Copper-mediated N- and O-arylations with arylboronic acids in a continuous flow microreactor: a new avenue for efficient scalability

Article abstract of DOI:10.1016/j.tetlet.2008.09.159

A continuous flow procedure has been elaborated for the copper(II)-mediated N- and O-arylation of a range of compounds with arylboronic acids using a commercial microreactor setup. The compounds could be continuously generated in good yields paving the way for efficient scalability.

Full text of DOI:10.1016/j.tetlet.2008.09.159

Tetrahedron Letters 50 (2009) 15–18
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper-mediated N- and O-arylations with arylboronic acids in a
continuous flow microreactor: a new avenue for efficient scalability
b
c
a,
*
Brajendra K. Singh a,c, Christian V. Stevens b, , Davy R. J. Acke , Virinder S. Parmar , Erik V. Van der Eycken
*
a Laboratory for Organic and Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, University of Leuven, Celestijnenlaan 200F, B-3001 Heverlee, Leuven, Belgium
b Research group SynBioC, Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure links 653, B-9000 Gent, Belgium
c Bioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi 110 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A continuous flow procedure has been elaborated for the copper(II)-mediated N- and O-arylation of a
range of compounds with arylboronic acids using a commercial microreactor setup. The compounds
could be continuously generated in good yields paving the way for efficient scalability.
Ó 2008 Published by Elsevier Ltd.
Received 19 August 2008
Revised 23 September 2008
Accepted 26 September 2008
Available online 2 October 2008
Keywords:
Copper-mediated
N-Arylation
O-Arylation
Arylboronic acid
Continuous flow
Microreactor
Scalability
Among the C-heteroatom bond forming reactions, the copper-
mediated heteroatom arylation has gained increasing importance.
Independently reported by the groups of Chan,1 Evans2 and Lam3 in
1998, this cross-coupling procedure resolved the long-standing
problem of the simple and mild formation of C(aryl)–O and
C(aryl)–N bonds using an arylboronic acid as the aryl donor in
combination with a base and copper acetate as the catalyst, as
these reactions can be conducted at room temperature in air, pro-
viding a practical advantage over the Buchwald–Hartwig cross-
coupling reaction.4 The method has proven to be applicable to a
wide range of nucleophilic reaction partners including phenols,
amines, anilines, amides, imides, ureas, carbamates, and sulfona-
mides. Also, aromatic heterocycles as imidazoles, pyrazoles, tria-
zoles, tetrazoles, benzimidazoles, and indazoles participate
efficiently in this copper(II)-mediated reaction.5 The scope of the
procedure was expanded by the potential of a catalytic variant
using less than stoichiometric amounts of Cu(OAc)2 employing
oxygen as oxidant or TEMPO/air, pyridinium N-oxide/air or
none scaffold in solution phase7 and on solid support.8 As 2(1H)-
pyrazinones have received considerable interest due to their valu-
able application as scaffolds for the generation of a diverse array of
biologically interesting compound libraries,9 we were keen to
know whether this cross-coupling protocol could be run in a con-
tinuous flow set up paving the way for efficient scalability. Mic-
roreactor technology is a rather new type of technology, which
has gained high interest during the last two decades. The first lit-
erature related to chemistry in microstructured devices appeared
in 1986 in a German patent that described how a microreactor
should be built.10 Since then the interest in the application of mic-
roreactors is growing steadily.11,12 The main scale-up problems of
organic reactions are associated with heat and mass transport,
and shortcomings can lead to thermal runaway reactions. Microre-
actors should guarantee a better mass transfer, a safer handling of
reactions, and a higher selectivity.13 However, the major advantage
of this technology is the scalability.14 A classic scale-up is a time-
consuming and expensive process. By contrast, once a process is
optimized under microreactor conditions, there is no need any-
more to scale up the reactor. Instead several microreactors are
placed in parallel to produce higher quantities. Using this method,
no modifications of the labscale conditions are necessary anymore.
