can be carried out also in water, dry deoxygenated solvents are
generally used.12 Even though ruthenium precatalysts are much
less oxygen and moisture sensitive than molybdenum and
tungsten species,13 studies concerning reactions performed in air
are quite scarce.14−17 Therefore, we turned our attention to the
ruthenium indenylidene precatalysts, since they were shown to
be more stable than their benzylidene counterparts.18−20 It is
known that steric modifications on the NHC’s moiety can induce
profound changes in the activity pattern of the resulting
indenylidene precatalysts furnishing complexes significantly
more active than the commercial [1,3-bis(2,4,6-trimethylphen-
yl)-2-imidazolidinylidene]dichloro-(3-phenyl-1H-inden-1-
ylidene)(tricyclohexylphosphine)ruthenium(II) - Umicore M2,
bearing a 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-
ylidene NHC ligand (SIMes).20,21 Though numerous Grubbs-
Recently we reported the synthesis and catalytic activity study
of the new ruthenium precatalysts 1−3 with unsymmetrical
benzyl-substituted NHC ligands (Figure 1).17 Precatalysts 1 and
Figure 1. New indenylidene type ruthenium precatalysts 1−7 with an
unsymmetrical NHC ligand and Umicore M2.
Received: September 24, 2013
Published: April 30, 2014
© 2014 American Chemical Society
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a
Scheme 1. Synthetic Pathways for the Synthesis of the New Indenylidene Precatalysts 4−6
a
Reaction conditions: (a) N-(2,4,6-trimethylphenyl)-1,2-diaminoethane, p-toluenesulfonic acid (PTSA) cat., then NaBH4; (b) 1,1′-carbon-
yldiimidazole (CDI), then N-(2,4,6-trimethylphenyl)-1,2-diaminoethane, and then LiAlH4; (c) HC(OEt)3, HCl; (d) potassium tert-amylate, M1.
a
Scheme 2. Synthetic Pathways for the Synthesis of the New Indenylidene Precatalyst 7
a
Reaction conditions: (a) N-(2,4,6-trimethylphenyl)-1,2-diaminoethane, p-toluenesulfonic acid (PTSA) cat., then NaBH4; (b) 11; (c) HC(OEt)3,
NH4BF4; (d) M1; (e) potassium tert-amylate, M1.
Figure 2. ORTEP representations of complexes 1, 4, and 5. Hydrogen atoms have been omitted for clarity. Thermal ellipsoids are shown at the 50%
probability level. Selected bond lengths (Å) are as follows: Ru−CNHC, 2.059(4) (1), 2.067(4) (4), 2.07(1) (5); Ru−Cbenzylidene, 1.863(4) (1), 1.866(5)
(4), 1.85(1) (5); Ru−P, 2.472(1) (1), 2.449(1) (4), 2.437(3) (5). Selected bond angles (deg) are as follows: CNHC−Ru−Cbenzylidene, 100.0(2) (1),
100.9(2) (4), 99.0(3) (5).
2 proved to be definitely more active at 30 °C than commercially
available Umicore M2, while precatalyst 3 was much less active.
In this report we wish to publish an extended study of
indenylidene second-generation precatalysts with unsymmetrical
benzyl-substituted NHC ligands about substituent, solvent, and
temperature effects on performance and stability as well as their
application in organic synthesis.
Precatalyst 7 was obtained from pentafluorobenzaldehyde 11
via diamine 12 and NHC salt 14 (Scheme 2). An alternative
route via the pentafluorophenyl adduct25,26 13 was less efficient,
presumably because of faster decomposition of the formed
product 7 at 90 °C.
X-ray Crystallographic Studies. Single crystals of the
precatalysts 1, 4, and 5 were grown by vapor diffusion of pentane
into the solution of the corresponding complex in dichloro-
methane and analyzed by X-ray diffraction (Figure 2). Attempts
to get good-quality crystals of complexes 3, 6, and 7 were
unsuccessful.
RESULTS AND DISCUSSION
■
Synthesis of Precatalysts. Precatalysts 4−6 were synthe-
sized according to a recently reported procedure using the
complex dichloro(3-phenyl-1H-inden-1-ylidene)bis(tricyclo-
hexylphosphine)ruthenium(II) Umicore M1 (Scheme 1).17
The crystal structure of 1 has been previously reported,17 and
its most important structural parameters were discussed. The
precatalysts 4 and 5 crystallize in the P21/n and C2/c monoclinic
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space groups with one molecule in the asymmetric unit of the
crystal lattice of each compound, respectively. In all studied
precatalysts the ruthenium atoms form trigonal bipyramids and
the corresponding bond lengths are the same within 3 standard
deviations. There is only one exception for the Ru−P distance,
the shortest of which is 2.437(3) Å (5) and the longest is
2.472(1) Å (1). Significant differences are present in the NHC
ligand (Figure 3). The torsion angle characterizing the twist of
Figure 4. Yield−time diagram for the RCM of diethyl diallylmalonate
(15; 0.1 M) in CD2Cl2 at 30 °C (solid lines) with 1 mol % precatalyst
and in C6D5CD3 at 60 °C (dashed lines) in nondegassed solvent in air.
Yields were calculated by 1H NMR spectroscopy.
the reaction precatalyst 2 with an NMe2 group on the NHC
ligand gave the highest rate of transformation. However, during
the course of the reaction it was outperformed by methoxy- and
iodo-functionalized precatalysts 1 and 5. Interestingly, despite
different steric and electronic factors for methoxy and iodo
substituents, both of these precatalysts showed practically the
same activity.
Figure 3. Overlay view of the molecules 1 (red), 4 (blue), and 5
(orange). Hydrogen atoms are omitted for clarity.
On the basis of the catalytic performance of precatalysts
(Figure 4) the influence of electronic factors is in fact minor, as
precatalysts with methoxy- (1), dimethylamino- (2), and iodo-
substituted (5) and unsubstituted benzyl arms (4) have quite
similar activities. Studies made by Plenio et al. concerning the
electronic impact of various substituents in SIMes-type NHC
ligand in Grubbs second-generation precatalysts reveal the
significant influence of functional groups on the catalytic
properties.28 However, in our case a methylene spacer effectively
suppresses electronic interaction through bond; therefore,
probably steric factors are pivotal. The low activity of precatalysts
7 with a pentafluorobenzyl arm and sulfur-containing 3 and 6 can
be explained by the interaction of heteroatoms from the benzyl
group with the ruthenium core, which lowers rotational freedom
of the benzyl arm and hampers the substrate’s approach.27
Coordination of a fluorine atom present in the aromatic ring of
an NHC ligand to ruthenium has already been described.29 In the
case of sulfur it is well-known that Ru−SII chelation is responsible
for the strongly decreased catalytic activity of the corresponding
ruthenium complexes.30,31 Also in the case of a thio analogue of
trans-dichloro Hoveyda precatalyst, very low catalytic potency
was observed.32,33 Differences in activities of precatalysts 3 and 6
are also connected with steric factors. Precatalyst 6 bearing a
bulky isopropylthio group gave product 16 with 16% yield in 1.5
h, while its analogue 3 with a less sterically demanding (and
better coordinating) methylthio group gave 6% yield in the same
period of time. The activities of precatalysts 3 and 6 could be
significantly increased by thermal activation (Figure 4, dashed
lines), but complete conversions could not be reached.
the phenyl ring around the methylene bridge is equal to 76.4(6),
61.0(6), and 55(1)° for 1, 4, and 5, respectively. This suggests
that a more bulky substituent in the benzyl ring strengthens the
repulsive interaction with the tricyclohexylphosphine ligand and
enforces a twist of the ring, precluding contact between the
heteroatom of the benzyl group and the ruthenium core.
The results of X-ray analysis of methoxy- and iodo-
functionalized precatalysts 1 and 5 did not confirm coordination
of the heteroatom of benzyl group to the ruthenium core. One
can expect that also in the case of methylthio- (3), isopropylthio-
(6), and fluoro-functionalized (7) complexes repulsive inter-
action with the tricyclohexylphosphine ligand prevents this
proximity. However, it is feasible that, after dissociation of
phosphine ligand, coordination might take place. Such
interactions have been proved by extensive studies on a similar
complex.27
Catalytic Performance Tests. In order to evaluate the
catalytic performance of precatalysts, RCM reactions with the
model substrate diethyl diallylmalonate (DEDAM, 15) were
tested (Scheme 3, Figure 4). In this transformation precatalysts
with methoxy- (1), dimethylamino- (2), and iodo-substituted
(5) and unsubstituted benzyl arms (4) significantly surpassed in
efficiency the referenced commercial precatalyst M2. Precatalyst
7 with a pentafluorobenzyl arm showed lower activity; however,
it was still higher than that of M2. Only sulfur-containing
precatalysts 3 and 6 were less active than M2. At the beginning of
Scheme 3. Model RCM Reaction of Diethyl Diallylmalonate
(15)
As more difficult substrates should better differentiate
precatalyst activity, we also tested four of our most active
complexes in RCM reaction of diethyl 2-allyl-2-(2-methylallyl)-
malonate (17) as a model substrate (Scheme 4, Figure 5).
