Novel synthetic route of aryl-aminopyrazine

Article abstract of DOI:10.1016/j.tet.2003.11.052

We report a novel synthetic route of aryl-aminopyrazine through a new cyclization reaction by using a hydroxylamine. Starting from Boc-glycine and aminonitrile, the aminopyrazine ring was prepared in several steps. After trifluoromethane sulfonylation of the aminopyrazinone, the resultant triflate was subjected to Suzuki-Miyaura coupling reaction with aryl boronic acid to afford coelenteramine.

Full text of DOI:10.1016/j.tet.2003.11.052

Tetrahedron 60 (2004) 835–840
Novel synthetic route of aryl-aminopyrazine
Masaki Kuse,a,b Nobuhiro Kondo,a Yuki Ohyabua and Minoru Isobea
,
*
aLaboratory of Organic Chemistry, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa,
Nagoya 464-8601, Japan
bChemical Instrument Center, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8601, Japan
Received 6 November 2003; revised 21 November 2003; accepted 21 November 2003
Abstract—We report a novel synthetic route of aryl-aminopyrazine through a new cyclization reaction by using a hydroxylamine. Starting
from Boc-glycine and aminonitrile, the aminopyrazine ring was prepared in several steps. After trifluoromethane sulfonylation of the
aminopyrazinone, the resultant triflate was subjected to Suzuki–Miyaura coupling reaction with aryl boronic acid to afford coelenteramine.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
coupling reaction with tin reagents having toxicity and
enforcing the tedious process in waste of the tin reagents.
Therefore, we aimed at new synthetic route of aminopyr-
azine derivatives, starting from N-Boc-glycine (8) and
aminonitrile hydrochloride (2), and we planned to make a 5-
aminopyrazine-2-O-triflate (6) as the coupling partner for
the coelenteramine synthesis. After getting 2-O-trifluoro-
methanesulfonyl-5-aminopyrazine (6), Suzuki–Miyaura
coupling6 reaction would enable us to synthesize various
aminopyrazine analogs.
Kishi and Goto established the synthetic route of coelenter-
azine (4) from coelenteramine (3) as a precursor, which was
prepared from the condensation of keto-oxime (1) and
aminonitrile (2) (Scheme 1).1 This has been so far the only
promised method for the synthesis of benzyl-aryl-amino-
pyrazines. Aminopyrazines are spread over many natural
products, especially in luminous marine organisms like
jellyfish (Aequorea aequorea),2 fireflysquid (Watasenia
scintillans),3 and flyingsquid Tobiika (Symplectoteuthis
oualaniensis L.),4 etc. Their luciferin has imidazopyrazi-
none ring structure (4) that has been synthesized from
aminopyrazine (Scheme 1). Since it is difficult to get many
kinds of keto-oximes, it has been requested to develop
alternative routes accessible to the various aryl-aminopyr-
azine analogs. And such methods would encourage those
who study on those luminous creatures. Nakamura reported
another synthetic way for coelenteramine (3) of great value
for these reasons,5 but their synthetic method needs 2-
aminopyrazine as a starting material. They use Stille
2. Results and discussion
2.1. Synthetic plan
During the research of molecular mechanism of symplectin
(a photoprotein of Symplectoteuthis oualaniensis L.),7 we
focused on the protein structure of symplectin active site
where dehydrocoelenterazine (5) binds.8 Due to the
limitation of the availability of variation of acetophenone
Scheme 1. Synthetic route of coelenterazine (4) from coelenteramine (3) by Kishi and Goto.1
Keywords: Aminopyrazine; Suzuki coupling; Hydroxylamine.
