Synthesis of 7-arylimidazo[1,2-a]pyrazin-8(7H)-one derivatives

Article abstract of DOI:10.1007/s10593-019-02469-7

[Figure not available: see fulltext.] A suitable approach to the synthesis of 7-arylimidazo[1,2-a]pyrazin-8(7H)-ones starting from esters of oxalic acid monoamides via cyclization of intermediate 3-aminopyrazin-2-ones with α-halocarbonyl compounds has bee

Full text of DOI:10.1007/s10593-019-02469-7

DOI 10.1007/s10593-019-02469-7
Chemistry of Heterocyclic Compounds 2019, 55(4/5), 386–391
Synthesis of 7-arylimidazo[1,2-a]pyrazin-8(7H)-one derivatives
Svitlana S. Kovalenko1, Oleksandr G. Drushlyak1*, Sergiy M. Kovalenko2,
Natalya D. Bunyatyan3,4, Dmitry V. Kravchenko5, Alexandre V. Ivachtchenko6
1 National University of Pharmacy,
53 Pushkinska St., Kharkiv 61002, Ukraine; е-mail: aldry18@hotmail.com
2 V. N. Karazin Kharkiv National University,
4 Svobody Sq., Kharkiv 61077, Ukraine; e-mail: kovalenko.sergiy.m@gmail.com
3 I. M. Sechenov First Moscow State Medical University (Sechenovskiy University),
8 Trubeckaya St., Moscow, 119991, Russia; e-mail: ndbun@mail.ru
4 Scientific Centre for Expert Evaluation of Medicinal Products,
8 Build. 2 Petrovsky Blvd., Moscow 127051, Russia
5 Chemical Diversity Research Institute,
2a-1 Rabochaya St., Khimki, Moscow Region 141400, Russia; e-mail: dk@chemrar.ru
6 ChemDiv, Inc.,
6605 Nancy Ridge Drive, San Diego, CA 92121, USA; e-mail: av@chemdiv.com
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2019, 55(4/5), 386–391
Submitted January 25, 2019
Accepted February 11, 2019
A suitable approach to the synthesis of 7-arylimidazo[1,2-a]pyrazin-8(7H)-ones starting from esters of oxalic acid monoamides via
cyclization of intermediate 3-aminopyrazin-2-ones with α-halocarbonyl compounds has been suggested.
Keywords: 3-aminopyrazin-2(1H)-one, 2-halophenylethanone, imidazo[1,2-a]pyrazin-8(7H)-one, 3-methoxypyrazin-2(1H)-one, pyrazine-
2,3-dione, cyclization.
Imidazo[1,2-a]pyrazin-8(7H)-one ring system is
relatively new, but constitutes a scaffold possessing diverse
biological activity. Imidazo[1,2-a]pyrazin-8(7H)-ones have
been reported as antiarrhythmics,1 as GABAA receptor
agonists for the treatment of anxiety,2 as inhibitors of
various kinases3–6 and CXCR3 antagonists with anti-
inflammatory action,7 as AMPA receptor modulators8 and
useful compounds for treatment neurological and psy-
chiatric deseases.9–11
However, synthesis of 7-arylimidazo[1,2-a]pyrazin-8(7H)-
ones 5 according to this method presents a problem, in our
opinion, and there are no examples reported.
Scheme 1
The most common imidazo[1,2-a]pyrazin-8(7H)-one
synthesis starts from 2,3-dichloropyrazine (1) and consists
of cyclization of the intermediate 3-amino-2-chloro-
pyrazine (2) by action of α-halocarbonyl reagents followed
by hydrolysis of the resulting 8-chloroimidazo[4,3-a]-
pyrazines 3 to imidazo[1,2-a]pyrazin-8(7H)-ones 4, which
can be alkylated by standard methods(Scheme 1).1–5,7–10,12
0009-3122/19/55(4/5)-0386©2019 Springer Science+Business Media, LLC
386

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 386–391
Scheme 2
Scheme 3
7-Arylimidazo[1,2-a]pyrazin-8(7H)-ones 10 have been
14a–d, already having the substituent, which shall occupy
position 7 of target imidazo[1,2-a]pyrazin-8(7H)-ones 21a–o,
could be easily obtained from corresponding amines and
diethyl oxalate or ethyl oxalyl chloride.15,16 Detailed procedure
for the synthesis of intermediate 3-chloropyrazin-2(1H)-
ones 17a–d was described in our previous publication.17
The chlorine atom in 3-chloropyrazin-2(1H)-ones 17 can
be easily replaced by the action of nucleophilic reagents.17
Therefore, compounds 17a–d were used without additional
purification and were converted into more stable
3-methoxypyrazin-2(1H)-ones 18a–d by treatment with
MeONa in MeOH. Nucleophilic substitution of methoxy
group was carried out by heating of products 18a–d in
molten dry ammonium acetate and led to 3-amino-2(1H)-
pyrazinones 19a–d, while 3-chloropyrazin-2(1H)-one 17d
by the same procedure gave product 19d in mixture with
20% of pyrazin-2,3-dione 16d as side product. A mixture
of these two products was also obtained by treatment of
3-chloropyrazin-2(1H)-one 17d with aqueous ammonia or
solution of aqueous ammonia in 1,4-dioxane. 3-Methoxy-
pyrazin-2(1H)-one 18d reacted with aqueous ammonia or
solution of aqueous ammonia in DMF very slowly and
gave a mixture of pyrazine-2,3-dione 16d and 3-amino-
2(1H)-pyrazinone 19d by prolonged reflux in DMF.
synthesized by another method (Scheme 2).13 Starting
α-aminonitriles 6 were treated with oxalyl bromide
providing the requisite 3,5-dibromo-2(1H)-pyrazinones 7.
Regioselective nucleophilic substitution of bromine by
35% aqueous ammonia in 1,4-dioxane led to 3-amino-
5-bromo-2(1H)-pyrazinones 8. After reductive substitution
of bromine, 3-amino-2(1H)-pyrazinones 9 were obtained
and were condenced with α-halocarbonyl reagents by
microwave irradiation resulted in imidazo[1,2-a]pyrazin-
8(7H)-ones 10. The disadvantage of this method is limited
set of commercially available α-aminonitriles 6 and usage
of high toxic cyanides for their synthesis.
