Synthesis of some 2,3,6,8-tetraarylimidazo[1,2-a]pyrazine derivatives by using either reflux or microwave irradiation method, and investigation their anticancer activities

Article abstract of DOI:10.3906/kim-1005-649

In this study, some 2,3,6,8-tetraarylimidazo[1,2-a]pyrazine derivatives were synthesized by reacting 1-(2-aryl-2-oxoethyl)-2-aryloyl-4,5- diarylimidazoles from 2-aryloyl-4,5-diarylimidazole and 2-bromoacetophenone derivatives with ammonium acetate in acetic acid by using the method that was previously developed and repeatedly tested in our studies. Structural elucidation of the compounds was performed by IR, ¹H-NMR, and MASS spectroscopic data and elemental analysis results. Anticancer activities of selected compounds were evaluated and the noticeable activity values were reported.

Full text of DOI:10.3906/kim-1005-649

Turk J Chem
35 (2011) , 13 – 24.
¨
˙
c
ꢀ TUBITAK
doi:10.3906/kim-1005-649
Synthesis of some 2,3,6,8-tetraarylimidazo[1,2-a]pyrazine
derivatives by using either reflux or microwave
irradiation method, and investigation their anticancer
activities
1,∗
2
˙
˘ ˙
˙
Ismail KAYAGIL and S¸eref DEMIRAYAK
1Department of Chemistry, Faculty of Arts & Science, Mehmet Akif Ersoy University,
15030, Burdur-TURKEY
e-mail: ikayagil@mehmetakif.edu.tr
2
˙
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Istanbul Medipol University,
˙
34083, Istanbul-TURKEY
Received 04.06.2010
In this study, some 2,3,6,8-tetraarylimidazo[1,2-a]pyrazine derivatives were synthesized by reacting 1-(2-
aryl-2-oxoethyl)-2-aryloyl-4,5-diarylimidazoles from 2-aryloyl-4,5-diarylimidazole and 2-bromoacetophenone
derivatives with ammonium acetate in acetic acid by using the method that was previously developed and
repeatedly tested in our studies. Structural elucidation of the compounds was performed by IR, 1 H-NMR,
and MASS spectroscopic data and elemental analysis results. Anticancer activities of selected compounds
were evaluated and the noticeable activity values were reported.
Key Words: Substituted imidazoles, imidazo[1,2-a]pyrazines, microwave irradiation, anticancer activity
Introduction
Cancer is the biggest health hazard and the most frightening disease for the world. In the course of identifying
numerous chemical substances that may serve as leads for designing novel antitumor agents,1 we were especially
interested in the present work, as in some our previous publications, with substituted imidazo[1,2-a]pyrazines.2
The importance of imidazo[1,2-a]pyrazines stems especially from their remarkable anticancer and antimi-
crobial activities, besides antihypertensive,3−7 antibronchospastic, and inotropic activities on the cardiovascular
∗Corresponding author
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Synthesis of some 2,3,6,8-tetraarylimidazo[1,2-a]pyrazine derivatives..., I. KAYAGIL, S¸. DEMIRAYAK
system.8−11 The great attention paid to these structures can be attributed to the fact that the chemilumi-
nescent compounds, such as luciferin from some Cypridina, Renilla, Oplophorus, and Watasenia species, are
imidazo[1,2-a]pyrazine derivatives.12−14
Motivated by the above observations and as an extension of our previous work on imidazo[1,2-a]pyrazine
and pyrazino[1,2-a]benzimidazoles, which show notable anticancer activities, especially on leukemia,2,15 we
report here on the synthesis and anticancer activity testing of some 2,3,6,8-tetraarylimidazo[1,2-a]pyrazine
derivatives.
Three general synthetic methods used for the formation of imidazo[1,2-a]pyrazine ring systems in the lit-
erature and a fourth method developed by us were summarized in our previous study.2 The first method involves
the reactions between 2-aminopyrazine and α-functional carbonyl compounds. In the second method, the inter-
mediate compounds obtained from 2-halopyrazine and an aminoethanol were first oxidized to give α-(pyrazine-
2-ylamino)ethanone. The ring closure was then achieved. In the third method, 2-(aminomethyl)imidazoles were
reacted with α-halocarbonyl compounds. In the fourth method, 2-aryloylimidazole derivatives were reacted
with 2-bromoacetophenones to give 1-(2-aryl-2-oxoethyl)-2-aryloylimidazoles. These diketo compounds were
reacted with ammonium acetate in acetic acid to obtain 6,8-diarylimidazo[1,2-a]pyrazines.
NH2
O
X
H
N
H
N
N
N
+
N
OH
O
[Ox]
N
N
N
1. Route
2. Route
N
N
N
N
3. Route
4. Route
O
X
N
+
N
+
O
CH3COONH4
N
NH2
O
H
Figure 1. Synthesis of imidazo[1,2-a]pyrazine reported in the literature.