*
Corresponding author. Tel.: þ81-52-789-4109; fax: þ81-52-789-4111; e-mail address: isobem@agr.nagoya-u.ac.jp
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.11.052

836
M. Kuse et al. / Tetrahedron 60 (2004) 835–840
as a photoprobe, we could not modify the aromatic ring in
6-position of dehydrocoelenterazine for photoaffinity label-
ing experiments. Therefore, we planned to make the novel
route for the synthesis of dehydrocoelenterazine having
various functions at the 6-position and to devise a new
synthetic route of aminopyrazine. Considering the Suzuki–
Miyaura coupling as the final functionalization of amino-
pyrazine, we retrosynthesized dehydrocoelenterazine (5) as
shown in Scheme 2. Since dehydrocoelenterazine (5) is
derived from coelenteramine (3), we must devise a synthetic
route of the triflate (6). We thought that the triflate (6) must
be derived from glycine (7) and aminonitrile hydrochloride
(2). Therefore, we started our synthesis from commercially
available N-Boc-glycine (8) and aminonitrile hydrochloride
(2).
2.2. Synthetic route
Schemes 3 and 4 show our novel synthetic route of the
synthesis of triflate (6). Condensation of N-Boc-glycine (8)
and aminonitrile hydrochloride (2) with EDC (1-(3-
(dimethylamino)propyl)-3-ethylcarbodiimide), HOBt
Scheme 2. Synthetic plan of dehydrocoelenterazine (5) from aminopyrazine triflate (6).
Scheme 3. Synthetic route for the formation of pyrazine core (11) by using the key reaction of hydroxyamine from Boc-glycine (8) and aminonitrile (2).
Scheme 4. Synthetic route for aminopyrazine (18a,b) by using triflate 15 as key intermediate.

M. Kuse et al. / Tetrahedron 60 (2004) 835–840
837
(hydroxybenzotriazole) and pyridine in dichloromethane
afforded the amide (9) in 69% yield.
herein. This method should enable us to prepare many kinds
of aminopyrazine analogs, which have potentiality many
functions at the 6-position in coelenteramine through
Suzuki–Miyaura coupling of triflate (15) with a variety of
boronic acid. Furthermore, the merit of the use of Suzuki–
Miyaura coupling is the convenience of boron reagents
compare to the tin reagents for Stille coupling. Further
progress of the current synthesis and the corresponding
luminescent activity is to be published elsewhere.
Isolation of amide (9) was turned out to be much easier than
the condensation by using DIC (diisopropylcarbodiimide),
since the urea produced from EDC was water soluble and
easily removed with acidic water. The Boc protecting group
of amide (9) was favorably removed by treatment with
trifluoroacetic acid to give amidoaminonitrile (10) as a
white powder in quantitative yield. Unfortunately, the direct
cyclization of 10 to cyclic amidine (12) was failed after
many trials, probably due to the weak nucleophilicity of
primary amine in the substrate (10). The subsequent
cyclization of amide-aminonitrile (10) with hydroxylamine
was the key step in this synthetic route to afford cyclic
oxime (11). It must be noted that stirring the reaction
mixture at room temperature over night should be followed
at 70 8C for 3 h for obtaining cyclized product in high yield.
On the other hand, stirring the reaction mixture at 70 8C for
3 h from the beginning gave the cyclic oxime (11) in low
yield. Hydrogenolysis of the oxime (11) was accomplished
with hydrogen under atmospheric pressure in methanol and
Raney nickel (W-2) as catalyst. Due to the insolubility of the
amidine (12) in many organic solvents, the protection of
amidine (12) was proved to be unsuccessful. However, by
using pyridine as the sole solvent, tosylation of the amidine
(12) successfully afforded ditosylate (13) in 78% yield. We
found the double bond migration of the ditosylate (13) from
the amidine (12), and we confirmed the protected position of
amine in 13 with two dimensional NMR analyses. The
removal of one of the tosyl groups in 13 with sodium
hydride in THF followed by recrystallization afforded
aromatized hydroxypyrazine (14) as yellow needles in
91% yield. Hydroxypyrazine (14) was converted to triflate
(15) with trifluoromethanesulfonic anhydride and N,N-
diisopropylethylamine as a base in dichloromethane. This
triflate (15) was the precursor of various aminopyrazine
analogs by using Suzuki–Miyaura coupling. In this report,
we selected both phenylboronic acid (16a) and 4-methoxy-
phenylboronic acid (16b) as coupling partners. Following
the procedure established by Suzuki,9 triflate (15) was
coupled with boronic acids (16a,b) by using Pd(PPh3)4 and
K3PO4 to afford N-tosylamidepyrazine (17a,b) in 85–89%
yield. The removal of tosyl group in N-tosylamidepyrazine
(17a,b) was accomplished by treatment with conc. H2SO4 at
0 8C to provide target aminopyrazine (18a,b) as a white
solid in 38–49% yield. In the case of 18b, the spectroscopic
data was identical with the data of aminopyrazine that was
synthesized by using Kishi and Goto route.10 Although we
purified each compound in each step for the spectroscopic
analysis, we noted here that it is also possible to obtain
hydroxyaminopyrazine (14) in 46% yield in 5 steps without
any purification process starting from N-Boc-amide (9).
