Synthesis of tetraaryl- and tetraalkenylpyrazines by Suzuki-Miyaura reactions of tetrachloropyrazine

Article abstract of DOI:10.1016/j.tet.2015.07.028

The first Suzuki-Miyaura reactions of tetrachloropyrazine allowed for a new and convenient approach to synthesize a variety of tetraarylpyrazines and tetraalkenylpyrazines, which were isolated in good to excellent yields. The products show strong fluoresc

Full text of DOI:10.1016/j.tet.2015.07.028

Accepted Manuscript
Synthesis of Tetraaryl- and Tetraalkenylpyrazines by Suzuki-Miyaura Reactions of
Tetrachloropyrazine
Andranik Petrosyan, Peter Ehlers, Sebastian Reimann, Tariel V. Ghochikyan, Ashot
S. Saghyan, Anke Spannenberg, Stefan Lochbrunner, Peter Langer
PII:
S0040-4020(15)01065-0
10.1016/j.tet.2015.07.028
TET 26973
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 29 May 2015
Revised Date: 9 July 2015
Accepted Date: 10 July 2015
Please cite this article as: Petrosyan A, Ehlers P, Reimann S, Ghochikyan TV, Saghyan AS,
Spannenberg A, Lochbrunner S, Langer P, Synthesis of Tetraaryl- and Tetraalkenylpyrazines by Suzuki-
Miyaura Reactions of Tetrachloropyrazine, Tetrahedron (2015), doi: 10.1016/j.tet.2015.07.028.
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1
ACCEPTED MANUSCRIPT
Synthesis of Tetraaryl- and Tetraalkenylpyrazines by Suzuki-Miyaura
Reactions of Tetrachloropyrazine
a,b,c
a,b
a,b
c
Andranik Petrosyan,
Peter Ehlers, Sebastian Reimann, Tariel V. Ghochikyan,
c,d
b
e
a,b
Ashot S. Saghyan, Anke Spannenberg, Stefan Lochbrunner, Peter Langer*
a
Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
Fax: +49(381)4986412; E-mail: peter.langer@uni-rostock.de
b
Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059
Rostock, Germany
c
Faculty of Chemistry, Yerevan State University, Alex Manoogian 1, 0025 Yerevan, Armenia
d
Scientific and Production Center “Armbiotechnology” of NAS RA, Gyurjyan Str. 14, 0056
Yerevan, Armenia
e
Institut für Physik, Universität Rostock, Universitätsplatz 3, 18051 Rostock, Germany
Abstract: The first Suzuki-Miyaura reactions of tetrachloropyrazine allowed for a new and
convenient approach to synthesize a variety of tetraarylpyrazines and tetraalkenylpyrazines
which were isolated in good to excellent yields. The products show strong fluorescence with
good quantum yields. The emission wavelength depends on the substitution pattern which
suggests an electronic interaction of the aryl groups with the pyrazine moiety.
Key words: pyrazines; Suzuki-Miyaura reaction; heterocycles; palladium; catalysis
Graphical Abstract
Ar
Ar
N
N
Ar
Ar
Cl
Cl
N
N
Cl
Cl
[Pd]
Ar
Ar
N
N
Ar
Ar
Suzuki-Miyaura

2
ACCEPTED MANUSCRIPT
Introduction
Pyrazines are of considerable pharmacological interest and are found in several natural
[1]
products. A range of aryl substituted pyrazines have been reported to show activity as anti-
[2]
[3]
[4]
platelet aggregants,
antihyperglycemics,
regulators of estrogen receptors (ER),
[5]
[6]
cannabinoid receptor 1 (CB1) antagonists,
COX-2 inhibitors,
and sphingosine-1-
[7]
phosphate (S1P) agonists. In addition, di-, tri- and tetraarylpyrazines are useful materials for
[8]
diagnostic imaging in medical applications, due to their absorption and emission properties.
Previous studies on tetraalkenylpyrazines and other analogous cross-shaped alkenyl
[9]
derivatives were focused on their electro-optical properties.
In particular,
tetraalkenylpyrazines show interesting two-photon absorption properties and are used as
[10]
selective sensors for the detection of thrombin.
Tetraarylated pyrazines have been previously prepared by reaction of α-hydroxyketones with
[11]
[12]
ammonium acetate,
by reaction of 2-nitrooxiranes with ammonia,
by cyclizations of
[13]
[14]
N,N’-dibenzylidene derivatives, and by dimerization of azirines. These procedures have
disadvantages, such as the availability of the starting materials, low yields, or requirement of
[15]
the use of high pressure. In recent years, palladium-catalyzed Suzuki-Miyaura-,
[16]
[17]
[18]
Sonogashira-,
Heck-,
and Stille
reactions of dichloropyrazines have been reported.
Suzuki-Miyaura reactions of tetrahalopyrazines have, to the best of our knowledge, not been
[19]
previously reported. Herein, we report, for the first time, an efficient protocol for tetrafold
Suzuki-Miyaura reactions of tetrachloropyrazine. These reactions provide a new approach to
symmetrical tetraarylpyrazines. In addition, the starting material is readily available. Our
procedure is more convenient and higher yielding than previously reported methods. In
addition, we report the Suzuki-Miyaura reactions of tetrachloropyrazine with
alkenylboronates, which offers an easy and straightforward access to tetraalkenylpyrazines. A
thorough optimization of the conditions and application of modern catalysts and ligands
allowed the preparation of a broad variety of target molecules in high yields and using small
amounts of catalyst. Some tetraalkenylpyrazines have been previously synthesized from
[
9g,9h,9i,10]
tetramethylpyrazine and the appropriate aldehydes under basic conditions.
However,
our protocol based on the Suzuki reaction is advantageous in terms of yield, selectivity, scope
and mildness of the conditions. In addition, we report that the tetraalkenylpyrazines prepared

3
ACCEPTED MANUSCRIPT
exhibit fluorescence properties with high quantum yields. The emission wavelength depends
on the substitution pattern which suggests an electronic interaction of the aryl groups with the
pyrazine moiety.
Results and Discussion
Tetrachloropyrazine 2 was prepared according to the procedure reported by Fleischauer et. al
[20]
(Scheme 1).
H
O
N
Cl
Cl
N
Cl
Cl
PCl , POCl
5
3
N
H
O
120 °C
N
1
2
Scheme 1. Synthesis of tetrachloropyrazine 2.
To evaluate the best catalyst system for the tetrafold arylation we tested various catalysts in
the Suzuki-Miyaura reaction of 2 with phenylboronic acid (Scheme 2). The application of
standard conditions, i.e. Pd(PPh ) (5 mol%) as the catalyst, toluene as the solvent and
3
4
potassium phosphate as the base, gave tetraphenylpyrazine 3a in 83% yield (Table 1, entry 1).
The yield could be improved to more than 90% when the reaction was carried out using
Pd(OAc) (5 mol%) in the presence of bulky monodentate phosphine ligands, such as S-
2
[21]
[22]
Phos,
CataCXium A,
or tricyclohexylphosphine (P(Cy) ) (Figure 1). Product 3a was
3
isolated in 97% yield when Pd(OAc) (5 mol%) in the presence of P(Cy) (10 mol%) was
2
3
employed (entry 4). It is important to note that the amounts of catalyst and ligand could be
reduced to 0.25 mol% and 0.5 mol% without any decrease of the yield, respectively (entries
7
-10). Further reduction of the catalyst loading (0.1 mol% of catalyst and 0.2 mol% of ligand)
resulted in a slight decrease of the yield (88%, entry 11). The reaction mixture was stirred for
8 h at 100 °C. A decrease of the yield to 82% was observed when the reaction time was
shortened to 10 h (entry 12). An excess of base and of phenylboronic acid was employed (8.0
1

4
ACCEPTED MANUSCRIPT
equiv.). The yields only slightly dropped when the amounts of the reagents were reduced to
.0 or 5.0 equiv. (entries 5 and 6).
6
Cl
Cl
N
Cl
Cl
Ph-B(OH)2
cf. Table 1)
Ph
Ph
N
Ph
Ph
(
N
N
2
3a
Scheme 2. Optimization of the synthesis of 3a.
Table 1. Optimization of the synthesis of 3a.
a
K PO /Ph-B(OH)
2
Time
[h]
Yield
[%]
3
4
Entry
Catalyst
[
equiv.]
8
/8
18
83
1
2
Pd(PPh ) (5 mol%)
3
4
Pd(OAc) (5 mol%)
2
8
/8
18
96
S-Phos (10 mol%)
Pd(OAc) (5 mol%)
2
8
/8
/8
18
18
92
97
3
4
CataCXium A (10 mol%)
Pd(OAc) (5 mol%)
2
8
P(Cy) (10 mol%)
3
Pd(OAc) (5 mol%)
2
5
6
/5
/6
18
18
86
90
5
6
P(Cy) (10 mol%)
3
Pd(OAc) (5 mol%)
2
P(Cy) (10 mol%)
3
Pd(OAc) (3 mol%)
2
8
8
8
/8
/8
/8
18
18
18
96
97
96
7
8
9
P(Cy) (6 mol%)
3
Pd(OAc) (1 mol%)
2
P(Cy) (2 mol%)
3
Pd(OAc) (0.5 mol%)
2
P(Cy) (1 mol%)
3
Pd(OAc) (0.25 mol%)
2
8
/8
/8
18
18
97
88
1
0
1
P(Cy) (0.5 mol%)
3
8
1
Pd(OAc) (0.1 mol%)
2

