Facile synthesis of imidazo[1,5-a]pyrazin-8(7H)-ones from mesoionic 1,3-oxazolium-5-olates via a multistep one-pot transformation

Article abstract of DOI:10.3987/COM-16-13551

A novel one-pot conversion of mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olates into imidazo[1,5-a]pyrazin-8(7H)-ones by the reaction with TosMIC is described. The structure of the product was determined by single-crystal X-ray analysis.

Full text of DOI:10.3987/COM-16-13551

HETEROCYCLES, Vol. 92, No. 11, 2016
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HETEROCYCLES, Vol. 92, No. 11, 2016, pp. 2047 - 2058. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 7th August, 2016, Accepted, 28th September, 2016, Published online, 14th October, 2016
DOI: 10.3987/COM-16-13551
FACILE SYNTHESIS OF IMIDAZO[1,5-a]PYRAZIN-8(7H)-ONES FROM
MESOIONIC 1,3-OXAZOLIUM-5-OLATES VIA
ONE-POT TRANSFORMATION
A
MULTISTEP
Ryosuke Saijo,a Hidemitsu Uno,b and Masami Kawasea*
aFaculty of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho,
b
Matsuyama, Ehime 790-8578, Japan, Department of Chemistry and Biology,
Graduate School of Science and Engineering, Ehime University, Matsuyama,
790-8577, Japan; E-mail: kawase@cc.matsuyama-u.ac.jp
Abstract
–
A
novel
one-pot
conversion
of
mesoionic
4-trifluoroacetyl-1,3-oxazolium-5-olates into imidazo[1,5-a]pyrazin-8(7H)-ones
by the reaction with TosMIC is described. The structure of the product was
determined by single-crystal X-ray analysis.
The imidazo[1,5-a]pyrazine A has a five-membered imidazole and a six-membered pyrazine ring with a
bridgehead nitrogen atom (Figure 1) and is one of the less known members of the azaindolizine family.1
On the other hand, the isomer imidazo[1,2-a]pyrazine B is a well-known scaffold in organic synthesis and
drug development.2 These imidazopyrazines have recently been attracting considerable interest because
they represent promising building blocks with potential pharmaceutical applications.1,2
N
N
N
N
N
N
A
B
OH
O
Cl
N
N
NH2
HO
O
F
N
H
N
N
N
N
H
N
HN
N
N
F
N
N
N
HN
N
O
N
BMS-279700 11
HN
I
G479 7
HN
OSI-9714
Figure 1. Bioactive imidazo[1,5-a]pyrazines

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HETEROCYCLES, Vol. 92, No. 11, 2016
Substituted imidazo[1,5-a]pyrazine compounds (Figure 1) have shown many interesting biological
activities as, for example, Factor Xa,3 insulin-like growth-factor-I receptor (IGF-IR),4 mammalian target
of rapamycin (mTor),5 activated Cdc42-associated kinase (ACK1),6 MAPK/ERK kinase (MEK),7 and
Bruton’s tyrosine kinase (BTK) inhibitors,8 as well as Corticotropin releasing hormone receptor ligands9
and smoothened (Smo) antagonists.10 Recently, the compound BMS-279700 has been identified as a
potent inhibitor of the Src-family kinase p56Lck with excellent in vivo anti-inflammatory activity.11
These reports suggest the critical role of imidazo[1,5-a]pyrazines in medicinal chemistry and requirement
of easy route for the synthesis of substituted imidazo[1,5-a]pyrazine derivatives.
Two approaches have been mainly reported in literature for the construction of the
imidazo[1,5-a]pyrazine ring system. The first approach involves the formation of an imidazole ring by
ring closure onto an existing (appropriately substituted) pyrazine intermediate.12 In the second approach,
an appropriately substituted imidazole is annulated by a pyrazine ring formation, which is the much lesser
known route.13
Whereas these approaches have proven very useful for the synthesis of
imidazo[1,5-a]pyrazines, they generally involve multistep synthetic operations and lack the possibility to
generate diversity. Indeed, the development of efficient and general access to functionalized
imidazo[1,5-a]pyrazines is of great interest.
This study
TosMIC (3 equiv.), DBU (4 equiv.), O2, DMF, rt, 5 h
R1
N
O
R1
N
R2
Ts
O
O
R2
Ts
O
CF3
TosMIC (1.5 equiv.)
DBU (2 equiv.)
R1
R2
+
(CF3CO)2O
N
-
R2
N
R1
CO2H
+
O
O2, DMF
N
N
O
N
4
1a-j
2a-j
3a-j
for 2a
TosMIC (1.5 equiv.), DBU (2 equiv.)