Despite the large interest in copper-mediated heteroatom ary-
lation during the last years,5 to our knowledge no studies are per-
formed yet on the use of microreactors for this purpose. The
microreactor that is used in our study is a commercially available
[{Cu(l-OH)(tmeda)}2]Cl2/oxygen in the presence of Cu(OAc)2 as
the Cu(II)-source.6
We recently reported the usefulness of this copper(II)-mediated
cross-coupling protocol for the N-arylation of the 2(1H)-pyrazi-
* Corresponding authors. Tel.: +32 16 327406.
E-mail addresses: chris.stevens@ugent.be (C. V. Stevens), erik.vandereycken@
chem.kuleuven.be (E. V. Van der Eycken).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.09.159

16
B. K. Singh et al. / Tetrahedron Letters 50 (2009) 15–18
Table 1
Optimization of the flow rate for the N-arylation of pyrazinone 1 using microreactor
technology
Entrya
Residence time (min)
Flow rate (ml/min)
Conversionb (%)
1
2
3
4
5
15
45
60
90
120
1.54
0.52
0.39
0.26
0.20
30
50
70
90
100c
a
All optimization reactions were performed at 25 °C on a 1.0 mmol scale of
pyrazinone 1. The pyrazinone 1 and boronic acid 2a (2 equiv) were dissolved in
DCM (40 mL) and Et3N (1.0 equiv), pyridine (2.0 equiv) and Cu(OAc)2 (1.0 equiv)
were separately dissolved in DCM (40 mL), and both mixtures were simultaneously
brought into the microcapillary by the aid of two separate pumps (with the same
pump rate).
b
The conversion was estimated by quantitative TLC.
This resulted in an isolated yield of 79%.
Figure 1. The applied microreactor: a CYTOSÒ College System, produced by CPC—
Cellular Process Chemistry Systems GmbH; (1) input reagents via two pumps; (2)
microreactor; (3) residence time unit; (4) output reaction mixture.
c
problems of the microreactor. In DMF, the reaction was faster as
compared to DCM as the reaction could be run at elevated temper-
ature. When the reaction was performed at 130 °C for 30 min, a
100% conversion was achieved delivering compound 3 in 72% yield.
However, isolation from the DMF mixture turned out to be diffi-
cult. Therefore, we decided to perform our further investigations
using DCM at rt. We then gradually increased the concentration
of different compounds to 5- and 10-fold, applying the optimized
conditions, that is, a flow rate of 0.2 mg/mL in DCM at rt. Both reac-
tions were running well without any problem. Applying the 10-
fold concentration, that is, reaction on 10.0 mmol of pyrazinone
1, we were able to continuously generate compound 3 in 21 mg
(0.066 mmol) per minute, opening the way for its synthesis on a
multigram scale. However, further increasing the concentration
to a 15-fold (15 mmol of pyrazinone 1) caused clogging problems
of the microreactor due to the low solubility of Cu(OAc)2 in DCM.
To the best of our knowledge, copper(II)-mediated C–N coupling
reactions have never been performed on a multigram scale apply-
ing microreactor technology.
After having established an efficient continuous flow microreac-
tor protocol16 for the N-arylation of pyrazinone 1, we evaluated the
applicability for differently substituted anilines (Scheme 2, Table
2). Thus, aniline 4a (1.0 mmol, 93 mg) and phenylboronic acid 2a
(2.0 mmol, 244 mg) were dissolved in DCM (40 mL), and mixed
in the microcapillary with a solution of Cu(OAc)2 (1.0 mmol,
182 mg), Et3N (1.0 mmol, 101 mg), and pyridine (2.0 mmol,
158 mg) in DCM (40 mL) applying both pumps with a flow rate
of 0.2 mL/min and a residence time of 2 h. The reaction proceeded
well yielding 71% of the N-arylated aniline 5a (Table 2, entry 1).
