An investigation of wall effects in microwave-assisted ring-closing metathesis and cyclotrimerization reactions

Article abstract of DOI:10.1021/jo1011703

(Figure presented) Challenging Ru-catalyzed ring-closing metathesis transformations leading to eight-membered-ring systems and Ni- or Co-catalyzed [2+2+2] cyclotrimerizations were evaluated at elevated temperatures applying microwave dielectric heating or

Full text of DOI:10.1021/jo1011703

pubs.acs.org/joc
An Investigation of Wall Effects in Microwave-Assisted Ring-Closing
Metathesis and Cyclotrimerization Reactions
Doris Dallinger, Muhammed Irfan, Amra Suljanovic, and C. Oliver Kappe*
Christian Doppler Laboratory for Microwave Chemistry (CDLMC) and Institute of Chemistry,
Karl-Franzens-University Graz, Heinrichstrasse 28, A-8010 Graz, Austria
oliver.kappe@uni-graz.at
Received June 15, 2010
Challenging Ru-catalyzed ring-closing metathesis transformations leading to eight-membered-ring
systems and Ni- or Co-catalyzed [2þ2þ2] cyclotrimerizations were evaluated at elevated tempera-
tures applying microwave dielectric heating or conventional thermal heating in order to investigate
the role of wall effects. All reactions were conducted in a dedicated reactor setup that allowed
accurate internal reaction temperature measurements using fiber-optic probes for both types of
heating modes. For ring-closing metathesis best results were achieved using an open vessel-gas
sparging protocol in 1,2-dichloroethane at reflux temperature (83 °C), while cyclotrimerizations were
performed under sealed vessel conditions in toluene between 80 and 160 °C. For all studied
transformations the results achieved in a single-mode microwave reactor could be reproduced by
conventional heating in an oil bath by carefully matching the temperature profiles as close as possible
during the entire heating and cooling cycle. In contrast to previous literature reports, no evidence that
direct in-core microwave heating can increase catalyst lifetime by minimization or elimination of wall
effects was obtained. At the same time, no indication for the involvement of nonthermal microwave
effects in these homogeneous transition metal-catalyzed transformations was seen.
Introduction
In contrast, microwave irradiation produces efficient in-
ternal heating (in-core volumetric heating) by direct coupling
of microwave energy with the molecules (solvents, reagents,
catalysts) that are present in the reaction mixture.1 Micro-
wave irradiation therefore raises the temperature of the
whole volume simultaneously (bulk heating) whereas in the
conventionally heated vessel, the reaction mixture in contact
with the vessel wall is heated first. Since the reaction vessels
employed in modern microwave reactors are typically made
Traditionally, organic synthesis in an elevated tempera-
ture regime is performed by conductive heating applying an
external heat source such as an oil-bath or heating mantle.
This is a comparatively slow and inefficient method for
transferring energy into the system since it depends on
convection currents and on the thermal conductivity of the
various materials that must be penetrated, and generally
results in the temperature of the reaction vessel being higher
than that of the reaction mixture. This is particularly true if
reactions are performed under reflux conditions, where the
temperature of the bath fluid or heating mantle is typically
kept 20-50 °C above the boiling point of the reaction
mixture in order to ensure an efficient reflux.
€
(1) (a) Microwave-Assisted Organic Synthesis; Lidstrom, P., Tierney,
J. P., Eds.; Blackwell Publishing: Oxford, U.K., 2005. (b) Kappe, C. O.;
Stadler, A. Microwaves in Organic and Medicinal Chemistry; Wiley-VCH:
Weinheim, Germany, 2005. (c) Microwaves in Organic Synthesis, 2nd ed.;
Loupy, A., Ed.; Wiley-VCH: Weinheim, Germany, 2006. (d) Microwave
Methods in Organic Synthesis; Larhed, M., Olofsson, K., Eds.; Springer:
Berlin, Germany, 2006. (e) Kappe, C. O.; Dallinger, D.; Murphree, S. S.
Practical Microwave Synthesis for Organic Chemists;Strategies, Instru-
ments, and Protocols; Wiley-VCH: Weinheim, Germany, 2009.
*To whom correspondence should be addressed. Phone: þ43-316-380-
5352. Fax: þ43-316-380-9840.
5278 J. Org. Chem. 2010, 75, 5278–5288
Published on Web 07/15/2010
DOI: 10.1021/jo1011703
r
2010 American Chemical Society

Dallinger et al.
JOCArticle
out of nearly microwave transparent materials such as
borosilicate glass, quartz, or Teflon, the radiation passes
through the walls of the vessel and the temperature at the
inner surface of the reactor wall will (initially) be lower than
that of the bulk liquid. The elimination of a hot vessel surface
has often been stated as being one of the key advantages of
using microwave technology in synthetic organic chemistry,1
in particular in transition metal-catalyzed transformations
where temperature sensitive catalysts can undergo decom-
position on hot reactor surfaces (wall effects).2 It has been
argued that the elimination of such a hot surface by in-core
volumetric heating can increase the lifetime of the catalyst
and therefore may lead to better conversions in a microwave
heated as compared to a conductively heated process.1,2
In this paper we present a detailed investigation on the
putative role and existence of wall effects in convention-
ally and microwave heated ring-closing metathesis trans-
formations.3 Ring-closing metathesis chemistry was cho-
sen as a suitable model system for several reasons. First
of all, it is well-known that many of the classical transi-
tion metal-based catalytic systems used today to perform
olefin metathesis chemistry are thermally unstable and
will degrade over time, especially when heated to higher
temperatures.3,4 Second, the use of microwave dielectric
heating to perform a range of transition metal-catalyzed
metathesis protocols,5 including ring-closing metathesis
(RCM),6-12 cross-metathesis (CM),13,14 ring-opening meta-
thesis polymerization (ROMP),15 and several types of alkyne
metathesis reactions16,17 is well documented. In virtually all of
these published examples, the use of microwave irradiation has
led to significant improvements in terms of reaction rates and/or
product yields and purities, compared to conventionally pro-
cessed reactions, in particular for otherwise difficult to perform
metathesis protocols.5-17 In addition, the use of microwave
heating has often allowed a significant reduction in catalyst
loading, and therefore an increase in catalyst turnover
numbers.5-17 As a scientific rationale for the observed effects
an increased catalyst lifetime by elimination of wall effects due
to direct in-core microwave heating was proposed in several
publications.5,7,14,17
The studies presented herein describe a series of carefully
executed experiments involving difficult to perform Ru-
catalyzed olefin ring-closing metathesis transformations for
the construction of eight-membered-ring systems. In addi-
tion, the putative role of wall effects and involvement of
nonthermal microwave effects in Ni- and Co-catalyzed
[2þ2þ2] cyclotrimerization reactions was also evaluated.18
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SCHEME 1. Ring-Closing Metathesis and Related Metathesis
Products of 1,2-Bis(allyloxy)benzene (2)
FIGURE 1. Ru-based olefin metathesis catalysts. Cy = cyclohexyl;
Mes = 2,4,6-phenyl.