5
ACCEPTED MANUSCRIPT
P(Cy) (0.2 mol%)
3
Pd(OAc) (0.25 mol%)
2
8
/8
10
82
1
2
P(Cy) (0.5 mol%)
3
a
Yields of isolated products; conditions: catalyst (see Table), 2, phenylboronic acid, K PO ,
3
4
toluene, 100 °C, 18 h.
H CO
3
OCH3
P
P(Cy)2
S-Phos
CataCXium A
Figure 1. Structures of S-Phos and CataCXium A.
Having efficient reaction conditions in hand (Table 1, entry 10), we studied the preparative
scope of the reaction (Scheme 3, Table 2). The Suzuki-Miyaura reaction of 2 with various
arylboronic acids afforded tetraarylpyrazines 3a-j in very good to excellent yields. The
reactions were carried out using 0.25 mol% of Pd(OAc) and 0.5 mol% of P(Cy) . In case of
2
3
3
k-p, the catalyst loading had to be increased to 2 mol% of Pd(OAc) and 4 mol% of P(Cy)3
2
in order to achieve good yields. Both electron-poor and -rich arylboronic acids were
successfully employed in the reaction and gave equally good yields. In addition, a vinyl group
[
12,23]
[24]
[5,12]
was tolerated (product 3l). The syntheses of 3a,
3c, and 3e
have been previously
reported. However, spectroscopic data were reported only for compounds 3a and 3e.
Cl
Cl
N
Cl
Cl
Ar-B(OH)2
Ar
Ar
N
Ar
Ar
N
i
N
2
3a-p
Scheme 3. Synthesis of 3a-p; i: 2, Ar-B(OH) (8 equiv.), K PO (8 equiv.), toluene, 100 °C,
2
3
4
1
8 h, for 3a-j: Pd(OAc) (0.25 mol%), P(Cy) (0.5 mol%), for 3k-p: Pd(OAc) (2 mol%),
2 3 2
P(Cy) (4 mol%).
3

6
ACCEPTED MANUSCRIPT
Table 2. Synthesis of 3a-p.
Yield
3
a
Ar-B(OH)
2
Product
a
[
%]
97
b
c
85
93
Me
Me
Me
Me
N
N
d
e
96
90
MeO
MeO
OMe
OMe
N
N
f
96
g
87
99
h
Me
Me
Me
Me
N
N
Me
Me
Me
Me
B(OH)
2
i
81
Me
Me

7
ACCEPTED MANUSCRIPT
Me
Me
Me
N
N
j
94
B(OH)
2
Me
Me
k
l
92
76
OMe
OMe
OMe
OMe
N
m
99
N
Me Me
N
n
o
99
74
N
Me Me
p
50
a
Yields of isolated products.
The molecular structure of 3b was independently confirmed by X-ray crystal structure
analysis. The aryl substituents were proven to be twisted out from the plane of the pyrazine
ring by 32-50° in a propeller-like arrangement (Figure 2). Due to the twisted conformation of
[
11b]
the peripheral substituents, tetraarylpyrazines can be used as solid-state luminogens
owing
[
25]
their aggregation-induced emission (AIE) characteristics.
Next, we studied the application of styrylboronic acid which gives access to
tetraalkenylpyrazines. Surprisingly, the developed reaction conditions discussed above gave
only low yields for the desired product. However, changing to the more bulky CataCXium A

8
ACCEPTED MANUSCRIPT
ligand and using 1,4-dioxane as solvent gave the desired tetrastyrylpyrazine 4a in quantitative
[
26]
yield.
Figure 2. ORTEP diagram of 3b. Displacement ellipsoids are drawn at the 30% probability
level.
Further studies were devoted to the reduction of the catalyst loading. Using 1-2 mol% of
palladium-catalyst, the product could be isolated in almost quantitative yield. However, the
yield dropped to 60% when only 0.25 mol% of Pd(dba) was employed. Thus, we employed
2
2
mol% of Pd(dba) and 4 mol% of the CataCXium A ligand for elaboration of the substrate
2
scope.
B(OH)2
Cl
Cl
N
Cl
Cl
Ph
Ph
N
Ph
Ph
Ph
N
(cf. Table 3)
N
2
4a
Scheme 4. Optimization of the synthesis of 4a.
Table 3. Optimization of the synthesis of 4a.
a
Yield
Entry
Catalyst
[
%]
Pd(OAc) (2 mol%)
2
b
1
2
1
2
P(Cy) (4 mol%)
3
Pd(dba) (5 mol%)
2
9
9
CataCXium A (10 mol%)

9
ACCEPTED MANUSCRIPT
Pd(dba) (4 mol%)
2
9
8
7
3
4
CataCXium A (8 mol%)
Pd(dba) (2 mol%)
2
9
CataCXium A (4 mol%)
Pd(dba) (1 mol%)
2
9
6
5
0
5
CataCXium A (2 mol%)
Pd(dba) (0.25 mol%)
2
6
CataCXium A (0.5 mol%)
a
Yields of isolated products; conditions: catalyst (see Table), 2, styrylboronic acid (8 equiv.),
b
K PO (8 equiv.), 1,4-dioxane, 100 °C, 20 h. conditions: same as for the synthesis of 3k-p
3
4
(Scheme 3).
B(OR)2
Cl
Cl
N
Cl
Cl
Ar
Ar
N
Ar
Ar
Ar
N
i
N
2
4a-e
Scheme 5. Synthesis of 4a-e; i: Pd(dba) (2 mol%), CataCXium A (4 mol%), 2, styrylboronic
2
acid or -pinacol ester (8 equiv.), K PO (8 equiv), 1,4-dioxane, 100 °C, 20 h.
3
4
Table 4. Synthesis of 4a-e.
Coupling
partner
Yield
[%]
4
Product
a
OH
B
OH
N
N
a
97
95
99
Me
Me
OH
N
N
B
b
Me
OH
Me
F
Me
F
OH
OH
N
N
B
c
F
F
F

1
0
ACCEPTED MANUSCRIPT
MeO
MeO
OMe
OH
OH
N
B
d
e
93
MeO
N
OMe
Me
Me
Me
Me
Me
O
O
N
N
B
70
a
Yields of isolated products.
All products were isolated in good to excellent yields. Styrylboronic acids containing
donating methyl- or methoxy-groups in para position gave slightly diminished yields (table 4,
compounds 4b and 4d), while the substitution with the strongly electronegative fluorine gave
quantitative yield of the desired product (compound 4c). A methyl group located in 3-position
(compound 4e) resulted in a decreased yield of 70 %.
UV/Vis and Fluorescence Properties
[
9d,9g,9i,10]
As tetraalkenylpyrazines are known to show interesting photophysical properties
we
decided to investigate the steady-state UV/Vis- and fluorescence properties of compounds 4a,
c and 4d (Figure 3). For the measurement of the optical properties it has to be considered
4
that solutions of all studied compounds undergo photochemical reactions in solution even
under exposition to daylight for some time. These reactions include for instance E/Z-
isomerisations, cyclizations or polymerisations and are quite common for such
[
27]
alkenylderivatives. All three absorption spectra consist of three conspicuous transitions in
the range of 323nm – 459 nm (Table 5). Compound 4d, containing a donating methoxy-group,
shows a bathochromic shift, while the UV/Vis-spectra of compounds 4a and 4c show almost
no difference between each other. The same trend is also observed in the fluorescence spectra
of these compounds. Tetraalkenylderivative 4d is bathochromically shifted with an emission
maximum at 522 nm while compounds 4a and 4c show emission maxima at 498 nm and
4
97 nm, respectively. The bathochromic effect can be explained by the push-pull substitution
pattern of 4d. This result suggests an electronic interaction of the aryl groups with the
pyrazine moiety. All three emission spectra possess at longer wavelengths a shoulder, due to a
vibrational progression. We determined the quantum yields of the synthesized compounds