The concentration could easily be increased to 10-fold resulting
in the formation of 5a at a rate of 10 mg/min. As a proof of concept,
when the reaction was run under conventional conditions applying
the same parameters, the arylation of 1 g of aniline with phenylbo-
ronic acid yielded the N-arylated aniline in 67% in 24 h clearly indi-
cating the usefulness of our microreactor protocol. However, upon
further scale up to 10-fold, we noticed that the reaction could not
CYTOSÒ College System, produced by CPC—Cellular Process Chem-
istry Systems GmbH (Fig. 1).15 The entire device consists of two
piston pumps, the microreactor itself and a residence time unit
(RTU). The microreactor consists of several stacked plates. In a
number of these plates, a path is etched. After stacking the plates
together, a fluid pathway is formed with dimensions in the submil-
limeter range. The microreactor has two inlets. Each inlet flow is
divided into four parallel, flows which are one by one mixed to-
gether in an interdigital mixer. After passing through a mixing
chamber, all parallel flows are once more divided in two flows
each. Finally, all eight flows come together to leave the microreac-
tor as one outlet flow (D).
Our initial investigations of this copper(II)-mediated cross-cou-
pling in a microreactor setup were performed using pyrazinone 1
and phenylboronic acid (Scheme 1). For this purpose, a mixture
of pyrazinone 1 (1 mmol, 238 mg) and boronic acid 2a (2 mmol,
244 mg) in dichloromethane (DCM; 40 mL) was brought into the
microreactor through one pump and a solution of Cu(OAc)2
(1 mmol, 182 mg), Et3N (1 mmol, 102 mg), and pyridine (2 mmol,
160 mg) in DCM (40 mL) through another pump allowing efficient
mixing at rt in the microcapillary (Fig. 1). Different flow rates
resulting in different residence times ranging from 15 to 120 min
were applied (Table 1). When the reaction was performed using
a relatively high flow rate of 1.54 mL/min, approximately 30% con-
version to the desired N-arylated pyrazinone was obtained after
15 min (Table 1, entry 1). Prolonging the residence time to
45 min by lowering the flow rate to 0.52 mL/min resulted in an in-
creased conversion of 50% (Table 1, entry 2). Consequently, when
the reaction was carried out for 120 min, a 100% conversion was
achieved delivering 79% of the desired N-arylated compound 3
after purification (Table 1, entry 5). This is much faster compared
to the required 12 h under conventional conditions.7 Alternative
solvents were screened, but only DMF seemed to be as efficient
as dichloroethane (DCE); acetonitrile and dioxane were unsuccess-
ful to dissolve the copper acetate efficiently resulting in clogging
B(OH)2
H
N
O
S
Microreactor
Cu(OAc)2
N
N
O
S
+
DCM, Et3N/Py (1:2 equiv), rt
Cl
Cl
N
2a
1
3
Scheme 1. N-Arylation of the pyrazinone 1 scaffold.

B. K. Singh et al. / Tetrahedron Letters 50 (2009) 15–18
17
Table 3
B(OH)2
NH2
O-Arylation of differently substituted phenols
H
N
Microreactor
Cu(OAc)2
Entry
Product
R1
R2
Isolated (g)
Yielda (%)
7a24
7b25
7c26
3-OCH3
2-I
4-Et
H
1.44
2.25
1.59
72
69
70
+
1
2
3
DCM, Et3N/Py (1:2 equiv),
rt, 2 h
4-OMe
4-OMe
R2
R2
R1
4 a-d
R1
5 a-f
2a,b
a
All reactions were performed at 130 °C on a 10.0 mmol scale of substituted
phenol. Phenol 6a–c and boronic acid 2a,c (2.0 equiv) were dissolved in DMF
(40 mL) and Et3N (1.0 equiv), pyridine (2.0 equiv) and Cu(OAc)2 (1.0 equiv) were
separately dissolved in DMF (40 mL), and both mixtures were simultaneously
brought into the microcapillary by the aid of two separate pumps at a flow rate of
0.20 mL/min resulting in a residence time of 2 h.
Scheme 2. N-Arylation of anilines using the continuous flow microreactor protocol.