Results and Discussion
Ru-Catalyzed Ring-Closing Metathesis. The mechanism of
Ru-catalyzed olefin metathesis has been the subject of in-
tense experimental19 and theoretical20 scrutiny. It is gener-
ally acknowledged that a metal carbene species is required
and that interaction with an olefin substrate leads to four-
membered metallacyclobutane intermediates or transition
states; cleavage of this intermediate in the opposite sense by
which it was formed leads to olefin metathesis, creating a new
carbon-carbon double bond and regenerating an active
metal carbene.19,20 The well-known Grubbs-type catalysts
(Figure 1) consist of a variety of Ru-based systems of the
general formula [Cl2(L)(L0)RudC(H)R], which in an initia-
tion step generate the reactive 14-electron alkylidene species
[Cl2(L)RudC(H)R] by reversible dissociation of L0 (PCy3 for
1a, 1b).21 The reaction temperatures required to overcome
this initiation step can lead to decreased catalyst lifetimes,
which therefore makes these transformations attractive
model reactions for the investigation of wall effects. Success-
ful improvements of the Grubbs first-generation catalyst (G I)
1a are modifications that either encourage loss of L0,22 or
reduce the tendency of the reactive species [Cl2(L)Rud
C(H)R] to recapture the liberated L0,23 which competes with
the olefin substrate for the unsaturated metal center in
[Cl2(L)RudC(H)R] (Grubbs second-generation catalyst, G
II, 1b). Alternatively, Hoveyda and co-workers have devel-
oped catalyst 1c (Hoveyda-Grubbs second generation cata-
lyst, HG II), in which L0 is incorporated into a loosely chelat-
ing group associated with the carbene ligand that is removed
upon the first metathesis event.24
contributing to a low decomposition rate.3,25 Clearly, the
utility of a given olefin metathesis catalyst will be a function
of the rate of olefin metathesis turnover to the rate of catalyst
decomposition.26 With this background the ring-closing
olefin metathesis of several difficult substrates utilizing Ru
metathesis catalysts 1a-c in an elevated temperature regime
was investigated.
In 2003, we reported on microwave-assisted ring-closing
olefin metathesis chemistry employing Ru catalyst 1b in
dichloromethane (DCM) and a set of standard diene sub-
strates.9 We have demonstrated that these undemanding
RCM reactions leading to five-, six-, and seven-membered
heterocycles could be significantly accelerated using micro-
wave heating as compared to reactions performed at room
temperature (e.g., 2 min at 60 °C versus 90 min at 25 °C with
0.5 mol % catalyst), but have also found that these rate
enhancements were due to a purely thermal effect and not
related to any special microwave effect.9,18 For the current
investigations, it was evident that a more difficult RCM
process needed to be chosen, requiring longer reaction times,
higher temperatures, and possibly also higher catalyst load-
ings to enforce the influence of wall effects on the overall
process. As a first model system we have chosen the RCM of
readily available 1,2-bis(allyloxy)benzene (2) to provide the
eight-membered 2,5-dihydro-1,6-benzodioxocin 3 (Scheme 1).
The synthesis of eight-membered rings, common structural
elements in numerous natural products, has proven a challen-
ging extension of the metathesis concept.3,4 Presumably, the kin-
etics of ring closure, the strain inherent in many eight-membered
rings, and the competing metathesis-based oligomerization of
reactants and/or products are among the factors contributing to
this problem.27 The RCM process shown in Scheme 1 was first
reported by Grubbs and co-workers in 1995, requiring 8 mol %
of the first generation Ru catalyst [Cl2(PCy3)2RudCHCHC-
(Ph)2], and 3 h at 55 °C in benzene to produce 75% of
The thermal decomposition of Ru olefin metathesis cata-
lysts 1a-c has been studied in detail, and the suggested quite
complex decomposition pathways vary significantly between
the individual catalyst types, and additionally are influenced
by the presence of olefin substrates and other additives.3,25
Significant catalyst decomposition is generally observed at
temperatures above 50 °C within a few hours.3,25 For most
catalysts, the rate of decomposition is related to the rate of
the initiation step;a slow rate of L0 dissociation likely to be
(19) For leading references, see: (a) Dias, E. L.; Nguyen, S. T.; Grubbs,
R. H. J. Am. Chem. Soc. 1997, 119, 3887. (b) Sanford, M. S.; Love, J. A.;
Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 6543.
(20) (a) Cavallo, L. J. Am. Chem. Soc. 2002, 124, 8965. (b) Adlhart, C.;
Hinderling, C.; Baumann, H.; Chen, P. J. Am. Chem. Soc. 2000, 122, 8204.
(21) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
(22) Love, J. A.; Sanford, M. S.; Day, M. W.; Grubbs, R. H. J. Am. Chem.
Soc. 2003, 125, 10103.
benzodioxocin 3.27 A subsequent study by Konig and Horn
(23) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc. 2001,
123, 6543.
€
(24) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168.
(25) Hong, S. H.; Wenzel, A. G.; Salguero, T. T.; Day, M. W.; Grubbs,
R. H. J. Am. Chem. Soc. 2007, 129, 7961.
(26) Ulmann, M.; Grubbs, R. H. J. Org. Chem. 1999, 64, 7202.
(27) Miller, S. J.; Kim, S.-H.; Chen, Z.-R.; Grubbs, R. H. J. Am. Chem.
Soc. 1995, 117, 2108.
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JOCArticle
demonstrated that applying 10 mol % catalyst 1a in DCM at
room temperature for 4 h resulted in only 15% of conversion to
the desired RCM product 3, in addition to the formation of the
acyclic diene metathesis (ADMET) oligomerization product 4
and the 14-membered macrocycle 5, resulting from an apparent
RCM of linear dimer 4 (10% each).28 Similar results were
observed by Fogg and co-workers: by using 5 mol % of G II
catalyst 1b and a substrate concentration of 0.1 M, an equili-
brium of 4, a cyclic trimer, and 3 was established. On the other
hand, at more dilute conditions (0.005 M), no oligomerization
products were obtained and direct cyclization to the RCM
product was favored, due to the small ring size and backbone
rigidity of 3.29 Apart from other studies on this RCM at room
temperature,30,31 the only microwave-assisted protocol for the
RCM 2 f 3 was reported by Comer and Organ, who achieved a
35% conversion with 1 mol % of G II catalyst 1b in toluene
within 4 min using a continuous flow process (temperature not
specified).10
Our investigations started with a solvent screen for the
RCM process 2 f 3 involving a set of common solvents
typically employed in Ru-catalyzed metathesis chemistry
such as DCM, 1,2-dichloroethane (DCE), benzene, and
toluene. On the basis of the results from these initial screen-
ing experiments and upon considering the boiling points of
these solvents we have selected DCE as the solvent of choice
for all metathesis chemistry described herein. DCE has
been frequently used in metathesis transformations in com-
bination with the Ru catalysts shown in Figures 13,4 includ-
ing reactions performed under microwave conditions.5-17
Because of its comparatively low microwave absorptivity
(loss tangent tanδ 0.123),32 a significant amount of micro-
wave energy is required to heat the reaction mixture. In
addition to investigating the potential role of wall effects, this
allowed us to concurrently evaluate the influence of selective
heating/activation of the polar Ru catalysts by microwave
irradiation, and thus the involvement of nonthermal micro-
wave effects.9,11,12,18 Since we anticipated that many of the
planned experiments would have to be performed under
open vessel reflux conditions in order to volatilize the formed
ethylene from the reaction mixture (see below), the atmos-
pheric boiling point of 83 °C for DCE appeared well suited
for these studies.
mation). In agreement with previously published results28,29
we find that apart from the desired RCM product 3, sub-
stantial amounts (20-25%) of oligomerization/cyclodimeri-
zation products 4/5 are also produced. It should be noted
that the formation of these byproducts is reversible and can
be minimized by proper choice of experimental conditions
(see below).29,33
Microwave experiments were conducted in a CEM Dis-
cover single mode microwave reactor equipped with a fiber-
optic (FO) probe provided by the instrument manufacturer
for directly controlling and monitoring the internal reaction
temperature in a 10 mL sealed reaction vessel.34 Recent evi-
dence has demonstrated that in several instances the use of an
external infrared (IR) sensor, recording the surface tempera-
ture of the vessel, does not accurately reflect the genuine
reaction temperature inside the reaction vial and therefore
may lead to erroneous results.34,35 As the G I Ru catalyst 1a
provided the best results at room temperature and we deli-
berately wanted to use a system that would react to thermal
stress such as 1a,3,25 this catalyst was used for all subsequent
RCM reactions 2 f 3. Applying sealed vessel microwave
heating at an 83 °C set temperature under otherwise identical
conditions (0.02 M, Ar atmosphere) resulted in a much faster
conversion of the diene. By using 1.5 mol % of catalyst 1a, a
60% conversion to 3 was obtained after only 5 min of
irradiation (1 min ramp time, 4 min hold time at 83 °C).
