A novel methodology for synthesis of 1,5,6-trisubstituted 2(1H)- Pyrazinones of biological interest

Article abstract of DOI:10.1248/cpb.c16-00830

In this report, we describe a new method for the synthesis of densely functionalized 2(1H)-pyrazinones. Treatment of mesoionic 1,3-oxazolium-5-olates with carbanions derived from activated methylene isocyanides (p-toluenesulfonylmethyl isocyanide (TosMIC)

Full text of DOI:10.1248/cpb.c16-00830

Vol. 65, No. 4
Chem. Pharm. Bull. 65, 365–372 (2017)
365
Regular Article
A Novel Methodology for Synthesis of 1,5,6-Trisubstituted 2(1H)-
Pyrazinones of Biological Interest
Ryosuke Saijo,a Hiroshi Sekiya,b Eiji Tamai,b Ken-ichi Kurihara,a Jun Maki,b
,a
Hiroshi Sakagami,c and Masami Kawase*
a Faculty of Pharmaceutical Sciences, Matsuyama University; Matsuyama, Ehime 790–8578, Japan: b Department
of Infectious Diseases, College of Pharmaceutical Sciences, Matsuyama University; Matsuyama, Ehime 790–8578,
c
Japan: and Division of Pharmacology, Meikai University School of Dentistry; Sakado, Saitama 350–0283, Japan.
Received October 24, 2016; accepted January 19, 2017
In this report, we describe a new method for the synthesis of densely functionalized 2(1H)-pyrazinones.
Treatment of mesoionic 1,3-oxazolium-5-olates with carbanions derived from activated methylene isocya-
nides (p-toluenesulfonylmethyl isocyanide (TosMIC) and ethyl isocyanoacetate) causes a novel ring transfor-
mation affording 2(1H)-pyrazinones in moderate to high yields. The cytotoxicity and antibacterial activity of
some of the obtained products were studied and some of the products exhibited tumor-specific cytotoxicity.
Key words ring transformation; mesoionic; pyrazinone; isocyanide
The 2(1H)-pyrazinone is an important privileged scaffold of 1 with TosMIC from the comparison with the reaction of
in medicinal chemistry, as well as in several alkaloids with the related mesoionic 1,3-thiazolium-5-olates (7) with TosMIC
diverse biological activity, including antitumor and antiviral in order to elucidate the presence of 4-trifluoroacetyl group
properties.1–6) Therefore, several methods for the synthesis of essential for the reaction; herein, efficient syntheses of multi-
2(1H)-pyrazinones have been described in the literature: (a) ply substituted 2(1H)-pyrazinones and their anti-bacterial and
condensation of α-aminoamides with α-diketones,7,8) (b) con- tumor-cytotoxic activities are reported.
densation of α-aminonitrile with oxalyl halides,6,9,10) and (c)
Ugi four-component reactions.11) Whereas these methods have
proven very useful for the synthesis of 2(1H)-pyrazinones,
Results and Discussion
In our previous communication,14) we examined the reac-
they generally involve multistep synthetic operations and/or tion of 1a with TosMIC under varying reaction conditions to
a hazardous cyanide source that limit the scope of these re- determine the optimum conditions and reported the isolated
actions. Indeed, it is still desirable to develop an efficient yields of 3a–i which were shown in Table 1. The best condi-
method for the synthesis of 2(1H)-pyrazinones.
tions to obtain the 2-pyrazinones 3a–i were achieved using
As a continuation of our studies on the synthetic potential 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the base in N,N-
of mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olates (1) for dimethylformamide (DMF) at 0°C under O2 atmosphere with
heterocyclic synthesis,12) we herein report a reaction of me- bubbling by O2 throughout the reaction. It was found that the
soionic oxazoles (1) with carbanions derived from activated reaction was very sensitive to the dioxygen and the yield of 3a
methylene isocyanides (p-toluenesulfonylmethyl isocyanide increased to 72% in the presence of dioxygen. The pathway
(TosMIC) and ethyl isocyanoacetate). The mesoionic oxazoles of the reaction was elucidated to conduct the reaction under
(1) are easily prepared from N-acyl-N-alkylglycines (2) in a an atmosphere of 18O2 and the carbonyl group of amide in 3a
one step through the cyclodehydration by trifluoroacetic an- contained more than 67% of the 18O label.14)
hydride followed by trifluoroacetylation at C-4 position of an
In this study, two new substrates 1j and k were subjected
to the reaction (Table 1, entries 10 and 11). In addition,
intermediary mesoionic 1,3-oxazolium-5-olates12) (Chart 1).
TosMIC is a versatile, widely applicable reagent bearing imidazo[1,5-a]pyrazin-8(7H)-one derivatives (4a–h, j, k) were
an active methylene group and readily forms a stabilized, also isolated as a side product as shown in Table 1. The reac-
nucleophilic carbanion, which will react with a variety of elec- tion of TosMIC with aldimines to form imidazoles is known
trophiles, such as aldehydes, ketones and imines.13) This class as the van Leusen imidazole synthesis.15) The imidazo[1,5-a]-
of reagent has most commonly been used in heterocyclic ring pyrazine core was reported to be synthesized via condensation
construction, in particular, of oxazole, pyrrole and imidazole with TosMIC with pyrazin-2-one derivative.16) Therefore, the
moieties.
formation of imidazo[1,5-a]pyrazin-8(7H)-one derivatives
We have preliminarily reported that the unexpected reaction (4) could be explained by the further reaction of the 3 with
of mesoionic oxazoles (1) with TosMIC proceeds via an initial excessive TosMIC. Indeed, the reaction of 3a with TosMIC
attack of TosMIC anions on the C-2 position of the ring fol-
lowed by autooxidation to afford 2(1H)-pyrazinones in good
yields.14) The origin of C-2 carbonyl oxygen in the 2(1H)-
pyrazinones was molecular oxygen.
We report here our detailed studies of the reactions of 1
with carbanions derived from activated methylene isocyanides
such as TosMIC and ethyl isocyanoacetate, and the behavior
Chart 1. Synthesis of Mesoionic 1 from N-Alkyl-N-acylglycines (2)
*To whom correspondence should be addressed. e-mail: kawase@cc.matsuyama-u.ac.jp
© 2017 The Pharmaceutical Society of Japan

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Chem. Pharm. Bull.
Vol. 65, No. 4 (2017)
Table 1. Reactions of Mesoionic 1 with TosMICa)
Entry
1
R1
R2
Conditions
Products (Yield, %)b)
1
2
a
b
c
d
e
f
Me
Ph
Ph
0°C, 3h
0°C, 3h
−40°C, 12h
0°C, 1h
0°C, 1h
0°C, 2h
0°C, 2h
0°C, 2h
0°C, 5h
0°C, 3h
0°C, 1h
3a (72), 4a (16)
3b (65), 4b (10)
3c (42), 4c (3)
3d (70), 4d (20)
3e (78), 4e (5)
3f (55), 4f (36)
3g (53), 4g (34)
3h (58), 4h (35)
3i (11), 4i (0)
Ph
3
Ph
Me
4
Me
4-BrC6H4
4-MeOC6H4
Ph
5
Me
C6H5CH2
4-MeOC6H4CH2
C6H5CH2
Me
6
7
g
h
i
Ph
8
4-MeOC6H4
t-Bu
9
10
11
j
Ph
4-NO2C6H4
4-MeOC6H4
3j (25), 4j (44)
3k (35), 4k (36)
k
Ph
a) Reactions were carried out using 1 (0.50mmol), TosMIC (0.75mmol) and DBU (1.00mmol) in DMF (3mL) under atmosphere of oxygen. b) Isolated yield.
