Microwave-assisted cross-coupling and hydrogenation chemistry by using heterogeneous transition-metal catalysts: An evaluation of the role of selective catalyst heating

Article abstract of DOI:10.1002/chem.200902044

The concept of specific microwave effects in solid/liquid catalytic processes resulting from the selective heating of a microwave-absorbing heterogeneous transition-metal catalyst by using 2.45 GHz microwave irradiation was evaluated. As model transformations Ni/C-, Cu/C-, Pd/C-, and Pd/ Al ₂O₃-catalyzed carbon-carbon/ carbon-heteroatom cross-couplings and hydrogenation reactions were investigated. To probe the existence of specific microwave effects by means of selective catalyst heating in these transformations, control experiments comparing microwave dielectric heating and conventional thermal heating at the same reaction temperature were performed. Although the supported metal catalysts were experimentally found to be strongly microwave absorbing, for all chemistry examples investigated herein no differences in reaction rate or selectivity between microwave and conventional heating experiments under carefully controlled conditions were observed. This was true also for reactions that use low-absorbing or microwave transparent solvents, and was independent of the microwave absorbtivity of the catalyst support material. In the case of hydrogenation reactions, the stirring speed was found to be a critical factor on the mass transfer between gas and liquid phase, influencing the rate of the hydrogenation in both microwave and conventionally heated experiments.

Full text of DOI:10.1002/chem.200902044

DOI: 10.1002/chem.200902044
Microwave-Assisted Cross-Coupling and Hydrogenation Chemistry by Using
Heterogeneous Transition-Metal Catalysts: An Evaluation of the Role of
Selective Catalyst Heating
Muhammed Irfan, Michael Fuchs, Toma N. Glasnov, and C. Oliver Kappe*[a]
Abstract: The concept of specific mi-
crowave effects in solid/liquid catalytic
processes resulting from the selective
heating of a microwave-absorbing het-
erogeneous transition-metal catalyst by
using 2.45 GHz microwave irradiation
was evaluated. As model transforma-
tions Ni/C-, Cu/C-, Pd/C-, and Pd/
ing microwave dielectric heating and
conventional thermal heating at the
same reaction temperature were per-
formed. Although the supported metal
catalysts were experimentally found to
be strongly microwave absorbing, for
all chemistry examples investigated
herein no differences in reaction rate
or selectivity between microwave and
conventional
heating
experiments
under carefully controlled conditions
were observed. This was true also for
reactions that use low-absorbing or mi-
crowave transparent solvents, and was
independent of the microwave absorb-
tivity of the catalyst support material.
In the case of hydrogenation reactions,
the stirring speed was found to be a
critical factor on the mass transfer be-
tween gas and liquid phase, influencing
the rate of the hydrogenation in both
microwave and conventionally heated
experiments.
Al2O3-catalyzed
carbon–carbon/
carbon–heteroatom cross-couplings and
hydrogenation reactions were investi-
gated. To probe the existence of specif-
ic microwave effects by means of selec-
tive catalyst heating in these transfor-
mations, control experiments compar-
Keywords: cross-coupling · hetero-
geneous catalysis · hydrogenations ·
mass
transfer
·
microwave
chemistry
Introduction
amples include the utilization of Pd/C,[5–7] Pd/SiO2,[8] PdEn-
Cat,[9] Pd/glass,[10,11] supported/stabilized Pd nanoparticles,[12]
Ni/C,[13] Ni/graphite,[14] Cu/C,[15] and other supported metal
species[16] in combination with microwave dielectric heating
for achieving highly efficient carbon–carbon and carbon–
heteroatom bond formation reactions. In addition, several
cases of microwave-enhanced hydrogenation reactions in-
volving Pd/C and related supported metal species have been
reported.[17,18]
However, the selective heating of metal (or other strongly
microwave absorbing) particles under microwave conditions
is a rather complex phenomenon depending strongly on the
type of support, particle size (surface-to-volume ratio), elec-
tromagnetic field strength (power density), and a variety of
other factors.[4,19] In heterogeneous gas-phase catalysis, the
rationale and advantages of using microwave irradiation to
selectively heat the often very strongly microwave absorbing
catalyst bed while the reactive gas—being inherently micro-
wave transparent—remains at a lower temperature are rea-
sonably well established.[20] In the case of solid/liquid trans-
formations, the genuine selective heating characteristics of
catalyst particles compared to the bulk reaction mixture and
the resulting influence on reaction rate and selectivity often
The use of microwave heating to perform chemical reactions
involving heterogeneous transition-metal catalysts is becom-
ing increasingly popular in the scientific community.[1–3] For
these transformations, the use of microwave heating appears
to be particularly attractive since heterogeneous supported
metal catalysts are generally strongly microwave absorb-
ing.[4] Therefore, selective heating of the heterogeneous cat-
alyst by microwave irradiation will occur under certain con-
ditions, which may result in differences in reaction rates and
selectivity relative to control experiments performed by
using conventional conductive heating at the same bulk tem-
perature (“specific microwave effects”).[5–18] Literature ex-
[a] M. Irfan, M. Fuchs, Dr. T. N. Glasnov, Prof. Dr. C. O. Kappe
Christian Doppler Laboratory for Microwave Chemistry (CDLMC)
and Institute of Chemistry, Karl-Franzens-University Graz
Heinrichstrasse 28, A-8010 Graz (Austria)
Fax : (+43)316-380-9840
E-mail: oliver.kappe@uni-graz.at
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902044.
11608
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 11608 – 11618

FULL PAPER
remain unclear.[5–18] In the present manuscript, we present a
critical reinvestigation of microwave-heated transition-
metal-catalyzed carbon–carbon/carbon–heteroatom cross-
coupling reactions and hydrogenation protocols, to elucidate
the role that microwave irradiation in conjunction with the
use of heterogeneous catalysts plays in these transforma-
tions.
wave-transparent dioxane[24] as the solvent, the chances to
observe selective heating of the metal catalyst appeared to
be high in these cases.
The starting point for the investigation of both transfor-
mations was to evaluate the microwave absorbtivity of the
involved catalysts. Both Ni/C and Cu/C were prepared ac-
cording to the detailed protocols reported by the Lipshutz
group starting from activated charcoal Darco KB-G and the
corresponding metal nitrate salts.[13,21] The loading of Ni and
Cu within the catalyst preparations was determined by ICP-
MS (inductively coupled plasma mass spectroscopy) analysis
to be 3.6% (w/w) for Ni and 8.1% (w/w) for Cu, respective-
ly. Similar to our recent studies involving Pd/C,[25] the micro-
wave absorbtivity of both catalysts in comparison to the
non-impregnated charcoal support was determined by sus-
pending samples of the solid materials in carbon tetrachlor-
ide as the microwave-transparent solvent and observing
bulk temperature changes on irradiation with constant mi-
crowave power. As can be seen in Figure 1, the Ni/C catalyst
Results and Discussion
Negishi and Ullmann-type cross-couplings by using Ni/C
and Cu/C catalysts: Our initial model transformations fo-
cused on cross-couplings that utilized Nickel-in-Charcoal
(Ni/C) and Copper-in-Charcoal (Cu/C) as heterogeneous
catalysts. In recent years, Lipshutz and co-workers have pub-
lished extensively on the use of these (and related) inexpen-
sive base metal heterogeneous catalysts to perform very effi-
cient microwave-assisted, for example, Ni-catalyzed Suzuki,
Negishi, and Kumada carbon–carbon cross-couplings,[13] Cu-
catalyzed azide-alkyne cycloadditions[21], and Ullmann-type
diarylether formations,[15] in addition to Ni-catalyzed amina-
tion, and reduction processes.[13] Importantly, compared to
previous studies by the same group employing conventional
heating in an oil bath dating back to the late 1990s,[22] the re-
action times for most of these transformations could be re-
duced from several hours to a few minutes by using sealed-
vessel microwave processing.[13–15,21] Choosing the Negishi
cross-coupling of aryl chloride 1 with organozinc reagent 2
as our first model reaction (Scheme 1a) we wanted to see if
the dramatic rate enhancement on going from 16 h employ-
ing oil-bath heating at 608C,[23] to 15 min under microwave
conditions at 1508C[13] was due to selective heating of the
strongly microwave-absorbing Ni/C catalyst (see below), or
could be rationalized by a simple thermal effect as a result
of the significantly higher reaction temperature.[24] As a
second example, we have selected the Cu/C-promoted Ull-
mann-type diaryl ether formation involving aryl bromide 4
and phenol 5 (Scheme 1b). According to Lipshutz and co-
workers, full conversion and a 86% yield of diaryl ether 6
can be obtained under microwave conditions at 1808C for
30 min (no data for conventional heating were provided).[15]
Since both cross-couplings were performed by using micro-
Figure 1. Microwave heating profiles for 100 mg samples of Ni/C, Cu/C,
and charcoal (C) suspended in CCl4 (2.0 mL) in a 10 mL quartz reaction
vessel at constant 150 W magnetron output power (single-mode reactor,
fiber-optic temperature measurement).
proved to be a significantly stronger microwave absorber
than untreated charcoal, whereas the Cu/C catalyst surpris-
ingly showed reduced microwave absorbtivity. It can be as-
sumed that the temperature of
the metal catalysts under these
conditions, at least for Ni/C,
must, therefore, be significant-
ly higher than the monitored
bulk mixture temperature.[25]
At this point, it needs to be
emphasized that the species in-
itially present in the charcoal
matrix in both catalysts pre-
pared by impregnation of Ni-
ACHUTNGERNU(NG NO3)2 or CuAHCTUNGTRENN(GUN NO3)2 and subse-
quent thermal treatment likely
Scheme 1. The Negishi and Ullmann-type cross-coupling as a model reaction.[13,15]
involve NiII and CuII oxides, re-
Chem. Eur. J. 2009, 15, 11608 – 11618
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11609

C. O. Kappe et al.
spectively.[21,22] For many of the subsequent cross-coupling
transformations, in particular for reactions involving Ni/C, a
reduction step to a zero-valent metal prior to coupling is re-
quired.[13,21,22,26,27]
the runs was achieved. Evaluating GC-FID conversions at
shorter time intervals (5 and 10 min) also did not provide
any indication of significant differences in reaction rate or
selectivities between the two heating modes.