The synthetic studies were performed under green chemistry conditions using a microwave irradiation
reaction apparatus and a minimum amount of solvent, in addition to the conventional reflux method.
Experimental
Chemistry
Microwave-irradiated reactions were performed using a Milestone MicroSYNTH apparatus. Melting points were
determined using an Electrothermal 9100 digital melting point apparatus and are uncorrected. Spectroscopic
data were recorded on the following instruments: IR, Shimadzu 8400 FTIR spectrophotometer; 1 H-NMR,
Bruker DPX 400 MHz and Bruker 500 MHz NMR spectrometers; MASS, Agilent 1100 MSD mass spectrometer.
Analyses for C, H, and N were within 0.4% of the theoretical values. The benzil, 4,5-diarylimidazole, and
14

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Synthesis of some 2,3,6,8-tetraarylimidazo[1,2-a]pyrazine derivatives..., I. KAYAGIL, S¸. DEMIRAYAK
2-bromoacetophenone derivatives used as starting materials were prepared according to the methods in the
literature.16−18
General procedure for the synthesis of 2-aryloyl-4,5-diarylimidazoles (IIa−l
)
A suitable 4,5-diarylimidazole (100 mmol) was completely dissolved in pyridine (30 mL), then added to tri-
ethylamine (28.4 mL). A suitable benzoylchloride (200 mmol) was gently and slowly dropped into the reaction
medium while the solution was stirred in an ice bath under atmosphere with nitrogen gas. The mixture was
then stirred at room temperature without a nitrogen atmosphere for 24 h. A NaOH solution (7.5 N, 6 g NaOH,
and 20 mL water) was added to the mixture and refluxed for 1 h. The reaction medium was poured into ice
water and kept in a refrigerator for 48 h. The residue was filtered and washed with water. The raw product
was recrystallized from ethanol.
2-(4-Methoxybenzoyl)-4,5-diphenylimidazole (IIb ): This compound was prepared according to
the general procedure above, in a yield of 85%, IR (potassium bromide): 1638 (C=O), 1597-1450 (C=C, C=N)
;
cm−1 1 H-NMR (DMSO-d6)δ (ppm): 3.83 (s, 3H), 7.21-7.43 (m, 10H), 7.49 (d, J = 8.60 Hz, 2H), 7.80 (d, J
= 7.46 Hz, 2H), 12.51 (s, 1H).
2-Benzoyl-4,5-di(4-methylphenyl)imidazole (IId ): This compound was prepared according to the
general procedure above, in a yield of 86%, IR (potassium bromide): 1642 (C=O), 1595-1448 (C=C, C=N)
;
cm−1 1 H-NMR (DMSO-d6)δ (ppm): 2.34 (s, 6H), 7.22 (d, J = 7.91 Hz, 4H), 7.36 (d, J = 8.12 Hz, 2H), 7.40
(d, J = 8.11 Hz, 2H), 7.61-7.71 (m, 3H), 8.53 (d, J = 7.56 Hz, 2H), 13.73 (s, 1H).
2-(4-Chlorobenzoyl)-4,5-di(4-methylphenyl)imidazole (IIf ): This compound was prepared ac-
cording to the general procedure above, in a yield of 87%, IR (potassium bromide): 1638 (C=O), 1598-1448
;
(C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δ (ppm): 2.35 (s, 6H), 7.14-7.22 (m, 4H), 7.36 (d, J = 8.44 Hz, 2H),
7.41 (d, J = 8.36 Hz, 2H), 7.68 (d, J = 8.59 Hz, 2H), 8.58 (d, J = 7.64 Hz, 2H), 13.81 (s, 1H).
2-(4-methoxybenzoyl)-4,5-di(4-chlorophenyl)imidazole (IIk ): This compound was prepared ac-
cording to the general procedure above, in a yield of 84%, IR (potassium bromide): 1636 (C=O), 1595-1446
(C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δ (ppm): 3.84 (s, 3H), 7.14-7.23 (m, 4H), 7.53 (d, J = 8.54 Hz, 2H),
;
7.62-7.71 (m, 4H), 8.52 (d, J = 7.61 Hz, 2H), 13.94 (s, 1H).
General procedure for the synthesis of 1-(2-aryl-2-oxoethyl)-2-aryloyl-4,5-diarylimidazoles
(1-36)
A mixture of suitable 2-aryloyl-4,5-diarylimidazole (5 mmol), ω-bromoacetophenone (5 mmol), and
potassium carbonate (5 mmol) in acetone (50 mL) was stirred at room temperature. Stirring was continued
at room temperature until the disappearance of the starting material (4-6 h, TLC analyses). The solvent was
evaporated under a vacuum. The residue was washed with water and then ethanol. The raw product was
recrystallized from ethanol.2
1-(2-Phenyl-2-oxoethyl)-2-benzoyl-4,5-diphenylimidazole (1): This compound was prepared ac-
cording to the general procedure above, in a yield of 89%, IR (potassium bromide): 1697, 1630 (C=O), 1597-1452
;
(C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δ (ppm): 5.73 (s, 2H), 7.24-7.31 (m, 3H), 7.37-7.39 (m, 2H), 7.46
(d, J = 7.09 Hz, 2H), 7.53-7.61 (m, 7H), 7.67-7.75 (m, 2H), 8.04 (d, J = 7.31 Hz, 2H), 8.36 (d, J = 7.25 Hz,
2H).