Table 2. Reactions of Mesoionic 1 with Ethyl Isocyanoacetatea)
Entry
1
R1
R2
Conditions
Products (Yield, %)b)
1
2
3
4
5
6
7
8
a
b
c
Me
Ph
Ph
0°C, 3h
0°C, 3h
5a (92)
5b (88)
5c (52)
5d (85)
5e (85)
5f (90)
5g (91)
5h (91)
Ph
Ph
Me
−40°C, 12h
0°C, 1h
d
e
Me
4-BrC6H4
4-MeOC6H4
Ph
Me
0°C, 1h
f
C6H5CH2
4-MeOC6H4CH2
C6H5CH2
0°C, 2h
g
h
Ph
0°C, 2h
4-MeOC6H4
0°C, 2h
a) Reactions were carried out using 1 (0.50mmol), TosMIC (0.75mmol) and DBU (1.00mmol) in DMF (3mL) under atmosphere of oxygen. b) Isolated yield.
was reported to give 4a in high yield.17) The C3-position is
elctrophilically reactive position in the pyrazinone core18–20)
and could undergo nucleophilic attack by nucleophiles such as
being part of an imine system.
On the basis of the above results, we tried to react 1a–h
with ethyl isocyanoacetate, using the same conditions for the
reaction with TosMIC.14) Gratifying, we found that the ring
transformation reaction could be efficiently occurred in high
Chart 2. Synthesis of Imidazo[1,5-a]pyrazin-8(7H)-one (6) from
Pyrazin-2(1H)-one (5a)
yields. Thus, the substituents on C2 and N3 of the mesoionic
ring on the reaction were investigated and the results are 1, 2).
shown in Table 2. In the reaction of ethyl isocyanoacetate,
We next examined the effect of 4-trifluoroacetyl group in
an imidazo[1,5-a]pyrazin-8(7H)-one derivative was not ob- mesoionic oxazoles 1. In our laboratory, we have synthesized
tained. In separate experiment, the reaction of 5a with ethyl 4-trifluoroacetyl- (7a), 4-acetyl- (7b)21) and 4-formyl-1,3-
isocyanoacetate failed to afford the expected imidazo[1,5-a]- thiazolium-5-olates (7c). Notably, there is much less infor-
pyrazin-8(7H)-one derivative under the comparable reaction mation about the reactivity of 1,3-thiazolium-5-olates in the
conditions. Also, the reaction of 3a with ethyl isocyanoacetate literature compared to 1,3-oxazolium-5-olates. A comparative
failed to afford the corresponding imidazo[1,5-a]pyrazine de- study of the suitability of 4-acyl group in the reaction of 7a–c
rivative. On the other hand, the reaction of 5a with TosMIC with TosMIC under the same reaction conditions with 1 was
gave 6 in 65% yield (Chart 2). Overall, the yields of the 2-pyr- undertaken. The results were shown in Table 3. The trifluoro-
azinone products are generally better for the reaction with acetyl derivative 7a worked well (entry 1). On the other hand,
ethyl isocyanoacetate than the reaction with TosMIC (Tables 4-acetyl (7b) and 4-formyl (7c) derivatives afforded poor con-

Vol. 65, No. 4 (2017)
Chem. Pharm. Bull.
367
Table 3. Reactions of Mesoionic Thiazoles with TosMICa)
Products (Yield, %)b)
Entry
7
R
Conditions
3a
4a
1
2
3
a
b
c
CF3
CH3
H
0°C, 2h
68
10
13
2
11
15
0°C, 12h
0°C, 12h
a) Reactions were carried out using 1 (0.50mmol), TosMIC (0.75mmol) and DBU (1.00mmol) in DMF (3mL) under atmosphere of oxygen. b) Isolated yield.
Table 4. Cytotoxicity of Selected Compounds against Human Oral Malignant and Non-malignant Cells with CC50 (µM)a)
Human oral squamous cell carcinoma cell lines
Human oral normal cells
SIb)
Compounds
Ca9–22
HSC-2
HSC-3
HSC-4
Mean (A)c)
HGF
HPLF
HPC
Mean (B)d)
B/A
3f
70
49
93
47
71
87
9.5
11
95
180
199
95
85
50
86 11
82 66
112 60
108 37
26 36
22 23
275
358
362
>400
138
>400
>400
62
>346
>386
124 57
>4.0
>4.7
1.1
3g
3j
75
101
87
173
5g
163
80
228
225
216
223
6
2.1
5-FU
7.8
12
<7.8
9.8
>1000
111
>1000
192
>1000
145
>1000
149 41
>38.5
6.8
Melphalan
57
a) The CC50 figure is the concentration of compound required to kill 50% of the cells and is the average of two independent determinations. b) The letter SI refer to the se-
lectivity index. c) Mean A is average CC50 value of the compound toward Ca9–22, HSC-2, HSC-3, and HSC-4 squamous cell carcinoma cell lines. d) Mean B is average CC50
value of the compound toward human non-malignant HGF gingival fibroblasts, HPLF periodontal ligament fibroblasts and HPC pulp cells.
version (entries 2 and 3).
much lower cytotoxicity. Out of these four compounds, 3g
The molecular structures of 3a14) and 4a17) were previously showed the highest tumor-specifity (TS=4.7), followed by 3f
confirmed by X-ray diffraction study of single crystals. A (TS=4.0). When tumor-selectivity was calculated by Ca9–22
tentative mechanism which accounts for the formation of 3 is and HGF cells, both derived from gingival tissues, 3g showed
described in the communication.14) Thus, initial nucleophilic higher tumor-specifity [TS=7.3 (358/49)], as compared with
attack by the TosMIC anion on C-2 of 1 gave rise to an adduct melphalan [TS=1.9 (111/57)] (Table 4). The rest of the assayed
which is converted to the 2-pyrazineones (3) via a ring closure compounds did not show any cytotoxicities against the studied
followed by auto-oxidation.
tumor cells (CC50>400µM). The compounds in 3 series are
The anti-microbial activities of new pyrazinones (3a–j and more potent than the analogs in 5 series in which the same
5a–h) for six Gram-negative bacteria and six Gram-positive substituents are present at 1 and 6 positions (data not shown).
bacteria (listed in Experimental section) were measured by Compounds 3g, f and 5g, with 1-(4-methoxyphenyl)methyl or
disc diffusion method.22) All the tested pyrazinones (3a–j and 1-benzyl and 6-phenyl groups, were found to be the deriva-
5a–h) showed no inhibition zone same as that of solvent con- tives with the highest cytotoxic activity of the two series. 3j
trol, whereas Gentamicin and Kanamycin showed inhibition with 4-nitrophenyl group showed moderate cyctotoxicity
zone (≥11mm) against tested Gram-negative bacteria except against Ca9–22 and HSC-2 cells. These results suggest that
for Pseudomonas aeruginosa 01 and Vancomycin showed further modification of these scaffolds might lead to com-
inhibition zone (≥10mm) against Gram-positive bacteria (data pounds with enhanced cytotoxic activities.
not shown). The tested compounds (3a–j and 5a–h) were
not active against the all tested microorganisms. Additional
compounds in this series will be prepared to try to improve
activity.
