Catalyst controlled regioselective Suzuki cross-coupling of 2-(4-bromophenyl)-5-chloropyrazine

Article abstract of DOI:10.1016/j.tetlet.2013.06.068

The Suzuki cross-coupling between 2-(4-bromophenyl)-5-chloropyrazine and a range of aryl boronic acids has been investigated. The regioselectivity of the reaction can be switched between the aryl bromide and pyrazinyl chloride positions by changing the ligand associated with the palladium catalyst. Xantphos has shown excellent selectivity for the pyrazinyl chloride, with most other ligands showing preferential selectivity for the aryl bromide.

Full text of DOI:10.1016/j.tetlet.2013.06.068

Tetrahedron Letters 54 (2013) 4529–4532
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Tetrahedron Letters
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Catalyst controlled regioselective Suzuki cross-coupling
of 2-(4-bromophenyl)-5-chloropyrazine
⇑
⇑
Christopher P. Ashcroft , Steven J. Fussell , Katie Wilford
Pfizer, Chemical Research & Development, Sandwich Laboratories, Sandwich CT13 9NJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The Suzuki cross-coupling between 2-(4-bromophenyl)-5-chloropyrazine and a range of aryl boronic
acids has been investigated. The regioselectivity of the reaction can be switched between the aryl bro-
mide and pyrazinyl chloride positions by changing the ligand associated with the palladium catalyst.
Xantphos has shown excellent selectivity for the pyrazinyl chloride, with most other ligands showing
preferential selectivity for the aryl bromide.
Received 16 April 2013
Revised 3 June 2013
Accepted 14 June 2013
Available online 24 June 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Suzuki
Chemoselectivity
Pyrazine
Xantphos
Boronate
The palladium-catalysed cross-coupling reaction of organobo-
ron compounds with organic halides and triflates (the Suzuki–
Miyaura reaction), is one of the most widely used reactions for
the formation of carbon–carbon bonds. First published by Akira Su-
zuki in 1979, the reaction is firmly established within the pharma-
ceutical industry as the method of choice for the preparation of
biaryl compounds.1 Whilst chemoselective discrimination between
halides and pseudohalides is relatively common in the Suzuki–
Miyaura literature,2,3 examples where the site of reactivity can
be efficiently switched by changing the ligand, are much rarer.
Herein we report the results of the chemoselective Suzuki–Miya-
ura cross coupling reaction between 2-(4-bromophenyl)-5-chloro-
pyrazine and a range of boronic esters and acids. The position of
reaction can be efficiently discriminated between the bromophe-
nyl and chloropyrazinyl sites by simply changing the ligand.
During the course of alternative route investigations for a series
of antiviral targets, the synthesis of a key triaryl intermediate 3
was required. It was hoped that 3 could be accessed via a chemo-
selective Suzuki–Miyaura cross-coupling between 2-(4-bromophe-
nyl)-5-chloropyrazine (1) and the benzimidazole boronic ester 2
(Scheme 1). As an initial starting point, two catalyst systems which
had given good results on related substrates were investigated
namely Pd(dppf)Cl 2ÁDCM and Pd(t-Bu3P)2.
switched to 1:20, again with appreciable levels of over-reaction
impurity 5. These somewhat surprising results prompted us to fur-
ther investigate this coupling reaction.
A preliminary investigation of the Suzuki–Miyaura coupling of 1
with 2 was initiated by examining a variety of pre-ligated palla-
dium catalysts supplied by Johnson Matthey. The aim was to afford
3 in high yields whilst minimising 4 and the over-reaction impu-
rity 5. Several bases and solvents were also studied and the results
are summarised in Table 1. Whereas high conversions (>65%) to 4
were generally observed with most electron-rich catalysts, entries
5–10, gratifyingly, high conversion into desired compound 3, with
negligible formation of regioisomer 4 or over reaction product 5,
was obtained using the wide bite angle or trans-spanning diphos-
phine, Pd(Xantphos)Cl2 with Na2CO3 as the base and 1,4-dioxane
as the solvent (entry 1). Compared with Pd(dtbpf)Cl2, entry 8, the
reaction goes with a complete switch in reactivity from the aryl
bromide to the chloropyrazine tail. Interestingly both Pd(dppf)Cl2
and Pd(PPh3)4 showed encouraging chemoselectively for the chlo-
ropyrazine, but suffered over-reaction to 5. However, the screening
data illustrated that the only catalyst to give high chemoselectivity
for the chloropyrazine position was in fact Pd(Xantphos)Cl2.
N
The regioselectivity observed for these two systems was
intriguing. Using Pd(dppf)Cl2ÁDCM, the ratio of products was 9:1
favouring regioisomer 3 over 4, with an appreciable amount of
the over-reaction impurity, 5. However, with Pd(t-Bu3P)2, the ratio
N
N
H
N
Boc
N
N
N
Boc
N
H
⇑
Corresponding authors. Tel.: +44 (0)1304646782; fax: +44 (0)1304652318.
E-mail address: Steven.Fussell@pfizer.com (S.J. Fussell).
5
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.068