No further improvement in conversion was experienced after
10 min or even 20 min of irradiation (Figure S2 in the Sup-
porting Information). As expected, lower catalyst loadings
furnished reduced conversions, but again no improvement
was seen by extending the reaction time. These results
suggested that either the catalyst essentially had decomposed
after 5 min, or that the metathesis system had reached an
equilibrium state. It should be emphasized that olefin me-
tathesis is essentially a fully reversible set of [2þ2] cyclo-
addition-cycloreversion equilibria, although in practice for
RCM complete reversibility is rare due to the release of
ethylene.29,33 In a sealed microwave vial, however, ethylene
cannot be removed from the equilibrium potentially leading
to unproductive metathetical exchange.33 Indeed, control ex-
periments have shown that benzodioxocin 3 when exposed to
ethylene and Ru catalysts 1a or 1b in a sealed reactor will
revert to diene 2 and oligomerization/cyclodimerization
products 4 and 5 (in particular under more concentrated
conditions).36
Comparing the performance of the Ru catalysts 1a-c at
room temperature at 1.5 mol % loading for the RCM 2 f 3
(Scheme 1, DCE, 0.02 M, Ar atmosphere) demonstrated that
all three catalysts operated with similar efficiency. For
example, a 53% conversion of the diene substrate to the
RCM product 3 was achieved with G I catalyst 1a after 3 h.
Slightly lower values were obtained for 1b (48%) and 1c
(43%). Longer exposure to the catalyst (24 h) only slightly in-
creased the conversion (Figure S1 in the Supporting Infor-
On the basis of these thoughts we next moved to an open
vessel microwave setup and an experimental protocol that
would ensure the complete volatilization of the formed ethyl-
ene gas. Reiser and co-workers have already demonstrated
in 2005 that the combination of microwave irradiation with
inert gas sparging (to remove ethylene from the equilibrium)
is a technique that can be successfully utilized to perform
challenging RCM transformations.8 For this purpose a
10 mL round-bottomed flask was attached to a reflux
condenser and placed in the cavity of a CEM Discover
€
(28) Konig, B.; Horn, C. Synlett 1996, 10.
(29) (a) Conrad, J. C.; Eelman, M. D.; Duarte Silva, J. A.; Monfette, S.;
Parnas, H. H.; Snelgrove, J. L.; Fogg, D. E. J. Am. Chem. Soc. 2007, 129,
1024. (b) Monfette, S.; Crane, A. K.; Duarte Silva, J. A.; Facey, G. A.; dos
Santos, E. N.; Araujo, M. H.; Fogg, D. E. Inorg. Chim. Acta 2010, 363, 481.
(30) Mamouni, R.; Soukri, M.; Lazar, S.; Akssira, M.; Guillaumet, G.
Tetrahedron Lett. 2004, 45, 2631.
(33) Monfette, S.; Fogg, D. E. Chem. Rev. 2009, 109, 3783.
(34) Hosseini, M.; Stiasni, N.; Barbieri, V.; Kappe, C. O. J. Org. Chem.
2007, 72, 1417.
(35) (a) Obermayer, D.; Kappe, C. O. Org. Biomol. Chem. 2010, 8, 114.
(b) Herrero, M. A.; Kremsner, J. M.; Kappe, C. O. J. Org. Chem. 2008,
73, 36.
(31) Maishal, T. K.; Sarkar, A. Synlett 2002, 1925.
(32) Solvents used for microwave synthesis can be classified as high (tan
δ > 0.5), medium (tan δ 0.1-0.5), and low microwave absorbing (tan δ<0.1).
For more details, see: Kappe, C. O.; Dallinger, D.; Murphree, S. S. Practical
Microwave Synthesis for Organic Chemists;Strategies, Instruments, and
Protocols; Wiley-VCH: Weinheim, Germany, 2009; Chapter 2.
(36) Suljanovic, A. Master Thesis, University of Graz, 2008.
J. Org. Chem. Vol. 75, No. 15, 2010 5281

Dallinger et al.
JOCArticle
period. As seen in Table 1, for low catalyst loadings (0.25
and 0.5 mol %) this pretreatment results in a significant re-
duction in metathesis activity, presumably as a result of
progressive catalyst decomposition. For higher catalyst
loadings (1.0 and 1.5 mol %) the effect is almost unnoticeable
as even after 15 min of catalyst preheating there appears to be
still enough active Ru catalyst present in the reaction mixture
to afford high levels of conversion in the metathesis event.
With these data on catalyst stability and an optimized
metathesis protocol in hand we ultimately performed com-
parison experiments between microwave and conventionally
heated RCM reactions 2 f 3 (Scheme 1). For this purpose
the complete open vessel reaction setup consisting of round-
bottomed flask, reflux condenser, gas sparging line, and FO
temperature sensor was moved from the microwave cavity
into a preheated oil bath placed on a conventional hot plate/
stirrer (Figure S3 in the Supporting Information). Using the
internal FO probe it was demonstrated that an oil bath
temperature of ∼180 °C leads to the same ramp time as
under microwave conditions, raising the temperature of the
5 mL reaction mixture from ambient conditions to 83 °C
within ∼50 s (Figure S4 in the Supporting Information). For
the actual RCM comparison experiments we have intentionally
used a suboptimal catalyst loading of only 0.5 mol % in order
to be able to detect any effect of increased catalyst decom-
position as a result of wall effects in the conventionally
heated experiment (cf. Table 1). To our surprise, the conver-
sion rates achieved by conventional heating at 83 °C;with
all other reaction parameters being the same;were virtually
identical for the corresponding microwave runs (Figure S5 in
the Supporting Information). When lower oil bath tempera-
tures were used (140 and 160 °C), the rate of the metathesis
reaction was slower during the first 1-2 min as a result of the
slower heating ramp to 83 °C, but finally reached nearly
the same conversion levels as the 180 °C bath temperature
experiments (see Figures S5 and S6 in the Supporting
Information). Therefore, despite an oil bath temperature
in the conventionally heated experiment of 180 °C, poten-
tially leading to a wall surface temperature nearly 100 °C
above the temperature of the reaction mixture of 83 °C, no
wall effects were evident. In fact, no apparent advantage of
performing this RCM transformation under microwave
dielectric heating compared to conductive heating was
observed and the HPLC-UV traces obtained from the
crude reaction mixtures of both types of heating experi-
ments were virtually identical (see Figure S7 in the Support-
ing Information).
FIGURE 2. Conversion over time for the ring-closing metathesis of
1,2-bis(allyloxy)benzene (2) to metathesis product 3 at different Ru
catalyst 1a concentrations (Scheme 1). Conditions: DCE (0.02 M),
open vessel microwave heating (150 W constant power), 83 °C
reflux, Ar sparging. HPLC peak area percent (215 nm).
microwave system. Inert gas sparging was provided by a
gentle Ar stream through a glass capillary fitted through the
reflux condenser. In addition, the flask contained a magnetic
stir bar and a fiber-optic (FO) temperature probe immersed
into the reaction mixture (5 mL) (see the Experimental
Section and Figure S3 in the Supporting Information for
further details). Microwave experiments were performed in
constant power mode under reflux conditions and magnetic
stirring, monitoring the temperature of the reaction mixture
by the FO sensor. A constant magnetron power of 150 W
resulted in a heating ramp of ∼55 s to achieve reflux
temperature (83 °C) and also ensured a steady reflux of the
reaction mixture for the duration of the experiment.