DMF, 0 °C to rt, 2 h
3a (94%)
Scheme 1
We
have
previously
reported
that
the
unexpected
reaction
of
mesoionic
4-trifluoroacetyl-1,3-oxazolium-5-olates 1a-h with p-toluenesulfonylmethyl isocyanide (TosMIC)
proceeds via an initial attack of TosMIC anions on the C-2 position of the ring followed by
auto-oxidation to afford pyrazin-2(1H)-ones 2a-h in good yields (Scheme 1).14 In these reactions, we
noticed the formation of imidazo[1,5-a]pyrazin-8(7H)-ones 3a-h as a side product, which could be
produced by the action of excess TosMIC during reaction. This finding prompted us to investigate the

HETEROCYCLES, Vol. 92, No. 11, 2016
2049
reaction of 1 with TosMIC more closely and to make it more efficient method for synthesis of
imidazo[1,5-a]pyrazines 3. Now we describe herein novel formation of
imidazo[1,5-a]pyrazin-8(7H)-one derivatives 3.
a
The mesoionic oxazoles 1a-h are easily prepared from N-acyl-N-alkylglycines 4 in a one step through the
cyclodehydration by trifluoroacetic anhydride followed by trifluoroacetylation at C-4 position of an
intermediary mesoionic 1,3-oxazolium-5-olates (Scheme 1).15
We found that, upon treatment of 1a with 3 molar equiv. of TosMIC in the presence of DBU and O2, a
clean reaction occurred, leading to the formation of imidazo[1,5-a]pyrazin-8(7H)-one 3a in 91% yield.
The substituents on C2 and N3 of the mesoionic ring on the reaction were investigated and the results are
shown in Table 1. Mesoionics bearing either alkyl or aryl substituents at the N3 position all functioned
well, giving imidazo[1,5-a]pyrazinones 3 in fair to excellent yields. 2-Arylmesoionic oxazoles 1a,b,d-j
were easily transformed to the products 3a,b,d-j in high yields (entries 1, 2, and 4-10). Unfortunately,
2-methylmesoionic 1c, bearing α-hydrogens, afforded the 3c only in 18% yield (entry 3).
Table 1. Imidazo[1,5-a]pyrazin-8(7H)-ones 3 from mesoionic oxazoles 1
TosMIC (3 equiv.), DBU (4 equiv.)
1a-j
3a-j
O2, DMF, rt, 5 h
R1
R2
Entry
1
Yield (%)
1
a
b
c
d
e
f
Me
Ph
3a (91)
3b (77)
3c (18)
3d (79)
3e (82)
3f (83)
3g (86)
3h (99)
3i (76)
3j (99)
2
Ph
Ph
3
Ph
Me
4
Me
4-BrC6H4
4-MeOC6H4
Ph
5
Me
6
PhCH2
7
g
h
i
4-MeOC6H4CH2
Ph
8
PhCH2
Ph
4-MeOC6H4
4-NO2C6H4
4-MeOC6H4
9
10
j
Ph
The molecular structure of 3a was unequivocally confirmed by X-ray diffraction study of single crystals
(Figure 2).16

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HETEROCYCLES, Vol. 92, No. 11, 2016
Figure 2. Ortep drawing of 3a (50% probability)
A tentative mechanism which accounts for the formation of the pyrazin-2(1H)-ones (2) is described in the
communication.14 Thus, initial nucleophilic attack by the TosMIC anion on C-2 of 1 gave rise to an
adduct which is converted to the 2-pyrazinones 2 via a ring closure followed by auto-oxidation.7 The
reaction of TosMIC with aldimines to form imidazoles is known as the van Leusen imidazole synthesis.17
The imidazo[1,5-a]pyrazine core was reported to be synthesized via condensation with TosMIC with
2-pyrazinone derivative.11,18 Therefore, the formation of imidazo[1,5-a]pyrazin-8(7H)-one derivatives
(3) could be explained by the further reaction of the 2 with second TosMIC. Indeed, the reaction of 2a
with TosMIC gave 3a in 94% yield (Scheme 1). The C3-position of 2 is elctrophilically reactive
position in the pyrazinone core19 and could undergo nucleophilic attack by nucleophiles such as being
part of an imine system.
We described herein a facile synthesis of imidazo[1,5-a]pyrazin-8(7H)-one derivatives 3 from mesoionic
oxazoles 1 in good yields. This unique ring transformation reaction of mesoionic oxazoles with TosMIC
was not anticipated but the reaction is general as evidenced by the examples indicated in Table 1. The
method appears to be useful and convenient in terms of the ready accessibility of the starting materials,
operational simplicity and mild condition. The obtained compounds are of interest for the investigation
of the potential biological activity.