1
1
ACCEPTED MANUSCRIPT
using quinine bisulfate as standard (Table 5). All compounds show good quantum yields
between 0.55-0.61. The substitution pattern of the tetrastyrylpyrazines has only a marginal
influence on the quantum yield. The fluorine and also the donating methoxy-group gave
slightly increased quantum yields as compared to compound 4a. Since the magnitude of the
Stoke shifts is rather low and the quantum yields are quite high, significant intramolecular
charge transfer contributions can be ruled out.
Figure 3. Normalized absorption and corrected emission
spectra of compounds 4a, 4c and 4d.
Table 3. UV/Vis absorption and fluorescence data for compounds 4a, 4c, 4d in
dichloromethane. For the measurement of the fluorescence quantum yields a solution of
[
28]
quinine bisulfate in 0.05 M H SO (ꢀ = 0.52) was applied as standard.
2
4
ꢁ
ꢁ
ꢐꢑꢋ
ꢂꢃꢄꢅ(ꢆꢃꢄꢅ
)
ꢇꢈ ꢉꢊꢋꢌꢍꢅ
ꢂ
ꢀ
ꢁꢐꢑꢋ
ꢎꢃꢏ
compd
4
-1
-1
-1
[
nm] ([10 M cm ])
[cm ]
[nm]
Quantum yield
3
23 (4.35)
4
a
373 (5.02)
2600
2560
2630
498
0.55
4
3
41 (2.63)
24 (4.45)
4
c
371 (5.46)
497
522
0.57
0.61
4
3
41 (2.66)
53 (5.05)
4
d
388 (6.02)
59 (3.15)
4

1
2
ACCEPTED MANUSCRIPT
Conclusion
In conclusion, we synthesized various tetraarylpyrazines using the Suzuki-Miyaura reaction.
After a thorough optimization the products were isolated in good to quantitative yields using
only 0.25 mol% of the palladium catalyst. Furthermore, we synthesized tetrastyrylpyrazines in
high yields by application of a modified protocol. Tetrastyrylpyrazines are promising
substrates for photonic applications due to their high fluorescence quantum yields. So far, we
have not been able to realize the selective reaction of tetrachloropyrazine with one or two
equivalents of the boronic acids as the reactions result in the formation of complex mixtures.
However, this project is topic of ongoing studies in our laboratories.
Acknowledgements
Financial support by the Volkswagenstiftung is gratefully acknowledged. We thank Mr.
Wolfgang Breitsprecher for the measurements of the fluorescence spectra.
Experimental Section
General. All reactions were carried out under argon atmosphere. All chemicals are commercially available
and were used without further purification. Column chromatography was performed using Merck Silicagel
6
0 (0.043 - 0.06 mm). NMR data were recorded on Bruker ARX 300, Bruker ARX 400 and Fourier 300
1
3
1
spectrometers. C and H NMR spectra were referenced to signals of deuterated solvent and residual
protonated solvent, respectively. Peak characterization: s = singlet, d = doublet, t = triplet, pt = pseudo
triplet, q = quartet, sept = septet, m = multiplet, bs = broad singlet, dd = doublet of doublet. Infrared Spectra
were recorded on Nicolet 550 FT – IR spectrometer with ATR sampling technique for solids as well as
liquids. Signal characterization: w = weak, m = medium, s = strong. Gas chromatography-mass analyses
were carried out on Agilent HP-5890 instrument with an Agilent HP-5973 Mass Selective Detector (EI) and
HP-5 capillary column using helium carrier gas. ESI HR-MS measurements were performed on an Agilent
1
969A TOF mass spectrometer. For High Resolution MS (HRMS) Finnigan MAT 95 XP was used. Only
the measurements with an average deviation from the theoretical mass of ± 2mDa were accounted as
correct. Elemental analyses (EA) were performed with a LecoMikroanalysator - TrueSpec CHNS Micro.
Melting points were determined on a Micro-Hot-Stage GalenTM III Cambridge Instruments, and are not
corrected. X-ray crystal structure data were collected on a STOE IPDS II diffractometer. The structure was
2
solved by direct methods and refined by full-matrix least-squares procedures on F with the SHELXTL
[
29] [30]
software package.
Absorption spectra were measured on an Analytik Jena Specord 50 or Perkin-

1
3
ACCEPTED MANUSCRIPT
Elmer UV/Vis spectrometer Lambda2. The fluorescence spectra were recorded with a Fluoromax-4
Spectrofluorometer (Horiba Scientific). For the absorption spectra dichloromethane was used as solvent
-6
and a concentration of 5 x 10 M was applied for the quantitative determination of the molar extinction
coefficient. A solution of quinine sulphate in 0.05 M sulphuric acid was applied as standard for the
[28]
measurement of the fluorescence quantum yields (φ = 0.52). Samples and standard were measured in
f
air-equilibrated solutions and exhibited an absorbance of ~ 0.1 at the excitation wavelength.
General Procedures and Experimental Data
Synthesis of tetraarylpyrazines
Prior to all, solutions of Pd(OAc) and P(Cy) were prepared in dried and argon filled Schlenk tubes (both
2
3
0
.0125 mmol, 5 mol%) using 1 mL of extra dry THF and toluene, respectively. Solutions were stirred at
room temperature for 10 min.
To an argon-flushed glass pressure tube 50 µL of Pd(OAc) solution (0.000625 mmol, 0.25 mol%) was
2
added (In cases of compounds 3k-p, 2 mol% (1.1 mg) of Pd(OAc) and 4 mol% (2.8mg) of P(Cy) were
2
3
used). After the removal of THF via evacuation of pressure tube, 100µL of earlier prepared solution of
P(Cy) (0.00125 mmol, 0.5 mol%), 2 (54 mg, 0.25 mmol), the appropriate arylboronic acid (2 mmol,
3
8
.0 equiv.) and K PO (2 mmol, 8.0 equiv.) were added, followed by the injection of dry toluene (3.5 mL).
3 4
The tube was closed with a teflon screw cap and the reaction mixture was stirred at 100 °C for 18 hours.
Subsequently, the mixture was cooled down to room temperature and diluted with water and
dichloromethane. The aqueous layer was extracted three times with dichloromethane. Combined organic
layers were dried over Na SO and filtered. Unless otherwise noted, solvent was evaporated and the residue
2
4
was purified by column chromatography on silica gel using mixture of hexane and dichloromethane as
eluent.
2
,3,5,6-Tetraphenylpyrazine (3a):
According to the general procedure, compound 3a was isolated as
a
white solid
1
(
93 mg, 97 %); mp. = 248 – 250 °C. H NMR (300 MHz, CDCl ): δ = 7.29 - 7.34 (m, 12H), 7.60 - 7.66 (m,
3
13
8
H). C NMR (75 MHz, CDCl ): δ = 128.2 (CH), 128.5 (CH), 129.8 (CH), 138.4 (C), 148.4 (C).
3
+
MS (EI, 70 eV): m/z (%) = 384 (M , 100), 305 (7), 178 (44), 152 (8), 103 (10). HRMS (ESI): calcd. for
+
-1
~
C H N ([M+H] ): 385.16993; found: 385.17036. IR (ATR, cm ):
ν
= 3038 (w), 1389 (m), 1170 (m),
28
21
2
1104 (m), 1011 (m), 762 (s), 692 (s), 536 (s).