Although 5 steps-yield was decreased probably due to the
impurities of each starting material, omission of each
purification process is more convenient for the preparation
of 2-hydroxy-5-aminopyrazine (14).
4. Experimental
4.1. General
All melting points were measured on Yanaco MP-S3 and
uncorrected. IR spectra were recorded on a PERKIN
ELMER Paragon 1000 FT-IR spectrophotometer. Proton
NMR spectra were recorded on a JEOL GSX 270 for
270 MHz, a Varian Gemini-2000 for 300 MHz, a JEOL
JNML-500 for 500 MHz or a Bruker AMX-600 for
600 MHz. Chemical shift (d) are given in parts per million
relative to tetramethylsilane (d 0.00) or CD3OD (d 3.30) or
DMSO-d6 (d 2.49) as internal standard. Coupling constants
(J) are given in Hz. Carbon NMR were recorded on a JEOL
GSX 270 for 67.8 Hz, or on a Varian Gemini-2000 for
75 MHz, or on a JEOL JNML-500 for 125.7 Hz, or on a
Bruker AMX-600 for 150.9 MHz. Chemical shifts are (d)
given in parts per million relative to CDCl3 (d 77.0) or
CD3OD (d 49.0) or DMSO-d6 (d 45.0) as internal standard.
Coupling constants (J) are given in Hz. Low-resolution EI
mass spectra and FAB mass spectra were measured with a
JEOL JMS-700 or JMS-600. High-resolution (HR) mass
spectra were measured with a JEOL JMS-700. Elemental
analysis and HRMS were performed by Analytical Labora-
tory of this school. Dichloromethane (CH2Cl2) was distilled
from calcium hydride. Tetrahydrofuran (THF) and 1,4-
dioxane were distilled from sodium metal in the presence of
sodium benzophenone ketyl as indicator. Pyridine was dried
over NaOH pellet and used without distillation. The other
solvents were of reagent grade. Analytical thin-layer
chromatography (tlc) was conducted on precoated tlc plates:
silica gel 60 F-254 [E.Merck (Art 5715) Darmstadt,
Germany], layer thickness 0.25 mm. Silica gel column
chromatography utilized Silica Gel 60 (spherical) 40–
50 mm [KANTO CHEMICAL CO., INC].
4.1.1. Boc-amidenitrile (9). To a solution of N-Boc-glycine
(8) (5.00 g, 28.6 mmol) and aminonitrile hydrochloride (2)
(5.49 g, 30.0 mmol, 1.1 equiv.) in CH2Cl2 (70 ml) and pyri-
dine (20 ml) was added hydroxybenzotriazole (4.24 g,
31.4 mmol, 1.1 equiv.) and 1-(3-(dimethylamino)propyl)-
3-ethylcarbodiimide hydrochloride (6.03 g, 31.4 mmol,
1.1 equiv.) at 0 8C in an ice bath under Ar atmosphere. This
mixturewasstirredfor15 hatroomtemperature. Theureawas
removed by washing with 1 N HCl aq, then the reaction
mixture was washed with water, saturated NaHCO3 and
diluted brine. Purification by column chromatography on
silicagelwithAcOEt/hexane(1:1)providedamide(9)(6.00 g,
69% yield) as a yellow curdy solid.
