4′-Methylbiphenyl-2-carbonitrile synthesis by continuous flow Suzuki-Miyaura reaction

Article abstract of DOI:10.1016/j.tetlet.2012.05.145

In the present work we report a high selective synthesis of the bicyclic core present in an important angiotensin II inhibitor family of drugs (Sartans) under continuous flow conditions. The key step in our approach was a Suzuki-Miyaura coupling using for the first time the recently described 4-toluylboronic acid MIDA ester.

Full text of DOI:10.1016/j.tetlet.2012.05.145

Tetrahedron Letters 53 (2012) 4166–4168
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
40-Methylbiphenyl-2-carbonitrile synthesis by continuous flow Suzuki–Miyaura
reaction
Gizelda O. D. Estrada a,b, Marcella C. Flores a, Joaquim F. M. da Silva b, Rodrigo O. M. A. de Souza a,
Leandro S. M. e Miranda a,
⇑
a Instituto de Química, Universidade Federal do Rio de Janeiro, Avenida Athos da Silveira Ramos 149, CT Bloco A 622, Cidade Universitária, Rio de Janeiro, CEP 21941-909, Brazil
b Instituto de Química, Universidade Federal do Rio de Janeiro, Rua Hélio de Almeida 40, Pólo de Xistoquímica Prof. Claudio Costa Neto, PXQmed A 107, Cidade Universitária, Rio
de Janeiro, CEP 21941-614, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
In the present work we report a high selective synthesis of the bicyclic core present in an important
angiotensin II inhibitor family of drugs (Sartans) under continuous flow conditions. The key step in our
approach was a Suzuki–Miyaura coupling using for the first time the recently described 4-toluylboronic
acid MIDA ester.
Received 6 May 2012
Revised 26 May 2012
Accepted 29 May 2012
Available online 7 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Sartan
4-Toluylboronic acid MIDA ester
Suzuki–Miyaura cross-coupling
Continuous flow
Introduction
icant effort has been devoted to develop a wide variety of contin-
uous flow techniques to facilitate organic synthesis. On the
The Suzuki–Miyaura reaction is the Pd-catalyzed reaction be-
tween organoboron compounds and an organic halide and is now-
adays the most important approach to the synthesis of biaryls.
These biaryl scaffolds find innumerous applications in the synthe-
sis of natural products,1 pharmaceutical intermediates,2 pesti-
cides,3 and covalent organic frameworks (COFs).4 This scenario
was established due to the low toxicity of the organoboron com-
pounds, the mild reaction conditions, the availability, and easy
preparation of the organoboron coupling partner that are behind
its high acceptance in the chemical synthetic community.5
Despite all these conveniences, a major challenge in these pal-
ladium catalyzed cross coupling reactions lies in separating the
product from the catalyst and as a consequence its recovery when
working on homogeneous systems, leaving the large scale produc-
tion expensive and difficult. On the other hand, solid supported Pd
catalysts have been developed for several cross-coupling reactions
allowing the catalyst’s recovery and recycle and enabling the pro-
duction of palladium free products which avoids the need to purge
the residual transition metal from the final active pharmaceutical
ingredient (API) product.6–10
Suzuki–Miyaura reaction, a board range of solid supports were re-
ported, such as, polymer beads, monolithic supports, silica, and
PdEnCat™. In addition, when compared to homogeneous catalysts,
heterogeneous catalytic systems present lower levels of residual
metals on the final product and the reactions are usually per-
formed in the absence of ligands such as organic phosphines.
For industrial purposes, continuous flow reactions are preferred
to batch reactors due to their greater process control, high produc-
tivity, and improvement of quality/purity and yield.11–13 Several
types of reactors can be used in continuous operation, and among
these, packed bed reactors (PBR) are the most popular due to their
high efficiency, low cost, and ease of construction, operation, and
maintenance.14
In the scope of the Suzuki–Miyaura cross-coupling reactions, the
one involving 2-bromobenzonitriles (1) and 4-methylphenylboron-
ic acid derivatives (2) is an important transformation in the context
of the synthesis of pharmaceutical intermediates,2 since the 40-
methylbiphenyl-2-carbonitrile (3) obtained is present in building
blocks of the angiotensin II inhibitors for the treatment of hyperten-
sion known as the ‘Sartan’ family (4, Fig. 1).
A review on cross coupling reactions under continuous flow
Despite the simplicity of this transformation at first sight, there
have been reports concerning many difficulties in this reaction. The
major drawback reported is the hydrolysis to the corresponding
amide and/or dehalogenation of the nitrile substrate.2 These
hydrolysis products require additional steps of purification which
protocol was published by Buchwald et al.11 and shows that signif-
⇑
Corresponding author.
E-mail
addresses:
leandrosoter@yahoo.com.br,
leandrosoter@iq.ufrj.br
(L.S.M. e Miranda).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.145