Conclusion
We described herein a novel type of ring transformation of
mesoionic oxazoles 1 into 2(1H)-pyrazinones 3 and 5 via an
The compounds 3a–j and 5a–h were evaluated for their initial attack of TosMIC or ethyl isocyanoacetate on the C-2
cytotoxicity against human oral squamous cell carcinoma cell position of the ring, opening of the oxazole ring, subsequent
lines (Ca9–22 derived from gingival tissue, and HSC-2, HSC-3 cyclization, and autoxidation. This unique ring transformation
and HSC-4 derived from tongue), and human normal oral reaction of mesoionic oxazoles with TosMIC was not antici-
cells (HGF gingival fibroblasts, HPLF periodontal ligament pated but the reaction is general as evidenced by the examples
fibroblasts and HPC pulp cells), using 5-fluorouracil (5-FU) indicated in Tables 1 and 2. The method appears to be useful
and melphalan as the positive controls. These data for the and convenient in terms of the ready accessibility of the start-
selected compounds are presented in Table 4. Among ten 3 se- ing materials, operational simplicity and mild condition. In
ries and eight 5 series, 3g showed the highest cytotoxicity, fol- addition, the 2(1H)-pyrazinones showed promising anticancer
lowed by 3f, 5g, and 3j, whereas the other compounds showed potency through preliminary biological studies.

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Chem. Pharm. Bull.
Vol. 65, No. 4 (2017)
4-Trif luoroacetyl-3-(4-methoxybenyl)-2-phenyl-1,3-
Experimental
General Remarks Melting points (mp) were measured oxazolium-5-olate (1g)
with a Yanaco MP-J3 melting point apparatus and are uncor-
White crystals, 75% yield. mp 147–148°C (mp27) 147–148°C).
3-Benzyl-4-trifluoroacetyl-2-(4-methoxyphenyl)-1,3-oxa-
rected. NMR spectra were recorded on a Bruker AVANCE500
1
(500MHz for H and 126MHz for 13C) with tetramethylsilane zolium-5-olate (1h)
(Me4Si) as an internal reference and CDCl3 as the solvent.
White crystals, 89% yield. mp 158–160°C (mp26) 158–160°C).
2-tert-Butyl-4-trifluoroacetyl-3-methyl-1,3-oxazolium-5-
1H- and 13C-NMR spectral data are reported in parts per
million (δ) relative to Me4Si. IR spectra were recorded on a olate (1i)
JASCO FT/IR-4100 spectrometer. Mass spectra were recorded
on JEOL JMS-GC mate II spectrometer with a direct inlet
White crystals, 67% yield. mp 120–121°C (mp28) 120–121°C).
4-Trifluoroacetyl-2-(4-nitrophenyl)-3-phenyl-1,3-oxazolium-
system at 70eV and a Bruker micrOTOF-Q mass spectrometer 5-olate (1j)
with methanol as the solvent. Elemental analyses were carried
Yellow crystals, 70% yield. mp 175–178°C (ethyl acetate/
out on a Yanaco CHN Corder MT-5 at the Integrated Center hexane). (mp17) 175–178°C).
for Science, Ehime University. Standard work-up means that
4-Trifluoroacetyl-2-(4-methoxyphenyl)-3-phenyl-1,3-
the organic layers were finally dried over anhyd. Na2SO4, filtered, oxazolium-5-olate (1k)
and concentrated in vacuo below 37°C using a rotary evapora-
tor.
Pale yellow crystals, 93% yield. mp 203–205°C (mp25)
182–185°C).
Materials The following compounds were prepared by
employing the reported method.
General Procedure for Synthesis of 2(1H)-Pyrazinones
(3) and Imidazo[1,5-a]pyrazin-8(7H)-ones (4) To a stirred
solution of TosMIC (146mg, 0.75mmol) in DMF (3mL)
was added DBU (152mg, 1.00mmol) at 0°C, and the mix-
ture was stirred for 1h under atmosphere of oxygen. To the
mixture was added 4-trifluoroacetyl-1,3-oxazolium-5-olate 1
(0.50mmol), and the whole was stirred at 0°C for an additional
several hours. After workup with aq. Na2CO3, the mixture was
extracted with AcOEt (×3). The combined organic layers were
washed with brine, dried over anhyd. Na2SO4, and evaporated.
The residue was purified by column chromatography (silica
gel, hexane–AcOEt=4:1 to 1:1) to give the products 3 and 4.
1-Methyl-5-[(4-methylphenyl)sulfonyl]-6-phenylpyrazin-
2(1H)-one (3a)
N-Benzoyl-N-methylglycine (2a)
mp 101–104°C (mp23) 102–104°C).
N-Benzoyl-N-phenylglycine (2b)
mp 126–128°C (mp23) 127–129°C).
N-Acetyl-N-phenylglycine (2c)
mp 196–198°C (mp24) 193–195°C).
N-(4-Bromobenzoyl)-N-methylglycine (2d)
mp 143–145°C (mp25) 147–150°C).
N-(4-Methoxybenzoyl)-N-methylglycine (2e)
mp 151–154°C (mp23) 155–160°C).
N-Benzoyl-N-benzylglycine (2f)
mp 103–104°C (mp26) 106–107°C).
N-Benzoyl-N-(4-methoxyphenylmethyl)glycine (2g)
mp 157–158°C (mp27) 157–158°C).
N-Benzyl-N-(4-methoxybenzoyl)glycine (2h)
mp 149–151°C (mp25) 149–151°C).
N-Methyl-N-pivaloylglycine (2i)
White crystals, 72% yield. mp 147–149°C (CHCl3–hexane).
1
IR (KBr) cm−1: 3057, 1674, 1662, 1487, 1322, 575. H-NMR
(500MHz, CDCl3) δ: 2.41 (s, 3H, ArCH3), 3.13 (s, 3H, NCH3),
7.21–7.27 (m, 4H, ArH), 7.51–7.59 (m, 5H, ArH), 8.13 (s, 1H,
H-3). 13C-NMR (126MHz, CDCl3) δ: 21.5 (CH3), 33.3 (NCH3),
128.3 (CH), 128.6 (CH), 128.9 (CH), 129.0 (C), 129.4 (CH),
130.6 (CH), 134.0 (C-5), 137.3 (C), 144.3 (C), 145.0 (C-6),
145.8 (C-3), 155.5 (CO). MS m/z: 313 (M+, 66), 58 (100). Anal.
Calcd for C18H16N2O3S: C, 63.51; H, 4.74; N, 8.23. Found: C,
63.32; H, 5.03; N, 8.09.
mp 65–68°C (mp28) 75–76°C).
N-(4-Nitrobenzoyl)-N-phenylglycine (2j)
mp 178–180°C (mp23) 172–175°C).
N-(4-Methoxybenzoyl)-N-phenylglycine (2k)
mp 135–137°C (mp23) 158–163°C).
4-Trifluoroacetyl-3-methyl-2-phenyl-1,3-oxazolium-5-olate
(1a)
5-[(4-Methylphenyl)sulfonyl]-1,6-diphenylpyrazin-2(1H)-
one (3b)
Pale yellow crystals, 95% yield. mp 161–163°C (mp29) 162–
163°C).
Yellow crystals, 65% yield. mp 228–230°C (CHCl3–hexane).
IR (KBr) cm−1: 3059, 3050, 1685, 1485, 1328, 1214, 1169, 1160,
1
4-Trifluoroacetyl-2,3-diphenyl-1,3-oxazolium-5-olate (1b)
806, 692, 681, 651, 585, 553. H-NMR (500MHz, CDCl3) δ:
Yellow crystals, 94% yield. mp 194–196°C (mp29) 194– 2.43 (s, 3H, ArCH3), 6.89–6.91 (m, 2H, ArH), 7.02–7.04 (m,
196°C).