3. Summary
We succeeded in developing up the novel synthetic route of
aminopyrazine by using these synthetic route reported
Compound 9: mp 85–88 8C. 1H NMR (300 MHz, CDCl3) d
1.45 (9H, s, t-Bu), 3.10–3.07 (2H, m, benzyl), 3.77 (1H, dd,

838
M. Kuse et al. / Tetrahedron 60 (2004) 835–840
J¼16.8, 5.7 Hz, C(O)CH2NH), 3.81 (1H, dd, J¼16.8,
4.8 Hz, C(O)CH2NH), 5.11 (1H, ddd, J¼15.0, 6.9, 6.9 Hz,
CNCH), 5.29 (1H, brd, BocNH), 7.14 (1H, brd, amide-NH),
7.38–7.25 (5H, m, Ph) ppm. 13C NMR (75 MHz) d 28.3,
37.4, 42.6, 43.0, 78.3, 119.2, 127.4, 128.6, 129.6, 135.8,
156.0, 169.8 ppm. IR (KBr): 3335, 2957, 1679, 1533, 1208,
1127 cm21. FAB-MS (NBA) m/z 304 (MHþ). Anal. calcd
for C16H21N3O3: C, 63.35; H, 6.98; N, 13.85. Found: C,
63.10; H, 7.05; N, 13.81.
(300 MHz, DMSO-d6) d 2.59 (1H, dt, J¼19.8, 1.7 Hz,
C(O)CH2N), 2.81 (1H, dd, J¼13.5, 4.5 Hz, benzyl), 2.98
(1H, dd, J¼13.5, 5.4 Hz, benzyl), 3.25 (1H, d, J¼19.8 Hz,
C(O)CH2NH), 4.08 (1H, brd, Bn-CH), 5.83 (2H, br, NH2),
7.13–7.25 (5H, m, Ph), 7.82 (1H, brd amide-NH) ppm. 13C
NMR (75 MHz, DMSO-d6) d 40.2, 49.6, 53.5, 126.9, 128.2,
130.3, 136.7, 157.3, 169.9 ppm. IR (KBr): 3425, 3192,
3032, 2742, 1681, 1329, 708 cm21. FAB-MS (NBA) m/z
204 (MHþ). Anal. calcd for C11H13N3O: C, 65.01; H, 6.45;
N, 20.68. Found: C, 65.02; H, 6.61; N, 20.61.
4.1.2. Amidenitrile TFA salt (10). To a solution of 9
(19.5 g, 64.3 mmol) in 60 ml of CH2Cl2 was added
trifluoroacetic acid (60 ml) at 0 8C under nitrogen. After
stirring for 1.5 h at 0 8C, this mixture was quenched with ice
and was evaporated to remove the solvents. Resulting white
solid was TFA salt (10) (20.4 g, quantitative yield).
4.1.5. Cyclic amidine ditosylamide (13). To a solution of
amidine (12) (256 mg, 1.26 mmol) in pyridine (5 ml) was
added p-toluenesulfonyl chloride (1.19 g, 6.26 mmol,
5.0 equiv.) at 0 8C under Ar atmosphere. This mixture was
stirred for 1 h at room temperature. Pyridine was removed
by diluting with toluene and concentrating in vacuo. The
resulting residue was dissolved in CH2Cl2–water and was
extracted with CH2Cl2 (X3). The combined organic layer
was washed with brine and was dried over Na2SO4. After
evaporated the crude product was purified by column
chromatography on silica gel with AcOEt–hexane (1:1),
Concentration of the solution afforded pale yellow solid (13)
(499 mg, 78% yield).
