Convenient synthesis of novel 2-substituted imidazopyrazinone derivatives

Article abstract of DOI:10.1080/00397911.2010.525774

Starting from commercially available piperazine-2-carboxylic acid, a series of novel 2-aryl and 2-benzyl substituted imidazopyrazinone were prepared. The intermediates 5a-g were obtained through facile Buchwald-Hartwig coupling reaction, and the effects of catalyst, base, and solvent on the coupling reaction were investigated. The optimal reaction conditions for the coupling reaction were PdCl₂(dppf)=NaO-t-Bu=toluene. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.525774

Synthetic Communications1, 42: 469–479, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.525774
CONVENIENT SYNTHESIS OF NOVEL 2-SUBSTITUTED
IMIDAZOPYRAZINONE DERIVATIVES
Yanyun Zhu,1 Gonghua Song,2 Peng Lu,2 Mingjie Zhu,2 and
Yilang Chen2
1Shanghai Key Laboratory of Chemical Biology, School of Pharmacy,
East China University of Science and Technology, Shanghai, China
2Shanghai Sun-Sail Pharmaceutical Science and Technology, Shanghai,
China
GRAPHICAL ABSTRACT
Abstract Starting from commercially available piperazine-2-carboxylic acid, a series of
novel 2-aryl and 2-benzyl substituted imidazopyrazinone were prepared. The intermediates
5a–g were obtained through facile Buchwald–Hartwig coupling reaction, and the effects of
catalyst, base, and solvent on the coupling reaction were investigated. The optimal reaction
conditions for the coupling reaction were PdCl2(dppf)=NaO-t-Bu=toluene.
Keywords Buchwald–Hartwig coupling; catalyst; imidazopyrazinone; Mitsunobu reaction
INTRODUCTION
The piperazine ring system undoubtedly belongs to the most important hetero-
cycles in nature, as it represent the main structure of many biologically significant
compounds. For this reason many analogs and derivatives of piperazine have been
synthesized and developed as pharmacologically active compounds or drugs.[1–3]
In addition, a large number of fused piperazines were recently created and intro-
duced as the key moieties of dipeptidyl peptidase IV (DPP-IV) inhibitor for the treat-
ment of type 2 diabetes.[4]
Received November 4, 2009.
Address correspondence to Gonghua Song, Shanghai Key Laboratory of Chemical Biology, School
of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. E-mail:
ghsong@ecust.edu.cn
469

470
Y. ZHU ET AL.
This article described the synthesis of 2-aryl and 2-benzyl substituted imidazo-
pyrazinone analogs 6a–g and 8a–i, as part of our ongoing research work, which
might have potential for inhibition of the DPP-IV enzyme.
RESULTS AND DISCUSSION
Various imidazopyrazinone derivatives were synthesized via the routes
depicted in Schemes 1–3. As shown in Scheme 1, compound 1 was easily accessible
in two steps starting from piperazine-2-carboxylic acid through a known pro-
cedure.[5] Subsequently, the conversion of 1 to primary amine 3 was completed under
a standard Mitsunobu reaction condition, followed by ammonolysis in refluxing
methylamine ethanol solution. The key intermediate 4 was successfully obtained in
excellent yield by refluxing 3 in tetrahydrofuran (THF) with NaH. No catalyst, such
[6]
[7]
as reported W(CO)6 and Ph3SbO=P4O10, was needed, and the selective depro-
tection of the Boc-group at the 7-position of the piperazine group was also unnecess-
ary when NaH was used. The coupling reaction of aryl halides and lactams 4 was
then investigated. When the coupling reaction was catalyzed by CuBr=ethyl 2-oxo-
cyclohexanecarboxylate with Cs2CO3 as base[8] (Scheme 2), only 19% of desired com-
pound 5a was gained.
Thus, the Buchwald–Hartwig reaction conditions were optimized by using the
coupling of 4-(trifluoromethyl)bromobenzene with 4 as the model reaction. First,
three palladium-containing catalysts, namely tris(dibenzylideneacetone) dipalladium
[Pd2(dba)3], Pd(OAc)2, and [1,10-bis(diphenylphosphino)ferrocene] dichloropalla-
dium [PdCl2(dppf)], were examined. As shown in Table 1, PdCl2(dppf) could cata-
lyze the coupling reaction with much greater efficiency than the other two catalysts.
Second, several bases including Cs2CO3, K2CO3, and NaO-t-Bu were examined in
the Pd2(dba)3-catalyzed coupling reaction. The yields with different bases were in
the order NaO-t-Bu > K2CO3 > Cs2CO3 (entries 1–3). Finally, the effect of solvents
such as toluene, 1,4-dioxane, and tetrahydrofuran (THF) was investigated (entries
7–9). Weak influence of solvents on yield was observed while relatively good yield
was obtained in toluene. PdCl2(dppf)=NaO-t-Bu=toluene was regarded as the opti-
mal reaction condition for the coupling reaction. It has the advantages such as (1)
excellent yields; (2) less catalyst (0.5 mol%) than previously reported (1–4 mol%)
[9]; and (3) no use of auxiliary ligands.
Scheme 1. Synthesis of intermediate 4.