To accurately compare the results obtained by direct mi-
crowave heating with the outcome of a conventionally
heated reaction at the same temperature we have used a re-
actor system that allows us to perform both types of trans-
formations in an identical reaction vessel and to monitor the
internal reaction temperature in both experiments directly
with a fiber-optic probe device.[28] This system has the ad-
vantage that the same reaction vessel and the same method
of temperature measurement is used. In this way, all param-
eters apart from the mode of heating are identical and,
therefore, a fair comparison between microwave heating
and thermal heating can be made. For the Negishi cross-cou-
pling reaction shown in Scheme 1a, the literature protocol
published by Lipshutz and co-workers was followed as close-
ly as possible.[13] In the event, 8.1 mol% of the Ni/C catalyst
and 30 mol% of triphenylphosphine ligand were suspended
in anhydrous dioxane. The NiII/C precatalyst was subse-
quently activated by addition of excess nBuLi in hexane, fol-
lowed by addition of the two coupling partners 1 and 2. For
the preparation of the organozinc reagent 2 we have devel-
oped a microwave modification of a recent general zincation
protocol reported by the Knochel group describing the in-
sertion of Zn dust into 4-iodotoluene in the presence of an-
hydrous LiCl in THF.[29,30] Applying sealed-vessel microwave
heating at 1508C, a reaction time of 30 min was sufficient to
achieve full conversion as monitored by GC-FID analysis.
The subsequent microwave-assisted Negishi cross-cou-
pling (Scheme 1a) was performed at 1508C (internal temper-
ature measurement) within 15 min hold time (~5 bar pres-
sure). This protocol consistently (three repetitions) led to
GC-FID conversions of ~96% (Æ1%) and provided a 93%
isolated product yield of biphenyl 3, in good agreement with
the results published by Lipshutz (94%).[13] For the control
experiments involving conventional heat transfer, the reac-
tor setup was immersed into an oil bath preheated to an ap-
propriate temperature to ensure an internal reaction tem-
perature of ~1508C. As already previously noted,[31] it has
to be emphasized that comparison studies between micro-
wave and conventional heating experiments must not only
take the final reaction temperature into account, but must
also provide for similar heating and cooling profiles. In par-
ticular, for short overall reaction times, the ramp time will
become important. In the present case, appropriate adjust-
ment of the utilized microwave power (27 W for 1 min and
10 W for 4 min initial microwave power) led to a ramp time
of ~5 min in the microwave run, which was comparable to
the heating profile experienced in the oil-bath experiment
(see Figure S1 in the Supporting Information). Interestingly,
the results for the conventionally heated Negishi cross-cou-
plings displayed no significant differences compared to the
microwave runs performed at the same temperature of
1508C. Conversions of 93% (Æ4%, three repetitions) with
an isolated yield of 87% of biphenyl product 3 from one of
Since the comparatively short reaction time of 15 min and
the complex processing nature of the Negishi cross-coupling
protocol—involving the initial independent preparation of
organozinc species 2 and a preactivation of the Ni/C cata-
lyst—was not ideal for a more detailed kinetic comparison
study between microwave and conventional heating, we
have selected the Ullmann-type diaryl ether formation
shown in Scheme 1b as a second example.[15] Here, activa-
tion of the Cu/C catalyst is not required and the two cou-
pling partners are commercially available. Again, the pub-
lished protocol was followed as closely as possible, applying
3.8 mol% of the Cu/C catalyst, 0.5 equivalents of 1,10-phe-
nanthroline ligand, 1.0 equivalent of phenol 5, and 1.5 equiv-
alents of aryl bromide 4.[15] Preliminary optimization experi-
ments indicated that high conversion levels to diaryl ether 6
could also be obtained at 1508C (instead of 1808C)[15] within
30 min, which made the transformation more practical for
the planned comparison studies. Similar to the case with the
Negishi cross-coupling discussed above, the heating profiles
for microwave and oil-bath runs were matched by applying
suitable microwave power levels and oil-bath temperatures,
respectively (see Figure S2 in the Supporting Information).
As shown in Table 1, the results obtained by microwave and
oil-bath heating experiments were virtually identical, clearly
indicating the absence of any “specific microwave effect” as
a result of selective catalyst heating.
Despite the fact that both transformations were per-
formed in a microwave transparent solvent and the data pre-
sented in Figure 1 provide clear evidence that at least one of
the catalysts (Ni/C) is strongly microwave absorbing, we
conclude that the rate enhancements seen in transforma-
Table 1. Comparison of microwave heating and conventional heating for
the Ullmann-type diaryl ether formation of aryl bromide 4 with phenol 5
(Scheme 1b).[a]
t[b] [min]
Heating method[c] ((150Æ4)8C)
Conversion[d] [%]
5
MW
49/44/43
conventional
MW
conventional
MW
conventional
MW
conventional
50/46/47
57/58/57
59/58/59
69/74/76
10
20
30
72/74/72
81/86/87 (81)[e]
84/84/85 (76)[e]
[a] Phenol 5 (1.0 mmol), aryl bromide 4 (1.5 equiv), 1,10-phenanthroline
(0.5 equiv), dioxane (2 mL), Cu/C (3.8 mol%). Microwave experiments
were carried out by using a CEM Discover system with a 10 mL fiber-
optic probe setup. Conventionally heated experiments were performed in
a preheated oil bath by selecting an appropriate bath temperature (see
Figure S2 in the Supporting Information). For further information see the
Experimental Section. [b] Fixed hold time, the ramp times were similar
(~6 min) for both heating modes (see Figure S2 in the Supporting Infor-
mation). [c] Internal reaction temperature measured by fiber-optic
sensor. [d] Determined by GC-MS analysis (peak area% of diaryl ether
6). Entries reflect multiple experiments. For a graphical representation,
see Figure S3 in the Supporting Information. [e] Isolated yields.
11610
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 11608 – 11618

Microwave-Assisted Cross-Coupling and Hydrogenation Chemistry
FULL PAPER
tions of this type[13–15,21] are essentially the result of a stan-
dard thermal effect, switching from reflux conditions to a
sealed-vessel microwave experiment at significantly higher
temperatures. As with other related examples recently in-
vestigated in our laboratories,[25,31] we ascribe the absence of
a “specific microwave effect” in these cases to the fact that
although the heterogeneous metal catalyst itself can be a
strongly microwave absorbing material when irradiated
under suitable conditions (Figure 1),[25] for the actual reac-
tion mixtures containing several other microwave-absorbing
components (substrates, ligand, additives, bases) any effect
derived from selective heating of the comparatively small
quantities of heterogeneous metal catalyst will be masked.
In addition, it should be emphasized that for both reactions
discussed in Scheme 1, experimental evidence suggests that
the actual catalytic process is of a homogeneous rather than
heterogeneous nature, involving soluble catalytic species of
Ni and Cu leaching from the charcoal support.[15,26]
temperature and/or flow of the external cooling gas, experi-
ments can be performed in which at constant bulk reaction
temperatures distinctly different microwave power levels
can be applied. We speculated that the previously observed
effects[6] could have been due to a “selective heating” of the
Pd/C catalyst by utilizing the simultaneous cooling condi-
tions.
Applying our reactor setup equipped with a fiber-optic in-
ternal temperature probe as described above and by follow-
ing as closely as possible the conditions reported in the orig-
inal reference[6] we have reproduced the Suzuki–Miyaura
coupling shown in Scheme 2. A Pd/C catalyst specifically op-
timized for cross-coupling chemistry was employed (E 104
CA/W 5% Pd), which is characterized by a high Pd disper-
sion, a low reduction degree, and a high water content.[37]
As described by Arvela and Leadbeater,[6] we found that ap-
plying 1 mol% of Pd/C catalyst, 1.3 equiv of boronic acid 8,
3.7 equiv of sodium carbonate base, and 1 equivalent of tet-
rabutylammonium bromide (TBAB) as additive provided
optimum results leading to the highest conversions. By using
a moderate 8 W of initial maximum magnetron output
power to ramp the temperature to the desired 1208C within
3-4 min (see Figure S4 in the Supporting Information), fol-
lowed by a 5 min hold time at 1208C consistently provided
GC-FID conversions to biaryl 9 in the region of 80-90%,
with only small amounts of starting material 7 (~10%) and
biphenyl homocoupling product (<3%) being observed
(Table 2, entry 1). These results were comparable to the
data published previously by Arvela and Leadbeater em-
ploying a slightly longer overall reaction time (10 min).[6] In-
creasing the initial maximum magnetron output power to
25 W shortened the ramp time to 1 min (overall irradiation
time 6 min), but otherwise did not change the outcome of
these coupling reactions (Table 2, entry 2). Although a con-
siderably higher amount of microwave power was applied
by using the simultaneous cooling method to reach and
maintain the same bulk temperature of 1208C (20 versus
7.6 W average power, see Figure S5 in the Supporting Infor-
mation), the results in our hands both in terms of conversion
and selectivity were more or less identical to the noncooled
runs (Table 2, entry 3). In fact, this outcome is in line with
more recent work published by the Leadbeater group, dem-
onstrating that simultaneous cooling in this cross-coupling
reaction is not required when working on a larger scale.[38]
Ultimately, the Suzuki–Miyaura cross-coupling was also per-
formed by using conventional heating, again matching heat-
ing profiles carefully by choosing an appropriate oil-bath
temperature (see Figure S4 in the Supporting Information).