2H, ArH), 7.17–7.27 (m, 8H, ArH), 7.62 (d, J=8.0Hz, 2H,
4-Trifluoroacetyl-2-methyl-3-phenyl-1,3-oxazolium-5-olate ArH), 8.24 (s, 1H, H-3). 13C-NMR (126MHz, CDCl3) δ: 21.7
(1c)
(CH3), 127.7 (CH), 128.3 (CH), 128.6 (CH), 128.7 (C), 129.2
White crystals, 90% yield. mp 200–203°C (mp29) 211–212°C). (C), 129.2 (CH), 129.5 (CH), 129.8 (CH), 130.0 (CH), 134.0
2-(4-Bromophenyl)-4-trifluoroacetyl-3-methyl-1,3-oxazolium- (C), 135.3 (C), 137.3 (C), 144.5 (CH), 144.8 (C), 147.6 (C-3),
5-olate (1d)
155.2 (CO). MS m/z: 402 (M+, 5.6), 180 (100). Anal. Calcd for
White crystals, 90% yield. mp 188–191°C (mp25) 188–191°C). C23H18N2O3S·0.5H2O: C, 67.14; H, 4.65; N, 6.81. Found: C,
4-Trifluoroacetyl-2-(4-methoxyphenyl)-3-methyl-1,3- 66.80; H, 4.73; N, 6.75.
oxazolium-5-olate (1e)
6-Methyl-5-[(4-methylphenyl)sulfonyl]-1-phenylpyrazin-
Pale yellow crystals, 82% yield. mp 142–143°C (ethyl ace- 2(1H)-one (3c)
tate/hexane). (mp17) 142–143°C).
Orange crystals, 42% yield. mp 212–215°C (CHCl3–hexane).
3-Benzyl-4-trifluoroacetyl-2-phenyl-1,3-oxazolium-5-olate IR (KBr) cm−1: 2926, 1680, 1508, 1491, 1305, 1159, 696, 675,
1
(1f)
586, 556. H-NMR (500MHz, CDCl3) δ: 2.46 (s, 6H, CH3 and
White crystals, 83% yield. mp 143–145°C (mp27) 143–145°C). ArCH3), 7.13 (d, J=7.5Hz, 2H, ArH), 7.37 (d, J=8.0Hz, 2H,

Vol. 65, No. 4 (2017)
Chem. Pharm. Bull.
369
ArH), 7.52–7.59 (m, 3H, ArH), 7.91 (d, J=8.5Hz, 2H, ArH), 137.3 (C), 144.5 (CH), 145.0 (C), 146.7 (C-3), 155.7 (CO),
8.03 (s, 1H, H-3). 13C-NMR (126MHz, CDCl3) δ: 17.3 (CH3), 159.3 (C). MS m/z: 446 (M+, 15.4), 121 (100). HR-MS (EI) for
21.7 (CH3), 127.2 (CH), 128.5 (CH), 129.8 (CH), 130.2 (C), C25H22N2O4S (M+): Calcd, 446.1300. Found, 446.1307.
130.5 (CH), 133.7 (C), 135.5 (C), 137.1 (C), 143.6 (C), 144.8
1-Benzyl-6-(4-methoxyphenyl)-5-[(4-methylphenyl)sulfon-
(C), 145.4 (C-3), 155.5 (CO). MS m/z: 340 (M+, 11.7), 118 yl]pyrazin-2(1H)-one (3h)
(100). Anal. Calcd for C18H16N2O3S·0.5H2O: C, 61.87; H, 4.90;
N, 8.02. Found: C, 62.21; H, 4.61; N, 8.24.
Yellow oil, 58% yield. IR (neat) cm−1: 3063, 3030, 2964,
1
1695, 1681, 1651. H-NMR (500MHz, CDCl3) δ: 2.40 (s, 3H,
6-(4-Bromophenyl)-1-methyl-5-[(4-methylphenyl)sulfon- ArCH3), 3.89 (s, 3H, ArOCH3), 4.96 (s, 2H, NCH2Ar), 6.79 (d,
yl]pyrazin-2(1H)-one (3d) J=8.2Hz, 2H, ArH), 6.85–6.93 (m, 4H, ArH), 7.17–7.26 (m,
Pale yellow crystals, 70% yield. mp 178–180°C (CHCl3– 5H, ArH), 7.55 (d, J=8.3Hz, 2H, ArH), 8.19 (s, 1H, ArH).
hexane). IR (KBr) cm−1: 3050, 2953, 2922, 1676, 1593, 1483, 13C-NMR (126MHz, CDCl3) δ: 21.6 (CH3), 48.7 (NCH2), 55.4
1
1323, 1136, 1010, 850, 655, 582. H-NMR (500MHz, CDCl3) (OCH3), 113.7 (CH), 120.1 (C), 127.3 (CH), 128.0 (C), 128.4
δ: 2.42 (s, 3H, ArCH3), 3.14 (s, 3H, NCH3), 7.13 (dd, J=8.4, (CH), 128.6 (CH), 129.5 (CH), 130.9 (CH), 134.8 (CH), 134.9
1.9Hz, 2H, ArH), 7.26–7.27 (m, 2H, ArH), 7.60 (dd, J=8.3, (C), 137.3 (C), 144.4 (C), 145.2 (C), 146.5 (C-3), 155.8 (CO),
1.7Hz, 2H ArH), 7.69 (dd, J=8.5, 1.9Hz, 2H, ArH), 8.13 (s, 161.2 (C). MS m/z: 446 (M+, 40.4), 91 (100). HR-MS (EI) for
1H, H-3). 13C-NMR (126MHz, CDCl3) δ: 21.7 (CH3), 33.4 C25H22N2O4S (M+): Calcd, 446.1281. Found, 446.1300.
(NCH3), 125.3 (C), 127.9 (C), 128.3 (CH), 129.6 (CH), 130.3
6-tert-Butyl-1-methyl-5-[(4-methylphenyl)sulfonyl]-
(CH), 132.3 (CH), 134.0 (C), 137.1 (C), 143.8 (C), 144.7 (C), pyrazin-2(1H)-one (3i)
146.2 (C-3), 155.4 (CO). MS m/z: 418 (4.2)+420 (4.3) (M+,
Pale yellow crystals, 11% yield. mp 128–130°C (CHCl3–
1:1), 196 (100). Anal. Calcd for C18H15BrN2O3S·0.5H2O: C, hexane). IR (KBr) cm−1: 2981, 1668, 1482, 1301, 1162, 658.
50.48; H, 3.77; N, 6.54. Found: C, 50.47; H, 3.77; N, 6.68.
6-(4-Methoxyphenyl)-1-methyl-5-[(4-methylphenyl)sulfon- 3H, ArCH3), 3.64 (s, 3H, NCH3), 7.29 (d, J=8.0Hz, 2H, ArH),
yl]pyrazin-2(1H)-one (3e)
7.62 (s, 1H, H-3), 7.77 (d, J=8.0Hz, 2H, ArH). 13C-NMR
1H-NMR (500MHz, CDCl3) δ: 1.80 (s, 9H, C(CH3)3), 2.43 (s,
Pale yellow crystals, 78% yield. mp 135–138°C (CHCl3– (126MHz, CDCl3) δ: 21.6 (CH3), 31.3 (C(CH3)), 38.3 (C(CH3)),
hexane). IR (KBr) cm−1: 2955, 2833, 1671, 1497, 1257, 1178, 39.6 (NCH3), 129.2 (CH), 129.2 (CH), 138.0 (C), 139.0 (C),
1
1152, 848, 658. H-NMR (500MHz, CDCl3) δ: 2.40 (s, 3H, 139.8 (CH), 144.2 (C), 156.6 (C), 156.8 (C). MS m/z: 320
ArCH3), 3.15 (s, 3H, NCH3), 3.90 (s, 3H, OCH3), 7.02 (d, (M+, 1.6), 240 (100). Anal. Calcd for C16H20N2O3S·0.5H2O: C,
J=8.7Hz, 2H, ArH), 7.13 (d, J=8.6Hz, 2H, ArH), 7.23 (d, 58.34; H, 6.43; N, 8.50. Found: C, 58.03; H, 6.14; N, 8.32.
