Combining enabling techniques in organic synthesis: Solid-phase-assisted catalysis under microwave conditions using a stable Pd(II)-precatalyst

Article abstract of DOI:10.1016/j.tet.2005.07.113

The catalytic activity of a 2-pyridinealdoxime-based Pd(II)-complex covalently anchored via the oxime moiety to a glass/polymer composite material was evaluated in Suzuki-Miyaura cross-coupling reactions of aryl and heteroaryl halides, including arylchlorides, with aryl and heteroaryl boronic acids both under thermal as well as microwave irradiating conditions in water. The stability and reusability of this Pd-precatalyst is part of the present study.

Full text of DOI:10.1016/j.tet.2005.07.113

Tetrahedron 61 (2005) 12121–12130
Combining enabling techniques in organic synthesis:
solid-phase-assisted catalysis under microwave conditions using
a stable Pd(II)-precatalyst
Kamal M. Dawooda,b and Andreas Kirschninga,
*
a
¨ ¨
Institut fur Organische Chemie der Universitat Hannover, Schneiderberg 1B, D-30167 Hannover, Germany
bDepartment of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
Received 30 June 2005; revised 8 July 2005; accepted 8 July 2005
Available online 26 October 2005
Abstract—The catalytic activity of a 2-pyridinealdoxime-based Pd(II)-complex covalently anchored via the oxime moiety to a glass/
polymer composite material was evaluated in Suzuki–Miyaura cross-coupling reactions of aryl and heteroaryl halides, including
arylchlorides, with aryl and heteroaryl boronic acids both under thermal as well as microwave irradiating conditions in water. The stability
and reusability of this Pd-precatalyst is part of the present study.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Organic synthesis seems to have become so very advanced
that basically every molecular target, how structurally
complex it may be, can be addressed. However, these
advances are not fully reflected in the industrial context.1
Many developments from the research laboratories lack
practicability as far as scale-up, easy and rapid workup and
product isolation as well as recyclability of catalysts are
concerned. New synthetic methods need to be combined
with new techniques termed ‘enabling technologies for
Figure 1.
In this context, we have combined solid-phase assisted
organic synthesis’ to achieve rapid incorporation into
synthesis with new continuous flow reactors (PASSflow)
industrial processes.2 Typical enabling technologies are
leading to an almost workup free procedure for carrying
microwave assistance,3 new solvent systems,4 continuous
out many different reactions including nucleophilic
flow reactors5 and immobilization of chemically active
substitutions, reductive aminations, oxidations, Horner–
Wadsworth–Emmons and Pd-catalyzed C–-C coupling
species such as reagents and homogeneous catalysts6 which
reactions in the flow through mode.7
have recently seen widespread applications in research
laboratories. Truly new synthetic technology platforms,
however, will not be based on the individual use of these
new techniques but will require the integration of two or
more of these enabling techniques (Fig. 1). Various
successful examples of combining two or more of these
techniques in order to achieve faster synthesis or improved
work-up have recently appeared in the literature, particu-
larly in the field of catalysis.
Other groups have combined microwave-assisted solid-
phase technique was applied in the synthesis of several
heterocycles,8 C–C cross couplings9 and natural products
derivatives.10 However, publications concerning the use of
insoluble Pd-catalyst under microwave irradiating con-
ditions are scarce.11 The combination of immobilized
homogeneous catalysts and microwave assistance is
particularly appealing in order to overcome the less
favourable kinetics of biphasic systems.
Keywords: Pd(II)-precatalyst; Microwave conditions; Suzuki–Miyaura
cross-coupling reaction.
Transition metal-mediated cross-coupling reactions, par-
ticularly those based on palladium, have become key
*
Corresponding author. Fax: C49 511 762 3011;
e-mail: andreas.kirschning@oci.uni-hannover.de
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.113

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K. M. Dawood, A. Kirschning / Tetrahedron 61 (2005) 12121–12130
transformations in organic synthesis. However, traditional
palladium catalysts often rely on phosphine ligands which
show various disadvantages. These are associated with their
high price, their air-sensitivity, and difficulties when the
ligands and their degradation by-products have to be
removed during workup. Recently, new catalytic candidates
have appeared in the literature, namely palladacycles which
exert high activity and often they are air stable (selected
examples are depicted in Fig. 2).12 In many cases, these
compounds are dimeric chloro-bridged ortho-palladated
complexes such as the acetophenone oxime-based pallada-
developed for incorporation inside a continuous flow reactor
as a monolithic material thereby combining two enabling
techniques.5 For this purpose different strategies of
attachment such as physisorption of Pd particles 5,17 and
immobilization of Najera’s catalyst to polyvinyl pyridine by
covalent linkage 618 were pursued. The resulting catalysts
were tested in a batch set up as well as under continuous
flow conditions using the PASSflow system.7 However, they
lack of stability under microwave irradiating conditions and
show substantial degree of leaching under continuous flow
conditions in PASSflow reactors when polar organic
solvents like DMF are required. In order to overcome
these drawbacks (a) stability under microwave irradiation
and (b) recyclability, search for an alternate Pd(0) catalyst
or an appropriate precatalyst were conducted. Here, we
report on the development of a new polymer-bound
palladium(II) complex 9 which is anchored to the glass/
polymer composite material. In order to evaluate its
suitability in Suzuki–Miyaura reactions under microwave
irradiating conditions we used a composite material shaped
as Raschig rings which is a material with relevance in
industrial applications (Fig. 3).