2-SUBSTITUTED HEXAHYDROIMIDAZOPYRAZINONE
471
Scheme 2. Synthesis of compound 5a.
To obtain the desired derivatives 5b–g, the optimized conditions were then
applied to the coupling reactions of intermediate 4 with various aryl bromides bearing
electron-withdrawing substitutes (Table 2). It was found that the electronic effect of
substituted groups exerted important influence on the yields of the coupling reactions.
Buchwald–Hartwig reactions of 4 with aryl bromides bearing electron-donating sub-
stitutes proceeded sluggishly. For an example, 4-fluorobromobenzene, which pos-
sesses a relatively weak electron-withdrawing substitute, resulted in poor yield
although the reaction time had been prolonged. On the other hand, according to
the synthesis of tetramethylurea derivatives,[10] the intermolecular amidation of aryl
or benzyl halides with lactams 4 was carried out successfully in the presence of
NaH in THF, without use of expensive Pd catalysts. Various corresponding benzyl
substituted products 7a–i were then obtained in acceptable yields (48–90%, Table 3).
Finally, after the removal of Boc-protection groups of 5a–g and 7a–i in HCl=
Et2O solution, the targeted free amines, 6a–g and 8a–i, were precipitated from the
reaction mixture and easily isolated by filtration in good yields (77–99%, Scheme 3).
The final products were pure enough for normal use even without further purification.
In conclusion, a series of novel 2-aryl and 2-benzyl substituted imidazopyrazi-
none derivatives had been prepared, and the facile protocol for the preparation of
target products by Buchwald–Hartwig coupling reaction or electrophilic substitution
was described. The application of these free amines in the development of novel
DPP-IV inhibitors is in progress and will be reported later.
EXPERIMENTAL
Melting points were obtained with a Mel-Temp apparatus and are uncorrected.
1H NMR and 13C NMR spectra were recorded respectively on Varian Mercury
Scheme 3. Synthesis of 6a–g and 8a–i.

472
Y. ZHU ET AL.
Table 1. Optimization of catalyst, base, and solvent in the synthesis of 5a
Entry
Catalyst
Base
Solvent
Conditions
Yield (%)a
1
2
3
4
5
6
7
8
9
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
Cs2CO3
K2CO3
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
1,4-Dioxane
THF
reflux, 24 h
reflux, 24 h
reflux, 24 h
reflux, 24 h
reflux, 24 h
reflux, 24 h
reflux, 12 h
reflux, 12 h
reflux, 12 h
34
41
55
0
NaO-t-Bu
Cs2CO3
K2CO3
0
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
0
98
92
89
aIsolated yields.
400-MHz or Mercury 300-MHz (Varian Inova) instruments with tetramethylsilane
(TMS) as an internal standard. Mass spectra (MS-ESI) were recorded with a Finnigan
MAT 95. Compound 1 was prepared following the literature procedure.[5]
Di-tert-butyl 2-((1,3-Dioxoisoindolin-2-yl)methyl)-piperazine-
1,4-dicarboxylate (2)
PPh3(16.2 g, 61.8 mmol) and phthalimide (9.1 g, 61.8 mmol) were added to a sol-
ution of 1 (15.0 g, 47.5 mmol) in anhydrous THF (250 mL) at 10 ꢀC. DIAD (12.0 mL,
Table 2. Palladium-catalyzed coupling of 4 with aryl bromides
Entry
R1
Reaction time (h)
Yield (%)a
Mp (ꢀC)b
5a
5b
5c
5d
5e
5f
4-CF3C6H4
2-pyridinyl
4-FC6H4
12
12
48
24
24
24
24
98
82
15
52
78
52
67
188–190
126–128
168–170
123–125
194–195
216–218
244–245
4-ClC6H4
4-CNC6H4
4-NO2C6H4
4-MeSO2C6H4
5g
aIsolated yields.
bMelting points are uncorrected.

2-SUBSTITUTED HEXAHYDROIMIDAZOPYRAZINONE
473
Table 3. Substitution reaction of lactam 4 with benzylhalides
Entry
R2-X
R2
Yielda (%)
Mpb (ꢀC)
7a
7b
7c
7d
7e
7f
BnBr
Bn
64
90
83
86
48
86
88
83
65
130–131
130–131
119–120
111–112
106–107
129–130
125–126
121–122
110–112
4-FC6H4CH2Br
4-ClC6H4CH2Br
4-OMeC6H4CH2Cl
4-MeC6H4CH2Br
3-FC6H4CH2Br
3-CNC6H4CH2Br
CH3I
4-FC6H4CH2
4-ClC6H4CH2
4-OMeC6H4CH2
4-MeC6H4CH2
3-FC6H4CH2
3-CNC6H4CH2
Me
7g
7h
7i
CH3CH2Br
Et
aIsolated yields.
bMelting points are uncorrected.