J=8.2Hz, 2H, ArH), 7.57 (d, J=8.2Hz, 2H, ArH), 8.11 (s, 1H,
5-[(4-Methylphenyl)sulfonyl]-6-(4-nitrophenyl)-1-phenyl-
H-3). 13C-NMR (126MHz, CDCl3) δ: 21.6 (CH3), 33.3 (NCH3), pyrazin-2(1H)-one (3j)
55.4 (OCH3), 114.3 (CH), 120.8 (C), 128.2 (CH), 129.4 (CH),
Pale orange crystals, 25% yield. mp >300°C (dec.) (CHCl3–
130.2 (CH), 134.4 (C), 137.5 (C), 144.3 (C), 145.3 (C), 145.5 hexane). IR (KBr) cm−1: 3065, 1693, 1520, 1489, 1350, 1329,
(C-3), 155.8 (CO), 161.2 (C). MS m/z: 370 (M+, 5.1), 148 (100). 1166, 862, 701. H-NMR (500MHz, CDCl3) δ: 2.45 (s, 3H,
1
Anal. Calcd for C19H18N2O4S·0.5H2O: C, 60.14; H, 5.05; N, ArCH3), 6.93 (dd, J=8.0, 2.2Hz, 2H, ArH), 7.25–7.34 (m,
7.38. Found: C, 60.02; H, 5.06; N, 7.35.
1-Benzyl-5-[(4-methylphenyl)sulfonyl]-6-phenylpyrazin- 2H, ArH), 8.25 (s, 1H, H-3). 13C-NMR (126MHz, CDCl3) δ:
2(1H)-one (3f) 21.7 (CH3), 122.9 (CH), 128.1 (CH), 128.7 (CH), 129.7 (CH),
7H, ArH), 7.69 (d, J=8.3Hz, 2H ArH), 8.09 (d, J=8.7Hz,
White crystals, 55% yield. mp 164–165°C (CHCl3–hex- 129.8 (CH), 129.9 (C), 131.1 (CH), 133.8 (C), 134.7 (C), 135.2
ane). IR (KBr) cm−1: 3063, 3046, 3030, 1668, 1327, 1162, (C), 136.6 (C), 142.1 (C), 145.2 (CH), 148.2 (C), 148.7 (C-3),
704, 654, 576. 1H-NMR (500MHz, CDCl3) δ: 2.41 (s, 3H, 154.6 (CO). MS m/z: 447 (M+, 1.5), 77 (100). Anal. Calcd for
ArCH3), 4.95 (s, 2H, NCH2Ar), 6.75 (d, J=7.0Hz, 2H, ArH), C23H17N3O5S·0.33H2O: C, 61.10; H, 4.33; N, 9.32. Found: C,
7.00 (d, J=7.0Hz, 2H, ArH), 7.05–7.30 (m, 5H, ArH), 7.37 61.14; H, 4.22; N, 9.26.
(t, J=8.0Hz, 2H, ArH), 7.54 (m, 3H, ArH), 8.21 (s, 1H, H-3).
6-(4-Methoxyphenyl)-5-[(4-methylphenyl)sulfonyl]-1-
13C-NMR (126MHz, CDCl3) δ: 21.6 (CH3), 48.7 (NCH2), phenylpyrazin-2(1H)-one (3k)
127.3 (CH), 128.0 (CH), 128.1 (C), 128.3 (CH), 128.4 (CH),
Pale orange crystals, 35% yield. mp 202–206°C (dec.)
128.5 (CH), 129.4 (CH), 129.5 (CH), 130.6 (CH), 134.4 (C), (CHCl3–hexane). IR (KBr) cm−1: 3026, 1676, 1596, 1446, 1359,
134.7 (C), 137.3 (C), 144.5 (C), 145.0 (C), 146.8 (C-3), 155.6 1340, 1258, 1162, 1087, 885, 810, 789, 658. 1H-NMR (500MHz,
(CO). MS m/z: 416 (M+, 22.8), 91 (100). Anal. Calcd for CDCl3) δ: 2.42 (s, 3H, ArCH3), 3.75 (s, 3H, OCH3), 6.69 (d,
C24H20N2O3S: C, 69.21; H, 4.84; N, 6.73. Found: C, 69.21; H, J=8.7Hz, 2H, ArH), 6.90 (dd, J=8.3, 1.7Hz, 2H, ArH), 6.93
4.79; N, 6.86.
(d, J=8.7Hz, 2H, ArH), 7.22–7.27 (m, 5H, ArH), 7.62 (d,
1-(4-Methoxyphenylmethyl)-5-[(4-methylphenyl)sulfonyl]-6- J=8.3Hz, 2H, ArH), 8.21 (s, 1H, H-3). 13C-NMR (126MHz,
phenylpyrazin-2(1H)-one (3g)
CDCl3) δ: 21.6 (CH3), 55.2 (OCH3), 113.2 (CH), 120.7 (C),
Pale yellow oil, 53% yield. IR (neat) cm−1: 3062, 2957, 128.2 (CH), 128.5 (CH), 129.1 (C), 129.3 (CH), 129.5 (CH),
1
3014, 1674, 1514, 1327, 1250, 1162, 795. H-NMR (500MHz, 131.5 (CH), 134.4 (C), 135.4 (C), 137.4 (C), 144.4 (CH), 144.9
CDCl3) δ: 2.40 (s, 3H, ArCH3), 3.75 (s, 3H, NCH3), 4.89 (s, (C), 147.2 (C-3), 155.4 (CO), 160.5 (C). MS m/z: 432 (M+, 7.8),
2H, NCH2Ar), 6.69 (s, 4H, ArH), 7.03 (d, J=8.3Hz, 2H, 210 (100). Anal. Calcd for C24H20N2O4S·0.25H2O: C, 65.96; H,
ArH), 7.22 (d, J=8.1Hz, 2H, ArH), 7.41 (t, J=8.1Hz, 2H, 4.73; N, 6.41. Found: C, 65.95; H, 4.64; N, 6.46.
ArH), 7.53–7.56 (m, 3H, ArH), 8.19 (s, 1H, H-3). 13C-NMR
7-Methyl-5-[(4-methylphenyl)sulfonyl]-6-phenyl-
(126MHz, CDCl3) δ: 21.6 (CH3), 48.3 (NCH2), 55.3 (OCH3), imidazo[1,5-a]pyrazin-8(7H)-one (4a)
113.8 (CH), 126.7 (C), 128.1 (C), 128.3 (CH), 128.4 (CH),
Pale yellow crystals, 16% yield. mp 178–180°C (CHCl3–
129.1 (CH), 129.5 (CH), 129.5 (CH), 130.6 (C), 134.3 (C), hexane).17)

370
Chem. Pharm. Bull.
Vol. 65, No. 4 (2017)
5-[(4-Methylphenyl)sulfonyl]-6,7-diphenylimidazo[1,5-a]-
pyrazin-8(7H)-one (4b)
Ethyl 4,5-Dihydro-5-oxo-3,4-diphenylpyrazine-2-carboxyl-
ate (5b)
Pale yellow crystals, 10% yield. mp 263–266°C (dec.)
Yellow crystals, 88% yield. mp 198–201°C (CHCl3–hexane).
