Synthesis of tetrasubstituted pyrazines and pyrazine N-oxides

Article abstract of DOI:10.1016/j.tetlet.2009.12.053

An efficient synthesis of tetrasubstituted unsymmetrical pyrazines and their related pyrazine N-oxides has been developed from commercially available 2-chloro-3-methylpyrazine. The procedure and scope of these synthesis routes are described.

Full text of DOI:10.1016/j.tetlet.2009.12.053

Tetrahedron Letters 51 (2010) 974–976
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Tetrahedron Letters
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Synthesis of tetrasubstituted pyrazines and pyrazine N-oxides
*
Jae Uk Jeong , Xiaoyang Dong, Attiq Rahman, Robert W. Marquis
Medicinal Chemistry, Immuno-Inflammation CEDD, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of tetrasubstituted unsymmetrical pyrazines and their related pyrazine N-oxides
has been developed from commercially available 2-chloro-3-methylpyrazine. The procedure and scope
of these synthesis routes are described.
Received 4 August 2009
Revised 9 December 2009
Accepted 10 December 2009
Available online 16 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Pyrazines are important pharmacophores present in an array of
biologically active compounds such as the antimycobacterial agent
pyrazinecarboxamide, the antibacterial agents Sulfaclozine and
Sulfalene, the antidiabetic agent Glipizide, and the hypnotic/seda-
tive agent Zopiclone.1 The most commonly utilized method for the
2a and 2b in moderate yield (53% and 54%, respectively). Oxidation
of 2a and 2b using m-CPBA in CH2Cl2 at room temperature pro-
vided the disubstituted pyrazine 1-oxides 4a and 4b (73% and
78% yield, respectively). Interestingly, the formation of either the
regioisomeric N-oxide or the N,N0-dioxide (not shown) was not ob-
served in these transformations. The regioselectivity of oxidation
to 4a and 4b was also confirmed by the oxidation5b of 1 to 3
(95% yield) directly followed by a subsequent palladium-catalyzed
synthesis of pyrazines is the condensation of
a-diketones with 1,2-
diamines or
a
-aminoketones followed by oxidation.1,2 This syn-
thetic methodology has broad applicability for the preparation of
symmetrical pyrazines (R1 = R3 and R2 = R4, Fig. 1). However, this
method has not found widespread applicability for the preparation
of unsymmetrical pyrazines due to issues associated with regiose-
lectivity. Recently several methods have been reported for the syn-
thesis of unsymmetrical pyrazines3 from various starting materials
such as epoxides,3b azirines,3c and chloropyrazines.3d To the best of
our knowledge, no efficient synthetic methods have been disclosed
for the synthesis of unsymmetrical pyrazines with four different
substituents (R1 – R2 – R3 – R4, alkyl, or aryl, Fig. 1). During the
course of our investigations to identify small molecule antagonists
of the calcium receptor, we became interested in preparing and
evaluating the biological effects of a series of unsymmetrical pyra-
zines and pyrazine N-oxides such as I and II as isosteric analogs of a
previously identified class of pyrimidinone antagonists generically
represented in structure III.4 Herein we report our work on the reg-
ioselective preparation of tetrasubstituted, unsymmetrical pyra-
O
O
R1
R2
N+
Ar
R4
R3
R4
R3
R1
R2
N
N
R
Ar'
N
N
N
I
II
III
Figure 1. Tetrasubstituted pyrazines and pyrazine N-oxides, and pyrimidinones.
1
2
R
N
N
Cl
N
a
Me
Me
N
3
zines
I as well as pyrazine N-oxides II (R1 = R3 = aryls and
2a: R = 5-methyl-2-thienyl
2b: R = Ph
R2 = R4 = alkyls) as mimetics of the pyrimidonone scaffold III (
Fig. 1).