The RCM reaction 2 f 3 shown in Scheme 1 (DCE,
0.02 M) was investigated under reflux conditions at 83 °C
with Ru catalyst 1a, using four different catalyst loadings:
0.25, 0.375, 0.5, and 1.0 mol %. As can be seen in Figure 2,
conversions compared to the sealed vessel experiments
(Figure S2 in the Supporting Information) were markedly
increased, with 85% conversion attained after 5 min with
1 mol % catalyst loading. Similar to the sealed vessel experi-
ments, however, after 3 min very little further improvements
in conversions were seen, suggesting complete catalyst de-
composition after this period. While in the initial phases of
the metathesis event the reaction mixture contained consid-
erable quantities of oligomerization and cyclodimerization
products 4 and 5, after 5 min the amount of the ADMET
product 4 was reduced to 3%, clearly demonstrating the
reversible nature of these Ru-catalyzed metathesis events
(Table S1 in the Supporting Information). The amount of
cyclodimerization product 5 could be minimized to ∼9% by
executing the RCM under more dilute conditions at 0.01 M
diene concentration. Using these carefully optimized condi-
tions (MW, 83 °C, 5 min, Ar sparging, 1 mol % 1a, 0.01 M)
provided the desired 2,5-dihydro-1,6-benzodioxocin 3 in
85% isolated yield after chromatography, a marked im-
provement over the previously published methods.10,27-31
At this stage the stability of G I Ru catalyst 1a in DCE at
the reaction temperature of 83 °C was evaluated. For this
purpose, samples of the catalyst were heated without sub-
strate in DCE under reaction conditions with microwave
irradiation for 5, 10, or 15 min, before adding the diene sub-
strate 2 and continued heating for an additional 5 min
We hypothesized that the catalyst amount utilized in the
RCM transformation 2 f 3 (Scheme 1) was possibly too low
in order to detect any effect of catalyst decomposition on the
hot reactor surface. Therefore, an even more demanding
RCM reaction involving the formation of a tetrasubstituted
double bond within an eight-membered-ring system was
considered. The formation of tetrasubstituted double bonds
is one of the most challenging transformations for Ru-based
olefin metathesis catalysts.3,4 This transformation typically
requires the application of second-generation-type catalysts
and high loadings.37 For ease of preparation and based
(37) (a) Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.; Grubbs,
R. H.; Schrodi, Y. Org. Lett. 2007, 9, 1589. (b) Clavier, H.; Nolan, S. P.
Chem.;Eur. J. 2007, 13, 8029. (c) Michrowska, A.; Bujok, R.; Harutyunan,
S.; Sashuk, V.; Dolgonos, G.; Grela, K. J. Am. Chem. Soc. 2004, 126, 9318.
5282 J. Org. Chem. Vol. 75, No. 15, 2010

Dallinger et al.
JOCArticle
TABLE 1. Effect of Catalyst Preheating on Conversion in the
Ring-Closing Metathesis of 1,2-Bis(allyloxy)benzene (2) (Scheme 1)a
catalyst loading 1a
(mol %)
preheating time
(min)
reaction time
(min)
conv
(%)b
0.25
0.25
0.25
0.25
0.5
0.5
0.5
0.5
1.0
1.0
1.0
1.0
1.5
0
5
10
15
0
5
5
5
5
5
5
5
5
5
5
5
5
5
5
46
20
11
7
74
62
58
47
83
83
82
80
85
85
5
10
15
0
5
10
15
10
15
1.5
FIGURE 3. Conversion over time for the ring-closing metathesis of
1,2-bis(2-methylallyloxy)benzene (6) to RCM product 7 at different
catalyst (1b) concentrations (Scheme 2). Conditions: DCE (0.02 M),
83 °C reflux, open vessel microwave heating (MW, 150 W constant
power) or oil bath heating (CONV, 180 °C bath temperature), Ar
sparging. HPLC peak area percent (215 nm).
aConditions: DCE (0.02 M), open vessel microwave heating (150 W
constant power), 83 °C reflux, Ar sparging. bHPLC-UV peak area
percent (215 nm). Overall conversion to metathesis product 3.
SCHEME 2. Ring-Closing Metathesis of 1,2-Bis(2-methylallyloxy)-
benzene (6)
due to unproductive metathetical exchange (Figure S8 in the
Supporting Information).33
To achieve complete conversion of diene 6 in the RCM, the
portionwise addition of catalyst 1b was evaluated.8 Adding an
additional amount of 10 mol % of 1b after 1 h open vessel-gas
sparging conditions at 83 °C (20 mol % in total, 0.02 M diene
concentration), complete conversion was achieved after an
additional 1 h heating period (Figure S9 in the Supporting
Information). From this experiment, the desired RCM pro-
duct benzodioxocin 7 was isolated after chromatography in
71% yield. Applying a 5 þ 5 mol % catalyst addition cycle
provided 87% overall conversion after 2 h. The fact that the
conversion following this stepwise regime is significantly high-
er compared to the experiment where 10 mol % of catalyst was
added in the beginning (64%) clearly points to catalyst decom-
position as being the limiting factor in this difficult RCM
reaction (Figure S9 in the Supporting Information).
Comparison experiments between microwave heating and
conventional heating were conducted as described above for
our first model reaction (Scheme 1) using open vessel-gas
sparging conditions and a 180 °C oil bath temperature to
mimic the heating profile obtained under microwave condi-
tions. As demonstrated in Figure 3, using carefully con-
trolled reaction conditions no difference between meta-
thesis experiments performed under microwave conditions
and in an oil bath could be detected, regardless if a 1.5, 5, or
10 mol % quantity of Ru catalyst 1b was employed. It
therefore appears that the putative hot reactor wall in the
oil bath experiment does not play any significant role in the
thermal decomposition of the metathesis catalyst (or of
intermediates in the catalytic cycle),38 and that direct in-core
microwave heating, conversely, cannot extend catalyst life-
time. Thus, no evidence for the existence of previously sug-
gested wall effects was seen in these elevated temperature
metathesis reactions.5,7,14,17 The results described herein are
on the apparent similarity with our first model system
(Scheme 1), we have decided to investigate the RCM reac-
tion of 1,2-bis(2-methylallyloxy)benzene (6) with the three
Ru-based catalysts 1a-c applying our optimized open
vessel-gas sparging conditions at elevated temperature
(Scheme 2). To the best of our knowledge, this RCM process
has never been reported in the literature.
Applying open vessel-gas sparging conditions with micro-
wave irradiation at 83 °C in DCE, the performance of
catalysts 1a-c was evaluated. In agreement with previous
studies,3,4,37 we found that the G I Ru system 1a exhibits
almost no activity in this exceedingly difficult RCM reaction
(Figure S8 in the Supporting Information). Both the G II
catalyst 1b and the HG II system 1c show significant activity
and by using 10 mol % of 1b diene conversions up to 64%
could be achieved after 2 h. Regardless of the catalyst loading
(1.5, 5, or 10 mol %), by using 1b as a metathesis catalyst a
plateau is reached in the conversion after ∼1 h with very little
progress being made after that period. It is interesting to note
that the HG II system 1c is evidently more stable than G II
catalyst 1b since even after 1 h of irradiation, metathesis
conversion still increases with Ru catalyst 1c, although the
overall level of conversion is lower compared to G II catalyst
1b (Figure S8 in the Supporting Information). This behavior
is related to the fact that in HG II catalyst 1c initiation
requires breakage of the comparatively strong Ru-O chela-
tion as a first step. Therefore, this catalyst is initialized much
more slowly than 1b and does need a high temperature to
reach a reasonable amount of activity.4 For our evaluation of
wall effects we have therefore selected the “less stable” Ru
catalyst 1b. Not surprisingly, conversions are significantly
lower when this reaction is performed under sealed vessel
conditions (∼25% with 10 mol % 1b), and little progress in
the metathesis event is made after the first 20 min probably
(38) We noted, however, that the deposition of Ru metal on the vessel
walls at the end of the metathesis reactions was significantly more prominent
in conventionally heated experiments as compared to the microwave runs
(confirmed by ICP-MS measurements). This phenomenon, while not having
any influence on the rate of the RCM transformations, is under further
investigation in our laboratories.
J. Org. Chem. Vol. 75, No. 15, 2010 5283

Dallinger et al.