EXPERIMENTAL
All melting points were determined using a Yanagimoto hot-stage melting point apparatus and are
uncorrected.
1H-NMR spectra were measured on Bruker AVANCE500 spectrometer with
tetramethylsilane (Me4Si) as an internal reference. 13C-NMR spectra were obtained on a Bruker
AVANCE500 spectrometer (at 126 MHz). Both 1H- and 13C-NMR spectral data are reported in parts per
million (δ) relative to Me4Si. Infrared (IR) spectra were recorded on a JASCO FT/IR-4100 spectrometer.

HETEROCYCLES, Vol. 92, No. 11, 2016
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Low- and high-resolution MS were obtained with a JEOL JMS-GC mate II spectrometer with a direct
inlet system at 70 eV and a Bruker micrOTOF-Q mass spectrometer with methanol as the solvent.
Elemental analyses were carried out on a Yanaco CHN Corder MT-5, and X-ray crystallographic data
were recorded on a Rigaku VariMax SaturnCCD724/α diffractometer using graphite monochromated
Mo-Kα radiation at the Advanced Research Support Center, Ehime University. Standard work-up
means that the organic layers were finally dried over Na2SO4, filtered, and concentrated in vacuo below
37 °C using a rotary evaporator.
Materials: The following compounds were prepared by employing the reported method.
N-Benzoyl-N-methylglycine (4a): mp 101−104 °C (mp20 102−104 °C).
N-Benzoyl-N-phenylglycine (4b): mp 126−128 °C (mp20 127−129 °C).
N-Acetyl-N-phenylglycine (4c): mp 196−198 °C (mp21 193−195 °C).
N-(4-Bromobenzoyl)-N-methylglycine (4d): mp 143–145 °C (mp22 147–150 °C).
N-(4-Methoxybenzoyl)-N-methylglycine (4e): mp 151–154 °C (mp20 155–160 °C).
N-Benzoyl-N-benzylglycine (4f): mp 103−104 °C (mp23 106−107 °C).
N-Benzoyl-N-(4-methoxyphenylmethyl)glycine (4g): mp 157−158 °C (mp24 157−158 °C).
N-Benzyl-N-(4-methoxybenzoyl)glycine (4h): mp 149−151 °C (mp22 149−151 °C).
N-(4-Nitrobenzoyl)-N-phenylglycine (4i): mp 178–180 °C (mp20 172–175 °C).
N-(4-Methoxybenzoyl)-N-phenylglycine (4j): mp 135–137 °C (mp20 158–163 °C).
General Procedure for Preparation of 4-Trifluoroacetyl-1,3-oxazolium-5-olates 1a-j: To a stirred
suspension of N-acyl-N-alkylglycine (5.2 mmol) in AcOEt (10 mL), TFAA (2.2 mL, 15.6 mmol) was
added at 0 °C, and then the solution was stirred at 0 °C for 3 h. To the mixture, hexane was added.
The precipitate was collected by filtration, dried, and recrystallized from hexane/AcOEt to give the
product 1a-f.
4-Trifluoroacetyl-3-methyl-2-phenyl-1,3-oxazolium-5-olate (1a): Pale yellow crystals, 95% yield.
mp 161−163 °C (mp25 162−163 °C).
4-Trifluoroacetyl-2,3-diphenyl-1,3-oxazolium-5-olate (1b):
Yellow crystals, 94% yield.
mp
194−196 °C (mp25 194−196 °C).
4-Trifluoroacetyl-2-methyl-3-phenyl-1,3-oxazolium-5-olate (1c): White crystals, 90% yield. mp
200−203 °C (mp25 211−212 °C).
2-(4-Bromophenyl)-4-trifluoroacetyl-3-methyl-1,3-oxazolium-5-olate (1d): White crystals, 90%
yield. mp 188–191 °C (mp22 188–191 °C).
4-Trifluoroacetyl-2-(4-methoxyphenyl)-3-methyl-1,3-oxazolium-5-olate (1e): Pale yellow crystals,
82% yield. mp 142–143 °C (AcOEt/hexane). IR (KBr) νmax 3027, 2958, 2897, 1789, 1629, 1601, 1513,
1431, 1264, 1185, 1155, 1015, 846, 736 cm-1. 1H NMR (500 MHz, CDCl3) δ = 3.93 (s, 3H, NCH3), 4.12

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(s, 3H, OCH3), 7.11 (d, J = 8.9 Hz, 2H, ArH), 7.73 (d, J = 9.0 Hz, 2H, ArH) ppm. 13C NMR (126 MHz,
1
CDCl3) δ = 37.5 (NCH3), 55.8 (OCH3), 97.3 (C), 112.2, 115.3, 116.9 (q, JC-F = 288.8 Hz, CF3), 131.6,
2
153.9 (C), 157.9 (C), 164.2 (C), 167.3 (q, JC-F = 37.6 Hz, COCF3) ppm. MS m/z: 301 (M+, 58.8), 135
(100). HRMS (EI) for C13H10F3NO4 (M+): Calcd, 301.0562. Found, 301.0547.