In general, the rates of conversions were lower for all applied
precatalyst; however, again precatalysts with methoxy- (1),
dimethylamino- (2), and iodo-substituted (5) and unsubstituted
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Scheme 4. Model RCM Reaction of Diethyl 2-Allyl-2-(2-
methylallyl)malonate (17)
Scheme 5. Model RCM Reaction of N,N-Bis(2-methylallyl)-p-
toluenesulfonamide (19)
Figure 5. Yield−time diagram for RCM of diethyl 2-allyl-2-(2-
methylallyl)malonate (17; 0.1 M) in CD2Cl2 at 30 °C with 1 mol %
precatalyst, in nondegassed solvent in air. Yields were calculated by 1H
NMR spectroscopy.
Figure 6. Yield−time diagram for RCM of N,N-bis(2-methylallyl)-p-
toluenesulfonamide (19; 0.1 M) in C6D5CD3 at 60 °C with 1 mol %
precatalyst in nondegassed solvent in air. Yields were calculated by 1H
NMR spectroscopy.
benzyl arms (4) significantly outperformed commercial
precatalyst M2. What more, as for the RCM reaction of diethyl
diallylmalonate (15) (Scheme 3, Figure 4) precatalysts 1, 2, and
5 were more active than complex 4. Also, we observed that
activity patterns for precatalysts 1 and 5 are again very similar,
which indicates that this is not a coincidence. Although reactions
with diethyl diallylmalonate (15) were faster than those with
diethyl 2-allyl-2-(2-methylallyl)malonate (17), it seems that
overall relative rates of the rate-determining step of the catalytic
cycles are similar. This is in accordance with structure of olefin
17, as molecule of the catalyst will preferentially react with the
same rate with one remaining allyl group. Diethyl diallylmalonate
(15) has two reactive allyl groups; therefore, in this case reaction
with a catalyst is faster. The reaction with the second olefinic
group is intramolecular and so does not depend on
concentration.
It is well-known that the formation of tetrasubstituted double
bonds via olefin metathesis is challenging and indenylidene
precatalysts in general are not suited for this transformation.
However, the Cazin group has developed for this reaction one of
the best state of the art indenylidene type precatalysts.34
Recently, we reported a very active indenylidene type precatalyst
with reduced steric bulk in an NHC ligand, which was also tested
in the formation of tetrasubstituted double bonds via RCM.20 As
our new precatalysts also have diminished steric demand in the
NHC ligand, we decided to test them in a reaction with N,N-
bis(2-methylallyl)-p-toluenesulfonamide (19) (Scheme 5, Figure
6). As at 30 °C this process was sluggish, we carried out the
reactions at 60 °C with 5 mol % precatalyst loading.
outperformed commercial precatalyst M2. However, after a short
time (5 min) they became less active, while M2 maintained its
activity over 30 min. We assume that in the case of fast initiators
1, 2, 4, and 5 decomposition at 60 °C took place much more
quickly, in comparison to the more slowly initiating precatalyst
M2, which is in turn more stable.
Therefore, it seems that the new precatalysts are not suitable
for the synthesis of tetrasubstituted double bonds. However, the
reaction profiles obtained in the case of the formation of di- and
trisubstituted olefins (Figures 4 and 5) revealed a great potential
for precatalysts with methoxy- (1), dimethylamino- (2), and
iodo-substituted (5) and unsubstituted benzyl arms (4), since all
of them significantly surpassed commercial precatalyst M2 in
efficiency.
Solvent Effect. It is well-known that the solvent can have a
profound effect on the rate of metathesis reactions.35−37 We were
interested in exploring the solvent-dependent differences in
activities of precatalysts on carrying out the model metathesis
reaction (Scheme 3) in the most frequently used solvents:
toluene and dichloromethane. The results of investigations with
M2 and benzyl- (4) and pentafluorobenzyl-functionalized (7)
precatalysts are depicted in Figure 7.
Precatalysts M2 and 4 were both more active in dichloro-
methane than in toluene. However, the influence on perform-
ance of precatalyst 4 bearing a unsubstituted benzyl arm was
much stronger. It is interesting that at the beginning precatalyst 7
had a higher formation rate of the product 16 in toluene than in
DCM. An initiation kinetics study of Grubbs second-generation
precatalyst showed that dissociation of phosphine is faster in
DCM than in toluene.35,37 We observed the same trend for
complexes M2 and 4; therefore, in these cases dissociation of
phosphine is probably the rate-determining step, as Nolan
already proposed for M2.38 Precatalysts with methoxy- (1),
Unfortunately, under these conditions none of the tested
precatalysts afforded quantitative yields of product 20. At the
beginning precatalysts with methoxy- (1), dimethylamino- (2),
and iodo-substituted (5) and unsubstituted benzyl arms (4)
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Figure 8. Yield−time diagram for RCM of diethyl diallylmalonate (15;
0.1 M) in C6D5CD3 with 1 mol % precatalyst in nondegassed solvent in
air: (solid lines) 60 °C; (dashed lines) 30 °C. Yields were calculated by
1H NMR spectroscopy.
Figure 7. Solvent-dependent yield−time diagram for RCM of diethyl
diallylmalonate (15; 0.1 M) at 30 °C with 1 mol % precatalyst in
nondegassed solvent in air: (solid lines) CD2Cl2; (dashed lines)
C6D5CD3. Yields were calculated by 1H NMR spectroscopy.
Thermal Stability Studies. To gain further insight into
catalytic activity differences of the studied complexes, we
checked the stabilities of our precatalysts in the absence of an
olefinic substrate in CD2Cl2 solution at 30 °C in air (Figure 9).
dimethylamino- (2), and iodo-substituted (5) and unsubstituted
benzyl arms (4) are highly active because the nonrigid benzyl
wing facilitates dissociation of phosphine by steric repulsion (this
is also suggested by X-ray diffraction studies). In the case of
precatalysts with methylthio- (3), isopropylthio- (6), and
pentafluoro-substituted (7) benzyl arms after dissociation of
phosphine coordination of heteroatom to ruthenium core takes
place and impedes association of the olefin.27 For these
precatalysts probably dissociation of phosphine is not the rate-
determining step, as for fluoro-functionalized precatalyst 7 the
initial rate of product formation is higher in toluene than in
DCM.
Stability of Precatalysts and Temperature Effect on
Their Performance. As we observed that sulfur-containing
precatalysts 3 and 6 were significantly more active at elevated
temperature (Figure 4), we decided to examine the behavior of
some other selected precatalysts. Experiments were done with
diethyl diallylmalonate (15) at 30 and 60 °C in toluene. As in
toluene the performance of M2 and the benzyl- (4) and
pentafluorobenzyl-functionalized (7) precatalysts was lower than
in DCM, we were interested how an increase of temperature
would compensate the deactivating properties of the solvent.
Elevated temperature caused a significant increase of activity
for all tested precatalysts (Figure 8). Especially, precatalyst M2
became highly active, giving a practically quantitative yield of the
product 16 (>98%) in just 20 min. We observed also that in
toluene at 30 and 60 °C at the beginning of the reaction
pentafluorobenzyl-functionalized precatalyst 7 outperformed its
benzyl analogue 4. However, 4 gave in 25 min practically full
consumption of the substrate 15 (ca. 95% yield of the product
16), while 7 at 30 °C (in DCM and toluene) gave finally only
partial conversion to the product 16. The kinetic profile of
precatalyst 7 resembles those for 3 and 6 (Figure 4), as they are
susceptible to temperature activation, though full conversion of
substrate 15 to the product 16 was never reached. A common
feature in the structure of these precatalysts is the presence of a
potentially electron donating heteroatom (sulfur or fluorine)
susceptible to coordination to the ruthenium center.29,39 This
causes shielding of the reactive metal center and therefore
hampers the substrate’s approach. It is known that such
coordination can deactivate the catalyst.27
Figure 9. Degradation of precatalysts in CD2Cl2 solution at 30 °C in
nondegassed solvent in air monitored by H NMR spectroscopy with
1,3,5-trimethoxybenzene as an internal standard. Precatalyst 5 fully
decomposed within less than 24 h.
1
Apart from iodo-functionalized precatalyst 5, which fully
decomposed within less than 24 h, all complexes showed
relatively high stability when the solutions were prepared in
commercial-grade CD2Cl2 in air. Precatalyst M2 was very stable,
as after 5 days more than 80% of the starting amount was present
in the solution. All of our precatalysts decomposed more quickly
than M2, which is in line with the reduced steric demand of the
NHC ligand. It is interesting that benzyl- and pentafluorobenzyl-
functionalized precatalysts 4 and 7 had practically the same
stability. This means that the postulated coordination of fluorine
to ruthenium has apparently no influence on the stability of the
precatalyst. This is confirmed by degradation profiles of sulfur-
containing complexes 3 and 6, which are among the most quickly
decomposing precatalysts studied by us. The observed behavior
of the methylthio- and isopropylthio-functionalized precatalysts
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Table 1. Preparative RCM and Ene−Yne Reactions
a
b
Reaction conditions: 0.1 M, CH2Cl2 (commercial-grade HPLC) in nondegassed solvent in air. Reactions at 50 °C were performed in toluene
c
(commercial-grade HPLC) in nondegassed solvent in air. Isolated yields after flash chromatography.