7-Arylimidazo[1,2-a]pyrazin-8(7H)-ones 13 could be
synthesized via condensation of the corresponding imidazole-
2-carboxamides 11.6,11,14 But this approach led to a mixture
of regioisomers, both intermediate imidazoles 12 and final
imidazo[1,2-a]pyrazin-8(7H)-ones 13, in the case of
different substituents in starting imidazole 1114 (Scheme 3).
We suggest here a suitable method of synthesis, which
allows to obtain more diverse imidazo[1,2-a]pyrazin-8(7H)-
ones 21a–o, containing aromatic substituents both in
pyrazine (position 7) and imidazole (position 2) rings
(Scheme 4). The starting esters of oxalic acid monoamides
Scheme 4
387

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 386–391
Condensation of 3-amino-2(1H)-pyrazinones 19a–d
(50 ml) under reflux. After cooling, the precipitate formed
was filtered off. Yield 28.3 g (64%), white solid, mp 75–
with α-halocarbonyl reagents 20a–d was carried out in
DMF by reflux for 2 h and resulted in imidazo[1,2-a]-
pyrazin-8(7H)-ones 21a–o. The purity and structures of
synthesized compounds were confirmed by 1H NMR
spectroscopy, as well as by 13C NMR spectroscopy for
imidazo[1,2-a]pyrazin-8(7H)-ones 21a–o.
1
76°C (EtOH) (mp 130°C18, mp 124–126°C19). H NMR
spectrum, δ, ppm (J, Hz): 1.28 (3H, t, J = 7.4, CH3CH2);
2.22 (6H, s, 2CH3); 4.26 (2H, q, J = 7.4, OCH2); 6.76 (1H,
s, H-4 Ar); 7.32 (2H, s, H-2,6 Ar); 10.50 (1H, s, NH).
Found, %: C 64.96; H 6.98; N 6.28. С12Н15NO3.
Calculated, %: C 65.14; H 6.93; N 6.33.
1
The H NMR spectra of imidazo[1,2-a]pyrazin-8(7H)-
ones 21a–o are characterized by the presence of the signals
of protons H-3 as singlets at 8.15–8.35 ppm and the signals
of protons H-5,6 as doublets at 7.12–7.16 and 7.57–7.62 ppm,
respectively. The chemical shifts of these signals are in
good correlation with those of analogous compounds
described previously.13 The signals of protons H-5,6 in the
1H NMR spectra of 3-aminopyrazin-2(1H)-ones 19a–d are
overlapped by the signals of the NH2 protons at 6.65–6.85 ppm.
Therefore, it is impossible both to determine their multi-
plicity and use their integral intensity to estimate the
amount of 3-amino-1-(3,5-dimethylphenyl)pyrazin-2(1H)-
one (19d) in crude products in the failed attempts to obtain this
compound. However, the molar percentage of 1-(3,5-di-
methylphenyl)-1,4-dihydropyrazine-2,3-dione (16d) in crude
product could be estimated by the ratio of integral intensity
of the triplet of H-5 proton at 6.36 ppm to integral intensity
of the singlet of CH3 protons at 2.28 ppm. Similarly, molar
content of 1-(3,5-dimethylphenyl)-3-methoxypyrazin-2(1H)-
one (18d) was evaluated by the ratio of integral intensity of
the singlet of OCH3 protons at 3.82 ppm to integral
intensity of the singlet of CH3 protons at 2.28 ppm.
Synthesis of N-substituted N'-(2,2-dimethoxyethyl)-
ethanediamides 15a,c,d (General method). 2,2-Dimethoxy-
ethanamine (34.5 g, 0.33 mol) was added to an agitated
solution of the corresponding ethyl amino(oxo)acetate
14a,c,d (0.3 mol) in DMF (300 ml). The reaction mixture
was refluxed for 3 h. After cooling, the solution was
diluted with i-PrOH (500 ml) and left overnight. The
precipitate was filtered off, washed with i-PrOH (300 ml),
and recrystallized from mixture of DMF (50 ml) and
i-PrOH (200 ml). Amides 15a,c,d were obtained as white
solids.
N-(2,2-Dimethoxyethyl)-N'-(3-fluorophenyl)ethane-
diamide (15a). Yield 64.1 g (79%). Decomp. temp. >200°C.
1H NMR spectrum, δ, ppm (J, Hz): 3.20 (6H, s, 2OCH3);
3.28 (2H, t, J = 5.4, NCH2); 4.50 (1H, t, J = 5.4, CH); 6.96
(1H, td, J = 8.2, J = 0.8, H-4 Ar); 7.38 (1H, q, J = 5.3, H-5 Ar);
7.63–7.77 (2H, m, H Ar); 8.94 (1H, t, J = 5.4, NHCH2);
10.90 (1H, s, NH). Found, %: C 53.15; H 5.54; N 10.40.
C12H15FN2O4. Calculated, %: C 53.33; H 5.59; N 10.37.
N'-(4-Chlorophenyl)-N-(2,2-dimethoxyethyl)ethane-
diamide (15c). Yield 69.7 g (81%). Decomp. temp. >200°C
1
In summary, we have proposed a suitable approach to
the synthesis of imidazo[1,2-a]pyrazin-8(7H)-ones starting
from esters of oxalic acid monoamides via intermediate
pyrazine-2,3-diones which are converted into 3-amino-
pyrazin-2-ones. The cyclization of the latter with α-halo-
carbonyl reagents leads to imidazo[1,2-a]pyrazin-8(7H)-
ones having various substituents both at 2 and 7 position.
(mp 130–132°C19,20). H NMR spectrum, δ, ppm (J, Hz):
3.22–3.28 (8H, m, NCH2, 2OCH3); 4.55 (1H, t, J = 5.0,
CH); 7.42 (2H, d, J = 8.0, H Ar); 7.83 (2H, d, J = 8.0,
H Ar); 8.90 (1H, t, J = 5.4, NHCH2); 10.80 (1H, s, NH).
