Arylation of pyridines via suzuki-miyaura cross-coupling and pyridine-directed C-H activation using a continuous-flow approach

Article abstract of DOI:10.1055/s-0033-1339870

Suzuki-Miyaura cross-coupling reactions between heteroaryl bromides and arylboronic acids were performed employing a continuous-flow approach using a simple flow reactor designed in-house. Pd(PPh₃)₄ was used as catalyst, and arylboronic acids containing both electron-withdrawing and electron-donating groups were applied. The coupling process required 23 minutes of residence time to be completed and generally good yields were obtained. Subsequent arylation of 2-phenyl pyridine was carried out via a C-H activation strategy using substituted bromobenzene compounds and a ruthenium(II) catalyst. To the best of our knowledge in this work we present for the first time the possibility of performing intermolecular C-H activation in a continuous-flow system. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1339870

LETTER
▌2411
lAettrerylation of Pyridines via Suzuki–Miyaura Cross-Coupling and Pyridine-
Directed C–H Activation Using a Continuous-Flow Approach
Arylation of Pyridines
Maria Christakakou, Michael Schön, Michael Schnürch,* Marko D. Mihovilovic
Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163-OC, 1060 Vienna, Austria
Fax +43(1)588019163616; E-mail: michael.schnuerch@tuwien.ac.at
Received: 31.07.2013; Accepted after revision: 05.09.2013
Dedicated to Professor Manfred Schlosser who is missing in the Swiss alps he loved so much
or neurons. The aforementioned compounds shall be synthesized via
continuous-flow chemistry to allow rapid library generation.
Abstract: Suzuki–Miyaura cross-coupling reactions between het-
eroaryl bromides and arylboronic acids were performed employing
a continuous-flow approach using a simple flow reactor designed
in-house. Pd(PPh3)4 was used as catalyst, and arylboronic acids con-
taining both electron-withdrawing and electron-donating groups
were applied. The coupling process required 23 minutes of resi-
dence time to be completed and generally good yields were ob-
tained. Subsequent arylation of 2-phenyl pyridine was carried out
via a C–H activation strategy using substituted bromobenzene com-
pounds and a ruthenium(II) catalyst. To the best of our knowledge
in this work we present for the first time the possibility of perform-
ing intermolecular C–H activation in a continuous-flow system.
Michael Schön (middle left) was born in Vienna (Austria) in 1984.
He finished his diploma studies in ‘Synthesis of pharmaceutically rel-
evant, disubstituted 5-membered heterocycles’ at the University of
Applied Sciences for Biotechnology (FH Campus Vienna) in 2007. In
2008, he started at Vienna University of Technology, synthesizing
colchicine derivatives. From January 2009 on, he is working on his
PhD thesis in the group of Prof. Marko D. Mihovilovic conducting re-
search in the field of furan derivatives from renewable carbohydrate
sources. During his work, implementation of flow chemistry methods
and custom reactor design play a major role.
Michael Schnürch (middle right) was born in Klagenfurt, Austria in
1978. He started to study chemistry in Vienna in 1996 and carried out
his diploma and PhD thesis in the group of Professor Peter Stanetty.
In 2005 he received his PhD from Vienna University of Technology
(VUT). During his PhD studies, he was on a four-month sabbatical in
Canada where he worked in the group of Professor Victor Snieckus at
Queens University (Kingston, Ontario). He was then postdoc with
Professor Dalibor Sames at the Columbia University in New York
City (as Erwin Schrödinger fellow) and conducted research in the
field of decarboxylative arylation reactions of sp3 centers. After his
return, he became full university assistant at VUT. He was granted a
noteworthy research grant by the Austrian Science Foundation (FWF)
which allows him to carry out independent research in the field of
asymmetric C–H activation. Additionally, he is about to defend his
habilitation to become assistent professor. His research interests are
located in the field of synthesis of heterocyclic compounds for the ma-
nipulation of cell differentiation, asymmetric C–H activation, green
chemistry, and flow chemistry.
Marko D. Mihovilovic (right) was born in Steyr, Upper Austria,
Austria in 1970. He is married to Dr. Barbara Krumpak-Mihovilovic
(14.7.2001) and has two children, Gregor and Martin. After the A-lev-
els in Linz, he started to study Technical Chemistry/Organic Chemis-
try in 1988 at the Vienna University of Technology (VUT), Vienna,
Austria. His diploma thesis was entitled ‘Synthesis of Thieno[2,3-
d]thiadiazole Derivatives’ and was supervised by Professor Peter Sta-
netty. He started his PhD thesis in 1994 (‘Synthesis of Azasteroid Par-
tial Structures as Potential Inhibitors of the Ergosterol Biosynthesis’)
again in the group of Professor Peter Stanetty and finished this work
in June 1996. From 1994 to 1998 he was research assistant at the In-
stitute of Organic Chemistry (IOC). He was then on two postdoctoral
stays as Erwin Schrödinger Fellow of the FWF (Project no. J1471-
CHEM ‘Designer Yeasts – New Bioreagents in Enantioselective Syn-
thesis’) with Professor Margaret M. Kayser, University of New
Brunswick, Saint John, N.B., Canada and Professor Jon D. Stewart,
University of Florida, Gainesville, Florida, USA. From 1999 to 2003
he was again university assistant at the Institute of Applied Synthetic
Chemistry (IAS, former IOC), VUT. In November 2003 he received
his habilitation (venia docendi) in the field of bioorganic chemistry
and was promoted to ‘University Dozent’ (assistant professor) at the
IAS, VUT. Since March 2004 he is associate university professor at
the IAS, VUT. In May 2008 he declined the appointment to full pro-
fessor in bioorganic chemistry at Johannes Kepler University Linz,
Austria. From 2009 up to now he coordinates the graduate school pro-
gram AB-Tec (Applied Bioscience Technology) at Vienna University
of Technology. Since January 2013 he is the head of institute at the
Institute of Applied Synthetic Chemistry (Vienna University of Tech-
nology, Vienna, Austria).