As can be seen from the data presented in Table 2 (entry 4),
it appears that a “specific mi-
Suzuki cross-couplings by using Pd/C and Pd/Al2O3 cata-
lysts: As an alternative example to the Ni and Cu-catalyzed
carbon–carbon and carbon–heteroatom bond-formation re-
actions discussed above (Scheme 1) we next turned our at-
tention to Pd-catalyzed Suzuki–Miyaura biaryl couplings[32]
that involve heterogeneous Pd catalysts. A plethora of ex-
amples of Suzuki–Miyaura cross-couplings utilizing different
forms of immobilized Pd catalysts have been reported,[33]
and in many cases the benefits of performing these process-
es by utilizing microwave heating—typically reducing reac-
tion times from hours to a few minutes—have been empha-
sized in the literature.[3,5–12] The specific example chosen for
our investigations discussed herein involved the cross-cou-
pling of aryl chloride 7 with phenylboronic acid (8) in the
presence of Pd/C under aqueous conditions (Scheme 2).
This Suzuki–Miyaura cross-coupling was chosen since work
by Arvela and Leadbeater published in 2005 has shown that
microwave irradiation in conjunction with simultaneous
cooling of the reaction mixture by compressed air—under
otherwise identical reaction conditions (1208C, 10 min)—led
to a markedly improved product yield (91% versus 60%)
relative to normal microwave heating.[6] Under “simultane-
ous cooling” conditions, the reaction vessel is cooled from
the outside by compressed air while being irradiated by mi-
crowaves.[34] This generally allows a higher level of micro-
wave power to be directly administered to the reaction mix-
ture thereby potentially enhancing any specific microwave
effects that are dependent on the electric field
strength.[6,9a,17,28,34–36] By monitoring internal reaction tem-
peratures with fiber-optic probes and carefully adjusting the
crowave effect” of any kind is
not in operation here. By in-
spection of GC-FID traces that
compare the crude reaction
mixture composition, no signif-
icant differences in conversion
or selectivities between runs
Scheme 2. The Suzuki–Miyaura cross-coupling as a model reaction.[6]
Chem. Eur. J. 2009, 15, 11608 – 11618
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11611

C. O. Kappe et al.
Table 2. Comparison of microwave heating and conventional heating for
the Suzuki–Miyaura cross-coupling of aryl chloride 7 with boronic acid 8
(Scheme 2).[a]
Entry Catalyst T [8C]/t [min] Heating method[b] Conversion[c] [%]
lyst, an increased reaction temperature of 140–1508C and an
extended reaction time of 20 min was required. Applying
the originally optimized 1208C/5 min conditions a moderate
~38% conversion was obtained by using both microwave
and oil-bath heating (Table 2, entries 5 and 6). Gratifyingly,
at 1508C, a 92% conversion was achieved under microwave
conditions (entry 7), closely matched by an 85% conversion
under oil-bath conditions when applying similar heating pro-
files (entry 8; see Figure S7 in the Supporting Information).
Therefore, it appears that for the Suzuki–Miyaura cross-
coupling shown in Scheme 2, which utilizes a heterogeneous
Pd catalyst with a microwave-transparent support, selective
heating of the transition metal is either not observed or has
no influence on reaction rate and selectivity. Given the fact
that here the reaction medium (H2O, Na2CO3, TBAB) is
strongly microwave absorbing—as evidenced by the compa-
ratively low microwave power required for heating (Fig-
ure S5)—this is perhaps not surprising. In addition, it should
be emphasized that as with the Ni/C and Cu/C chemistry de-
scribed above (Scheme 1), there is substantial evidence in
the literature that transition-metal-catalyzed cross-coupling
reactions that utilize Pd/C as a catalyst do in fact involve ho-
mogeneous Pd species.[37,40,41] The insoluble Pd/C catalyst
acts as a reservoir of soluble, active Pd species, generated
under the reaction conditions by chemical interaction of the
catalyst with one or more of the components of the liquid
phase.[40,41] Thus, although the used metal catalyst is of a het-
erogeneous nature, it is not clear if selective heating of the
catalyst by microwave irradiation can have an influence on
a subsequent reaction step occurring in solution phase. The
results obtained herein are in agreement with our recent
work on Heck–Mizoroki couplings catalyzed by Pd/C.[31]
1
2
3
4
5
6
7
8
Pd/C
Pd/C
Pd/C
Pd/C
Pd/Al2O3 120/5
Pd/Al2O3 120/5
Pd/Al2O3 150/20
Pd/Al2O3 150/20
120/5
120/5
120/5
120/5
MW (8 W)
MW (25 W)
MW (sim. cooling) 86
conventional
MW (8 W)
conventional
MW (12 W)
conventional
87/87/85/84 (80)[d]
83
87/90/83/81 (82)[d]
37/38/40
38/37/35
92
85
[a] Aryl chloride
7 (1.0 mmol), phenylboronic acid (8) (1.3 equiv),
Na2CO3 (3.7 equiv), TBAB (1.0 equiv), Pd/C (1 mol%, 5% w/w) or Pd/
Al2O3 (1 mol%, 10% w/w) catalyst, H2O (2 mL). Microwave experi-
ments were carried out by using a CEM Discover system with a 10 mL
fiber-optic probe setup. Conventionally heated experiments were per-
formed in a preheated oil bath by selecting an appropriate bath tempera-
ture (see Figures S4, S5, and S7 in the Supporting Information). For fur-
ther information see the Experimental Section. [b] The maximum nomi-
nal magnetron microwave power is given in parentheses. [c] Determined
by GC-FID analysis (peak area% of biphenyl 9). Entries reflect multiple
experiments (where appropriate). [d] Isolated yields.
performed in an oil bath or under microwave conditions
(with or without simultaneous cooling) were seen (see
ACHTUNGTRENNUNGFigure S6 in the Supporting Information). Isolated yields in
the range of 80% were also comparable.
At this stage, we considered the use of a different support
material for the Pd-metal catalyst. Since charcoal itself is a
strongly microwave-absorbing material (Figure 1),[39] most of
the microwave energy absorbed by the solid catalyst (Ni/C,
Cu/C, Pd/C) may in fact be absorbed by the support and not
by the metal impregnated on the support. Therefore, we re-
peated the Suzuki–Miyaura cross-coupling shown in
Scheme 2 by utilizing Pd/Al2O3 as a heterogeneous cata-
lyst,[8b] with Al2O3 being essentially microwave transparent
(tan d=0.006604).[4b,18f] A comparison of heating profiles
under microwave conditions for Pd/C and Pd/Al2O3 con-
firmed that Pd/C is a far better microwave absorber than
Pd/Al2O3 (Figure 2). To achieve high conversions for the
Suzuki–Miyaura cross-coupling with 1 mol% Pd/Al2O3 cata-
Hydrogenation reactions by using Pd/C and Pd/Al2O3 cata-
lysts: At this point, it became evident that in the cross-cou-
pling chemistry examples described above in Schemes 1
and 2, specific microwave effects by selective heating of the
heterogeneous catalysts do not play a role, because 1) there
were generally too many other microwave absorbing species
present in the reaction mixture masking any “superheating”
of the catalyst and/or 2) since the mechanism of these cross-
couplings is likely to be of a homogeneous nature; therefore,
the rate-determining step may occur in solution phase and
not on the surface of the microwave absorbing catalyst.
Therefore, we considered hydrogenation reactions as almost
ideal model transformations to study the role of specific mi-
crowave effects resulting from selective catalyst heating. Hy-
drogenations involving molecular hydrogen and a heteroge-
neous precious-metal catalysts are genuinely heterogeneous
in nature, with the hydrogenation step occurring at the sur-
face of the heterogeneous catalyst.[42] Since microwave-
transparent hydrogen is the only required reagent and the
solvent can often be of an unpolar—low microwave absorb-
ing—nature, the hydrogenation of standard olefins appeared
to be an ideal model reaction to evaluate the occurrence of
specific microwave effects and the role of selective catalyst
heating. In fact, recently published work by Vanier compar-
Figure 2. Microwave heating profiles for 100 mg samples of Pd/C (10%
w/w) and Pd/Al2O3 (10% w/w) suspended in CCl4 (2.0 mL) in a 10 mL
quartz reaction vessel at constant 150 W magnetron output power
(single-mode reactor, fiber-optic temperature measurement).
