Unravelling the olefin cross metathesis on solid support. Factors affecting the reaction outcome

Article abstract of DOI:10.1039/c004729e

Olefin cross metathesis on solid support under a variety of conditions is described. A comprehensive analysis considering diverse factors governing the reaction outcome gives a series of patterns for the application of this useful methodology in organic synthesis. If the intrasite reaction is not possible, homodimerization of the soluble olefin is crucial. When the homodimer is less reactive than its monomer, reaction outcome depends on the homodimerization rate, which, in turn, depends on the precatalyst used and the reaction conditions. If the site-site interaction is a feasible process, the cross metathesis product is obtained exclusively when the newly-formed double bond is resilient to further metathetic events. Taking into account these considerations, we have demonstrated that excellent results in terms of cross metathesis coupling can be obtained under the optimized conditions, and that microwave irradiation is also an interesting alternative for the development of a practical and energy-efficient cross metathesis on solid support.

Full text of DOI:10.1039/c004729e

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Unravelling the olefin cross metathesis on solid support. Factors affecting
the reaction outcome†
Andre´s A. Poeylaut-Palena and Ernesto G. Mata*
Received 6th April 2010, Accepted 3rd June 2010
First published as an Advance Article on the web 1st July 2010
DOI: 10.1039/c004729e
Olefin cross metathesis on solid support under a variety of conditions is described. A comprehensive
analysis considering diverse factors governing the reaction outcome gives a series of patterns for the
application of this useful methodology in organic synthesis. If the intrasite reaction is not possible,
homodimerization of the soluble olefin is crucial. When the homodimer is less reactive than its
monomer, reaction outcome depends on the homodimerization rate, which, in turn, depends on the
precatalyst used and the reaction conditions. If the site–site interaction is a feasible process, the cross
metathesis product is obtained exclusively when the newly-formed double bond is resilient to further
metathetic events. Taking into account these considerations, we have demonstrated that excellent results
in terms of cross metathesis coupling can be obtained under the optimized conditions, and that
microwave irradiation is also an interesting alternative for the development of a practical and
energy-efficient cross metathesis on solid support.
an olefin to form a metallocyclobutane (Scheme 1a, step ii),
which go back to generate a new metal–carbene complex and
Introduction
Due to their central role in modern organic synthesis,
a new olefin (step iii). This is a reversible process that eventually
organometallic chemistry has been a logical target for the devel-
reaches equilibrium and a statistical mixture of olefins is obtained
opment of solid-phase chemistry, and its synthetic applications
(Scheme 1b).
have grown substantially in the last decade.1 However, such
development is still far from being completed.
Ruthenium catalyzed cross metathesis has become a powerful
synthetic tool in modern organic and polymer synthesis,2 repre-
senting a very interesting alternative to more traditional carbon–
carbon bond forming reactions. Cross metathesis (CM) has an
advantage over Stille, Heck and Suzuki reactions since alkenes are
easier to prepare compared to stannanes, halides and boronates,
or they can be obtained from many natural products. On the other
hand, CM is particularly helpful in stepwise syntheses since the
olefin metathesis precatalysts (1–3) (Fig. 1) ensure mild reaction
conditions, together with high functional group tolerance, activity
and stability.
Scheme 1 Catalytic cycle proposed by Chauvin for olefin cross metathesis.
(a) After an initiation step (i), the catalytic process proceeds through
cycloaddition (ii and iv) and cycloreversion (iii and v) reactions between
olefins and ruthenium–carbene complexes. (b) Cross metathesis process, a
mixture of compounds can be obtained.
Fig. 1 Most commonly employed commercially available metathesis
precatalysts.
Recently, Grubbs et al. reported an olefin classification in order
The commonly accepted mechanism for olefin metathesis has
to understand and predict the olefin cross metathesis selectivity.4
Four categories of olefins were determined: type-I olefins are those
that undergo fast homodimerization and secondary metathesis on
been proposed by He´risson and Chauvin3 and it involves the
cycloaddition reaction between a metal–carbene complex and
the homodimers, type-II go through a slow homodimerization
and homodimers are sparingly reactive, type-III do not undergo
homodimerization while type-IV are just spectators to CM. Which
olefin belongs to which category depends on the precatalyst used.
According to this empirical approach, product selectivity can
Instituto de Qu´ımica Rosario (CONICET - UNR), Facultad de Ciencias
Bioqu´ımicas y Farmace´uticas, Universidad Nacional de Rosario, Suipacha
531, 2000, Rosario, Argentina. E-mail: mata@iquir-conicet.gov.ar
† Electronic supplementary information (ESI) available: Open vessel
system description and NMR spectra. See DOI: 10.1039/c004729e
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be achieved by using olefins from two different types, in order
to suppress the rate of homodimerization of one component
and controlling the rate of secondary metathesis on the desired
cross product. However, avoiding the formation of unwanted
homodimeric products is not always an easy task5 and, in many
of the cases, addition of an excess of one of the olefin is necessary
to ensure high yield,4 compelling to a careful chromatographic
purification.