1
As outlined in Scheme 1, commercially available 2-chloro-3-
methylpyrazine 15a was used as the starting material for our syn-
thesis to prepare the key intermediates disubstituted pyrazine 1-
oxides 4a and 4b. Palladium-catalyzed cross-coupling of 2-
chloro-3-methylpyrazine 1 with arylboronic acids such as (5-
methyl-2-thienyl)boronic acid and phenylboronic acid in the pres-
ence of Pd(P-t-Bu3)4 (5 mol %) provided the disubstituted pyrazines
b
b
3
R
N
a
Cl
N
5
6
2
N+
O
Me
N+
O
Me
1
3
4a: R = 5-methyl-2-thienyl
4b: R = Ph
* Corresponding author. Tel.: +1 610 917 7207; fax: +1 610 917 6020.
E-mail address: jae.u.jeong@gsk.com (J.U. Jeong).
Scheme 1. Reagents and conditions: (a) RB(OH)2, Pd(P-t-Bu3)4, Na2CO3, toluene–
EtOH–H2O (100:1:1), reflux, 5 h; (b) m-CPBA, CH2Cl2, rt.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.053

J. U. Jeong et al. / Tetrahedron Letters 51 (2010) 974–976
975
N
N
N
R
N
Cl
N
R
OMe
b
5
6
b
a
a
3
N+
O
+
Me
N+
O
Me
Me
N
Me
O
PMBO
BnO
12
11
4a: R = 5-methyl-2-thienyl
4b: R = Ph
5a: R = 5-methyl-2-thienyl
5b: R = Ph
O
O
+
+
N
N
S
d
c
N
R
N
N
Cl
R
OMe
c
Me
N
Me
N
Me
N
Me
PMBO
PMBO
13
14
MeO
6a: R = 5-methyl-2-thienyl
6b: R = Ph
7a: R = 5-methyl-2-thienyl
7b: R = Ph
O
+
N
N
N
Scheme 2. Reagents and conditions: (a) 1-bromo-2-(methyloxy)benzene, Pd(OAc)2,
K2CO3, P-t-Bu2Me–HBF4, toluene, 110 °C, 16 h; (b) POCl3, 110 °C, 30 min; (c)
PhCH2CH2ZnBr, PEPPSI-IPr, THF/DMI, LiBr, microwave, 100 °C, 10 min.
S
S
e
+
Me
Me
N
PMBO
16(6%)
PMBO
15(62%)
cross-coupling reaction to provide analogs 4a (an unoptimized
yield of 49%) and 4b.
Scheme 4. Reagents, conditions, and yields: (a) 1-bromo-2-[(phenyl-
methyl)oxy]benzene, Pd(OAc)2, K2CO3, P-t-Bu2Me–HBF4, toluene, 110 °C, 16 h,
63%; (b) (i) Pd/C, HCO2NH4, MeOH, 50 °C, 16 h, 82%; (ii) PMBCl, n-Bu4NI, K2CO3,
DMF, rt, 16 h, 81%; (c) m-CPBA, CH2Cl2, rt, 2 h, 77%; (d) 2-bromo-5-methylthioph-
ene, Pd(OAc)2, K2CO3, P-t-Bu2Me–HBF4, toluene, 110 °C, 16 h, 70%; (e)
PhCH2CH2MgBr, ꢀ30 °C, THF, 2 h, then O2, 1 h.
The regioselective introduction of the N-oxide of 4a and 4b was
instrumental for the subsequent incorporation of the C6 aryl as
well as the C5 phenethyl substituents (Scheme 2). Utilizing the
procedure originally described by Fagnou and co-workers for the
direct arylation of pyridine N-oxides,6 the N-oxide moiety of the
pyrazine 1-oxide 4a facilitated regioselective arylation with 1-bro-
mo-2-(methyloxy)benzene to provide the trisubstituted pyrazine
1-oxide 5a in 64% yield7,8 followed by a conversion to 5-chloropyr-
azine 6a using POCl3 at 110 °C in 88% yield. Cross-coupling of 5-
chloropyrazine 6a with phenethylzinc bromide in the presence of
PEPPSI-IPr9 under microwave conditions with heating provided
the tetrasubstituted pyrazine 7a in 68% yield.10
This cross-coupling reaction could be utilized with a variety of
substrates to introduce various alkyl groups (sp2–sp3 cross-cou-
pling reactions) as well as aryl groups (sp2–sp2 cross-coupling
reactions). The 2-phenylpyrazine 7b was obtained from 4b using
the reaction conditions described above in similar yields (33% for
3 steps). In addition, Pd-catalyzed cross-coupling conditions such
as those detailed by Suzuki, Stille, and Negishi could also be incor-
porated into this synthesis sequence.