(CHCl3–hexane).17)
IR (KBr) cm−1: 3001, 2983, 1712, 1681, 1569, 1484, 1389,
1
6-Methyl-5-[(4-methylphenyl)sulfonyl]-7-phenylimidazo[1,5- 1378, 1323, 1126, 1004, 928, 754, 710. H-NMR (500MHz,
a]pyrazin-8(7H)-one (4c)
CDCl3) δ: 1.03 (t, J=7.0Hz, 3H, CH2CH3), 4.11 (q, J=7.0Hz,
A yellow solid, 3% yield. mp 232–235°C (dec.) (CHCl3–hex- 2H, OCH2), 6.96–6.98 (m, 2H, ArH), 7.02–7.07 (m, 2H,
ane).17)
ArH), 7.17–7.28 (m, 6H, ArH), 8.36 (s, 1H, H-6). 13C-NMR
6-(4-Bromophenyl)-7-methyl-5-[(4-methylphenyl)sulfonyl]- (126MHz, CDCl3) δ: 13.8 (CH2CH3), 61.4 (OCH2), 124.5 (C),
imidazo[1,5-a]pyrazin-8(7H)-one (4d)
127.8 (CH), 128.4 (CH), 129.0 (CH), 129.1 (CH), 129.2 (CH),
White crystals, 20% yield. mp 180–183°C (acetone–hex- 129.2 (CH), 131.5 (C), 135.8 (C), 145.7 (C), 147.8 (C-3), 155.7
ane).21)
(CO), 164.3 (CO). MS m/z: 320 (M+, 100). HR-MS (EI) for
6-(4-Methoxyphenyl)-7-methyl-5-[(4-methylphenyl)sulfonyl]- C19H16N2O3: Calcd, 320.1161. Found: 320.1149. Anal. Calcd
imidazo[1,5-a]pyrazin-8(7H)-one (4e)
for C19H16N2O3·0.33H2O: C, 69.94; H, 5.15; N, 8.59. Found: C,
Ocher crystals, 5% yield. mp 173–176°C (CHCl3–hexane).17) 69.95; H, 4.98; N, 8.41.
7-Benzyl-5-[(4-methylphenyl)sulfonyl]-6-phenyl-
imidazo[1,5-a]pyrazin-8(7H)-one (4f)
Ethyl 4,5-Dihydro-3-methyl-5-oxo-4-phenylpyrazine-2-carboxyl-
ate (5c)
Pale yellow crystals, 36% yield. mp 232–235°C (dec.)
Yellow crystals, 52% yield. mp 150–153°C (CHCl3–hex-
(CHCl3–hexane).17)
ane). IR (KBr) cm−1: 3060, 2976, 1705, 1671, 1517, 1385,
1
7-(4-Methoxyphenylmethyl)-5-[(4-methylphenyl)sulfon- 1306, 1230, 1095, 776, 709. H-NMR (500MHz, CDCl3) δ:
yl]-6-phenylimidazo[1,5-a]pyrazin-8(7H)-one (4g)
Pale yellow crystals, 34% yield. mp 183–185°C (CHCl3– J=7.0Hz, 2H, OCH2), 7.16–7.18 (m, 2H, ArH), 7.52–7.60 (m,
hexane).17) 3H, ArH), 8.20 (s, 1H, H-6). 13C-NMR (126MHz, CDCl3)
7-Benzyl-6-(4-methoxyphenyl)-5-[(4-methylphenyl)sulfon- δ: 14.4 (CH2CH3), 18.2 (CH3), 61.7 (OCH2), 123.7 (C), 127.2
1.43 (t, J=7.0Hz, 3H, CH2CH3), 2.40 (s, 3H, 6-CH3), 4.43 (q,
yl]imidazo[1,5-a]pyrazin-8(7H)-one (4h)
(CH), 129.9 (CH), 130.3 (CH), 136.1 (C), 145.3 (C-3), 146.0
A pale yellow oil, 35% yield.17)
(C), 156.0 (CO), 165.0 (CO). MS m/z: 258 (M+, 100). HR-MS
5-[(4-Methylphenyl)sulfonyl]-6-(4-nitrophenyl)-7- (EI) for C14H14N2O3: Calcd, 258.1004. Found: 258.1006. Anal.
phenylimidazo[1,5-a]pyrazin-8(7H)-one (4j) Calcd for C14H14N2O3·0.33H2O: C, 63.64; H, 5.59; N, 10.60.
Yellow crystals, 44% yield. mp 244–245°C (CHCl3–hex- Found: C, 63.73; H, 5.42; N, 10.26.
ane).17)
Ethyl 3-(4-Bromophenyl)-4,5-dihydro-4-methyl-5-oxopyr-
6-(4-Methoxyphenyl)-5-[(4-methylphenyl)sulfonyl]-7- azine-2-carboxylate (5d)
phenylimidazo[1,5-a]pyrazin-8(7H)-one (4k)
Crystals, 85% yield. mp 183–185°C (CHCl3–hexane). IR
Pale yellow crystals, 36% yield. mp 253–256°C (dec.) (KBr) cm−1: 2982, 2901, 1723, 1662, 1485, 1423, 1379, 1313,
(CHCl3–hexane).17)
1177, 1013, 876, 833, 803, 677. H-NMR (500MHz, CDCl3) δ:
1
General Procedure for Synthesis of Ethyl 5-Oxo- 1.12 (t, J=7.0Hz, 3H, CH2CH3), 3.23 (s, 3H, NCH3), 4.13 (q,
3-phenylpyrazine-2-carboxylates (5) To a stirred solution J=7.0Hz, 2H, OCH2), 7.16 (d, J=8.5Hz, 2H, ArH), 7.69 (d,
of ethyl isocyanoacetate (85mg, 0.75mmol) in DMF (3mL) J=8.5Hz, 2H, ArH), 8.24 (s, 1H, H-6). 13C-NMR (126MHz,
was added DBU (152mg, 1.00mmol) at 0°C, and the mix- CDCl3) δ: 13.9 (CH2CH3), 33.5 (NCH3), 61.5 (OCH2), 124.2
ture was stirred for 1h under atmosphere of oxygen. To the (C), 124.5 (C), 129.5 (CH), 130.7 (C), 132.4 (CH), 145.2 (C),
mixture was added 4-trifluoroacetyl-1,3-oxazolium-5-olate 1 146.5 (C-3), 155.9 (CO), 163.8 (CO). MS m/z: 338 (M+, 55.7),
(0.50mmol), and the whole was stirred at 0°C for an addition- 263 (100). HR-MS (EI) for C14H13BrN2O3: Calcd, 336.0110.
al several hours. After workup with aq. Na2CO3, the mixture Found: 336.0131. Anal. Calcd for C14H13BrN2O3: C, 49.87; H,
was extracted with AcOEt (×3). The combined organic layers 3.89; N, 8.31. Found: C, 49.94; H, 3.89; N, 8.55.
were washed with brine, dried over anhyd. Na2SO4, and evap-
Ethyl
4,5-Dihydro-3-(4-methoxyphenyl)-4-methyl-5-oxo-
orated. The residue was purified by column chromatography pyrazine-2-carboxylate (5e)
(silica gel, hexane–AcOEt=4:1 to 1:1) to give the product 5.