Comparing to its homogeneous-phase counterpart, the olefin
cross metathesis on solid-phase has several potential advantages.
Immobilization of one of the olefin substrates makes, under certain
conditions, its homodimerization a less favorable process due
to the site isolation, while the olefin that remains in solution
can be eliminated by a simple filtration (Scheme 2). Ruthenium
contamination of synthetic products is another less important
issue in solid-phase metathesis.6 Furthermore, solid-supported
organic synthesis permits easier purification, automation, and
parallelization, for the rapid generation of compound libraries.7
(5a–f) (Table 1). When an excess of allyl benzene (5a) reacted
with the resin-bound olefin 4, in the presence of second-generation
Grubbs precatalyst (2), methyl 4-(3-phenyl-propenyl)benzoate (7a)
was obtained in excellent isolated yield (86%) (entry 1, column
6), after releasing into solution with 10% TFA/DCM followed
by esterification with diazomethane. Here, as in most of the
cases under scrutiny, complete E selectivity was obtained. When
analyzing this successful coupling outcome, it has to be taken
into account that a number of metathesis events can occur when a
type I non-immobilized olefin, such as 5a, reacts under precatalyst
2 with an also very reactive resin-bound olefin, like 4. Since
solid-phase reactions are usually considered as proceeding at
a lower rate than their homogeneous-phase counterparts,14 and
the non-immobilized olefin is added in excess, coupling between
two of these molecules is statistically more probable and the
corresponding homodimer is actually the omnipresent olefin.
To confirm this assumption, the homodimer 5¢a was prepared
and treated with resin 4 and precatalyst 2 under the optimized
conditions to give the expected product 7a in an almost similar
yield to that obtained starting from olefin 5a (entries 1 and 2). The
same rationale can be applied to explain the reaction outcome
using 4-methyl styrene (5b), which gave the CM product, methyl
4-(4-methylstyryl)benzoate (7b), only in 31% yield (entry 3). The
corresponding homodimer 5¢b was unreactive to resin-bound
olefin 4 under our solid-phase conditions (entry 4) indicating
that, despite the high reactivity of 4-methyl styrene (5b) the low
yield was due to the rapid formation of the unreactive dimer
5¢b. On the other hand, if the homodimerization is very slow,
such as in the case of the 4-vinylbenzyl chloride (5c) (entry 5),
the heterocoupling prevails and the active monomer contributes
largely to the formation of the CM product (7c) (80% yield). In
this case, the use of the homodimer 5¢c as substrate made the CM
coupling a less efficient process, since olefin 7c was obtained in
58% yield (entry 6).
Interestingly, an electron-deficient olefin, such as crotonic acid
(5e), gave the coupling product (7e) in a 97% yield (entry 9).
While homodimerization was negligible, metathesis between resin
4 and crotonic acid (5e) was favored by the forced conditions
(reflux, large excess of olefin) leading to a product (7e) which
is, in turn, reluctant to further metathetic events. In the case of
2-bromo styrene (5f), that also behaves as a type-II olefin when
using precatalyst 2, the expected CM product (7f) was obtained
in lower yield (43%) (entry 10). The additional steric hindrance of
the bromine atom can be the reason for this yield by affecting the
approach to the polymer matrix.
From these results it is clear that the solid-supported olefin cross
metathesis can go through two pathways (Scheme 3), and system
reactivity is modulated by the differential reactivity between
monomer and homodimer, and the velocity of dimerization. When
the soluble olefin does not dimerize, or dimerizes, but monomer
and dimer are equally reactive, the effect of the homodimerization
of this olefin is negligible. The problem arises when monomer is
significantly more reactive than the homodimer; then, the more
rapid the dimerization is, the worse the yield of the CM product
is.
Scheme 2 Solid-supported version of olefin cross metathesis. Potentially,
most of the olefin by-products generated during the reaction can be
eliminated by filtration.
Despite these advantages, the alkene solid-phase cross metathe-
sis field has not been well explored to date and it is far below
its maximum potential. While there is a considerable number
of examples of metathesis reactions where a substrate has been
immobilized to a solid support, most of them refer to the ring
closing version of the coupling.8 Probably the limited success
of first generation Grubbs precatalyst 19 in solid-phase cross
metathesis could be blamed for the delayed development of this
methodology.10 Only recently, this subject has been addressed
again by us and others,11 exploring the application of a new genera-
tion of precatalysts, such as second-generation Grubbs precatalyst
(2)12 and Hoveyda–Grubbs precatalyst (3),13 to the preparation
of biologically promising molecules. Although preliminary, these
reports have offered the promise of a more general application
of solid-supported olefin cross metathesis for the generation of
libraries of complex organic structures.
