Microwave-Accelerated Ruthenium-Catalyzed Olefin Metathesis

Article abstract of DOI:10.1021/ol025789s

(matrix presented) Microwave heating is an efficient method for the acceleration of ring-closing metathesis reactions using ruthenium-based catalysts. The reaction can be rapidly conducted in either ionic liquids, such as 1-butyl-3-methylimidazolium tetrafluoroborate (bmim), or in a microwave transparent solvent (MTS) such as dichloromethane.

Full text of DOI:10.1021/ol025789s

ORGANIC
LETTERS
2
002
Vol. 4, No. 9
567-1570
Microwave-Accelerated
Ruthenium-Catalyzed Olefin Metathesis
1
Kelly G. Mayo, Eliza H. Nearhoof, and James J. Kiddle*
Department of Chemistry, UniVersity of North Carolina at Wilmington,
Wilmington, North Carolina, 28403
kiddlej@uncwil.edu
Received February 27, 2002
ABSTRACT
Microwave heating is an efficient method for the acceleration of ring-closing metathesis reactions using ruthenium-based catalysts. The
reaction can be rapidly conducted in either ionic liquids, such as 1-butyl-3-methylimidazolium tetrafluoroborate (bmim), or in a microwave
transparent solvent (MTS) such as dichloromethane.
During the past decade, ring-closing metathesis (RCM) has
emerged as a powerful tool for the construction of small,
medium, and macrocyclic ring systems. A large part of the
in the synthesis of several types of organophosphorus
compounds. Carrying out reactions using microwave heat-
5
1
ing, as opposed to conventional heating, has the major
advantage of shorter reaction times because of the rapid core
heating associated with microwaves. Consequently, reactions
exhibit cleaner products and more facile workup procedures.
Our interest in this area has prompted us to explore its
application in reactions other than the synthesis of organo-
phosphorus compounds. Herein, we report a systematic
analysis of the effect of microwave heating in ring-closing
success of this reaction has been due to the availability of
2
well-defined catalysts such as those developed by Shrock
(
3
1-Mo) and Grubbs (2-Ru, 3-Ru) (Figure 1). However, the
6
metathesis reactions using Grubbs catalysts.
Our initial goal was to investigate the use of room
temperature ionic liquids as environmentally friendly solvents
in microwave heating reactions. The ionic liquids seemed
advantageous since they would couple with microwaves
(1) For recent reviews on olefin metathesis, see: (a) Grubbs, R. H.;
Chang, S. Tetrahedron 1998, 54, 4413. (b) Armstrong, S. K. J. Chem. Soc.,
Perkin Trans. 1 1998, 371. (c) Wright, D. L. Curr. Org. Chem. 1999, 3,
Figure 1.
211. (d) Fhrstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012.
(2) (a) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare,
M.; O’Regan, M. J. Am. Chem. Soc. 1990, 112, 3875. (b) Bazan, G. C.;
Oskam, J. H.; Cho, H.-N.; Park, L. Y.; Schrock, R. R. J. Am. Chem. Soc.
catalysts developed by Grubbs have proven to be more useful
in synthetic transformations due to their low sensitivity to
air and moisture, as well as their tolerance of a variety of
common organic functional groups.4
1
991, 113, 6899.
(3) (a) Nguyen, S. T.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc.
993, 115, 9858. (b) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org.
1
Lett. 1999, 1, 953.
4) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
(
Recently, this laboratory has focused on the application
of microwave heating in organic synthesis. The initial
investigations centered on the utility of microwave heating
(5) (a) Kiddle, J. J.; Gurley, A. F. Phosphorus, Sulfur, Silicon 2000, 160,
95. (b) Kiddle, J. J. Tetrahedron Lett. 2000, 41, 1339.
1
(6) For the first example of RCM under microwave activation, see:
Varray, S.; Gauzy, C.; Lamaty, F. J. Org. Chem. 2000, 65, 6787.
1
0.1021/ol025789s CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/10/2002