Crystals, 85% yield. mp 148–150°C (CHCl3–hexane). IR
Ethyl 4,5-Dihydro-4-methyl-5-oxo-3-phenylpyrazine-2-car- (KBr) cm−1: 2983, 2931, 2836, 1714, 1669, 1504, 1315, 1247,
boxylate (5a)
1182, 1029, 871, 816, 694. 1H-NMR (500MHz, CDCl3) δ:
Yellow crystals, 92% yield. mp 111–113°C (CHCl3–hexane). 1.11 (t, J=7.0Hz, 3H, CH2CH3), 3.25 (s, 3H, NCH3), 3.88 (s,
IR (KBr) cm−1: 2986, 1713, 1671, 1491, 1376, 1317, 1137, 1025, 3H, OCH3), 4.13 (q, J=7.0Hz, 2H, OCH2), 7.04 (d, J=8.5Hz,
866, 760, 711. 1H-NMR (500MHz, CDCl3) δ: 1.05 (t, J=7.0Hz, 2H, ArH), 7.19 (d, J=9.0Hz, 2H, ArH), 8.21 (s, 1H, H-6).
3H, CH2CH3), 3.23 (s, 3H, NCH3), 4.09 (q, J=7.0Hz, 2H, 13C-NMR (126MHz, CDCl3) δ: 13.9 (CH2CH3), 33.4 (NCH3),
OCH2), 7.26–7.28 (m, 2H, ArH), 7.52–7.55 (m, 3H, ArH), 8.24 55.4 (OCH3), 61.3 (OCH2), 114.5 (CH), 123.8 (C), 124.9 (C),
(s, 1H, H-6). 13C-NMR (126MHz, CDCl3) δ: 13.8 (CH2CH3), 129.4 (CH), 145.9 (C-3), 146.1 (C), 156.3 (CO), 160.7 (C),
33.5 (NCH3), 61.3 (OCH2), 124.4 (C), 127.9 (CH), 129.0 (CH), 164.2 (CO). MS m/z: 288 (M+, 75.8), 215 (100). HR-MS (EI)
129.9 (CH), 131.9 (C), 146.1 (C-3), 146.2 (C), 156.1 (CO), for C15H16N2O4: Calcd, 288.1110. Found: 288.1112. Anal. Calcd
164.0 (CO). MS m/z: 258 (M+, 99), 185 (100). HR-MS (EI) for for C15H16N2O4·0.33H2O: C, 61.23; H, 5.71; N, 9.52. Found: C,
C14H14N2O3: Calcd, 258.1004. Found: 258.1006. Anal. Calcd 61.24; H, 5.38; N, 9.54.
for C14H14N2O3: C, 65.11; H, 5.46; N, 10.85. Found: C, 65.14;
H, 5.43; N, 10.79.
Ethyl 4-Benzyl-4,5-dihydro-5-oxo-3-phenylpyrazine-2-car-
boxylate (5f)
Yellow crystals, 90% yield. mp 116–119°C (CHCl3–hexane).

Vol. 65, No. 4 (2017)
Chem. Pharm. Bull.
371
IR (KBr) cm−1: 3032, 2984, 1715, 1664, 1567, 1519, 1398, 3H, NCH3), 3.96 (q, J=7.2Hz, 2H, OCH2), 7.30–7.32 (m, 2H,
1
1307, 1197, 1130, 1020, 905, 767, 700. H-NMR (500MHz, ArH), 7.49–7.54 (m, 3H, ArH), 8.06 (s, 1H, H-1), 8.83 (s, 1H,
CDCl3) δ: 1.01 (t, J=7.0Hz, 3H, CH2CH3), 4.06 (q, J=7.0Hz, H-3). 13C-NMR (126MHz, CDCl3) δ: 13.2 (CH2CH3), 32.2
2H, OCH2), 5.04 (s, 2H, NCH2Ar), 6.78–6.80 (m, 2H, ArH), (NCH3), 61.5 (OCH2), 109.0 (C), 122.0 (C), 128.8 (CH), 129.6
7.03–7.05 (m, 2H, ArH), 7.17–7.19 (m, 3H, ArH), 7.35–7.38 (CH), 131.4 (CH), 133.2 (CH), 135.0 (CH), 139.2 (C), 155.6
(m, 2H, ArH), 7.46–7.49 (m, 1H, ArH), 8.33 (s, 1H, H-6). (CO), 161.9 (CO). MS m/z: 297 (M+, 100). HR-MS (EI) for
13C-NMR (126MHz, CDCl3) δ: 13.7 (CH2CH3), 48.7 (NCH2), C16H15N3O3: Calcd, 297.1113. Found: 297.1104. Anal. Calcd for
61.3 (OCH2), 124.9 (C), 127.1 (CH), 127.8 (CH), 128.4 (CH), C16H15N3O3: C, 64.64; H, 5.09; N, 14.13. Found: C, 64.66; H,
128.5 (CH), 129.9 (CH), 131.0 (C), 135.1 (C), 146.0 (C), 147.0 5.07; N, 13.88.
(C-3), 156.0 (CO), 164.0 (CO). MS m/z: 334 (M+, 82.3), 91
(100). HR-MS (EI) for C20H18N2O3: Calcd, 334.1317. Found: (7a–c)
Procedures for Synthesis of 1,3-Thiazolium-5-olates
334.1312. Anal. Calcd for C20H18N2O3: C, 71.84; H, 5.43; N,
8.38. Found: C, 71.54; H, 5.40; N, 8.27.
Ethyl 4,5-Dihydro-4-(4-methoxyphenylmethyl)-5-oxo-3-phenyl-
pyrazine-2-carboxylate (5g)
4-Trifluoroacetyl-3-methyl-2-phenyl-1,3-thiazolium-5-olate
(7a)
To a stirred suspension of N-methyl-N-thiobenzoylglycine
(1.00g, 4.78mmol) in tert butyl methyl ether (10mL) was
Crystals, 91% yield. mp 75–77°C (CHCl3–hexane). IR added trifluoroacetic anhydride (TFAA) (2mL, 14.3mmol) at
(KBr) cm−1: 2966, 2935, 2837, 1723, 1661, 1510, 1297, 1250, 0°C, and the solution was stirred at 0°C for 3h. After workup
1132, 1028, 805, 764, 712. 1H-NMR (500MHz, CDCl3) δ: with aq. Na2CO3, the mixture was extracted with AcOEt
0.99 (t, J=7.2Hz, 3H, CH2CH3), 3.74 (s, 3H, OCH3), 4.04 (q, (×3). The combined organic layers were washed with brine,
J=7.2Hz, 2H, OCH2), 4.98 (s, 2H, NCH2Ar), 6.39–6.74 (m, dried over anhyd. Na2SO4, and evaporated. The residue was
4H, ArH), 7.07 (d, J=7.2Hz, 2H, ArH), 7.40 (t, J=7.5Hz, washed with diethyl ether, and recrystallized from hexane–
2H, ArH), 7.49 (t, J=7.5Hz, 1H, ArH), 8.29 (s, 1H, H-6). ethyl acetate to give the product 7a as yellow crystals (1.17g,
13C-NMR (126MHz, CDCl3) δ: 13.7 (CH2CH3), 48.2 (NCH2), 85% yield). mp 131–133°C (AcOEt–hexane). IR (KBr) cm−1:
55.2 (OCH3), 61.2 (OCH2), 113.8 (CH), 124.9 (C), 127.2 (C), 3062, 3044, 2970, 1673, 1620, 1451, 1396, 1327, 1310, 1261,
1
128.4 (CH), 128.7 (CH), 128.8 (CH), 129.8 (CH), 131.1 (C), 1237, 1081, 1049, 1025, 997, 946, 791, 766, 736, 700. H-NMR
145.9 (C), 147.0 (C-3), 156.0 (CO), 159.2 (C), 164.0 (CO). MS (500MHz, CDCl3) δ: 4.04 (s, 3H, NCH3), 7.50 (d, J=7.5Hz,
m/z: 364 (M+, 60.5), 121 (100). HR-MS (EI) for C21H20N2O4: 2H, ArH), 7.59 (t, J=7.5Hz, 2H, ArH), 7.63–7.66 (m, 1H,
Calcd, 364.1423. Found: 364.1411. Anal. Calcd for C21H20N2O4: ArH). 13C-NMR (126MHz, CDCl3) δ: 42.5 (NCH3), 115.5
1
C, 69.22; H, 5.53; N, 7.69. Found: C, 68.99; H, 5.42; N, 7.87.