JOCArticle
in agreement with recent studies reported from our labo-
ratory utilizing reaction vessels made out of strongly micro-
wave-absorbing silicon carbide (SiC) in microwave-assisted
transformations.39 Using this technique the occurrence of
wall effects has to be expected since the SiC ceramic will heat
rapidly and will transfer the heat by standard conductive
mechanisms to the reaction mixture. However, for virtually
all studied cases, including transition metal-catalyzed trans-
formations, no significant difference in conversion, yield, or
product purity was seen comparing microwave chemistry
performed in SiC vials with experiments conducted in stan-
dard Pyrex vessels at the same reaction temperature.39 This is
also in line with other microwave/oil bath comparison
studies involving metal-catalyzed transformations recently
performed in our laboratories.40
SCHEME 3. Ni- and Co-Catalyzed [2þ2þ2] Cyclotrimerization
Reactions
Since the metathesis reactions were performed with 150 W
of constant power and the chosen solvent DCE is only
moderately microwave absorbing, it is also evident that the
electromagnetic field does not exert any nonthermal micro-
wave9,12 or “activation/reenergizing”11 effects on the Ru
catalyst in solution, or influences the catalytic cycle or the
metathesis events in any other way than involving changes in
the bulk reaction temperature.
Ni- and Co-Catalyzed [2þ2þ2] Cyclotrimerizations. Dur-
ing the past few decades the transition metal-catalyzed
[2þ2þ2] cyclotrimerization reaction of alkynes and other
reaction partners has emerged as an efficient method for the
synthesis of carbo- and heterocyclic structures, including
applications in total synthesis.41 The classical [2þ2þ2] cyclo-
trimerization reaction involves the reaction of three alkynes
or two alkynes and a nitrile to form benzenes or pyridines.
Such reactions are typically conducted under homogeneous
Co, Ni, Ru, and Rh catalysis, although other transition
metals have been used as well.41 It is assumed that in the
first steps of the cyclotrimerization reaction two alkyne
molecules sequentially displace two ligand molecules (often
CO) from the metal center. The resulting π complex rear-
ranges to produce a reactive metallocyclopentene intermedi-
ate that subsequently adds the remaining alkyne (or nitrile)
to ultimately produce a six-membered aromatic ring.41 Since
2006, an increasing number of reports have advocated
the use of microwave heating for these transition metal-
catalyzed processes, generally providing improved yields in
shorter reaction times.42-46 In some instances, control ex-
periments performed by conductive heating at the same
monitored temperature were reported to result in much
lower conversions/product yields,43-46 and in other cases
provided no product at all.45,46
Evaluating the published examples,42-46 we initially hypo-
thesized that the reported enhancements seen in micro-
wave-assisted [2þ2þ2] cyclotrimerization chemistry, rather
than being the result of nonthermal microwave effects,46
could be due to the minimization of wall effects using direct
in-core microwave heating, leading to enhanced catalyst
lifetimes. To elucidate the role of microwave irradiation in
these [2þ2þ2] cyclotrimerizations in more detail we decided
to reinvestigate three recently published examples, where the
reported differences between sealed vessel microwave and
conventional heating at the same temperature were most
prominent (Scheme 3). To accurately compare the results
obtained by direct sealed vessel microwave heating with the
outcome of a conventionally heated reaction at the same
temperature we have used a sealed 10 mL Pyrex vial in
combination with a CEM Discover microwave system that
allows us to perform both types of transformations in the
identical reaction vessel and to monitor the internal reaction
temperature in both experiments directly with a FO probe
device.34 This system has the advantage that the same
reaction vessel and the same method of temperature mea-
surement is used. In this way all parameters apart from the
mode of heating are identical and therefore a fair comparison
(39) Obermayer, D.; Gutmann, B.; Kappe, C. O. Angew. Chem., Int. Ed.
2009, 48, 8321.
(40) (a) Irfan, M.; Fuchs, M.; Glasnov, T. N.; Kappe, C. O. Chem.;Eur.
J. 2009, 15, 11608. (b) Irfan, M.; Petricci, E.; Glasnov, T. N.; Taddei, M.;
Kappe, C. O. Eur. J. Org. Chem. 2009, 1326. (c) Glasnov, T. N.; Findenig, S.;
Kappe, C. O. Chem.;Eur. J. 2009, 15, 1001. (d) Razzaq, T.; Kremsner,
J. M.; Kappe, C. O. J. Org. Chem. 2008, 73, 6321. (e) Prokopcova, H.; Kappe,
C. O. J. Org. Chem. 2007, 72, 4440.
(41) (a) Chopade, P. R.; Louie, J. Adv. Synth. Catal. 2006, 348, 2307.
(b) Gandon, V.; Aubert, C.; Malacria, M. Chem. Commun. 2006, 2009.
(c) Kotha, S.; Brahmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741.
(d) Yamamoto, Y. Curr. Org. Chem. 2005, 9, 503. (e) Nakamura, I.;
Yamamoto, Y. Chem. Rev. 2004, 104, 2127. (f) Saito, S.; Yamamoto, Y.
Chem. Rev. 2000, 100, 2901. (g) Shore, N. E. Chem. Rev. 1988, 88, 1081.
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M. Tetrahedron: Asymmetry 2006, 17, 3185. (b) Shanmugasundaram, M.;
Aguirre, A. L.; Leyva, M.; Quan, B.; Martinez, L. Tetrahedron Lett. 2007, 48,
7698. (c) Young, D. D.; Sripada, L.; Deiters, A. J. Comb. Chem. 2007, 9, 735.
(d) Zhou, Y.; Porco, J. A.; Snyder, J. K. J. Comb. Chem. 2007, 9, 393.
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(e) Turek, P.; Hocek, M.; Pohl, R.; Klepetarova, B.; Kotora, M. Eur. J. Org.
Chem. 2008, 3335. (f) McIver, A.; Young, D. D.; Deiters, A. Chem. Commun.
2008, 4750. (g) Teske, J. A.; Deiters, A. Org. Lett. 2008, 10, 2195. (h) Lin,
Y.-Y.;Tsai, S.-C.;Yu,S. J. J. Org. Chem. 2008, 73, 4920. (i) Jones, A. L.; Snyder,
J. K. J. Org. Chem. 2009, 74, 2907. (j) Geny, A.; Agenet, N.; Iannazzo, L.;
Malacria, M.; Aubert, C.; Gandon, V. Angew. Chem., Int. Ed. 2009, 48, 1810.
(43) (a) Sripada, L.; Teske, J. A.; Deiters, A. Org. Biomol. Chem. 2008, 6,
263. (b) Young, D. D.; Teske, J. A.; Deiters, A. Synthesis 2009, 3785.
(44) Zou, Y.; Young, D. D.; Cruz-Montanez, A.; Deiters, A. Org. Lett.
2008, 10, 4661.
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5284 J. Org. Chem. Vol. 75, No. 15, 2010

Dallinger et al.
JOCArticle
between microwave heating and thermal heating can be
made.34
The first model system (Scheme 3a) involved the [2þ2þ2]
cyclotrimerization of diethyl dipropargyl malonate (8) with
1-hexyne in toluene leading to the fused benzene 9. Using
10 mol % Ni(CO)2(PPh3)2 as a catalyst and 10 equiv of
1-hexyne, Teske and Deiters were able to achieve complete
conversion of 8 and a 78% isolated yield of product 9 within
only 2 min of microwave irradiation.45 These experiments
were conducted in power control mode with 300 W of
constant magnetron output power, leading to a continuous
temperature rise from 25 to 82 °C (IR sensor) within the
2 min duration of the experiment. Remarkably, repeating the
exact same experiment in an oil bath (82 °C final tempera-
ture, 92 °C bath temperature) for 2 min did not lead to any
cyclotrimerization product 9.45 Repeating the general ex-
perimental conditions reported by Teske and Deiters as close
as possible, but performing temperature-controlled micro-
wave experiments in combination with an internal FO sen-
sor, we were able to obtain comparable results. Using 300 W
of maximum magnetron power and a ∼3 min heating ramp
to 82 °C, followed by a 2 min hold time at 82 °C also provided
consistently complete conversion of diyne 8 (GC-MS) and
led to a 70% yield of cyclotrimerization product 9. The re-
asons for performing a temperature-controlled run rather
than a power-controlled experiment are related to the better
control of reaction temperature, which is an important factor
if accurate comparisons with conventionally heated experi-
ments are required.34,35 In this context, it should be empha-
sized that comparison studies between microwave and con-
ventional heating experiments should not only take the final
reaction temperature into account, but must also provide for
similar heating and cooling profiles. In particular for short
overall reaction times, the ramp time will become important.
