An easy route for the synthesis of pyrazine-2,3-dicarbonitrile 5,6-bis-substituted derivatives using a palladium catalyst

Article abstract of DOI:10.1016/j.tetlet.2012.06.102

An easy synthetic method for the preparation of pyrazine-2,3-dicarbonitrile 5,6-bis-substituted derivatives using Pd-catalyzed cross coupling reaction (Sonogashira, Suzuki, Heck) is described. The reaction conditions allow preparing symmetrical and unsymmetrical bis-substituted products in moderate to high yields, as precursors for the preparation of highly substituted symmetrical and non-symmetrical aza-phthalocyanines with well-defined spectral properties.

Full text of DOI:10.1016/j.tetlet.2012.06.102

Tetrahedron Letters 53 (2012) 4824–4827
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An easy route for the synthesis of pyrazine-2,3-dicarbonitrile 5,6-bis-substituted
derivatives using a palladium catalyst
⇑
Hasrat Ali, Johan E. van Lier
Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12th Avenue North, Sherbrooke, QC, Canada J1H 5N4
a r t i c l e i n f o
a b s t r a c t
Article history:
An easy synthetic method for the preparation of pyrazine-2,3-dicarbonitrile 5,6-bis-substituted deriva-
tives using Pd-catalyzed cross coupling reaction (Sonogashira, Suzuki, Heck) is described. The reaction
conditions allow preparing symmetrical and unsymmetrical bis-substituted products in moderate to high
yields, as precursors for the preparation of highly substituted symmetrical and non-symmetrical
aza-phthalocyanines with well-defined spectral properties.
Received 5 June 2012
Revised 19 June 2012
Accepted 24 June 2012
Available online 14 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
5,6-Disubstituted-2,3-pyrazine
Porphyrazines
Pd-catalyst cross coupling reaction
PDT
Phthalocyanines
Photodynamic therapy (PDT) is a new alternative treatment of
cancer involving the combined action of a photosensitizer (PS),
molecular oxygen, and light.1 Most PS advanced for PDT are based
on the porphyrin and phthalocyanine (Pc) chromophore. The aza
analogs of Pc (aza-Pc) are heterocyclic Pc analogs that likewise
can serve as PS for PDT.2 The interest in such structural modification
is related to the simultaneous introduction of both electron-donat-
ing and -accepting groups across a delocalized organic framework.
The extent of the hypsochromic shift of the Q-band in the electronic
spectra of the aza analogs of Pc, naphthalocyanines (NPc), and
anthracyanines is strongly influenced by the presence of exocyclic
nitrogen atoms resulting from the aza substitution in the fused
benzo rings. Applications of these macrocyclic chromophores range
from optical data storage, signal processing, and optical imaging, to
biological, diagnostic, and therapeutic applications.3 The signifi-
cance of organic materials chemistry is contrasted by its limited
synthetic accessibility. The ability to form C–C bonds in a single step
makes this one of the most attractive approaches to create or mod-
ify organic molecules. Transition metal catalysts with wide spread
activities expand the application of metal-catalyzed coupling reac-
tions to a variety of functionalities to be introduced into selected
substrates. This in turn allows the preparation of more elaborate
and multifunctional synthons to access a variety of building
blocks.4 Pd-catalysts have emerged as extremely powerful tools
for the construction of carbon–carbon bonds.5 Considerable
progress has been made in the use of cross coupling reactions
developed by Sonogashira,6 Suzuki,7 Heck,8 Stille, 9 and Buchwald.10
Consequently Pd-catalysts have also been exploited for modifi-
cations of porphyrins and Pc derivatives.11 The phthalonitriles and
their nitrogen-rich congeners, the pyrazines, serve as convenient
starting materials for the preparation of functionalized Pc and
aza-Pc. The generation of suitable precursors has been the key to
the success of these reactions.
Tetrapyrazinoporpyrazines are conveniently assembled by a
base-induced cyclotetramerization of dicyanopyrazines, which in
turn are obtained by the condensation of diaminomaleonitrile (3)
with an appropriate
a-diketone in acetic acid. Compared to the
availability of phthalonitrile derivatives, methods for the prepara-
tion of pyrazine-2,3-dicarbonitrile are limited and thus there exists
a need for efficient methods to synthesize such building blocks. In
this communication we studied Pd-catalyzed coupling procedures
to obtain a variety of 5,6-substituted pyrazine-2,3-dicarbonitrile
derivatives.
The strong electron withdrawing capability of the 2,3-dicyano-
pyrazine moiety makes it possible to afford various nucleophilic
substitutions at 5- and 6-positions. Thus various nucleophiles,12
including amines,13 thiolates,14 or alkyloxides15 were used to syn-
thesize many types of pyrazine oriented heterocyclics.16
The effect of aza substitution on the absorption spectra becomes
more pronounced in the case of linearly conjugated aza-Pc. Acety-
lenic units enlarge the
p-systems of the chromophore, inducing
bathochromic shifts in the electron absorption and emission spec-
tra. Furthermore, terminal alkynyl groups can serve as covalent
linkers for the assembly of delocalized multi-chromosphere chains.
⇑
Corresponding author. Tel.: +1 819 564 5409; fax: +1 819 564 5442.
E-mail address: johan.e.vanlier@usherbrooke.ca (J.E. van Lier).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.102