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Synthesis of some 2,3,6,8-tetraarylimidazo[1,2-a]pyrazine derivatives..., I. KAYAGIL, S¸. DEMIRAYAK
1-(2-(4-Methoxyphenyl)-2-oxoethyl)-2-benzoyl-4,5-diphenylimidazole (2): This compound was
prepared according to the general procedure above, in a yield of 88%, IR (potassium bromide): 1698, 1632
;
(C=O), 1595-1449 (C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δ (ppm): 3.87 (s, 3H), 5.69 (s, 2H), 7.09 (d, J =
8.91 Hz, 2H), 7.23-7.26 (m, 1H), 7.28-7.31 (m, 2H), 7.36-7.38 (m, 2H), 7.46 (d, J = 7.16 Hz, 2H), 7.52-7.55 (m,
3H), 7.58-7.61 (m, 2H), 7.68-7.71 (m, 1H), 8.01 (d, J = 7.04 Hz, 2H), 8.35 (d, J = 7.15 Hz, 2H).
1-(2-(4-Chlorophenyl)-2-oxoethyl)-2-benzoyl-4,5-diphenylimidazole (3): This compound was
prepared according to the general procedure above, in a yield of 87%, IR (potassium bromide): 1697, 1639
(C=O), 1597-1452 (C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δ (ppm): 5.72 (s, 2H), 7.23-7.31 (m, 3H), 7.38-
;
7.39 (m, 2H), 7.46 (d, J = 7.07 Hz, 2H), 7.53-7.61 (m, 5H), 7.65-7.71 (m, 3H), 8.06 (d, J = 8.63 Hz, 2H), 8.35
(d, J = 7.13 Hz, 2H).
1-(2-Phenyl-2-oxoethyl)-2-(4-chlorobenzoyl)-4,5-diphenylimidazole (7): This compound was
prepared according to the general procedure above, in a yield of 89%, IR (potassium bromide): 1699, 1634
;
(C=O), 1596-1448 (C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δ (ppm): 5.74 (s, 2H), 7.25-7.32 (m, 3H), 7.36-
7.38 (m, 2H), 7.46 (d, J = 7.05 Hz, 2H), 7.53-7.60 (m, 5H), 7.67 (d, J = 8.60 Hz, 2H), 7.71-7.73 (m, 1H), 8.03
(d, J = 8.12 Hz, 2H), 8.40 (d, J = 8.59 Hz, 2H).
1-(2-(4-Methoxyphenyl)-2-oxoethyl)-2-(4-chlorobenzoyl)-4,5-diphenylimidazole (8): This com-
pound was prepared according to the general procedure above, in a yield of 84%, IR (potassium bromide): 1698,
;
1635 (C=O), 1596-1449 (C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δ (ppm): 3.86 (s, 3H), 5.66 (s, 2H), 7.09 (d,
J = 8.93 Hz, 2H), 7.23-7.31 (m, 3H), 7.34-7.36 (m, 2H), 7.45 (d, J = 7.06 Hz, 2H), 7.52-7.55 (m, 3H), 7.67 (d,
J = 8.62 Hz, 2H), 8.00 (d, J = 8.90 Hz, 2H), 8.38 (d, J = 8.63 Hz, 2H).
1-(2-Phenyl-2-oxoethyl)-2-benzoyl-4,5-di(4-methylphenyl)imidazole (10): This compound was
prepared according to the general procedure above, in a yield of 88%, IR (potassium bromide): 1701, 1637
;
(C=O), 1595-1454 (C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δ (ppm): 2.27 (s, 3H), 2.36 (s, 3H), 5.72 (s, 2H),
7.11 (d, J = 8.09 Hz, 2H), 7.24 (d, J = 8.02 Hz, 2H), 7.33 (d, J = 8.19 Hz, 2H), 7.36 (d, J = 8.18 Hz, 2H),
7.56-7.60 (m, 4H), 7.66-7.75 (m, 2H), 8.04 (d, J = 7.28 Hz, 2H), 8.34 (d, J = 7.16 Hz, 2H).