In the present case, an appropriate adjustment of the utilized
maximum microwave power (300 W) led to a ramp time of
∼3 min in the microwave run, which was comparable to the
heating profile that could be achieved in an oil bath experi-
ment (Figure S10 in the Supporting Information). In our
hands, performing the cyclotrimerization reaction 8 f 9 with
conductive heating using the same 10 mL sealed Pyrex vessel
fitted with an internal FO probe, but immersing the complete
setup into a preheated oil bath led in essence to the same
result as using microwave heating: conversions of >99%
with an isolated yield of 61% of cyclotrimerization product
3 were achieved. Importantly, as shown in Figure S10
(Supporting Information) the reaction temperature profiles
for both the conventionally and the microwave heated
cyclotrimerizations were very similar.
FIGURE 4. Temperature profiles obtained with internal FO sen-
sors for conventionally (CONV) and microwave (MW) heated
[2þ2þ2] cyclotrimerizations of 1,2-dipropargylbenzene (10) with
propargyl alcohol in toluene (Scheme 3b). Conditions: 300 W
maximum microwave power, 120 °C set temperature; 135 °C oil
bath temperature.
wave power, which allowed ramping the temperature from
25 °C to the desired set temperature of 120 °C within 4 min.
This was followed by a 5 min hold time at 120 °C (total irradi-
ation time of 9 min), and a subsequent cooling step to 50 °C
within ∼5 min (overall processing time 14 min). For this ex-
periment standard cooling by compressed air in the micro-
wave instrument was switched off in order to match the
cooling obtained in the conventionally heated experiment
(Figure S11 in the Supporting Information). This protocol
consistently provided complete conversion of starting diyne
10 and led to a 64% isolated yield of 9,10-dihydroanthra-
cene 11. In our hands, control experiments with conduc-
tive heating in an oil bath following a similar temperature
profile (Figure S11 in the Supporting Information) also
led to complete GC-MS conversion and furnished a 67%
yield of 11.
To obtain further insights into the kinetics of this cyclo-
trimerization we have performed additional experiments
evaluating the progress of the reaction after only 5 min over-
all reaction time. To our surprise, under these conditions the
conventionally heated cyclotrimerization went to complete
conversion, whereas the microwave heated run furnished only
18% conversion. A further reduction of the reaction time to
4 min provided a similar situation: 56% conversion for the
conventionally heated experiment and 11% conversion for
the microwave heated run. Based on a careful evaluation of
the temperature-time histories for these experiments we be-
lieve that these results are a consequence of the fact that the
heating of 4 mL of toluene in an oil bath to 120 °C is actually
faster than applying microwave heating (Figure 4). Since
toluene is a low-absorbing solvent (tanδ 0.040),32 microwave
dielectric heating to 120 °C in a 300 W single-mode reactor is
not particularly efficient.47 Integration of the reaction tem-
perature profiles obtained with internal FO probes shown in
Figure 4 revealed that the average temperature during the
ramp time period (0-4 min) is significantly higher in the oil
bath experiment (94 °C) as compared to the microwave run
(79 °C). Therefore, the higher conversions with conventional
heating are not surprising.
Since a reaction time of 2 min is not well suited for an
accurate kinetic study comparing microwave and conven-
tional heating, the Ni-catalyzed [2þ2þ2] cyclotrimerization
of 1,2-dipropargylbenzene (10) with propargyl alcohol was
selected as a more appropriate example (Scheme 3b). Deiters
and coworkes have reported that using 10 mol % of Ni(CO)2-
(PPh3)2 catalyst and 10 equiv of propargyl alcohol a 66%
yield of 9,10-dihydroanthracene 11 was obtained after 10 min
of microwave heating in toluene at 120 °C.44 Applying con-
ventional heating under otherwise identical conditions furn-
ished only 35% of the target compound 11.44 Again, for
comparison purposes, a temperature-controlled microwave
experiment was performed applying 300 W of initial micro-
(47) Robinson, J.; Kingman, S.; Irvine, D.; Licence, P.; Smith, A.;
Dimitrakis, G.; Obermayer, D.; Kappe, C. O. Phys. Chem. Chem. Phys.
2010, 12, 4750.
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Dallinger et al.
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Since it appeared that the Ni-catalyzed [2þ2þ2] cyclo-
trimerization 10 f 11 is rather sensitive to temperature we
additionally evaluated this transformation at a lower reaction
temperature. At 100 °C the cyclotrimerization was exceed-
ingly slow, with only 5-15% conversion being observed after
5 min for both the conventionally and microwave heated
experiments. Prolongation of the reaction time to 10 or 20 min
at 100 °C did not lead to any improvement in conversion for
both modes of heating. To determine if catalyst decomposi-
tion has a role in these events we performed a microwave ex-
periment where the reaction mixture was first heated to 100 °C
for 10 min, followed immediately by heating to 120 °C for an
additional 10 min. Since the second heating step at the
optimum reaction temperature did not lead to any improve-
ment in conversion it can be assumed that the 10 min treat-
ment at 100 °C provided sufficient thermal energy to trigger a
deactivation of the Ni catalyst
As a final example in this series we studied the Co-
catalyzed [2þ2þ2] cyclotrimerization of diyne 10 with
benzonitrile leading to 9,10-dihydro-2-azaanthracene 12
(Scheme 3c). Using 120 °C reaction temperature for 20 min
intoluene, 10equiv of benzonitrile, and20 mol% CpCo(CO)2
as catalyst, Deiters and co-workers have reported an 87%
isolated yield of 2-azaanthracene 12 under microwave condi-
tions, compared to only 8% applying conventional heating.44
In our hands, this Co-catalyzed [2þ2þ2] cyclotrimerization
required 160 °C to lead to complete conversion within 20 min
under microwave conditions and furnished a 78% isolated
product yield of 12. Performing an oil bath experiment with a
similar temperature profile as in the microwave run (Figure
S12 in the Supporting Information) also gave full conversion
and a similar isolated product yield (75%). At a temperature
of 150 °C, for example, the level of conversion for both types
of experiments was significantly lower, but in the same range
(62% microwave versus 59% oil bath).