61.8 mmol) was then added slowly to the reaction mixture at 10 ꢀC. The reaction was
stirred at 10 ꢀC for an additional 2 h. After the reaction was completed, the reaction
mixture was treated with 1N HCl (100 mL) and then extracted with ethyl acetate. The
extract was washed with 5% aqueous NaHCO3 (100 mL), dried and concentrated in
vacuo. The residue was purified by silica-gel chromatography to give the title com-
1
pound (19.9 g, 93%) as a white solid. Mp 95–96 ꢀC; H NMR (CDCl3, 400 MHz) d
1.02 (m, 9H), 1.44 (m, 9H), 2.73–2.84 (m, 1H), 2.93–3.01 (m, 1H), 3.28–3.40 (m,
1H), 3.55 (m, 1H), 3.65–4.15 (m, 4H), 4.48–4.66 (m, 1H), 7.67–7.84 (m, 4H).
Di-tert-butyl 2-(Aminomethyl)piperazine-1,4-dicarboxylate (3)
The solution of 2 (14.1 g, 31.7 mmol) in EtOH (100 mL) was treated with
methylamine alcohol solution (32%, 100 mL), heated at reflux for 4 h, cooled to room
temperature, and concentrated. The resulting residue was dissolved in H2O (50 mL),
acidified to pH ¼ 3 with 2N HCl, and extracted with methyl-tert-butyl ether. The pH
was adjusted to 10 with 2N NaOH, and the mixture was extracted with ethyl acetate.
The extract was dried and filtered, and the solvent was removed under reduced press-
ure to give the title compound (7.7 g, 77%) as a white solid. Mp 92–93 ꢀC; 1H NMR
(CDCl3, 400 MHz) d 1.45 (s, 18H), 2.73–2.92 (m, 5H), 3.82–4.16 (m, 4H); MS (ESI)
m=z: 316.2 (M þ H)þ.
tert-Butyl Hexahydro-3-oxoimidazo[1,5-a]pyrazine-7(1H)-
carboxylate (4)
The solution of 3 (7.7 g, 24.2 mmol) in anhydrous THF (50 mL) was added
dropwise to a suspension of NaH (60% dispersion in mineral oil, 0.7 g, 48.4 mmol)

474
Y. ZHU ET AL.
in THF (50 mL) at 0 ꢀC. The reaction mixture was heated at reflux for 3 h. Upon
cooling to room temperature, the mixture was poured into ice H2O (50 mL) and
extracted with ethyl acetate. The extracts were washed with H2O and brine, dried,
filtered, and concentrated to give the desired product (5.3 g, 90%). mp 212–213 ꢀC;
1H NMR (CDCl3, 400 MHz) d 1.44 (s, 9H), 2.68–2.87 (m, 3H), 3.03 (m, 1H), 3.53
(t, J ¼ 12.0 Hz, 1H), 3.62–3.71 (m, 1H), 3.76 (d, J ¼ 12.8 Hz, 1H), 3.98–4.19 (m,
2H), 5.18–5.36 (m, 1H); MS (ESI) m=z: 264.2 (M þ Na)þ.
General Procedure for the Synthesis of Compounds 5a–g
Compound 4 (480 mg, 2.0 mmol) was dissolved in toluene (20 mL) under nitro-
gen. Then aryl bromides (4.0 mmol), NaO-t-Bu (384 mg, 4.0 mmol), and PdCl2(dppf)
(10 mg, 0.01 mmol) were added to the mixture and refluxed for 12–48 h. Upon cool-
ing, the mixture was concentrated, and the residue was dissolved in H2O (30 mL) and
extracted with ethyl acetate. The extract was washed with brine, dried, filtered, and
concentrated. The residue was purified by column chromatography to give the
compounds 5a–g.
General Procedure for the Synthesis of Compounds 7a–i
Benzylhalide (2.0 mmol) was added to the solution of 4 (241 mg, 1.0 mmol) in
anhydrous THF (10 mL). Then the mixed solution was added dropwise to a suspen-
sion of NaH (60% dispersion in mineral oil, 4.0 mmol) in THF (20 mL) at 0 ꢀC. The
mixture was refluxed for 3–8 h. Upon cooling, the mixture was poured into ice H2O
(50 mL) and extracted with ethyl acetate. The combined extracts were washed with
H2O and brine, dried, filtered, and concentrated to give the desired products 7a–i
as yellow solids.
General Procedure for the Synthesis of Compounds 6a–g and 8a–i
HCl=Et2O solution (1.7 mL, 4.0 M, 6.8 mmol) was added to a solution of 5a–g
or 7a–i (1.0 mmol) in CH2Cl2 (15 mL). After being stirred overnight, the precipitated
solids were filtered and washed with Et2O to give the desired compounds.
Data
tert-Butyl 2-(4-(trifluoromethyl)phenyl)-hexahydro-3-oxoimidazo[1,5-
a]pyrazine-7(1H)-carboxylate (5a). Yield: 98%; mp 188–190 ꢀC; 1H NMR
(CDCl3, 400 MHz) d 1.47 (m, 9H), 2.64–2.71 (m, 1H), 2.81–2.86 (m, 1H), 2.93–3.02
(m, 1H), 3.43–3.57 (m, 1H), 3.73–3.81 (m, 1H), 3.92–3.98 (m, 2H), 4.06–4.15 (m,
1H), 4.28–4.33 (m, 1H), 7.57 (d, J ¼ 9.4 Hz, 2H), 7.66 (d, J ¼ 8.5 Hz, 2H); MS (ESI)
m=z: 408.4 (M þ Na)þ.