11612
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 11608 – 11618

Microwave-Assisted Cross-Coupling and Hydrogenation Chemistry
FULL PAPER
Table 3. Comparison of microwave heating and conventional heating in
dependence on the stirring speed for the hydrogenation of (E,E)-1,4-di-
phenyl-1,3,-butadiene (Scheme 3).[a]
ing conventional and microwave-heated hydrogenations cat-
alyzed by Pd/C for a variety of substrates has indicated a
special role that microwave irradiation plays in these pro-
cesses (apart from heating).[17] Applying otherwise identical
reaction conditions (solvent, time, temperature, hydrogen
pressure), significant differences in conversions between
conventionally heated and microwave-irradiated hydrogena-
tions with Pd/C were reported.[17] To gain further insight
into the potential involvement of selective heating effects in
these heterogeneous hydrogenations, we have reinvestigated
two of the examples described in the original reference.
Our first case study involved the hydrogenation of diene
10 to the saturated butane 11 employing low-absorbing
ethyl acetate (tan d=0.059)[24] as the solvent and a standard
10% Pd/C catalyst (Scheme 3). By using an 808C reaction
Entry
Heating
Stirring rate
Conversion/selectivity[c] [%]
10/11/12
method[b]
1
2
MW
MW
–
low
26/51/23
1/80/19
3
4
5
6
7
8
9
10
MW
MW
medium
high
–
0/>99/0
0/>99/0
36/43/21
22/57/21
17/60/23
11/66/23
1/84/15
conventional
conventional
conventional
conventional
conventional
conventional
100
200
400
800
1200
0/>99/0
[a] Diene 10 (0.5 mmol), Pd (1 mol%, 10% Pd/C), H2 (4 bar), 808C,
EtOAc (2 mL), 20 W maximum magnetron output power. [b] Microwave
experiments were carried out by using a CEM Discover system with a
10 mL fiber-optic probe setup in conjunction with a gas-loading system.
Conventionally heated experiments were performed by using the same
setup in a preheated oil bath by selecting an appropriate bath tempera-
ture (see Figure S8 in the Supporting Information). For further informa-
tion see the Experimental Section. [c] Product composition analyzed by
GC-FID (peak area%). Entries reflect the median values of three ex-
periments (s.d. Æ5%).
Scheme 3. Hydrogenation of (E,E)-1,4-diphenyl-1,3-butadiene (10).[17]
temperature, 50 psi (3.5 bar) hydrogen pressure and
a
ensure statistical relevance. For the microwave experiments,
the four available stirring levels on the single-mode reactor
(off, low, medium, high)[44] were compared to a range of stir-
ring speeds (0–1200 rpm) available on the magnetic stirrer/
hotplate used to heat the oil bath for the conventionally
heated runs. As can be clearly seen, stirring plays a domi-
nant role on these hydrogenations. Without stirring, compa-
ratively moderate conversions were experienced for both
the microwave (74%, entry 1) and the oil-bath runs (64%,
entry 5). Going to higher stirring speeds consistently im-
proved conversions in both heating modes. It should be par-
ticularly emphasized that full conversion to the desired
butane 11 was also obtained in a conventionally heated ex-
periment (Table 3, entry 10). The perhaps surprisingly large
influence that the stirring speed exerts on the outcome of
these hydrogenations[45] can be interpreted as a classic exam-
ple of mass-transfer limitation, as hydrogen contained in the
top part of the reaction vial (headspace) needs to diffuse to
the liquid phase in the bottom part in which the catalytic
process occurs and hydrogen is consumed.[46] Increased stir-
ring influences the gas–liquid interfacial area and thus ef-
fects the hydrogenation rate, which is a known phenomenon
in hydrogenation chemistry.[46] From a chemical engineering
standpoint it is apparent, that the 10 mL cylindrical tube
used for most microwave experiments in single-mode reac-
tors today, in particular, in combination with a comparative-
ly ineffective magnetic stirring system, is not an ideal reac-
tor for gaseous transformations of this type.
1 mol% Pd catalyst loading, Vanier has reported full conver-
sion to 11 in the microwave run, relative to only 55% by ap-
plying conventional heating in a preheated oil bath after a
5 min reaction time (hold time). The temperature profiles
were carefully matched by using a fiber-optic probe setup to
ensure the validity of the results.[17]
We have repeated the hydrogenation of diene 10 by fol-
lowing the conditions reported by Vanier as close a possible,
by using the identical pre-pressurized single-mode micro-
wave reactor setup fitted with an internal fiber-optic temper-
ature probe.[17,18c] The progress of the hydrogenation could
be nicely followed online by monitoring the hydrogen pres-
sure decrease in the sealed-vessel experiments and offline
by GC-FID monitoring. Indeed, in the first trials, we have
observed that the microwave experiments at 808C provided
complete conversion to butane 11 (97% isolated yield),
whereas in the conventionally heated runs that utilize a pre-
heated oil bath at the same internal temperature and apply
a very similar temperature profile (see Figure S8 in the Sup-
porting Information) the conversions were significantly
lower (70-80%). In addition, the formation of a partially hy-
drogenated product 12,[43] not mentioned in the original
study,[17] was also observed. These experiments were repeat-
ed numerous times but the results essentially remained un-
changed.
After considerable experimentation and variations of con-
ditions we realized that the stirring speed applied in both
types of heating experiments plays a critical role on the out-
come of the hydrogenation processes. A systematic analysis
of the stirring speed on the hydrogenation of diene 10 under
both microwave and oil-bath conditions is presented in
Table 3, with each experiment being repeated three times to
Following the arguments made above for the Suzuki–
Miyaura cross-coupling we have additionally evaluated the
use of a Pd/Al2O3 catalyst for the hydrogenation of diene
10. The results were almost identical to those observed for
Pd/C, with no indication of any selective heating effects on
Chem. Eur. J. 2009, 15, 11608 – 11618
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11613

C. O. Kappe et al.
the Pd-metal catalyst (see Table S1 in the Supporting Infor-
mation).
As the stirring speeds in the microwave reactor are un-
known,[44] it is not possible to directly correlate the results
obtained under microwave conditions with the conversions
seen in the oil-bath experiments. In our opinion, however, it
is evident that stirring plays a dominant role in these hydro-
genations and it, therefore, appears likely that the previous-
ly observed differences between conventionally and micro-
wave heated hydrogenations of
As a final example in this investigation we have looked at
the more challenging hydrogenation of cholesterol (13) to
cholestanol (14) (Scheme 4),[47] since in this case a dramatic
difference between the microwave hydrogenation compared
to the oil-bath run was reported by Vanier.[17] While under
diene 10 and cholesterol
(13)[17] were in fact due to dif-
ferent stirring speeds in the
two sets of heating experi-
ments, rather than to a selec-
tive heating effect of the cata-
lyst.
Scheme 4. Hydrogenation of cholesterol (13).[17]
To confirm if—in addition to
the effect of stirring—selective
heating of the Pd/C catalyst by
microwave conditions with simultaneous cooling full conver-
sion was obtained, the conventional hydrogenation employ-
ing otherwise identical reaction conditions produced only
3% product.[17] In our hands, the major effect that magnetic
stirring plays in these transformations again became imme-
diately evident (Table 4). As in the case of diene 10, we
found that full conversion to the reduced product 14 at
808C and 4 bar H2 pressure could also be achieved by em-
ploying conventional heating with an appropriate stirring
speed that ensures adequate mass transfer of H2 from the
gas to the liquid phase. Interestingly, in this case, in which
only one equivalent of H2 is required, the conversions after
5 min without stirring were very low (<10%) for both heat-
ing modes (Table 4, entries 1 and 5). Note that in our hands
microwave experiments with a high stirring rate led to full
conversion without the necessity to utilize the simultaneous
cooling option (Table 4, entry 4).
microwave irradiation plays any role in this transformation,
an experiment that utilizes simultaneous cooling (see
above)[34–36] of the reaction mixture was performed. By using
the microwave-assisted hydrogenation of diene 10 under
“low” stirring conditions leading to an incomplete conver-
sion as a reference (Table 3, entry 2), the same experiment
was repeated with simultaneous cooling at the same 808C
internal reaction temperature by using compressed air. In
contrast to the standard microwave experiment, this allowed
a considerably higher amount of microwave power to be de-
livered to the reaction mixture and the Pd/C catalyst (55
versus 20 W, see Figure S10). However, the outcome of the
hydrogenation was more or less identical with only minor
changes (<5%) in conversion/selectivity being observed.
The involvement of any significant contribution of selective
heating of the Pd/C catalyst in these hydrogenation reac-
tions therefore seems unlikely.
In a final set of experiments both olefinic substrates 10
and 13 were also hydrogenated over a Pd/C catalyst in a
continuous flow high pressure/high temperature hydrogena-
tion device (H-Cube).[48] Employing 808C and a substrate
concentration of 0.1m in ethyl acetate full conversions were
achieved up to a flow rate of 0.5 mLminÀ1, which resulted in
near quantitative isolated product yields (see Experimental
Section for details).