Therefore, for all three examples of [2þ2þ2] cyclotrimeri-
zations studied herein (Scheme 3), it is evident that micro-
wave heated experiments;within experimental error;will
give the same results as conventionally heated experiments
provided that similar temperature-time histories are rea-
lized for both types of heating modes. For the comparatively
short overall reaction times of these [2þ2þ2] cyclotrimeriza-
tions it is essential to not only take the final reaction
temperature into account when comparing different heating
modes, but also to match heating and cooling profiles as
close as possible. As demonstrated for the Ni-catalyzed
[2þ2þ2] cyclotrimerization of 1,2-dipropargylbenzene (10)
with propargyl alcohol (Scheme 3b), a mismatch in the
heating ramp can lead to significant differences in product
distribution, in particular if the reaction is sensitive to minor
changes in reaction temperature. We believe that previous
claims to the observations of apparent microwave enhance-
ments in these transformations are due to inaccurate tem-
perature measurements, in particular to the use of external
IR sensors.43-46
chemistry. It can be argued that the elimination of such wall
effects by direct in-core microwave heating can increase the
lifetime of catalysts or other temperature-sensitive species in
the reaction mixture and therefore may lead to better con-
versions in a microwave heated as compared to a conduc-
tively heated process. In this paper we have presented a
detailed investigation of the putative role and existence of
wall effects in conventionally and microwave heated Ru-
catalyzed ring-closing metathesis and Ni- and Co-catalyzed
[2þ2þ2] cyclotrimerizations. These synthetically valuable
processes were chosen as model transformations since sev-
eral previous reports have found significant rate and yield
enhancements when these reactions were performed with
microwave heating compared to the results obtained in an oil
bath at the same measured reaction temperature. In our
hands, carefully conducted control experiments for challen-
ging ring-closing metathesis reactions and [2þ2þ2] cyclo-
trimerizations revealed that in all cases the results obtained
with microwave irradiation could be reproduced also with
conventional heating. The lifetime and activity of the transi-
tion metal catalysts was not influenced in any way by the
heating mode, clearly demonstrating the absence of any
specific or nonthermal microwave effects, and also revealing
no apparent involvement of wall effects. Of critical impor-
tance for our control experiments was the use of internal
fiber-optic probes as accurate temperature measurement
devices in both the microwave and the conventionally heated
reactors, and a careful matching of not only the final reac-
tion temperatures and times but also of heating and cool-
ing ramps. For reactions lasting only a few minutes, the
temperature-time history during the heating and cooling
stages will be important and must be carefully matched in
order to obtain valid results. We suspect that in the previously
published studies referred to herein, the claimed differences
between microwave and conventional heating were the result
of inaccurate temperature measurements often using exter-
nal IR temperature probes, in addition to the fact that other
important process parameters such as stirring rate or vessel
geometry were most likely not properly considered. On the
basis of the results presented herein it appears that the often
suggested ability of a hot reactor wall to trigger unwanted
thermal side reactions for well-agitated small scale organic
reaction mixtures of low viscosity needs to be reconsidered.
Correspondingly, the notion that microwave heating will
have a significant advantage over conventional heating in
minimizing or eliminating these wall effects needs to be
reevaluated.
Experimental Section
Microwave Irradiation Experiments. All microwave irradia-
tion experiments described herein were performed with a single-
mode Discover Labmate System from CEM Corporation, using
either a standard cylindrical Pyrex vessel for sealed vessel proces-
sing (capacity 10 mL) or a 10 mL Pyrex round-bottomed flask for
open vessel reflux chemistry. Experiments were performed with
temperature control mode (sealed vessel processing) or in con-
stant power mode (open vessel reflux processing). In all experi-
ments the internal reaction temperature was monitored by a FO
probe sensor as previously reported.34 Conventional heating was
performed with a standard hot plate/magnetic stirrer, using a
diethylene glycol bath.34,35 All relevant comparison experiments
were repeated at least three times in order to guarantee statistical
Conclusion
The elimination of a hot reactor surface common to
conductive heat transfer principles using external heating
sources has often been stated as being one of the key advan-
tages of using microwave technology in synthetic organic
5286 J. Org. Chem. Vol. 75, No. 15, 2010

Dallinger et al.
JOCArticle
relevance. The given values of conversion in the text refer to the
mean value of typically three experiments.
(>98% HPLC at 215 nm) from more concentrated metathesis
experiments (0.30 M for 4; 0.09 M for 5) with use of G I catalyst
1a.36 Data for linear dimer 4: colorless solid, mp 84 °C. 1H NMR
(300 MHz, CDCl3) δ 6.91 (s, 8H), 6.05-6.12 (m, 4H), 5.43(d, J =
14.4 Hz, 2H), 5.29 (d, J = 10.8, 2H), 4.61-4.65 (m, 8H). 13C
NMR (90MHz, CDCl3) δ 148.5, 133.5, 128.6, 121.3, 117.5, 114.4,
76.6, 69.9. MS-EI m/z 352 (Mþ). Cyclodimer 5: colorless solid,
mp 145-158 °C. 1H NMR (300 MHz, CDCl3) δ 6.94-6.96
(m, 8H), 6.17 (m, 4H), 4.62 (m, 8H). 13C NMR (90 MHz, CDCl3)
δ 149.7, 128.4, 122.2, 116.9, 70.3. MS-EI m/z 324 (Mþ). The
spectroscopic data of these materials were in agreement with
published values.28,29
[2þ2þ2] Cyclotrimerization Reaction of Diethyl Dipropargyl
Malonate (8) with 1-Hexyne (Scheme 3a). To a flame-dried
10 mL CEM microwave process vial equipped with a stir bar were
added diethyl dipropargyl malonate (8)51 (12 mg, 0.05 mmol)
and anhydrous toluene (2 mL). The vial was purged with Ar for
10 min before 1-hexyne (58 μL, 0.50 mmol) and Ni(CO)2(PPh3)2
catalyst (3.20 mg, 0.005 mmol) were added. The reaction mix-
ture was purged again with Ar for 20 min before being sealed
tight by using the CEM Discover pressure/fiber-optic atten-
uator34 and was subsequently placed into the CEM Discover
microwave unit or a preheated oil bath (86 °C) to be heated for
5 min (Figure S10, Supporting Information, see main text for
details). After allowing the reaction mixture to cool to room
temperature, a 50 μL sample was transferred into a syringe, filte-
red via a syringe filter, diluted with EtOAc (1 mL), and subjected
to GC-MS analysis. For isolation, the crude reaction mixtures
from three experiments were pooled, concentrated under vacuo,
and purified by flash chromatography with hexanes/EtOAc as
eluent to provide 33.4 mg (70%, microwave) and 29 mg (61%,
oil bath), respectively, of pure diethyl 5-butyl-1H-indene-2,2-
dicarboxylate (9) as a colorless oil. 1H NMR (300 MHz, CDCl3)
δ 0.93 (t, J = 7.2 Hz, 3 H), 1.25 (t, J = 7.1 Hz, 6 H), 1.34 (m,
2 H), 1.58 (m, 2 H), 2.56 (t, J = 7.8 Hz, 2 H), 3.57 (s, 4 H), 4.20 (q,
J = 7.1 Hz, 4 H), 6.97 (d, J = 7.6 Hz, 1H), 7.01 (s, 1H), 7.08 (d,
J = 7.6 Hz, 1 H). 13C NMR (75 MHz, CDCl3) δ 13.9, 14.0, 22.4,
33.8, 35.5, 40.1, 40.4, 60.6, 61.6, 123.8, 124.1, 127.1, 137.1, 140.0,
141.7, 171.8. The spectral data are in agreement with the
previously published values.52
Ring-Closing Metathesis Reactions under Open Vessel Condi-
tions: General Procedure. In an oven-dried 10 mL round-
bottomed flask equipped with a magnetic stir bar, 0.1 mmol of diene
starting material 248 or 6,49 respectively, was purged for 5 min
with Ar. Subsequently, the given amounts of Ru catalysts (stock
solution in DCE) in Figures 2 and 3 and Figures S1, S5, S8, and
S9 in the Supporting Information, respectively, and DCE (so
that a total volume of 5 mL is reached) were added. A reflux
condenser was attached, the fiber-optic probe and glass capil-
lary for Ar purging were immersed through the reflux condenser
into the solution (Figure S3, Supporting Information), and the
setup was placed in either the microwave instrument (irradiation
at 150 W constant power) or in a preheated oil bath for the times
specified in Figures 1 and 2 and Figures S1, S5, S8 and S9 in the
Supporting Information, respectively. For reaction monitoring
50 μL samples were taken with a glass capillary after the indi-
cated times (see Figures 2 and 3 and Figures S1, S5, S8, and S9 in
the Supporting Information) and diluted with 0.8 mL MeCN for
HPLC analysis.