tert-Butyl 2-(pyridin-2-yl)-hexahydro-3-oxoimidazo[1,5-a]pyrazine-7(1-
1
H)-carboxylate (5b). Yield: 82%; mp 126–128 ꢀC; H NMR (CDCl3, 300 MHz) d
1.47 (m, 9H), 2.60–2.72 (m, 1H), 2.78–2.83 (m, 1H), 3.00 (m, 1H), 3.67–3.73

2-SUBSTITUTED HEXAHYDROIMIDAZOPYRAZINONE
475
(m, 2H), 3.93 (m, 1H), 4.11–4.26 (m, 3H), 6.89–6.94 (m, 1H), 7.60–7.66 (m, 1H), 8.27
(m, 2H); MS (ESI) m=z: 319.3 (M þ H)þ.
tert-Butyl 2-(4-fluorophenyl)-hexahydro-3-oxoimidazo[1,5-a]pyrazine-
7(1H)-carboxylate (5c). Yield: 15%; mp 168–170 ꢀC; 1H NMR (CDCl3,
300 MHz) d 1.42–1.48 (m, 9H), 2.66–2.72 (m, 1H), 2.80–2.88 (m, 1H), 2.90–3.00
(m, 1H), 3.41 (m, 1H), 3.67–3.77 (m, 1H), 3.87–3.94 (m, 2H), 4.06–4.12 (m, 1H),
4.18–4.24 (m, 1H), 7.00–7.06 (m, 2H), 7.46–7.51 (m, 2H); MS (ESI) m=z: 358.3
(M þ Na)þ.
tert-Butyl 2-(4-chlorophenyl)-hexahydro-3-oxoimidazo[1,5-a]pyrazine-
7(1H)-carboxylate (5d). Yield: 52%; mp 123–125 ꢀC; 1H NMR (CDCl3,
400 MHz) d 1.47 (m, 9H), 2.60–2.74 (m, 1H), 2.80–2.87 (m, 1H), 2.94 (m, 1H),
3.41 (m, 1H), 3.73 (m, 1H), 3.87–3.94 (m, 2H), 4.02–4.15 (m, 1H), 4.20–4.37 (m,
1H), 7.28 (d, J ¼ 10.0 Hz, 2H), 7.49 (d, J ¼ 9.9 Hz, 2H); MS (ESI) m=z : 374.3
(M þ Na)þ.
tert-Butyl 2-(4-cyanophenyl)-hexahydro-3-oxoimidazo[1,5-a]pyrazine-
7(1H)-carboxylate (5e). Yield: 78%; mp 194–195 ꢀC; 1H NMR (CDCl3,
300 MHz) d 1.46 (m, 9H), 2.64–2.71 (m, 1H), 2.82–2.89 (m, 1H), 2.94–3.04 (m,
1H), 3.43–3.48 (m, 1H), 3.73–3.83 (m, 1H), 3.93–3.99 (m, 2H), 4.09–4.40 (m, 2H),
7.62 (d, J ¼ 9.0 Hz, 2H), 7.68 (d, J ¼ 9.0 Hz, 2H); MS (ESI) m=z: 365 (M þ Na)þ.
tert-Butyl
2-(4-nitrophenyl)-hexahydro-3-oxoimidazo[1,5-a]pyrazine-
7(1H)-carboxylate (5f). Yield: 52%; mp 216–218 ꢀC; 1H NMR (CDCl3,
400 MHz) d 1.42–1.51 (m, 9H), 2.64–2.70 (m, 1H), 2.83–2.89 (m, 1H), 2.96–3.02
(m, 1H), 3.50 (m, 1H), 3.77–3.82 (m, 1H), 3.93–4.03 (m, 2H), 4.11–4.18 (m, 1H),
4.23–4.37 (m, 1H), 7.71 (d, J ¼ 7.3 Hz, 2H), 8.22 (d, J ¼ 7.3 Hz, 2H); MS (ESI)
m=z: 385.3 (M þ Na)þ.
tert-Butyl 2-(4-(methylsulfonyl)phenyl)-hexahydro-3-oxoimidazo[1,5-
a]pyrazine-7(1H)-carboxylate (5g). Yield: 67%; mp 244–245 ꢀC; 1H NMR
(CDCl3, 400 MHz) d 1.49 (m, 9H), 2.64–2.71 (m, 1H), 2.80–2.87 (m, 1H),
2.88–2.99 (m, 1H), 3.03 (s, 3H), 3.48 (m, 1H), 3.75–3.82 (m, 1H), 3.92–4.01 (m,
2H), 4.09–4.13 (m, 1H), 4.15–4.37 (m, 1H), 7.75 (d, J ¼ 9.0 Hz, 2H), 7.89 (d,
J ¼ 8.9 Hz, 2H); MS (ESI) m=z: 418.3 (M þ Na)þ.
tert-Butyl
2-benzyl-hexahydro-3-oxoimidazo[1,5-a]pyrazine-7(1H)-
carboxylate (7a). Yield: 64%; mp 130–131 ꢀC; 1H NMR (CDCl3, 300 MHz) d
1.43 (s, 9H), 2.59–2.91 (m, 4H), 3.26–3.31 (m, 1H), 3.54 (m, 1H), 3.84–3.89 (m,
1H), 3.98–4.06 (m, 2H), 4.38 (s, 2H), 7.23–7.36 (m, 5H); MS (ESI) m=z: 354.3
(M þ Na)þ.