4530
C. P. Ashcroft et al. / Tetrahedron Letters 54 (2013) 4529–4532
Br
N
N
Cl
Pd catalyst, ligand,
N
N
Cl
N
O
B
base, solvent
N
O
+
N
N
N
N
Boc
N
H
Br
N
Boc
N
H
N
Boc
N
H
1
2
3
4
Scheme 1.
the donating properties of the oxygen, and dicyclohexylphosphino
ferrocene 10 to investigate a different structural moiety with a
similar bite angle. t-Bu-Xantphos 7 was also chosen to investigate
the effect of increased steric bulk around the chelating
phosphines.
The results in Table 2 seemingly indicate no obvious correla-
tion between regioselectivity and bite angle, when comparing
ligand 6 to either 9 or 10. Alternative Xantphos type ligands
7–9 resulted in reactions with a reduction in regioselective
control, giving higher levels of both 4 and 5. Nixantphos 8
intriguingly gave increased levels of the desired product 3 com-
pared with DPEPhos 9, suggesting that a rigid catalyst structure
is preferred. However, Xantphos 6 was the only catalyst system
to afford 3 with high conversions illustrating the unique proper-
ties of this catalyst system.
Table 1
Palladium catalysed Suzuki–Miyaura screen performed in a range of solvents at 80 °C
for 16 h
Entry Catalyst
Base
Solvent
% 3a % 4a % 5a
1
2
3
4
5
6
7
8
9
Pd(Xantphos)Cl2
Na2CO3 1,4-Dioxane
Cs2CO3
Cs2CO3
Na2CO3 MeCN
K3PO4
83
48
32
3
1
6
21
6
3
23
23
1
Pd(dppf)Cl2
Pd(PPh3)4
MeCN
1,4-Dioxane
Pd(XPhos)Clb
Pd(amphos)Cl2
Pd(t-Bu3P)2
1,4-Dioxane
0
0
0
0
0
0
69
74
77
82
87
88
5
10
9
6
6
Na2CO3 1,4-,1,4-Dioxane
PdCl2[P(o-Tol)3]2 K3PO4
1,4-Dioxane
Pd(dtbpf)Cl2
Pd(QPhos)2
cataCXiumÒ
Na2CO3 MeCN
Na2CO3 1,4-Dioxane
Cs2CO3
10
C
1,4-Dioxane
5
a
Conversion by HPLC.
High levels of protodeboration observed.
b
The most chemoselective catalyst systems for both the chloro-
pyrazine (Xantphos) and bromophenyl positions (dtbpf) were se-
lected for scale up (see Supplementary data for detailed
procedures). Gratifyingly, these reactions performed very similarly
to the screen leads. The Xantphos reaction gave 1.7% of the regio-
isomer 4, which was reduced to none detected after crystallisation,
with an isolated yield of 3 at 76%. The dtbpf reaction resulted in a
75% yield with no regioisomer detected after crystallisation.
Table 2
Palladium-catalysed Suzuki–Miyaura screen performed in 1,4-dioxane/water, with
Na2CO3 as the base and Pd(OAc)2 as the precatalyst, 80 °C, for 24 h
a
a
Ligand
Bite angle (°)
% 3a
% 4
% 5
6b
7c
8
9
10
108
130
111
107
108
83
5
45
18
25
1
2
14
22
20
3
1
19
17
18
a
b
c
O
O
Conversion by HPLC.
Preformed Johnson Matthey catalyst used.
High levels of chloropyrazine remained.
P
P
P
P
Ph
Ph Ph
Ph
t-Bu t-Bu t-Bu t-Bu
6
7
N
Reports in the literature of chemoselective cross-couplings
O
O
using a Xantphos (6) complex are infrequent. In the palladium cat-
alysed carbonylative Sonogashira reaction a Xantphos ligand was
used to selectively couple an aryl triflate with phenyl acetylene
in the presence of an aryl chloride.4 Furthermore, in the amination
of 5-bromo-2-chloropyridine a palladium-Xantphos complex is re-
ported to give 5-amino-2-chloropyridine as the major product.5
More recently a chemoselective alkyl–alkyl Suzuki–Miyaura cou-
pling utilising an iron–Xantphos complex has been illustrated.6
Strotman et al. also reported the unique properties of a palla-
dium-Xantphos catalyst in Suzuki coupling of 2,4-diiodooxazole.7
As in our example, the Xantphos ligand was shown to mediate
highly selective coupling where alternative ligands tested, PPh3,
X-Phos and dppf, gave large amounts of the unwanted bis-arylated
product from over-reaction. This literature report, coupled with
the success of the Pd(Xantphos)Cl2 catalyst in our system, encour-
aged us to further probe into the effect of ligands on the regioselec-
tivity of this Suzuki reaction.
P
P
P
P
Ph
Ph Ph
Ph
Ph
Ph Ph
Ph
9
8
P
P
Fe
10
To study the general applicability of the catalytic control for the
regioselective coupling we investigated a range of alternative aryl-
boronic acids and esters with 2-(4-bromophenyl)-5-chloropyra-
zine (1). As illustrated in Table 3, Pd(Xantphos)Cl2 was able to
catalyse the coupling of a range of arylboronic acids at the chloro-
pyrazine position, to give substituted biaryl products in excellent
yields. Conversely, Pd(dtbpf)Cl2 switched the selectivity to the
A range of ligands was chosen based on the ligand type with a
bite angle similar to that of Xantphos. To investigate the influence
of the electronic properties and bite angle, Nixantphos 8 was
chosen as a good comparison. DPEPhos 9 was selected to assess