Key words: heterocycles, cross coupling, flow chemistry, C–H ac-
tivation, catalysis
The formation of arylated heterocycles is a process of
great importance due to their presence in molecules with
interesting biological activities or interesting properties in
material science.1 To synthesize such compounds, the Su-
zuki–Miyaura cross-coupling reaction is a very successful
method and is considered as a general and versatile protocol
for the formation of C–C bonds.2 Beneficial features are
the stability of the boronic acids towards moisture and air
as well as the comparatively low toxicity of byproducts.
Many examples of Suzuki–Miyaura reactions have been
reported in the literature using standard batch conditions.
Recently, significant scientific interest has been raised to
further develop this strategy in a process-friendly fashion.3
Maria Christakakou (left) received her degree in chemistry from
Aristotle University of Thessaloniki and then she continued her stud-
ies with a Master of Science in Chemical Research under the supervi-
sion of Professor Laurence Harwood. After the completion of her
master thesis she joined Professor’s Marko Mihovilovic group as a re-
search assistant and subsequently continued with a PhD thesis under
his supervision. Her research project aims at the development of syn-
thetic small molecules (SSMs) which have the ability to convert an
easily accessible cell type, for example, a muscle cell, into nerve cells
SYNLETT 2013, 24, 2411–2418
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DOI: 10.1055/s-0033-1339870; Art ID: ST-2013-D0723-L
© Georg Thieme Verlag Stuttgart · New York

2412
M. Christakakou et al.
LETTER
In this regard, continuous-flow chemistry has gained in-
creasing recognition in the synthetic community due to
several advantages such as rapid optimization of reaction
conditions, easy scale up, high reaction rates, efficient
heat transfer, and potential automation.4 The latter point is
of particular interest to the pharmaceutical industry since
it enables accelerated synthesis of diverse compound li-
braries leading to more time-efficient structure–activity
relationship studies. Furthermore, performing reactions in
flow provides an inherently safer process which has many
additional advantages such as increased surface-to-vol-
ume ratios, excellent mass and heat transfer capabilities,
facile scale-up, and eventually even higher product
yields.5 Several examples for cross-coupling reactions in
continuous flow have been reported to date.6
Table 1 Screening Conditions for Palladium-Catalyzed Suzuki–Mi-
yaura Cross-Coupling Reactions between 2-Bromopyridine (1) and
Phenyl Boronic Acid (2a)
B(OH)2
"Pd"
+
N
N
Br
"base"
1a
2a
3a
Entrya
Base
[Pd]b
Conv. (%)c
1
K3PO4
K3PO4
Cs2CO3
Cs2CO3
K2CO3
K2CO3
diti
Pd(OAc)2
Pd(PPh3)4
Pd(OAc)2
Pd(PPh3)4
Pd(OAc)2
Pd(PPh3)4
45
82
52
90
35
92
2
3
4
Within this work, our efforts were focused on synthesiz-
ing several arylated pyridines and further decorating these
products via C–H activation chemistry taking advantage
of an in-house developed continuous-flow reactor system.
Recently, C–C bond formation via C–H activation has
stirred much attention since these transformations allow
direct use of a C–H bond for the C–C coupling step.7 To
the best of our knowledge this is the first example of a in-
termolecular direct arylation reaction under continuous-
flow conditions since only one intramolecular example
was disclosed, so far.8
5
6
a R ti
1 (1 i ) 2 (1 2
i ) 1
l% t l t
col to the respective flow system. Initially, it was tried to
use an immobilized palladium catalyst in a prepacked car-
tridge but due to significant leaching of the catalyst and
concomitant lower conversion over time this approach
was abandoned early on.
Alternatively we used a flow system designed in our lab-
oratory consisting of one (or potentially more) syringe
pump(s) and an aluminum reactor. The reactor is wrapped
around with a coil which can be of different materials such
as steel or perfluoroalkoxy (PFA). The reactor is placed
on top of a hot plate (see Supporting Information) in order
to adjust to the required temperature. The syringe pump is
connected with the reactor through the coil. This system
allows performing reactions with ease in flow when it is
not required to pressurize a reaction mixture. Early on
Pd(PPh3)4 was identified as best performing catalyst and
hence it was chosen for further optimization of the reac-
We began our investigation optimizing the reaction con-
ditions for the Suzuki–Miyaura coupling of 2-bromopyri-
dine (1) and phenylboronic acid (2a). Since the reactions
should be carried out in continuous flow ultimately, it had
to be assured that the reaction solution is homogeneous at
all times at room temperature. This is a prerequisite since
before and after the heated reaction zone the tubing is at
room temperature. Hence, we conducted several batch ex-
periments with microwave irradiation initially, using dif-
ferent catalysts, bases, solvents, and temperatures in order
to identify conditions enabling a transfer of the procedure
to continuous flow without clogging the system. Selected
screening results are summarized in Table 1 (for a com-
plete list see Supporting Information). In all cases biphe-
nyl and bipyridine were observed as side products (see
Supporting Information). It has to be mentioned that in the
initial series of batch experiments encapsulated palladium
catalysts were used since such heterogeneous catalysts
could be packed in a cartridge eventually. However, when
such a method was used in flow significant palladium
leaching occurred and this approach was abandoned.