H. Ali, J. E. van Lier / Tetrahedron Letters 53 (2012) 4824–4827
4825
This structural motif can be exploited to devise materials with un-
R
R
R
ique electronic and/or optical properties for organic light-emitting
diodes, chromophores with non-linear optical properties, and effi-
cient PS for PDT.
The key building block for such reactions requires the presence
of an acetylenic a-diketone (2). The earlier reported method to pre-
Cl
Cl
N
CN
CN
(PPh3)4Pd(0)
N
CN
CN
CuI, Na2CO3
N
N
THF, 80-85 °C
5
6
R =
pare 2 from pentyllithium and oxalyl chloride (1) is not generally
applicable.17 This rather lengthy, four-step procedure starts from
the readily available propargyl aldehyde diethyl acetals. An alter-
native approach for the synthesis of this key component involves
the reaction of two equivalents of LiBr, Cu-acetylide (prepared
in situ by transmetallation of Li-acetylide with CuBr) to convert
oxalyl chloride into the corresponding compound 2 in 50–80%
yields (Scheme 1).18
The Pd-catalyzed reaction of terminal alkynes with aryl/vinyl
halides and triflated derivatives is usually achieved in the presence
of copper, known as the Sonogashira reaction. Organic iodide, bro-
mide, and triflate are frequently used as substrates while the use of
organic chloride is noticeably uncommon, although the latter are
available at low cost and with wider diversity. It has however been
reported that coupling of activated arylchloride, particularly nitro-
gen containing heteroaryl chloride, affords N-heteroaromatic
compounds.19
(b)
(a)
(65%)
(60%)
OH
OH
c
( )
d
( )
(75%)
(60%)
(e)
(f)
(g)
C4H9
CF3
(80%)
(70%)
(80%)
(i)
h
( )
N
(j)
Fe
(65%)
(80%)
Scheme 2.
(70%)
Based on this information we initially attempted Sonogashira
cross coupling with alkynyl derivatives using the commercially
available, low cost precursor 2,3-dicyano-5,6-bis-chloropyrazine
(5). In a typical reaction, compound 5 was coupled with 1-hexade-
cyne using (TPP3)4Pd(0), copper iodide and sodium carbonate as a
base in THF at 80–85 °C for 4 h. After purification, the product was
isolated in 60% yield. Using this protocol, the coupling reaction was
also performed with various alkynyl derivatives having different
functional groups and aromatic moieties (Scheme 2). Using trieth-
ylamine as a base either gave low yields or undesired products. At-
tempts to couple 3-ethynyl pyridine and 10-undecynoic acid under
these reaction conditions failed. Attempted coupling reactions
using other Pd-catalysts with or without ligand, also were
unsuccessful.
together with unreacted starting material. The chloro group of
the mono-substituted product was further reacted to prepare
unsymmetrical bis-substituted pyrazine derivatives. Treatment of
7 and 8 with substituted alkynyl derivatives, gave compounds 9
and 10 in good yields using the above Sonogashira Pd–Cu catalyzed
reaction conditions (Scheme 3).
5-Amino-6-chloro-2,3-dicyanopyrazine (11) is also commer-
cially available and was likewise used as a starting material for
Cl
Cl
N
CN
CN
N
A previously reported coupling procedure can only provide
symmetrically, bis-substituted pyrazine derivatives.16 In order to
prepare unsymmetrical 5,6-bis-substituted derivatives we devel-
oped coupling conditions using stoichiometry, yielding isolated
mono-chlorinated, mono-substituted products that were subjected
to different Pd-catalyzed coupling reaction conditions to afford the
desired unsymmetrical products. Thus coupling of compound 5
with phenyl acetylene or 4-ethynyl-N,N-dimethylaniline in equal
molar ratio under Sonogashira catalyzed reaction conditions, gave
mono-substituted mono-chlorinated derivatives 7 and 8 in 70–75%
yields along with bis-substituted products 6e and 6h in 10–15%
5
R
CuI, Na2CO3
THF, 80-85 °C
(PPh3)4Pd(0)
N
N
N
CN
CN
N
CN
CN
Cl
(75%)
(70%)
Cl
7
N
8
N
N
CN
CN
O
O
R
N
N
CN
CN
R
H
Cl
Cl
N
9
BuLi, CuBr,
LiBr
R
O
O
R
2
1
R =
10
(75%)
NC
NC
R
NH2
(a)
Fe
(75%)
AcOH
NH2
3
CN
b
( )
70%
Fe
N
N
CN
CN
c
( )
R
4
(80%)
Scheme 1.
Scheme 3.