To support the hypothesis that selective heating of the
generally strongly microwave-absorbing Pd catalysts does
not play a major role in the kinetics of the hydrogenations
shown in Schemes 3 and 4 we have additionally studied the
morphology of the catalysts exposed to microwave irradia-
tion and conventional heating by SEM. Strong superheating
of the conducting Pd particles on the catalyst surface by in-
teraction with a microwave field to temperatures above the
measured bulk temperatures of 808C may be evidenced by
modifications of either the Pd species present on the support
and/or a catalyst surface restructuring of the heterogeneous
catalyst particles (sintering).[8b,12b,18e,49] In the case of the hy-
drogenation reactions of diene 10 at 808C bulk temperature
no detectable changes in the morphology of the used cat-
Table 4. Comparison of microwave heating and conventional heating in
dependence on the stirring speed for the hydrogenation of cholesterol
(13) (Scheme 4).[a]
Entry
Heating method[b]
Stirring rate
Conversion[c] [%]
1
2
MW
MW
–
low
9
95
3
4
5
6
7
8
9
10
MW
MW
medium
high
0
94
>99
5
49
89
93
97
>99
conventional
conventional
conventional
conventional
conventional
conventional
100
200
400
800
1200
[a] Cholesterol (13) (0.5 mmol), Pd (1 mol%, 10% Pd/C), H2 (4 bar),
808C, EtOAc (2 mL), 20 W maximum magnetron output power. [b] Mi-
crowave experiments were carried out by using a CEM Discover system
with a 10 mL fiber-optic probe setup in conjunction with a gas-loading
system. Conventionally heated experiments were performed by using the
same setup in a preheated oil bath by selecting an appropriate bath tem-
perature (see Figure S9 in the Supporting Information). For further infor-
mation see the Experimental Section. [c] Conversion analyzed by GC-
FID (peak area%). Entries reflect the median values of three experi-
ments (s.d. Æ4%).
11614
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 11608 – 11618

Microwave-Assisted Cross-Coupling and Hydrogenation Chemistry
FULL PAPER
mospheric pressure chemical ionization (APCI) in positive or negative
mode. GC-FID analysis was performed on a Trace-GC (ThermoFisher)
ACHTUNGTRENNUNGalyst particles were seen for both Pd/C and Pd/Al2O3 when
comparing microwave and oil-bath conditions. Even for cat-
alyst samples exposed to high levels of microwave power in
a microwave transparent medium (as in Figure 2) no differ-
ences in particle morphology to catalysts exposed to conven-
tional heating were seen (see Figures S11 and S12 in the
Supporting Information).
with
a flame ionization detector by using a HP5 column (30 mꢁ
0.250 mmꢁ0.025 mm). After 1 min at 508C, the temperature was in-
creased in 258CminÀ1 steps up to 3008C and kept at 3008C for 4 min.
The detector gas for the flame ionization is H2 and compressed air (5.0
quality). GC-MS spectra were recorded by using a Thermo Focus GC
coupled with a Thermo DSQ II (EI, 70 eV). A HP5-MS column (30 m ꢁ
0.250 mm
ꢁ 0.025 mm) was used with helium as the carrier gas
(1 mLminÀ1 constant flow). The injector temperature was set to 2808C.
After 1 min at 508C, the temperature was increased in 258CminÀ1 steps
up to 3008C and kept at 3008C for 4 min.
Conclusion
Microwave irradiation experiments were generally carried out in a CEM
Discover instrument with appropriate internal fiber-optic temperature
control by using 10 mL Pyrex vials.[28] Zinc insertion reactions were car-
ried out in a Emrys Optimizer EXP (Biotage AB, Uppsala, Sweden).
Flow hydrogenations were performed in an H-Cube from Thales Nano-
technology (Budapest, Hungary).[48] Flash chromatography separations
were performed on a Biotage SP1 instrument by using petroleum ether/
ethyl acetate mixtures as the eluent. All products synthesized in this
study are known in the literature and have been identified and character-
In summary, we have performed a critical investigation of
several transition-metal-catalyzed carbon–carbon/carbon–
heteroatom cross-coupling protocols and hydrogenation re-
actions carried out by microwave heating employing strong-
ly microwave-absorbing heterogeneous catalysts. Employing
a suitable reactor equipped with internal fiber-optic temper-
ature probes, comparison studies between microwave and
conventional heating at the same reaction temperature were
performed, which demonstrated that essentially no differen-
ces between the two heating modes existed. Anticipated
changes in reactivity and/or selectivity resulting from selec-
tive heating of the generally strongly microwave absorbing
catalysts (“specific microwave effects”) were not seen. We
ascribe this to the fact that although the heterogeneous
metal catalyst itself can be a strongly microwave absorbing
material when irradiated under suitable conditions, for the
actual reaction mixtures typically containing several other
microwave-absorbing components (solvent, substrates,
ligand, additives, bases) any effect derived from selective
heating of the comparatively small quantities of heterogene-
ous metal catalyst will be masked, even when using a low-
absorbing solvent, such as ethyl acetate. In general, the se-
lective heating of solid-metal catalysts under microwave
conditions is a rather complex phenomenon depending
strongly on the type of support, particle size (surface-to-
volume ratio), electromagnetic field strength (power densi-
ty), and a variety of other factors. More research is there-
fore required to ascertain under what conditions microwave-
induced selective heating effects in metal-catalyzed solid–
liquid reactions can be exploited for organic synthesis.
1
ized by H NMR spectroscopy and MS analysis. Ni/C[13] and Cu/C[15] were
prepared according to literature protocols from activated charcoal Darco
KB-G (Aldrich, catalog no. 675326). 5% Pd/C (E 104 CA/W 5% Pd, cat-
alog no. 643181–10G), 10% Pd/C (catalog no. 205699–10G) and 10% Pd/
Al2O3 (catalog no. 76000–10G) were also obtained from Aldrich. For the
insertion reaction zinc dust from Strem (catalog no. 93–3060, 325 mesh)
was used. All other chemicals were obtained from Aldrich, Acros Organ-
ics, or Alfa Aesar and used as received.
Preparation of 4-tolyl-zinc iodide: Zinc dust (817 mg, 12.5 mmol) and an-
hydrous LiCl (211 mg, 5 mmol) were placed into a flame-dried, argon-
purged 10 mL Biotage microwave process vial. The vial was capped and
dry THF (1.5 mL) was added. The slurry was stirred and 1,2-dibromo-
ethane (0.03 mL, 2.18 mg, 0.35 mmol) was added through the septum.
The reaction mixture was heated until ebullition. Subsequently, trimethyl-
chlorosilane (0.01 mL, 8.58 mg, 0.08 mmol) was added and the mixture
was again heated until ebullition (in some cases heating was not necessa-
ry because ebullition started spontaneously). In the next step, 4-iodoto-
luene (545 mg, 2.5 mmol) was dissolved in dry THF (1.0 mL) and added
to the reaction mixture. The sealed microwave vial was placed into an
Emrys Optimizer EXP microwave reactor and subjected to microwave ir-
radiation at 1508C for 30 min (pre-stirring 30 s, sample absorption:
normal). After the microwave irradiation was completed, the remaining
zinc dust was allowed to sediment and a sample was taken, hydrolyzed,
and subjected to GC-FID analysis (in every case the conversion was
>97%). The remaining solution was taken up into a syringe and used for
the subsequent Negishi reaction.
Negishi coupling of aryl chloride 1 with 4-tolyl-zinc iodide (Scheme 1a):
Under a positive argonflow, Ni/C (135 mg, 8.2 mol%, 3.6% Ni/C loading
(w/w), 0.082 mmol Ni) and triphenylphosphine (70 mg, 0.27 mmol) were
put into a flame-dried, argon-purged 10 mL CEM microwave process
vial. The vial was capped with a Teflon-coated septum and an alumina
crimp, dry 1,4-dioxane (1.0 mL) was added by a cannula and syringe and
the reaction mixture was stirred for 20 min. n-Butyllithium (0.06 mL,
2.5m in hexane, 0.15 mmol) was added dropwise and the reaction mixture
was stirred for another 5 min. The vial was opened and under a positive
argon flow 4-chlorobenzonitrile (1) (137 mg, 1.0 mmol) and 4-tolyl-zinc
chloride (2) (1.0m in dry THF, 1.5 mL, 1.5 mmol, see above) were added
and the vial sealed tight by using the CEM Discover pressure/fiber-optic
attenuator[28] and placed into the CEM discover microwave unit or a pre-
heated oil bath to be heated under the following conditions (see Fig-
ure S1 in the Supporting Information): 1) Microwave: 1 min 27 W maxi-
mum microwave power, 4 min 10 W maximum microwave power, and
15 min 17 W of maximum microwave power with a set temperature of
1508C. Stirring was set at high. 2) Oil bath: The oil-bath temperature was
set to 1908C and stirring was set to 400 rpm. The vial assembly was put
into the oil bath for 20 min, which included 5 min for an inner tempera-
ture of 1508C to be reached. This temperature remained constant
Additionally, we have observed that for hydrogenation re-
actions agitation plays a major role in controlling mass
transfer from the gas to the liquid phase, and therefore sig-
nificantly influences the rate of hydrogenation. Careful at-
tention must thus be given to the stirring rate in microwave-
assisted hydrogenations, in particular when comparisons
with conventionally heated experiments are performed.
Experimental Section
General remarks: 1H NMR spectra were recorded on a Bruker 300 MHz
instrument. 13C NMR spectra were recorded on the same instrument at
75 MHz. Chemical shifts (d) are expressed in ppm downfield from TMS
as internal standard. The letters s, d, t, q, and m are used to indicate sin-
glet, doublet, triplet, quadruplet, and multiplet. Low-resolution mass
spectra were obtained on an Agilent 1100 LC/MS instrument by using at-
Chem. Eur. J. 2009, 15, 11608 – 11618
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11615

C. O. Kappe et al.
(Æ28C) for the following 15 min (hold time). After the reaction mixture
was cooled down to ambient temperature, a 100 mL sample was trans-
ferred into a syringe, filtered by using a syringe filter, diluted with
EtOAc (1 mL) and subjected to GC-MS analysis. For the purpose of iso-
lation, the reaction mixture was filtered through a pad of Celite that was
then washed with EtOAc (50 mL). The organic phase was washed with
an aqueous H2O2 solution (10 wt%, 50 mL). The phases were separated,
the aqueous phase was re-extracted with EtOAc (20 mL), and the com-
bined organic phases were dried over Mg2SO4. The solvent was evaporat-
ed and the obtained residue was taken up in a small amount of EtOAc
and transferred to a silica-samplet, which was then dried for 2 h at 708C.