Table 2 Optimization in Flowa
Entry
Catalyst load Flow rate Residence time Conv.
(mol%)
(mL/min) (min)
(%)b
1
2
3
4
5
6
0.35
0.35
1.05
1.4
0.5
0.5
0.5
0.5
0.5
0.5
8
23
23
23
23
23
30
40
59
63
80
82
We screened two different catalysts, Pd(PPh3)4 and
Pd(OAc)2, three different bases, K3PO4, Cs2CO3, and
K2CO3 with 180 seconds hold time. Pd(OAc)2 performed
1.7
2.1
significantly worse than Pd(PPh3)4. The different bases a Reaction conditions: 1 (1equiv), 2a (1.2 equiv), K2CO3, Pd(PPh3)4,
dioxane–H2O (1:1), 90 °C, 0.05 M; steel coil.
showed only negligible differences in conversion. Over-
all, we observed the best relation between conversion, ho-
b As determined by GC using dodecane as internal standard.
mogeneity, and reaction time using the conditions shown
in Table 1, entry 6.
Transferring these conditions to a flow process required a
second round of optimization in order to adjust the proto-
Synlett 2013, 24, 2411–2418
© Georg Thieme Verlag Stuttgart · New York

LETTER
Arylation of Pyridines
2413
tion conditions in flow (Table 2) under homogeneous con- boronic acid were used the PFA coil performed signifi-
ditions. cantly better.
Starting with low catalyst loading (0.35 mol%) and a res- Electron-donating substituents on the boronic acids gave
idence time of eight minutes gave only 30% conversion generally better yields. This is also true for sterically hin-
(Table 2, entry 1). Extending the reaction time to 23 min- dered o-tolylboronic acid (2c) where 91% yield were ob-
utes gave only a minor improvement to 40% (Table 2, en- tained in the PFA coil (Table 3, entry 9). p-
try 2). However, increasing the catalyst loading to an Methoxyphenylboronic acid (2d) gave a good yield al-
amount of 2.1% ultimately gave a satisfying conversion of ready in the steel coil (Table 3, entries 10 and 11). 3-Ni-
82% (Table 2, entry 6). These conditions are a good com- trophenylboronic acid (2e) gave a low yield of 12% in the
promise between catalyst loading and flow rate and, steel coil using 1.2 equivalents of 2e (Table 3, entry 12).
hence, subsequent substrate-scope investigations were Increasing this to 3.0 equivalents improved the yield to
performed using this protocol. It has to be mentioned that 51% (Table 3, entry 13). A comparable yield was obtained
the process in flow takes significantly longer than the in the PFA coil with 1.2 equivalents of 2e already (Table
batch experiment. This can be attributed to a difference in 3, entry 14). 3-Cyanophenylboronic acid (2f) gave an ac-
temperature eventually: temperature measurement in mi- ceptable yield only in the PFA coil and 3.0 equivalents of
crowave is usually very accurate. In the flow process we 2f (Table 3, entry 19).
measure the temperature of our aluminum block but can-
not measure the temperature inside the coil. Hence there
Using 4 as substrate in combination with 2a gave the best
results using 3.0 equivalents of 2a and the PFA coil (80%,
could be a significant difference. Additionally, a higher
Table 3, entry 23). Hence, all subsequent coupling reac-
temperature at the metal center in microwave cannot be
tions on 4 were carried out under these conditions. Best
excluded due to the better microwave absorbing capacity
tolerated were methyl substituents no matter whether in 2-
of the metal compared to the solvent.
or 4-position of the boronic acid (Table 3, entries 24 and
Then, 2-bromopyridine and 3-bromopyridine were cou- 25). 4-Methoxy-, 3-nitro-, and 3-cyanophenylboronic ac-
pled with various boronic acids bearing electron-donating ids gave similar yields just below 60% (Table 3, entries
or electron-withdrawing groups (Scheme 1). We were 26–28).
also interested to investigate if the material of the coil had
Comparing results using the steel and the PFA coil mate-
any influence on reaction performance. Therefore we con-
rial it was found that PFA performed significantly better.
ducted experiments either using a steel coil or a PFA coil
The overall better performance of the PFA coil could be
and in some cases both for comparison. The advantage of
due to the fact that the metal coil might undergo metal–
the PFA coil is the easier handling and the lower price (ap-
metal interactions with the metal center of our palladium
prox. 40% less) and easier to wash and unclog when it is
catalyst resulting in decreased catalyst activity. However,
necessary.
for a detailed explanation more experiments would be
necessary (e.g., analyzing the inner surface of the steel
coil) which was beyond the scope of this work.
R1
Besides Suzuki–Miyaura coupling, we were also interest-
N
ed in direct arylation reactions under continuous flow.