Found, %: C 50.46; H 5.30; N 9.82. C12H15ClN2O4.
Calculated, %: C 50.27; H 5.27; N 9.77.
N-(2,2-Dimethoxyethyl)-N'-(3,5-dimethylphenyl)ethane-
diamide (15d). Yield 64.8 g (77%). Decomp. temp. >200°C
1
(mp 134–136°C19,20). H NMR spectrum, δ, ppm (J, Hz):
Experimental
1H NMR spectra were recorded on a Varian WXR-400
(200 MHz) spectrometer. 13C NMR spectra were recorded
on a Bruker DRX-300 (75 MHz) spectrometer. For all
NMR spectra, DMSO-d6 was used as solvent, and the
chemical shift values were referred to residual protons
(δ 2.49 ppm) and carbons (δ 39.6 ppm) of the solvent as
internal standard. Elemental analysis was performed on a
EuroEA-3000 CHNS-O Analyzer. Melting points were
determined with a Buchi B-520 melting point apparatus.
Ethyl phenylamino(oxo)acetates 14a,c were commer-
cially available. Detailed procedure of 1-(4-methoxy-
phenyl)-1,4-dihydropyrazine-2,3-dione (16b) synthesis
have been reported.17
Ethyl [2-(3,5-dimethylphenyl)amino]-2-oxoacetate (14d).
A solution of 3,5-dimethylaniline (24.2 g, 0.2 mol) in
diethyl oxalate (100 ml, 0.74 mol) was heated at 150°C for
6 h. After cooling, the solution was diluted with EtOH
(100 ml) and left overnight to form a precipitate of the
diamide side product, which was separated by filtration.
The filtrate was diluted with water (200 ml). On next day,
the oil that formed on the bottom was dissolved in EtOH
2.23 (6H, s, 2CH3); 3.25 (6H, s, 2OCH3); 3.32 (2H, t, J = 5.4,
NCH2); 4.52 (1H, t, J = 5.4, CH); 6.85 (1H, s, H-4 Ar);
7.42 (2H, s, H-2,6 Ar); 8.80 (1H, t, J = 5.4, NHCH2); 10.40
(1H, s, NH). Found, %: C 60.15; H 7.14; N 11.09.
С14Н20N2O4. Calculated, %: C 59.99; H 7.19; N 9.99.
Synthesis of 1,4-dihydropyrazine-2,3-diones 16a,c,d
(General method). A solution of the appropriate oxalamide
15a,c,d (0.2 mol) in a mixture of AcOH (200 ml) and TFA
(20 ml) was refluxed for 8 h. After cooling, the reaction
mixture was diluted with i-PrOH (500 ml) and left
overnight. The precipitate was filtered off, washed with
i-PrOH (200 ml), and recrystallized from mixture of DMF
(50 ml) and i-PrOH (200 ml). Compounds 16a,c,d were
obtained as white solids.
1-(3-Fluorophenyl)-1,4-dihydropyrazine-2,3-dione (16a).
1
Yield 32.2 g (78%). Mp >300°C. H NMR spectrum,
δ, ppm (J, Hz): 6.37 (1H, t, J = 4.8, H-5); 6.53 (1H, d,
J = 4.8, H-6); 7.22–7.38 (3H, m, H-2,4,5 Ar); 7.54 (1H, q,
J = 5.2, H-6 Ar); 11.33 (1H, s, NH). Found, %: C 58.42;
H 3.40; N 13.50. C10H7FN2O2. Calculated, %: C 58.26;
H 3.42; N 13.59.
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Chemistry of Heterocyclic Compounds 2019, 55(4/5), 386–391
1-(4-Chlorophenyl)-1,4-dihydropyrazine-2,3-dione (16c).
Synthesis of 3-aminopyrazin-2(1H)-ones 19a–d (General
method). 3-Methoxypyrazin-2(1H)-one 18a–d (0.05 mol)
was added to a stirred liquid melt of NH4OAc (38.5 g,
0.5 mol), and the mixture was stirred for 8 h at 140°C.
After cooling to 80–90°C, the reaction mixture was poured
into water (500 ml). The formed precipitate was filtered
off, washed with water (100 ml), and purified by
crystallization from a mixture of CHCl3 (200 ml) and
hexane (200 ml). Compounds 19a–d were obtained as
cream-colored solids.
1
Yield 37.4 g (84%). Mp >300°C. H NMR spectrum, δ, ppm
(J, Hz): 6.36 (1H, t, J = 4.8, H-5); 6.51 (1H, d, J = 4.8, H-6);
7.45 (2H, d, J = 8.0, H Ar); 7.56 (2H, d, J = 8.0, H Ar);
11.30 (1H, s, NH). Found, %: C 54.16; H 3.24; N 12.46.
C10H7ClN2O2. Calculated, %: C 53.95; H 3.17; N 12.58.
1-(3,5-Dimethylphenyl)-1,4-dihydropyrazine-2,3-dione
(16d). Yield 34.2 g (79%). Mp >300°C (mp 200–202°C19,20).
1H NMR spectrum, δ, ppm (J, Hz): 2.23 (6H, s, 2CH3);
6.36 (1H, t, J = 4.8, H-5); 6.44 (1H, d, J = 4.8, H-6); 6.97
(2H, s, H-2,6 Ar); 7.05 (1H, s, H-4 Ar); 11.30 (1H, s, NH).
Found, %: C 66.46; H 5.54; N 13.08. C12H12N2O2.
Calculated, %: C 66.65; H 5.59; N 12.96.
3-Amino-1-(3-fluorophenyl)pyrazin-2(1H)-one (19a).
1
Yield 6.98 g (68%). Decomp. temp. >250°C. H NMR
spectrum, δ, ppm (J, Hz): 6.70 (1H, d, J = 4.0, H-5(6));
6.75–6.85 (3H, m, H-6(5), NH2); 7.40–7.64 (4H, m, H Ar).