3-Benzyl-4-trifluoroacetyl-2-phenyl-1,3-oxazolium-5-olate (1f): White crystals, 83% yield. mp
143−145 °C (mp24 143–145 °C).
4-Trifluoroacetyl-3-(4-methoxybenyl)-2-phenyl-1,3-oxazolium-5-olate (1g): White crystals, 75%
yield. mp 147–148 °C (mp24 147–148 °C).
3-Benzyl-4-trifluoroacetyl-2-(4-methoxyphenyl)-1,3-oxazolium-5-olate (1h): White crystals, 89%
yield. mp 158−160 °C (mp23 158−160 °C).
4-Trifluoroacetyl-2-(4-nitrophenyl)-3-phenyl-1,3-oxazolium-5-olate (1i): Yellow crystals, 70% yield.
mp 175–178 °C (AcOEt/hexane). IR (KBr) νmax 3080, 2917, 2850, 1779, 1645, 1523, 1353, 1261, 1208,
1153, 855, 826, 721 cm-1. 1H NMR (500 MHz, CDCl3) δ = 7.45 (d, J = 8.1 Hz, 2H, ArH), 7.64 (d, J =
9.0 Hz, 2H, ArH), 7.63 (t, J = 8.0 Hz, 2H, ArH), 7.70 (t, J = 7.6 Hz, 1H, ArH), 8.18 (d, J = 9.0 Hz, 2H,
1
ArH) ppm. 13C NMR (126 MHz, CDCl3) δ = 98.4 (C), 116.4 (q, JC-F = 289.1 Hz, CF3), 124.2, 126.1,
127.5, 130.5, 130.6, 131.8, 133.8, 149.3 (C), 150.0 (C), 157.1 (C), 166.7 (q, 2JC-F = 38.4 Hz, COCF3) ppm.
MS m/z: 378 (M+, 0.8), 150 (100). HRMS (EI) for C17H9F3N2O5 (M+): Calcd, 378.0464. Found,
378.0461.
4-Trifluoroacetyl-2-(4-methoxyphenyl)-3-phenyl-1,3-oxazolium-5-olate (1j): Pale yellow crystals,
93% yield. mp 203–205 °C (mp22 182–185 °C).
General Procedure for Synthesis of Imidazo[1,5-a]pyrazin-8(7H)-ones 3a-j: To a stirred solution of
TosMIC (293 mg, 1.50 mmol) in DMF (3 mL), DBU (304 mg, 2.00 mmol) was added at 0 °C, and then
the mixture was stirred for
1
h
under atmosphere of oxygen.
To the mixture,
4-trifluoroacetyl-1,3-oxazolium-5-olate 1a-j (0.50 mmol) was added, and then the whole was stirred at
0 °C for an additional 5 h. After workup with aq. Na2CO3, the mixture was extracted with AcOEt (30
mL x 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 = 1:1 to
1:3) to give the product 3a-j.
7-Methyl-5-[(4-methylphenyl)sulfonyl]-6-phenylimidazo[1,5-a]pyrazin-8(7H)-one (3a): Pale yellow
crystals, 91% yield. mp 178–180 °C (CHCl3/hexane). IR (KBr) νmax 3165, 3055, 2923, 1674, 1663,
1595, 1336, 1321, 1152, 924, 875, 790, 701 cm-1. 1H NMR (500 MHz, CDCl3) δ = 2.40 (s, 3H, ArCH3),
2.98 (s, 3H, NCH3), 7.21–7.23 (m, 4H, ArH), 7.47 (d, J = 8.4 Hz, 2H, ArH), 7.50 (t, J = 7.3 Hz, 2H, ArH),
7.57 (tt, J = 7.5, 1.2 Hz, 1H, ArH), 8.07 (d, J = 0.4 Hz, 1H, H-1), 8.96 (d, J = 0.5 Hz, 1H, H-3) ppm. 13C
NMR (126 MHz, CDCl3) δ = 21.6 (CH3), 32.2 (NCH3), 117.7 (C), 122.4 (C), 127.1 (CH), 128.7 (CH),

HETEROCYCLES, Vol. 92, No. 11, 2016
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129.8 (CH), 129.9 (CH), 130.4 (CH), 131.9 (C-1), 134.9 (C-3), 137.5 (C), 139.5 (C-6), 145.5 (C), 155.2
(CO) ppm. MS m/z: 379 (M+, 100). Anal. Calcd for C20H17N3O3S: C, 63.31; H, 4.52; N, 11.07.