G. O. D. Estrada et al. / Tetrahedron Letters 53 (2012) 4166–4168
4167
N N
HN
N
R2
CN
CN
Br
"Pd"
+
R2B
4
2
3
1
4'-methyl-[1,1'-biphenyl]-2-carbonitrile "Sartan" Family Drugs
Figure 1. Building block of the ‘Sartan’ family.
are costly, lowering the chemical and economical efficiency of the
reaction.
Table 2
Suzuki–Miyaura reaction between 2-bromobenzonitrile and 4-toluylboronic acid
MIDA ester (7) under continuous flow
O
Results and discussion
CN
CN
N
O
B
As a first step we have optimized the reaction parameters, that
is, catalyst type, flow rate, and temperature in the reaction be-
tween 2-bromobenzonitrile (1a) and phenylboronic acid (5) as a
model for our target and the results are shown in Table 1.
Br
FibreCat 1007
K2CO3
EtOH:H2O (1:1)
O
+
O
1a
Entry Catalyst
7
3
As it has been shown in Table 1, the FibreCat 1007, when com-
pared with other catalysts, gave the cross-coupling product 6 in
high yields. With this catalyst, on the reaction with 2-bromobenzo-
nitrile (1a) as substrate, we can observe that higher residence time
and higher temperatures can lead to a decrease in yield of the de-
sired product, which is associated with an increase of the dehalo-
Temperature
Flow rate
(mL/min)
Residence time 3a
(°C)
(min)
(%)
1
2
3
4
FibreCat
1007
110
110
120
130
0.3
1.0
0.6
1.0
2
0.6
1
25
25
34
25
0.6
genated product (11%), entry 11. This behavior indicates
a
a
Based on CG-MS analysis. Reaction conditions: 2-Bromobenzonitrile (1,
narrow temperature/flow rate window for optimization. The Fibre-
Cat 1007 catalyst was also essayed in the reaction between the less
reactive 2-chlorobenzonitrile (1b) (entries 13–16) and phenylbo-
ronic acid (5). It can be observed the same influence of flow rate
and temperature on the yields, however with a lower conversion.
The selectivity is dropped with lower flow rates, in this case
not only due to dehalogenation of the nitrile substrate but also
by homocoupling reaction and protodeboration of starting
materials.
1.0 mmol), 4-toluylboronic acid MIDA ester (7, 1.2 mmol), K2CO3 (1.2 mmol),
ethanol/water (12.5 mL:12.5 mL).
MIDA ester (7) and 2-bromobenzonitrile (1a). The choice of work-
ing with the 4-toluylboronic acid MIDA ester (7) comes from the
fact that this group is used for protection of the boronic acid func-
tionality. The development of a cross coupling methodology under
continuous flow conditions for these protected boronic acid deriv-
atives is of great importance once it allows the functionalization of
these derivatives without worrying with the boron Lewis acidity
and the need for deprotection before the cross coupling reaction.
We believe it is an important aspect for the development of boron
based synthetic strategies such as those developed for the ‘Sartan’
family.
With the temperature, catalyst, and flow set for the model reac-
tion, the reaction was performed with the 4-toluylboronic acid
Table 1
Optimization of a Suzuki–Miyaura reaction between 2-halobenzonitrile and phenyl-
boronic acid (5) under continuous flow
The results obtained by the use of the 4-toluylboronic acid
MIDA ester (7) to the synthesis of intermediate 3, is presented in
Table 2.
CN
CN
X
B(OH)2
Pd Cartridge
K2CO3
+
EtOH:H2O (1:1)
5
6
1a-b
Table 3
Recycle continuous flow analysis
Entry Catalyst
X
Temperature
(°C)
Flow rate
(mL/min)
Residence
time (min)
6a
(%)
O
1
2
3
4
5
6
7
8
9
10
11
12
13
14
16
FibreCat
1001
Br
(1a)
110
0.3
1.0
0.3
1.0
0.3
1.0
0.3
1.0
0.3
1.0
0.3
1.0
0.2
0.5
1.0
2
0.6
2
0.6
2
0.6
2
0.6
2
0.6
2
0.6
3
1.2
0.6
15
53
23
91
41
48
24
41
98
97
73
99
53
30
45
CN
CN
N
O
B
Br
Fibrecat 1007
130
110
130
110
130
130
O
+
K2CO3
O
EtOH:H2O (1:1)
Flow rate: 0.6 mL/min
Temp: 120ºC
FibreCat
X00017
Br
(1a)
1a
7
3
Entry
Catalyst
FibreCat 1007
Recirculation time (min)
3a,b (%)
FibreCat
1007
Br
(1a)
1
2
3
4
5
30
60
90
120
150
12
28
37
47
54
Cl
(1b)
a
Based on CG-MS analysis; Reaction conditions: 2-Bromobenzonitrile (1, 1.0
a
Based on CG-MS analysis. Reaction conditions: 2-Halobenzonitrile (1.0 mmol),
phenylboronic acid (5, 1.2 mmol), K2CO3 (1.2 mmol), ethanol/water
(12.5 mL:12.5 mL).
mmol), 4-toluylboronic acid MIDA ester (7, 1.2 mmol), K2CO3 (1.2 mmol), ethanol/
water (12.5 mL:12.5 mL).
b
Isolated yields.