1
4
ACCEPTED MANUSCRIPT
2
,3,5,6-Tetrakis(4-(trifluoromethyl)phenyl)pyrazine (3b):
According to the general procedure, compound 3b was isolated as
a
white solid
1
3
(
(
F
139 mg, 85 %); mp. = 265 – 266 °C. H NMR (300 MHz, CDCl ): δ = 7.62 (d, 8H, J = 8.2 Hz), 7.74
3
3
13
1
3
d, 8H, J = 8.2 Hz). C NMR (75 MHz, CDCl ): δ = 123.8 (q, J = 272.3 Hz, CF ), 125.5 (q, J
3
C–F
3
C–
2
=
3.8 Hz,
CH),
130.1
(CH),
131.3
(q,
JC–F = 32.6 Hz,
C),
140.8
(C),
147.9
19
+
(
C). F NMR (282 MHz, CDCl ): δ = -62.3 (s, 12F, CF ). MS (EI, 70 eV): m/z (%) = 656 (M , 100), 637
3
3
(15), 587 (14), 314 (77), 295 (15), 264 (10), 225 (7), 171 (7). HRMS (ESI): calcd. For
+
-1
~
C H F N ([M+H] ): 657.11946; found: 657.1192. IR (ATR, cm ):
ν
= 1322 (s), 1167 (m), 1105 (s),
32
17 12
2
1
011 (m), 849 (s), 631 (m), 535 (m). EA: calcd. for C H F N (656.46): C, 58.55; H, 2.46; N, 4.27;
3
2
16 12
2
found: C, 57.92; H, 2.32; N, 4.23.
2
,3,5,6-Tetra-p-tolylpyrazine (3c):
According to the general procedure, compound 3c was isolated as
a
white solid
1
(
103 mg, 93 %); mp. = 284 – 286 °C. H NMR (300 MHz, CDCl ): δ = 2.35 (s, 12H, CH ), 7.09 - 7.13 (m,
3
3
1
3
8
1
H), 7.52 - 7.56 (m, 8H). C NMR (75 MHz, CDCl ): δ = 21.3 (CH ), 128.9 (CH), 129.6 (CH), 135.8 (C),
3 3
+
38.3 (C), 147.7 (C). MS (EI, 70 eV): m/z (%) = 440 (M , 100), 425 (10), 206 (19), 189 (8).
+
HRMS (ESI): calcd. for C H N
2
([M+H] ): 441.23253; found: 441.23245. IR (ATR,
3
2
29
-
1
~
cm ):
ν
= 2917 (w), 1385 (s), 1172 (m), 1096 (m), 1009 (m), 820 (s), 728 (s), 626 (m), 530 (s), 513 (s).
2
,3,5,6-Tetrakis(4-isopropylphenyl)pyrazine (3d):
According to the general procedure, compound 3d was isolated as yellowish-white solid
1
3
(
133 mg, 96 %); mp. = 279 – 281 °C. H NMR (300 MHz, CDCl ): δ = 1.24 (d, 24H, J = 6.9 Hz, CH ),
3
3
3
2
.90
(sept, 4H,
J = 6.9 Hz, CHi-Pr),
7.13 - 7.17 (m,
8H), 7.56 - 7.60
(m,
8H).
1
3
C NMR (75 MHz, CDCl ): δ = 23.8 (CH ), 33.8 (C Hi-Pr), 126.2 (CH), 129.7 (CH), 136.1 (C), 147.5 (C),
3
3
+
1
49.2 (C). MS (EI, 70 eV): m/z (%) = 552 (M , 100), 537 (11), 509 (7). HRMS (ESI): calcd. for C H N
40 45 2
+
-1
~
(
[M+H] ): 553.35773; found: 553.35861. IR (ATR, cm ):
ν
= 2959 (m), 2926 (w), 2866 (w), 1388 (s),
1181 (m), 1098 (m), 1006 (m), 839 (s), 632 (m), 552 (s).
2
,3,5,6-Tetrakis(4-methoxyphenyl)pyrazine (3e):
According to the general procedure, compound 3e was isolated as a light brown solid
1
(
(
(
113 mg, 90 %); mp. = 278 – 280 °C. H NMR (300 MHz, CDCl ): δ = 3.81 (s, 12H, OCH ), 6.81 - 6.86
3
3
1
3
m, 8H), 7.56 - 7.61 (m, 8H). C NMR (75 MHz, CDCl ): δ = 55.2 (OCH ), 113.6 (CH), 131.0 (CH), 131.2
3
3
+
C), 146.8 (C), 159.8 (C). MS (EI, 70 eV): m/z (%) = 504 (M , 100), 252 (12), 238 (15), 223 (34), 195 (10),
-
1
52 (12), 133 (11). HRMS (EI, 70 eV): calcd. for C H N O : 504.20436; found: 504.20469. IR (ATR, cm
32 28 2 4
1
~
):
ν
= 2926 (w), 2834 (w), 1602 (s), 1573 (m), 1511 (s), 1418 (m), 1381 (s), 1295 (s), 1244 (s), 1164 (s),
1
027 (s), 830 (s), 796 (s), 740 (m), 529 (s).

1
5
ACCEPTED MANUSCRIPT
2
,3,5,6-Tetrakis(3-(trifluoromethyl)phenyl)pyrazine (3f):
According to the general procedure, compound 3f was isolated as
a
white solid
1
3
(
157 mg, 96 %); mp. = 165 – 167 °C. H NMR (300 MHz, CDCl ): δ = 7.48 (pt, 4H, J = 7.8 Hz), 7.65
3
3
3
13
(
d, 4H, J = 7.8 Hz), 7.75 (d, 4H, J = 7.8 Hz), 7.86 (bs, 4H). C NMR (75 MHz, CDCl ): δ = 123.6 (q,
3
1
3
3
JC–F = 271.9 Hz, CF ), 125.9 (q, J = 3.6 Hz, CH), 126.7 (q, J = 3.8 Hz, CH), 129.1 (CH), 131.1 (q,
3
C–F
C–F
2
19
JC–F = 32.6 Hz, C), 133.0 (CH), 138.0 (C), 148.1 (C). F NMR (282 MHz, CDCl ): δ = -62.5 (s, 12F,
3
+
CF ). MS (EI, 70 eV): m/z (%) = 656 (M , 100), 637 (12), 314 (99), 295 (10), 264 (7), 225 (11), 171 (17).
3
-1
~
HRMS (EI, 70 eV): calcd. for C H F N : 656.11164; found: 656.11102. IR (ATR, cm ):
ν
= 1323 (s),
3
2
16 12
2
1
280 (m), 1164 (s), 1127 (s), 1069 (s), 908 (m), 801 (m), 700 (s). EA: calcd. for C H F N (656.46):
3
2
16 12
2
C, 58.55; H, 2.46; N, 4.27; found: C, 58.85; H, 2.28; N, 4.35.
2
,3,5,6-Tetrakis(4-ethylphenyl)pyrazine (3g):
According to the general procedure, compound 3g was isolated as
a
white solid
1
3
(
108 mg, 87 %); mp. = 235 – 236 °C. H NMR (300 MHz, CDCl ): δ = 1.23 (t, 12H, J = 7.5 Hz, CH ),
3
3
3
2
.65
(q,
8H,
J = 7.5 Hz,
CH2),
7.12 - 7.14
(m,
8H),
7.55 - 7.59
(m,
8H).
1
3
C NMR (75 MHz, CDCl ): δ = 15.3 (CH ), 28.6 (CH ), 127.7 (CH), 129.7 (CH), 136.0 (C), 144.6 (C),
3
3
2
+
1
47.6 (C). MS (EI, 70 eV): m/z (%) = 496 (M , 100), 467 (12), 219 (28), 204 (14), 116 (11).
-1
~
HRMS (EI, 70 eV): calcd. for C H N : 496.28730; found: 496.28760. IR (ATR, cm ):
ν
= 2961 (m),
929 (w), 2870 (w), 1387 (s), 1180 (s), 1097 (m), 1007 (m), 632 (m), 536 (m). EA: calcd. for C H N
2
3
6
36
2
2
3
6
36
(496.68): C, 87.05; H, 7.31; N, 5.64; found: C, 86.96; H, 7.31; N, 5.63.
2
,3,5,6-Tetrakis(4-fluorophenyl)pyrazine (3h):
According to the general procedure, compound 3h was isolated as
a
white solid
1
(
113 mg, 99 %); mp. = 233 – 234 °C. H NMR (300 MHz, CDCl ): δ = 6.97 - 7.05 (m, 8H), 7.54 - 7.61
3
1
3
2
3
(
m, 8H). C NMR (75 MHz, CDCl ): δ = 115.4 (d, J = 21.8 Hz, CH), 131.6 (d, J = 8.3 Hz, CH),
3 C–F C-F
4
1
19
1
34.0 (d, J = 3.2 Hz, C), 147.3 (C), 163.1 (d, J = 250.1 Hz, CF). F NMR (282 MHz, CDCl3):
C-F C–F
+
δ = -111.7 (s, 4F, CF). MS (EI, 70 eV): m/z (%) = 456 (M , 100), 359 (6), 214 (36).
-
1
HRMS (EI, 70 eV): calcd.
~
for
C H F N :
456.12441;
found:
456.12366.IR (ATR, cm ):
2
8
16
4
2
ν
= 1602 (s), 1510 (s), 1415 (m), 1384 (s), 1226 (s), 1152 (s), 1108 (m), 1011 (m), 839 (s), 735 (m), 617
(
m), 526 (s). EA: calcd. for C H F N (456.43): C, 73.68; H, 3.53; N, 6.14; found: C, 73.64; H, 3.33;
28 16 4 2
N, 6.09.
2
,3,5,6-Tetrakis(3,5-dimethylphenyl)pyrazine (3i):
According to the general procedure, compound 3i was isolated as
a
white solid
1
(
101 mg, 81 %); mp. = 275 – 277 °C. H NMR (300 MHz, CDCl ): δ = 2.24 (s, 24H, CH ), 6.94 (bs, 4H),
3
3

