Facile synthesis of diarylpyrazines using suzuki coupling of dichloropyrazines with aryl boronic acids

Article abstract of DOI:10.3987/com-03-9789

The palladium-catalyzed coupling of dichloropyrazines with aryl boronic acids is reported. The reaction proceeds smoothly under anaerobic conditions to give moderate to good yields of the corresponding diarylpyrazines.

Full text of DOI:10.3987/com-03-9789

HETEROCYCLES, Vol. 60, No. 8, 2003, pp. 1891 - 1897
Received, 21st April, 2003, Accepted, 24th June, 2003, Published online, 30th June, 2003
FACILE SYNTHESIS OF DIARYLPYRAZINES USING SUZUKI
COUPLING OF DICHLOROPYRAZINES WITH ARYL BORONIC
ACIDS
Nate Schultheiss and Eric Bosch*
Department of Chemistry, Southwest Missouri State University, Springfield,
MO 65804, USA
erb625f@smsu.edu
Abstract – The palladium-catalyzed coupling of dichloropyrazines with aryl
boronic acids is reported. The reaction proceeds smoothly under anaerobic
conditions to give moderate to good yields of the corresponding diarylpyrazines.
INTRODUCTION
Arylpyrazines are of interest due to their potential application as versatile intermediates in the synthesis of
pharmaceuticals and as agrochemicals1 and food flavorings.2 A variety of traditional synthetic
procedures have been developed for the preparation of this family of compounds based on the
cyclocondensation of α-amino ketones, or related derivatives3 and, more recently, the transition metal
catalyzed Suzuki coupling of halopyrazines with arylmetals.4 The latter strategy provides a procedure
for the regiocontroled introduction of a range of aryl substitutents starting from the appropriate
halopyrazine. Thus Ohta reported the coupling reaction of chloropyrazines with tetraphenyltin to form
phenylpyrazines in moderate to good yields.5 McKillop6 and Mitchell,7 however, noted that the coupling
of aryl boronic acids with π-deficient heteroaryl chlorides including chloropyrazine was feasible but
sensitive to the nature of the palladium catalyst
-
both authors reporting that
[1,4-bis(diphenylphosphine)butane]palladium(II) dichloride was the most effective catalyst. Thompson
noted that [1,1’-bis(diphenylphosphino)ferrocene]palladium(II) diacetate was the most efficient catalyst.8
The Suzuki coupling of halopyrazines with arylboronic acids has proven to be a useful tool for the
synthesis of complex molecules.9 The reaction has also been used in total syntheses of natural products
including Dragmacidin D10 and analogues of psoralen11 and coelenterazine.12 In this paper we report the

synthesis of diarylpyrazines using the readily available bis(triphenylphosphine)palladium(II) dichloride as
catalyst.
RESULTS AND DISCUSSION
A range of arylpyrazines were prepared by palladium-catalyzed cross coupling of chloropyrazines with
arylboronic acids according to equation 1. The results are tabulated in Table 1.
We used bis(triphenylphosphine)palladium(II) dichloride as a catalyst and performed the reaction with
mild heating under basic and heterogeneous conditions in a mixture of acetonitrile and aqueous sodium
carbonate. We obtained similar yields of products when tetrahydrofuran was used as the organic solvent.
It is important to note that during our first trials we isolated significant amounts of biaryls, derived from
the arylboronic acids, when the reaction was performed under an atmosphere of air. Thus, for example,
20-30% of biphenyl was formed during reaction of phenylboronic acid with 2,6-dichloropyrazine. This
side reaction was effectively stopped when we purged the reaction mixture with argon and performed the
reaction under an argon atmosphere. In this regard it is relevant to note that Moreno-Mañas reported the
palladium catalyzed homocoupling of arylboronic acids to yield biaryls in an oxygen atmosphere or in
air.13 Those authors also noted that biaryl formation was significantly retarded in a nitrogen atmosphere.
We were surprised to note that reaction of 2,3-dichloropyrazine with an excess of
2,6-dimethylphenylboronic acid yielded the corresponding monoarylated product as the exclusive product
even after extended reaction. We isolated the product (13) in 52% yield. All attempts to subsequently
add a second aryl group were unsuccessful. The same selectivity was not observed with arylboronic
1
acids that did not contain the ortho methyl substituents. Thus H NMR spectral monitoring of the
reaction of 2,3-dichloropyrazine with 3,5-dimethylphenylboronic acid indicated that a mixture of mono-
and diarylated pyrazine were formed during the reaction. The reaction of 2,6-dichloropyrazine with
1
2,6-dimethylphenylboronic acid was also monitored by H NMR at intermediate times. This clearly
indicated that the reaction was unselective and reaction with one equivalent of the arylboronic acid
yielded a roughly statistical mixture of monoarylated product in about 50 % yield along with
approximately 25 % of each of the monoarylated product and the unreacted dichloropyrazine. The
monoarylated pyrazine (5) was separated by flash chromatography on silica gel and isolated in moderate
yield.
Subsequent coupling of the monochloropyrazine (5) with the isomeric boronic acid,
3,5-dimethylphenylboronic acid, gave the mixed arylpyrazine (6) in 84 % yield.