1-(2-Phenyl-2-oxoethyl)-2-(4-chlorobenzoyl)-4,5-di(4-methylphenyl)imidazole (16): This com-
pound was prepared according to the general procedure above, in a yield of 85%, IR (potassium bromide): 1699,
;
1634 (C=O), 1585-1448 (C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δ (ppm): 2.27 (s, 3H), 2.36 (s, 3H), 5.71 (s,
2H), 7.11 (d, J = 7.96 Hz, 2H), 7.23 (d, J = 8.02 Hz, 2H), 7.32-7.37 (m, 4H), 7.57-7.61 (m, 2H), 7.66 (d, J =
8.66 Hz, 2H), 7.72-7.73 (m, 1H), 8.04 (d, J = 7.29 Hz, 2H), 8.38 (d, J = 8.64 Hz, 2H).
1-(2-(4-Chlorophenyl)-2-oxoethyl)-2-(4-chlorobenzoyl)-4,5-di(4-methylphenyl)imidazole (18):
This compound was prepared according to the general procedure above, in a yield of 86%, IR (potassium bro-
;
mide): 1698, 1635 (C=O), 1589-1450 (C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δ (ppm): 3.73 (s, 3H), 3.79 (s,
3H), 5.68 (s, 2H), 6.88 (d, J = 8.91 Hz, 2H), 7.08 (d, J = 8.85 Hz, 2H), 7.26 (d, J = 8.67 Hz, 2H), 7.40 (d, J =
8.86 Hz, 2H), 7.64-7.68 (m, 4H), 8.06 (d, J = 8.62 Hz, 2H), 8.37 (d, J = 8.63 Hz, 2H).
1-(2-Phenyl-2-oxoethyl)-2-benzoyl-4,5-di(4-methoxyphenyl)imidazole (19): This compound
was prepared according to the general procedure above, in a yield of 87%, IR (potassium bromide): 1701,
;
1646 (C=O), 1571-1452 (C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δ (ppm): 3.73 (s, 3H), 3.79 (s, 3H), 5.70 (s,
2H), 6.88 (d, J = 8.62 Hz, 2H), 7.08 (d, J = 8.45 Hz, 2H), 7.28 (d, J = 8.46 Hz, 2H), 7.41 (d, J = 8.57 Hz, 2H),
7.56-7.61 (m, 4H), 7.66-7.73 (m, 2H), 8.05 (d, J = 7.88 Hz, 2H), 8.34 (d, J = 7.81 Hz, 2H).
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Synthesis of some 2,3,6,8-tetraarylimidazo[1,2-a]pyrazine derivatives..., I. KAYAGIL, S¸. DEMIRAYAK
1-(2-(4-Methoxyphenyl)-2-oxoethyl)-2-benzoyl-4,5-di(4-methoxyphenyl)imidazole (20): This
compound was prepared according to the general procedure above, in a yield of 88%, IR (potassium bromide):
;
1701, 1635 (C=O), 1587-1447 (C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δ (ppm): 3.72 (s, 3H), 3.78 (s, 3H),
3.86 (s, 3H), 5.66 (s, 2H), 6.87 (d, J = 8.85 Hz, 2H), 7.06-7.10 (m, 4H), 7.26 (d, J = 8.60 Hz, 2H), 7.39 (d, J =
8.81 Hz, 2H), 7.55-7.59 (m, 2H), 7.66-7.69 (m, 1H), 8.01 (d, J = 8.86 Hz, 2H), 8.32 (d, J = 7.27 Hz, 2H).
1-(2-(4-Chlorophenyl)-2-oxoethyl)-2-benzoyl-4,5-di(4-methoxyphenyl)imidazole (21): This
compound was prepared according to the general procedure above, in a yield of 84%, IR (potassium bromide):
1699, 1638 (C=O), 1585-1449 (C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δ (ppm): 3.73 (s, 3H), 3.80 (s, 3H),
;
5.68 (s, 2H), 6.88 (d, J = 8.88 Hz, 2H), 7.08 (d, J = 8.82 Hz, 2H), 7.27 (d, J = 8.66 Hz, 2H), 7.40 (d, J = 8.88
Hz, 2H), 7.56-7.59 (m, 2H), 7.66-7.69 (m, 3H), 8.07 (d, J = 8.60 Hz, 2H), 8.33 (d, J = 7.15 Hz, 2H).
1-(2-Phenyl-2-oxoethyl)-2-(4-chlorobenzoyl)-4,5-di(4-methoxyphenyl)imidazole (25): This
compound was prepared according to the general procedure above, in a yield of 85%, IR (potassium bro-
mide): 1695, 1651 (C=O), 1614-1448 (C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δ (ppm): 3.74 (s, 3H), 3.79 (s,
;
3H), 5.70 (s, 2H), 6.88 (d, J = 8.87 Hz, 2H), 7.08 (d, J = 8.78 Hz, 2H), 7.27 (d, J = 8.66 Hz, 2H), 7.41 (d, J =
8.81 Hz, 2H), 7.57-7.61 (m, 2H), 7.65 (d, J = 8.62 Hz, 2H), 7.72-7.75 (m, 1H), 8.04 (d, J = 7.27 Hz, 2H), 8.39
(d, J = 7.62 Hz, 2H).