Now, a comprehensive study of this methodology is provided
with an emphasis on the many effects involved in the reaction
outcome, and on the combined used of solid-supported chemistry
and microwave irradiation.
Results and discussion
From the beginning, it was clear that solid-supported olefin cross
metathesis was a complex reaction system in terms of the many
factors affecting the reaction outcome. Along with those factors
related to the nature of the polymer, such as the effect of the
resin loading, linker’s length and flexibility; the reactivity of the
immobilized olefin, the role of the soluble olefin and the effect of
the precatalyst have to be studied in depth.
In order to understand the influence of the soluble olefin
reactivity on the reaction outcome, the Wang resin-immobilized
olefin (4) was used for the coupling with different olefin partners
Regarding the precatalyst’s nature, as in conventional solution-
phase synthesis, the less reactive first generation Grubbs pre-
catalyst (1) gave a much lower yield than second-generation
Grubbs precatalyst (2). Thus, under a similar protocol to that
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Table 1 Cross-metathesis by ruthenium carbene complexes on the resin-bound 4-vinyl benzoic acid (4)a
Yield (%)c
Soluble olefin
Homo-dimerizationb
Yes, in 15 min
Product
Precatalyst 1
Precatalyst 2
Precatalyst 3
1
2
3
5a R¢ = H, R =
7a R =
22d
86
84
5¢a R¢ = R =
—
7a R =
7b R =
72
31
5b R¢ = H, R =
Yes, in 2 h
32
4
5
6
7
5¢b R¢ = R =
5c R¢ = H, R =
5¢c R¢ = R =
—
7b R =
7c R =
7c R =
7d R =
NR
80
Yes, in 20 h
—
28e
58
5d R¢ = H, R =
Yes, in 5 h
57
8
5¢d R¢ = R =
—
7d R =
39
9
5e R¢ = CH3, R = –CO2H
5f R¢ = H, R =
No
No
7e R = –CO2Me
7f R =
NRf
97
43
10
43
a Conditions: (i) olefin 5(5¢) (5 eq), Ru precatalyst (5 mol%), DCM, reflux 20 h. (ii) 10% TFA in DCM at r.t. for 1 h, (iii) CH2N2 in DCM at 0 ◦C for
1
30 min. b Time for total dimerization employing precatalyst 2. c Overall isolated yield after flash column chromatography. E isomer exclusively, by H
NMR. d 44% staring material recovered. e Homodimerization of the soluble olefin occurs in 5h. f No reaction, starting material recovered.
yield was obtained with precatalyst 2 (entry 9, columns 5 and 6).
On the other hand, the Hoveyda–Grubbs precatalyst (3), seems
to have a similar reactivity than precatalyst 2 (entries 1, 3 and 10,
columns 6 and 7), except in the case of 7c, where the isolated yield
decreased from 80 to 28% by changing from precatalyst 2 to 3
(entry 5, columns 6 and 7). This result can be attributed to a faster
formation of the homodimer 5¢c (5 h instead of 20 h), which is less
reactive than its corresponding monomer 5c.
Scheme 3 System variation depending on soluble olefin homodimeriza-
tion. Metathesis reaction proceeds through either pathway a, b or both of
Changing the immobilized component to a “type II” olefin,
such as 8, cross metathesis in the presence of precatalyst 2 mostly
them. Reactivity of the system (rs) depends on the monomer and dimer
resulted in slower reaction rates, with yields up to 35% (Table 2,
reactivity (r5 and r5¢ respectively), and their concentration in the system.
column 5). However, precatalyst 3 generally increased those yields
(Table 2, column 6). In the case of type-I soluble olefins, such
as allyl benzene (5a), 4-vinylbenzyl chloride (5c) and 4-phenyl-1-
butene (5d) yields were increased at least two-fold (entries 1–3,
columns 5 and 6). These results are in agreement with literature
data on solution-phase chemistry, where precatalyst 3 is considered
the best for cross metathesis involving a,b-unsaturated carbonyl
derivatives.15
used with precatalyst 2, the immobilized olefin 4 reacted with
excess of allyl benzene (5a) in the presence of precatalyst 1 to
afford, after separation and methylation, the methyl 4-(3-phenyl-
propenyl)benzoate (7a) in only 22% yield with 44% of recovered
starting material (Table 1, entry 1, column 5). In the case of using
the moderately reactive crotonic acid (5e) as the non-immobilized
olefin, precatalyst 1 gave no reaction at all, while a quantitative
When immobilized pentenoic acid (11) was used, we noted that
this resin-bound olefin was able to undergo site–site interference
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Table 2 Cross-metathesis by ruthenium carbene complexes on an immobilized a,b-unsaturated carbonyl olefin (8)a
Yield (%)c
Entry
1
Soluble olefin
Homo-dimerizationb
Yes, in 15 min
Product
Precatalyst 2
Precatalyst 3
5a R¢ = H, R =
10a R =
35
11
59
2
3
5c R¢ = H, R =
5d R¢ = H, R =
Yes, in 20 h
Yes, in 5 h
10c R =
10d R =
23
68
26
10
4
5f R¢ = H, R =
No
10f R =
16
a Conditions: (i) olefin 5 (5 eq), Ru precatalyst (5 mol%), DCM, reflux 20 h. (ii) 10% TFA in DCM at r.t. for 1 h, (iii) CH2N2 in DCM at 0 ◦C for 30 min.