We believe that the selective monosubstitution shown with 2,3-dichloropyrazine is the result of the
increased steric demand of the ortho-methyl on the aryl group that effectively blocks the adjacent reaction
site. In 2,6-dichloropyrazine the two reaction sites are separated by the N-atom and the reaction is not
selective.

EXPERIMENTAL
Materials. The dichloropyrazines, arylboronic acids and solvents were purchased from Aldrich and used
as received. The palladium catalyst was purchased from Strem. NMR spectra were recorded on a
Varian Gemini 200 MHz spectrometer and elemental analyses were performed by Atlantic Microlabs.
Typical experimental procedure for alkylarylboronic acids: 2,6-Dichloropyrazine (1.61 g, 10.77 mmol),
phenylboronic acid (2.62 g, 21.49 mmol), sodium carbonate (2.30 g, 21.9 mmol) and
bis(triphenylphosphine)palladium(II) dichloride (0.10 g, 0.14 mmol, 0.6 mol%) were added to a round
bottom flask. MeCN (40 mL) and H2O (40 mL) were then added and argon bubbled through the
o
resultant mixture for 15 min. The mixture was heated at 70 C under an Ar atmosphere until TLC
indicated that the reaction was complete. Conventional workup followed by flash chromatography and
recrystallization from ethanol yielded the product 2,6-diphenylpyrazine (2).14
Characteristic physical
o
o
data of the products are: 2,6-Diphenylpyrazine (2): mp 86-88 C (lit.,1b mp 93 C);
2,6-Bis(3’,5’-dimethylphenyl)pyrazine (3): mp 111-113 oC; 1H NMR (CDCl3) δ 8.90 (s, 2H), 7.73 (s, 4H),
13
7.12 (s, 2H), 2.43 (s, 12H); C NMR (CDCl3) δ 151.96, 139.94, 138.54, 136.59, 131.50, 124.90, 21.43;
Anal. Calcd for C20H20N2: C, 83.30; H, 6.99; N, 9.71. Found: C, 83.35; H, 7.16; N, 9.68.
o
1
2,6-Bis(2’,6’-dimethylphenyl)pyrazine (4): mp 125-127 C; H NMR (CDCl3) δ 8.52 (s, 2H), 7.27-7.11
(m, 6H), 2.10 (s, 12H); 13C NMR (CDCl3) δ 155.11, 143.20, 136.79, 135.98, 128.59, 127.59, 20.23; Anal.
Calcd for C20H20N2: C, 83.30; H, 6.99; N, 9.71. Found: C, 83.00; H, 6.98; N, 9.72.
2-Chloro-6-(2’,6’-dimethylphenyl)pyrazine (5): pale yellow oil; 1H NMR (CDCl3) δ 8.59 (s, 1H), 8.45 (s,
13
1H), 7.26 (dd, J=6.4, 8.4 Hz, 1H), 7.13 (d, J=7.4 Hz, 1H), 2.09 (s, 6H); C NMR (CDCl3) δ 155.17,
148.91, 143.31, 142.49, 136.20, 135.23, 129.13, 127.87, 20.26; Anal. Calcd for C12H11N2Cl: C, 65.91; H,
5 . 0 7 ; N , 1 2 . 8 1 .
F o u n d : C , 6 5 . 8 8 ; H , 5 . 2 2 ; N , 1 2 . 7 1 .
2-(2’,6’-Dimethylphenyl)-6-(3”,5”-dimethylphenyl)pyrazine (6): 1H NMR (CDCl3) δ 8.97 (s, 1H), 8.44 (s,
13
1H), 7.67 (s, 2H), 7.30-7.11 (m, 4H), 2.40 (s, 6H), 2.13 (s, 6H); C NMR (CDCl3) δ 154.52, 152.48,
143.29, 139.88, 138.59, 137.12, 136.39, 131.54, 128.66, 127.84, 124.92, 21.37, 20.44; Anal. Calcd for
C2 0 H2 0 N2 : C, 83.30; H, 6.99; N, 9.71. Found: C, 83.10; H, 6.87; N, 9.56.
2,6-Bis(3’-carboxyphenyl)pyrazine (7): 2,6-Dichloropyrazine (0.19 g, 1.269 mmol),
3-carboxyphenylboronic acid (0.45 g, 2.680 mmol), Na2CO3 (0.28 g, 2.7 mmol) and Pd(PPh3)2Cl2 (0.025
g, 0.035 mmol, 1.3 mol %) were added to a round bottom flask. H2O (8 mL) and MeCN (7 mL) were
added and N2 bubbled through the mixture for 20 min. The reaction was heated at 60 °C under a N2
atmosphere for 48 h later and let cool to rt. The MeCN was removed with a rotary evaporator. The
precipitate was filtered and the aqueous solution acidified with 4 mL of 1.0 M HCl and a white precipitate
formed. The precipitates were combined and dissolved in 1.0 M K2CO3. The solution was washed with
dichloromethane (2 x 20 mL) and the organic layer discarded. The aqueous phase was reacidified with