Found: C, 63.21; H, 4.80; N, 11.00.
5-[(4-Methylphenyl)sulfonyl]-6,7-diphenylimidazo[1,5-a]pyrazin-8(7H)-one (3b):
Pale yellow
crystals, 77% yield. mp 263–266 °C (dec.) (CHCl3/hexane). IR (KBr) νmax 3182, 3051, 1692, 1583,
1493, 1433, 1342, 1324, 1267, 1169, 1151, 1086, 991, 817, 786 cm-1. 1H NMR (500 MHz, CDCl3) δ =
2.40 (s, 3H, ArCH3), 6.91 (d, J = 8.1 Hz, 2H, ArH), 6.99 (d, J = 7.8 Hz, 2H, ArH), 7.10–7.22 (m, 8H,
ArH), 7.47 (d, J = 8.3 Hz, 2H, ArH), 8.13 (s, 1H, H-1), 9.08 (s, 1H, H-3) ppm. 13C NMR (126 MHz,
CDCl3) δ = 21.7 (CH3), 118.1, 122.6, 127.3, 127.4, 128.5, 128.8, 129.4, 129.5, 129.8, 129.9, 131.3, 132.9,
135.5, 135.8, 137.5, 139.6, 145.4, 154.9 (CO) ppm. MS m/z: 441 (M+, 60.7), 77 (100). HRMS (EI) for
C25H19N3O3S (M+): Calcd, 441.1147. Found, 441.1152.
6-Methyl-5-[(4-methylphenyl)sulfonyl]-7-phenylimidazo[1,5-a]pyrazin-8(7H)-one (3c): A yellow
solid, 18% yield. mp 232–235 °C (dec.) (CHCl3/hexane). IR (KBr) νmax 3194, 3065, 2927, 1691, 1592,
1492, 1375, 1326, 1161, 1089, 944, 894, 818, 770 cm-1. 1H NMR (500 MHz, CDCl3) δ = 2.39 (s, 3H,
ArCH3), 2.44 (s, 3H, CCH3), 7.18 (d, J = 7.0 Hz, 2H, ArH), 7.37 (d, J = 8.0 Hz, 2H, ArH), 7.48–7.55 (m,
3H, ArH), 7.83 (d, J = 8.2 Hz, 2H, ArH), 8.02 (s, 1H, H-1), 8.92 (s, 1H, H-3) ppm. 13C NMR (126 MHz,
CDCl3) δ = 17.8 (CH3), 21.7 (CH3), 116.8, 122.2, 126.6, 128.8, 129.7, 130.0, 130.4, 132.7, 134.8, 136.1,
137.5, 137.6, 145.8, 154.9 (CO) ppm. MS m/z: 379 (M+, 62), 77 (100). HRMS (EI) for C20H17N3O3S
(M+): Calcd, 379.0991. Found, 379.0974.
6-(4-Bromophenyl)-7-methyl-5-[(4-methylphenyl)sulfonyl]imidazo[1,5-a]pyrazin-8(7H)-one
(3d):
White crystals, 79% yield. mp 180–183 °C (acetone/hexane). IR (KBr) νmax 3185, 2970, 1671, 1598,
1438, 1371, 1338, 1154, 1010, 831, 745 cm-1. 1H NMR (500 MHz, CDCl3) δ = 2.41 (s, 3H, ArCH3),
2.98 (s, 3H, NCH3), 7.11 (d, J = 8.4 Hz, 2H, ArH), 7.25 (d, J = 8.2 Hz, 2H, ArH), 7.47 (d, J = 8.4 Hz, 2H,
ArH), 7.64 (d, J = 6.8 Hz, 2H, ArH), 8.04 (s, 1H, H-1), 8.94 (s, 1H, H-3) ppm. 13C NMR (126 MHz,
CDCl3) δ = 21.7 (CH3), 32.2 (NCH3), 117.9, 122.3, 125.1, 127.0, 128.8, 130.0, 131.4, 132.0, 132.1, 134.9,
137.3, 138.2, 145.7, 155.0 (CO) ppm. MS m/z: 459 (M++2, 90.7), 457 (M+, 86.7), 54 (100). HRMS
(EI) for C20H16BrN3O3S (M+): Calcd, 457.0096. Found, 457.0093.