tert-Butyl 2-(4-fluorobenzyl)-hexahydro-3-oxoimidazo[1,5-a]pyrazine-
7(1H)-carboxylate (7b). Yield: 90%; mp 130–131 ꢀC; 1H NMR (CDCl3,
400 MHz) d 1.45 (s, 9H), 2.53–2.58 (m, 1H), 2.78 (q, J ¼ 4.8 Hz, 2H), 2.89 (dt,
J1 ¼ 12.9 Hz, J2 ¼ 3.0 Hz, 1H), 3.28 (t, J ¼ 8.7 Hz, 1H), 3.51–3.58 (m, 1H), 3.85 (d,
J ¼ 10.2 Hz, 1H), 3.95–4.08 (m, 2H), 4.30–4.69 (m, 2H), 6.98–7.04 (m, 2H), 7.21
(m, 2H); MS (ESI) m=z: 372.3(M þ Na)þ.

476
Y. ZHU ET AL.
tert-Butyl 2-(4-chlorobenzyl)-hexahydro-3-oxoimidazo[1,5-a]pyrazine-
7(1H)-carboxylate (7c). Yield: 83%; mp 119–120 ꢀC; 1H NMR (CDCl3,
400 MHz) d 1.45 (s, 9H), 2.52–2.60 (m, 1H), 2.75 (q, J ¼ 4.6 Hz, 2H), 2.90 (dt,
J1 ¼ 13.1 Hz, J2 ¼ 3.1 Hz, 1H), 3.28 (t, J ¼ 8.9 Hz, 1H), 3.51–3.58 (m, 1H), 3.85
(dd, J1 ¼ 13.1 Hz, J2 ¼ 3.1 Hz, 1H), 3.95–4.12 (m, 2H), 4.30–4.38 (m, 2H), 7.18 (m,
2H), 7.28–7.31 (m, 2H); MS (ESI) m=z: 388.2 (M þ Na)þ.
tert-Butyl 2-(4-methoxybenzyl)-hexahydro-3-oxoimidazo[1,5-a]pyrazine-
1
7(1H)-carboxylate (7d). Yield: 86%; mp 111–112 ꢀC; H NMR (CDCl3, 400 MHz)
d 1.45 (s, 9H), 2.53–2.60 (m, 1H), 2.77 (q, J ¼ 4.8 Hz, 2H), 2.88 (dt, J1 ¼ 12.9 Hz,
J2 ¼ 2.8 Hz, 1H), 3.26 (t, J ¼ 8.4 Hz, 1H), 3.49–3.56 (m, 1H), 3.79 (s, 3H), 3.84 (d,
J ¼ 10.5 Hz, 1H), 3.95–4.12 (m, 2H), 4.31 (m, 2H), 6.98 (d, J ¼ 6.6 Hz, 2H), 7.29
(d, J ¼ 6.7 Hz, 2H); MS (ESI) m=z: 384.3 (M þ Na)þ.
tert-Butyl 2-(4-methylbenzyl)-hexahydro-3-oxoimidazo[1,5-a]pyrazine-
7(1H)-carboxylate (7e). Yield: 48%; mp 106–107 ꢀC; 1H NMR (CDCl3,
400 MHz) d 1.45 (s, 9H), 2.33 (s, 3H), 2.53–2.60 (m, 1H), 2.77 (q, J ¼ 6.0 Hz, 2H),
2.90 (dt, J1 ¼ 17.2 Hz, J2 ¼ 4.0 Hz, 1H), 3.27 (t, J ¼ 8.4 Hz, 1H), 3.48–3.57 (m, 1H),
3.86 (d, J ¼ 14.0 Hz, 1H), 3.94–4.10 (m, 2H), 4.33 (s, 2H), 7.11 (s, 4H); MS (ESI)
m=z: 368.3 (M þ Na)þ.
tert-Butyl 2-(3-fluorobenzyl)-hexahydro-3-oxoimidazo[1,5-a]pyrazine-
7(1H)-carboxylate (7f). 1H NMR (CDCl3, 400 MHz) d 1.46 (s, 9H), 2.55–2.60
(m, 1H), 2.80 (q, J ¼ 4.6 Hz, 2H), 2.90 (dt, J1 ¼ 12.7 Hz, J2 ¼ 2.9 Hz, 1H), 3.31 (t,
J ¼ 8.7 Hz, 1H), 3.53–3.60 (m, 1H), 3.86 (d, J ¼ 9.9 Hz, 1H), 3.97–4.12 (m, 2H),
4.33–4.41 (m, 2H), 6.94–7.03 (m, 3H), 7.27–7.31 (m, 1H); MS (ESI) m=z: 372.3
(M þ Na)þ.