N
Br
Br
K2CO3
Pd(PPh3)4
Due to the ubiquity of C–H bonds, their use as a ‘function-
al group’ has been explored in recent years by an increas-
ing number of research groups.9 One common substrate
for direct functionalization reactions is 2-phenylpyridine
where the pyridine nitrogen directs the catalyst in ortho
position of the adjacent phenyl ring.10 Since we could ef-
ficiently synthesize this compound with our flow process,
we decided to investigate its further application in C–H
activation chemistry, also via a continuous-flow ap-
proach. To the best of our knowledge there is no literature
precedence for direct intermolecular arylation in continu-
ous-flow systems. Recently, one example of intramolecu-
lar direct arylation of aryl bromides was reported.8
Syringe pumps were used as the preferred flow system,
and ultrasound irradiation was employed for avoiding
clogging of the microreactors due to a precipitate formed
during the experiment, a technique applied previously by
Buchwald and Jensen.11
1
3a–f
R1
+
dioxane–H2O
90 °C
B(OH)2
2a–f
R1
N
N
4
5a–f
Scheme 1 Suzuki reaction with 2-bromopyridine and 3-bromopyri-
dine with arylboronic acids in dioxane–H2O (1:1). Reagents and con-
ditions: (a) 1 (1equiv), 2a (1.2 equiv), K2CO3, Pd(PPh3)4, dioxane–
H2O (1:1), 90 °C, 0.05 M. (b) As determined by GC using dodecane
as internal standard.
Table 3, entries 1–4 show the coupling reaction of 1 with
phenylboronic acid (1.2 or 3.0 equiv) in both coil materi-
als. It can be seen that when 1.2 equiv of boronic acid
were used the results are comparable for both coil materi-
als (Table 3, entries 1 and 3). However, when 3.0 equiv
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2411–2418

2414
M. Christakakou et al.
LETTER
Table 3 Suzuki Reaction with 2-Bromopyridine and 3-Bromopyridine with Arylboronic Acids in Dioxane–H2O (1:1) and 2.1 mol% Catalyst
Loading
Entry
Substrate
Boronic acid
Boronic acid (equiv) Coil type Product
Yield (%)
(HO)2B
1
2
3
4
1
1
1
1
1.2
3.0
1.2
3.0
steel
steel
PFA
PFA
64
76
68
93
N
N
N
N
2a
3a
3b
3c
(HO)2B
1
1
5
6
1.2
3.0
steel
steel
60
61
2b
(HO)2B
7
8
9
1
1
1
1.2
3.0
1.2
steel
steel
PFA
62
64
91
2c
(HO)2B
1
1
10
11
1.2
3.0
steel
steel
85
89
OMe
NO2
OMe
NO2
2d
3d
3e
3f
(HO)2B
12
13
14
15
1
1
1
1
1.2
3.0
1.2
3.0
steel
steel
PFA
PFA
12
51
44
45
N
N
2e
(HO)2B
CN
16
17
18
19
1
1
1
1
1.2
3.0
1.2
3.0
steel
steel
PFA
PFA
4
6
24
45
CN
2f
(HO)2B
20
21
22
23
4
4
4
4
1.2
3.0
1.2
3.0
steel
steel
PFA
PFA
18
53
64
80
N
N
N
2a
5a
5b
5c
(HO)2B
24
25
4
4
3.0
3.0
PFA
PFA
87
75
2b
(HO)2B
2c
Synlett 2013, 24, 2411–2418
© Georg Thieme Verlag Stuttgart · New York

LETTER
Arylation of Pyridines
2415
Table 3 Suzuki Reaction with 2-Bromopyridine and 3-Bromopyridine with Arylboronic Acids in Dioxane–H2O (1:1) and 2.1 mol% Catalyst
Loading (continued)
Entry
Substrate
Boronic acid
Boronic acid (equiv) Coil type Product
Yield (%)
OMe
(HO)2B
26
4
3.0
PFA
58
OMe
NO2
N
N
N
2d
5d
5e
5f
(HO)2B
NO2
27
28
4
4
3.0
3.0
PFA
PFA
58
2e
(HO)2B
CN
CN
56
2f
Prerequisites for direct arylation in flow are of course the
same as for cross-coupling, most importantly homogenei-
ty of the reaction solution at all times. Initially, we wanted
to use a palladium catalyst as well since then it would be
possible to combine both reaction steps in a single opera-
tion potentially. When testing literature-known palladi-
um-catalyzed protocols12 it turned out that they did not
result in homogeneous solutions and, additionally, reac-
tion times of 24 hours were required in batch; far too long
for a useful continuous-flow process. Therefore, we aban-
doned palladium-catalyzed methods and decided to
switch to ruthenium catalysts which have been used in
many C–H activation protocols effectively.13
Ph
N
7a
Br
Ru(II) complex
Ph3P, base
N
+
Ph
3a
6a
N
Ph
8a
Scheme 2 Ruthenium-catalyzed ortho arylation of 2-phenyl pyri-
dine with bromobenzene
Again we started screening for homogeneous reaction
conditions. A promising method was reported by Oi et
al.14,15 where NMP was used as solvent, benzenerutheni-
um(II) chloride dimer as catalyst, and K2CO3 as a base at
120 °C for 20 hours. Even though the base is insoluble in
this case, NMP allows increasing the reaction temperature
and shorten the reaction time below one hour simultane-
ously. The initial screening was conducted with 3a as sub-
strate, bromobenzene 6a as aryl source, and different
bases under microwave irradiation (Scheme 2). Addition-
ally, different temperatures and ruthenium(II) catalysts
were tested (see Supporting Information for details).