6-(4-Methoxyphenyl)-7-methyl-5-[(4-methylphenyl)sulfonyl]imidazo[1,5-a]pyrazin-8(7H)-one (3e):
Ocher crystals, 82% yield. mp 173–176 °C (CHCl3/hexane). IR (KBr) νmax 3155, 2966, 2925, 1696,
1609, 1508, 1438, 1318, 1254, 1169, 1152, 1083, 1025, 992, 851, 804 cm-1. 1H NMR (500 MHz,
CDCl3) δ = 2.40 (s, 3H, ArCH3), 2.99 (s, 3H, NCH3), 3.91 (s, 3H, OCH3), 6.98 (d, J = 8.7 Hz, 2H, ArH),
7.10 (d, J = 8.7 Hz, 2H, ArH), 7.21 (d, J = 8.2 Hz, 2H, ArH), 7.45 (d, J = 8.4 Hz, 2H, ArH), 8.06 (s, 1H,
H-1), 8.99 (s, 1H, H-3) ppm. 13C NMR (126 MHz, CDCl3) δ = 21.6 (CH3), 32.1 (NCH3), 55.4 (OCH3),
114.1, 118.0, 121.6, 122.5, 127.0, 129.8, 131.3, 131.7, 134.9, 137.7, 139.5, 145.3, 155.3 (CO), 161.1 (C)

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HETEROCYCLES, Vol. 92, No. 11, 2016
ppm. MS m/z: 409 (M+, 100). HRMS (EI) for C21H19N3O4S (M+): Calcd, 409.1096. Found,
409.1077.
7-Benzyl-5-[(4-methylphenyl)sulfonyl]-6-phenylimidazo[1,5-a]pyrazin-8(7H)-one (3f): Pale yellow
crystals, 83% yield. mp 232–235 °C (dec.) (CHCl3/hexane). IR (KBr) νmax 3158, 3059, 3026, 1676,
1596, 1446, 1359, 1340, 1258, 1162, 1087, 885, 810, 789 cm-1. 1H NMR (500 MHz, CDCl3) δ = 2.39 (s,
3H, ArCH3), 4.85 (s, 2H, NCH2Ar), 6.71 (d, J = 6.8 Hz, 2H, ArH), 6.95 (d, J = 7.1 Hz, 2H, ArH),
7.14–7.21 (m, 5H, ArH), 7.29 (t, J = 7.7 Hz, 2H, ArH), 7.43 (d, J = 8.4 Hz, 2H, ArH), 7.48 (t, J = 7.6 Hz,
1H, ArH), 8.14 (s, 1H, H-1), 9.00 (s, 1H, H-3) ppm. 13C NMR (126 MHz, CDCl3) δ = 21.6 (CH3), 47.3
(NCH2), 118.3, 122.5, 126.8, 127.1, 127.5, 127.9, 128.4, 128.7, 129.9, 130.3, 130.6, 132.6, 135.2, 136.2,
137.4, 139.4, 145.5, 155.3 (CO) ppm. MS m/z: 455 (M+, 41.6), 91 (100). HRMS (EI) for
C26H21N3O3S (M+): Calcd, 455.1304. Found, 455.1319.
7-(4-Methoxyphenylmethyl)-5-[(4-methylphenyl)sulfonyl]-6-phenylimidazo[1,5-a]pyrazin-8(7H)-
one (3g): Pale yellow crystals, 86% yield. mp 183–185 °C (CHCl3/hexane). IR (KBr) νmax 3144,
3051, 2968, 1676, 1591, 1511, 1440, 1354, 1340, 1252, 1162, 1086, 1031, 921, 810, 786 cm-1. 1H NMR
(500 MHz, CDCl3) δ = 2.39 (s, 3H, ArCH3), 3.75 (s, 3H, OCH3), 4.78 (s, 2H, NCH2Ar), 6.64 (d, J = 8.8
Hz, 2H, ArH), 6.68 (d, J = 8.8 Hz, 2H, ArH), 6.97 (d, J = 7.2 Hz, 2H, ArH), 7.20 (d, J = 8.2 Hz, 2H, ArH),
7.33 (t, J = 7.7 Hz, 2H, ArH), 7.42 (d, J = 8.3 Hz, 2H, ArH), 7.50 (t, J = 7.6 Hz, 1H, ArH), 8.12 (s, 1H,
H-1), 8.99 (s, 1H, H-3) ppm. 13C NMR (126 MHz, CDCl3) δ = 21.6 (CH3), 46.8 (NCH2), 55.2 (OCH3),
113.7, 118.1, 122.5, 127.1, 127.9, 128.3, 128.5, 128.8, 129.9, 130.3, 130.7, 132.5, 135.1, 137.5, 139.4,
145.4, 155.4 (CO), 159.0 (C) ppm. MS m/z: 485 (M+, 35.6), 121 (100). HRMS (EI) for C27H23N3O4S
(M+): Calcd, 485.1409. Found, 485.1419.