Subsequent automated silica-gel flash chromatography with petroleum
ether/EtOAc (0 to 40% gradient) as the eluent gives diaryl 3 as a pale-
opened and the contents poured into a separation funnel. Water (30 mL)
and ethyl acetate (30 mL) were added and the organic material extracted
and removed. After further extraction of the aqueous layer with ethyl
acetate, combining the organic washings and drying them over MgSO4,
the solvent was removed under reduced pressure, leaving the crude
biaryl product 9. The product was purified and isolated by chromatogra-
phy with hexane/ethyl acetate as eluent to provide the pure substance.
1
M.p. 878C (lit.[50] 87–888C); H NMR (300 MHz, CDCl3): d=3.87 (s, 3H;
OCH3), 6.99 (d, J=8.8 Hz, 2H; aromatic), 7.34 (t, J=7.4 Hz, 1H; aro-
matic), 7.43 (t, J=7.7 Hz, 2H; aromatic), 7.54–7.59 ppm (m, 4H; aromat-
ic); MS (pos. APCI): m/z (%): 184 (100) [M+1]+.
Hydrogenation of diene 10 and cholesterol (13) (Schemes 3 and 4,
Tables 3 and 4): General procedure for batch experiments: 10% Pd/C
(5.3 mg, 0.005 mmol) in a 10 mL CEM microwave process vial was added
to a solution of 1,4-diphenyl-1,3-butadiene (10, 103 mg, 0.500 mmol) or
cholesterol (13, 193 mg, 0.500 mmol) in EtOAc (2.0 mL). The vessel was
flushed with argon for 2 min before being sealed tight by using the CEM
Discover pressure/fiber-optic attenuator[28] and placed into the CEM Dis-
cover microwave unit or a preheated oil bath to be heated under the con-
ditions given in Tables 3 and 4. A gas addition accessory for the micro-
wave unit was used for H2 loading.[18c] The reaction vial was connected to
a H2 cylinder and to an external pressure controlling system equipped
with a valve and an exit tube for venting the vial at the end of the reac-
tion. The reaction mixture was purged two times with hydrogen, charged
to 4 bar, and then closed off to the source of hydrogen. The reaction was
heated in a preheated oil bath or by microwave irradiation to 808C and
held for 5 min (see Figures S8 and S9 in the Supporting Information).
Upon cooling to ambient temperature, internal gas was released and the
reaction mixture was filtered through Celite and evaporated to give the
desired products 11/12 and 14. For the GC-MS analysis of cholesterol, a
microwave-assisted derivatization protocol was carried out by employing
acetic anhydride and pyridine (3:2 v/v) at 1008C for 25 min.[51]
1,4-Diphenylbutane (11): White solid; m.p. 538C (lit.[17,52] 52–538C);
1H NMR (300 MHz, CDCl3): d=1.72 (dt, J=7.0, 3.2 Hz, 4H; 2CH2), 2.62
(t, J=6.7 Hz, 4H; 2CH2), 7.20–7.24 (m, 6H; aromatic), 7.28–7.34 ppm
(m, 4H; aromatic). 13C NMR (75 MHz, CDCl3): d=142.6, 128.4, 128.2,
125.6, 35.8, 31.1 ppm; MS (pos. APCI): m/z (%): 210 (100) [M+1]+.
1,4-Diphenyl-1-butene (12): Comparison of the 1H NMR spectrum with
literature data[53] confirmed the identity of this compound. 1H NMR
(300 MHz, CDCl3): d=2.74–2.82 (m, 2H; CH2); 3.02 (t, J=8.2 Hz, 2H;
CH2), 6.40 (dt, J=15.8, 6.6 Hz, 1H; CH), 6.67 (d, J=15.8 Hz, 1H; CH),
7.51–7.27 ppm (m, 10H; aromatic).
1
yellow solid with the following physical properties: M.p. 1018C; H NMR
(300 MHz, CDCl3): d=2.45 (s, 3H; CH3), 7.32 (d, J=8.0 Hz, 2H; aro-
matic), 7.52 (d, J=8.0 Hz, 2H; aromatic), 7.68 (d, J=8.6 Hz, 2H; aro-
matic), 7.72 ppm (d, J=8.6 Hz, 2H; aromatic); 13C NMR (75 MHz,
CDCl3): d=145.6, 138.8, 136.3, 132.6, 129.9, 127.5, 127.1, 119.1, 110.6,
21.2 ppm; GC-EIMS: m/z (%): 193 (100), 178 (11), 91 ppm (9).
Ullmann-type diaryl ether formation of aryl bromide 4 and phenol 5
(Scheme 1b, Table 1): Cu/C (30.0 mg, 3.8 mol%, 8.1% Cu/C (w/w),
0.038 mmol Cu), 4-hydroxyanisole (5) (124.0 mg, 1.0 mmol), Cs2CO3
(390.0 mg, 1.2 mmol), and 1,10-phenanthroline (90.0 mg, 0.5 mmol) were
placed into a flame-dried, argon-purged 10 mL CEM microwave process
vial equipped with a magnetic stir bar. The vial was capped with a
Teflon-coated septum and an alumina crimp, purged with argon and dry
1,4-dioxane (2 mL) was added. The reaction mixture was stirred for
30 min at 250 rpm. The vial was opened and under a positive argon flow
4-bromoacetophenone (4) (298.6 mg, 1.5 equiv) was added and the vial
was sealed tight by using the CEM Discover pressure/fiber-optic attenua-
tor[28] and placed into the CEM Discover microwave unit or a preheated
oil bath to be heated under the following conditions (see Figure S2 in the
Supporting Information): 1) Microwave: 3 min ramp time at 32 W maxi-
mum microwave power, 3 min ramp time at 25 W maximum microwave
power, and 25 W maximum microwave power for the indicated hold
times (Table 1). Stirring was set at high. The maximum temperature was
set to 1508C. 2) Oil bath: The oil-bath temperature was set to 1708C and
stirring was set to 400 rpm. The vial was put into the oil bath for the indi-
cated hold time plus 6 min ramp time, which was needed to reach an
inner temperature of 1508C. This temperature remained constant (Æ
48C) for the following hold time. After the reaction was stopped and
cooled down to ambient temperature, a 100 mL sample of the reaction
mixture was transferred into a syringe, filtered by using a syringe filter,
diluted with EtOAc (1 mL), and subjected to GC-MS analysis. For the
purpose of isolation, the reaction mixture was filtered through a pad of
Celite, which was washed with EtOAc (50 mL). The filtrate was concen-
trated under reduced pressure, the residue was taken up in a small
amount of EtOAc and transferred to a silica-samplet, which was dried
for 2 h at 708C. Subsequent automated silica-gel flash chromatography
with petroleum ether/EtOAc (0–20%) gave diarylether 6 as white solid.
1
Cholestanol (14): White crystals; m.p. 1418C (lit.[54] 1428C); the H NMR
spectrum of this sample was in full agreement with the spectrum ob-
tained from a commercial sample of 14; MS (pos. APCI): m/z (%): 388
(100) [M+1]+.
Flow hydrogenations of diene 10 and cholesterol (13): General proce-
dure:[48] A 25 mL stock solution of diene 10 (0.1m) and cholesterol (13)
(0.1m) in EtOAc was prepared in a glass vial. The reaction parameters
(0.5 mLminÀ1 flow rate, full H2) were selected on the H-Cube fitted with
a 10% Pd/C CatCart and the processing was started, whereby initially
only pure solvent was pumped through the system until the instrument
had achieved the desired reaction parameters and stable processing is as-
sured. At that point, the sample inlet line was switched to the vial con-
taining the substrate. For preparative experiments, the total reaction mix-
ture (5 mL, 0.5 mmol) is collected and the cartridge subsequently washed
with pure solvent for 5 min to remove any substrate/product still ad-
sorbed on the catalyst. Evaporation of the solvent provides the desired
products 12 (97% yield) and 14 (95% yield), respectively, which were
isolated and characterized as described above.
1
M.p. 498C; H NMR (300 MHz, CDCl3): d=2.57 (s, 3H; C(O)CH3), 3.84
(s, 3H; OCH3), 6.99 (m, 6H; aromatic), 7.93 ppm (d, 2H; aromatic);
13C NMR (75 MHz, CDCl3): d=196.7, 162.9, 156.7, 148.5, 131.4, 130.6,
121.7, 116.4, 115.1, 55.7, 26.4 ppm. GC-EIMS: m/z (%): 242 (67), 227
(100).
Suzuki–Miyaura coupling of aryl chloride 7 with phenylboronic acid (8)
(Scheme 2, Table 2): Aryl chloride 7 (142.5 mg, 1.0 mmol), phenylboronic
acid (8) (158.5 mg, 1.3 mmol), Na2CO3 (392 mg, 3.7 mmol), TBAB
(322 mg, 1.0 mmol), 5% Pd/C (48 mg, 0.01 mmol Pd, 56% water) or
10% Pd/Al2O3 catalyst (10.6 mg, 0.01 mmol Pd), water (2 mL), and a
magnetic stir bar were placed in a 10 mL CEM microwave process vial.