3 and 6 is also indicative that steric factors may influence the
catalyst’s stability, with the bulkier 6 being more stable than 3.
The very low stability of precatalyst 5 is in accordance with
Caryl−I activation as a decomposition pathway.29
coordination of the pentafluorobenzyl wing to the ruthenium
core. The steric hindrance of the benzyl group substituted with
OMe and NMe2 groups in precatalysts 1 and 2 is larger;
therefore, dissociation rate constants are also larger and thus the
stability is lower. Following this way of argumentation, sulfur-
containing complexes 3 and 6 have high rate constants for
phosphine dissociation, but their activities are significantly
reduced due to the strong sulfur−ruthenium interaction.
An important point is understanding how the stability of a
given precatalyst influences its performance. Though being one
of the most active initiators tested by us, complex 5 was seen to
decompose in a much shorter time than the other precatalysts
(Figure 9). For the remaining complexes, the time required to
reach 10% decomposition (several hours) appears to be much
longer than the metathesis reaction time. It can thus be
concluded that the stability of these precatalysts has only a
negligible impact on their performance, at least for the reactions
carried out at 30 °C. However, the observed stabilities and
activities of precatalysts have a close relationship. We suppose
that decomposition and initiation of the studied second-
generation precatalysts is connected with dissociation of the
phosphine and formation of the unstable 14-electron species.40,41
Complex M2 is very stable and at the same time has lower activity
due to a lower phosphine dissociation rate constant. Precatalysts
with methoxy- (1) and dimethylamino-substituted (2) and
unsubstituted benzyl arms (4) are much more active and less
stable because repulsive interaction of the benzyl wing and
phosphine facilitates dissociation of the latter. Complexes 4 and
fluoro-functionalized 7 had practically the same stability; thus,
probably their rate constants for phosphine dissociation are very
similar. Benzyl and pentafluorobenzyl wing are sterically similar;
thus, repulsive interactions with phosphine are also similar.
Differences in activities of these precatalysts are attributable to
Scope of New Precatalysts in Organic Synthesis.
Encouraged by the results obtained in the initial catalytic tests,
we decided to investigate the performance of the most active
precatalysts 1 and 2 on a wider range of substrates in comparison
with commercial analogue M2 (Table 1). In general, the
reactions were monitored by GC until full consumption of the
substrate or no further progress of the reaction was observed. For
the ring-closing ene−yne metathesis reaction (RCEYM) the
standard test substrate 21 was used (Table 1, entry 1). In this
reaction precatalyst 1 was slightly slower than its analogue 2 but
faster than precatalyst M2. In the reaction of amide-based
substrate 23 (Table 1, entry 2) the best result was obtained with
precatalyst 1. Precatalyst M2 needed 8 h to cyclize 25 to the
seven-membered-ring product 26 (Table 1, entry 3), while
complexes 1 and 2 gave full conversion in just 3 h. Also in the
RCM of ketone 27 and sulfone 29 (Table 1, entries 4 and 5)
precatalysts 1 and 2 were much more active than M2. In the case
of substrate 31 (Table 1, entry 6), the coordinating ability of the
nitrile group slows down the reaction and for precatalyst M2
even precludes full conversion of the substrate. It is known that
indenylidene type precatalysts are strongly inhibited by
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acetonitrile.21 Summing up the results presented in Table 1, it is
clearly seen that the new precatalysts 1 and 2 with unsymmetrical
NHC ligands surpass the commercial analogue M2 in reaction
time and/or yield in all tested transformations.
Cross-Metathesis Reaction (CM). In order to evaluate the
effectiveness of our selected methoxy- (1) and dimethylamino-
functionalized (2) precatalysts in CM, we applied them in
reactions with allylbenzene (33) and cis-1,4-diacetoxy-2-butene
(34) (Scheme 6).
amount of the homodimerization product of pregnenolone
derivative 36 formed.
Table 3. Results of CM of Pregnenolone Derivative 36 with 2-
a
Methyl-2-butene (37) in Air
b
c
precatalyst
conversion (%)
isolated yield (%)
81
d
1
2
88
e
85
78
a
Reaction conditions: 2-methyl-2-butene (37) as a solvent (60 equiv),
b
[Ru] 2.5 mol %, 2 h, 22 °C, in nondegassed solvent in air. GC
conversion. Isolated yields after flash chromatography. Formation of
the homodimer of pregnenolone derivative 36 was observed. 6% of
Scheme 6. Cross Metathesis of Allylbenzene 33 with 2 equiv of
cis-1,4-Diacetoxy-2-butene (34) in Nondegassed Solvent in
Air
c
d
e
the homodimer of pregnenolone derivative 36 was isolated.
Macrocyclization. Macrocyclization is a special case of an
RCM reaction, as it is an intramolecular process. However,
entropy factors render this transformation difficult. Owing to its
importance, numerous reports addressing this issue were
published.46−53
In our study we decided to test dimethylamino-functionalized
complex 2 in a challenging macrocyclization of diene 39 (Scheme
8).54 The reaction was finished in 3 h, leading to the formation of
40 in good yield (72% after isolation).
In this transformation the new precatalyst 1 gave the highest
yield of product; however, the commercial precatalyst M2 had
better stereoselectivity (Table 2). It is known that CM leads to
Table 2. Results of CM of Allylbenzene (33) and cis-1,4-
Diacetoxy-2-butene (34)
Scheme 8. Macrocyclization of Diene 39 in Nondegassed
Solvent in Air
a
b
c
precatalyst
isolated yield (%)
E:Z
1
80
74
74
8:1
9:1
2
M2
11:1
a
Reaction conditions: allylbenzene (33) 0.1 M, cis-1,4-diacetoxy-2-
butene (34) 2 equiv, [Ru] = 2.5 mol %, CH2Cl2 (commercial-grade
b
HPLC), 20 h, 30 °C, in nondegassed solvent in air. Isolated yields
c
1
after flash chromatography. E:Z ratio was determined by H NMR
spectroscopy.
Diastereoselective Ring-Rearrangement Metathesis
(dRRM). Blechert et al. showed that diastereoselective ring
rearrangement metathesis of cyclopentene 41 (Scheme 9) with
good initial Z selectivity, but due to a secondary isomerization
reaction the thermodynamically more stable product E is
formed.42 As after a long time (20 h) precatalysts 1 and 2 gave
a slightly lower E/Z ratio than precatalyst M2, it seems that
asymmetry in the NHC ligand affects the stereochemistry of this
reaction.43 However, probably the structure of precatalysts 1 and
2 with a dangling benzyl arm on the NHC ligand is not rigid
enough to efficiently differentiate isomers E and Z.
Scheme 9. Diastereoselective Ring Rearrangement Metathesis
of Cyclopentene 41 in Nondegassed Solvent in Air
An interesting CM partner is 2-methyl-2-butene (37).44 Stolz
et al. successfully applied this reaction as a key step in the
synthesis of the biologically active molecule garsubellin A, an
Alzheimer’s therapeutic.45 To test the capability of our most
active precatalysts, we employed complexes 1 and 2 in the CM of
a pregnenolone derivative 36 with 2-methyl-2-butene 37
(Scheme 7). After 2 h of reaction both precatalysts furnished
the desired product in good yield (Table 3) with only a small
Grubbs first-generation and Hoveyda−Grubbs first-generation
precatalysts does not proceed in a diastereoselective manner,
while their second-generation analogues gave poor diastereose-
Scheme 7. Cross Metathesis of Pregnenolone Derivative 36 with 2-Methyl-2-butene (37) in Nondegassed Solvent in Air
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Organometallics
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lectivities (trans:cis dr = 2:1) (Table 4).55 We expected that an
unsymmetrical NHC moiety would increase the diastereose-
dissociation of the phosphine ligand, the rate-determining step
for our most active precatalysts. The 14-electron unstable species
formed in this way is likely responsible for the lower stability of
these new precatalysts. Studies of the challenging dRRM reaction
revealed that improvement in diastereoselectivity could be
reached not only by using the rigid architecture of the NHC
ligand, as in complex 44, but also by changing the substituents on
the nitrogen atoms in NHC ligand, leading to breakage of the
symmetry.
Table 4. Results of dRRM with Different Precatalysts
precatalyst
conversion (%)
trans:cis dr
a
a
Gru I, Hov I
95
1:1
a
a
Gru II, Hov II
95
2:1
b
b
1
2
4
>95
3.5:1
b
b
>95
4.7:1
b
b
>95
3.8:1
EXPERIMENTAL SECTION
■
b
b
M2
>95
1:8:1
All reagents were purchased from Sigma-Aldrich, Strem, TCI, and Alfa
Aesar and used without further purification. The precatalyst dichloro(3-
phenyl-1H-inden-1-ylidene)bis(tricyclohexylphosphine)ruthenium(II)
(M1) was obtained from Umicore AG. N-(2,4,6-Trimethylphenyl)-1,2-
diaminoethane was prepared according to Marshall’s procedure.57 2-
Iodobenzyl alcohol was prepared by a modified procedure58 (see the
Supporting Information). All reactions involving the synthesis of metal
complexes were carried out in oven- or flame-dried glassware with
magnetic stirring under an argon atmosphere with anhydrous solvents,
using standard Schlenk techniques. Toluene and diethyl ether were
distilled over K, while DMF was distilled over CaH2 under an
atmosphere of argon. To test the activity of precatalysts, HPLC-grade
solvents (Aldrich) CH2Cl2 and toluene were used as received. Analytical
thin-layer chromatography (TLC) was performed using silica gel 60 F254
precoated plates (0.25 mm thickness) with a fluorescent indicator.