Found, %: C 58.76; H 4.02; N 20.36. C10H8FN3O.
Calculated, %: C 58.53; H 3.93; N 20.48.
Synthesis of 3-methoxypyrazin-2(1H)-ones 18a–d
(General method). Anhydrous DMF (8 ml, 0.1 mol) was
added to a stirred suspension of the appropriate 1,4-dihydro-
pyrazine-2,3-dione 16a–d (0.1 mol) in dichloroethane (200 ml).
Then SOCl2 (8 ml, 0.11 mol) was added dropwise with
vigorous stirring. The suspension was refluxed with stirring
until the dissolution of the precipitate (1–2 h). After cooling,
the reaction mixture was diluted with hexane (500 ml).
Formed precipitate was filtered off and washed with hexane
(200 ml) to obtain crude 3-chloropyrazin-2(1H)-one 17a–d
that was used for the next step without additional purifi-
cation and immediately added to a solution of MeONa (from
9.16 g of Na, 0.4 mol) in dry MeOH (300 ml). The reaction
mixture was refluxed for 10 min. The excess of MeOH was
evaporated to final volume of the reaction mixture about
100 ml. The reaction mixture was diluted with water (500 ml).
On the next day, the precipitate formed was filtered off,
washed with water (200 ml), and recrystallized from a mixture
of DMF (30 ml) and i-PrOH (200 ml). Compounds 18a–d
were obtained as cream-colored solids.
3-Amino-1-(4-methoxyphenyl)pyrazin-2(1H)-one (19b).
1
Yield 7.49 g (69%). Decomp. temp. >250°C. H NMR
spectrum, δ, ppm (J, Hz): 3.78 (3H, s, 4-OCH3 Ar); 6.65–
6.85 (4H, m, H-5,6, NH2); 7.04 (2H, d, J = 7.8, H Ar); 7.35
(2H, d, J = 7.8, H Ar). Found, %: C 60.53; H 5.02; N 19.46.
C11H11N3O2. Calculated, %: C 60.82; H 5.10; N 19.34.
3-Amino-1-(4-chlorophenyl)pyrazin-2(1H)-one (19c).
1
Yield 7.98 g (72%). Decomp. temp. >250°C. H NMR
spectrum, δ, ppm (J, Hz): 6.65–6.85 (4H, m, H-5,6, NH2);
7.45 (2H, d, J = 8.0, H Ar); 7.56 (2H, d, J = 8.0, H Ar).
Found, %: C 54.29; H 3.56; N 19.13. C10H8ClN3O.
Calculated, %: C 54.19; H 3.64; N 18.96.
3-Amino-1-(3,5-dimethylphenyl)pyrazin-2(1H)-one (19d).
1
Yield 7.21 g (67%). Decomp. temp. >250°C. H NMR
spectrum, δ, ppm (J, Hz): 2.28 (6H, s, 2CH3); 6.65–6.85
(4H, m, H-5,6, NH2); 7.02 (2H, s, H-2,6 Ar); 7.08 (1H, s,
H-4 Ar). Found, %: C 66.74; H 6.12; N 19.36. C12H13N3O.
Calculated, %: C 66.96; H 6.09; N 19.52.
1-(3-Fluorophenyl)-3-methoxypyrazin-2(1H)-one (18a).
1
Yield 18.1 g (82%). Mp 206–208°C. H NMR spectrum,
Reaction of 3-chloro-1-(3,5-dimethylphenyl)pyrazin-
2(1H)-one (17d) with NH4OAc. Crude 3-chloro-1-(3,5-di-
methylphenyl)pyrazin-2(1H)-one (17d) (2.35 g, 0.01 mol)
was added to a stirred liquid melt of NH4OAc (5.7 g,
0.01 mol), and the mixture was stirred for 8 h at 140°C.
After cooling to 80–90°C, the reaction mixture was poured
into water (100 ml). The formed precipitate was filtered
off, washed with water (20 ml), and dried. The crude
product (2.09 g) contained compound 19d with 20% molar
admixture of compound 16d.
Reaction of 3-chloro-1-(3,5-dimethylphenyl)pyrazin-
2(1H)-one (17d) with ammonia. Crude 3-chloro-1-(3,5-di-
methylphenyl)pyrazin-2(1H)-one (17d) (2.35 g, 0.01 mol) was
added to a mixture of 35% aqueous NH3 (1 ml, 0.16 mol) and
dry 1,4-dioxane (30 ml). The reaction mixture was refluxed
for 1 h. After cooling, the reaction mixture was diluted with
water (100 ml). The formed precipitate was filtered off,
washed with water (20 ml), and dried. The crude product
(2.06 g) contained compound 19d with 35% molar
admixture of compound 16d.
δ, ppm (J, Hz): 3.84 (3H, s, 3-OCH3); 6.88 (1H, d, J = 4.0,
H-5); 7.24 (1H, d, J = 4.0, H-6); 7.40–7.64 (4H, m, H Ar).
Found, %: C 59.84; H 4.05; N 12.59. C11H9FN2O2.
Calculated, %: C 60.00; H 4.12; N 12.72.
3-Methoxy-1-(4-methoxyphenyl)pyrazin-2(1H)-one (18b).
1
Yield 19.7 g (85%). Mp 198–199°C. H NMR spectrum,
δ, ppm (J, Hz): 3.78 (3H, s, 4-OCH3 Ar); 3.84 (3H, s,
3-OCH3); 6.85 (1H, d, J = 4.0, H-5); 7.04 (2H, d, J = 7.8,
H Ar); 7.17 (1H, d, J = 4.0, H-6); 7.35 (2H, d, J = 7.8,
H Ar). Found, %: C 61.91; H 5.20; N 11.89. C12H12N2O3.
Calculated, %: C 62.06; H 5.21; N 12.06.
1-(4-Chlorophenyl)-3-methoxypyrazin-2(1H)-one (18c).