cycle 1 utilized by Najera et al.13 a versatile complex which
´
is able to catalyze various carbon–carbon coupling reactions
such as Suzuki–Miyaura and Heck cross-couplings. Garcia
and co-workers14 covalently anchored these thermally
stable palladacycles via an aryl ether linkage to modified
silica support yielding catalyst 214 allowing facile recycling
of the catalytic species. This species was tested in Suzuki–
Miyaura reactions and was found to be a highly active and
recyclable complex when heating the reaction mixture
conventionally under nitrogen atmosphere. Related
examples of immobilized Pd catalysts were disclosed by
Nowotny et al.15 and Bedford et al.16 who studied
palladium(II) complexes 3 and 4 immobilized on poly-
styrene and silica, respectively. These complexes were
found to be highly active in Heck and Suzuki–Miyaura cross
coupling reactions, respectively, but were not well suited for
recycling protocols. More precisely, the precatalyst 3 lost its
activity after the first run of the Heck reaction between
iodobenzene and styrene in NMP whereas catalyst 4 was
tested in Suzuki–Miyaura cross coupling of only aryl
bromides and with recyclability far from being ideal.
Recently, evidence has been collected that complexes
described here serve as ‘dormant species’12a that are not
involved in the real catalytic cycle but are a source of a
catalytically active species of unknown nature. Thus,
solvents like NMP may coordinate and stabilize Pd species
that have left the solid phase and therefore, seem not to be
well suited as solvents for immobilized Pd species.
Figure 3. Megaporous glass Raschig rings.
2. Results and discussion
2.1. Preparation of Pd-precatalyst
For generating immobilized Pd-precatalyst 9 (Scheme 1),
first the monolithic glass/polymer composite phase 7 had to
be prepared by precipitation polymerization inside the pores
of porous glass which was shaped as Raschig rings
according to the protocol that we recently described in
detail.7 2-Pyridinealdoxime was then coupled to the
polymer matrix 7 by heating it at 80 8C in DMF in the
presence of sodium hydride. Finally, the heterogeneous
precatalyst 9 was obtained by treatment of 8 with a solution
Figure 2.
Recently, we initiated a program dedicated to the
immobilization of catalytically active Pd species inside a
megaporous glass/polymer composite material which we
Scheme 1.

K. M. Dawood, A. Kirschning / Tetrahedron 61 (2005) 12121–12130
12123
of sodium tetrachloropalladate in methanol. The loading of
catalyst 9 was estimated to be ca. 0.09 mmol/g Raschig
rings according to weight increase.19
2.2. Optimization of conditions for catalysis
The high price of palladium renders processes based on this
metal less attractive unless very active species or catalytic
species easy to recycle are available.20 Therefore, we firstly
studied the factors affecting the optimization of the catalytic
activity of the Pd-precatalyst 9. Thus, the effect of
concentration of palladium precatalyst 9 on the coupling
reaction between phenylboronic acid and p-bromoaceto-
phenone under thermal conditions in water at 100 8C was
evaluated. At first, the reaction was conducted using
0.7 mol% of precatalyst 9 with a molar ratio of p-bromo-
acetophenone/phenylboronic acid/tetrabutylammonium
bromide/potassium hydroxide: 1/1.2/0.6/2, to give 98%
isolated yield of 4-acetyl-1,10-biphenyl (10). In the second
experiment, we used 0.3 mol% of the catalyst to give full
conversion in 97% isolated yield. The reaction was repeated
with different catalytic mol% as shown in Scheme 2. Almost
full conversion was obtained even in the presence of
0.005 mol% of the catalyst 9 using p-bromoacetophenone
(40 mmol), phenylboronic acid (48 mmol), tetrabutyl-
ammoium bromide (24 mmol), potassium hydroxide
(80 mmol) and water (100 mL) to give the 4-acetyl-1,10-
biphenyl (10) in 95% (GC-analysis; 92% isolated yield),
revealing the good activity of the catalytic system.
Scheme 3. Recyclability of the Pd-precatalyst 9 under thermal and
microwave heating. Conditions: bromide/boronic acid/base/TBAB/water
(mL): 1/1.2/2/0.6/3.5, 0.7 mol% Pd precatalyst 9, 100 8C/2 h for thermal
heating; 160 8C/250 W/3 min for microwave irradiation.
purification in 95% yield. At this point, the Pd-precatalyst 9
was removed, washed with ethyl acetate and water and
subsequently dried.21 This used catalyst was reemployed in
nine successive runs under identical conditions promoted
for the first run. Nearly full conversion was achieved within
2 h up to the 9th run as depicted in Scheme 3. Recyclability
of the precatalyst 9 under microwave irradiation conditions
was next evaluated using the same model reaction described
above at 160 8C and 250 watt for ten successive runs as
shown in Scheme 3. Under these conditions, the precatalyst
9 was highly active with almost full transformation up to the
7th run and even at the 10th run it was still active (45%
transformation). It is noteworthy to mention that the
reaction is highly selective as only the cross-coupled
product was formed up to the 7th run and from run 8 to
10 the starting p-bromoacetophenone was still present along
with the product. Homo-coupled products, which are well
known by-products in Suzuki–Miyaura reactions were
analyzed to be formed in the range of 1–8%. These results
indicate the high stability of precatalyst under microwave
irradiating conditions which allows to simply reuse it.