1.0 M HCl (5 mL) to precipitate the product that was recrystallized from DMSO as colorless blocks. mp
>300 oC; 1H NMR (C2D6SO) δ 9.33(s, 2H), 8.78 (s, 2H), 8.53 (d, J= 6.8 Hz, 2H), 8.14 (d, J=6.4 Hz, 2H),
13
7.78 (t, J=6.5 Hz, 2 H); C NMR (C2D6SO) δ 167.1, 149.7, 140.9, 136.3, 131.8, 131.1, 130.8, 129.5,
127.6; Anal. Calcd for C18H12N2O4.C2H6SO: C, 60.29; H, 4.55; N, 6.93. Found: C, 60.26; H, 4.48; N,
6.93. 2,6-Bis(4’-carboxyphenyl)pyrazine (8): A similar procedure was followed for the 4-carboxy
derivative and the product was recrystallized from DMSO as a fine white powder. mp >300 oC; 1H NMR
13
(C2D6SO) δ 13.18 (s, 2H), 9.36 (s, 2H), 8.44 (d, J=6.4 Hz, 4H), 8.15 (d, J=6.4 Hz, 4H); C NMR
(C2D6SO) δ 166.96, 149.52, 141.47, 139.65, 132.02, 129.97, 127.08; Anal. Calcd for C18H12N2O4.0.2 H-
2O: C, 66.81; H, 3.77; N, 8.66. Found: C, 66.76; H, 4.00; N, 8.58.
2,6-Bis(4’-formylphenyl)pyrazine
(9): 2,6-Dichloropyrazine (0.45 g, 3.01 mmol), 4-formylphenylboronic acid (0.44 g, 2.680 mmol),
Na2CO3 (0.28 g, 2.7 mmol) and Pd(PPh3)2Cl2 (0.025 g, 0.035 mmol, 1.2 mol %) were added to a round
bottom flask. MeCN (10 mL) and H2O (10 mL) were added and N2 bubbled through mixture for 20 min.
The reaction was refluxed for 48 h during which time an extra 5 mL of MeCN was added. The resultant
o
light green precipitate was filtered off allowed to dry and recrystallized from DMSO. mp 186-188 C;
13
1H NMR (C2D6SO) δ 10.14 (s, 2H), 9.43 (s, 2H), 8.56 (d, J=8.4 Hz, 4H), 8.14 (d, J=8.4 Hz, 4H); C
NMR (C2D6SO) δ 191.72, 150.48, 141.54, 141.31, 137.23, 130.35, 127.65; Anal. Calcd for C18H12N2O2:
13
C, 74.99; H, 4.20; N, 9.72. Found: C, 73.10; H, 4.21; N, 9.25. An impurity was detected in C NMR
spectrum (142.90, 142.50, 134.80 ppm).
2,6-Bis(3’-hydroxyphenyl)pyrazine (10):
2,6-Dichloropyrazine (0.45 g, 3.00 mmol), 3-hydroxyphenylboronic acid (0.90 g, 6.493 mmol), K2CO3
(0.45, 3.2 mmol), PPh3 (0.034 g, 0.13 mmol) and Pd(PPh3)2Cl2 (51.3 mg, 0.07 mmol, 1.1 mol %) were