The vial was sealed tight by using the CEM Discover pressure/fiber-optic
attenuator[28] and placed into the CEM Discover microwave unit or a pre-
heated oil bath to be heated under the conditions given in Table 2.
Before the reaction was run, the mixture was stirred for 20 s to ensure
sufficient mixing of the reagents. After allowing the reaction mixture to
cool down to RT, a 50 mL sample was transferred into a syringe, filtered
by using a syringe filter, diluted with EtOAc (1 mL) and subjected to
GC-MS analysis. For the purpose of isolation, the reaction vessel was
Determination of metal loading in Ni/C and Cu/C catalysts by ICP-MS:
Ni/C and Cu/C samples from the freshly prepared catalysts (dried at
1208C) were analyzed in the following way: Aliquots (~50 mg, weighed
to 0.1 mg) of the samples were mixed with HNO3 conc. (5 mL) and di-
gested in an MLS Ultraclave III microwave reactor (EMLS/Milestone) at
2508C for 30 min. The digested samples were further diluted and Ni and
Cu determined with ICP-MS.
11616
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 11608 – 11618

Microwave-Assisted Cross-Coupling and Hydrogenation Chemistry
FULL PAPER
SEM of Pd/C and Pd/Al2O3 catalysts: Microscopy was performed on a
SEM ZEISS Ultra55 high-resolution scanning microscope equipped with
an in lens SE (secondary electron) detector for high contrast topography
imaging and an in-column ESB (electron-selective backscattered elec-
tron) detector for low kV high resolution imaging. The microscope is
equipped with an energy-dispersive X-ray spectrometer (EDAX Genesis)
for elemental analysis.
[15] B. H. Lipshutz, J. B. Unger, B. R. Taft, Org. Lett. 2007, 9, 1089.
[16] a) U. Kazmaier, S. Hꢃhn, T. D. Weiss, R. Kautenburger, W. F. Maier,
Synlett 2007, 2579; b) S. P. Andrews, A. F. Stepan, H. Tanaka, S. V.
Ley, M. D. Smith, Adv. Synth. Catal. 2005, 347, 647.
[17] G. S. Vanier, Synlett 2007, 0131.
[18] a) E. Heller, W. Lautenschlꢃger, U. Holzgrabe, Tetrahedron Lett.
2005, 46, 1247; b) A. N. Parvulescu, E. Van der Eycken, P. A. Jacobs,
D. E. De Vos, J. Catal. 2008, 255, 206; c) L. Piras, E. Genesio, C.
Ghiron, M. Taddei, Synlett 2008, 1125; d) U. R. Pillai, E. Sahle-De-
messie, R. S. Varma, Green Chem. 2004, 6, 295; e) B. Toukoniitty, O.
Roche, J.-P. Mikkola, E. Toukoniitty, F. Klingstedt, K. Erꢃnen, T.
Salmi, D. Y. Murzin, Chem. Eng. J. 2007, 126, 103; f) B. Toukoniitty,
J. Wꢃrnꢄ, J.-P- Mikkola, M. Helle, H. Saxꢅn, D. Y. Murzin, T. Salmi,
Chem. Eng. Process. 2009, 48, 837; g) Y.-M. Ma, X.-Y. Wei, X. Zho,
K.-Y. Cai, Y.-L. Peng, R.-L. Xie, Y. Zong, Y.-B. Wei, Z.-M. Zong,
Energy Fuels 2009, 23, 638.
[19] a) R. Cecilia, U. Kunz, T. Turek, Chem. Eng. Process. 2007, 46, 870;
b) M. H. C. L. Dressen, B. H. P. van de Kruijs, J. Meuldijk, J. A. J. M.
Vekemans, L. A. Hulshof, Org. Process Res. Dev. 2007, 11, 865;
c) A. H. Whittaker, D. M. P. Mingos, J. Chem. Soc. Dalton Trans.
2000, 1521; d) W. L. Perry, D. W. Cooke, J. D. Katz, A. K. Datye,
Catal. Lett. 1997, 47, 1.
[20] a) H. Will, P. Scholz, B. Ondruschka, Chem. Ing. Tech. 2002, 74,
1057 and references therein; b) T. Durka, T. Van Gerven, A. Stan-
kiewicz, Chem. Eng. Technol. 2009, 32, 1.
[21] B. H. Lipshutz, B. R. Taft, Angew. Chem. 2006, 118, 8415; Angew.
Chem. Int. Ed. 2006, 45, 8235.
[22] B. H. Lipshutz, Adv. Synth. Catal. 2001, 343, 313, and references
therein.
[23] B. H. Lipshutz, P. A. Blomgren, J. Am. Chem. Soc. 1999, 121, 5819.
[24] C. O. Kappe, Angew. Chem. 2004, 116, 6408; Angew. Chem. Int. Ed.
2004, 43, 6250.
[25] T. Razzaq, J. M. Kremsner, C. O. Kappe, J. Org. Chem. 2008, 73,
6321. See in particular the Supporting Information, Figure S14 and
S15.
[26] a) S. Tasler, B. H. Lipshutz, J. Org. Chem. 2003, 68, 1190; b) B. H.
Lipshutz, S. Tasler, W. Chrisman, B. Spliethoff, B. Tesche, J. Org.
Chem. 2003, 68, 1177.
[27] The differences in microwave absorption of the two unactivated cat-
alysts shown in Figure 1 are therefore likely due to the different
heating behavior of NiO and CuO at 2.45 GHz microwave irradia-
tion (ref. [4b]), and may not necessarily reflect the heating charac-
teristics of the activated zero-valent supported metal catalysts.
[28] M. Hosseini, N. Stiasni, V. Barbieri, C. O. Kappe, J. Org. Chem.
2007, 72, 1417.
[29] A. Krasovskiy, V. Malakhov, A. Gavryushin, P. Knochel, Angew.
Chem. 2006, 118, 6186; Angew. Chem. Int. Ed. 2006, 45, 6040.
[30] P. Walla, C. O. Kappe, Chem. Commun. 2004, 564.
[31] T. N. Glasnov, S. Findenig, C. O. Kappe, Chem. Eur. J. 2009, 15,
1001.
Acknowledgements
This work was supported by a grant from the Christian Doppler Society
(CDG) and (in part) by BASF AG. M.I. thanks the Higher Education
Commission of Pakistan for a Ph.D. scholarship. We thank Thales Nano-
technology for the provision of the H-Cube reactor, Prof. W. Gçssler
(University of Graz) for performing ICP-MS analyses and Dr. S. Mitsche
(FELMI, Graz University of Technology) for SEM analyses.
[1] M. Hajek in Microwaves in Organic Synthesis, 2nd ed. (Ed.: A.
Loupy), Wiley-VCH, Weinheim, 2006, pp. 615–652.
[2] a) B. Desai, C. O. Kappe, Top. Curr. Chem. 2004, 242, 177; b) B. Tou-
koniitty, J.-P. Mikkola, D. Y. Murzin, T. Salmi, Appl. Catal. A 2005,
279, 1.
[3] For general reviews on microwave-assisted transition-metal catalysis,
see: a) P. Appukkuttan, E. Van der Eycken, Eur. J. Org. Chem. 2008,
1133; b) P. Nilsson, K. Olofsson, M. Larhed, Top. Curr. Chem. 2006,
266, 103; c) N. E. Leadbeater, Chem. Commun. 2005, 2881; d) C. O.
Kappe, D. Dallinger, Mol. Diversity 2009, 13, 71; e) M. Larhed, C.
Moberg, A. Hallberg, Acc. Chem. Res. 2002, 35, 717.
[4] a) M. Gupta, E. Wong Wei Leong, Microwaves and Metals, Wiley,
New York, 2007; b) D. R. Baghurst, D. M. P. Mingos, Chem. Soc.
Rev. 1991, 20, 1; c) C. Gabriel, S. Gabriel, E. H. Grant, B. S. Hal-
stead, D. M. P. Mingos, Chem. Soc. Rev. 1998, 27, 213.
[5] a) M. G. Organ, S. Mayer, F. Lepifre, B. N’Zemba, Mol. Diversity
2003, 7, 211; b) G. Palmisano, W. Bonrath, L. Boffa, D. Garella, A.
Barge, G. Cravotto, Adv. Synth. Catal. 2007, 349, 2338; c) X. Xie, J.
Lu, B. Chen, J. Han, X. She, X. Pan, Tetrahedron Lett. 2004, 45, 809.
[6] R. K. Arvela, N. E. Leadbeater, Org. Lett. 2005, 7, 2101.
[7] A. Stadler, B. H. Yousefi, D. Dallinger, P. Walla, E. Van der Eycken,
N. Kaval, C. O. Kappe, Org. Process Res. Dev. 2003, 7, 707.
[8] a) M. S. Pillai, A. Wali, S. Satish, US Patent 200300625, 2003; b) P.
He, S. J. Haswell, P. D. I. Fletcher, Appl. Catal. A 2004, 274, 111.
[9] a) I. R. Baxendale, C. M. Griffith-Jones, S. V. Ley, G. K. Tranmer,
Chem. Eur. J. 2006, 12, 4407; b) A. K. Sharma, J. K. Gowdahalli, S.