Furthermore, we studied the recyclability of Pd-precatalyst
9 in a second model Suzuki–Miyaura cross-coupling
reaction using 3,4-methylenedioxyphenylboronic acid
(1.2 equiv) and p-bromoacetophenone (1 equiv) in the
presence of precatalyst 9 (0.7 mol%) in water (3.5 mL) at
100 8C under air, and potassium hydroxide (2 equiv) as base
and tetrabutylammonium bromide (TBAB) (0.6 equiv) as
phase transfer agent (Scheme 3). Under these conditions, the
reaction was completed within 2 h (GC-monitoring). The
product of the reaction, 3,4-methylenedioxy-40-acetyl-1,10-
biphenyl (11), was isolated after flash chromatographic
Additionally, we optimized the reaction temperature under
thermal conditions for the coupling between 3,4-methyl-
enedioxyphenylboronic acid (1.2 equiv) and p-bromoaceto-
phenone (1 equiv) in the presence of precatalyst 9 (0.7 mol
%) in water (3.5 mL), potassium hydroxide (2 equiv) and
Scheme 2. Effect of concentration of the Pd-precatalyst 9 on the
transformation rate. Conditions: Bromide/boronic acid/KOH/TBAB/water
(mL): 1/1.2/2/0.6/3.5 mL, reaction time for runs 1–5 was 2 h and for runs
6–7 was 3 h.
Figure 4. Effect of temperature on the transformation of p-bromoaceto-
phenone into 11. Conditions: Bromide/boronic acid/base/TBAB/water
(mL): 1/1.2/2/0.6/3.5, 0.7 mol% Pd-precatalyst 9, 2 h.

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K. M. Dawood, A. Kirschning / Tetrahedron 61 (2005) 12121–12130
Table 1. Suzuki–Miyaura reactions of aryl chlorides under thermal and microwave heating
Ar
Base
Product
Thermal heatinga
mw heatinga
Time (min)
Yield%b
Time (h)
Yield%b
1
2
A
B
10
10
16
16
65
85 (76)
30
30
84
98 (92)
3
4
A
B
11
11
16
16
17
93 (91)
15
30
53
97 (90)
5
6
A
B
12
12
16
16
2
22
15
30
11
31
a Molar ratio of chloride/boronic acid/base/TBAB is 1/1.2/2/0.6, water (3.5 mL), precatalyst 9 (2.8 mol%); thermal heating at 100 8C, microwave heating at
160 8C (250 watt), base AZCs2CO3; BZKOH.
b GC-yields; values in parentheses refer to isolated yields of pure products.
TBAB (0.6 equiv). The reaction time was fixed in all cases
at two hours. As shown in Figure 4, conversion is best
achieved at 100 8C. Interestingly, when the reaction was left
shaking at room temperature for an extended time of 20 h,
full conversion was also achieved.
tetrabutylammonium bromide (0.6 equiv) and potassium
hydroxide (2 equiv) in the presence of the precatalyst 9
(2.8 mol%) in water (3.5 mL) at 100 8C under air for 16 h
resulted in the formation of 4-acetyl-1,10-biphenyl (10) in
76% isolated yield. When this transformation was repeated
under identical conditions except that heating was con-
ducted for 30 min with microwave irradiation (160 8C,
250 watt), the coupling product 10 was isolated in 92%
yield. The microwave conditions were optimized with
respect to energy and reaction time. Therefore, the degree of
conversion under microwave heating (160 8C, 250 watt) for
the coupling of phenylboronic acid with p-chloroaceto-
phenone was analyzed after 2 min (16%), 4 min (45%),
8 min (63%), 15 min (78%) and 30 min (84%; entry 1,
Table 1). When reducing the amount (0.7 mol%) of Pd-
precatalyst 9 the product 10 was obtained in 55% after
30 min of microwave irradiation. Suzuki–Miyaura reactions
of p-chloroacetophenone were also conducted with 3,4-
methylenedioxyphenylboronic acid (entry 4, Table 1) and
with 3-thienylboronic acid (entry 6, Table 1) both under
thermal as well as microwave irradiating conditions using
potassium hydroxide as base. For comparison reason also,
cesium carbonate was employed which has been found by
Glorius et al.27 and Mino et al.28 to be an effective base for
transformations of aryl chlorides into biaryls in Suzuki cross
couplings. However, the former base turned out to be
superior to cesium carbonate. Homo-coupled products,
which are by-products commonly observed in Suzuki–
Miyaura reactions were found to be well below 5% as
determined by GC-analysis.