tempted as outlined in Scheme 3. Unfortunately, oxidation of 7a
with 1.7 equiv of m-CPBA in CH2Cl2 at room temperature gave
the undesired tetrasubstituted pyrazine 1-oxide 8 as a major prod-
uct (48%, isolated yield).11 Other oxidation conditions such as urea/
hydrogen peroxide and hydrogen peroxide with MeReO3 did not
provide the desired product 9 in any substantial quantity. Alterna-
tively, the oxidation of 5-chloropyrazine 6a with K2S2O8 and H2SO4
to give the 4-oxide 10 also met with limited success.12
In order to address the vexing undesired regioselective oxida-
tion of pyrazine 7a, we developed an efficient synthetic route to
obtain the tetrasubstituted pyrazine 4-oxide 15 as shown in
Scheme 4. Palladium-catalyzed cross coupling of 3-chloropyrazine
1-oxide 3 with o-benzyloxy-phenyl bromide provided intermedi-
ate 11 in 63% yield. Reduction of 11 with ammonium acetate and
Pd/C followed by reprotection of phenol using p-methoxybenzyl
chloride provided the 1,5-disubstituted pyrazine 12. Oxidation of
To obtain the desired tetrasubstituted pyrazine 4-oxide 9, a di-
rect oxidation of the tetrasubstituted pyrazine analog 7a was at-
O
4
+
4
N
4
N
S
S
N
S
3
N+
O
1
N
1
m-CPBA
N
2
1
O
Bn
BnO
BnO
9
8 (48%)
7a
O
N
N
Cl
N+ Cl
S
S
N
BnO
BnO
10
6a
Scheme 3. Oxidation of tetrasubstituted pyrazines.

976
J. U. Jeong et al. / Tetrahedron Letters 51 (2010) 974–976
5. The synthesis of 2-chloro-3-methylpyrazine
1
could be applied to the
12 using m-CPBA provided 1,5-disubstituted pyrazine 4-oxide 13
(77%) as the major N-oxide along with the trace amount of the
undesired regioisomeric N0-oxide (not shown, <5%). Palladium-cat-
alyzed cross-coupling of 13 with 5-methylthienyl bromide pro-
vided the desired trisubstituted pyrazine 4-oxide 14 in 70% yield.
The regioselectivity of this transformation is likely a result of the
greater steric bulk of the C6 aryl moiety over that of the smaller
C2 methyl group. Installation of the C5 phenethyl moiety from
14 was accomplished utilizing a direct alkylation method13 with
an excess (3 equiv) phenethyl magnesium bromide in THF at
ꢀ30 °C followed by stirring with air-bubbling to provide the de-
sired tetrasubstituted pyrazine 4-oxide 15 in 62% yield.14 The tet-
rasubstituted pyrazine 16 was also obtained as a side product
(6%) resulting from the elimination of magnesium hydroxide from
the reaction intermediate, which was originally described in the
reaction of quinoline N-oxides by Goto and co-workers.13 The tri-
substituted pyrazine 4-oxide 14 is also a versatile intermediate
which may be utilized in sp2–sp2 cross-coupling reactions to fur-
ther explore the preparation of additional tetrasubstituted pyra-
zine analogs within this template.9,15
preparation of additional 2-chloro-3-alkylpyrazines: (a) Ohta, A.; Watanabe,
T.; Akita, Y.; Yoshida, M.; Toda, S.; Akamatsu, T.; Ohno, H.; Suzuki, A. J.