Visualization of TLC plates was performed by UV light with either
KMnO4 or I2 stains. Flash chromatography was performed using silica
gel 60 (230−400 mesh). NMR spectra were recorded on an Agilent 400-
MR DD2 400 MHz spectrometer. NMR chemical shifts are reported in
ppm and referred to residual solvent peaks at 7.26 and 77.16 ppm for 1H
and 13C in CDCl3, 5.32 and 53.84 ppm for 1H and 13C in CD2Cl2, 2.50
a
55 b
1
Determined by H NMR spectroscopy. Determined by GC using
durene as an internal standard.
lectivity of the precatalysts. Therefore, we studied precatalysts
with methoxy- (1) and dimethylamino-substituted (2) and
unsubstituted benzyl arms (4) as well as commercially available
precatalyst M2 in this particular reaction.
As we expected, precatalyst M2 gave almost the same result
(Table 4, trans:cis dr = 1.8:1) as Grubbs and Hoveyda−Grubbs
second-generation precatalysts. However, application of the new
precatalysts 1 and 2 resulted in much higher diastereoselectivity:
trans:cis dr = 3.5:1 for 1, trans:cis dr = 4.7:1 for 2, and trans:cis dr =
3.8:1 for 4 (Table 4). Precatalyst 2, bearing a dimethylamino
substituent, showed the highest diastereoselectivity in compar-
ison with the previously tested commercial precatalysts.55 Better
diastereoselectivity (trans:cis dr = 9:1) was reported by Blechert
for precatalyst 44 with a rigid structure of the NHC ligand
(Figure 10); however, at the expense of yield (58%).56
1
and 39.52 ppm for H and 13C in DMSO-d6, and 0.00 ppm for 31P in
H3PO4 85% (aqueous), respectively. The following abbreviations are
used in reporting NMR data: s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), br (broad). Coupling constants (J) are in Hz.
Spectra are reported as follows: chemical shift (δ, ppm), multiplicity,
integration, coupling constants (Hz). IR spectra were recorded on a
Perkin-Elmer Spectrum One FTIR spectrometer with a diamond ATR
accessory. Wavenumbers are given in cm−1. GC analyses were
performed using Clarus 580 chromatograph using durene as an internal
standard. Microanalyses were made using Vario EL III apparatus.
Melting points were recorded on an OptiMelt SRS apparatus with a
heating rate of 10 °C/min. High-resolution electrospray mass spectra
(ESI-HRMS) were recorded on a Quattro LC triple-quadrupole mass
spectrometer. The mass spectrometer was calibrated with an internal
standard solution of sodium formate or sodium iodide in MeOH.
N1-(2-(Isopropylthio)benzyl)-N2-(2,4,6-trimethylphenyl)-
ethane-1,2-benzamide. To a vigorously stirred solution of 2-
(isopropylthio)benzoic acid59 (4.38 g, 22.3 mmol) in MeCN (60 mL)
was added 1,1′-carbonyldiimidazole (CDI; 4.48 g, 26.8 mmol)
portionwise over 5 min. The resulting mixture was stirred for 30 min
at 60 °C. Then, the resulting mixture was placed in an ice-cooled bath
and stirred for 5 min. Next, N-(2,4,6-trimethylphenyl)-1,2-diamino-
ethane (4.77 g, 26.8 mmol) in MeCN (10 mL) was added dropwise. The
ice-cooled bath was removed and the reaction mixture was stirred at
room temperature for 10 min. Then, the flask was placed in an oil bath
and stirred for 2 h at 60 °C. The progress of the reaction was monitored
by TLC (cyclohexane/EtOAc, 3/7). After full consumption of the
substrates the reaction mixture was cooled to room temperature and the
solvent was evaporated, delivering an orange oil. The oil was washed
with NaHCO3(aq) (5%, 2 × 50 mL) and brine (2 × 50 mL). The
mixture was extracted with DCM (2 × 100 mL), and the combined
organic layers were dried over MgSO4, filtered, and concentrated.
Purification by silica gel chromatography (cyclohexane/EtOAc, 1/3)
yielded the product as a white powder (7.40 g, 93%), mp 64−66 °C.
1H NMR (400 MHz, CDCl3): δ 7.73 (dd, 1H, J = 8.0, 4.0, NH), 7.48−
7.46 (m, 1H, Ar-H), 7.38−7.28 (m, 3H, Ar-H), 6.82 (s, 2H, Mes-H),
3.78−3.67 (m, 2H, ImdCH2), 3.43−3.33 (m, 1H, iPr-H), 3.21 (t, 2H, J =
Figure 10. Tetrahydroquinoline-based precatalyst.56
CONCLUSIONS
■
In summary, we have disclosed the synthesis and full character-
ization of seven new ruthenium indenylidene complexes bearing
unsymmetrical NHCs, in which a substituted benzyl arm was
present on one nitrogen. The highest metathesis activity was
found for methoxy- (1) and dimethylamino-substituted species
(2) utilized in air, in commercial-grade, nondegassed solvents. At
30 or 50 °C, 1 and 2 were more competent than their
commercially available analogue, the Umicore indenylidene
catalyst M2. The preferred solvent for metathesis reactions was
DCM, as toluene lowered the performance of the studied
precatalysts. However, performing reactions at elevated temper-
atures could overcome the deactivating effect of toluene. X-ray
studies revealed that, in the solid state, there is no interaction of
the benzyl arm in the NHC ligand with the ruthenium core.
However, the observed latent behavior of sulfur-containing
precatalysts 3 and 6, and the reduced activity of pentafluoro-
substituted precatalyst 7, may be caused by coordination of a
heteroatom in the hemilabile benzyl arm to the ruthenium core
after dissociation of the phosphine ligand. Repulsion between the
dangling benzyl arm and tricyclohexylphosphine accelerates
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4.0, ImdCH2), 2.28 (s, 6H, Mes-CH3), 2.22 (s, 3H, Mes-CH3), 1.27−
1.26 (d, 6H, J = 4.0, iPr-H). 13C NMR (100 MHz, CDCl3): δ 168.5,
138.0, 133.7, 130.5, 130.2, 127.5, 48.2, 41.0, 39.4, 23.1, 20.7, 18.6. IR
(film from CH2Cl2): ν 3349, 3057, 2961, 2919, 2862, 1589, 1486, 1442,
1240, 1155, 1113, 1038, 853, 751, cm−1. Anal. Calcd for C21H28N2OS: C,
70.75; H, 7.92; N, 7.86. Found: C, 70.28; H, 7.75; N, 7.56. HRMS (ESI):
m/z calcd for C21H28N2OS: [M + Na]+ 379.1820, found 379.1823.
N1-(2-(Isopropylthio)benzyl)-N2-(2,4,6-trimethylphenyl)-
ethane-1,2-diamine (9c). To a vigorously stirred suspension of
LiAlH4 (2.14 g, 53.8 mmol) in THF (50 mL) at 0 °C was added N1-(2-
(isopropylthio)benzyl)-N2-(2,4,6-trimethylphenyl)ethane-1,2-benza-
mide (5.20 g, 14.6 mmol) in THF (30 mL) dropwise. Next, the cooling
bath was removed and the resulting mixture was stirred at room
temperature for 10 min and then placed in an oil bath and refluxed for 6
h. The progress of the reaction was monitored by TLC (CH2Cl2/
MeOH, 19/1). After consumption of the starting material the reaction
mixture was cooled in an ice bath and the excess LiAlH4 was quenched
with water (30 mL, dropwise addition), followed by NaOH(aq) (10%,
15 mL). The resulting mixture was filtered through a Celite pad. The
filtrate was concentrated under reduced pressure, and the product was
extracted with EtOAc (2 × 50 mL). The organic phase was washed with
brine (2 × 50 mL), and the combined organic layers were dried over
MgSO4, filtered, and concentrated. Purification by silica gel chromatog-
raphy (CH2Cl2/MeOH, 20/1) yielded 9c as a yellow oil (3.50 g, 70%).
1H NMR (400 MHz, CDCl3): δ 7.42−7.30 (m, 2H, ArH), 7.22−7.16
(m, 2H, Ar-H), 6.78 (s, 2H, Mes-H), 3.92 (s, 2H, CH2), 3.44−3.30 (m,
1H, iPr-H), 3.04−2.99 (m, 2H, ImdCH2), 2.80−2.75 (m, 2H, ImdCH2),
2.24 (s, 6H, Mes-CH3), 2.20 (s, 3H, Mes-CH3), 1.27 (d, 6H, J = 12.0,
iPr-H). 13C NMR (100 MHz, CDCl3): δ 144.0, 141.4, 135.1, 130.5,
132.1, 131.1, 129.8, 129.6, 127.6, 126.8, 52.1, 49.4, 48.5, 38.5, 23.4, 20.7,
18.7. IR (KBr): ν 3378, 3350, 3246, 3065, 2924, 2861, 1631, 1541, 1482,
1427, 1312, 1216, 1106, 1033, 946, 850, 735, 702, 650, 481 cm−1. Anal.