1
6
ACCEPTED MANUSCRIPT
1
3
7
.19 (bs, 8H). C NMR (75 MHz, CDCl ): δ = 21.2 (CH ), 127.6 (CH), 129.9 (CH), 137.3 (C), 138.5 (C),
3 3
+
1
48.8 (C). MS (EI, 70 eV): m/z (%) = 496 (M , 100), 248 (10), 133 (22). HRMS (EI, 70 eV): calcd. for
-1
~
C H N : 496.28730; found: 496.28686. IR (ATR, cm ):
ν
= 3025 (w), 2912 (m), 2855 (w), 1600 (m),
36
36
2
1
391 (s), 1374 (s), 1187 (m), 1154 (m), 855 (s), 843 (s), 691 (s), 424 (m). EA: calcd. for C H N (496.68):
3
6
36
2
C, 87.05; H, 7.31; N, 5.64; found: C, 86.89; H, 7.44; N, 5.39.
2
,3,5,6-Tetra-m-tolylpyrazine (3j):
According to the general procedure, compound 3j was isolated as
a
white solid
1
(
104 mg, 94 %); mp. = 153 – 154 °C. H NMR (300 MHz, CDCl ): δ = 2.33 (s, 12H, CH ), 7.13 - 7.16 (m,
3
3
1
3
8
H), 7.28 - 7.32 (m, 4H), 7.55 (bs, 4H). C NMR (75 MHz, CDCl ): δ = 21.4 (CH ), 127.0 (CH), 127.8
3 3
+
(
CH), 129.2 (CH), 130.4 (CH), 137.8 (C), 138.5 (C), 148.6 (C). MS (EI, 70 eV): m/z (%) = 440 (M , 100),
4
25 (12), 384 (26), 258 (16), 206 (11), 102 (17), 69 (13), 57 (13). HRMS (EI, 70 eV): calcd. for C H N :
32 28 2
-1
~
4
ν
40.22470; found: 440.22433. IR (ATR, cm ): = 3034 (w), 2915 (w), 1371 (m), 1167 (m), 847 (m), 778
(
s), 704 (s), 471 (s), 447 (m). EA: calcd. for C H N (440.58): C, 87.24; H, 6.41; N, 6.36; found: C, 87.30;
32 28 2
H, 6.36; N, 6.32.
2
,3,5,6-Tetrakis(4-isopropoxyphenyl)pyrazine (3k):
In agreement with the general procedure, but with 2 mol% (1.1 mg) of Pd(OAc) and 4 mol% (2.8mg) of
2
P(Cy) , compound 3k was isolated as a white solid (142 mg, 92 %); mp. = 241 – 243 °C.
3
1
3
3
H NMR (300 MHz, CDCl ): δ = 1.33 (d, 24H, J = 6.1 Hz, CH ), 4.55 (sept, 4H, J = 6.1 Hz, CHi-Pr),
3
3
1
3
6
.79 - 6.82 (m, 8H), 7.55 - 7.59 (m, 8H). C NMR (75 MHz, CDCl ): δ = 22.0 (CH ), 69.7 (C Hi-Pr), 115.3
3 3
+
(
CH), 131.0 (CH), 131.0 (C), 146.7 (C), 158.1 (C). MS (EI, 70 eV): m/z (%) = 616 (M , 100), 574 (13),
4
47 (37), 224 (12), 210 (16), 57 (14), 43 (14). HRMS (EI, 70 eV): calcd. for C H N O : 616.32956;
4
0
44
2
4
-1
~
found: 616.32852. IR (ATR, cm ):
ν
= 2974 (m), 2923 (w), 1603 (s), 1510 (s), 1382 (s), 1287 (m), 1240
(s), 1163 (s), 1116 (s), 948 (s), 834 (s), 742 (m), 742 (m), 623 (m), 536 (s).
2
,3,5,6-Tetrakis(4-vinylphenyl)pyrazine (3l):
In agreement with the general procedure, but with 2 mol% (1.1 mg) of Pd(OAc) and 4 mol% (2.8mg) of
2
P(Cy) , compound 3l was isolated as a yellowish-white solid (93 mg, 76 %); mp. > 375 °C.
3
1
3
2
H NMR (300 MHz, CDCl ): δ = 5.27 (dd, 4H, J = 10.9 Hz, J = 0.7 Hz, CH=CH -H), 5.77 (dd, 4H,
3
cis
gem
cis
3
2
3
3
Jtrans = 17.5 Hz, J = 0.7 Hz, CH=CH-Htrans), 6.71 (dd, 4H, J
= 17.5 Hz, J = 10.9 Hz, CH=CH ),
cis 2
gem
trans
1
3
7
.34 - 7.38 (m, 8H), 7.60 - 7.64 (m, 8H). C NMR (75 MHz, CDCl ): δ = 114.5 (CH), 126.1 (CH), 130.0
3
+
(
CH), 136.3 (CH), 137.7 (C), 137.8 (C), 147.5 (C). MS (EI, 70 eV): m/z (%) = 488 (M , 100), 461 (4), 230
(
17), 202 (5), 71 (4). HRMS (EI, 70 eV): calcd. for C H N : 488.22470; found: 488.22447. IR (ATR,
3
6
28
2
-
1
~
cm ):
ν
= 2950 (w), 2917 (w), 2851 (w), 1627 (m), 1388 (s), 1174 (m), 1101 (m), 987 (s), 901 (s), 845 (s),
5
34 (s).

1
7
ACCEPTED MANUSCRIPT
2
,3,5,6-Tetrakis(3-methoxyphenyl)pyrazine (3m):
In agreement with the general procedure, but with 2 mol% (1.1 mg) of Pd(OAc) and 4 mol% (2.8mg) of
2
P(Cy) , compound 3m was isolated as a light brown solid (125 mg, 99 %); mp. = 170 –
3
1
1
72 °C. H NMR (300 MHz, CDCl ): δ = 3.69 (s, 12H, OCH ), 6.85 - 6.89 (m, 4H), 7.15 - 7.22 (m, 12H).
3
3
1
3
C NMR (75 MHz, CDCl ): δ = 55.2 (OCH ), 114.8 (2 x CH), 122.4 (CH), 129.2 (CH), 139.6 (C), 148.2
3
3
+
(
C), 159.2 (C). MS (EI, 70 eV): m/z (%) = 504 (M , 100), 262 (12), 207 (9), 188 (16), 145 (14), 117 (10),
7
3 (10). 60 (12), 43 (15). HRMS (EI, 70 eV): calcd. for C H N O : 504.20436; found: 504.20339.
3
2
28
2
4
-
1
~
IR (ATR, cm ):
ν
= 3006 (w), 2921 (m), 2853 (w), 1578 (s), 1424 (m), 1377 (s), 1290 (m), 1229 (s), 1028
(
s), 775 (s), 719 (s). EA: calcd. for C H N O (504.58): C, 76.17; H, 5.59; N, 5.55; found: C, 76.49;
3
2
28
2
4
H, 5.50; N, 5.42.
2
,3,5,6-Tetra-o-tolylpyrazine (3n):
In agreement with the general procedure, but with 2 mol% (1.1 mg) of Pd(OAc) and 4 mol% (2.8mg) of
2
P(Cy) , compound 3n was isolated as a white solid (109 mg, 99 %); mp. = 252 – 254 °C.
3
1
H NMR (300 MHz, CDCl ): δ = 2.27 (s, 12H, CH ), 6.99 - 7.06 (m, 4H), 7.08 - 7.15 (m, 12H).
3
3
1
3
C NMR (75 MHz, CDCl ): δ = 20.1 (CH ), 125.2 (CH), 128.2 (CH), 130.2 (CH), 130.4 (CH), 136.2 (C),
3
3
+
1
37.7 (C), 151.6 (C). MS (EI, 70 eV): m/z (%) = 440 (M , 100), 425 (60), 349 (16), 205 (12), 73 (16), 60
-
(
17), 43 (14). HRMS (EI, 70 eV): calcd. for C H N : 440.22470; found: 440.22351. IR (ATR, cm
32 28 2
1
~
ν
): = 3016 (w), 2921 (w), 2852 (w), 1382 (s), 1081 (m), 1016 (m), 757 (s), 723 (s), 460 (s). EA: calcd.
for C H N (440.58): C, 87.24; H, 6.41; N, 6.36; found: C, 87.47; H, 6.69; N, 6.20.
32
28
2
2
,3,5,6-Tetrakis(2,5-dimethoxyphenyl)pyrazine (3o):
Reaction was made according to the general procedure, but with 2 mol% (1.1 mg) of Pd(OAc)2 and
mol% (2.8mg) of P(Cy) . After combined organic layers were dried over sodium sulphate, filtered and
4
3
solvent was removed, compound 3o was isolated as a white solid by recrystallization of crude mixture from
1
warm dichloromethane (116 mg, 74 %); mp. = 260 – 262 °C. H NMR (300 MHz, CDCl ): δ = 3.36 (s,
3
3
1
2H, OCH3), 3.70 (s, 12H, OCH3), 6.64 (d, 4H,
J = 8.9 Hz), 6.77 (dd, 4H,
3
4
4
13
J = 8.9 Hz, J = 3.0 Hz), 7.05 (d, J = 3.0 Hz, 4H). C NMR (75 MHz, CDCl ): δ = 55.4 (OCH ), 55.8
3
3
(
OCH ), 111.9 (CH), 115.3 (CH), 116.6 (CH), 129.4 (C), 149.4 (C), 150.8 (C), 153.3 (C).
3
+
MS (EI, 70 eV): m/z (%) = 624 (M , 100), 609 (45), 593 (71), 579 (12), 487 (23), 312 (11), 60 (10).
-1
~
HRMS (EI, 70 eV): calcd. for C H N O : 624.24662; found: 624.24559. IR (ATR, cm ):
ν
= 3002 (w),
3
6
36
2
8
2
8
960 (w), 2833 (w), 1499 (s), 1447 (m), 1424 (s), 1275 (s), 1229 (s), 1079 (m), 1042 (s), 1016 (s), 873 (m),
02 (s). EA: calcd. for C H N O (624.68): C, 69.22; H, 5.81; N, 4.48; found: C, 69.58; H, 5.74; N, 4.66.
3
6
36
2
8