1
Yield 20.8 g (88%). Mp 238–239°C. H NMR spectrum,
δ, ppm (J, Hz): 3.84 (3H, s, 3-OCH3); 6.88 (1H, d, J = 4.0,
H-5); 7.22 (1H, d, J = 4.0, H-6); 7.45 (2H, d, J = 8.0, H Ar);
7.56 (2H, d, J = 8.0, H Ar). Found, %: C 55.61; H 3.91; N 11.69.
C11H9ClN2O2. Calculated, %: C 55.83; H 3.83; N 11.84.
1-(3,5-Dimethylphenyl)-3-methoxypyrazin-2(1H)-one
1
(18d). Yield 18.6 g (81%). Mp 182–183°C. H NMR
spectrum, δ, ppm (J, Hz): 2.28 (6H, s, 2CH3); 3.82 (3H, s,
3-OCH3); 6.85 (1H, d, J = 4.0, H-5); 7.02 (2H, s, H-2,6 Ar);
7.08 (1H, s, H-4 Ar); 7.16 (1H, d, J = 4.0, H-6). Found, %:
C 67.71; H 6.04; N 12.30. C13H14N2O2. Calculated, %:
C 67.81; H 6.13; N 12.17.
Reaction of 3-methoxy-1-(3,5-dimethylphenyl)pyrazin-
2(1H)-one (18d) with ammonia. 3-Methoxy-1-(3,5-di-
methylphenyl)pyrazin-2(1H)-one (18d) (2.30 g, 0.01 mol)
was dissolved in a mixture of 35% aqueous NH3 (1 ml,
0.16 mol) and dry DMF (15 ml). The solution was refluxed
389

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 386–391
for 12 h. After cooling, the reaction mixture was diluted
137.3; 141.2 (d, JCF = 9, C Ar1); 143.3; 152.3; 162.0 (d,
JCF = 246, C-3 Ar1). Found, %: C 63.85; H 3.31; N 12.18.
C18H11ClFN3O. Calculated, %: C 63.63; H 3.26; N 12.37.
2-(4-Ethylphenyl)-7-(4-methoxyphenyl)imidazo[1,2-a]-
pyrazin-8(7H)-one (21e). Yield 0.28 g (82%). Mp >300°C.
1H NMR spectrum, δ, ppm (J, Hz): 1.22 (3H, t, J = 7.7,
CH3CH2); 2.62 (2H, q, J = 7.7, CH3CH2); 3.78 (3H, s,
OCH3); 7.06 (2H, d, J = 7.8, H Ar1); 7.12 (1H, d, J = 4.0,
H-5); 7.24 (2H, d, J = 7.8, H Ar2); 7.38 (2H, d, J = 7.8,
H Ar1); 7.59 (1H, d, J = 4.0, H-6); 7.84 (2H, d, J = 7.8,
H Ar2); 8.26 (1H, s, H-3). 13C NMR spectrum, δ, ppm: 15.5
(CH3); 28.0 (CH2); 55.5 (OCH3); 107.0; 113.2; 114.3 (2C);
121.4; 125.4 (2C); 128.1 (2C); 128.2 (2C); 130.6; 132.6;
137.2; 143.6; 144.3; 152.7; 158.8. Found, %: C 72.86; H 5.62;
N 12.36. C21H19N3O2. Calculated, %: C 73.03; H 5.54;
N 12.17.
with water (100 ml). The formed precipitate was filtered
off, washed with water (20 ml), and dried. The crude
product (2.06 g) contained compound 19d with 25% molar
admixture of compound 16d and 10% molar of the starting
compound 18d.
Synthesis of imidazo[1,2-a]pyrazin-8(7H)-ones 21a–o
(General method). The appropriate 2-bromoacetophenone
20a–d (1.1 mmol) was added to a stirred solution of 3-amino-
pyrazin-2(1H)-one 19a–d (1 mmol) in anhydrous DMF
(5 ml). The reaction mixture was refluxed for 2 h. After
cooling, the reaction mixture was diluted with 10%
aqueous NH3 solution (50 ml). The precipitate that formed
was filtered off, washed with MeOH (5 ml), and recrystal-
lized from a mixture of DMF (5 ml) and MeOH (20 ml).
Compounds 21a–o were obtained as white solids.
2-(4-Ethylphenyl)-7-(3-fluorophenyl)imidazo[1,2-a]-
pyrazin-8(7H)-one (21a). Yield 0.28 g (85%). Mp >300°C.
1H NMR spectrum, δ, ppm (J, Hz): 1.22 (3H, t, J = 7.7,
CH3CH2); 2.62 (2H, q, J = 7.7, CH3CH2); 7.14 (1H, d,
J = 4.0, H-5); 7.20–7.66 (7H, m, H-6, H Ar1, H Ar2); 7.84
(2H, d, J = 7.8, H Ar2); 8.26 (1H, s, H-3). 13C NMR
spectrum, δ, ppm (J, Hz): 15.5 (CH3); 28.0 (CH2); 107.4;
113.1; 114.3–115.2 (2C, m); 121.1; 123.1; 125.4 (2C);
128.2 (2C); 130.6; 130.8 (d, JCF = 9.0, C Ar1); 137.2; 141.2
(d, JCF = 9.0, C Ar1); 143.6; 144.3; 152.3; 161.8 (d, JCF = 245.0,
C-3 Ar1). Found, %: C 71.89; H 4.89; N 12.58.
C20H16FN3O. Calculated, %: C 72.06; H 4.84; N 12.61.
2-(4-Ethoxyphenyl)-7-(3-fluorophenyl)imidazo[1,2-a]-
pyrazin-8(7H)-one (21b). Yield 0.29 g (82%). Mp >300°C.
1H NMR spectrum, δ, ppm (J, Hz): 1.30 (3H, t, J = 7.7,
CH3CH2); 4.00 (2H, q, J = 7.7, CH3CH2); 6.98 (2H, d,
J = 7.8, H Ar2); 7.18 (1H, d, J = 4.0, H-5); 7.40–7.64 (5H,
m, H-6, H Ar1); 7.82 (2H, d, J = 7.8, H Ar2); 8.18 (1H, s,
H-3). 13C NMR spectrum, δ, ppm (J, Hz): 14.7 (CH3CH2);
63.1 (OCH2); 107.4; 112.7; 114.3–115.2 (4C, m); 121.2;
123.0; 125.6; 126.7 (2C); 130.7 (d, JCF = 9.0, C Ar1); 137.3;
141.2 (d, JCF = 9.0, C Ar1); 144.3; 152.4; 158.4; 161.8 (d,
2-(4-Ethoxyphenyl)-7-(4-methoxyphenyl)imidazo[1,2-a]-
pyrazin-8(7H)-one (21f). Yield 0.29 g (81%). Mp >300°C.