Ethyl
pyrazine-2-carboxylate (5h)
(C), 116.9 (q, J=288.5Hz, CF3), 127.1 (C), 129.3 (CH), 129.7
4-Benzyl-4,5-dihydro-3-(4-methoxyphenyl)-5-oxo- (CH), 132.6 (CH), 158.5 (C), 168.6 (q, 2J=38.1Hz, CCF3),
174.2 (C). MS m/z: 287 (M+, 67.5), 121 (100). HR-MS (EI) for
Crystals, 91% yield. mp 78–81°C (CHCl3–hexane). IR (KBr) C12H8F3NO2S: Calcd, 287.0228. Found: 287.0217.
cm−1: 2979, 2843, 1727, 1666, 1609, 1504, 1311, 1250, 1129,
1023, 857, 729, 695. H-NMR (500MHz, CDCl3) δ: 1.07 (t,
4-Acetyl-3-methyl-2-phenyl-1,3-thiazolium-5-olate (7b)
mixture of N-methyl-N-thiobenzoylglycine (1.00g,
1
A
J=7.1Hz, 3H, CH2CH3), 3.84 (s, 3H, OCH3), 4.09 (q, J=7.1Hz, 4.78mmol) and acetic anhydride (15mL) was heated at 120°C
2H, OCH2), 5.06 (s, 2H, NCH2Ar), 6.83–6.84 (m, 2H, for 4h. After workup with aq. Na2CO3, the mixture was ex-
ArH), 6.88 (d, J=8.8Hz, 2H, ArH), 6.96 (d, J=8.5Hz, 2H, tracted with AcOEt (×3). The combined organic layers were
ArH), 7.20–7.22 (m, 3H, ArH), 8.30 (s, 1H, H-6). 13C-NMR washed with brine, dried over anhyd. Na2SO4, and evaporated.
(126MHz, CDCl3) δ: 13.9 (CH2CH3), 48.6 (NCH2), 55.3 The residue was purified by column chromatography (silica
(OCH3), 61.3 (OCH2), 113.8 (CH), 123.1 (C), 125.4 (C), 127.1 gel, hexane–AcOEt=4:1 to 1:1) to give the product 7b as
(CH), 127.8 (CH), 128.5 (CH), 130.0 (CH), 135.3 (C), 145.9 yellow crystals (0.903g, 81% yield). mp 131–132°C (AcOEt–
(C), 146.9 (C-3), 156.2 (CO), 160.7 (C), 164.2 (CO). MS m/z: hexane) (mp21) 133–134°C). IR (KBr) cm−1: 3057, 3000, 2920,
364 (M+, 63), 135 (100). HR-MS (EI) for C21H20N2O4: Calcd, 1648, 1622, 1375, 1341, 1252, 1173, 1083, 946, 764, 695.
364.1423. Found: 364.1411. Anal. Calcd for C21H20N2O4: C, 1H-NMR (500MHz, CDCl3) δ: 2.53 (s, 3H, CCH3), 4.06 (s,
69.22; H, 5.53; N, 7.69. Found: C, 69.01; H, 5.60; N, 7.59.
3H, NCH3), 7.46 (dd, J=8.0, 1.5Hz, 2H, ArH), 7.53–7.60 (m,
Conversion of 2(1H)-Pyrazinone (5a) to Imidazo[1,5-a]- 3H, ArH). 13C-NMR (126MHz, CDCl3) δ: 29.7 (CH3), 42.1
pyrazin-8(7H)-one (6) To a stirred solution of TosMIC (NCH3), 119.0 (C), 127.7 (C), 129.4 (CH), 129.5 (CH), 131.7
(57mg, 0.290mmol) in DMF (1mL) was added DBU (88mg, (CH), 151.3 (C), 176.5 (C), 187.7 (C). MS m/z: 233 (M+, 36.7),
0.581mmol) at 0°C, and the mixture was stirred for 1h under 118 (100). HR-MS (EI) for C12H11NO2S: Calcd, 233.0510.
atmosphere of argon. To the mixture was added 5a (50mg, Found: 233.0504.
0.194mmol), and the whole was stirred at room temperature
(r.t.) for an additional 24h. After workup with aq. Na2CO3,
4-Formyl-3-methyl-2-phenyl-1,3-thiazolium-5-olate (7c)
To a mixture of pyridine (0.805mL, 10mmol) and DMF
the mixture was extracted with AcOEt (×3). The combined (1.925mL, 25mmol) in toluene (15mL) was added phospho-
organic layers were washed with brine, dried over anhyd. ryl chloride (1.2mL, 12.5mmol) at 0°C, and the solution was
Na2SO4, and evaporated. The residue was purified by col- stirred at 0°C for 1h. To the mixture was added N-methyl-N-
umn chromatography (silica gel, hexane–AcOEt=1:1) to thiobenzoylglycine (0.522g, 2.5mmol) and the whole was
give ethyl 7,8-dihydro-7-methyl-8-oxo-6-phenylimidazo[1,5- heated at 80°C for an additional 3h. After workup with aq.
a]pyrazine-5-carboxylate 6 as colorless crystals, 65% yield. Na2CO3, the mixture was extracted with AcOEt (×3). The
mp 163–165°C (CHCl3–hexane). IR (KBr) cm−1: 3146, 2979, combined organic layers were washed with brine, dried over
2934, 1709, 1667, 1336, 1321, 1207, 1065, 719. 1H-NMR anhyd. Na2SO4, and evaporated. The residue was recrystal-
(500MHz, CDCl3) δ: 0.78 (t, J=7.2Hz, 2H, CH2CH3), 3.11 (s, lized from hexane–ethyl acetate to give 7c as amber crystals

372
Chem. Pharm. Bull.
Vol. 65, No. 4 (2017)
(0.318g, 58% yield). mp 160–162°C (AcOEt–hexane). IR
(KBr) cm−1: 3056, 3027, 2829, 2782, 2757, 1670, 1604, 1365,
1326, 1307, 1239, 1152, 1051, 859, 774, 759, 697. 1H-NMR
(500MHz, CDCl3) δ: 4.11 (s, 3H, NCH3), 7.47–7.49 (m, 2H,
ArH), 7.55–7.63 (m, 3H, ArH), 9.57 (s, 1H, CHO). 13C-NMR
(126MHz, CDCl3) δ: 40.2 (NCH3), 118.1 (C), 127.1 (C), 129.4
(CH), 129.6 (CH), 132.1 (CH), 152.0 (C), 176.2 (C), 178.4
(C). MS m/z: 219 (M+, 30.8), 118 (100). HR-MS (EI) for
C11H9NO2S: Calcd, 219.0354. Found: 219.0346.
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Acknowledgments The authors gratefully acknowledge
Ms. Ayaka Uematsu and Mr. Daichi Kameda for conducting
in vitro antibacterial assay. This work was partially supported
by KAKENHI from the Japan Society for the Promotion of
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Scientific Research (C) 16K11519).
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Conflict of Interest The authors declare no conflict of
interest.
Supplementary Materials The online version of this ar-
ticle contains supplementary materials.