Calcd for C21H30N2S: C, 73.63; H, 8.83; N, 8.18. Found: C, 73.70; H,
8.74; N, 8.36. HRMS (ESI): m/z calcd for C21H30N2S: [M + Na]+
365.2027, found 365.2021.
General Procedure for the Preparation of Diamines via One-
Pot Aldehyde−Amine Condensation and Reduction. To the
solution of an appropriate aldehyde (1−1.2 mmol) in methanol were
added a catalytic amount of p-toluenesulfonic acid (PTSA, ca. 5−7 mg)
and N-(2,4,6-trimethylphenyl)-1,2-diaminoethane (1 mmol). The
resulting mixture was stirred for 24 h at room temperature. Then, to
the resulting mixture was added MeOH (10−30 mL), and the flask was
placed in an ice-cooled bath. After that, NaBH4 (5 mmol) was added
portionwise (with 10 min intervals during 30 min) and the mixture was
stirred for 2 h at room temperature. The solvent was evaporated, and the
crude mixture was washed with saturated NaHCO3(aq) solution until
the pH became slightly basic. The product was extracted with EtOAc (3
× 40 mL). Purification of the crude mixture was accomplished by silica
gel chromatography (cyclohexane/EtOAc). The fractions containing
the desired product were concentrated. The flask with a product
(powder or oil) was charged with a stirring bar and vigorously stirred in
vacuo.
(8b; 2 g, 8.62 mmol) in MeOH (12 mL), PTSA (ca. 5−7 mg), N-(2,4,6-
trimethylphenyl)-1,2-diaminoethane (1.34 g, 7.5 mmol), and NaBH4
(1.13 g, 30 mmol) were used. Purification by silica gel chromatography
(cyclohexane/EtOAc, 5/1, followed by cyclohexane/EtOAc, 4/1)
yielded 9b as a white powder (1.97 g, 66%), mp 47−49 °C.
1H NMR (400 MHz, CDCl3): δ 7.85 (dd, 1H, J = 8.0, 0.8, Ar-H), 7.40
(dd, 1H, J = 7.4, 1.6, Ar-H), 7.33 (td, 1H, J = 7.4, 1.2, Ar-H), 6.98 (td,
1H, J = 7.8, 2.0, Ar-H), 6.83 (s, 2H, Mes-H), 3.88 (s, 2H, CH2), 3.10−
3.07 (m, 2H, Imd-CH2), 2.87−2.84 (m, 2H, Imd-CH2), 2.82−2.74 (brs,
1H, NH), 2.29 (s, 6H, CH3), 2.24 (s, 3H, Mes-CH3). 13C NMR (100
MHz, CDCl3): δ 143.8, 142.1, 139.6, 131.2, 129.8, 129.7, 129.5, 129.0,
128.4, 99.8, 58.0, 49.2, 48.3, 20.7, 18.6. IR (KBr): ν 3352, 3279, 2962,
2888, 2841, 1484, 1446, 1433, 1334, 1245, 1114, 1011, 859, 791, 749,
706, 652 cm−1. Anal. Calcd for C18H23IN2: C, 54.83; H, 5.88; N, 7.10.
Found: C, 54.65; H, 5.70; N, 7.11. HRMS (ESI): m/z calcd for
C18H23IN2 [M + Na]+ 417.0804, found 417.0797.
N1-(2,4,6-Trimethylphenyl)-N2-(2,3,4,5,6-pentafluorobenzyl)-1,2-
diaminoethane (12). Following the general procedure, a solution of
pentafluorobenzaldehyde (11; 2.5 g, 12.5 mmol) in MeOH (15 mL),
PTSA (5−7 mg), N-(2,4,6-trimethylphenyl)-1,2-diaminoethane (2.23 g,
12.5 mmol), and NaBH4 (1.89 g, 50 mmol) were used. Purification by
silica gel chromatography (cyclohexane/EtOAc, 4/1, followed by
cyclohexane/EtOAc, 1/1) yielded 12 as a white powder (3.10 g,
69%), mp 85−87 °C.
1H NMR (400 MHz, CDCl3): δ 6.82 (s, 2H, Ar-H), 3.98 (s, 2H,
CH2), 3.06−3.03 (m, 2H, Imd-CH2), 2.80−2.77 (m, 2H, Imd-CH2),
2.75−2.54 (brs, 1H, NH), 2.25 (s, 6H, CH3), 2.23 (s, 3H, Mes-CH3),
2.15 (s, 3H, Mes-CH3). 13C NMR (100 MHz, CDCl3): δ 143.3, 131.5,
130.0, 129.5, 49.0, 48.0, 40.4, 20.7, 18.4. 19F NMR (376 MHz, CDCl3): δ
−(144.0−144.1) (m, 2F, Ar-F), −155.40 (t, J = 22.0, 2F, Ar-F),
−(162.1−161.9) (m, 2F, Ar-F). IR (KBr): ν 3337, 2967, 2940, 2921,
2857, 1740, 1658, 1523, 1503, 1442, 1364, 1342, 1298, 1232, 1123,
1034, 999, 961, 934, 857, 745, 712, 670, 611, 570, 534 cm−1. Anal. Calcd
for C18H19F5N2: C, 60.33; H, 5.34; N, 7.82. Found: C, 60.11; H, 5.32; N,
7.76. HRMS (ESI): m/z calcd for C18H19F5N2 [M + Na]+ 381.1366,
found 381.1355.
General Procedure for the Preparation of Dihydroimidazo-
lium Salts by the Ring Closure of Diamines. A mixture of diamine
(1 mmol), triethyl orthoformate (10 mmol), and HCl in dioxane (4 M,
2.1 mmol) was heated in an open vessel at 90 °C for 12 h and then at 105
°C for 2 h. Next, the reaction mixture was cooled to room temperature
and the solvent was evaporated to one-third of its volume. Then, the
mixture was cooled. Subsequent filtration and washing with cold diethyl
ether yielded the pure imidazolium salt as a white powder.
N1-(Benzyl)-N3-(2,4,6-trimethylphenyl)-4,5-dihydro-1H-imidazol-
3-ium Chloride (10a). Following the general procedure, from N1-(2,4,6-
trimethylphenyl)-N2-(2-methoxybenzyl)-1,2-diaminoethane (9a; 1.50
g, 5.03 mmol), triethyl orthoformate (8.5 mL), and HCl (4 M solution,
2.64 mL) 10a was obtained as a white powder (1.31 g, 76%), mp 214−
216 °C.
1H NMR (400 MHz, CDCl3): δ 10.25 (s, 1H, CH-Imd), 7.46−7.44
(m, 2H, Ar-H), 7.36−7.32 (m, 3H, Ar-H), 6.84 (s, 2H, Mes-H), 5.14 (s,
2H, CH2), 4.05 (s, 4H, Imd-CH2), 2.23 (s, 6H, Mes-CH3), 2.22 (s, 3H,
Mes-CH3). 13C NMR (100 MHz, CDCl3): δ 159.7, 140.2, 135.1, 133.0,
131.0, 130.8, 129.3, 129.2, 129.1, 52.1, 51.0, 48.1, 21.0, 18.1. IR (KBr): ν
2971, 2943, 2909, 2854, 1636, 1509, 1486, 1454, 1379, 1300, 1262,
1224, 1140, 879, 758, 706 cm−1. Anal. Calcd for C19H23ClN2: C, 72.48;
H, 7.36; Cl, 11.26; N, 8.90. Found: C, 72.47; H, 7.39; Cl, 11.10; N, 9.04.
HRMS (ESI): m/z calcd for C19H23ClN2 [M − Cl]+ 279.1861, found
279.1872.
N1-(2,4,6-Trimethylphenyl)-N2-benzyl-1,2-diaminoethane (9a).
Following the general procedure, a solution of benzaldehyde 8a (1.79
g, 12.32 mmol) in MeOH (12 mL), PTSA (ca. 5−7 mg), N-(2,4,6-
trimethylphenyl)-1,2-diaminoethane (2 g, 11.2 mmol), and NaBH4
(1.70 g, 44.8 mmol) were used. Purification by silica gel chromatography
(cyclohexane/EtOAc, 4/1, followed by cyclohexane/EtOAc, 1/1)
yielded 9a as a yellow oil (2.12 g, 71%).
1H NMR (400 MHz, CDCl3): δ 7.38−7.33 (m, 4H, Ar-H), 7.30−7.27
(m, 1H, Ar-H), 6.83 (s, 2H, Mes-H), 3.86 (s, 2H, CH2), 3.08−3.06 (m,
2H, ImdCH2), 2.88−2.86 (m, 2H, ImdCH2), 2.29 (s, 6H, Mes-CH3),
2.24 (s, 3H, Mes-CH3). 13C NMR (100 MHz, CDCl3): δ 143.8, 140.2,
131.2, 129.7, 129.5, 128.6, 128.3, 127.2, 53.9, 49.5, 48.3, 20.7, 18.6. IR
(film from CH2Cl2): ν 3351, 3026, 2915, 2853, 1485, 1453, 1234, 1114,
1028, 854, 734, 697 cm−1. Anal. Calcd for C18H24N2: C, 80.55; H, 9.01;
N, 10.44. Found: C, 80.42; H, 9.28; N, 10.28. HRMS (ESI): m/z calcd
for C18H24N2 [M + Na]+ 291.1837, found 291.1835.