The effect of the absence of tetrabutylammonium bromide
(TBAB) and/or palladium catalyst on the above mentioned
conversion was also evaluated. Leadbeater and
co-workers22 recently revised there results23 on a palladium
free Suzuki–Miyaura reaction by disclosing that impurities
of Pd present in reagents added such as the base K2CO3 can
result in C–C-coupling of aryl halides and arylboronic acids.
In the present case, no product formation was observed
without palladium catalyst but in the presence of TBAB and
KOH in water both under thermal (2 h) as well as
microwave irradiating conditions (3 min). When the
reaction was conducted in the presence of palladium
precatalyst 9 but without TBAB, the conversion was only
59 and 79% under thermal (2 h) and microwave irradiating
conditions (3 min), respectively. These findings show the
importance of the palladium source and TBAB in carrying
out Suzuki–Miyaura coupling reactions. It is noteworthy to
report here, that, when the same reaction was repeated with
microwave heating for 3 min in the absence of palladium
precatalyst 9 but in glassware that had been used before in
Pd-catalysed reactions and that obviously had not been
thoroughly cleaned, product 11 was formed in 37% yield.
2.3. Scope and limitations of the precatalyst 9
To test the scope and limitations of precatalyst 9 in Suzuki–
Miyaura reactions we first chose aryl chlorides24 as
substrates and applied aqueous conditions which would be
beneficial when accelerating the C–C-coupling under
microwave irradiating condtions.25,26
In the following we investigated the general utility of
precatalyst 9 in Suzuki–Miyaura cross-coupling reactions
(Scheme 4 and Table 2). Aryl and heteroaryl bromides were
Thus, we therefore focused on the reaction of p-chloro-
acetophenone with various aryl and heteroarylboronic acids.
The results for thermal as well as microwave heating are
summarized in Table 1. Treatment of p-chloroacetophenone
(1 equiv) with phenylboronic acid (1.2 equiv),
Scheme 4. For details refer to Table 2.

Table 2
(Het)1Ar-X
a
a
Thermal
Microwavea
Yield%b
Time (min)
Thermal
Microwavea
Yield%b
Time (min)
Thermal a
Yield%b
Time (h)
Microwavea
Yield%b
Time (min)
Yield%b
Time (h)
Yield%b
Time (h)
11
12
15
10
100 (97)
2
100 (98)
2
100 (90)
2
100 (95)
3
94
7
100 (75)
3
13
14
17
20
100
6
4
7
100 (92)
7
64
7
4
7
77 (61)
100 (88)
17
10
85
6
2
4
100 (91)
100 (93)
96 (79)
10
16
18
21
100 (81)
100
5
100 (85)
8
100
4
19
11
100 (91)
15
12
15
35
15
24
23
22
100 (97)
4
4
100 (94)
8
100 (78)
6
7
100 (93)
10
10
100 (88)
4
8
94
50
11
10
27
26
25
64
100 (89)
10
100 (96)
92
92 (84)

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K. M. Dawood, A. Kirschning / Tetrahedron 61 (2005) 12121–12130
coupled with boronic acids both under thermal as well as
microwave irradiating conditions. The reaction conditions
and molar ratios of the reaction components are cited in the
legend of Table 2.
Again heating under microwave conditions led to an
acceleration of the C–C-coupling reaction. In some cases,
yields dramatically improved when switching from con-
ventional heating to microwave heating as is particularly
well demonstrated for the formation of biaryls 19, 21, and
25. Chemoselectivity was encountered in the formation of
biaryls 16 to 18. However, the catalyst derived from
precatalyst 9 is even not reactive enough to efficiently
couple 2-bromothiazole under Suzuki–Miyaura cross-
coupling reactions when microwave irradiating conditions
are employed.
Although there had been speculations that palladacycles
may operate through a Pd(II)/(IV) cycle,29 studies by
Hartwig et al.30 strongly suggest that, as expected, Pd(0)
species have to be made responsible as active catalysts.
Therefore, complexes that are listed in Figure 2 as well as 9
may serve as reservoirs that are not involved in the real
catalytic cycle12a but are a source of coordinative
unsaturated ‘PdLn’ species of unknown nature or release a
considerable amount of colloidal Pd(0) which also can show
catalytic activity at low concentrations. Indeed, De Vries
and co-workers noted for Heck reactions that low
concentrations of Pd(0) in solution will aggregate and
deactivate much more slowly than high concentrations.31
For related SCS–Pd complexes strong evidence has been
collected in Heck reactions that they are actually reservoirs
of a catalytically active but ill-defined form of Pd(0).32
However, the picture is more complex as the choice of
solvent is crucial in this context, specifically its complexing
properties. Other solvents than water (which we applied in
our studies) such as DMF or NMP can give supernatants
which unlike in cases of aqueous solvents still show
catalytic activity in Heck reactions.15 However, the pyridine
ligand present on our polymeric phase still has the potential
to scavenge any catalytic species that may have leached into
solution during the catalytic process which would explain
the low amount of Pd (1.6!10K3–1.28!10K3%) that we
determined by ICP-MS after having cooled the reaction
mixture to room temperature. In addition, this process may
retard the formation and growth of colloids.