4826
H. Ali, J. E. van Lier / Tetrahedron Letters 53 (2012) 4824–4827
Pd-catalyzed coupling reactions. Compound 11 was treated with a
number of alkynes using, CuI, Na2CO3 in THF at 80 °C. After purifi-
cation the HRMS analysis of the products revealed a single cou-
pling product. Furthermore both aliphatic and aromatic alkynes
reacted under these conditions and various functional groups were
tolerated (Scheme 4). Compared to the unsuccessful reaction of
compound 5, compound 11 gave coupling product with both 3-
ethynyl pyridine and 10-undecynoic acid. While our work was in
progress, Keivanloo et al.20 reported the reaction of 5-(alkyl-aryla-
mino)-6-chloropyrazine-2,3-dicarbonitrile with phenyl acetylene,
catalyzed by Pd–Cu in the presence of sodium lauryl sulfate as a
surfactant in water, which gave 5,6-bis-substituted-5H-pyr-
role{2,3-b}pyrazine-2,3-dicarbonitrile, while aliphatic alkynes
gave only reduced product. In contrast to this recent report our
reaction conditions did not yield any cyclized product, instead a
broad range of non-cyclized coupling products were obtained.
Pyrazine derivatives directly attached to aryl and heteroaryl
derivatives were prepared using diaminomaleonitrile and corre-
NC
NC
NH2
NH2
O
O
R
R
+
3
13
AcOH
N
Cl
Cl
N
CN
CN
R
CN
CN
Ligand
Pd2(dba)3,
THF, H2O, K2CO3
80-85 °C
N
R
N
5
14
R =
a
( )
b
( )
C4H9
(65%)
(60%)
OCH3
c
( )
(60%)
Scheme 5.
sponding a
-diketone (Scheme 5).21 Among Pd-catalyzed cross-cou-
pling processes, the Suzuki reaction using aryl or vinyl halide with
boronic acids has emerged as the most versatile reaction amiable
to industrial application. A general and efficient synthesis of 5-aryl
imidazo[1,5-a]pyrazines by palladium-catalyzed coupling of the
corresponding 8-substituted derivatives with aryl halides has been
described.22 We developed an alternative method to prepare such
compounds using the Suzuki reaction. Compound 5 treated with
phenylboronic acid as the coupling partner, in the presence of aq.
sodium bicarbonate, (TPh3)4Pd(0) in toluene did not afford the de-
sired product. Using K3PO4, Pd(OAc)2, and 2-(di-t-butylphosphi-
no)biphenyl as ligand, gave bis-substituted 14a in very low
yields along the mono-chlorinated substituted product and its re-
duced analog.
gave symmetrical bis-substituted derivatives 14b–c in 70–80%
yields (Scheme 5).
In order to prepare unsymmetrical pyrazine derivatives, com-
pounds 7 and 8 were used as staring materials. Using the above
reaction conditions products 15 and 16 substituted with two dif-
ferent groups, one directly attached and the second group attached
via a triple bond, were obtained (Scheme 6). Subsequently com-
pound 11 was also treated under the Suzuki reaction condition,
which gave pyrazine derivatives 17 bearing an amino and directly
attached aryl group (Scheme 7).
The UV spectra of the bis-substituted pyrazines bearing alkyl
substitutions were similar to those of the parent molecule. In con-
trast aryl substituted pyrazines showed a red-shift when compared
to the parent molecule (e.g., 6b vs 6e, 346 vs 379 nm). The aryl
derivative containing an N-methyl group gave a pronounced
blue-shift (e.g., 6h vs 6b, 494 vs 379 nm). The effect of the naph-
thalene substituent on the absorption spectrum is an even stronger
bathochromic shift, showing a maximum at 424 nm compared to
378 nm for the analog substituted with a phenyl group. The site
of attachment of the aryl substituent also affects the absorption
maximum. Thus when the aryl group is directly attached to the
pyrazine moiety, as in 14a, the bathochromic shift is less
Changing the ligand to 20-dicyclohexylphosphino-2,6-dime-
thoxy-3-sulfonato-1,10biphenyl hydrate sodium salt in the pres-
ence of K2CO3 in H2O:CH3CN resulted in 60% conversion
providing product 14a in 50% yield. Trifluoroborate coupling sys-
tems proved to be more reactive than the corresponding boronic
acids. Thus compound 5 treated with Pot.2-methoxyphenyltrifluo-
roborate and 4-t-Bu-phenyltrifluoroborate in the presence of
tris(dibenzylideneacetone)dipalladium(0) and cesium carbonate
R
R
Cl
N
CN
CN
N
CN
CN
(PPh3)4Pd(0)
a
H2N
N
H2N
N
N
N
CN
CN
7
CuI, Na2CO3
THF, 80-85 °C
11
12
(80%)
R =
H
(60%)
a
b
( )
( )
c
( )
(85%)
N
15
(70%)
(85%)
(70%)
e
( )
a
d
( )
OH
N
CN
CN
8
CF3
CO2H
16
f
( )
R =
(85%)
N
R
N
(a)
(b)
N
c
( )
(75%)
(85%)
h
( )
g
( )
OCH3
O2N
(75%)
(85%)
(70%)
(75%)
(j
)
Fe
i
( )
(85%)
a: Pd2(dba)3, Ligand,K2CO3,
THF, H2O, 80-85°C
Scheme 4.
Scheme 6.