N1-(2-Iodobenzyl)-N3-(2,4,6-trimethylphenyl)-4,5-dihydro-1H-imi-
dazol-3-ium Chloride (10b). Following the general procedure, from N1-
(2-(dimethylamino)benzyl)-N2-(2,4,6-trimethylphenyl)-1,2-diamino-
ethane (9b; 1.20 g, 3.85 mmol), triethyl orthoformate (6.8 mL), and
HCl (4 M solution, 2 mL) 10b was obtained as a white powder (1.10 g,
80%), mp decomposes above 255 °C.
1H NMR (400 MHz, CDCl3): δ 9.71 (s, 1H, Imd-H), 7.85 (dd, J =
8.0, 1.0, 1H, Ar-H), 7.78 (dd, 1H, J = 8.0, 1.0, Ar-H), 7.39 (td, 1H, J = 7.4,
1.2, Ar-H), 7.06 (td, 1H, J = 7.8, 1.6, Ar-H), 6.87 (s, 2H, Mes-H), 5.27 (s,
2H, CH2), 4.13 (m, 4H, Imd-CH2), 2.29 (s, 6H, CH3), 2.23 (s, 3H, Mes-
N1-(2,4,6-Trimethylphenyl)-N2-(2-iodobenzyl)-1,2-diaminoethane
(9b). Following the general procedure, a solution of 2-iodobenzaldehyde
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CH3). 13C NMR (100 MHz, CDCl3): δ 160.0, 140.4, 140.1, 135.6,
135.3, 132.3, 131.1, 130.6, 130.0, 129.6, 100.3, 56.3, 51.0, 48.5, 21.1,
18.2. IR (KBr): ν 3375, 2992, 2945, 2874, 1640, 1506, 1467, 1445, 1368,
1266, 1214, 1144, 1014, 853, 772, 731, 575 cm−1. Anal. Calcd for
C19H22ClIN2: C, 51.78; H, 5.03; N, 6.36. Found: C, 51.52; H, 4.91; N,
6.23. HRMS (ESI): m/z calcd for C19H22ClIN2 [M − Cl]+ 405.0828,
found 405.0838.
(1.7 M in toluene, 1.1 mmol) dropwise at room temperature. After the
solution became clear (about 5−10 min), the indenylidene catalyst M1
(1 mmol) was added at once and the reaction vessel was submerged into
a preheated (65 °C) oil bath. The progress of the reaction was
monitored by TLC (cyclohexane/EtOAc, 4/1). After 25 min the
reaction mixture was cooled to room temperature and the solvent was
evaporated. Purification by silica gel chromatography (cyclohexane/
EtOAc, 19/1, followed by cyclohexane/EtOAc, 9/1) yielded a carmine
film. Next, pentane was added and the flask was submerged in an
ultrasound bath for 10 min. Further decantation provided a micro-
crystalline solid which was dried in vacuo.
[1-(2,4,6-Trimethylphenyl)-3-(benzyl)-2-imidazolidinylidene]-
dichloro(3-phenyl-1H-inden-1-ylidene)(tricyclohexylphosphine)-
ruthenium(II) (4). Following the general procedure, 10a (200 mg, 0.580
mmol), potassium tert-amylate (1.7 M in toluene, 339 μL, 0.580 mmol),
M1 (487 mg, 0.527 mmol), and toluene (29 mL) were used. Purification
by silica gel chromatography (cyclohexane/EtOAc, 19/1) yielded 4, as a
carmine microcrystalline solid (280 mg, 56%).
N1-(2-(Isopropylthio)benzyl)-N3-(2,4,6-trimethylphenyl)-4,5-dihy-
dro-1H-imidazol-3-ium Chloride (10c). Following the general
procedure, from N1-(2-(isopropylthio)benzyl)-N2-(2,4,6-
trimethylphenyl)ethane-1,2-diamine (9c; 2.41 g, 7.04 mmol), triethyl
orthoformate (12 mL), and HCl (4 M solution, 3.7 mL) 10c was
obtained as a white powder (2.62 g, 96%), mp 213-215 °C.
1H NMR (400 MHz, CDCl3): δ 9.43 (s, 1H, Imd-H), 7.72 (d, 1H, J =
8.0, ArH), 7.47 (d, 1H, J = 4.0, Ar-H), 7.38−7.29 (m, 3H, Ar-H), 6.91 (s,
2H, Mes-H), 5.33 (s, 2H, CH2), 4.09 (s, 4H, ImdCH2), 3.45−3.38 (m,
1H, iPr-H), 2.30 (s, 6H, Mes-CH3), 2.26 (s, 3H, Mes-CH3), 1.29−1.28
(d, 6H, J = 4.0, iPr-H). 13C NMR (100 MHz, CDCl3): δ 159.6, 140.4,
136.1, 130.5, 135.5, 134.0, 132.9, 132.0, 130.7, 130.0, 128.2, 51.1, 50.9,
48.3, 39.4, 23.2, 21.1, 18.2. IR (KBr): ν 3147, 2959, 2909, 2863, 2751,
2604, 2580, 2502, 2036, 1678, 1639, 1588, 1515, 1485, 1471, 1443,
1370, 1262, 1218, 1203, 1139, 1064, 1042, 1003, 844, 776, 747, 685, 572,
474 cm−1. Anal. Calcd for C22H29ClN2S: C, 67.93; H, 7.51; N, 7.20.
Found: C, 67.78; H, 7.44; N, 7.16. HRMS (ESI): m/z calcd for
C22H29ClN2S [M − Cl]+ 353.2051, found 353.2065.
1H NMR (400 MHz, CD2Cl2): δ 8.41 (d, 1H, J = 8.0, Ar-H), 7.81 (d,
2H, J = 8.0, Ar-H), 7.71 (d, 2H, J = 8.0, Ar-H), 7.52 (t, 1H, J = 8.0, Ar-H),
7.48−7.38 (m, 5H, Ar-H), 7.25−7.22 (m, 1H, Ar-H), 7.18−7.15 (m, 2H,
Ar-H), 7.04 (d, 1H, J = 8.0, Ar-H), 6.39 (s, 1H, Mes-H), 6.00 (s, 1H,
Mes-H), 5.73−5.60 (m, 2H, CH2), 3.76−3.60 (m, 4H, Imd-CH2),
2.41−2.30 (m, 3H, Cy), 2.10 (s, 3H, Mes-CH3), 2.00 (s, 3H, Mes-CH3),
1.87 (s, 3H, Mes-CH3), 1.83−1.67 (m, 7H, Cy), 1.59−1.47 (m, 12H,
Cy), 1.39−1.26 (m, 7H, Cy), 1.14−1.01 (m, 7H, Cy), 0.97−0.83 (m,
6H, Cy). 13C NMR (100 MHz, CD2Cl2): δ 291.5, 217.0, 216.4, 144.5,
141.2, 138.1, 137.7, 137.5, 137.4, 137.3, 137.2, 136.5, 136.3, 129.9, 129.4,
129.2, 129.1, 129.0, 128.8, 128.4, 128.2, 127.7, 126.9, 116.6, 52.6, 48.8,
34.6, 33.0, 32.9, 30.0, 28.4, 28.3, 28.2, 27.1, 22.9, 21.3, 18.7, 18.6. 31P
NMR (162 MHz, CD2Cl2): δ 35.08. IR (KBr): ν 3053, 2920, 2849,
1488, 1444, 1354, 1266, 1224, 846, 775, 753, 699 cm−1. Anal. Calcd for
C52H65Cl2N2PRu: C, 67.81; H, 7.11; Cl, 7.70; N, 3.04. Found: C, 67.90;
H, 7.36; Cl, 7.74; N, 3.06. HRMS (ESI): m/z calcd for
C52H6535Cl2N2P102Ru [M − Cl]+ 885.3629, found 885.3623.
N1-(2,3,4,5,6-Pentafluorobenzyl)-2-(perfluorophenyl)-N3-(2,4,6-
trimethylphenyl)imidazolidine (13). To a stirred solution of
pentafluorobenzaldehyde (11; 1.28 g, 6.42 mmol) in MeOH (15 mL)
was added PTSA (ca. 5−7 mg). Next, N1-(2,3,4,5,6-pentafluorobenzyl)-
N3-(2,4,6-trimethylphenyl)ethane-1,2-diamine (12; 2.30 g, 6.42 mmol)
was added and, the mixture was stirred at room temperature for 4 h. The
progress of the reaction was monitored by TLC analysis (cyclohexane/
EtOAc, 4/1). Purification by silica gel chromatography (cyclohexane/
EtOAc, 4/1) yielded 13 as a white powder (3.20 g, 93%), mp 100−102
°C.