Heterocyclic. Chem. 1982, 19, 1061–1067; The regioselectivity of the oxidation
of 2-chloropyrazine was determined by the relative basicity of nitrogens in the
ring: (b) Mixan, C. E.; Pews, R. G. J. Org. Chem. 1977, 42, 1869–1871.
6. (a) Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005, 127,
18020–18021; (b) Leclerc, J.-P.; Fagnou, K. Angew. Chem., Int. Ed. 2006, 45,
7781–7786.
7. The preparation of 5a: K2CO3 (0.87 g, 6.30 mmol), P-t-Bu2Me–HBF4 (0.16 g,
0.63 mmol), Pd(OAc)2 (0.14 g, 0.63 mmol), and 2-methyl-3-(5-methyl-2-
thienyl)pyrazine 1-oxide (0.65 g, 3.15 mmol) were weighed to air and placed
in
a 10 mL round-bottomed flask. 1-Bromo-2-(methyloxy)benzene (0.59 g,
3.15 mmol) was added under N2 followed by the addition of toluene (2 mL).
The reaction mixture was then heated to 110 °C overnight. The solution was
cooled to room temperature and filtered. The filtrate was evaporated under
reduced pressure and the residue was purified by flash column chromatograph
to provide 0.63 g of the title product (64%); LC–MS: [MH]+ = 313.2; 1H NMR
(CDCl3, 400 MHz), d (ppm): 2.58 (s, 3H), 2.81 (s, 3H), 3.85 (s, 3H), 6.86 (d,
J = 2.4 Hz, 1H), 7.10 (m, 2H), 7.32 (d, J = 2.4 Hz, 2H), 7.49 (m, 2H), 8.41 (s, 1H);
13C NMR (CDCl3, 100 MHz), d (ppm): 14.70, 15.46, 55.80, 111.34, 119.34,
120.62, 126.26, 129.04, 131.06, 131.42, 138.66, 140.01, 141.32, 144.14, 144.92,
149.54, 157.73; TLC Rf = 0.20 (eluent: 20% EtOAc in hexane).
8. All new compounds were characterized by 1H NMR and LC–MS.
9. Organ, M. G.; Avola, S.; Dubovyk, I.; Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.;
Valente, C. Chem. Eur. J. 2006, 12, 4749–4755.
10. The preparation of 7a: LiBr (38 mg, 0.45 mmol) and PEPPSI-IPR (10 mg,
0.015 mmol) were added to a solution of 0.5 mL of DMI (1,3-dimethyl-2-
imidazolidinone) and 0.5 mL of THF. The solution was allowed to stir under N2
until the solid was dissolved. 0.48 mL of phenethylzinc bromide (0.5 M in
THF) and 2-chloro-5-methyl-3-[2-(methyloxy)phenyl]-6-(5-methyl-2-thienyl)
pyrazine 6a (50 mg, 0.15 mmol) were then added. The reaction mixture was
heated under microwave at 100 °C for 10 min. The solution was diluted with
CH2Cl2, washed with water and brine, and dried over Na2SO4. After filtration,
the solvent was evaporated and the residue was purified by flash column
chromatograph to provide 41 mg of the title product (68%); LC–MS:
[MH]+ = 401.2; 1H NMR (CDCl3, 400 MHz), d (ppm): 2.60 (s, 3H), 2.85 (s, 3H),
2.88 (br, 2H), 3.09 (br s, 2H), 3.78 (s, 3H), 6.86 (d, J = 2.4 Hz, 1H), 6.97 (d,
J = 7.8 Hz, 1H), 6.99–7.22 (m, 7H), 7.44 (m, 2H). 13C NMR (CDCl3, 151 MHz), d
(ppm): 15.51, 23.99, 34.25, 35.63, 55.33, 110.72, 120.93, 125.67, 126.35,
127.49, 127.63, 128.19 (2C), 128.42 (2C), 130.02, 130.79, 141.32, 142.04,
143.18, 144.89, 145.24, 147.87, 151.76, 156.61; TLC Rf = 0.27 (eluent: 10%
EtOAc in hexane).