b Time for total dimerization employing precatalyst 2. c Overall isolated yield after flash column chromatography. E isomer exclusively, by 1H NMR.
(Table 3). A unique property of solid-phase organic synthesis is
the pseudo-dilution effect. When a reactive group is attached to
a polymer support, intermolecular reaction between those groups
is, in theory, a less favorable process, leading to a virtually infinite
dilution.16 Although this site–site isolation is achieved in most of
the cases, under determined circumstances intrasite interactions
can occur affecting the reaction outcome. There are some ways
to reduce site–site interactions, such as increase cross-linking and
decrease resin loading; however, these actions would lead to lower
reaction rates17 and lower resin throughput, respectively. A more
generally accepted idea to minimize those interactions is the use
of a large excess of the soluble substrate (normally 5 equivalents).
Because of that excess, most of the active sites in the polymer
react with the molecules in solution instead of reacting with each
other. Nevertheless, linker’s length and flexibility can be factors
that make intrasite reactions difficult to avoid; this is the case of
resin 11. We have performed a series of experiments to understand
the influence of different factors on such interference.
As already mentioned, a large number of metathetic events
occur when a very reactive non-immobilized olefin reacts with
an also very reactive immobilized olefin, and a new player enters
in the game if the site–site interaction is a feasible process. Thus,
when the resin-bound pentenoic acid (11) was treated under CM
conditions with a soluble olefin (5) many possible processes could
take place (Scheme 4). Since ethylene departs from the system, the
fate of the reaction depends on 12 and 13, one leading to the desired
CM product while the other lead to the site–site by-product.
When excess of allyl benzene (5a) was subjected to cross
metathesis with resin 11 and precatalyst 2, only the expected
heterodimer 14a was obtained in low yield (18%), after releasing
from the resin and esterification with diazomethane (Table 3, entry
1). This result was due to the extensive formation the intrasite CM
product, which was isolated as the 4-octenedioic acid dimethyl
ester (15) in 70% yield. In fact, in the absence of any soluble olefin,
similar reaction led to the homodimeric ester 15 in 85% yield
(entry 2).18 However, a significantly different result was obtained
when less active type-II, non-immobilized olefins were used. For
instance, in the case of crotonic acid (5e), the desired CM product
was afforded in excellent yield (entry 3) and no intrasite-derived
product was observed. More predictable results were obtained
with even less reactive type-III olefins, such as b-pinene (5g)
and linonene oxide (5h) (entries 4 and 5). These olefins are very
resilient to cross metathesis compared with the olefin linked to
the polymer so, in both cases, the intrasite homodimer 15 was
the only detected product in very high yield (85%). These results
suggest that highly reactive olefins, such as 5a, are capable to
participate in all the pathways showed in Scheme 4, indicating their
tendency to give a product equilibration. The intrasite product 13
is the major component in equilibrium, probably due to that the
immobilized olefin 11 may be considered as highly concentrated
and unable to be diluted. When going down in reactivity, using
non-homodimerizable olefins, such as 5e, coupling product 12e
was essentially inactive to further CM events, preventing any
return from 12e to 13 (path d, Scheme 4). For this reason the
CM product was formed exclusively. Inactive olefins such as 5g
and 5h, gave place to the site–site product since all the paths but
path b are blocked.
In terms of the precatalyst effect on site–site interference, the
experimental results indicate that highly active precatalysts tend
to displace the reaction outcome to product equilibration while
with less active precatalyst that tendency is toward the site–site
by-product (Table 3, entries 6 to 11). This pattern is in agreement
with the increase in reactivity of the soluble olefin when a more
active precatalyst is used. Thus, coupling of 11 with a reactive, non-
immobilized alkene such as 5c in the presence of first generation
Grubbs precatalyst (1) gave increasing amounts of the intrasite
by-product 15 (70%) (entry 6), comparing with similar cross
metathesis performed with precatalysts 2 and 3 (entries 7 and 8).