1H NMR (400 MHz, CDCl3): δ 6.79 (s, 2H, Mes-H), 5.60 (s, 1H,
CH-Imd), 3.84−3.70 (m, 2H, CH2− and 1H, Imd-CH2), 3.34−3.39 (m,
1H, Imd-CH2), 3.25−3.20 (m, 1H, Imd-CH2), 3.17−3.10 (m, 1H, Imd-
CH2) 2.20 (s, 9H, Mes-CH3). 13C NMR (100 MHz, CDCl3): δ 139.9,
136.1, 75.4, 52.2, 51.2, 42.5, 20.9, 18.7. 19F NMR (376 MHz, CDCl3): δ
−143.3 (dd, 2F, J = 24.0, 8.0, Ar-F), −154.9 to −154.6 (m, 2F, Ar-F),−
162.1 to −162.0 (m, 2F, Ar-F). IR (KBr): ν 3002, 2934, 2920, 2876,
2829, 2723, 2417, 1716, 1652, 1501, 1388, 1339, 1308, 1189, 1132,
1042, 1001, 957, 931, 908, 871, 846, 768, 656, 623, 580. Anal. Calcd for
C25H18F10N2: C, 55.93; H, 3.24; N, 5.21. Found: C, 55.98; H, 3.38; N,
5.22. HRMS (ESI): m/z calcd for C25H18F10N2 [M − C6F5]+ 369.1390,
found 369.1387.
[1-(2,4,6-Trimethylphenyl)-3-(2-iodobenzyl)-2-imidazolidinyl-
idene]dichloro(3-phenyl-1H-inden-1-ylidene)(tricyclohexylphos-
phine)ruthenium(II) (5). Following the general procedure, 10b (220
mg, 0.5 mmol), potassium tert-amylate (1.7 M in toluene, 294 μL, 0.5
mmol), M1 (419 mg, 0.454 mmol), and toluene (30 mL) were used.
Purification by silica gel chromatography (cyclohexane/EtOAc, 19/1),
yielded 5 as a cherry red microcrystalline solid (260 mg, 55%).
1H NMR (400 MHz, CD2Cl2): δ 8.41 (d, 1H, J = 8.0, Ar-H), 8.26 (d,
1H, J = 4.0, Ar-H), 7.95 (d, 1H, J = 8.0, Ar-H), 7.72 (d, 2H, J = 8.0, Ar-
H), 7.55−7.38 (m, 5H, Ar-H), 7.26−7.04 (m, 6H, Ar-H), 6.40 (s, 1H,
CH2), 6.32 (s, 1H, CH2), 3.72−3.69 (m, 4H, Imd-CH2), 2.39−2.33 (m,
3H, Cy) 2.13 (s, 3H, Mes-CH3), 2.02 (s, 3H, Mes-CH3), 1.88 (s, 3H,
Mes-CH3), 1.83−1.50 (m, 22H, Cy), 1.38−1.27 (m, 8H, Cy), 1.13−
0.84 (m, 15H, Cy). 13C NMR (100 MHz, CD2Cl2): δ 291.6, 217.6,
216.9, 144.2, 141.0, 139.8, 138.2, 138.1, 137.5, 137.4, 137.1, 137.0, 136.9,
136.3, 130.4, 129.4, 129.4, 129.0, 128.9, 128.8, 128.3, 128.0, 127.6, 126.7,
116.5, 100.6, 60.3, 52.6, 52.5, 48.9, 48.9, 33.0, 32.8, 29.8, 28.2, 28.1, 28.0,
27.9, 27.3, 26.9, 21.0, 18.6, 18.5. 31P (162 MHz, CD2Cl2): δ 34.37. IR
(KBr): ν 3052, 2923, 2847, 1703, 1487, 1444, 1267, 1011, 847, 774, 753,
697 cm−1. Anal. Calcd for C52H64Cl2N2IPRu: C, 59.66; H, 6.16; N, 2.68.
Found: C, 61.16; H, 6.24; N, 2.52 (although these results are outside the
range viewed as establishing analytical purity, they are provided to
illustrate the best values obtained to date). HRMS (ESI): m/z calcd for
C52H6435Cl2N2IP102Ru [M − Cl]+ 1011.2595, found 1011.2585.
[1-(2,4,6-Trimethylphenyl)-3-(2-thioisopropylbenzyl)-2-imidazo-
lidinylidene]dichloro(3-phenyl-1H-inden-1-ylidene)(tricyclohexyl-
phosphine)ruthenium(II) (6). Following the general procedure, 10c
(200 mg, 0.514 mmol), potassium tert-amylate (1.7 M in toluene, 316
μL, 0.538 mmol), M1 (431 mg, 0.467 mmol), and toluene (30 mL) were
used. Purification by silica gel chromatography (cyclohexane/EtOAc,
19/1) yielded 6 as a cherry red microcrystalline solid (224 mg, 48%).
1H NMR (400 MHz, CD2Cl2): δ 8.43 (d, 1H, J = 7.2, Ar-H), 8.27 (d,
1H, J = 7.2, Ar-H), 7.71 (d, 2H, J = 8.0, Ar-H), 7.58−7.51 (m, 2H, Ar-H),
7.45−7.33 (m, 4H, Ar-H), 7.26−7.05 (m, 3H, Ar-H), 7.04 (d, 1H, J =
8.0, Ar-H), 6.40 (s, 1H, CH2), 6.00 (s, 1H, CH2), 3.70−3.64 (m, 4H,
N1-(2,3,4,5,6-Pentafluorobenzyl)-N3-(2,4,6-trimethylphenyl)-4,5-
dihydro-1H-imidazol-3-ium Tetrafluoroborate (14). Following the
general procedure, from N1-(2,4,6-trimethylphenyl)-N2-(2,3,4,5,6-
pentafluorobenzyl)-1,2-diaminoethane (12; 6.10 g, 17 mmol), triethyl
orthoformate (15 mL), and NH4BF4 (2.21 g, 20.4 mmol) 14 was
obtained as a white powder (5.30 g, 68%), mp 220−222 °C.
1H NMR (400 MHz, DMSO-d6): δ 8.99 (s, 1H, CH-Imd), 7.05 (s,
1H, Mes-H), 4.94 (s, 2H, CH2−), 4.20−4.06 (m, 4H, Imd-CH2), 2.27
(s, 3H, Mes-CH3), 2.24 (s, 6H, Mes-CH3). 13C NMR (100 MHz,
DMSO-d6): δ 159.4, 139.5, 135.4, 131.0, 129.4, 50.9, 48.3, 39.5, 20.5,
17.1. 19F NMR (376 MHz, DMSO-d6): δ −143.30 (dd, 2F, J = 24.0, 8.0,
Ar-F), −148.50 (s, 3F, BF4), −153.95 (t, 1F, J = 22.0, Ar-F), −162.20 to
−162.10 (m, 2F, Ar-F). IR (KBr): ν 3090, 2962, 1646, 1513, 1452, 1372,
1338, 1301, 1276, 1223, 1183, 1126, 1068, 964, 924, 854, 761, 626, 571.
Anal. Calcd for C19H18BF9N2: C, 50.03; H, 3.98; N, 6.14. Found: C,
49.76; H, 3.87; N, 6.07. HRMS (ESI): m/z calcd for C19H18BF9N2: [M
− BF4]+ 369.1390, found 369.1387.
General Procedure for the Preparation of Precatalysts 4−7. In
a flame-dried Schlenk tube the corresponding imidazolium salt (1.1
mmol) was dried under vacuum at 80 °C for 3 h. Then, toluene was
added under an atmosphere of argon (to obtain concentration of
carbene c = 0.02 mmol/mL), and to the resulting vigorously stirred
suspension of the imidazolium salt was added potassium tert-amylate
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Organometallics
Article
Imd-CH2), 3.49−3.42 (m, 1H, iPr-CH), 2.40−2.31 (m, 3H, Cy), 2.12 (s,
3H, Mes-CH3), 2.01 (s, 3H, Mes-CH3), 1.87 (s, 3H, Mes-CH3), 1.81−
1.78 (m, 4H, Cy), 1.71−1.68 (m, 4H, Cy), 1.58−1.49 (m, 10H, Cy),
1.38−1.24 (m, 15H, Cy), 1.12−1.01 (m, 7H, Cy), 0.96−0.87 (m, 6H,
Cy). 13C NMR (100 MHz, CD2Cl2): 13C NMR (100 MHz, CD2Cl2): δ
291.3, 216.9, 216.2, 144.3, 141.0, 137.9, 137.8, 137.6, 137.5, 137.3, 137.2,
137.1, 137.0, 136.4, 136.1, 133.1, 131.3, 129.3, 129.0, 128.9, 128.8, 128.3,
128.0, 127.5, 126.7, 116.5, 53.8, 52.8, 52.4, 48.8, 48.7, 32.9, 32.8, 29.9,
29.8, 28.3, 28.2, 28.1, 28.0, 26.9, 23.3, 23.2 18.6. 31P NMR (162 MHz,
CD2Cl2): δ 34.30. IR (KBr): ν 3053, 2922, 2847, 1487, 1444, 1266, 847,
774, 752, 697 cm−1. Anal. Calcd for C55H71Cl2N2PRuS: C, 66.31; H,
7.28; N, 2.81. Found: C, 66.82; H, 7.11; N, 2.69 (although these results
are outside the range viewed as establishing analytical purity, they are
provided to illustrate the best values obtained to date). HRMS (ESI): m/
z calcd for C55H7135Cl2N2P102RuS [M − Cl]+ 959.3820, found 959.3851.