tert-Butyl 2-(3-cyanobenzyl)-hexahydro-3-oxoimidazo[1,5-a]pyrazine-
7(1H)-carboxylate (7g). 1H NMR (CDCl3, 400 MHz) d 1.45 (s, 9H), 2.54–2.62
(m, 1H), 2.79 (q, J ¼ 4.4 Hz, 2H), 2.91 (dt, J1 ¼ 12.7 Hz, J2 ¼ 3.1 Hz, 1H), 3.31 (t,
J ¼ 8.9 Hz, 1H), 3.54–3.61 (m, 1H), 3.85 (d, J ¼ 13.2 Hz, 1H), 3.97–4.15 (m, 2H),
4.33–4.46 (m, 2H), 7.42–7.58 (m, 4H); MS (ESI) m=z: 379.3 (10%, M þ Na)þ.
tert-Butyl
2-methyl-hexahydro-3-oxoimidazo[1,5-a]pyrazine-7(1H)-
carboxylate (7h). 1H NMR (CDCl3, 300 MHz) d 1.46 (s, 9 H), 2.60–2.76 (m,
2H), 2.78 (s, 3H), 2.85 (dd, J1 ¼ 13.0 Hz, J2 ¼ 3.1 Hz, 1H), 2.91 (q, J ¼ 4.8 Hz, 1H),
3.40 (t, J ¼ 8.5 Hz, 1H), 3.51–3.58 (m, 1H), 3.77–3.82 (m, 1H), 4.07–4.12 (m, 2H);
MS (ESI) m=z: 278.2 (M þ Na)þ.
tert-Butyl
2-ethyl-hexahydro-3-oxoimidazo[1,5-a]pyrazine-7(1H)-
carboxylate (7i). 1H NMR (CDCl3, 300 MHz) d 1.08 (t, J ¼ 7.3 Hz, 3H), 1.44 (s,
9H), 2.60–2.84 (m, 3H), 2.90 (q, J ¼ 4.4 Hz, 1H), 3.23 (q, J ¼ 6.3 Hz, 2H), 3.39 (t,
J ¼ 8.4 Hz, 1H), 3.49–3.56 (m, 1H), 3.75–3.81 (m, 1H), 3.96–4.10 (m, 2H); MS
(ESI) m=z: 292.3 (M þ Na)þ.
Hexahydro-2-(4-trifluoromethylphenyl)-imidazo[1,5-a]pyrazin-3-one (6a).
Yield: 78%; mp 233–235 ꢀC; 1H NMR (CF3COOD, 400 MHz) d 3.29–3.36 (m,
2H), 3.54–3.72 (m, 2H), 3.76 (m, 1H), 3.86 (m, 1H), 4.11–4.29 (m, 2H), 4.48 (m,
1H), 7.48 (d, J ¼ 8.6 Hz, 2H), 7.60 (d, J ¼ 8.5 Hz, 2H); 13C NMR (DMSO-d6,

2-SUBSTITUTED HEXAHYDROIMIDAZOPYRAZINONE
477
100 MHz) d 37.3, 42.3, 45.7, 47.1, 50.3, 117.2, 126.3, 126.4, 143.9, 155.3, 160.3;
HRMS (ESI): C13H14N3OF3Na, calc. 308.0987; found 308.0992.
Hexahydro-2-(pyridin-2-yl)-imidazo[1,5-a]pyrazin-3(5h)-one (6b). Yield:
90%; mp 170–171 ꢀC; 1H NMR (CF3COOD, 400 MHz) d 3.41–3.53 (m, 2H),
3.63–3.76 (m, 2H), 3.87–3.97 (m, 2H), 4.30–4.48 (m, 2H), 4.68 (m, 1H), 7.28 (m,
1H), 7.53 (m, 1H), 8.35–8.42 (m, 2H); 13C NMR (DMSO-d6, 100 MHz) d 28.4,
37.2, 45.0, 45.7, 47.0, 112.3, 118.4, 131.2, 138.1, 148.1, 155.1; HRMS (ESI):
C11H14N4ONa, calc. 241.1065; found 241.1057.
Hexahydro-2-(4-fluorophenyl)-imidazo[1,5-a]pyrazin-3-one (6c). Yield:
81%; mp 336–338 ꢀC; 1H NMR (CF3COOD, 400 MHz) d 3.37–3.47 (m, 2H),
3.60–3.66 (m, 3H), 3.69–3.76 (m, 1H), 4.14–4.29 (m, 1H), 4.26–4.32 (m, 1H),
4.38–4.52 (m, 1H), 7.05–7.11 (m, 2H), 7.30 (m, 2H); 13C NMR (D2O, 100 MHz) d
37.1, 42.4, 45.3, 46.9, 47.6, 115.8, 121.9, 134.8, 157.4, 160.4; HRMS (ESI):
C12H14N3OFNa, calc. 258.1019; found 258.1037.
Hexahydro-2-(4-chlorophenyl)-imidazo[1,5-a]pyrazin-3-one (6d). Yield:
95%; mp 127–129 ꢀC; 1H NMR (CF3COOD, 300 MHz) d 3.30–3.45 (m, 2H),
3.56–3.77 (m, 3H), 3.82–3.89 (m, 1H), 4.15–4.21 (m, 1H), 4.27–4.32 (m, 1H),
4.45–4.52 (m, 1H), 7.25 (d, J ¼ 7.8 Hz, 2H), 7.33 (d, J ¼ 8.9 Hz, 2H); 13C NMR
(DMSO-d6, 100 MHz) d 37.3, 42.3, 45.6, 45.8, 47.1, 119.0, 126.4, 129.0, 139.5,
155.5; HRMS (ESI): C12H14N3OClNa, calc. 274.0723; found 274.0733.