1
Compound 10: mp 155 8C. H NMR (300 MHz, CDCl3) d
3.17–3.05 (2H, m, benzyl), 3.35 (2H, s, C(O)CH2NH),
5.18–5.11 (1H, dd, J¼6.6, 6.9 Hz, CNCH) 7.40–7.27 (5H,
m, Ph) 7.85 (1H, d, J¼7.8 Hz, amide-NH) ppm. 13C NMR
(75 MHz, CDCl3) d 38.8, 41.0, 44.2, 118.1, 127.9, 128.9,
129.4, 134.4, 172.3 ppm. IR (KBr): 3335, 2960, 1678, 1532,
1209, 1126 cm21. EI-MS m/z 203 (Mþ). Anal. calcd for
C13H14N3O3F3:C, 49.21; H, 4.45; N, 13.25. Found: C,
49.21; H, 4.63; N, 13.18.
Compound 13: mp 87–92 8C. 1H NMR (500 MHz, DMSO-
d6) d 2.31 (3H, s, Ts), 2.36 (3H, s, Ts), 3.29 (2H, s, benzyl),
3.91 (2H, s, C (O) CH2), 7.12 (2H, d, J¼7.9 Hz, Ts), 7.18–
7.26 (5H, m, Ph), 7.31 (2H, d, J¼8.2 Hz, Ts), 7.49 (2H, d,
J¼7.9 Hz, Ts), 7.74 (2H, d, J¼8.2 Hz, Ts), 9.26 (1H, s,
amide-NH), 9.48 (1H, s, NH) ppm. 13C NMR (125 MHz,
DMSO-d6) d 20.9, 21.0, 33.3, 49.5, 110.7, 126.3, 126.9,
127.9, 128.4, 128.8, 129.2, 129.4, 133.4, 133.9, 136.4,
138.4, 142.6, 144.0, 164.9 ppm. IR (KBr): 3271, 2959,
1672, 1511, 1378, 1217 cm21. FAB-MS (NBA) m/z 287
(MHþ). Anal. calcd for C25H25N3O5S2:C, 58.69; H, 4.93; N,
8.21. Found: C, 58.58; H, 5.05; N, 8.12.
4.1.3. Cyclic oxime (11). To a solution of HCl·NH2OH
(458 mg, 6.59 mmol, 2.0 equiv.) and Na2CO3 (350 mg,
3.30 mmol, 1.0 equiv.) in EtOH (5 ml) and water (5 ml) was
added compound 10 (1.05 g, 3.30 mmol) at room tempera-
ture under Ar. After stirring for 16 h at room temperature,
the reaction mixture was brought up to 70 8C, and then was
continued to stir for 3 h. After evaporated the solvents, the
obtained residue was dissolved in AcOEt–water and was
extracted with AcOEt (5X). Resulted organic layer was
dried over Na2SO4, and was evaporated to afford oxime (11)
as a white solid (633 mg, 88% yield).
4.1.6. 5-N-Tosylamide-2-hydroxypyrazine (14). To a
solution of di-Ts-amidine (13) (102 mg, 0.20 mmol) in
THF (4 ml), was added NaH (60% in mineral oil, 24.0 mg,
0.6 mmol, 3.0 equiv.) at 0 8C. After stirring for 2 h at room
temperature, the reaction mixture was quenched with some
drops of MeOH and was evaporated. The resulting residue
was dissolved in AcOEt–water, and was extracted with
AcOEt (X5). The organic layer was dried over Na2SO4.
After evaporation, the residue was purified by column
chromatography on silica gel with AcOEt–hexane (3:1) to
give 5-N-tosylamide-2-hydroxypyrazine (14) as a white
solid (64.5 mg, 91% yield).