These results are in accordance with early literature examples of
solid-phase olefin cross metathesis using precatalyst 1, that showed
high influence of site–site interaction on the reaction outcome.10
As expected, in the case of a less reactive soluble olefin, such
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Table 3 Cross-metathesis by ruthenium carbene complexes on immobilized pentenoic acid (11)a
Entry
1
Soluble olefin
Homo-dimerizationb
Yes, in 15 min
Precatalyst
2
CM product
14 (%)c
15 (%)
5a R¢ = H, R =
14a R =
18d
70
2
3
4
None
—
2
2
2
—
—
100
0
85
0
5e R¢ = CH3, R = CO2H
No
No
14e R = –CO2Me
5g
14g
85
5
5h
No
2
14h
0
85
6
7
8
9
5c R¢ = H, R =
5c R¢ = H, R =
5c R¢ = H, R =
5f R¢ = H, R =
No
1
2
3
1
14c R =
14c R =
14c R =
14f R =
14
45
43
6
70
35
33
83
Yes, in 20 h
Yes, in 5 h
No
10
11
5f R¢ = H, R =
5f R¢ = H, R =
No
2
3
14f R =
14f R =
87
57
0
partially
17
a Conditions: (i) olefin 5(5¢) (5 eq), Ru precatalyst (5 mol%), DCM, reflux 20 h. (ii) 10% TFA in DCM at r.t. for 1 h, (iii) CH2N2 in DCM at 0 ◦C for
1
30 min. b Time for total dimerization employing precatalyst 2. c Overall isolated yield after flash column chromatography. E isomer exclusively, by H
NMR. d Inseparable mixture of E–Z isomers [(83 : 17) determined by 1H NMR].
as 2-bromo styrene (5f), precatalyst 1 gave almost exclusively the
intrasite homodimer 15 (83%) (entry 9) while precatalyst 2 afforded
the cross-coupled product 14f as the only detectable product (entry
10), due to the unreactivity of the immobilized heterocoupled
product 12f. Conversely, precatalyst 3 gave mixture of 14f and the
by-product 15 (entry 11). This is clearly due to the increase in olefin
reactivity by using a more active precatalyst. As a consequence of
such reactivity, there is a major tendency to displace the reaction
outcome toward product equilibration.
high reaction temperatures.19 Over the last decade, microwave-
assisted chemistry has reached a matured state and its importance
has been enhanced by the necessity of a sustainable chemistry in
terms of a reduction in the amount of solvents and hazardous
substances and a more efficient use of energy.20 On the other
hand, microwave-assisted organic synthesis (MAOS) is having
substantial impact on drug discovery programs. Reaction times
are reduced by orders of magnitude and are readily scalable. Thus,
exploratory reactions can be carried out in much shorter time and
SAR studies can be dynamized by a rapid synthesis of compound
libraries.21
The effect of microwave irradiation
While microwave irradiation has been applied to CM reactions,
there are no reports on the corresponding solid-phase version.22
Under this perspective, resin-bound olefin 4, 4-vinylbenzyl
Microwave irradiation offers a promising alternative to conven-
tional heating sources, providing a practical and rapid way to reach
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Scheme 4 Metathetic system for a homodimerizable immobilized olefin.
chloride (5c), and precatalyst 2 were used as model for studying
the◦effect of microwave irradiation. First attempted conditions,
60 C for 10 min. in a sealed tube, gave only 58% of the desired
alkene 7c, and 24% of the recovered starting material in the
form of methyl 4-vinylbenzoate. In contrast, conventional heating
gave 80% of 7c as the exclusive product (Table 1, entry 5). In
further attempts to improve microwave yields we noticed that,
when temperature or time were increased, the reaction reached a
stationary point from where no further increase in conversion was
possible. We thought that this problem was caused by the presence
of ethylene in the closed system. Being a reversible process, ethylene
helps to maintain a point of equilibrium and the reaction does
not displace to products. This results are in divergence with
reports of CM in homogeneous phase, where sealed systems are
successfully employed.23 Analyzing the conditions used in the
solid-phase version, it is clear that the effect of the ethylene is
much more significant than in the solution-phase counterpart. As
a consequence of the excess of the non-immobilized olefin used,
the pressure of ethylene generated is such that blocks the reaction
progression (Scheme 5).
to the volatility of the crotonic acid which was evaporated under
the open-vessel conditions before the reaction was complete. In
fact, this assumption was corroborated by using a less volatile
derivative, such as the benzyl crotonate 5i. CM coupling of
immobilized olefin 4 and 5i in the presence of precatalyst 2 under
open-vessel microwave conditions gave the expected CM product
7i in quantitative yield (entry 8). The role of the homodimerization
of the non-immobilized olefin has also to be taking into account
under microwave irradiation. Probably, the reason for the lack of
yield increase when using 4-methylstyrene (5b) (entry 2), is that,
although the coupling becomes faster, the homodimerization also
goes faster (5 min), and that homodimer (5¢b) is almost unreactive
under microwave conditions (entry 3).