Hexahydro-2-(4-cyanophenyl)-imidazo[1,5-a]pyrazin-3-one (6e). Yield:
79%; mp 154–155 ꢀC; 1H NMR (CF3COOD, 400 MHz) d 3.27–3.40 (m, 2H),
3.51–3.59 (m, 1H), 3.67 (m, 1H), 3.74–3.83 (m, 2H), 4.16–4.22 (m, 1H), 4.25–4.30
(m, 1H), 4.38 (m, 1H), 7.58 (d, J ¼ 8.8 Hz, 2H), 7.69 (d, J ¼ 8.8 Hz, 2H); 13C
NMR (DMSO-d6, 100 MHz) d 37.3, 42.3, 45.5, 45.6, 47.0, 104.0, 117.3, 119.6,
133.5, 144.5, 155.1; HRMS (ESI): C13H14N4ONa, calc. 265.1065; found 265.1087.
Hexahydro-2-(4-nitrophenyl)-imidazo[1,5-a]pyrazin-3-one
(6f). Yield:
72%; mp 183–184 ꢀC;1H NMR (D2O, 400 MHz) d 2.95–3.01 (m, 2H), 3.19–3.36
(m, 1H), 3.19–3.36 (m, 1H), 3.22 (dt, J1 ¼ 15.0 Hz, J2 ¼ 3.0 Hz, 1H), 3.34 (dd,
J1 ¼ 12.6 Hz, J2 ¼ 2.5 Hz, 1H), 3.48 (dd, J1 ¼ 12.3 Hz, J2 ¼ 3.3 Hz, 1H), 3.64 (m,
1H), 3.96 (dd, J1 ¼ 13.1 Hz, J2 ¼ 2.2 Hz, 1H), 4.06 (m, 2H), 7.52 (m, 2H), 8.10 (m,
2H); 13C NMR (DMSO-d6, 100 MHz) d 37.2, 42.2, 45.6, 45.9, 46.9, 116.8, 125.3,
141.5, 146.5, 154.9; HRMS (ESI): C12H15N4O3, calc. 263.1144; found 263.1131.
Hexahydro-2-(4-(methylsulfonyl)phenyl)-imidazo[1,5-a]pyrazin-3-one (6g).
Yield: 78%; mp 297–300 ꢀC; 1H NMR (CF3COOD, 400 MHz) d 3.13 (s, 3H),
3.20–3.39 (m, 2H), 3.42–4.12 (m, 4H), 4.32 (m, 2H), 4.39–4.46 (m, 1H), 7.76–7.88
(m, 2H), 7.99–8.11 (m, 2H);13C NMR (D2OþDMSO-d6, 100 MHz) d 36.9, 42.4,
43.7, 45.6, 45.9, 47.2, 117.2, 126.4, 132.3, 144.4, 156.3; HRMS (ESI):
C13H17N3O3SNa, calc. 318.0888; found 318.0909.
Hexahydro-2-benzyl-imidazo[1,5-a]pyrazin-3-one (8a). Yield: 99%; mp
1
214–215 ꢀC; H NMR (DMSO-d6, 400 MHz) d 2.74 (t, J ¼ 8.0 Hz, 1H), 2.82 (dt,
J2 ¼ 9.6 Hz, J2 ¼ 4.0 Hz, 1H), 2.91 (dd, J2 ¼ 12.4 Hz, J2 ¼ 4.8 Hz, 1H), 3.16–3.30
(m, 4H), 3.78 (dd, J1 ¼ 14.8 Hz, J2 ¼ 3.8 Hz, 1H), 3.92–3.97 (m, 1H), 4.30 (m, 2H),

478
Y. ZHU ET AL.
7.22–7.27 (m, 3H), 7.33–7.37 (m, 2H); 13C NMR (DMSO-d6, 100 MHz) d 37.4, 42.2,
44.9, 45.4, 47.3, 47.9, 127.7, 128.1, 129.0, 137.6, 158.8; HRMS (ESI): C13H17N3ONa,
calc. 254.1269; found 254.1277.
Hexahydro-2-(4-fluorobenzyl)-imidazo[1,5-a]pyrazin-3-one (8b). Yield:
91%; mp 219–220 ꢀC; 1H NMR (DMSO-d6, 400 MHz) d 2.69–2.91 (m, 3H),
3.16–3.29 (m, 3H), 3.45–3.62 (m, 1H), 3.76 (m, 1H), 3.91–3.97 (m, 1H), 4.19–4.30
(m, 2H), 7.12–7.17 (m, 2H), 7.23–7.29 (m, 2H); 13C NMR (DMSO-d6, 100 MHz) d
37.4, 42.2, 44.9, 45.4, 46.5, 47.9, 115.9, 130.1, 130.2, 133.8, 158.7; HRMS (ESI):
C13H16FN3ONa, calc. 272.1175; found 272.1181.