1
Compound 11: mp 200–203 8C (decomposed). H NMR
(300 MHz, DMSO-d6) d 2.91 (2H, d, J¼6.3 Hz, benzyl),
3.12 (1H, dd, J¼23.4, 1.5 Hz, C (O) CH2NH), 3.34 (1H, dd,
J¼23.4, 3.6 Hz, C(O)CH2NH), 3.98 (1H, broad d,
J¼4.5 Hz, CNCH), 6.26 (1H, br, NH), 7.29–7.149 (5H,
m, Ph), 8.07 (1H, d, J¼3.6 Hz amide-NH), 9.10 (1H, d,
J¼1.5 Hz, OH) ppm. 13C NMR (75 MHz, DMSO-d6) d
41.8, 44.4, 52.2, 126.8, 128.4, 130.1, 137.1, 148.3,
169.0 ppm. IR (KBr): 3221, 1665, 1439, 1316,1087,
701 cm21. EI-MS m/z 219 (Mþ). Anal. calcd for
C11H13N3O2: C, 60.26; H, 5.98; N, 19.17. Found: C,
60.26; H, 5.80; N, 18.91.
Compound 14: mp 228 8C (decomposed). FL (MeOH) Em.
1
435 nm (Ex. 350 nm). H NMR (500 MHz, DMSO-d6) d
4.1.4. Cyclic amidine (12). In a 300 ml round shaped flask,
Raney-Ni W2 (about 2 g, ethanol wet) and MeOH (50 ml)
were charged with Ar. To this suspension was added a
solution of oxime (11) (3.50 g, 16.0 mmol) in MeOH
(100 ml), then the flask was changed with hydrogen from
Ar. After stirring for 3 h at room temperature, the reaction
mixture was filtered through a pad of Celite washing with
MeOH. Evaporation of the resultant solution afforded pale
yellow solid (12) (3.34 g, quantitative yield).
2.37 (3H, s, Ts), 3.30 (1H, s, OH), 4.03 (2H, s, benzyl),
7.19–7.30 (5H, m, Ph), 7.34 (2H, d, J¼8.3 Hz, Ts), 7.56
(1H, s, C (OH) CH), 7.65 (2H, d, J¼8.3 Hz, Ts), 9.86 (1H, s,
NHTs) ppm. 13C NMR (125 MHz, DMSO-d6)11 d 20.9,
126.4, 126.9, 128.4, 128.7, 129.3, 138.4, 142.7 ppm. IR
(KBr): 3424, 3244, 1672, 1336, 1164, 693 cm21. FAB-MS
(NBA) m/z 356 (MHþ). HRMS (EI) calcd for C18H17N3O3S
355.0991, found 355.1018 (Mþ). Anal. calcd for
C18H17N3O3S:C, 60.83; H, 4.82; N, 11.82. Found: C,
60.84; H, 4.79; N, 11.77.
Compound 12: mp 220 8C (decomposed). 1H NMR

M. Kuse et al. / Tetrahedron 60 (2004) 835–840
839
4.1.7. 5-N-(p-Toluenesulfonyl)amide-6-benzyl-2-O-tri-
fluoromethanesulfonyloxy-pyrazine (15). To a solu-
tion of 5-N-Ts-amide-2-hydroxypyrazine (14) (222 mg,
0.625 mmol) in CH2Cl2 (10 ml) and i-Pr2NEt (300 ml,
1.74 mmol, 2.8 equiv.) was added trifluoromethansulfonic
anhydride (147 ml, 0.875 mmol, 1.4 equiv.) at 0 8C under Ar
atmosphere. After stirring for 2 h at 0 8C, ice water was
added to the reaction mixture. This mixture was extracted
with CH2Cl2 (X3). The organic layer was dried over
Na2SO4, and the solvent was evaporated. The resulting
residue was purified by column chromatography on silica
gel with AcOEt–hexane (1:3) to give orange solid (15)
(259 mg, 85% yield).
CDCl3) d 4.20 (2H, s, benzyl), 4.46 (2H, s, amine-NH2),
7.25–7.34 (5H, m, Ph), 7.37 (1H, dt, J¼7.3, 1.2 Hz, Ph),
7.46 (2H, t, J¼8.2, 7.3 Hz, Ph), 7.95 (2H, dd, J¼8.2, 1.2 Hz,
Ph), 8.39 (1H, s, Py) ppm. 13C NMR (150 MHz, CDCl3) d
41.3, 125.2, 126.3, 128.2, 128.3, 128.4, 128.5, 128.6, 129.3,
129.5, 136.8, 137.2, 138.0, 151.7 ppm. FAB-MS (NBA): m/
z 262 (MHþ). HRMS (FAB/NBA) calcd for C17H16N3
262.1344, found 262.1357 (MHþ). Anal. calcd for
C17H15N3: C, 78.13; H, 5.79; N, 16.08. Found: C, 78.33;
H, 5.77; N, 16.01.