3. Conclusions
In conclusion, we demonstrated that Pd-complex 9 is an
efficient and highly active, reusable solid-phase anchored
precatalyst with extraordinary potential for Suzuki–Miyaura
cross-coupling reactions in aqueous media. Importantly, it
not only shows activity under thermal but also under
microwave irradiating conditions in water thereby showing
sufficient reactivity even for arylchlorides. Having tested
this precatalyst on the megaporous monolith glass/polymer
composite allows us to utilize this material under continuous
flow conditions in PASSflow reactors. These are ongoing
studies in our laboratories.

K. M. Dawood, A. Kirschning / Tetrahedron 61 (2005) 12121–12130
12127
4. Experimental
4.1. Materials and methods
scales of 2, 5, 10 and 20 mmol of p-bromoacetophenone,
respectively). Finally, the same reaction was repeated using
40 mmol of p-bromoacetophenone and only 0.005 mol%
palladium-complex 9 and the reaction mixture was heated in
this case for 3 h at 100 8C under air. The molar ratio of the
reaction components were in all cases as follows;
p-bromoacetophenone, phenylboronic acid, tetrabutyl-
ammonium bromide (TBAB), KOH: 1/1.2/0.6/2 (in
3.5 mL water). The conversion (in %) versus concentration
of palladium catalyst is shown in Scheme 2.
NMR spectra were recorded with a Bruker DPX-400
spectrometer at 400 MHz (1H NMR) and at 100 MHz (13C
NMR) using CDCl3 as solvent and internal standard (dZ
7.26 and 77.36 ppm, for 1H NMR and 13C NMR,
respectively). Mass spectra (EI) were obtained at 70 eV
with a type VG autospec apparatus (Micromass). GC
analyses were conducted using an HPGC series 6890 Series
Hewlett Packard equipped with an SE-54 capillar column
(25 m, Macherey–Nagel) and an FID detector 19231 D/E.
Melting points were determined in open glass capillaries
with a Gallenkamp apparatus and are uncorrected.
Analytical thin-layer chromatography was performed
using precoated silica gel 60 F254 plates (Merck,
Darmstadt), and the spots were visualised with UV light at
254 nm. Merck silica gel 60 (230–400 mesh) was used for
flash column chromatography. Microwave experiments
were carried out using a CEM Discover LabmateTM
microwave apparatus (300 W with ChemDriverTM Soft-
ware). Commercially available reagents and dry solvents
were used as received.
4.4. Recycling of the palladium precatalyst 9 with
thermal heating in water
A mixture of p-bromoacetophenone (1 mmol), 3,4-
methylenedioxyphenyl boronic acid (1.2 mmol), TBAB
(0.6 mmol), palladium catalyst 9 (0.7 mol%), KOH
(2 mmol) and water (3.5 mL) was shaken at 100 8C under
air for 2 h (monitored by GC). The solid catalyst was
removed by filtration, washed with water followed by
EtOAc, dried and then reused in a new reaction mixture with
the same molar ratio of components mentioned above. Then
the mixture was shaken again at 100 8C under air for 2 h.
This experiment was repeated in another nine runs (2 h for
each run), as shown in Scheme 3. The product was purified
by flash column chromatography on silica gel using EtOAc/
petroleum ether (1:10) as eluent.
4.2. Preparation of Pd-precatalyst 9
To a mixture of glass/polymer composite shaped Raschig
rings (10 g, 5 mmol) containing 10% chloromethylpoly-
styrene-divinyl benzene polymer (0.53 mmol polymer/g
Raschig rings) 7 and cisK2-pyridinealdoxime (3.66 g,
30 mmol) in dimethylformamide (DMF) (50 mL), sodium
hydride (0.72 g, 60% in oil, 30 mmol) was added
portionwise over a period of 20 min. The mixture was
shaken at 80 8C for three days then cooled to room
temperature and quenched with water (100 mL). The
Raschig rings were filtered and washed successively with
DMF, water, ethanol, dichloromethane and again with
ethanol (20 mL, each time) and finally well-dried under
vacuum. These well-dried Raschig rings to which cis-2-
pyridinealdoxime was bound 8 (6.92 g) were added to a
solution of sodium tetrachloropalladate (1.2 g, 4 mmol) in
methanol (80 mL) and the mixture was left to be shaken at
room temperature for additional three days. The resulting
Raschig rings were dried in vacuo and the loading of
catalyst 9 was estimated to be ca. 0.09 mmol/g Raschig
rings according to weight increase (the weight increase of
each single raschig ring was determined; each ring was
loaded with about 2.8 mol% palladium with reference of
1 mmol scaled reactions).
4.5. Recycling of the palladium precatalyst 9 under
microwave irradiating conditions in water
The same reaction mixture used under thermal conditions
was mixed in a properly capped process vial and thereafter
the mixture was subjected to microwave irradiating
conditions at 160 8C and 250 watt for 3 min (monitored by
GC). The solid catalyst was removed, washed with water
followed by EtOAc, dried and then re-used for the next run
with the same molar ratio of components. As shown in
Scheme 3, the experiment was repeated in another nine runs,
each time irradiating for 3 min.