C. P. Ashcroft et al. / Tetrahedron Letters 54 (2013) 4529–4532
4531
Table 3
Palladium catalysed Suzuki–Miyaura screen performed with range of boronate esters and 1 in dioxane/water, with Na2CO3 as the base, at 80 °C, for 24 h
R
R
N
N
Cl
N
N
N
N
Br
R
R
11
12
13
Entry
1
Boronate
Catalyst
% 11a
% 12a
% 13a
HO
OH
Pd(Xantphos)Cl2
Pd(dtbpf)Cl2
68
0
0
66
17
27
B
OH
HO
Pd(Xantphos)Cl2
Pd(dtbpf)Cl2
75
0
0
88
9
12
B
2
3
HO
HO
HO
OH
Pd(Xantphos)Cl2
Pd(dtbpf)Cl2
74
0
0
98
6
2
B
OMe
OH
Pd(Xantphos)Cl2
Pd(dtbpf)Cl2
47
3
0
93
7
0
B
4
5
6
Ac
OH
Pd(Xantphos)Cl2
Pd(dtbpf)Cl2
44
5
0
78
10
7
B
NO2
O
Pd(Xantphos)Cl2
Pd(dtbpf)Cl2
73
0
0
87
12
13
O
B
Pd(Xantphos)Cl2
Pd(dtbpf)Cl2
73
0
0
86
12
9
O
O
B
7
OH
a
Conversion by HPLC.
bromophenyl position, to give the regioisomeric biaryl products in
very high yields (Table 3, entries 1–3).
way to extend this methodology to alternative bi-functional
cross-coupling reactions.
In conclusion, we have demonstrated the chemoselective Pd-
catalysed Suzuki–Miyaura cross-coupling of 2-(4-bromophenyl)-
5-chloropyrazine with a range of heteroaryl boronic acids. The
ligand associated with various Pd catalysts has been shown to
play a crucial role in determining the chemoselectivity of the
cross-coupling reaction. By selecting the appropriate ligand, the
aryl group can be installed at either the bromophenyl or chloro-
pyrazine positions giving access to both regioisomers During the
experimental survey, the Pd(Xantphos)Cl2 catalyst was shown to
be unique at facilitating the highly chemoselective coupling at
the chloropyrazine position, whereas other ligands tended to
show selectivity for the bromophenyl position. Studies are under-
Acknowledgments
We would like to thank Robert Walton, David Blakemore, Alan
Happe, Lorraine Murtagh and Michael Paradowski for useful dis-
cussions and input during the progress of this work.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.06.
068.

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