2,5-Dihydrobenzo-1,6-dioxocin (3, Scheme 1). In an oven-
dried 25 mL round-bottomed flask equipped with a magnetic
stir bar, 28.5 mg (0.15 mmol) of diene 248 was purged for 5 min
with Ar. A 1 mol % sample of G I (600 μL of a 2 mM stock
solution in DCE) and 14.4 mL of DCE (total volume of 15 mL)
were added. A reflux condenser was attached, the fiber-optic
probe and glass capillary for Ar purging were immersed through
the reflux condenser into the solution, and the setup was placed
in the microwave instrument and irradiated at 150 W constant
power (FO temperature 83 °C) with Ar-sparging for 5 min. The
solvent was evaporated and the mixture was purified by silica gel
column chromatography (petroleum ether/ethyl acetate: 10/1)
to give 28 mg (85%) of RCM product 3 as a light yellow oil and
96% purity (HPLC at 215 nm). 1H NMR (300 MHz, DMSO-d6)
δ 6.95 (s, 4H), 5.88-5.91 (m, 2H), 4.86 (d, J = 4.3 Hz, 4H). 13C
NMR (90 MHz, CDCl3) δ 148.0, 129.4 123.7, 122.5, 70.1. MS-
EI m/z 162 (Mþ). The spectroscopic data of this material were in
agreement with published values.27
3,4-Dimethyl-2,5-dihydrobenzo-1,6-dioxocin (7, Scheme 2). In
an oven-dried 10 mL round-bottomed flask equipped with a
magnetic stir bar, 21.8 mg (0.1 mmol) of diene 649 was purged for
5 min with Ar. A 10 mol % sample of G II (1 mL of a 0.01 M
stock solution in DCE) and 4 mL of DCE (that a total volume of
5 mL is reached) were added. A reflux condenser was attached,
the fiber-optic probe and glass capillary for Ar purging were
immersed through the reflux condenser into the solution, and
the setup was placed in the microwave instrument and irradiated
at 150 W constant power (FO temperature 83 °C) with Ar-
sparging for 1 h. After cooling to 50 °C another 10 mol % of G II
was added and again heated at 150 W constant power with Ar-
sparging for 1 h. For isolation two experiments were combined
(total 0.2 mmol). The solvent was evaporated and the mixture
was purified by silica gel column chromatography (petroleum
ether/ethyl acetate: 15/1) to provide 27 mg (71%) of RCM
product 7 as a light yellow oil in 93% purity (HPLC at 215
nm). 1H NMR (300 MHz, DMSO-d6) δ 6.92 (s, 4H) 4.78 (s, 4H),
1.57 (s, 6H). MS-EI m/z 218 (Mþ). The spectroscopic data of this
material were in agreement with published values.50
[2þ2þ2] Cyclotrimerization Reaction of 1,2-Dipropargyl-
benzene (10) with Propargyl Alcohol (Scheme 3b). To a flame-
dried 10 mL CEM microwave process vial equipped with a stir bar
were added 1,2-dipropargylbenzene (10)53 (20 mg, 0.13 mmol)
and anhydrous toluene (4 mL). The vial was purged with Ar for
10 min before adding propargyl alcohol (77 μL, 1.3 mmol) and
Ni(CO)2(PPh3)2 catalyst (8.30 mg, 0.013 mmol). The reaction
mixture was purged again with Ar for 20 min before being sealed
tight by using the CEM Discover pressure/fiber-optic attenua-
tor34 and was subsequently placed into the CEM Discover
microwave unit or a preheated oil bath (135 °C) to be heated
for 10 min (Figure S11, Supporting Information; see main text
for details). After the reaction mixture was allowed to cool to
room temperature, a 50 μL sample was transferred into a syri-
nge, filtered via a syringe filter, diluted with EtOAc (1 mL), and
subjected to GC-MS analysis. For isolation, the crude reaction
mixtures from three experiments were pooled, concentrated
under vacuo, and purified by flash chromatography with hexanes/
EtOAc as eluent to provide 52 mg (64%, microwave) and
55 mg (67%, oil bath), respectively, of pure 9,10-dihydro-2-
(hydroxymethyl)anthracene (11) as a yellow solid. 1H NMR
(300 MHz, CDCl3) δ 1.59 (s, 1 H), 3.92 (s, 3 H), 4.65 (s, 2H), 7.16
1,4-Bis(2-(allyloxy)phenoxy)but-2-ene (4) and 6,9,16,19-Tetra-
hydrodibenzo[b,j][1,4,9,12]tetraoxacyclohexadecin (5, Scheme 1).
The known28,29 byproducts 4 and 5 were obtained in pure form
(48) Hayashida, M.; Ishizaki, M.; Hara, H. Chem. Pharm. Bull. 2006, 54,
1299.
(49) Deodhar, V. B.; Dalavoy, V. S.; Nayak, U. R. Org. Prep. Proced. Int.
1993, 25, 583.
(50) Schroth, W.; Kaufmann, W. Z. Chem. 1977, 17, 331.
(51) Eglinton, G.; Galbraith, A. R. J. Chem. Soc. 1959, 889.
(52) Saino, N.; Amemiya, F.; Tanabe, E.; Kase, K.; Okamoto, S. Org.
Lett. 2006, 8, 1439.
(53) Takahashi, T.; Li, S.; Huang, W. Y.; Kong, F. Z.; Nakajima, K.;
Shen, B. J.; Ohe, T.; Kanno, K. J. Org. Chem. 2006, 71, 7967.
J. Org. Chem. Vol. 75, No. 15, 2010 5287

Dallinger et al.
JOCArticle
(m, 3 H), 7.28 (m, 4 H). 13C NMR (75 MHz, CDCl3) δ 36.1, 36.4,
65.6, 125.1, 126.4, 126.9, 127.2, 127.6, 127.8, 136.5, 136.8, 137.3,
139.0, 142.8. The spectral data are in agreement with previously
published values.44 The product is unstable and will oxidize
easily to the aromatic anthracene product.44
and 75 mg (75%, oil bath) of pure 3-phenyl-5,10-dihydrobenzo-
isoquinoline (12) as yellow solid. 1H NMR (300 MHz, CDCl3)
δ 3.97 (m, 4H), 7.23 (m, 2H), 7.30 (m, 2H), 7.39 (d, J = 6.4 Hz,
1H), 7.46 (t, J = 7.6 Hz, 2H), 7.63 (s, 1H), 7.97 (d, J = 8.0 Hz,
2H), 8.59 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 32.7, 35.8,
119.4, 126.7, 126.8, 127.0, 127.9, 128.0, 128.8, 128.9, 131.1,
135.0, 135.6, 139.7, 146.5, 148.4, 155.6. The spectral data are
in agreement with previously published values.44 The product is
unstable and will oxidize easily to the aromatic aza-anthracene
product.44
[2þ2þ2] Cyclotrimerization Reaction of 1,2-Dipropargyl-
benzene (10) with Benzonitrile (Scheme 3c). To a flame-dried
10 mL CEM microwave process vial equipped with a stir bar
were added 1,2-dipropargylbenzene (10)53 (20 mg, 0.13 mmol),
benzonitrile (134 μL, 1.3 mmol), and anhydrous toluene (4 mL).
The capped vial was purged with Ar for 30 min before add-
ing CpCo(CO)2 catalyst (1.60 μL, 0.013 mmol). The reaction
vial was sealed tight by using the CEM Discover pressure/
fiber-optic attenuator34 and was subsequently placed into the CEM
Discover microwave unit or a preheated oil bath (180 °C) to be
heated for 20 min (Figure S12, Supporting Information; see the
main text for details). After the reaction mixture was allowed to
cool to room temperature, a 50 μL sample was transferred into a
syringe, filtered via a syringe filter, diluted with EtOAc (1 mL),
and subjected to GC-MS analysis. For isolation, the crude
reaction mixtures from three experiments were pooled, concen-
trated under vacuo, and purified by flash chromatography with
hexanes/EtOAc as eluent to provide 78 mg (78%, microwave)
Acknowledgment. This work was supported by a grant
from the Christian Doppler Research Society (CDG). M.I.
thanks the Higher Education Commission of Pakistan for
a Ph.D. scholarship. We also acknowledge Prof. Walter
€
Gossler (University of Graz) for performing ICP-MS
analyses.
Supporting Information Available: Description of general
experimental procedures, images, and heating profiles for all
reactions. This material is available free of charge via the
Internet at http://pubs.acs.org.
5288 J. Org. Chem. Vol. 75, No. 15, 2010