1-(2-Phenyl-2-oxoethyl)-2-benzoyl-4,5-di(4-chlorophenyl)imidazole (28): This compound was
prepared according to the general procedure above, in a yield of 89%, IR (potassium bromide): 1705, 1638
;
(C=O), 1593-1454 (C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δ (ppm): 5.76 (s, 2H), 7.39-7.46 (m, 6H), 7.56-
7.62 (m, 6H), 7.67-7.74 (m, 2H), 8.04 (d, J = 8.12 Hz, 2H), 8.32 (d, J = 7.45 Hz, 2H).
1-(2-Phenyl-2-oxoethyl)-2-(4-chlorobenzoyl)-4,5-di(4-chlorophenyl)imidazole (34): This com-
pound was prepared according to the general procedure above, in a yield of 88%, IR (potassium bromide): 1695,
;
1642 (C=O), 1589-1444 (C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δ (ppm): 5.75 (s, 2H), 7.38-7.47 (m, 6H),
7.59-7.61 (m, 6H), 7.63-7.67 (m, 1H), 8.04 (d, 2H, J = 7.25 Hz), 8.36 (d, J = 8.66 Hz, 2H).
General procedure for the synthesis of 2,3,6,8-tetraarylimidazo[1,2-a]pyrazines
(37-72)
Method A
A mixture of suitable 1-36 (3 mmol) and ammonium acetate (30 mmol) in 50 mL of acetic acid was
refluxed for 3 h. The solution was cooled, poured into ice water, and neutralized with sodium carbonate. The
precipitate formed was filtered and crystallized in ethanol.2
Method B
A mixture of suitable 1-36 (1 mmol) and ammonium acetate (10 mmol) in 0.5 mL of acetic acid was
taken in a 25 mL Erlenmeyer flask covered with a watch glass. The mixture was irradiated at a power of 600
W in the MicroSYNTH oven for 1-2 min. The work-up was as described under Method A.
2,3,6,8-Tetraphenylimidazo[1,2-a]pyrazine (37): This compound was prepared according to the
general procedures above, in yields of 77% for Method A and 85% for Method B, IR (potassium bromide):
1601-1471 (C=C, C=N) cm−1
;
1 H-NMR (DMSO-d6)δ (ppm): 7.35-7.46 (m, 4H), 7.50-7.54 (m, 2H), 7.63-7.71
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Synthesis of some 2,3,6,8-tetraarylimidazo[1,2-a]pyrazine derivatives..., I. KAYAGIL, S¸. DEMIRAYAK
(m, 10H), 8.09 (d, J = 7.36 Hz, 2H), 8.38 (s, 1H), 9.02 (d, J = 7.08 Hz, 2H); ms: (35 eV, electron spray) m/z
424 (M+1, 100%), 425 (M+2, 29%), 426 (M+3, 4%).
2,3,8-Triphenyl-6-(4-methylphenyl)imidazo[1,2-a]pyrazine (38): This compound was prepared
according to the general procedures above, in yields of 79% for Method A and 86% for Method B, IR (potassium
;
bromide): 1602-1473 (C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δgppm): 3.82 (s, 3H), 7.07 (d, J = 8.87 Hz,
2H), 7.33-7.41 (m, 3H), 7.62-7.70 (m, 10H), 8.02 (d, J = 8.83 Hz, 2H), 8.28 (s, 1H), 9.00 (d, J = 7.17 Hz, 2H).
2,3,8-Triphenyl-6-(4-chlorophenyl)imidazo[1,2-a]pyrazine (39): This compound was prepared
according to the general procedures above, in yields of 77% for Method A and 87% for Method B, IR (potassium
;
bromide): 1601-1472 (C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δgppm): 7.37-7.41 (m, 3H), 7.60 (d, J = 8.61
Hz, 2H), 7.62-7.70 (m, 10H), 8.15 (d, J = 8.61 Hz, 2H), 8.44 (s, 1H), 9.01 (d, J = 7.10 Hz, 2H).
2,3,6-Triphenyl-8-(4-chlorophenyl)imidazo[1,2-a]pyrazine (43): This compound was prepared
according to the general procedures above, in yields of 78% for Method A and 86% for Method B, IR (potassium
;
bromide): 1600-1471 (C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δgppm): 7.36-7.46 (m, 4H), 7.50-7.54 (m, 2H),
7.67-7.70 (m, 7H), 7.76 (d, J = 8.53 Hz, 2H), 8.08 (d, J = 7.50 Hz, 2H), 8.39 (s, 1H), 9.09 (d, J = 8.47 Hz, 2H).