4.6. General procedure for the Suzuki–Miyaura
coupling of p-chloroacetophenone in water with thermal
heating
A mixture of p-chloroacetophenone (1 mmol), aryl(hetero-
aryl) boronic acid (1.2 mmol), tetrabutylammonium
bromide (TBAB) (0.6 mmol), palladium precatalyst 9
(2.8 mol%), KOH or Cs2CO3 (2 mmol) and distilled water
(3.5 mL) was shaken at 100 8C under air for 16 h. The solid
catalyst was removed by filtration, washed with water
followed by EtOAc. The combined washings were extracted
with EtOAc (3!20 mL). The combined organic extracts
were dried over anhydrous MgSO4 then filtered and the
solvent was evaporated under reduced pressure. The product
was purified as described above.
4.3. Effect of concentration of the palladium catalyst 9 on
the Suzuki–Miyaura coupling in water with thermal
heating
A mixture of p-bromoacetophenone (1 mmol), phenyl-
boronic acid (1.2 mmol), TBAB (0.6 mmol), palladium
catalyst 9 (0.7 mol%), KOH (2 mmol) and water (3.5 mL)
was shaken at 100 8C under air for 2 h (monitored by GC).
The same experiment was repeated using 0.3 mol% of
palladium precatalyst. The amount (mol%) of the palladium
precatalyst 9 was changed with respect to p-bromoaceto-
phenone (0.1, 0.07, 0.03 and 0.01 mol% Pd-catalyst with
4.7. General procedure for the Suzuki–Miyaura
coupling of p-chloroacetophenone in water under
microwave heating
A mixture of p-chloroacetophenone (1 mmol), aryl(hetero-
aryl) boronic acid (1.2 mmol), TBAB (0.6 mmol),

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K. M. Dawood, A. Kirschning / Tetrahedron 61 (2005) 12121–12130
palladium catalyst 9 (2.8 mol%), KOH or Cs2CO3 as a base
(2 mmol) and water (3.5 mL) were mixed in a process vial.
The vial was capped properly, and thereafter the mixture
was heated under microwave irradiating conditions at
160 8C and 250 watt for the appropriate reaction time as
listed in Table 1. After the reaction was completed
(monitored by GC), the solid catalyst was removed by
filtration and washed. The reaction mixture was extracted
with EtOAc (3!10 mL) and combined with the washings.
After drying over MgSO4, and concentration in vacuo, the
product was isolated by flash column chromatography.
7.57–7.58 (m, 1H), 7.68 (d, 2H, JZ8.52 Hz), 7.98 (d, 2H,
JZ8.52 Hz); 13C NMR d 26.9, 122.4, 126.5, 126.7, 127.1,
129.4, 135.9, 140.5, 141.4, 197.9; MS (m/e) 202 (MC), 187,
159, 115, 93, 79.
4.9.4. 3-Phenylpyridine (13).35 Colorless oil; 1H NMR
(CDCl3) d 7.33–7.61 (m, 6H), 7.84–7.90 (m, 1H), 8.59 (dd,
1H, JZ4.86, 1.62 Hz), 8.85 (d, 1H, JZ1.76 Hz); MS (m/e)
155 (MC), 127, 102, 87, 77, 64.
4.9.5. 3-(3,4-Methylenedioxyphenyl)pyridine (14). Pale
brown crystals, mp 99–100 8C; 1H NMR (CDCl3) d 5.99 (s,
2H, –OCH2O–), 6.89 (d, 1H, JZ8.5 Hz), 7.01–7.04 (m,
2H), 7.29–7.32 (dd, 1H, JZ7.9, 7.9 Hz), 7.76–7.78 (m, 1H),
8.54 (dd, 1H, JZ4.8, 1.5 Hz), 8.77 (d, 1H, JZ1.9 Hz); 13C
NMR d 101.6, 107.7, 109.1, 121, 123.7, 132.2, 134.2, 136.6,
148, 148.3, 148.3, 148.6; MS (m/e) 198 (MC), 140, 114, 99,
86, 62. Anal. Calcd for C12H9NO2: C, 72.35; H, 4.55; N,
7.03. Found: C, 72.20; H, 4.32; N, 6.96.
4.8. General procedure for the Suzuki–Miyaura
coupling of aryl(heteroaryl) bromides in water with
thermal heating
A
mixture of aryl(heteroaryl) bromide (1 mmol),
aryl(heteroaryl) boronic acid (1.2 mmol), TBAB
(0.6 mmol), palladium catalyst 9 (0.7 mol%), KOH
(2 mmol) and distilled water (3.5 mL) was shaken at
100 8C under air for the appropriate reaction time listed in
Table 2. After the reaction was completed (monitored by
GC), the solid catalyst was removed by filtration, washed
with water then EtOAc, and the washings were added to
the reaction mixture which was then extracted with EtOAc
(3!20 mL). The products were purified as described above
for the procedure with p-bromoacetophenone.