The biggest issue was the bad solubility of the base. We
tested several bases. Some of them were the following:
K2CO3, Cs2CO3, NaOH, KOAc, KOt-Bu, and NaOt-Bu.
With Cs2CO3 we received promising GC yields of 7a and
8a (MW, 1.5 equiv of bromobenzene, 2 equiv of the base,
120 °C, 30 min, 74% GC yield), but the reaction mixture
was not homogeneous and when adding various amounts
of water to dissolve the base a significant drop of the GC
yield was observed. In other solvents such as DMF, anis-
ole, or mixtures of NMP–EtOAc, the base was not soluble
at all (see Supporting Information).
We found that both catalysts investigated, benzeneruthe-
nium(II) chloride dimer and dichloro(p-cymene)rutheni-
um(II) gave almost identical results in terms of
conversion. Since the latter is significantly cheaper we
continued further optimization using this catalyst.
When KOt-Bu and NaOt-Bu were used, we observed bet-
ter solubility but again a significant drop of the GC yield
to only 2–3%. Using NaOH or KOAc gave inhomoge-
neous solutions as well.
Changing to an organic base such as DABCO or Hünig’s
base solved the solubility issue but led again to a signifi-
cant drop in yield (1–3% GC yield). Attempts to improve
solubility by changing the concentration did not help ei-
ther.
Furthermore we observed no difference under inert condi-
tions (as used by Oi et al.) or under air. Therefore all
screening reactions as well as compound syntheses have
been carried out under air.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2411–2418

2416
M. Christakakou et al.
LETTER
The breakthrough came by switching to DBU where we Overall these results show that an increase in electron
obtained a homogeneous solution which we used for fur- density favors monoarylation and vice versa.
ther optimization in flow. We performed several screen-
ings regarding equivalents of bromobenzene, DBU,
R
catalyst loading, and a synopsis of the most important re-
sults is provided in Table 4 (for a more comprehensive ta-
ble see Supporting Information). In all cases we found that
mixtures of 7a and 8a were formed. However, for the op-
N
timization we looked at overall conversion and yield.
7a–e
Table 4 Optimization in Flowa
Br
(p-cymene)Ru(II)Cl2
+
+
R
N
Entry
Aryl source DBU
Cat. load
(mol%)
GC yield of
Ph3P, DBU, 160 °C
R
(equiv)
(equiv)
7a + 8a (%)b
3a
6a–e
1
2
3
4
5
1.5
1.5
1.5
3
1
2
4
4
4
2.5
2.5
2.5
2.5
5
29
35
55
58
89
N
8a–e
R
3
Scheme 3 Arylation of 2-phenylpyridine (3a) with substituted bro-
mobenzenes
a Reaction conditions: DBU, dichloro(p-cymene)ruthenium(II)chlo-
ride dimer, 10 mol% Ph3P, NMP, 0.25 M, 30 min residence time, 160
°C.
Table 5 Isolated Yieldsa
b As determined by GC using dodecane as internal standard.
Entry
R
7a–e (%) 8a–e (%) Combined yield (%)
One equivalent of DBU gave 29% GC yield of 7a and 8a
(Table 4, entry 1). Increasing the amount up to four equiv-
alents gave an improvement to 55% (Table 4, entry 3). In-
creasing the catalyst loading to 5% and the equivalents of
bromobenzene to three finally gave a good GC yield of
89% of 7a and 8a (Table 4, entry 5). Next we tried to
transfer these conditions to a continuous-flow process.
1
2
3
4
5
6a H
26
59
17
3
69
0
95
59
51b
74
0
6b OMe
6c Me
6d CF3
6e NO2
34
71
0
0
a Reaction conditions: aryl source (3 equiv), DBU (4 equiv), 5 mol%
Applying the optimized conditions (Table 3, entry 5), we
were able to isolate 7a in 26% and 8a in 69% yield, re- catalyst, 10 mol% Ph3P, NMP, 0.25 M, 30 min residence time, 160
°C.
spectively (ratio 1:2.65). This result differs from Oi’s
findings where a total yield of 82% of the same two prod-
ucts was obtained but in favor of the monoarylated one
b For this example we isolated an inseparable mixture of the mono-
and bisarylated product and the ratio of mono- to bisphenylated prod-
uct was determined as 1:2 by NMR analysis.
(6.7:1). However, in his case only one equivalents of bro-
mobenzene was used. Using 2.214 or 3.015 equivalents, 8a
Next, we aimed at the synthesis of bisarylated compounds
bearing two different aryl substituents. Monoarylated
products 7a and 7b were used as starting materials for a
second arylation step with bromobenzene (Scheme 4).
was formed exclusively. Of course a different base was
applied which can be responsible for the observed differ-
ences.
The electronic nature of the halide had a significant influ-
ence on the product distribution (Scheme 3). Electron-rich
bromoanisole gave exclusively the monoarylated product
7b (59%, Table 5, entry 2). Bromotoluene favored the for-
mation of bisarylated 8c over monoarylated 7c (1:2, Table
5, entry 3). When an electron-withdrawing substituent
was present as in 4-bromo-trifluoromethylbenzene, the
bisarylated product was massively favored (1:23.7) with
good overall yield (Table 5, entry 4). A nitro group was
not tolerated (Table 5, entry 5), however, this we have ob-
served in ruthenium-catalyzed arylations previously and
can be attributed to the ability of the nitro group to coor-
dinate to ruthenium leading to catalyst inactivation.16
R
R
Br
(p-cymene)Ru(II)Cl2
N
+
Ph3P, DBU, 160 °C
N
7a–b
6a–e
8a,f
8a: R = H 44% (5 mol% cat.)