4.1.10. 2-N-(p-Toluenesulfonyl)amide-3-benzyl-5-(4-
methoxyphenyl)pyrazine (17b). To a solution of triflate
(15) (14.2 mg, 0.029 mmol) and boronic acid (16b)
(10.9 mg, 0.072 mmol, 2.5 equiv.) in dioxane (0.6 ml) was
added K3PO4 (10.2 mg, 0.048 mmol, 1.6 equiv.), PPh3
(5.2 mg, 0.020 mmol, 0.7 equiv.) and Pd(dba)2 (3.0 mg,
5.2 mmol, 0.2 equiv.) successively at room temperature.
After stirring for 3 h at 80 8C in an oil bath, the reaction
mixture was extracted with AcOEt (X2). The organic layer
was washed with brine once and dried over Na2SO4.
Purification by preparative TLC provided N-Ts-amidepyra-
zine (17b) (11.6 mg, 89% yield) as a yellow solid.
Compound 15: mp 141–143 8C. FL (MeOH) Em. 419 nm
1
(Ex. 350 nm). H NMR (500 MHz, CDCl3) d 2.40 (3H, s,
Ts), 4.15 (2H, s, benzyl), 7.39–7.17 (7H, m, PhþTs), 7.70
(2H, d, J¼8.6 Hz, Ts), 8.06 (1H, s, CH-6) ppm. 13C NMR
(125 MHz, CDCl3) d 21.6, 39.8, 128.0, 128.4, 128.7, 129.5,
132.5, 134.4, 135.7, 142.5, 144.8, 145.9, 147.5 ppm. IR
(KBr): 3424, 2926, 1604, 1431, 1219, 1163 cm21. EI-MS
m/z 487 (Mþ). Anal. calcd for C19H16F3N3O5S2:C, 46.81;
H, 3.31; N, 8.62. Found: C, 46.80; H, 3.26; N, 8.48.
1
4.1.8. 2-N-(p-Toluenesulfonyl)amide-3-benzyl-5-phenyl-
pyrazine (17a). A mixture of triflate (15) (25.0 mg,
0.051 mmol) and phenylboronic acid (16a) (9.4 mg,
0.077 mmol, 1.5 equiv.) and Pd(PPh3)4 (5.8 mg,
0.0051 mmol, 0.1 equiv.) and K3PO4·3H2O (20.5 mg,
0.077 mmol, 1.5 equiv.) in dioxane (1 ml) was heated to
80 8C for 1.5 h. The mixture was diluted with toluene (2 ml)
and treated with aqueous 3 M NaOH (3 drops) and 30%
H2O2 (3 drops) for 1 h at room temperature to oxidize the
residual borane. The product was extracted with ether (X3),
and dried over Na2SO4. After evaporated, the residue was
purified by column chromatography on silica gel with
AcOEt–hexane (1:3) to give 17a as a pale yellow solid
(17.9 mg, 85% yield).
Compound 17b: mp 169.0–169.5 8C. H NMR (600 MHz,
CDCl3) d 2.38 (3H, s, Ts), 3.85 (3H, s, OCH3), 4.24 (2H, s,
benzyl), 6.98 (2H, d, J¼8.4 Hz, anisole), 7.17–7.36 (8H, m,
Ar), 7.70 (2H, d, J¼8.4 Hz, anisole), 7.88 (2H, d, J¼7.8 Hz,
Ts), 8.46 (1H, s, Py) ppm. 13C NMR (150 MHz, CDCl3) d
22.0, 40.6, 54.9, 114.9, 127.2, 127.6, 128.8, 129.2, 129.8,
136.0, 136.2, 136.5, 137.2, 143.6, 143.8, 146.8, 160.7 ppm.