1H NMR spectrum, δ, ppm (J, Hz): 1.30 (3H, t, J = 7.7,
CH3CH2); 3.78 (3H, s, OCH3); 4.00 (2H, q, J = 7.7,
CH3CH2); 6.98 (2H, d, J = 7.8, H Ar2); 7.03–7.14 (3H, m,
H-5, Ar1); 7.36 (2H, d, J = 7.8, H Ar1); 7.57 (1H, d, J = 4.0,
H-6); 7.82 (2H, d, J = 7.8, H Ar2); 8.15 (1H, s, H-3).
13C NMR spectrum, δ, ppm: 14.7 (CH3CH2); 55.5 (OCH3);
63.1 (OCH2); 107.1; 112.6; 114.3 (2C); 114.7 (2C); 121.8;
125.6; 126.7 (2C); 128.0 (2C); 132.8; 137.1; 144.4; 152.4;
158.4; 158.8. Found, %: C 70.01; H 5.25; N 11.55.
C21H19N3O3. Calculated, %: C 69.79; H 5.30; N 11.63.
2-(3,4-Dimethoxyphenyl)-7-(4-methoxyphenyl)imidazo-
[1,2-a]pyrazin-8(7H)-one (21g). Yield 0.32 g (85%).
1
Mp >300°C. H NMR spectrum, δ, ppm (J, Hz): 3.78 (3H,
s, OCH3); 3.80 (3H, s, OCH3); 3.84 (3H, s, OCH3); 7.02–
7.12 (4H, m, H Ar); 7.38 (2H, d, J = 7.8, H Ar1); 7.47 (1H,
d, J = 7.9, H-6 Ar2); 7.53 (1H, s, H-2 Ar2); 7.58 (1H, d,
J = 4.0, H-6); 8.18 (1H, s, H-3). 13C NMR spectrum,
δ, ppm: 55.6 (OCH3); 55.9 (2OCH3); 107.0; 109.9; 112.8
(2C); 114.5 (2C); 118.2; 121.6; 126.3; 128.0 (2C); 132.8;
137.1; 144.5; 149.2; 149.4; 152.7; 158.9. Found, %:
C 67.12; H 5.12; N 11.04. C21H19N3O4. Calculated, %:
C 66.83; H 5.07; N 11.13.
2-(4-Chlorophenyl)-7-(4-methoxyphenyl)imidazo[1,2-a]-
pyrazin-8(7H)-one (21h). Yield 0.31 g (87%). Mp >300°C.
1H NMR spectrum, δ, ppm (J, Hz): 3.78 (3H, s, 4-OCH3);
7.06 (2H, d, J = 7.8, H Ar1); 7.13 (1H, d, J = 4.0, H-5);
7.38 (2H, d, J = 7.8, H Ar1); 7.48 (2H, d, J = 8.0, H Ar2);
7.62 (1H, d, J = 4.0, H-6); 7.96 (2H, d, J = 8.0, H Ar2);
8.35 (1H, s, H-3). 13C NMR spectrum, δ, ppm: 55.5
(OCH3); 107.0; 114.0; 114.3 (2C); 121.8; 127.1 (2C); 128.0
(2C); 128.9 (2C); 132.0; 132.3; 132.8; 137.1; 144.6; 152.6;
158.8. Found, %: C 65.09; H 4.07; N 11.84. C19H14ClN3O2.
Calculated, %: C 64.87; H 4.01; N 11.94.
7-(4-Chlorophenyl)-2-(4-ethylphenyl)imidazo[1,2-a]-
pyrazin-8(7H)-one (21i). Yield 0.30 g (87%). Mp >300°C.
1H NMR spectrum, δ, ppm (J, Hz): 1.22 (3H, t, J = 7.7,
CH3CH2); 2.62 (2H, q, J = 7.7, CH3CH2); 7.16 (1H, d,
J = 4.0, H-5); 7.26 (2H, d, J = 7.8, H Ar2); 7.52–7.64 (5H,
m, H-6, H Ar1); 7.84 (2H, d, J = 7.8, H Ar2); 8.24 (1H, s, H-3).
13C NMR spectrum, δ, ppm: 15.3 (CH3); 27.9 (CH2); 107.4;
113.3; 121.0; 125.5 (2C); 128.1 (2C); 128.8 (2C); 129.1
J
CF = 245.0, C-3 Ar1). Found, %: C 68.96; H 4.66; N 11.86.
C20H16FN3O2. Calculated, %: C 68.76; H 4.62; N 12.03.
2-(3,4-Dimethoxyphenyl)-7-(3-fluorophenyl)imidazo-
[1,2-a]pyrazin-8(7H)-one (21c). Yield 0.31 g (85%).
1
Mp >300°C. H NMR spectrum, δ, ppm (J, Hz): 3.78 (3H,
s, OCH3); 3.84 (3H, s, OCH3); 7.02 (1H, d, J = 7.8, H-5
Ar2); 7.16 (1H, d, J = 4.0, H-5); 7.28–7.68 (7H, m, H Ar);
8.25 (1H, s, H-3). 13C NMR spectrum, δ, ppm (J, Hz): 55.6
(2OCH3); 107.4; 109.0; 112.2; 113.1; 114.5–115.3 (2C, m);
117.9; 121.0; 123.2; 125.9; 130.8 (d, JCF = 9.0, C Ar1);
136.8; 141.1 (d, JCF = 10.0, C Ar1); 144.5; 148.9; 149.1;
152.3; 161.8 (d, JCF = 245.0, C-3 Ar1). Found, %: C 65.92;
H 4.47; N 11.38. C20H16FN3O3. Calculated, %: C 65.75;
H 4.41; N 11.50.