1
8
ACCEPTED MANUSCRIPT
2
,3,5,6-Tetrakis(3-cyanophenyl)pyrazine (3p):
In agreement with the general procedure, but with 2 mol% (1.1 mg) of Pd(OAc) and 4 mol% (2.8mg) of
2
P(Cy) , compound 3p was isolated as a white solid (61 mg, 50 %); mp. = 296 – 297 °C.
3
1
3
H NMR (300 MHz, CDCl ): δ = 7.48 (pt, 4H, J = 7.8 Hz), 7.70 - 7.76 (m, 8H), 7.96 (bs, 4H).
3
1
3
C NMR (75 MHz, CDCl ): δ = 113.4 (C), 117.9 (C), 129.6 (CH), 133.1 (CH), 133.2 (CH), 133.8 (CH),
3
+
1
4
38.0 (C), 147.2 (C). MS (EI, 70 eV): m/z (%) = 484 (M , 100), 380 (7), 355 (5), 228 (38), 201 (8), 60 (5),
-1
~
4 (5). HRMS (EI, 70 eV): calcd. for C H N : 484.14310; found: 484.14195. IR (ATR, cm ):
ν
= 3062
3
2
16
6
(w), 2953 (w), 2227 (m), 1371 (m), 1164 (m), 917 (m), 799 (s), 697 (s), 515 (m).
Synthesis of tetraalkenylpyrazines
An argon-flushed glass pressure tube was charged with Pd(dba) (0.005 mmol, 2 mol%), CataCXium A
2
(0.01 mmol, 4 mol%), 2 (54.4 mg, 0.25 mmol), the appropriate alkenylboronic acid or pinacol ester
(
2 mmol, 8.0 eq.), K PO (2 mmol, 8.0 eq.) and anhydrous 1,4-dioxane (4 mL). The tube was sealed with a
3
4
teflon cap and the reaction mixture was stirred at 100 °C for 20 hours. Resulting mixture was cooled down
to room temperature, diluted with water and extracted with dichloromethane. The combined organic layers
were dried over Na SO , filtered and the solvent was evaporated. After, the crude residue was purified by
2
4
column chromatography on silica gel using mixture of hexane and dichloromethane as eluent. Gained
solids in the end, were washed with cold hexane to give pure orange-coloured products.
2
,3,5,6-Tetra((E)-styryl)pyrazine (4a):
According to the general procedure, compound 4a was isolated as an orange solid
1
(
119 mg, 97 %); mp. = 258 – 259 °C. H NMR (400 MHz, CDCl ): δ = 7.31 - 7.35 (m, 4H, CH), 7.39 - 7.43
3
3
3
(
m, 8H, CH), 7.54 (d, 4H, J = 15.5 Hz, CH=CH), 7.66 - 7.68 (m, 8H, CH), 7.96 (d, 4H, J = 15.5 Hz,
13
CH=CH). C NMR (100 MHz, CDCl ): δ = 122.2 (CH=CH), 127.4, 128.6, 128.8 (CH), 135.9 (CH=CH),
3
+
1
36.8, 145.2 (C). MS (EI, 70 eV): m/z (%) = 488 (M , 100), 411 (63), 397 (34), 320 (14), 167 (10), 115
-
(
11), 91 (16). HRMS (EI, 70 eV): calcd. for C H N : 488.22470; found: 488.22372. IR (ATR, cm
36 28 2
1
~
ν
): = 3019 (w), 1622 (m), 1493 (m), 1381 (m), 1165 (s), 955 (s), 740 (s), 685 (s), 588 (s), 457 (s).
EA: calcd. for C H N (488.62): C, 88.49; H, 5.78; N, 5.73; found: C, 88.64; H, 5.54; N, 5.71.
3
6
28
2
2
,3,5,6-Tetrakis((E)-4-methylstyryl)pyrazine (4b):
According to the general procedure, compound 4b was isolated as an orange solid
1
(
129 mg, 95 %); mp. = 292 – 294 °C. H NMR (300 MHz, CDCl ): δ = 2.39 (s, 12H, CH ), 7.21 (d, 8H,
3
3
3
3
3
J = 7.9 Hz, CH), 7.48 (d, 4H, J = 15.5 Hz, CH=CH), 7.55 (d, 8H, J = 7.9 Hz, CH), 7.91 (d, 4H,
3
13
J = 15.5 Hz, CH=CH). C NMR (75 MHz, CDCl ): δ = 21.4 (CH ), 121.3 (CH=CH), 127.3, 129.4 (CH),
3
3
+
1
34.2 (C), 135.5 (CH=CH), 138.6, 145.1 (C). MS (EI, 70 eV): m/z (%) = 544 (M , 100), 453 (35), 439
(
28), 287 (13), 195 (21), 119 (14), 105 (19), 44 (17), 36 (10). HRMS (EI, 70 eV): calcd. for C H N :
40 36 2

1
9
ACCEPTED MANUSCRIPT
-1
~
5
44.28730; found: 544.28748. IR (ATR, cm ):
ν
= 2913 (w), 1622 (m), 1508 (m), 1382 (m), 1165 (s), 956
(
s), 797 (s), 474 (s). EA: calcd. for C H N (544.73): C, 88.20; H, 6.66; N, 5.14; found: C, 88.05; H, 6.61;
4
0
36
2
N, 5.07.
2
,3,5,6-Tetrakis((E)-4-fluorostyryl)pyrazine (4c):
According to the general procedure, compound 4c was isolated as an orange solid
1
(
139 mg, 99 %); mp. = 284 – 286 °C. H NMR (300 MHz, DMSO-d ): δ = 7.25 - 7.33 (m, 8H, CH), 7.88
6
3
13
(
d, 4H, J = 15.5 Hz, CH=CH), 7.97 - 8.05 (m, 12H, CH, CH=CH). C NMR (75 MHz, DMSO-
2
3
4
d ): δ = 115.8 (d, J = 21.6 Hz, CH), 121.9 (CH=CH), 130.2 (d, J = 8.3 Hz, CH), 133.3 (d, J
6
C–F
C-F
C-
1
=
3.2 Hz,
C),
134.5
(CH=CH),
144.8
(C),
162.5
(d,
JC–F = 246.2 Hz,
CF).
F
1
9
+
F NMR (282 MHz, CDCl ): δ = -111.6 (s, 4F, CF). MS (EI, 70 eV): m/z (%) = 560 (M , 100), 465 (38),
3
+
4
51 (19), 356 (10), 109 (16), 69 (11), 44 (13). HRMS (ESI): calcd. for C H F N ([M+H] ): 561.19484;
3
6
24
4
2
-1
~
found: 561.19421. IR (ATR, cm ):
ν
= 1590 (m), 1503 (s), 1415 (m), 1226 (s), 1153 (s), 1091 (m), 964 (s),
8
13 (s), 529 (s), 479 (s). EA: calcd. for C H F N (560.58): C, 77.13; H, 4.32; N, 5.00; found: C, 77.44;
3
6
24
4
2
H, 4.42; N, 4.99.
2
,3,5,6-Tetrakis((E)-4-methoxystyryl)pyrazine (4d):
According to the general procedure, compound 4d was isolated as an orange solid
1
(
142 mg, 93 %); mp. = 229 – 230 °C. H NMR (300 MHz, CDCl ): δ = 3.85 (s, 12H, OCH ), 6.93 (d, 8H,
3
3
3
3
3
J = 8.5 Hz, CH), 7.35 (d, 4H, J = 15.5 Hz, CH=CH), 7.58 (d, 8H, J = 8.5 Hz, CH), 7.85 (d, 4H,
3
13
J = 15.5 Hz, CH=CH). C NMR (75 MHz, CDCl ): δ = 55.3 (OCH ), 114.1(CH), 120.2 (CH=CH), 128.7
3
3
+
(
CH), 129.8 (C), 134.7 (CH=CH), 144.9, 159.9 (C). MS (EI, 70 eV): m/z (%) = 608 (M , 100), 501 (34),
+
4
87 (18), 227 (18), 121 (74). HRMS (ESI): calcd. for C H N O ([M+H] ): 609.27478; found: 609.27537.
4
0
36
2
4
-
1
~
IR (ATR, cm ):
ν
= 3007 (w), 2929 (w), 2834 (w), 1602 (s), 1573 (m), 1508 (s), 1420 (m), 1245 (s), 1162
(s), 1028 (s), 965 (s), 810 (s), 561 (s).
2
,3,5,6-Tetrakis((E)-3-methylstyryl)pyrazine (4e):
According to the general procedure, compound 4e was isolated as an orange solid
1
(
96 mg, 70 %); mp. = 200 – 202 °C. H NMR (300 MHz, CDCl ): δ = 2.41 (s, 12H, CH ), 7.16 (d, 4H,
3
3
3
3
J = 7.5 Hz, CH), 7.28 - 7.33 (m, 4H, CH), 7.44 - 7.50 (m, 12H, CH, CH=CH), 7.90 (d, 4H, J = 15.5 Hz,
13
CH=CH). C NMR (75 MHz, CDCl ): δ = 21.4 (CH ), 122.0 (CH=CH), 124.5, 128.2, 128.6, 129.4 (CH),
3
3
+
1
1
5
35.8 (CH=CH), 136.8, 138.3, 145.2 (C). MS (EI, 70 eV): m/z (%) = 544 (M , 100), 453 (43), 439 (27),
+
95 (12), 119 (10), 105 (15), 44 (12). HRMS (ESI): calcd. for C H N ([M+H] ): 545.29513; found:
4
0
36
2
-1
~
45.29509. IR (ATR, cm ):
ν
= 2913 (w), 1623 (m), 1597 (m), 1371 (m), 1232 (m), 1156 (m), 962 (s), 766
(
s), 685 (s), 431 (s). EA: calcd. for C H N (544.73): C, 88.20; H, 6.66; N, 5.14; found: C, 87.99; H, 6.64;
40 36 2
N, 5.15.