7
through a dielectric heating mechanism, were reasonably
polar, can dissolve organic compounds, have relatively high
boiling points (>200 °C), and a low volatility. The low
Table 2. Microwave-Accelerated RCM in bmim
8
volatility of the ionic liquids was of particular importance
since our microwave reactions were conducted in sealed
Teflon-capped pressure tubes. We thought this would not
be compatible with the typical RCM solvent dichloro-
methane; however, upon further investigation we have found
that this is not the case.
As a first step, we examined the RCM reaction of diethyl
diallylmalonate in 1-butyl-3-methylimidazolium tetrafluoro-
borate (bmim) with three ruthenium-based catalysts to
determine which one would be most effective in an ionic
liquid (Table 1).
Table 1. Microwave-Accelerated RCM with Grubbs Catalysts
in Ionic Liquids
a
E ) CO2Et, 0.02-0.04 M, 2-3 mol % 3-Ru. b Determined from H
NMR. c Thermal reactions were conducted under conditions identical to
those used in the microwave experiments. The temperature used in the
thermal reactions was the highest temperature observed in the microwave
reactions (33 °C except entries d and e which were 54 and 61 °C,
respectively).
1
solvent, the results of which are shown in Table 2.10 In all
cases the RCM reactions were complete in 60 s or less, often
with 100% conversion. To determine the efficiency of
microwave heating in RCM reactions, control experiments
were conducted using thermal heating under identical reac-
tion conditions. In all but two cases, the rate of the reaction
under microwave heating was significantly greater than those
performed under identical thermal conditions, providing clear
evidence for an acceleration of RCM reactions through
microwave activation. The low conversion of 1,6-heptadien-
4-ol (entry e) was unexpected since previous work by Grubbs
showed a quantitative conversion to the product using 3-Ru.
a
1
b
Determined from H NMR. Bound to vinyl polystyrene.
The results from the model study in Table 1 were not
surprising since catalyst 3-Ru has been reported to be more
active than 2-Ru in RCM reactions. In addition, the lower
conversion with the polymer-bound Grubbs catalyst has been
previously reported to be about 2 orders of magnitude less
reactive than the homogeneous analogue 2-Ru which is
3b
9
similar to our results. Although the reactivity profile of the
catalysts was not unexpected, the extremely short reaction
time suggested that RCM reactions could easily be acceler-
ated by microwave heating. In addition, the fact that no other
precautions were taken in the reaction (i.e., exclusion of air/
moisture) demonstrated that the typical RCM reaction could
also be easily adapted to microwave heating.
However, those reactions were conducted in CD
2 2
Cl and may
account for the difference in conversion. In the case of the
allyl ether (entry f), no product was formed possibly due to
vaporization of the ether (bp 94 °C) caused by the rapid
heating associated with microwave energy. Recently, a report
has appeared in the literature concerning the use of ruthenium
11
We then turned our attention to a more comprehensive
examination of RCM reactions using 3-Ru in bmim as
catalysts in ionic liquids for olefin metathesis. The authors
reported reaction times of 1 h at 80 °C to achieve 100%
conversion of the same substrate in entries a and c (Table
(7) Gabriel, C.; Gabriel, S.; Grant, E. H.; Halstead, B. S. J.; Mingos, D.
2
) that required only 15 s each under microwave heating.
M. P. Chem. Soc. ReV. 1998, 27, 213.
Although this suggests a significant reduction in reaction time
using microwave heating, it should be noted that the authors
utilized the less reactive catalyst 2-Ru in their experiments.
In addition, the ionic liquid used had a different anion
(
(
(
8) Welton, T. Chem. ReV. 1999, 99, 2071.
9) Nguyen, S. T.; Grubbs, R. H. J. Organomet. Chem. 1995, 497, 195.
10) General procedure for microwave-accelerated RCM: Caution!
It is hazardous to heat organic reactions in closed vessels by either
conventional or microwave means. Therefore, caution should be exercised
when conducting reactions of this type. Substrate and 1 mL of solvent (bmim
or CD2Cl2) were combined in a pressure tube to yield solutions with a
concentration between 0.02 and 0.04 M. Next, the catalyst was weighed
into the pressure tube that is immediately sealed finger tight with a threaded
Teflon cap. The pressure tube was put into a beaker and then placed in the
center of a Panasonic 1100W microwave oven (Model NN-S758). The
reaction mixture is then heated for the appropriate time on a power setting
of 10% (approximately 110 W). Once the heating cycle is complete, the
reaction mixture is either extracted with ethyl acetate (bmim) or used directly
(hexafluorophosphate vs tetrafluoroborate) than ours. It is,
however, unlikely that these differences would have a
major impact on the reactions and account for the
dramatic reduction in reaction time seen with microwave
heating.
(11) Buijsman, R. C.; van Vuuren, E.; Sterrenburg, J. G. Org. Lett. 2001,
3, 3785.
1
to determine the conversion by H NMR.
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Org. Lett., Vol. 4, No. 9, 2002