When the “flexible” immobilized resin 11 was used as substrate,
CM under open-vessel microwave conditions gave similar results
to that of conventional heating. As in the cases shown in Table 3,
highly active soluble olefins gave mostly a mixture of the expected
CM product and the site–site by-product,24 while unreactive
soluble olefins gave only the intrasite by-product. CM products
were only favored when the newly formed olefin was essentially
inactive to further CM events, avoiding any equilibration.
Comparison between microwave and conventional heating
Although beneficial effects of microwave irradiation have been
reported for more than two decades in the literature, a direct
comparison with conventional heating has not been always
carried out. Since our microwave conditions were changed during
optimization, we decided to perform a direct comparison between
conventional and microwave heating by developing some reactions
at strictly the same CM conditions. Thus, when resin-bound olefin
4 was reacted with soluble olefin 5c in the presence of precatalyst 2
by conventional heating, under identical conditions to that used in
microwave heating, the CM product 7c was obtained in virtually
the same yield (84%) (Table 5, entry 1). This result demonstrates
that 24 h reflux in DCM is excessive in order to obtain a very
high yield of the desired coupling product, since the reaction can
be complete in just 25 min at 75 ◦C. More interestingly, a similar
comparison using Hoveyda–Grubbs precatalyst (3) gave the CM
product in 85%, which is about the same yield as obtained by
microwave irradiation and implies a great increase comparing to
Scheme 5 Effect of ethylene on solid-phase cross metathesis under a
closed microwave system.
Therefore, it was expected that, under an open-vessel microwave
system, the efficiency of the CM would be improved. To our
delight, coupling of 4 with 5c in the presence of 2 under mild
conditions (75 ◦C, 15 min.) gave the desired alkene 7c in 78% yield
and 16% of recovered starting material. Optimized conditions
were reached when the time was extended to 25 min, affording
product olefin 7c exclusively in 90% yield (Table 4, entry 4). The
generality of this procedure has been demonstrated by a series of
examples (Table 4). In almost all the cases, yields were similar
or better than the CM coupling under conventional heating.
The only notable exception was the metathesis using crotonic
acid (5e) as soluble substrate, that led to only 35% of the CM
product 7e (entry 6). This unexpected result was firstly attributed
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Table 4 Cross-metathesis by precatalyst 2 on the resin-bound 4-vinyl benzoic acid (4), under open-vessel microwave conditionsa
Yield (%)b
Entry
1
Soluble olefin
Product
Microwave
79
Classical Conditions
86c
5a R¢ = H, R =
7a R =
2
3
4
5
5b R¢ = H, R =
5b R¢ = R =
7b R =
7b R =
7c R =
7d R =
30
15d
90
86
31c
NRc,e
80c
5c R¢ = H, R =
5d R¢ = H, R =
57c
6
7
5e R¢ = –CH3, R = –CO2H
5f R¢ = H, R =
7e R = –CO2Me
7f R =
35
80
97c
43c
8
9
5i R¢ = –CH3, R = –CO2Bn
5j R¢ = H, R =
7i R = –CO2Bn
7j R =
100
82
96
—
10
11
5k R¢ = H, R =
7k R =
85
—
5g
7g
NR
NR
12
5h
7h
NR
NR
a Conditions: (i) olefin 5 (5 eq), precatalyst 2 (5 mol%), toluene, open vessel microwave irradiation, 75 ◦C (120 W) for 25 min. (ii) 10% TFA in DCM at
r.t. for 1 h, (iii) CH2N2 in DCM at 0 ◦C for 30 min b Overall isolated yield after flash column chromatography. E isomer exclusively, by 1H NMR. c Taken
from Table 1. d Soluble olefin monomer dimerizes in 5 min. e Soluble olefin monomer dimerizes in 2 h.
previous thermal conditions (28%) (entry 2). A similar result was
obtained when a less reactive soluble olefin (5f) was subjected to
CM under precatalyst 2 (entry 3).
the optimized conventional heating conditions can to be found
into the short reaction time (25 min against 20 h), which avoids
unnecessary metathetic and non-metathetic events that lead to
abnormal products.27
Based on the results presented herein, it is clear that the
heating effects on the reaction outcome are thermal and not
related to any electromagnetic field, which is in agreement with
the conclusions recently reported by Kappe and co-workers.25,26
They have developed a critical analysis of the effects involved
in microwave heating, not only in homogeneous-phase,25 but
also in solid-phase chemistry.26 They have found no evidence of
nonthermal effects on microwave irradiation, establishing that,
under an efficient agitation of the reaction mixture, nearly identical
results in terms of yields, selectivity and racemization rate (in the
case of solid-phase peptide synthesis) can be obtained.