2
0
ACCEPTED MANUSCRIPT
Acknowledgements. Financial support by the State of Mecklenburg-Vorpommern (scholarship of the
interdisciplinary faculty of the University of Rostock/Dept. LLM for S. R.) and by the Volkswagenstiftung
(Project-lD Az 86 223) is gratefully acknowledged.
Notes and References
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0. S. Yan, R. Huang, Y. Zhou, M. Zhang, M. Deng, X. Wang, X. Weng, X. Zhou, Chem.
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3. S. C. Joshi, K. N. Mehrotra, Indian J. Chem., Sect. B, 1983, 22, 396-397.
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417.
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6. (a) Y. Akita, A. Inoue, A. Ohta, Chem. Pharm. Bull., 1986, 34, 1447-1458; (b) T. A.
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Chem. Soc. 2005, 127, 4270-4285; (c) F. Bures, H. Cermakova, J. Kulhanek, M. Ludwig,

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7. I. Malik, M. Hussain, A. Ali, S. M. T. Toguem, F. Z. Basha, C. Fischer, P. Langer,
Tetrahedron, 2010, 66, 1637-1642.
1
1
8. A. Ohta, M. Ohta, T. Watanabe, Heterocycles, 1986, 24, 785-792.
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Young, M. M. Haley, J. Org. Chem., 2011, 76, 4043-4051.
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0. J. Fleischhauer, S. Zahn, R. Beckert, U. W. Grummt, E. Birckner, H. Görls, Chem. Eur.
J., 2012, 18, 4549-4557.
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1. T. E. Barder, S. D. Walker, J. R. Martinelli, S. L. Buchwald, J. Am. Chem. Soc., 2005,
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27, 4685-4696.
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2
2. A. Zapf, A. Ehrentraut, M. Beller, Angew. Chem., Int. Ed., 2000, 39, 4153-4155.
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3
1
002, 39, 759-766; (b) C. Yu, M. Lei, W. Su, Y. Xie, Synth. Commun., 2007, 37, 3301-
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4. (a) K. Curtius, K. Kastner, J. Prakt. Chem., 1911, 2, 225; (b) R. Kuhn H. Kainer,
Biochim. Biophys. Acta, 1953, 12, 325-327.
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Rev., 2011, 40, 5361-5388.
2
6. Similar conditions were previously used for the tetraalkenylation of tetrachloropyridine:
P. Ehlers, A. Hakobyan, A. Neubauer, S. Lochbrunner, P. Langer, Adv. Synth. Catal.,
2
013, 355, 1849-1858.
2
7. (a) A. Schulz, H. Meier, Tetrahedron, 2007, 63, 11429-11435; (b) Y. Nakamura, Y.
Hayashida, Y. Wada, J. Nishimura, Tetrahedron, 1997, 53, 4593-4600; (c) E. Müller, H.
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Cuppen, R. J. F. Nivard, Tetrahedron, 1970, 26, 1069-1083; (e) A. Böhm, M. Adam, H.
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8. S. R. Meech, D. Phillips, J. Photochem., 1983, 23, 193-217.
2
2
9. G. M. Sheldrick, Acta Crystallogr. 2008, A64, 112-122.

2
3
ACCEPTED MANUSCRIPT
3
0. CCDC-945041 contains all crystallographic details of this publication which are available
free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or can be ordered from the
following address: Cambridge Crystallographic Data Centre, 12 Union Road, GB-
Cambridge CB21EZ; Fax:(+44)1223-336-033; or deposit@ccdc.cam.ac.uk).

ACCEPTED MANUSCRIPT
Supporting Information
Synthesis of Tetraaryl- and Tetraalkenylpyrazines by Suzuki-Miyaura
Reactions of Tetrachloropyrazine
Andranik Petrosyan, Peter Ehlers, Sebastian Reimann, Tariel V. Ghochikyan,
Ashot S. Saghyan, Anke Spannenberg, Stefan Lochbrunner, Peter Langer
Contents
1
2
3
4
. General Remarks................................................................................................................. 2
. General Procedures and Experimental Data ....................................................................... 4
1
13
.
H- and C-NMR spectra ................................................................................................. 15
. Data of Crystal Structure Analysis ................................................................................... 36

ACCEPTED MANUSCRIPT
1
. General Remarks
All reactions were carried out under argon atmosphere. All chemicals are commercially
available and were used without further purification.
Column chromatography was performed using Merck Silicagel 60 (0.043 - 0.06 mm).
NMR data were recorded on Bruker ARX 300, Bruker ARX 400 and Fourier 300
1
3
1
spectrometers. C and H NMR spectra were referenced to signals of deuterated solvent and
residual protonated solvent, respectively. Peak characterization: s = singlet, d = doublet,
t = triplet, pt = pseudo triplet, q = quartet, sept = septet, m = multiplet, bs = broad singlet,
dd = doublet of doublet.
Infrared Spectra were recorded on Nicolet 550 FT – IR spectrometer with ATR sampling
technique for solids as well as liquids. Signal characterization: w = weak, m = medium,
s = strong.
Gas chromatography-mass analyses were carried out on Agilent HP-5890 instrument with an
Agilent HP-5973 Mass Selective Detector (EI) and HP-5 capillary column using helium
carrier gas.
ESI HR-MS measurements were performed on an Agilent 1969A TOF mass spectrometer.
For High Resolution MS (HRMS) Finnigan MAT 95 XP was used. Only the measurements
with an average deviation from the theoretical mass of ± 2mDa were accounted as correct.
Elemental analyses (EA) were performed with a LecoMikroanalysator - TrueSpec CHNS
Micro.
Melting points were determined on a Micro-Hot-Stage GalenTM III Cambridge Instruments,
and are not corrected.
X-ray crystal structure data were collected on a STOE IPDS II diffractometer. The structure
2
was solved by direct methods and refined by full-matrix least-squares procedures on F with
1
the SHELXTL software package.
Absorption spectra were measured on an Analytik Jena Specord 50 or Perkin-Elmer UV/Vis
spectrometer Lambda2. The fluorescence spectra were recorded with a Fluoromax-4
Spectrofluorometer (Horiba Scientific). For the absorption spectra dichloromethane was used
-6
as solvent and a concentration of 5 x 10 M was applied for the quantitative determination of
1
G. M. Sheldrick, Acta Crystallogr. 2008, A64, 112-122.
2

ACCEPTED MANUSCRIPT
the molar extinction coefficient. A solution of quinine sulphate in 0.05 M sulphuric acid was
2
applied as standard for the measurement of the fluorescence quantum yields (φ = 0.52).
f
Sample and standard were excited with an absorbance of ~ 0.1 in air-equilibrated solution.
2
Meech, S. R., Phillips, D. J. Photochem.1983, 23, 193-217
3