2,3-Diphenyl-6-(4-methoxyphenyl)-8-(4-chlorophenyl)imidazo[1,2-a]pyrazine (44): This com-
pound was prepared according to the general procedures above, in yields of 78% for Method A and 87% for
;
Method B, IR (potassium bromide): 1602-1473 (C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δgppm): 3.82 (s,
3H), 7.07 (d, J = 8.83 Hz, 2H), 7.36-7.41 (m, 3H), 7.64-7.70 (m, 7H), 7.75 (d, J = 8.66 Hz, 2H), 8.02 (d, J =
8.79 Hz, 2H), 8.30 (s, 1H), 9.08 (d, J = 8.67 Hz, 2H).
2,3-Diphenyl-6-(4-chlorophenyl)-8-(4-chlorophenyl)imidazo[1,2-a]pyrazine (45): This com-
pound was prepared according to the general procedures above, in yields of 79% for Method A and 91% for
;
Method B, IR (potassium bromide): 1601-1471 (C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δgppm): 7.36-7.41
(m, 3H), 7.57 (d, J = 8.58 Hz, 2H), 7.64-7.69 (m, 7H), 7.76 (d, J = 8.66 Hz, 2H), 8.14 (d, J = 8.58 Hz, 2H),
8.45 (s, 1H), 9.08 (d, J = 8.64 Hz, 2H).
2,3-Di(4-methylphenyl)-6,8-diphenylimidazo[1,2-a]pyrazine (46): This compound was prepared
according to the general procedures above, in yields of 77% for Method A and 85% for Method B, IR (potassium
;
bromide): 1602-1479 (C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δgppm): 2.32 (s, 3H), 2.48 (s, 3H), 7.21 (d, J
= 8.08 Hz, 2H), 7.43-7.69 (m, 12H), 8.08 (d, J = 7.37 Hz, 2H), 8.36 (s, 1H), 9.01 (d, J = 7.22 Hz, 2H).
2,3-Di(4-methylphenyl)-6-phenyl-8-(4-chlorophenyl)imidazo[1,2-a]pyrazine (52): This com-
pound was prepared according to the general procedures above, in yields of 79% for Method A and 88% for
Method B, IR (potassium bromide): 1599-1475 (C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δgppm): 2.32 (s,
;
3H), 2.48 (s, 3H), 7.21 (d, J = 8.02 Hz, 2H), 7.44-7.54 (m, 7H), 7.59 (d, J = 8.13 Hz, 2H), 7.75 (d, J = 8.71
Hz, 2H), 8.08 (d, J = 7.21 Hz, 2H), 8.38 (s, 1H), 9.08 (d, J = 8.71 Hz, 2H); ms: (35 eV, electron spray) m/z
486 (M+1, 100%), 487 (M+2, 35%), 488 (M+3, 32%), 489 (M+4, 14%).
2,3-Di(4-methoxyphenyl)-6,8-diphenylimidazo[1,2-a]pyrazine (55): This compound was pre-
pared according to the general procedures above, in yields of 76% for Method A and 85% for Method B,
;
IR (potassium bromide): 1608-1477 (C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δgppm): z.78 (s, 3H), 3.90 (s,
3H), 6.97 (d, J = 8.94 Hz, 2H), 7.22 (d, J = 8.79 Hz, 2H), 7.43-7.53 (m, 3H), 7.60 (d, J = 8.76 Hz, 2H), 7.61-7.69
(m, 5H), 8.08 (d, J = 7.18 Hz, 2H), 8.33 (s, 1H), 9.01 (d, J = 7.06 Hz, 2H); ms: (35 eV, electron spray) m/z
484 (M+1, 100%), 485 (M+2, 32%), 486 (M+3, 6%).
18

˙
˘ ˙
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Synthesis of some 2,3,6,8-tetraarylimidazo[1,2-a]pyrazine derivatives..., I. KAYAGIL, S¸. DEMIRAYAK
2,3,6-Tri(4-methoxyphenyl)-8-phenylimidazo[1,2-a]pyrazine (56): This compound was prepared
according to the general procedures above, in yields of 75% for Method A and 87% for Method B, IR (potassium
;
bromide): 1608-1477 (C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δgppm): z.77 (s, 3H), 3.82 (s, 3H), 3.90 (s,
3H), 6.97 (d, J = 8.87 Hz, 2H), 7.06 (d, J = 8.86 Hz, 2H), 7.22 (d, J = 8.72 Hz, 2H), 7.56 (d, J = 8.67 Hz, 2H),
7.61-7.68 (m, 5H), 8.01 (d, J = 8.81 Hz, 2H), 8.23 (s, 1H), 8.99 (d, J = 7.20 Hz, 2H).