4.9.6. 3-(3-Thienyl)pyridine (15).36 Colorless crystals, mp
76–77 8C (Ref.36 mp 73–74 8C); 1H NMR (CDCl3) d 7.26–
7.32 (m, 1H), 7.37–7.44 (m, 2H), 7.50–7.52 (m, 1H), 7.84
(m, 1H), 8.52 (dd, 1H, JZ4.8, 1.72 Hz), 8.86 (d, 1H, JZ
1.72 Hz); 13C NMR d 121.7, 123.9, 126.2, 127.3, 131.8,
133.8, 139.1, 147.9, 148.5; MS (m/e) 161 (MC), 134, 117,
108, 81, 63, 45.
4.9.7. 2-Chloro-5-phenylpyridine (16).37 Colorless
crystals, mp 54–55 8C (Ref.37 mp 55–56 8C); 1H NMR
(CDCl3) d 7.37–7.58 (m, 6H), 7.81–7.87 (dd, 1H, JZ8.26,
2.52 Hz), 8.61 (d, 1H, JZ2 Hz); MS (m/e) 189 (MC), 154,
127, 102, 95, 63, 51.
4.9. General procedure for the Suzuki–Miyaura
coupling of aryl(heteroaryl) bromides in water under
microwave irradiating conditions
A mixture of the appropriate aryl(heteroaryl) bromide
(1 mmol), aryl(heteroaryl) boronic acid (1.2 mmol),
TBAB (0.6 mmol), palladium catalyst 9 (0.7 mol%), KOH
(2 mmol) and water (3.5 mL) were mixed in a process vial.
The vial was capped properly, and thereafter the mixture
was heated under microwave irradiating conditions at
160 8C and 250 watt for the appropriate reaction time as
listed in Table 2. The products were purified according to
the procedure described above for p-bromoacetophenone.
4.9.8. 2-Chloro-5-(3,4-methylenedioxyphenyl)pyridine
(17). Pale yellow powder, mp 150–151 8C; 1H NMR
(CDCl3) d 6.02 (s, 2H, –OCH2O–), 6.90 (d, 1H, JZ
8.6 Hz), 6.99–7.02 (m, 2H), 7.35 (d, 1H, JZ8.3 Hz), 7.75
(dd, 1H, JZ8.3, 2.5 Hz), 8.52 (d, 1H, JZ2.4 Hz); 13C NMR
d 101.8, 107.7, 109.3, 121.1, 124.4, 130.9, 135.7, 137.2,
148, 148.4, 148.9, 150.2; MS (m/e) 233 (MC), 140, 113, 99,
85. Anal. Calcd for C12H8ClNO2: C, 61.69; H, 3.45; N, 5.99.
Found: C, 61.62; H, 3.32; N, 5.97.
4.9.1. 4-Acetyl-1,10-biphenyl (10). Colorless crystals, mp
1
119–120 8C (Ref.33 mp 118–120 8C); H NMR (CDCl3) d
2.64 (s, 3H, CH3CO), 7.36–7.42 (m, 1H), 7.46–7.49 (m,
2H), 7.62–7.65 (m, 2H), 7.69 (d, 2H, JZ8.52 Hz), 8.03 (d,
2H, JZ8.52 Hz); 13C NMR d 27.0, 127.5, 127.6, 128.6,
129.2, 129.3, 136.2, 140.2, 146.1, 198.1; MS (m/e) 196
(MC), 181, 152, 127, 102, 91, 76.
4.9.9. 2-Chloro-5-(3-thienyl)pyridine (18). Colorless
crystals, mp 95–96 8C; H NMR (CDCl3) d 7.33–7.35 (m,
1
2H), 7.44–7.46 (m, 1H), 7.50–7.51 (m, 1H), 7.81 (dd, 1H,
JZ8.3, 2.6 Hz), 8.61 (d, 1H, JZ2 Hz); 13C NMR d 122.1,
124.6, 126, 127.6, 130.8, 136.6, 137.7, 147.6, 150.1; MS
(m/e) 195 (MC), 160, 133, 116, 89, 63. HRMS, calcd for
C9H6ClNS: 195.9988. Found: 195.9981. Anal. Calcd for
C9H6ClNS: C, 55.24; H, 3.09; N, 7.16. Found: C, 55.81; H,
3.19; N, 6.99.
4.9.2. 3,4-Methylenedioxy-40-acetylbiphenyl (11). Color-
less crystal, mp 140–141 8C; H NMR (CDCl3) d 2.62 (s,
1
3H, CH3CO), 6.01 (s, 2H, –OCH2O–), 6.89 (d, 1H, JZ
8.3 Hz), 7.09–7.13 (m, 2H), 7.59 (d, 2H, JZ8.4 Hz), 7.99
(d, 2H, JZ8.4 Hz); 13C NMR d 26.9, 101.7, 107.9, 109.1,
121.4, 127.1, 129.2, 134.4, 135.8, 145.7, 148.2, 148.7,
197.9; MS (m/e) 240 (MC), 225, 197, 167, 139, 112, 98, 69.
Anal. Calcd for C15H12O3: C, 74.99; H, 5.03. Found: C,
74.96; H, 4.83.