8f: R = OMe 24% (7.5 mol% cat.)
Scheme 4 Arylation of the monophenylated product with bromoben-
zene
Synlett 2013, 24, 2411–2418
© Georg Thieme Verlag Stuttgart · New York

LETTER
Arylation of Pyridines
2417
To our surprise the yield of 8a (Scheme 4) was signifi- electron-donating and electron-withdrawing groups were
cantly lower starting from 7a (44%) compared to the reac- obtained in good yields and within 23 minutes residence
tion starting from 2-phenylpyridine (3a). The reason for time.
this observation is not clear. A possible explanation is that
Furthermore, to the best of our knowledge, in this work
after the insertion of the Ru(II) into the C–H bond and the
we present for the first time the possibility of performing
first arylation, ruthenium stays coordinated to the pyridine
metal-catalyzed C–H activation, using a continuous-flow
nitrogen (to some extent) leading to a second arylation
process in an intermolecular fashion. Both transforma-
rapidly. However, when the substrate is the already mono-
tions are operationally simple since they do not require in-
substituted compound 7a the phenyl group exhibits steric
ert techniques making them user-friendly and effective at
hindrance, and precoordination of ruthenium to the pyri-
dine nitrogen might be more difficult and hence the reac-
tion might be slower overall. Since at 160 °C catalyst
decomposition/inactivation is also an issue, a lower reac-
tion rate will give lower yields. By increasing the catalyst
loading to 7.5 mol% we received 59% yield which is in
the same time.17
Acknowledgment
The authors gratefully acknowledge the Austrian Science Fund
(FWF, projects P21202-N17 and S107) and the Vienna University
agreement with our explanation. In order to support our of Technology Doctorate Program ‘Catalysis Materials and Tech-
nology – CatMat’ for financial support.
hypothesis further, we performed a time course for the ar-
ylation of 3a with bromobenzene. If the catalyst dissoci-
ates from pyridine completely after the first arylation step
Supporting Information for this article is available online at
we should see accumulation of 7a at the beginning and
only small amounts of 8a. When the concentration of 7a
increases and simultaneously that of 3a decreases, 7a be-
comes the preferred substrate and the amount of 8a will
increase. However, if our hypothesis is true, we should see
formation of 8a to a similar extent compared to 7a already
from the beginning and no accumulation of 7a. Indeed, 8a
is the major product from the very beginning (Table 6, en-
tries 1–5) which supports our line of argument.
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
References and Notes
(1) (a) Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N.
Beilstein J. Org. Chem. 2011, 7, 442. (b) Heterocycles in
Life and Society: An Introduction to Heterocyclic Chemistry
and Biochemistry and the Role of Heterocycles in Science,
Technology, Medicine, and Agriculture; Pozharsky, A. F.;
Soldatenkov, A. T.; Katritzky, A. R., Eds.; John Wiley and
Sons: Chichester, 1997. (c) Bellus, D. Lect. Heterocycl.
Chem. 1987, 9, 65. (d) Muller, T.; Bräse, S. Angew. Chem.
Int. Ed. 2011, 50, 11844. (e) Rasmussen, S. C.; Schwiderski,
R. L.; Mulholland, M. E. Chem. Commun. 2011, 47, 11394.
(f) Maly, K. E. J. Mat. Chem. 2009, 19, 1781. (g) Elbing, M.;
Bazan, G. C. Angew. Chem. Int. Ed. 2008, 47, 834.
(2) For reviews on cross-coupling on heterocyclic substrates,
see: (a) Schnürch, M.; Flasik, R.; Khan, A. F.; Spina, M.;
Mihovilovic, M. D.; Stanetty, P. Eur. J. Org. Chem. 2006,
3283. (b) Schroeter, S.; Stock, C.; Bach, T. Tetrahedron
2005, 61, 2245. (c) Wang, J.-R.; Manabe, K. Synthesis 2009,
1405. (d) Djakovitch, L.; Batail, N.; Genelot, M. Molecules
2011, 16, 5241. (e) Slagt, V. F.; de Vries, A. H. M.; de Vries,
J. G.; Kellog, R. M. Org. Process Res. Dev. 2010, 14, 30.
(f) Fairlamb, I. J. S. Chem. Soc. Rev. 2007, 36, 1036.
(g) Banwell, M. G.; Goodwin, T. E.; Ng, S.; Smith, J. A.;
Wong, D. J. Eur. J. Org. Chem. 2006, 3043. (h) Nicolaou, K.
C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44,
4442. (i) Magano, J.; Dunetz, J. R. Chem. Rev. 2011, 111,
2177.
We also subjected 7b to a second arylation step. From the
previous result (Table 5, entry 2), it can be expected that
arylation of 7b might be difficult and slow. Indeed, a yield
of only 24% was obtained (with 7.5 mol% catalyst) which
underlines the importance of electronic effects on the aryl
substituents.
Table 6 Time Course
Entry
Time (min)
7a (%)a
8a (%)a
1
2
3
4
5
5
10
20
30
60
33
30
20
15
9
45
62
76
82
88
(3) Noël, T.; Buchwald, S. L. Chem. Soc. Rev. 2011, 40, 5010.