2-(4-Chlorophenyl)-7-(3-fluorophenyl)imidazo[1,2-a]-
pyrazin-8(7H)-one (21d). Yield 0.29 g (84%). Mp >300°C.
1H NMR spectrum, δ, ppm (J, Hz): 7.22 (1H, d, J = 4.0, H-5);
7.26–7.66 (7H, m, H Ar1); 7.96 (2H, d, J = 8.0, H Ar2);
8.35 (1H, s, H-3). 13C NMR spectrum, δ, ppm (J, Hz):
107.4; 114.1; 114.3–115.2 (m, 2C Ar1); 121.2; 123.0; 127.2
(2C); 128.8 (2C); 130.7 (d, JCF = 9, C Ar1); 132.1; 132.5;
390

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 386–391
(2C); 130.6; 132.7; 136.9; 138.6; 143.6; 144.6; 152.4.
2-(4-Chlorophenyl)-7-(3,5-dimethylphenyl)imidazo-
Found, %: C 68.46; H 4.54; N 11.93. C20H16ClN3O.
Calculated, %: C 68.67; H 4.61; N 12.01.
[1,2-a]pyrazin-8(7H)-one (21o). Yield 0.29 g (84%).
1
Mp >300°C. H NMR spectrum, δ, ppm (J, Hz): 2.28 (6H,
7-(4-Chlorophenyl)-2-(4-ethoxyphenyl)imidazo[1,2-a]-
pyrazin-8(7H)-one (21j). Yield 0.31 g (86%). Mp >300°C.
1H NMR spectrum, δ, ppm (J, Hz): 1.30 (3H, t, J = 7.7,
CH3CH2); 4.00 (2H, q, J = 7.7, CH3CH2); 6.98 (2H, d,
J = 7.8, H Ar2); 7.16 (1H, d, J = 4.0, H-5); 7.52–7.64 (5H,
m, H-6, H Ar1); 7.82 (2H, d, J = 7.8, H Ar2); 8.18 (1H, s,
H-3). 13C NMR spectrum, δ, ppm: 14.7 (CH3CH2); 63.1
(OCH2); 107.4; 112.6; 114.7 (2C); 121.0; 125.6; 126.7
(2C); 128.8 (2C); 129.1 (2C); 132.7; 136.9; 138.6; 144.7;
152.4; 158.4. Found, %: C 65.46; H 4.54; N 11.62.
C20H16ClN3O2. Calculated, %: C 65.67; H 4.41; N 11.49.
7-(4-Chlorophenyl)-2-(3,4-dimethoxyphenyl)imidazo-
[1,2-a]pyrazin-8(7H)-one (21k). Yield 0.32 g (84%).
s, 2CH3); 7.02–7.15 (4H, m, H-5, H Ar1); 7.48 (2H, d, J = 8.0,
H Ar2); 7.62 (1H, d, J = 4.0, H-6); 7.96 (2H, d, J = 8.0,
H Ar2); 8.35 (1H, s, H-3). 13C NMR spectrum, δ, ppm: 20.8
(2CH3); 107.1; 114.0; 121.7; 124.5 (2C); 127.1 (2C); 128.9
(2C); 129.6; 132.0; 132.3; 137.4; 138.5 (2C); 139.6; 143.0;
152.5. Found, %: C 68.83; H 4.66; N 11.89. C20H16ClN3O.
Calculated, %: C 68.67; H 4.61; N 12.01.
References
1. Plouvier, B. M. C.; Fedida, D.; Beatch, G. N.; Chou, D. T. H.;
Yifru, A. S.; Jung, G. WO Patent 2005034837.
2. Goodacre, S. C.; Hallett, D. J.; Carling, R. W.; Castro, J. L.;
Reynolds, D. S.; Pike, A.; Wafford, K. A.; Newman, R.;
Atack, J. R.; Street L. J. Bioorg. Med. Chem. Lett. 2006, 16,
1582.
3. Breinlinger, E. C.; Calderwood, D. J.; Frank, K. E.;
Betschmann, P.; Hirst, G. C.; Morytko, M. J.; Dixon, R. W.
WO Patent 2007028051.
4. Baerfacker, L.; Scott, W.; Hägebarth, A.; Ince, S.; Rehwinkel, H.;
Politz, O.; Neuhaus, R.; Bömer, U. WO Patent 2013104610.
5. Allen, S.; Andrews, S. W.; Blake, J. F.; Brandhuber, B. J.;
Jiang, Y.; Kercher, T.; Winski, S. L. WO Patent 2014078372.
6. Bonafoux, D.; Davis, H. M.; Frank, K. E.; Friedman, M. M.;
Herold, J. M.; Hoemann, M. Z.; Huntley, R.; Osuma, A.;
Sheppard, G.; Somal, G. K.; Van Camp, J.; Van Epps, S. A.;
Vasudevan, A.; Wallace, G. A.; Wang, L.; Wang, L.; Wang, Z.;
Wilson, N. S.; Xu, X. WO Patent 2014210255.
7. Du, X.; Gustin, D. J.; Chen, X.; Duquette, J.; McGee, L. R.;
Wang, Z.; Ebsworth, K.; Henne, K.; Lemon, B.; Ma, J.; Miao, S.;
Sabalan, E.; Sullivan, T. J.; Tonn, G.; Collins, T. L.;
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Patent 2016176457.
1
Mp >300°C. H NMR spectrum, δ, ppm (J, Hz): 3.78 (3H,
s, OCH3); 3.84 (3H, s, OCH3); 7.02 (1H, d, J = 7.8, H-5
Ar2); 7.12 (1H, d, J = 4.0, H-5); 7.44–7.66 (7H, m, H Ar);
8.20 (1H, s, H-3). 13C NMR spectrum, δ, ppm: 55.9
(2OCH3); 107.4; 109.9; 112.8; 113.0; 118.2; 120.9; 126.3;
128.8 (2C); 129.1 (2C); 132.7; 136.9; 138.6; 144.7; 149.2;
149.4; 152.4. Found, %: C 63.14; H 4.18; N 10.86.