In this Letter we have detailed the development of efficient syn-
thesis routes to tetrasubstituted unsymmetrical pyrazines and pyr-
azine N-oxides which are important pharmacophores present in a
variety of biologically active compounds. The methods described
here could also have broader application in the synthesis of other
disubstituted and trisubstituted pyrazines as outlined in Schemes
2 and 4.
Acknowledgments
We thank Joshi Ramanjulu and Yunfeng Lan for initial discus-
sion and their preliminary works and Minghui Wang for his assis-
tance with characterization of compounds by NMR.
11. The starting material 7a (19%) and other further oxidized product such as
dioxide (14%) and trioxide (19%) were detected by LC–MS. Yields are based on
LC–MS. Dioxide and trioxide were not isolated for full characterization.
12. Sato, N.; Matsumoto, K.; Takishima, M.; Mochizuki, K. J. Chem. Soc., Perkin Trans.
1 1997, 3167–3172.
References and notes
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278; (b) Sato, N. Sci. Synth. 2004, 16, 751–844. and references therein..
2. (a) Smith, S. C.; Heathcock, C. H. J. Org. Chem. 1992, 57, 6379–6380; (b)
Heathcock, C. H.; Smith, S. C. J. Org. Chem. 1994, 59, 6828–6839; (c) Pan, Y.;
Merriman, R. L.; Tanzer, L. R.; Fuchs, P. L. Bioorg. Med. Chem. Lett. 1992, 2, 967–
972.
3. (a) Guo, C.; Bhandaru, S.; Fuchs, P. L.; Boyd, M. R. J. Am. Chem. Soc. 1996, 118,
10672–10673; (b) Taber, D. F.; DeMatteo, P. W.; Taluskie, K. V. J. Org. Chem.
2007, 72, 1492–1494; (c) Palacios, F.; Retana, A. M. O.; Gil, J. I.; Munain, R. L.
Org. Lett. 2002, 4, 2405–2408; (d) Sato, N.; Matsuura, T. J. Chem. Soc., Perkin
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Org. Chem. 1989, 54, 640–643; (f) Guram, A. S.; Jordan, R. F. J. Org. Chem. 1992,
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Balandrin, M. F.; Fox, J.; Heaton, W. L.; Conklin, R. L. Bioorg. Med. Chem. Lett.
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14. The preparation of 15: To
a
solution of 3-methyl-5-[2-({[4-
1-
(methyloxy)phenyl]methyl}oxy)phenyl]-2-(5-methyl-2-thienyl)pyrazine
oxide 14 (42 mg, 0.1 mmol) in 1.5 mL of THF at ꢀ30 °C was slowly added
0.3 mL of phenethyl magnesium bromide (0.3 mmol, 1M in THF). The reaction
mixture was stirred at ꢀ30 °C for 2 h and stirred with air-bubbling for 1 h. The
reaction was quenched with saturated aqueous NH4Cl at 0 °C. The aqueous
layer was extracted with EtOAc and the combined organic solution was dried
over Na2SO4. After filtration, the solvent was evaporated and the residue was
purified by flash column chromatograph to provide 36 mg of the title product
(62%); LC–MS: [MH]+ = 523.2; 1H NMR (CDCl3, 400 MHz), d (ppm): 2.59 (s, 3H),
2.61 (s, 3H), 2.88 (m, 4H), 3.78 (s, 3H), 5.02 (d, J = 2.4 Hz, 2H), 6.80 (d, 1H),
6.82–7.22 (m, 12H), 7.40 (m, 2H). 13C NMR (CDCl3, 100 MHz), d (ppm): 15.10,
25.17, 30.61, 31.12, 55.22, 70.35, 113.05, 113.92, 121.22, 124.40, 125.85,
125.89, 127.29, 127.78, 128.18, 128.29, 128.41, 128.43, 128.57, 128.78, 130.10,
130.49, 131.27, 137.37, 141.36, 142.04, 143.23, 144.12, 151.13, 151.69, 155.56,
159.31; TLC Rf = 0.23 (eluent: 30% EtOAc in hexane).
15. Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130, 9254–9256.