[1-(2,4,6-Trimethylphenyl)-3-(2,3,4,5,6-pentafluorobenzyl)-2-
imidazolidinylidene]dichloro(3-phenyl-1H-inden-1-ylidene)(tricyclo-
hexylphosphine)ruthenium(II) (7). Method A. Following the general
procedure, 14 (200 mg, 0.438 mmol), potassium tert-amylate (1.7 M in
toluene, 258 μL, 0.438 mmol), M1 (368 mg, 0.399 mmol), and toluene
(29 mL) were used. Purification by silica gel chromatography
(cyclohexane/EtOAc, 19/1) yielded 7 as a brown microcrystalline
solid (193 mg, 48%).
2.50 (m, 1H, CH), 2.40−1.92 (m, 13H, CH2), 1.90−1.80 (m, 2H, CH2),
1.72−1.38 (m, 9H, CH3 and CH2), 1.30−1.05 (m, 4H, CH2), 1.02 (s,
4H, CH2), 0.62 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3): δ 209.7,
172.6, 139.8, 136.9, 122.5, 115.6, 73.9, 63.8, 57.0, 50.0, 4 38.9, 38.2, 37.1,
34.0, 32.0, 31.9, 31.8, 29.1, 27.9, 24.6, 23.9, 22.9, 21.2, 19.5, 13.4. IR
(KBr): ν 3441, 3387, 2966, 2942, 2870, 2847, 1734, 1708, 1643, 1470,
1450, 1386, 1357, 1277, 1183, 1014, 998, 980, 954, 909, 796, 717, 632,
591 cm−1. Anal. Calcd for C26H38O3: C, 78.35; H, 9.61. Found: C, 78.36;
H, 9.54. HRMS (ESI): m/z calcd C26H38O3 [M + Na]+ 421.2719, found
421.2724.
Cross Metathesis of 2-Methyl-2-butene (37) with Pregneno-
lone Derivative 36. To a solution of 36 (100 mg, 0.251 mmol) in 2-
methyl-2-butene (37; 1.6 mL, 15.6 mmol) was added precatalyst 1 or 2
(0.0125 mmol, 2.5 mol %). The resulting solution was stirred at room
temperature (22 °C). After that aliquots (25 μL) were taken every 30
min and added to a solution of ethyl vinyl ether in DCM (3 M, 300 μL).
The sample was shaken well and then allowed to stand for 5 min and
analyzed by GC. After completion of the reaction the solvent was
evaporated and the crude product was purified via column
chromatography (cyclohexane/EtOAc, 7/3 followed by cyclohexane/
EtOAc, 1/1), yielding 38 as colorless crystals (176 mg and 166 mg, 82%
and 78%, respectively, for precatalysts 1 and 2, respectively), mp 88−90
°C. For the reaction with precatalyst 2 product of self-metathesis of 36
was also isolated (22 mg, 6%, for the characterization see the Supporting
Information).
Method B. To a mixture of 13 (262 mg, 0.487 mmol) and M1 (300
mg, 0.325 mmol) in a Schlenk flask was added toluene (10 mL). The
resulting mixture was placed in an oil bath and stirred at 90 °C for 30
min. Purification by silica gel chromatography (cyclohexane/EtOAc,
19/1) yielded 7 as a brown microcrystalline solid (70 mg, 21%).
1H NMR (400 MHz, CD2Cl2): δ 8.34 (d, 1H, J = 8.0, Ar-H), 7.72 (d,
2H, J = 8.0, Ar-H), 7.53 (d, 2H, Ar-H), 7.44 (t, 3H, J = 8.0, Ar-H), 7.26−
7.02 (m, 5H, Ar-H), 6.40 (s, 1H, Mes-H), 6.00−5.84 (m, 1H, Mes-H
and 2H, CH2), 3.72−3.67 (m, 4H, Imd-CH2), 2.43−2.32 (m, 3H, Cy),
2.11 (s, 3H, Mes-CH3), 1.98 (s, 3H, Mes-CH3), 1.87 (s, 3H, Mes-CH3),
1.75−1.50 (m, 24H, Cy), 1.48−1.25 (m, 12H, Cy), 1.19−0.87 (m, 14H,
Cy). 13C NMR (100 MHz, CD2Cl2): δ 292.0, 219.7, 219.0, 143.6, 140.4,
138.1, 137.1, 137.0, 136.5, 136.3, 135.8, 129.2, 128.9, 128.8, 128.4, 128.0,
127.7, 127.3, 126.3, 126.0, 116.1, 52.0, 48.6, 43.6, 32.5, 32.3, 29.5, 27.8,
27.7, 27.6, 27.5, 26.9, 26.6, 20.7, 18.0, 17.9. 31P NMR (162 MHz,
CD2Cl2): δ 33.70. 19F NMR (376 MHz, CD2Cl2): δ −153.4 (t, 2F, J =
22, Ar-F), −(139.27−139.45) (m, 1F, Ar-F), −(161.9−161.7) (m, 2F,
Ar-F). IR (KBr): ν 2925, 2849, 1523, 1504, 1488, 1445, 1267, 1046,
1007, 848, 755, 753, 697 cm−1. Anal. Calcd for C52H60Cl2F5N2PRu: C,
61.78; H, 5.98; Cl, 7.01; N, 2.77; F, 9.40. Found: C, 61.89; H, 5.82; Cl,
6.84; N, 2.79; F, 9.51. HRMS (ESI): m/z calcd for
C52H6035Cl2F5N2P102Ru [M − Cl]+ 975.3158, found 975.3143.
38. 1H NMR (400 MHz, CDCl3): δ 5.39−5.34 (m, 1H, CH), 5.11−
5.04 (m, 1H, CH), 4.67−4.54 (m, 1H, CH), 2.57−2.48 (m, 1H, CH),
2.36−2.25 (m, 6H, CH2), 2.20−2.14 (m, 1H, CH), 2.12 (s, 3H, CH3),
2.06−1.94 (m, 2H, CH2), 1.90−1.80 (m, 2H, CH2), 1.72−1.40 (m, 15H,
CH3 + CH2), 1.28−1.08 (m, 4H, CH2), 1.01 (s, 4H, CH2), 0.62 (s, 3H,
CH3). 13C NMR (100 MHz, CDCl3): δ 209.7, 173.0, 139.8, 133.0,
122.6, 122.4, 73.7, 63.8, 57.0, 50.0, 44.1, 38.9, 38.2, 37.1, 36.7, 35.0, 31.9,
31.8, 31.7, 27.9, 25.8, 24.6, 23.9, 22.9, 21.2, 19.4, 17.9, 13.4. IR (KBr): ν
3442, 3389, 2970, 2945, 2899, 2845, 1730, 1705, 1465, 1442, 1381,
1356, 1343, 1275, 1170, 1137, 979, 954, 922, 800, 743, 594 cm−1. Anal.
Calcd for C28H42O3: C, 78.83; H, 9.92. Found: C, 78.64; H, 9.98. HRMS
(ESI): m/z calcd C28H42O3 [M + Na]+ 449.3032, found 449.3033.
ASSOCIATED CONTENT
* Supporting Information
■
S
Text giving details of the synthesis of substrates and
spectroscopic characterization of all new compounds, text,
figures, and tables giving details of kinetic as well as the X-ray
crystallographic information for complexes 1, 4 and 5; crystal
data are also available as CIF files. This material is available free of
charge via the Internet at http://pubs.acs.org.
Synthesis of Pregnenolone Derivative 36. To a well-stirred
solution of pregnenolone (6.00 g, 19 mmol) in DCM (HPLC grade, 80
AUTHOR INFORMATION
Corresponding Author
*K.G.: tel, +48-22-8220211 ext. 420; fax, +48-22-8220211; e-
mail, klgrela@gmail.com.
■
Notes
The authors declare no competing financial interest.
mL) was added pyridine (3 mL, 37.9 mmol). The resulting mixture was
placed in an ice-cooled bath and cooled to 0 °C. After 10 min pentenoyl
chloride (2.46 mL, 21.8 mmol) was added dropwise. The resulting
mixture was stirred for 10 min, and then the cooling bath was removed
and the mixture was stirred at room temperature for 3 h. The progress of
the reaction was monitored by TLC (cyclohexane/EtOAc, 4/1). Then
the reaction mixture was washed with saturated NaHCO3(aq) (2 × 50
mL) and brine (2 × 50 mL). The organic phase was dried over MgSO4,
and the solvent was evaporated. The crude product was purified via
column chromatography (cyclohexane/EtOAc, 9/1), yielding 36 as
colorless crystals which were additionally recrystallized from ethanol
(6.60 g, 87%).
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge the TEAM project operated
within the Foundation for Polish Science Team Program
cofinanced by the EU European Regional Development Fund,
Operational Program Innovative Economy 2009-2013, for the
financial support. OA thanks A. Ablalimov for the processing of
the kinetic studies. W. Kopcha is kindly acknowledged for
proofreading of the manuscript.
REFERENCES
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