Table 2
N-Arylation of differently substituted anilines
Entry
Product
R1
R2
Isolated (g)
Yielda (%)
1
2
3
4
5
6
5a19
5b20
5c21
5d22
5e
H (4a)
H (4a)
4-Cl (4b)
4-Cl (4b)
2,4,6-Cl (4c)
2,4-NO2 (4d)
H (2a)
3-OEt (2b)
H (2a)
3-OEt (2b)
3-OEt (2b)
3-OEt (2b)
1.2
1.5
1.3
1.7
71
73
67
69
—
B(OH)2
OH
O
Microreactor
Cu(OAc)2
No reactionb
1.7
+
5f23
56
DMF, Et3N/Py (1:2 equiv),
130 °C, 2 h
R2
R2
R1
a
R1
All reactions were performed at 25 °C on a 10.0 mmol scale of the anilines 4a–d.
The aniline 4a–d and boronic acid (2.0 equiv) were dissolved in DCM (40 mL) and
Et3N (1 equiv), pyridine (2.0 equiv) and Cu(OAc)2 (1.0 equiv) were separately dis-
solved in DCM (40 mL), and both mixtures were simultaneously brought into the
microcapillary by the aid of two separate pumps at a flow rate of 0.20 mL/min
resulting in a residence time of 2 h.
6a-c
2a,c
7a-c
Scheme 3. O-Alkylation of substituted phenols.
b
Acknowledgment
Only starting aniline was recovered.
Support was provided by the research fund of the University of
Leuven and the FWO (Fund for Scientific Research—Flanders
(Belgium)).
finish even in 5 days, and the desired N-arylated aniline was iso-
lated in a poor 51% yield next to some unidentified side products
as was indicated by TLC. The optimized microreactor protocol
was further applied to variously substituted anilines, and the cor-
responding N-arylated amines were isolated in gram quantities
with moderate to good yields ranging from 56% to 73% (Table 2, en-
tries 2–4 and 6) except for 2,4,6-trichloroaniline, which is probably
too sterically encumbered (Table 2, entry 5).
The optimized protocol was also demonstrated to work well for
the N-arylation of the aliphatic cyclohexyl amine with phenylbo-
ronic acid. Thus, upon mixing at rt in the microcapillary a solution
of cyclohexyl amine (10 mmol, 990 mg) and phenylboronic acid
(20 mmol, 2.44 g) in DCM (40 mL) with a mixture of Cu(OAc)2
(10 mmol, 1.82 g), Et3N (10 mmol, 1.01 g), and pyridine (20 mmol,
1.58 g) in DCM (40 mL) with a flow rate of 0.2 mL/min, the desired
phenylated compound17 was continuously delivered in 11 mg/min
with an isolated 71% yield.
We could also broaden the scope of the protocol to amides.
Thus, using the same procedure we were able to generate the N-
phenylated caprolactam18 on a 10 mmol scale (1.13 g). The desired
compound was delivered in 83% yield at a rate of 13 mg/min.
Finally, we examined the applicability of the optimized protocol
for the O-arylation of some substituted phenols 6a–c. To our disap-
pointment, when the reaction was run with 6a only a 60% conver-
sion could be achieved even after a residence time of 2 h. However,
when the reaction was performed in DMF at 130 °C in 2 h at a flow
rate of 0.2 mL/min, 100% conversation were obtained, and the com-
pounds 7a–c were isolated in good yields in all the cases (Table 3)
(see Scheme 3).
In conclusion, we have demonstrated that microreactor tech-
nology could be efficiently used for the copper(II)-mediated N-
and O-arylation of various compounds with arylboronic acids. For
the investigated N-arylations, best results were obtained when
performing the reactions in DCM at rt for 2 h, where under conven-
tional conditions these require 12–72 h.1,3,7 However, for the O-
arylation of the investigated phenols it has been proven that
DMF at 130 °C is the condition of choice. These results are opening
the way for efficient scalability of this type of reaction, avoiding te-
dious scaling-up procedures.
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a solution of Cu(OAc)2 (10 mmol, 1.82 g), Et3N (10 mmol, 1.01 g), and pyridine
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