Experimental section
General
Chemical reagents were purchased from commercial sources and
were used without further purification unless noted otherwise.
Solvents were analytical grade or were purified by standard
procedures prior to use. 1H NMR spectra were recorded at
300 MHz in CDCl3, in the presence of TMS (0.00 ppm) as
the internal standard. Conventional and gel-phase 13C NMR
spectra were recorded on the same apparatus at 75 MHz with
In the case of the solid-phase version of the cross metathesis, the
reason for the success of the microwave irradiation approach and
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Table 5 Comparison of solid-phase cross-metathesis under classical and microwave conditions
Yield (%)a
Thermal optimized
Entry Soluble olefin
Product
Precatalyst Initial thermal conditionsb Microwave irradiationc conditionsd
1
2
3
5c R¢ = H, R =
5c R¢ = H, R =
5f R¢ = H, R =
7c R =
2
3
2
80
28
43
90
80
80
84
85
80
7c R =
7f R =
a Overall isolated yield after flash column chromatography. b Conditions: olefin 5 (5 eq), Ru precatalyst (5 mol%), DCM, conventional heating, reflux
20 h. (taken from Table 1) c Conditions: olefin 5 (5 eq), Ru precatalyst (5 mol%), toluene, open vessel microwave irradiation, 75 ◦C (120 W) for 25 min.
d Conditions: olefin 5 (5 eq), Ru precatalyst (5 mol%), toluene, conventional heating, 75 ◦C for 25 min.
CDCl3 as solvent and reference (76.9 ppm). Analytical thin-
layer chromatography (TLC) was carried out with silica gel 60
F254 pre-coated aluminium sheets. Flash column chromatography
was performed using silica gel 60 (230–400 mesh). Microwave
irradiations were performed on a CEM Discover LabMate reactor
and the reaction temperature was measured with the internal
infrared control system from the apparatus. Compounds 5¢a,28
5¢b–c,11d 5¢d,29 7a,11d 7b–d,11d 7e,30 7f,31 10a,32 10c,33 10d,32,34
10f,35 14a,36 14c,11f 14e,37 14f11f and 15,38 have been previously
reported.
General procedure for the solid-phase cross-metathesis by
ruthenium carbene complexes under thermal optimized conditions
Utilizing the same glassware apparatus described above in the
microwave protocol, resin-bound olefin 4 (0.15 mmol) was sus-
pended in anhydrous toluene (3 mL) and the non–immobilized
olefin 5 (0.75 mmol, 5.0 eq) was added via syringe under a nitrogen
atmosphere. Precatalyst 2 (7.5 mmol, 5 mol%) was added and the
system was heated in an oil bath at 75 ◦C for 25 min with magnetic
stirring. Resin was washed with DCM, MeOH, DCM, and dried
under high vacuum. Resin-bound olefin 6 (0.15 mmol) was treated
with 5 mL of 10% TFA in DCM for 1 h. The mixture was filtered
and the filtrate was evaporated under reduced pressure to give the
crude product. This crude material was dissolved in DCM and
treated with diazomethane at 0 ◦C for 30 min. Desired product 7
was purified by flash column chromatography (hexane–AcOEt).
General procedure for the solid-phase cross-metathesis by
ruthenium carbene complexes under microwave irradiation
In
a 10 mL round-bottomed flask, resin-bound olefin 4
(0.15 mmol) was suspended in anhydrous toluene (3 mL) and
the non-immobilized olefin 5 (0.75 mmol, 5.0 eq) was added via
syringe under a nitrogen atmosphere. The precatalyst 2 (7.5 mmol,
5 mol%) was added and the flask fitted with a straight connecting
adapter and a condenser (see the ESI†). A polypropylene cannula
was passed through the septum and brought close to the reaction
mixture in order to maintain an open vessel system with a dry
nitrogen flow and a fast ethylene removal. This apparatus was
placed in the microwave reactor and irradiated under a standard
heating protocol at 75 ◦C for 25 min (maximum power = 120 W)
with magnetic stirring. The resin was filtered, washed with DCM
(3 ¥ 4 mL), MeOH (3 ¥ 4 mL), DCM (1 ¥ 4 mL), and dried under
high vacuum. Resin-bound olefin 6 (0.15 mmol) was treated with
5 mL of 10% TFA in DCM for 1 h. The mixture was filtered and
the filtrate was evaporated under reduced pressure to give crude
product. This crude material was dissolved in DCM and treated
with diazomethane at 0 ◦C for 30 min. The solvent was evaporated
under reduced pressure and the crude material was purified by
flash column chromatography (hexane–AcOEt) to provide the
desired product 7.
(E)-methyl 4-(3-(benzyloxy)-3-oxoprop-1-enyl)benzoate (7i).