4.9.10. 2-Phenylpyrimidine (19).38 Pale yellow oil (Ref.38
1
mp 36–38 8C); H NMR (CDCl3) d 7.18 (dd, 1H, JZ4.88,
4.76 Hz), 7.44–7.51 (m, 3H), 8.42–8.48 (m, 2H), 8.81 (d,
2H, JZ4.78 Hz); MS (m/e) 156 (MC), 128, 103, 76, 51.
4.9.11. 2-(3-Thienyl)pyrimidine (21).39 Pale yellow
powder, mp 95–97 8C (Ref.39 mp 95 8C); 1H NMR
(CDCl3) d 7.12 (dd, 1H, JZ4.90, 4.76 Hz), 7.36–7.41 (dd,
1H, JZ5.02, 1.12 Hz), 7.28–7.30 (dd, 1H, JZ3.02,
4.9.3. p-(3-Thienyl)acetophenone (12).34 Colorless
crystals, mp 149–150 8C (no mp given in Ref.34); 1H
NMR (CDCl3) d 2.62 (s, 3H, CH3CO), 7.42–7.44 (m, 2H),

K. M. Dawood, A. Kirschning / Tetrahedron 61 (2005) 12121–12130
12129
1.12 Hz), 8.74 (d, 1H, JZ4.90 Hz); MS (m/e) 162 (MC),
135, 109, 81, 45.
1H), 7.07 (m, 2H), 7.14 (d, 1H, JZ3.9 Hz), 7.18 (d, 1H, JZ
5 Hz); 13C NMR d 101.5, 106.9, 108.9, 120, 122.8, 124.3,
128.2, 129.1, 144.6, 147.4, 148.4; MS (m/e) 204 (MC), 145,
102, 87, 63. Anal. Calcd for C11H8O2S: C, 64.69; H, 3.95.
Found: C, 64.67; H, 3.84.
4.9.12. 3-Phenylquinoline (22).40 Pale yellow powder, mp
49–50 8C (Ref.40 mp 52 8C); 1H NMR (CDCl3) d 7.36–7.56
(m, 4H), 7.64–7.73 (m, 3H), 7.80 (d, 1H, JZ8.4 Hz), 8.15
(d, 1H, JZ8.4 Hz), 8.22 (d, 1H, JZ1.88 Hz), 9.18 (d, 1H,
JZ2.28 Hz); MS (m/e) 205 (MC), 176, 151, 126, 102, 88,
76, 63.
4.9.20. 2,30-Bithienyl (33).45 Brown crystals, mp 64–66 8C
(Ref.45 mp 62–64 8C); 1H NMR (CDCl3) d 7.02 (dd, 1H, JZ
4.38, 4.26 Hz), 7.17 (s, 1H), 7.18–7.20 (m, 1H), 7.29–7.31
(m, 2H), 7.34–7.37 (m, 1H); MS (m/e) 166 (MC), 134, 121,
108, 90, 69, 45.
4.9.13. 3-(3,4-Methylenedioxyphenyl)quinoline (23). Pale
yellow powder, mp 110–111 8C; H NMR (CDCl3) d 6.02
1
(s, 2H, –OCH2O–), 6.94 (d, 1H, JZ8.5 Hz), 7.13–7.19 (m,
2H), 7.51–7.59 (m, 1H), 7.65–7.73 (m, 1H), 7.81 (d, 1H, JZ
7.7 Hz), 8.12 (d, 1H, JZ8.3 Hz), 8.18 (d, 1H, JZ2 Hz),
9.11 (d, 1H, JZ2.2 Hz); 13C NMR d 101.7, 108, 109.3,
121.4, 127.3, 128.2, 128.3, 129.4, 129.5, 132.2, 133, 133.8,
147.3, 148.1, 148.8, 150; MS (m/e) 249 (MC), 190, 163,
124, 110, 96, 81, 62. Anal. Calcd for C16H11NO2: C, 77.10;
H, 4.45; N, 5.62. Found: C, 77.00; H, 4.23; N, 5.54.
Acknowledgements
This work was supported by the DFG (Ki 397/6-1). K. M.
Dawood is deeply indebted to the Alexander-von-Humboldt
Foundation for granting him a postdoctoral fellowship
(AGY1113724STP). We thank U. Kunz (Technical
University of Clausthal) for providing us with polymer
glass composite material.
4.9.14. 3-(3-Thienyl)quinoline (24).41 Pale yellow powder;
1
mp 88–89 8C (Ref.41 mp 86–88 8C); H NMR (CDCl3) d
7.45–7.58 (m, 3H), 7.63–7.74 (m, 2H), 7.81–7.86 (dd, 1H,
JZ8.14, 1.12 Hz), 8.12 (d, 1H, JZ8.24 Hz), 8.27 (d, 1H,
JZ2 Hz), 9.20 (d, 1H, JZ2 Hz); 13C NMR d 121.9, 126.4,
127.4, 128.2, 128.4, 129.1, 129.5, 129.6, 132.4, 139.1,
147.4, 149.7; MS (m/e) 211 (MC), 179, 167, 139, 105, 92,
79.
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