2,3-Di(4-methoxyphenyl)-6-phenyl-8-(4-chlorophenyl)imidazo[1,2-a]pyrazine (61): This com-
pound was prepared according to the general procedures above, in yields of 79% for Method A and 91% for
;
Method B, IR (potassium bromide): 1608-1479 (C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δgppm): z.78 (s,
3H), 3.90 (s, 3H), 6.98 (d, J = 8.83 Hz, 2H), 7.23 (d, J = 8.67 Hz, 2H), 7.42-7.45 (m, 2H), 7.50-7.53 (m, 1H),
7.57 (d, J = 8.64 Hz, 2H), 7.66 (d, J = 8.78 Hz, 2H), 7.75 (d, J = 8.72 Hz, 2H), 8.08 (d, J = 7.29 Hz, 2H), 8.35
(s, 1H), 9.09 (d, J = 8.70 Hz, 2H).
2,3-Di(4-methoxyphenyl)-6-(4-methoxyphenyl)-8-(4-chlorophenyl)imidazo[1,2-a]pyrazine
(62): This compound was prepared according to the general procedures above, in yields of 74% for Method A
;
and 86% for Method B, IR (potassium bromide): 1606-1478 (C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δgppm):
z.77 (s, 3H), 3.81 (s, 3H), 3.90 (s, 3H), 6.95 (d, J = 8.86 Hz, 2H), 7.04 (d, J = 8.83 Hz, 2H), 7.21 (d, J = 8.69
Hz, 2H), 7.54 (d, J = 8.66 Hz, 2H), 7.63 (d, J = 8.82 Hz, 2H), 7.72 (d, J = 8.65 Hz, 2H), 7.99 (d, J = 8.78 Hz,
2H), 8.22 (s, 1H), 9.05 (d, J = 8.64 Hz, 2H).
2,3-Di(4-chlorophenyl)-6,8-diphenylimidazo[1,2-a]pyrazine (64): This compound was prepared
according to the general procedures above, in yields of 78% for Method A and 89% for Method B, IR (potassium
;
bromide): 1601-1471 (C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δgppm): 7.44-7.54 (m, 5H), 7.63-7.75 (m, 9H),
8.14 (d, J = 7.28 Hz, 2H), 8.46 (s, 1H), 8.99 (d, J = 7.06 Hz, 2H).
2,3-Di(4-chlorophenyl)-6-phenyl-8-(4-chlorophenyl)imidazo[1,2-a]pyrazine (70): This com-
pound was prepared according to the general procedures above, in yields of 78% for Method A and 88% for
;
Method B, IR (potassium bromide): 1598-1469 (C=C, C=N) cm−1 1 H-NMR (DMSO-d6)δgppm): 7.43-7.54
(m, 5H), 7.67-7.76 (m, 8H), 8.13 (d, J = 7.56 Hz, 2H), 8.47 (s, 1H), 9.06 (d, J = 8.51 Hz, 2H); ms: (35 eV,
electron spray) m/z 526 (M+1, 100%), 527 (M+2, 31%), 528 (M+3, 93%), 529 (M+4, 31%), 530 (M+5, 32%),
531 (M+6, 10%), 532 (M+7, 5%).
Anticancer activity tests
The cytotoxic and/or growth inhibitory effects of the compounds were evaluated in vitro against approximately
66 human tumor cell lines derived from 9 neoplastic diseases, namely leukemia (L), non-small cell lung cancer
(NSCLC), colon cancer (CC), central nervous system cancer (CNSC), melanoma (M), ovarian cancer (OC),
renal cancer (RC), prostate cancer (PC), and breast cancer (BC). The evaluation of anticancer activity was
performed at the National Cancer Institute (NCI) of Bethesda, USA, following the in vitro screening program,
which was based on the use of multiple panels of 66 human tumor cell lines against which our compounds
were tested at 10-fold dilutions of 5 concentrations, ranging from 10−4 to 10−8 M. The percentage growth
was evaluated spectrophotometrically versus controls not treated with test agents. A 48 h continuous drug
exposure protocol was followed and a sulforhodamine B (SRB) protein assay was used to estimate cell viability
of growth.19 Activity test results are given in Table 2.
19

˙
˘ ˙
˙
Synthesis of some 2,3,6,8-tetraarylimidazo[1,2-a]pyrazine derivatives..., I. KAYAGIL, S¸. DEMIRAYAK
Table 1. The synthesized compounds and their properties.
Comp.