(4) Glasnov, T. N.; Kappe, C. O. Adv. Synth. Catal. 2010, 352,
3089.
a Conversion as determined by GC using dodecane as internal stan-
dard.
(5) (a) Baxendale, I. R.; Hayward, J. J.; Lanners, S.; Ley, S. V.;
Smith, C. D. In Microreactors in Organic Synthesis and
Catalysis; Wirth, T., Ed.; Wiley-VCH: Weinheim, 2008,
84–122. (b) Irfan, M.; Glasnov, T. N.; Kappe, C. O.
ChemSusChem 2011, 4, 300.
Overall, we have synthesized a series of Suzuki–Miyaura
coupling products employing the efficient and robust
technology of a continuous-flow system, using a reactor
designed in-house and Pd(PPh3)4 as cheap catalyst. The
low cost required for the production of the reactor and its
simple design makes it readily available to synthetic
chemists (construction plans are provided in the Support-
ing Information). Suzuki–Miyaura coupling products of
pyridine bromides and arylboronic acids containing both
(6) For selected examples, see: (a) Kirschning, A.; Solodenko,
W.; Mennecke, K. Chem. Eur. J. 2006, 12, 5972.
(b) Wegner, J.; Ceylan, S.; Kirschning, A. Adv. Synth. Catal.
2012, 354, 17. (c) Solodenko, W.; Wen, H.; Leue, S.;
Stuhlmann, F.; Sourkouni-Argirusi, G.; Jas, G.; Schönfeld,
H.; Kunz, U.; Kirschning, A. Eur. J. Org. Chem. 2004, 3601.
(d) He, P.; Haswell, S. J.; Fletcher, P. D. I. Appl. Catal., A
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2411–2418

2418
M. Christakakou et al.
LETTER
(15) Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.; Miyano, S.;
2004, 274, 111. (e) Wilson, N. S.; Sarko, C. R.; Roth, G. P.
Org. Process Res. Dev. 2004, 8, 535. (f) Baxendale, I. R.;
Griffiths-Jones, C. M.; Ley, S. V.; Tranmer, G. K. Chem.
Eur. J. 2006, 12, 4407. (g) Nagaki, A.; Kenmoku, A.;
Moriwaki, Y.; Hayashi, A.; Yoshida, J.-i. Angew. Chem. Int.
Ed. 2010, 49, 7543. (h) Noel, T.; Musacchio, A. J. Org. Lett.
2011, 13, 5180. (i) Noel, T.; Kuhn, S.; Musacchio, A. J.;
Jensen, K. F.; Buchwald, S. L. Angew. Chem. Int. Ed. 2011,
50, 5943.
Inoue, Y. Org. Lett. 2001, 3, 2579.
(16) (a) Dastbaravardeh, N.; Kirchner, K.; Schnürch, M.;
Mihovilovic, M. D. J. Org. Chem. 2012, 78, 658.
(b) Dastbaravardeh, N.; Schnürch, M.; Mihovilovic, M. D.
Eur. J. Org. Chem. 2013, 2878. (c) Dastbaravardeh, N.;
Schnürch, M.; Mihovilovic, M. D. Org. Lett. 2012, 14, 1930.
(d) Dastbaravardeh, N.; Schnürch, M.; Mihovilovic, M. D.
Org. Lett. 2012, 14, 3792.
(7) (a) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110,
1147. (b) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q.
Angew. Chem. Int. Ed. 2009, 48, 5094.
(8) Zhang, L.; Geng, M.; Teng, P.; Zhao, D.; Lu, X.; Li, J.-X.
Ultrason. Sonochem. 2012, 19, 250.
(17) Preparation of 2-Aryl- and 3-Aryl Derivatives 3a–f and
5a–f
To a round-bottomed flask was added the appropriate
amount of 2-bromo- or 3-bromopyridine (1 or 4, 1 equiv, 1
mmol), boronic acid 2a–f (1.2 equiv, 1.2 mmol), K2CO3 (2
equiv, 276 mg, 2 mmol), Pd(PPh3)4 (2.1 mol%, 24 mg, 0.021
mmol), and a dioxane–H2O mixture as solvent (1:1, 20 mL).
The mixture was stirred for 5 min at r.t. and was then filtered
through filter paper, before being transferred to the syringe
pump. The residence time was 23 min, and the temperature
of the heating plate was set to 90 °C. The inner diameter of
the capillary was 1 mm. The flow rate was 0.695 mL/min,
and the volume of the reactor was 16 mL.
(9) For reviews on C–H activation, see: (a) Engle, K. M.; Mei,
T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788.
(b) Du Bois, J. Chemtracts 2005, 18, 1. (c) Davies, H. M. L.;
Loe, O. Synthesis 2004, 16, 2595. (d) Davies, H. M. L.;
Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861. (e) Godula,
K.; Sames, D. Science 2006, 312, 67. (f) Yeung, C. S.; Dong,
V. M. Chem. Rev. 2011, 111, 1215. (g) Zhang, C.; Tang, T.;
Jiao, N. Chem. Soc. Rev. 2012, 41, 3464. (h) Ackermann, L.
Chem. Rev. 2011, 111, 1315. (i) Jazzar, R.; Hitce, J.;
Renaudat, A.; Sofack-Kreitzer, J.; Baudoin, O. Chem. Eur. J.
2010, 16, 2654. (j) Schnürch, M.; Dastbaravardeh, N.;
Ghobrial, M.; Mrozek, B.; Mihovilovic, M. D. Curr. Org.