Amin, J. Org. Chem. 2007, 72, 8987; c) J. Gil-Moltꢂ, S. Karlstrçm, C.
Najera, Tetrahedron 2005, 61, 12168; d) M. R. Pitts, Platinum Met.
Rev. 2008, 52, 64.
[10] C. Schmçger, T. Szuppa, A. Tied, F. Schneider, A. Stolle, B. On-
druschka, ChemSusChem 2008, 1, 339.
[32] N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457.
[33] a) L. Yin, J. Liebscher, Chem. Rev. 2007, 107, 133; b) F.-X. Felpin, T.
Ayad, S. Mitra, Eur. J. Org. Chem. 2006, 2679; c) M. Seki, Synthesis
2006, 2975.
[34] a) B. L. Hayes, M. J. Collins, Jr., World Patent, WO 04002617, 2004;
b) B. L. Hayes, Aldrichimica Acta 2004, 37, 66.
[11] a) G. Shore, S. Morin, M. G. Organ, Angew. Chem. 2006, 118, 2827;
Angew. Chem. Int. Ed. 2006, 45, 2761; b) E. Comer, M. G. Organ, J.
Am. Chem. Soc. 2005, 127, 8160; c) G. Shore, M. G. Organ, Chem.
Commun. 2008, 735; d) G. Shore, S. Morin, D. Mallik, M. G. Organ,
Chem. Eur. J. 2008, 14, 1351.
[35] a) B. K. Singh, P. Appukkuttan, S. Claerhout, V. S. Parmar, E. Van
der Eycken, Org. Lett. 2006, 8, 1863; b) P. Appukkuttan, M. Husain,
R. K. Gupta, V. S. Parmar, E. Van der Eycken, Synlett 2006, 1491;
c) B. Singh, V. P. Mehta, V. S. Parmar, E. Van der Eycken, Org.
Biomol. Chem. 2007, 5, 2962.
[12] a) B. M. Choudary, S. Madhi, N. S. Chowdari, M. L. Kantam, B.
Sreedhar, J. Am. Chem. Soc. 2002, 124, 14127; b) K. Mennecke, R.
Cecilia, T. N. Glasnov, S. Gruhl, C. Vogt, A. Feldhoff, M. A. L.
Vargas, C. O. Kappe, U. Kunz, A. Kirschning, Adv. Synth. Catal.
2008, 350, 717; c) A. Barau, V. Budarin, A. Caragheorgheopol, R.
Luque, D. J. Macquarrie, A. Prelle, V. S. Teodorescu, M. Zaharescu,
[36] M. A. Herrero, J. M. Kremsner, C. O. Kappe, J. Org. Chem. 2008,
73, 36.
ˇ
ˇ
ˇ
Catal. Lett. 2008, 124, 204; d) J. Demel, S.-E. Park, J. Cejka, P. Step-
ˇ
[37] a) R. G. Heidenreich, K. Kçhler, J. G. E. Krauter, J. Pietsch, Synlett
2002, 1118; b) K. Kçhler, R. G. Heidereich, J. G. E. Krauter, J.
Pietsch, Chem. Eur. J. 2002, 8, 622; c) R. G. Heidereich, J. G. E.
Krauter, J. Pietsch K. Kçhler, J. Mol. Catal. A 2002, 182–183, 499;
K. Kçhler, R. G. Heidenreich, S. S. Soomro, S. S. Prçckl, Adv. Synth.
Catal. 2008, 350, 2930.
nicka, Catal. Today 2008, 132, 63.
[13] B. H. Lipshutz, B. A. Frieman, C.-T. Lee, A. Lower, D. M. Nihan,
B. R. Taft, Chem. Asian J. 2006, 1, 417.
[14] a) T. A. Butler, E. C. Swift, B. H. Lipshutz, Org. Biomol. Chem.
2008, 6, 19; b) B. H. Lipshutz, T. Butler, E. Swift, Org. Lett. 2008,
10, 697.
Chem. Eur. J. 2009, 15, 11608 – 11618
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11617

C. O. Kappe et al.
[38] M. D. Bowman, J. R. Schmink, C. M. McGowan, C. M. Kormos,
N. E. Leadbeater, Org. Process Res. Dev. 2008, 12, 7078.
[39] T. Besson, V. Thiery, J. Dubac in Microwaves in Organic Synthesis,
2nd ed. (Ed.: A. Loupy), Wiley-VCH, Weinheim, 2006, pp. 416–455.
[40] For a critical review, see: N. T. S. Phan, M. Van der Sluys, C. W.
Jones, Adv. Synth. Catal. 2006, 348, 609.
[41] For other key references, see: a) A. Biffis, M. Zecca, M. Basato, J.
Mol. Catal. A 2001, 173, 249; b) D. Astruc, F. Lu, J. R. Aranzaes,
Angew. Chem. 2005, 117, 8062; Angew. Chem. Int. Ed. 2005, 44,
7852; c) J. G. de Vries, Dalton Trans. 2006, 421; d) D. Astruc, Inorg.
Chem. 2007, 46, 1884; e) A. M. Trzeciak, J. J. Ziꢂłkowski, Coord.
Chem. Rev. 2007, 251, 1281; f) A. Svennebring, P. J. R. Sjoeberg, M.
Larhed, P. Nilsson, Tetrahedron 2008, 64, 1808.
J. A. Moulijn, Chem. Eng. Sci. 2004, 59, 259; c) N. Pestre, V. Meille,
C. de Bellefon, J. Mol. Catal. A 2006, 252, 85; d) Y. Sun, R. N.
Landau, J. Wang, C. LeBlond, D. G. Blackmond, J. Am. Chem. Soc.
1996, 118, 1348.
[47] a) S. Nishimura, M. Murai, M. Shiota, Chem. Lett. 1980, 1239;
b) E. B. Hershberg, E. Oliveto, M. Rubin, H. Staeudle, L. Kuhlen, J.
Am. Chem. Soc. 1951, 73, 1144; c) H. R. Nace, J. Am. Chem. Soc.
1951, 73, 2379; d) S. Nishimura, I. Takahashi, M. Shiota, M. Ishige,
Chem. Lett. 1981, 877; e) R. P. A. Sneeden, R. B. Turner, J. Am.
Chem. Soc. 1955, 77, 190; f) N. Ravasio, J. Org. Chem. 1991, 56,
4329; g) N. Ravasio, M. Gargano, J. Org. Chem. 1993, 58, 1259;
h) M. S. Kwon, N. Kim, C. M. Park, J. S. Lee, K. Y. Kang, J. Park,
Org. Lett. 2005, 7, 1077.
[42] a) S. Nishimura, Handbook of Heterogeneous Catalytic Hydrogena-
tion for Organic Synthesis, Wiley-Interscience, New York, 2001;
b) P. N. Rylander, Hydrogenation Methods, Academic Press, New
York, 1990; c) P. N. Rylander, Catalytic Hydrogenation in Organic
Synthesis, Academic Press, New York, 1979.
[43] a) I. S. Cho, H. Alper, Tetrahedron Lett. 1995, 36, 5673; b) R. O.
Hutchins, Suchismita, Tetrahedron Lett. 1989, 30, 55; c) B. M. Chou-
dary, G. V. M. Sharma, P. Bharathi, Angew. Chem. 1989, 101, 506;
Angew. Chem. Int. Ed. Engl. 1989, 28, 465.
[48] M. Irfan, E. Petricci, T. N. Glasnov, M. Taddei, C. O. Kappe, Eur. J.
Org. Chem. 2009, 1327, and references therein.
[49] a) S. Horikoshi, J. Tsuzuki, F. Sakai, M. Kajitani, N. Serpone, Chem.
Commun. 2008, 4501; b) B. Nigrovski, P. Scholz, T. Krech, N. V. Qui,
K. Pollok, T. Keller, B. Ondruschka, Catal. Commun. 2009, 10, 1473.
[50] L. Bai, Y. M. Zhang, J.-X. Wang, Adv. Synth. Catal. 2008, 350, 315.
[51] M. Damm, G. Rechberger, M. Kollroser, C. O. Kappe, J. Chroma-
togr. A 2009, 1216, 5875.
[52] a) J. K. Kochi, J. Org. Chem. 1963, 28, 1960; b) R. Akiyama, S. Ko-
bayashi, J. Am. Chem. Soc. 2003, 125, 3412; S, Kobayashi, J. Am.
Chem. Soc. 2003, 125, 3412.
[44] The correlation with actual stirring speeds in rpm are not disclosed
by the instrument vendor.
[45] An analysis of the effect of stirring on the Suzuki–Miyaura reaction
(Scheme 2) demonstrated only minor variations in the product dis-
tribution as a result of choosing different stirring speeds on the mi-
crowave reactor.
[53] D. Habrant, B. Stengel, St. Meunier, C. Mioskowski, Chem. Eur. J.
2007, 13, 5433.
[54] Y. M. Sheikh, M. Kaisin, C. Djerassi, Steroids 1973, 22, 835.
[46] a) J. Wang, Y. Wang, S. Xie, M. Qiao, H. Li, K. Fan, Appl. Catal. A
2004, 272, 29; b) B. W. Hoffer, P. H. J. Schoenmakers, P. R. M.
Mooijman, G. M. Hamminga, R. J. Berger, A. D. van Langeveld,
Received: July 22, 2009
Published online: September 22, 2009
11618
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 11608 – 11618