ACCEPTED MANUSCRIPT
2
. General Procedures and Experimental Data
Synthesis of tetraarylpyrazines
Prior to all, solutions of Pd(OAc) and P(Cy) were prepared in dried and argon filled Schlenk
2
3
tubes (both 0.0125 mmol, 5 mol%) using 1 mL of extra dry THF and toluene, respectively.
Solutions were stirred at room temperature for 10 min.
To an argon-flushed glass pressure tube 50 µL of Pd(OAc) solution (0.000625 mmol,
2
3
0
.25 mol%) was added . After the removal of THF via evacuation of pressure tube, 100µL of
earlier prepared solution of P(Cy) (0.00125 mmol, 0.5 mol%), 2 (54 mg, 0.25 mmol), the
3
appropriate arylboronic acid (2 mmol, 8.0 equiv.) and K PO (2 mmol, 8.0 equiv.) were
3
4
added, followed by the injection of dry toluene (3.5 mL). The tube was closed with a teflon
screw cap and the reaction mixture was stirred at 100 °C for 18 hours. Subsequently, the
mixture was cooled down to room temperature and diluted with water and dichloromethane.
The aqueous layer was extracted three times with dichloromethane. Combined organic layers
were dried over Na SO and filtered. Unless otherwise noted, solvent was evaporated and the
2
4
residue was purified by column chromatography on silica gel using mixture of hexane and
dichloromethane as eluent.
2
,3,5,6-Tetraphenylpyrazine (3a):
According to the general procedure, compound 3a was isolated as a white solid
(93 mg, 97 %); mp. = 248 – 250 °C.
1
H NMR (300 MHz, CDCl ): δ = 7.29 - 7.34 (m, 12H), 7.60 - 7.66 (m,
3
1
3
8
1
H). C NMR (75 MHz, CDCl ): δ = 128.2 (CH), 128.5 (CH), 129.8 (CH),
3
+
38.4 (C), 148.4 (C). MS (EI, 70 eV): m/z (%) = 384 (M , 100), 305 (7),
+
1
3
6
78 (44), 152 (8), 103 (10). HRMS (ESI): calcd. for C H N ([M+H] ): 385.16993; found:
2
8
21
2
-1
~
85.17036. IR (ATR, cm ):
92 (s), 536 (s).

= 3038 (w), 1389 (m), 1170 (m), 1104 (m), 1011 (m), 762 (s),
3
In cases of compounds 3k-p, 2 mol% (1.1 mg) of Pd(OAc) and 4 mol% (2.8mg) of P(Cy) were used.
2
3
4

ACCEPTED MANUSCRIPT
2
,3,5,6-Tetrakis(4-(trifluoromethyl)phenyl)pyrazine (3b):
According to the general procedure, compound 3b was isolated as a white solid
(139 mg, 85 %); mp. = 265 – 266 °C.
1
3
H NMR (300 MHz, CDCl ): δ = 7.62 (d, 8H, J = 8.2 Hz), 7.74
3
3
13
(
(
(
d, 8H,
J = 8.2 Hz).
C NMR (75 MHz, CDCl ): δ = 123.8
3
1
3
q, J = 272.3 Hz, CF ), 125.5 (q, J = 3.8 Hz, CH), 130.1
C–F
3
C–F
2
CH), 131.3 (q, JC–F = 32.6 Hz, C), 140.8 (C), 147.9
1
9
(
C). F NMR (282 MHz, CDCl ): δ = -62.3 (s, 12F, CF ). MS (EI, 70 eV): m/z (%) = 656
3 3
+
(
M , 100), 637 (15), 587 (14), 314 (77), 295 (15), 264 (10), 225 (7), 171 (7).
+
HRMS (ESI): calcd. for C H F N ([M+H] ): 657.11946; found: 657.1192. IR (ATR,
32
17 12
2
-
1
~
cm ):

= 1322 (s), 1167 (m), 1105 (s), 1011 (m), 849 (s), 631 (m), 535 (m). EA: calcd. for
C H F N (656.46): C, 58.55; H, 2.46; N, 4.27; found: C, 57.92; H, 2.32; N, 4.23.
32
16 12
2
2
,3,5,6-Tetra-p-tolylpyrazine (3c):
According to the general procedure, compound 3c was isolated as a white solid
(103 mg, 93 %); mp. = 284 – 286 °C.
1
H NMR (300 MHz, CDCl ): δ = 2.35 (s, 12H, CH ), 7.09 - 7.13 (m,
3
3
1
3
8
1
H), 7.52 - 7.56 (m, 8H). C NMR (75 MHz, CDCl ): δ = 21.3 (CH ),
3
3
28.9 (CH), 129.6 (CH), 135.8 (C), 138.3 (C), 147.7 (C).
+
MS (EI, 70 eV): m/z (%) = 440 (M , 100), 425 (10), 206 (19), 189 (8).
+
HRMS (ESI): calcd. for C H N ([M+H] ): 441.23253; found: 441.23245. IR (ATR,
3
2
29
2
-
1
~
cm ):

= 2917 (w), 1385 (s), 1172 (m), 1096 (m), 1009 (m), 820 (s), 728 (s), 626 (m), 530
(s), 513 (s).
5

ACCEPTED MANUSCRIPT
2
,3,5,6-Tetrakis(4-isopropylphenyl)pyrazine (3d):
According to the general procedure, compound 3d was isolated as yellowish-white solid
(133 mg, 96 %); mp. = 279 – 281 °C.
1
3
H NMR (300 MHz, CDCl ): δ = 1.24 (d, 24H, J = 6.9 Hz, CH ),
3
3
3
2
.90 (sept, 4H, J = 6.9 Hz, CH ), 7.13 - 7.17 (m, 8H), 7.56 - 7.60
i-Pr
1
3
(
m, 8H). C NMR (75 MHz, CDCl ): δ = 23.8 (CH ), 33.8 (C H ),
3 3 i-Pr
1
26.2 (CH), 129.7 (CH), 136.1 (C), 147.5 (C), 149.2 (C).
+
MS (EI, 70 eV): m/z (%) = 552 (M , 100), 537 (11), 509 (7).
+
HRMS (ESI): calcd. for C H N ([M+H] ): 553.35773; found: 553.35861. IR (ATR,
40
45
2
-
1
~
cm ):

= 2959 (m), 2926 (w), 2866 (w), 1388 (s), 1181 (m), 1098 (m), 1006 (m), 839 (s),
6
32 (m), 552 (s).
2
,3,5,6-Tetrakis(4-methoxyphenyl)pyrazine (3e):
According to the general procedure, compound 3e was isolated as a light brown solid
(113 mg, 90 %); mp. = 278 – 280 °C.
1
H NMR (300 MHz, CDCl ): δ = 3.81 (s, 12H, OCH ), 6.81 - 6.86
3
3
1
3
(
m, 8H), 7.56 - 7.61 (m, 8H). C NMR (75 MHz, CDCl ): δ = 55.2
3
(
OCH ), 113.6 (CH), 131.0 (CH), 131.2 (C), 146.8 (C), 159.8 (C).
3
+
MS (EI, 70 eV): m/z (%) = 504 (M , 100), 252 (12), 238 (15), 223
(
34), 195 (10), 152 (12), 133 (11). HRMS (EI, 70 eV): calcd. for C H N O : 504.20436;
3
2
28
2
4
-1
~
found: 504.20469. IR (ATR, cm ):

= 2926 (w), 2834 (w), 1602 (s), 1573 (m), 1511 (s),
1
418 (m), 1381 (s), 1295 (s), 1244 (s), 1164 (s), 1027 (s), 830 (s), 796 (s), 740 (m), 529 (s).
2
,3,5,6-Tetrakis(3-(trifluoromethyl)phenyl)pyrazine (3f):
According to the general procedure, compound 3f was isolated as a white solid
(157 mg, 96 %); mp. = 165 – 167 °C.
1
3
H NMR (300 MHz, CDCl ): δ = 7.48 (pt, 4H,
J = 7.8 Hz), 7.65
3
3
3
(
d, 4H, J = 7.8 Hz), 7.75 (d, 4H, J = 7.8 Hz), 7.86 (bs, 4H).
1
3
1
C NMR (75 MHz, CDCl ): δ = 123.6
(q,
JC–F = 271.9 Hz,
CF3),
3
3
3
1
1
25.9 (q, J = 3.6 Hz, CH), 126.7 (q, J = 3.8 Hz, CH), 129.1 (CH),
C–F
C–F
2
31.1 (q, JC–F = 32.6 Hz, C), 133.0 (CH), 138.0 (C), 148.1 (C).
6