added to a round bottom flask. MeCN (12 mL) and H2O (12 mL) were added and N2 bubbled through
mixture for 20 min. The mixture was heated at 60 °C under a N2 atmosphere for 5 d. The precipitated
product was filtered off and the remaining solution was washed with 100 mL of hexane/EtOAc (1/1).
The organic layer was separated and the aqueous layer was allowed to evaporate slowly and to precipitate
more product. The combined precipitate was dissolved in hot Me2CO, filtered and reprecipitated as an
o
1
off-white powder, mp 229-231 C; H NMR (C2D6SO) δ 9.04 (s, 2H), 7.76 (s, 2H), 7.71 (d, J=7.2 Hz,
13
2H), 7.40 (t, J=7.0 Hz, 2H), 7.01 (d, J=7.8 Hz, 2H), 4.7-3.6 (br m, 2H); C NMR (C2D6SO) δ 158.90,
151.74, 140.75, 138.70, 130.84, 118.71, 117.72, 114.42; Anal. Calcd for C18H12N2O4.0.2 C3H6O
(acetone): C, 72.27; H, 4.82; N, 10.15.
Found: C, 72.00; H, 4.64; N, 10.48.
2,3-Bis(3’,5’-dimethylphenyl)pyrazine (11): mp 93-97 oC; 1H NMR (CDCl3) δ 8.55 (s, 2H), 7.06 (s, 4H),
6.96 (s, 2H), 2.23 (s, 12H); 13C NMR (CDCl3) δ 153.04, 141.72, 138.42, 137.50, 130.16, 127.531, 21.17;
Anal. Calcd for C20H20N2: C, 83.30; H, 6.99; N, 9.71. Found: C, 83.17; H, 7.04; N, 9.63.

2,3-Diphenylpyrazine (12): mp 112-114oC.14 2-Chloro-3-(2’,6’-dimethylphenyl)pyrazine (13): mp
o
1
13
104-106 C; H NMR (CDCl3) δ 8.64 (s, 1H), 8.40 (s, 1H), 7.32-12 (m, 3H), 2.01 (s, 6H); C NMR
(CDCl3) δ 154.93, 149.28, 142.58, 142.49, 135.78, 135.64, 128.99, 127.59, 19.54; Anal. Calcd for
C12H11N2Cl: C, 65.85; H, 5.07; N, 12.81. Found: C, 65.87; H, 5.09; N, 12.62.
ACKNOWLEDGEMENTS
Acknowledgement is made to the Donors of The Petroleum Research Fund, administered by the
American Chemical Society, for partial support of this research. We also thank the Graduate College at
SMSU for funding and NSF for a NMR upgrade (Grant #CCLI-9950853) and for a GK-12 Fellowship for
Nate Schultheiss (Grant # DGE-0086335).
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