Chem. 2011, 15, 2694.
(10) (a) Sersen, S.; Kljun, J.; Pozgan, F.; Stefane, B.; Turel, I.
Organometallics 2013, 32, 609. (b) Pozgan, F.; Dixneuf, P.
H. Adv. Synth. Catal. 2009, 351, 1737. (c) Oezdemir, I.;
Demir, S.; Cetinkaya, B.; Gourlaouen, C.; Maseras, F.;
Bruneau, C.; Dixneuf, P. H. J. Am. Chem. Soc. 2008, 130,
1156. (d) Oi, S.; Fukita, S.; Inoue, Y. Chem. Commun. 1998,
2439. (e) Yu, B.; Yan, X.; Wang, S.; Tang, N.; Xi, C.
Organometallics 2010, 29, 3222. (f) Yoshikai, N.;
Matsumoto, A.; Norinder, J.; Nakamura, E. Synlett 2010,
313. (g) Prades, A.; Poyatos, M.; Peris, E. Adv. Synth. Catal.
2010, 352, 1155.
(11) (a) Hartman, R. L.; Naber, J. R.; Zaborenko, N.; Buchwald,
S. L.; Jensen, K. V. Org. Process Res. Dev. 2010, 14, 1347.
(b) Noel, T.; Naber, J. R.; Hartman, R. L.; McMullen, J. P.;
Jensen, K. F.; Buchwald, S. L. Chem. Sci. 2011, 2, 287.
(c) Kuhn, S.; Noel, T.; Gu, L.; Heider, P. L.; Jensen, K. V.
Lab-on-a-Chip 2011, 11, 2488.
(12) (a) Koley, M.; Dastbaravardeh, N.; Schnürch, M.;
Mihovilovic, M. D. ChemCatChem 2012, 4, 1696. (b) Chu,
J.-H.; Tsai, S.-L.; Wu, M.-J. ChemInform 2010, 41, 3757.
(13) For reviews, see: (a) Wencel-Delord, J.; Droge, T.; Liu, F.;
Glorius, F. Chem. Soc. Rev. 2011, 40, 4740. (b) Arockiam,
P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112,
5879. (c) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev.
2002, 102, 1731. (d) Kakiuchi, F.; Chatani, N. Ruthenium-
Catalyzed Reactions via sp C–H, sp2 C–H, sp3 C–H, and C–
Halogen Bond Activations, In Ruthenium in Organic
Synthesis; Murahashi, S.-I., Ed.; Wiley-VCH: Weinheim,
2004, 219–255.
Reference NMR Spectra for 2-(4-methoxyphenyl)-
pyridine (3d)
1H (200 MHz CDCl3): δ = 3.86 (s, 3 H), 6.95–7.05 (m, 2 H),
7.13–7.23 (m, 1 H), 7.62–7.79 (m, 2 H), 7.90–8.01 (m, 2 H),
8.60–8.71 (m, 1 H). 13C (50 MHz, CDCl3): δ = 55.5 (q),
114.3 (d), 120.0 (d), 121.6 (d), 128.3 (d), 132.1 (s), 136.9 (d),
149.6 (d), 157.2 (s), 160.6 (s).
Preparation of ortho-Arylated 2-Phenylpyridine
Derivatives 7a–e, 8a–f
To a round-bottomed flask was added the appropriate
amount of 2-arylpyridine derivative 7a or 7b (1 equiv, 0.25
mmol), the appropriate bromobenzene derivative 6a–e (3
equiv, 0.75 mmol), DBU (4 equiv, 152 mg, 1 mmol), Ph3P
(10 mol%, 6.5 mg, 0.025 mmol), dichloro(p-
cymene)ruthenium(II) dimer [5 mol%, 7.6 mg, 0.0125
mmol; with the exception of the synthesis of 8f, in which 7.5
mol% of dichloro(p-cymene)ruthenium(II) dimer were used
(7.5 mol%, 11.5 mg, 0.01875 mmol) and NMP as solvent (1
mL)]. The mixture was stirred at r.t. until complete
dissolution of all reagents. Then this solution was transferred
to the syringe pump system. The flow rate was set to 0.533
mL/min which corresponded to a residence time of 30 min,
and the temperature of the heating plate was set to 160 °C.
After pumping through the reaction mixture, 20 mL pure
solvent was pumped through as well. The inner diameter of
the capillary was 1 mm. The volume of the reactor was 16
mL.
Reference NMR spectra for 2-[4′-methoxy-(1,1′-
biphenyl)-2-yl]pyridine (7b)
1H (200MHz, CDCl3): δ = 3.78 (s, 3 H), 6.72–6.82 (m, 2 H),
6.90 (dt, J = 7.8, 1.0 Hz, 1 H), 7.01–7.15 (m, 3 H), 7.33–7.50
(m, 4 H), 7.61–7.73 (m, 1 H). 13C (50 MHz, CDCl3): δ = 55.3
(q), 113.7 (d), 121.4 (d), 125.6 (d), 127.4 (d), 128.6 (d),
130.6 (d), 130.6 (d), 130.9 (d), 133.8 (s), 135.4 (d), 139.5 (s),
140.3 (s), 149.6 (d), 158.6 (s), 159.6 (s).
(14) Oi, S.; Funayama, R.; Hattori, T.; Inoue, Y. Tetrahedron
2008, 64, 6051.
Synlett 2013, 24, 2411–2418
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