Mp: 55–56 ◦C (from DCM, white needles). IR (film) nmax 3034,
2952, 1720, 1436, 1308, 1280, 1166, 1107. 1H NMR (CDCl3,
300 MHz): dH 8.04 (d, J = 8.2 Hz, 2H, ArH), 7.74 (d, J = 16.1 Hz,
1H, H5), 7.57 (d, J = 8.2 Hz, 2H, ArH), 7.43–7.32 (m, 5H, ArH),
6.56 (d, J = 16.1 Hz, 1H, H6), 5.26 (s, 2H, H10), 3.93 (s, 3H,
CH3O). 13C NMR (CDCl3, 75 MHz): dC 166.3, 166.2, 143.6, 138.4,
135.7, 131.3, 130.0, 128.5, 128.2, 127.8, 120.2, 66.0, 52.0. HRMS
(ESI) m/z 319.0944 [(M + Na+); calcd for C18H16O4: 319.0940].
(E)-methyl 4-(2-cyclohexylvinyl)benzoate (7j). Mp: 60–61 ◦C
(from DCM, colourless needles). IR (film) nmax 2929, 1719, 1284,
1104. 1H NMR (CDCl3, 300 MHz): dH 7.95 (dt, J = 1.8 Hz, J =
8.5 Hz, 2H, ArH), 7.39 (dt, J = 1.8 Hz, J = 8.5 Hz, 2H, ArH),
6.38 (d, J = 16.1 Hz, 1H, H5), 6.30 (dd, J = 16.1 Hz, J = 6.0 Hz,
1H, H6), 3.90 (s, 3H, CH3O), 2.21–210 (m, 1H, H7), 1.80–0.80 (m,
10H, H8-10). 13C NMR (CDCl3, 75 MHz): dC 166.9, 142.6, 139.6,
129.7, 128.1, 126.5, 125.7, 51.9, 41.2, 32.6, 26.0, 25.9. HRMS (ESI)
m/z 267.1349 [(M + Na+); calcd for C16H20O2Na: 267.1355].
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(E)-methyl 4-(4-acetoxystyryl)benzoate (7k). Mp: 189–190 ◦C
(from DCM, white amorphous solid). IR (film) nmax 3022, 2954,
1761, 1718, 1287, 1112. H NMR (CDCl3, 300 MHz): dH 8.07–
7.99 (m, 2H, H8), 7.61–7.50 (m, 4H, H2–3), 7.19 (d, J = 16.5 Hz,
1H, H5), 7.11 (dt, J = 2.0 Hz, J = 8.8 Hz, 2H, H9), 7.06 (d,
J = 16.5 Hz, 1H, H6), 3.92 (s, 3H, CH3O), 2.31 (s, 3H, H12).
13C NMR (CDCl3, 75 MHz): dC 169.3, 166.7, 150.4, 141.5, 134.4,
130.0, 129.9, 128.9, 127.6, 126.5, 126.2, 121.8, 52.0, 21.0. HRMS
(ESI) m/z 319.0936 [(M + Na+); calcd for C18H16O4: 319.0940].
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This study demonstrates that the success of the olefin cross
metathesis on solid support depends on many different factors
influencing many metathetic events taking part during the reac-
tion. Thus, flexible and long support linkers open the door to the
formation of intrasite products. Exclusive obtention of the CM
product can only be achieved if the new double bond is resistant
to further metathetic events, while highly active non-immobilized
olefins gave mostly a mixture of the desired CM product and the
site–site by-product. Virtually unreactive soluble olefins gave only
the intrasite by-product. If the intrasite reaction is not possible, the
role of the homodimerization of the non-immobilized olefin can
be crucial. If the homodimer is less reactive than its monomer,
reaction outcome depends on the homodimerization rate. But
homodimerization rate, of course, depends on the precatalyst used
and the reaction conditions. This means that just the use of a
more reactive precatalyst or improved reaction conditions does not
always give a better yield of the desired product. Aside from that,
it is clear that optimized conditions give excellent results in short
reaction time (25 min) and, particularly, microwave irradiation
offers an interesting alternative to achieve good results in a very
practical way and with a more efficient use of the energy. In
summary, we think that this comprehensive analysis expands our
knowledge on the solid-phase cross metathesis, an underdeveloped
methodology, in order to exploit its undoubted potential.
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Acknowledgements
Financial support from Consejo Nacional de Investigaciones
Cient´ıficas y Te´cnicas (CONICET) (Argentina); Agencia Na-
cional de Promocio´n Cient´ıfica y Tecnolo´gica (Argentina); Fun-
dacio´n Prats (Argentina), and Universidad Nacional de Rosario
(Argentina) is gratefully acknowledged. AAPP thanks CONICET
for fellowships.
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