7-Benzyl-6-(4-methoxyphenyl)-5-[(4-methylphenyl)sulfonyl]imidazo[1,5-a]pyrazin-8(7H)-one (3h):
A pale yellow oil, 99% yield. IR (neat) νmax 3174, 3031, 2959, 1683, 1609, 1539, 1508, 1437, 1357,
1295, 1252, 1157, 1087, 1027, 927, 835, 749 cm-1. 1H NMR (500 MHz, CDCl3) δ = 2.39 (s, 3H,
ArCH3), 3.86 (s, 3H, OCH3), 4.86 (s, 2H, NCH2Ar), 6.75 (d, J = 7.1 Hz, 2H, ArH), 6.78 (d, J = 8.9 Hz,
2H, ArH), 6.83 (d, J = 8.6 Hz, 2H, ArH), 7.14–7.20 (m, 5H, ArH), 7.42 (d, J = 8.3 Hz, 2H, ArH), 8.12 (s,
1H, H-1), 9.02 (s, 1H, H-3) ppm. 13C NMR (126 MHz, CDCl3) δ = 21.6 (CH3), 47.2 (NCH2), 55.4
(OCH3), 113.4, 118.6, 120.6, 122.5, 126.8, 127.1, 127.5, 128.4, 129.8, 132.1, 132.4, 135.2, 136.3, 137.6,
139.4, 145.3, 155.4 (CO), 161.0 (C) ppm. MS m/z: 485 (M+, 77.8), 91 (100). HRMS (EI) for
C27H23N3O4S (M+): Calcd, 485.1409. Found, 485.1419.
6-(4-Nitrophenyl)-5-[(4-methylphenyl)sulfonyl]-7-phenylimidazo[1,5-a]pyrazin-8(7H)-one
(3i):
Yellow crystals, 76% yield. mp 244–245 °C (CHCl3/hexane). IR (KBr) νmax 3181, 3006, 2980, 1684,
1587, 1531, 1492, 1341, 1324, 1153, 1084, 866, 815, 747 cm-1. 1H NMR (500 MHz, CDCl3) δ = 2.43 (s,
3H, ArCH3), 6.94 (dd, J = 8.0, 2.1 Hz, 2H, ArH), 7.16–7.22 (m, 3H, ArH), 7.28 (t, J = 8.3 Hz, 4H, ArH),

HETEROCYCLES, Vol. 92, No. 11, 2016
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7.53 (d, J = 8.4 Hz, 2H, ArH), 8.00 (d, J = 8.7 Hz, 2H, ArH), 8.10 (s, 1H, H-1), 8.98 (s, 1H, H-3) ppm.
13C NMR (126 MHz, CDCl3) δ = 21.7 (CH3), 118.0, 122.3, 122.5, 127.2, 129.2, 129.3, 129.7, 130.3,
132.3, 133.3, 135.4, 136.2, 136.9, 137.1, 140.4, 146.3, 148.0, 154.5 (CO) ppm. MS m/z: 486 (M+, 66.9),
77 (100). HRMS (EI) for C25H18N4O5S (M+): Calcd, 486.0998. Found, 486.1024.
6-(4-Methoxyphenyl)-5-[(4-methylphenyl)sulfonyl]-7-phenylimidazo[1,5-a]pyrazin-8(7H)-one (3j):
Pale yellow crystals, 99% yield. mp 253–256 °C (dec.) (CHCl3/hexane). IR (KBr) νmax 3155, 2966,
2925, 1695, 1609, 1508, 1438, 1317, 1254, 1169, 1152, 1083, 851, 804, 708 cm-1. 1H NMR (500 MHz,
CDCl3) δ = 2.40 (s, 3H, ArCH3), 3.74 (s, 3H, OCH3), 6.60 (d, J = 8.7 Hz, 2H, ArH), 6.85–6.91 (m, 4H,
ArH), 7.13–7.21 (m, 5H, ArH), 7.45 (d, J = 8.4 Hz, 2H, ArH), 8.12 (s, 1H, H-1), 9.09 (s, 1H, H-3) ppm.
13C NMR (126 MHz, CDCl3) δ = 21.6 (CH3), 55.2 (OCH3), 112.9, 118.4, 121.2, 122.8, 127.2, 128.4,
128.8, 129.7, 129.8, 132.8, 132.8, 135.5, 136.0, 137.7, 139.6, 145.3, 155.0 (CO), 160.3 (C) ppm. MS
m/z: 471 (M+, 100). HRMS (EI) for C26H21N3O4S (M+): Calcd, 471.1253. Found, 471.1255.