Although the RCM reactions in ionic liquids under
microwave heating were very successful, we were concerned
about the limited data to which we could compare our results.
Therefore, we decided to extend our investigation to further
validate the utility of microwave heating in RCM reactions.
To this end, we next focused our attention on using
dichloromethane as a solvent for our microwave-accelerated
RCM reactions.
to establish the most effective catalyst for the microwave-
accelerated RCM reactions in dichloromethane. Not surpris-
ingly, catalyst 3-Ru proved to be superior to the other two
catalysts as was previously noted in the reactions utilizing
ionic liquids as solvents (Table 3). Also, during the course
of this model study it was found that for the complete
conversion of diethyl diallylmalonate to the cycloalkene
using 3-Ru required 120 s in dichloromethane. This time
was established as a baseline for comparison of the micro-
wave heating data.
Initially, the use of dichloromethane was not considered
since the reactions are carried out in sealed tubes and it was
prudent to avoid low-boiling solvents under these conditions.
With the most effective catalyst and a standard reaction
time determined, we then examined the microwave-acceler-
ated RCM reaction of several substrates in dichloromethane
(Table 4).
s
However, the dielectric constant (ꢀ ) of dichloromethane is
9.1 and we hypothesized that it might be transparent to
microwave energy and thus show little or no heating when
subjected to microwaves. These conditions would then allow
the direct coupling of the microwave energy to the reactants
in the mixture.
To test this hypothesis, it was first necessary to determine
the microwave heating profile of dichloromethane. Figure 2
Table 4. Microwave-Accelerated RCM in Dichloromethane
Figure 2. Microwave heating profile of dichloromethane.
a
E ) CO2Et, 0.02-0.04 M, 2-3 mol % 3-Ru, 120 s. b Determined from
shows the microwave heating profile of dichloromethane over
a period of 3 min. The graph clearly shows that dichloro-
methane is reasonably transparent to microwave energy and
in fact does not reach its boiling point (40 °C) within the
time of the experiment. For comparison, methanol will reach
its boiling point (65 °C) in less than 1 min of microwave
1
H NMR. c Thermal reactions were conducted under conditions identical
to those used in the microwave experiments. The temperature used in the
thermal reactions was the highest temperature observed in the microwave
reactions (33 °C).
As illustrated in Table 4, the extension of the microwave
heating methodology to RCM reactions in dichloromethane
behaved in a fashion similar to those in ionic liquids. The
reaction times were reduced, but not to the extent seen with
the ionic liquids. However, in comparison to the thermal
control experiments under identical conditions, the micro-
wave reactions did show enhanced conversions with every
substrate. In addition to the evidence of a rate enhancement
seen by comparing the microwave experiments to the
controls, Grubbs and co-workers have reported the complete
thermal conversion of the substrates in entries h and i to
6
heating.
Following confirmation that dichloromethane was indeed
a transparent solvent in microwave heating, we then sought
Table 3. Microwave-Accelerated RCM with Grubbs Catalysts
in Dichloromethane
8
products after 10 min in refluxing dichloromethane. In our
microwave experiments, the substrate in entry h shows
complete conversion in one-fifth the time required in the
experiments conducted by Grubbs. In addition, although the
substrate in entry i showed only a 79% conversion after 120
s, the substrate could be completely converted to product
by heating for an additional 60 s (180 s total) in comparison
to the 10 min necessary in the thermal reaction described
a
1
b
Determined from H NMR. Bound to vinyl polystyrene.
Org. Lett., Vol. 4, No. 9, 2002
1569

above. Although there was not a dramatic reduction in
reaction time using dichloromethane as the solvent, it is
important to note that none of the microwave reactions
exceeded 33 °C. This fact suggests that the microwave energy
is producing nonthermal effects that may involve direct
coupling to one of the two or both reactants in these
transformations. However, in preliminary experiments it has
not been possible to ascertain which component(s) are
coupling with the microwave energy or if other factors related
to the medium are influencing the microwave heating. Even
without a clear understanding of the heating mechanism, one
practical consideration would be that RCM reactions carried
out under microwave heating would be more useful for
substrates which were sensitive to prolonged exposure to
heat.
In conclusion, we have reported an effective and efficient
method to accelerate ring-closing metathesis reactions in both
ionic liquids and dichloromethane through microwave heat-
ing. Although, the reactions in dichloromethane are not
significantly more rapid than those of similarly reported
model studies under thermal heating, they do provide an
alternative method that does not necessitate heating the
substrate at reflux. Further research will be directed toward
a better understanding of the mechanisms involved in
microwave heating of organic reactions.
12
Acknowledgment. The authors thank the North Carolina
Biotechnolgy Center Institutional Development Grant Pro-
gram (9610-IDG-1009) for the purchase of the Bruker DRX
4
00 MHz NMR used in this study.
(12) Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199.
OL025789S
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Org. Lett., Vol. 4, No. 9, 2002