Hexahydro-2-(4-chlorobenzyl)-imidazo[1,5-a]pyrazin-3-one (8c). Yield:
89%; mp 197–198 ꢀC; 1H NMR (DMSO-d6, 300 MHz) d 2.72–2.93 (m, 3H),
3.15–3.29 (m, 4H), 3.78–4.05 (m, 2H), 4.23–4.34 (m, 2H), 7.25 (d, J ¼ 8.2 Hz, 2H),
7.35 (d, J ¼ 8.2 Hz, 2H); 13C NMR (DMSO-d6, 100 MHz) d 37.5, 42.2, 44.9, 45.4,
46.8, 47.9, 129.6, 130.1, 133.6, 135.1, 158.8; HRMS (ESI): C13H16ClN3ONa, calc.
288.0880; found 288.0875.
Hexahydro-2-(4-methoxybenzyl)-imidazo[1,5-a]pyrazin-3-one (8d). Yield:
99%; mp 204–205 ꢀC; 1H NMR (DMSO-d6, 400 MHz) d 2.67 (m, 1H), 2.78 (m, 1H),
2.86 (dd, J1 ¼ 15.6 Hz, J2 ¼ 4.2 Hz, 1H), 3.14–3.24 (m, 4H), 3.71 (s, 3H), 3.76 (dd,
J1 ¼ 13.6 Hz, J2 ¼ 2.4 Hz, 1H), 3.87–3.93 (m, 1H), 4.16–4.25 (m, 2H), 6.99 (d,
J ¼ 8.6 Hz, 2H), 7.14 (d, J ¼ 8.5 Hz, 2H); 13C NMR (DMSO-d6, 100 MHz) d 37.4,
42.2, 44.9, 45.3, 47.0, 47.9, 114.5, 129.6, 128.1, 158.2, 158.8; HRMS (ESI):
C14H19N3O2Na, calc. 284.1375; found 284.1377.
Hexahydro-2-(4-methylbenzyl)-imidazo[1,5-a]pyrazin-3-one (8e). Yield:
71%; mp 194–195 ꢀC; 1H NMR (CDCl3, 400 MHz) d 2.33 (s, 3H), 2.53 (t,
J ¼ 11.1 Hz, 1H), 2.66–2.77 (m, 2H), 2.90–2.96 (m, 3H), 3.25 (t, J ¼ 8.7 Hz, 1H),
3.51–3.58 (m, 1H), 3.85 (d, J ¼ 12.9 Hz, 1H), 4.28–4.38 (m, 2H), 7.13 (s, 4H);
13C NMR (DMSO-d6, 100 MHz) d 21.6, 37.5, 42.2, 44.9, 45.3, 47.0, 47.9, 128.2,
129.6, 134.4, 136.9, 158.8; HRMS (ESI): C14H19N3ONa, calc. 268.1426; found
268.1414.
Hexahydro-2-(3-fluorobenzyl)-imidazo[1,5-a]pyrazin-3-one (8f). Yield:
91%; mp 216–217 ꢀC; 1H NMR (DMSO-d6, 400 MHz) d 2.75–2.96 (m, 3H),
3.18–3.34 (m, 3H), 3.56–3.64 (m, 1H), 3.78–3.87 (m, 1H), 3.93–3.98 (m, 1H), 4.29
(m, 2H), 7.02–7.12 (m, 3H), 7.38 (m, 1H); MS (ESI) m=z: 250.2 (M þ H)þ.
Hexahydro-2-(3-cyanobenzyl)-imidazo[1,5-a]pyrazin-3-one (8g). Yield:
1
99%; mp 199–201 ꢀC; H NMR (DMSO-d6, 400 MHz) d 2.80–2.86 (m, 2H), 2.96
(dd, J1 ¼ 9.7 Hz, J2 ¼ 4.2 Hz, 1H), 3.19–3.27 (m, 3H), 3.32–3.38 (m, 1H), 3.79 (dd,
J1 ¼ 13.6 Hz, J2 ¼ 2.7 Hz, 1H), 3.95–3.98 (m, 1H), 4.31–4.40 (m, 2H), 7.54–7.61 (m,
2H), 7.71–7.77 (m, 2H); MS (ESI) m=z: 257.1 (M þ H)þ.
Hexahydro-2-methyl-imidazo[1,5-a]pyrazin-3-one (8h). Yield: 87%; mp
207–208 ꢀC; 1H NMR (CDCl3, 300 MHz) d 2.69–2.93 (m, 4H), 3.04 (m, 1H),
3.12–3.58 (m, 5H), 3.89–3.96 (m, 1H), 4.09–4.17 (m, 1H); MS (ESI) m=z: 156.1
(M þ H)þ.

2-SUBSTITUTED HEXAHYDROIMIDAZOPYRAZINONE
479
Hexahydro-2-ethyl-imidazo[1,5-a]pyrazin-3-one (8i). Yield: 85%; mp
1
201–203 ꢀC; H NMR (DMSO-d6, 400 MHz) d 0.98 (t, J ¼ 7.3 Hz, 3H), 2.67–2.78
(m, 2H), 3.02 (m, 1H), 3.08–3.18 (m, 4H), 3.21–3.27 (m, 1H), 3.40 (t, J ¼ 8.8 Hz,
1H), 3.70 (m, 1H), 3.91–3.96 (m, 1H); MS (ESI) m=z: 170.1 (M þ H)þ.
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