Conversion of 1-Methyl-5-[(4-methylphenyl)sulfonyl]-6-phenylpyrazin-2(1H)-one (2a) to
7-Methyl-5-[(4-methylphenyl)sulfonyl]-6-phenylimidazo[1,5-a]pyrazin-8(7H)-one (3a): To a stirred
solution of TosMIC (43 mg, 0.220 mmol) in DMF (1 mL), DBU (46 mg, 0.294 mmol) was added at 0 °C,
and then the mixture was stirred for 30 min under atmosphere of argon. To the mixture, 2a (50 mg,
0.147 mmol) was added, and then the whole was stirred at rt for an additional 2 h. After workup with aq.
Na2CO3, the mixture was extracted with AcOEt (30 mL x 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 = 1:1 to 1:2) to give the product 3a (52 mg, 94% yield).
Crystal Data Refinements Details
Data Collection: A colorless prism crystal of C20H17N3O3S (3a; CCDC no. 1047969) having
approximate dimensions of 0.200 x 0.160 x 0.100 mm was mounted on a glass fiber. All measurements
were made on an Rigaku Saturn 724 diffractometer using multi-layer mirror monochromated Mo-Kα
radiation. The crystal-to-detector distance was 45.00 mm.
Cell constants and an orientation matrix for data collection corresponded to a primitive monoclinic cell
with dimensions: a = 11.948(2) Å, b = 31.727(5) Å, c = 9.897(2) Å, β = 97.513(2)°, V = 3719.5(10) Å3.
For Z = 8 and F.W. = 379.43, the calculated density is 1.355 g/cm3. The reflection conditions of: h0l: l =
2n, 0k0: k = 2n, uniquely determine the space group to be: P21/n (#14).
The data were collected at a temperature of −172 ± 1 °C to a maximum 2θ value of 62.9°. A total of
1440 oscillation images were collected. A sweep of data was done using ω oscillations from −110.0 to
70.0° in 0.5° steps. The exposure rate was 2.0 [sec./°]. The detector swing angle was −19.97°. A
second sweep was performed using ω oscillations from −110.0 to 70.0° in 0.5° steps. The exposure rate
was 2.0 [sec./°]. The detector swing angle was −19.97°. Another sweep was performed using ω

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HETEROCYCLES, Vol. 92, No. 11, 2016
oscillations from −110.0 to 70.0° in 0.5° steps. The exposure rate was 2.0 [sec./°]. The detector swing
angle was −19.97°. Another sweep was performed using ω oscillations from −110.0 to 70.0° in 0.5°
steps. The exposure rate was 2.0 [sec./°].
The detector swing angle was −19.97°.
The
crystal-to-detector distance was 45.00 mm. Readout was performed in the 0.141 mm pixel mode.
Data Reduction: Of the 60923 reflections that were collected, 8539 were unique (Rint = 0.0445). Data
were collected and processed using CrystalClear (Rigaku).26
The linear absorption coefficient, μ, for Mo-Kα radiation is 1.997 cm-1. An empirical absorption
correction was applied which resulted in transmission factors ranging from 0.892 to 0.980. The data
were corrected for Lorentz and polarization effects.
Structure Solution and Refinement: The structure was solved by direct methods27 and expanded
using Fourier techniques. The non-hydrogen atoms were refined anisotropically. Hydrogen atoms
were refined using the riding model. The final cycle of full-matrix least-squares refinement28 on F2 was
based on 8539 observed reflections and 491 variable parameters and converged (largest parameter shift
was 0.00 times its esd) with unweighted and weighted agreement factors of: R1 = Σ ||Fo| - |Fc|| / Σ |Fo| =
0.0400, wR2 = [ Σ ( w (Fo2 - Fc2)2 )/ Σ w(Fo2)2]1/2 = 0.0981.
The standard deviation of an observation of unit weight29 was 1.05. Unit weights were used. The
3
-
maximum and minimum peaks on the final difference Fourier map corresponded to 0.34 and −0.50 e /Å ,
respectively.
Neutral atom scattering factors were taken from Cromer and Waber.30 Anomalous dispersion effects
were included in Fcalc;31 the values for Δf' and Δf" were those of Creagh and McAuley.32 The values
for the mass attenuation coefficients are those of Creagh and Hubbell.33 All calculations were
performed using the CrystalStructure34 crystallographic software package except for refinement, which
was performed using SHELXL-97.35
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