C20H16ClN3O3. Calculated, %: C 62.91; H 4.22; N 11.01.
7-(3,5-Dimethylphenyl)-2-(4-ethylphenyl)imidazo[1,2-a]-
pyrazin-8(7H)-one (21l). Yield 0.28 g (82%). Mp 290–
1
293°C. H NMR spectrum, δ, ppm (J, Hz): 1.22 (3H, t,
J = 7.7, CH3CH2); 2.28 (6H, s, 2CH3); 2.62 (2H, q, J = 7.7,
CH3CH2); 7.03–7.14 (4H, m, H-5, H Ar1); 7.24 (2H, d,
J = 7.8, H Ar2); 7.59 (1H, d, J = 4.0, H-6); 7.82 (2H, d,
J = 7.8, H Ar2); 8.24 (1H, s, H-3). 13C NMR spectrum,
δ, ppm: 15.5 (CH3CH2); 20.8 (2CH3); 28.0 (CH2); 107.1;
113.2; 121.5; 124.5 (2C); 125.4 (2C); 128.2 (2C); 129.6;
130.6; 137.1; 138.5 (2C); 139.7; 143.5; 144.4; 152.5.
Found, %: C 76.72; H 6.08; N 12.33. C22H21N3O. Calcu-
lated, %: C 76.94; H 6.16; N 12.24.
9. Bartolomé-Nebreda, J. M.; Conde-Ceide, S.; Macdonald, G. J.;
Pastor-Fernández, J.; Van Gool, M. L. M.; Martín-Martín, M. L.;
Vanhoof, G. C. P. WO Patent 2011110545.
7-(3,5-Dimethylphenyl)-2-(4-ethoxyphenyl)imidazo-
[1,2-a]pyrazin-8(7H)-one (21m). Yield 0.30 g (83%).
10. Bartolomé-Nebreda, J. M.; Delgado, F.; Martín-Martín, M. L.;
Martínez-Viturro, C. M.; Pastor, J.; Tong, H. M.; Iturrino, L.;
Macdonald, G. J.; Sanderson, W.; Megens, A.; Langlois, X.;
Somers, M.; Vanhoof, G.; Conde-Ceide, S. J. Med. Chem.
2014, 57, 4196.
1
Mp 287–289°C. H NMR spectrum, δ, ppm (J, Hz): 1.30
(3H, t, J = 7.7, CH3CH2); 2.28 (6H, s, 2CH3); 4.00 (2H, q,
J = 7.7, CH3CH2); 6.98 (2H, d, J = 7.8, H Ar2); 7.03–7.14
(4H, m, H-5, H Ar1); 7.57 (1H, d, J = 4.0, H-6); 7.82 (2H,
d, J = 7.8, H Ar2); 8.18 (1H, s, H-3). 13C NMR spectrum,
δ, ppm: 14.7 (CH3CH2); 20.8 (2CH3); 63.1 (OCH2); 107.1;
112.6; 114.7 (2C); 121.4; 124.5 (2C); 125.6; 126.7 (2C);
129.6; 137.0; 138.5 (2C); 139.7; 144.3; 152.4; 158.4.
Found, %: C 73.66; H 6.00; N 11.53. C22H21N3O2. Calcu-
lated, %: C 73.52; H 5.89; N 11.69.
11. Fukaya, T.; Masumoto, H.; Tsuda, Y. Jpn. Kokai Tokkyo
Koho 2013166727.
12. Yamamoto, K.; Tamura, T.; Nakamura, R.; Ueno, K.; Hosoe, S.
WO Patent 2013018899.
13. Raubo, P.; Ladwa, N. Synlett 2012, 2935.
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US Patent 20100160303.
15. Krapcho, A. P.; Maresch, M. J.; Gallagher, C. E.; Hacker, M. P.;
Menta, E.; Oliva, A.; Di Domenico, R.; Spinelli, G. Da Re, S.
J. Heterocycl. Chem. 1995, 32, 1693.
2-(3,4-Dimethoxyphenyl)-7-(3,5-dimethylphenyl)-
imidazo[1,2-a]pyrazin-8(7H)-one (21n). Yield 0.30 g
(81%). Mp 304–306°C. 1H NMR spectrum, δ, ppm (J, Hz):
2.28 (6H, s, 2CH3); 3.78 (3H, s, OCH3); 3.84 (3H, s, OCH3);
7.02–7.15 (5H, m, H Ar); 7.47 (1H, d, J = 7.9, H-6 Ar2);
7.54 (1H, s, H-2 Ar2); 7.58 (1H, d, J = 4.0, H-6); 8.18 (1H,
s, H-3). 13C NMR spectrum, δ, ppm: 20.7 (2CH3); 55.9
(2OCH3); 107.0; 109.9; 112.9 (2C); 118.2; 121.3; 124.4
(2C); 126.3; 129.5; 137.1; 138.5 (2C); 139.9; 144.6; 149.2;
149.4; 152.4. Found, %: C 70.11; H 5.56; N 11.05.
C22H21N3O3. Calculated, %: C 70.38; H 5.64; N 11.19.
16. Fleitz, F. J.; Lyle, T. A.; Zheng, N.; Armstrong, J. D.;
Volante, R. P. Synth. Commun. 2000, 30, 3171.
17. Kovalenko, S. S.; Kulikovska, K. Yu.; Drushlyak, O. G.;
Zhuravel, I. O.; Kovalenko, S. M.; Chernykh, V. P. Chem.
Heterocycl. Compd. 2014, 50, 1147. [Khim. Geterotsikl.
Soedin. 2014, 1243.]
18. Langer, P.; Schroeder, R. Eur. J. Org. Chem. 2004, 1025.
19. Heorhiyants, V. A.; Shin'ova, N. V.; Perekhoda, L. O.; Sich, I. A.
Med. Khim. 2007, 9(2), 82.
20. Shynyova, N. V. Theses Dr. Sci. (Pharm.); Kharkiv, 2009.
391