FAB-MS (NBA) m/z 446 (MHþ). HRMS (FAB/NBA) calcd
for C25H24N3O3S 446.1538, found 446.1515 (MHþ). Anal.
calcd for C25H23N3O3S: C, 67.39; H, 5.20; N, 9.43. Found:
C, 67.38; H, 5.17; N, 9.41.
4.1.11. 2-Amino-3-benzyl-5-(4-methoxyphenyl)pyrazine
(18b). N-Ts-amidepyrazine (17b) (25.5 mg, 0.057 mmol)
was dissolved in 1.0 ml of conc. H2SO4 at 0 8C in an ice
bath. After stirring for 20 min at 0 8C, ice was poured into
the reaction. The reaction mixture was extracted with
CH2Cl2 (X3). The organic layer was washed with brine once
and then dried over Na2SO4. Purification by preparative
TLC provided aminopyrazine (18b) (8.2 mg, 49% yield) as
a yellow solid and N-Ts-amidepyrazine (17b) (6.6 mg, 26%
yield) as recovered starting material.
Compound 17a: mp 167–169 8C. 1H NMR (500 MHz,
CDCl3) d 2.38 (3H, s, Ts), 4.27 (2H, s, benzyl), 6.92 (1H, s,
TsNH), 7.48–7.20 (10H, m, 2PhþTs), 7.70 (2H, d,
J¼8.3 Hz, Ts), 7.93 (2H, d, J¼7.1 Hz, Ph), 8.53 (1H, s,
CH-6) ppm. 13C NMR (125 MHz, CDCl3) d 21.6, 40.8,
126.3, 127.6, 128.3, 128.7, 129.0, 129.3, 129.5, 136.0,
137.3, 143.4, 144.2, 144.6, 146.8 ppm. IR (KBr): 3450,
1586, 1452, 1167, 1088, 695 cm21. FAB-MS (NBA) m/z
416 (MHþ). HRMS (FAB/NBA) calcd for C24H22N3O2S
416.1433, found 416.1435 (MHþ). Anal. calcd for
C24H21N3O2S:C, 69.37; H, 5.09; N, 10.11. Found: C,
69.37; H, 5.21; N, 9.99.
Compound 18b: 1H NMR (500 MHz, CDCl3) d 3.84 (3H, s,
OCH3), 4.16 (2H, s, benzyl), 4.32 (2H, s, amine-NH2), 6.97
(2H, d, J¼8.8 Hz, anisole), 7.22–7.32 (5H, m, Ph), 7.86
(2H, d, J¼8.8 Hz, anisole), 8.31 (1H, s, Py) ppm. All the
other spectroscopic data were identical with reported data in
Ref 10).
4.1.9. 2-Amino-3-benzyl-5-phenylpyrazine (18a). N-Ts-
amidepyrazine (17a) (62.9 mg, 0.15 mmol) was dissolved in
1.0 ml of conc. H2SO4 at 0 8C in an ice bath. After stirring
for 10 min at 0 8C, ice was poured into the reaction. It was
extracted with AcOEt (X3), and the organic layer was
washed with brine once. After neutralization with NaHCO3,
the organic layer was dried over Na2SO4. Purification by
preparative TLC provided aminopyrazine (18a) (14.9 mg,
38% yield) as a yellow solid.
Acknowledgements
The authors are grateful for financial support from JSPS-
RFTF 96L00504, Grant-in-Aid for Encouragement of
Young Scientists (15780085), The Naito Foundation,
SUNBOR and The Fujisawa Foundation for financial
support.
Compound 18a: mp 133–136 8C. 1H NMR (600 MHz,

840
M. Kuse et al. / Tetrahedron 60 (2004) 835–840
5. Nakamura, H.; Takeuchi, D.; Murai, A. Synlett 1995,
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