H. Ali, J. E. van Lier / Tetrahedron Letters 53 (2012) 4824–4827
4827
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Cl
N
CN
CN
Pd2(dba)3,
R
N
CN
CN
Ligand, THF,
H2O, K2CO3
80-85°C
H2N
N
H2N
N
17
11
R =
a
( )
b
(75%) ( )
OH
(85%)
(80%)
(c)
(d)
C4H9 (d)
(70%)
OCH3
(55%)
S
(e)
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pronounced as compared to the analog with the aryl group at-
tached via the ethynyl side chain, as in 6e. The presence of an ami-
no group also affects the spectral properties of the pyrazine
derivatives. Thus compounds containing both an amino group
and an ethynyl phenyl or phenyl group gave a bathochromic shift
when compared to the mono-substituted analog.
In conclusion, we have developed an efficient synthetic method
for the preparation of pyrazine-2,3-dicarbonitrile 5,6-bis-substi-
tuted derivatives using Pd-catalyzed cross coupling reactions. This
procedure greatly increases the access to a large variety of homo
and hetero bis-substituted pyrazine derivatives that in turn can
serve as precursors for the synthesis of selected aza-phthalocya-
nine analogs using commercially available substrates.
Acknowledgments
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Supported by the Jeanne and J.-Louis Lévesque Chair in radiobi-
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