4168
G. O. D. Estrada et al. / Tetrahedron Letters 53 (2012) 4166–4168
Table 4
ready discussed in Tables 1 and 2, an increase in residence time
leads to a decrease in selectivity which is mainly due to dehalogen-
ation of the halonitrile partner, what prevented us from increasing
the length of the catalyst bed or decrease the flow rate.
Suzuki–Miyaura reaction between aryl halides and 4-toluylboronic acid MIDA ester
(7) under continuous flow
O
On the other hand, an increase in residence time could be
achieved by recirculation of the solution through the cartridge, in a
flow rate high enough to maintain the selectivity. We then per-
formed a study under the best condition developed in Table 2 with
different recirculation cycles and the results are presented in Table 3.
With this strategy a great improvement was observed on yield
after 150 min of recirculating the reaction media, which was
accompanied by a very small drop in selectivity, representing a
very important aspect for further developments.
Fibrecat 1007
N
O
Recirculation Time: 150 min
X
Ar
B
Ar
+
K2CO3
O
O
EtOH:H2O (1:1)
Flow rate: 0.6 mL/min
Temp: 120ºC
8a - 8f
7
9a - 9d
Entry
1
Ar–X
9a–9fa (%)
I
The success in the reaction depicted in Table 3 prompted us to
evaluate the scope of the methodology developed, and the results
are presented in Table 4.
(63%)
8a
9a
9b
9c
As it can be seen in Table 4 the methodology developed for the
cross coupling of 4-toluylboronic acid MIDA ester (7) with aryl ha-
lides (8a–f) under continuous flow conditions can be expanded on
aryl iodides and bromines as long as these substrates do not carry
electron releasing groups. These substrates lead to moderate and
good yields as can be seen in entries 1–3 and 5.
O
I
(86%)
2
3
4
O
8b
O
I
Conclusion
(74%)
In conclusion we report the development of the first methodol-
ogy for cross coupling of 4-toluylboronic acid MIDA ester with aryl
halides under continuous flow conditions. This methodology leads
to a high selective synthesis of the bicyclic core present in the ‘Sar-
tan’ drug family.
O
8c
I
NH2
NH2
O
(38%)
8d
Acknowledgment
9d
Br
Br
We thank CAPES, CNPq, FAPERJ, and FINEP for financial support.
References and notes
(56%)
(15%)
5
6
O
O
8e
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9e
9f
O
8f
a
Based on CG-MS analysis. Reaction conditions: Aryl halides (0.5 mmol), 4-tol-
uylboronic acid MIDA ester (7, 0.6 mmol), K2CO3 (0.6 mmol), ethanol/water
(12.5 mL:12.5 mL).
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It is important to note that to the best of our knowledge, this is
the first study of the Suzuki reaction using boronic acid MIDA ester
under continuous flow conditions. As can be seen the 4-toluylbo-
ronic acid MIDA ester (7) presents lower conversion than the phen-
ylboronic acid (5). An attempt to increase the yield would be to
increase the residence through lower flow rates. As we have al-
11. Buchwald, S. T.; Noel, T. Chem. Soc. Rev. 2011, 40, 5010–5029.
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