IIa
R
H
R’
H
R”
Molecular Formula
C22H16N2O
MP (◦C)
Ref. 21∗
-
IIb
H
OCH3
Cl
-
C23H18N2O2
190-192
Ref. 21∗
IIc
H
-
C22H15ClN2O
IId
CH3
CH3
CH3
OCH3
H
-
C24H20N2O
212-213
IIe
OCH3
Cl
-
C25H22N2O2
252-253
IIf
-
C24H19ClN2O
238-239
Ref. 22∗
IIg
H
-
C24H20N2O3
IIh
OCH3 OCH3
-
C25H22N2O4
Ref. 22∗
Ref. 22∗
Ref. 23∗
IIi
OCH3
Cl
Cl
H
-
C24H19ClN2O3
IIj
-
C22H14Cl2N2O
IIk
Cl
OCH3
Cl
-
-
C23H16Cl2N2O2
215-216
IIl
Cl
C22H13Cl3N2O
260-261
1, 37
2, 38
3, 39
4, 40
5, 41
6, 42
7, 43
8, 44
9, 45
10, 46
11, 47
12, 48
13, 49
14, 50
15, 51
16, 52
17, 53
18, 54
H
H
H
C30H22N2O2, C30H21N3
C31H24N2O3, C31H23N3O
C30H21ClN2O2, C30H20ClN3
C31H24N2O3, C31H23N3O
C32H26N2O4, C32H25N3O2
152-153, 277-278
142-144, 260-261
146-148, 277-278
128-129, 258-261
149-150, 272-273
H
H
OCH3
Cl
H
H
H
OCH3
H
H
OCH3 OCH3
H
OCH3
Cl
Cl
H
C31H23ClN2O3, C31H22ClN3O 113-114, 251-252
C30H21ClN2O2, C30H20ClN3 156-158, 237-239
H
H
Cl
OCH3 C31H23ClN2O3, C31H22ClN3O 176-177, 248-249
H
Cl
Cl
H
C30H20Cl2N2O2, C30H19Cl2N3
C32H26N2O2, C32H25N3
178-179, >300
176-177, 260-261
201-202, 296-297
223-224, 283-284
160-162, 234-235
177-178, 268-270
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
OCH3
Cl
C33H28N2O3, C33H27N3O
C32H25ClN2O2, C32H24ClN3
C33H28N2O3, C33H27N3O
C34H30N2O4, C34H29N3O2
H
OCH3
H
OCH3 OCH3
OCH3
Cl
Cl
H
C33H27ClN2O3, C33H26ClN3O 156-157, 201-204
C32H25ClN2O2, C32H24ClN3 187-188, 210-212
Cl
OCH3 C33H27ClN2O3, C33H26ClN3O 161-163, 231-237
Cl
Cl
H
C32H24Cl2N2O2, C32H23Cl2N3 182-183, 272-273
19, 55 OCH3
20, 56 OCH3
21, 57 OCH3
H
C32H26N2O4, C32H25N3O2
C33H28N2O5, C33H27N3O3
191-193, 255-257
188-189, 255-256
H
OCH3
Cl
H
C32H25ClN2O4, C32H24ClN3O2 195-196, 244-245
22 ,58 OCH3 OCH3
H
C33H28N2O5, C33H27N3O3
C34H30N2O6, C34H29N3O4
189-190, >300
181-182, >300
23, 59 OCH3 OCH3 OCH3
24, 60 OCH3 OCH3
25, 61 OCH3 Cl
Cl
H
C33H27ClN2O5, C33H26ClN3O3 172-173, 263-265
C32H25ClN2O4, C32H24ClN3O2 162-164, 254-255
20

˙
˘ ˙
˙
Synthesis of some 2,3,6,8-tetraarylimidazo[1,2-a]pyrazine derivatives..., I. KAYAGIL, S¸. DEMIRAYAK
Table 1. Continued.
Comp.
R
R’
Cl
R”
OCH3
Cl
Molecular Formula
MP (◦C)
> 300, > 300
187-188, >300
182-184, 245-246
183-184, >300
225-226, >300
> 300, > 300
26, 62 OCH3
27, 63 OCH3
C33H27ClN2O5, C33H26ClN3O3
C32H24Cl2N2O4, C32H23Cl2N3O2
C30H20Cl2N2O2, C30H19Cl2N3
Cl
28, 64
29, 65
30, 66
31, 67
32, 68
33, 69
34, 70
35, 71
36, 72
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
H
H
OCH3 C31H22Cl2N2O3, C31H21Cl2N3O
H
Cl
H
C30H19Cl3N2O2, C30H18Cl3N3
C31H22Cl2N2O3, C31H21Cl2N3O
OCH3
OCH3 OCH3 C32H24Cl2N2O4, C32H23Cl2N3O2 155-156, 242-253
OCH3
Cl
Cl
H
C31H21Cl3N2O3, C31H20Cl3N3O 163-164, 286-287
C30H19Cl3N2O2, C30H18Cl3N3
212-213, 250-252
193-194, >300
> 300, > 300
Cl
OCH3 C31H21Cl3N2O3, C31H20Cl3N3O
Cl C30H18Cl4N2O2, C31H22ClN3O
Cl
∗ Only references were given, instead of melting points, for the compounds that were not original.
Table 2. Log10 GI50 values.
Compounds
L
NSCLC
-4.15
-4.07
-4.10
-4.08
-4.00
-4.10
-4.09
-4.00
-4.42
-5.17
-6.20
CC
CNSC
M
OC
RC
PC
BC
MG-MID
-4.10
-4.01
-4.02
-4.09
-4.01
-4.02
-4.08
-4.00
-4.42
-5.09
-6.20
11
12
19
20
21
34
55
64
70
A
-4.00
-4.00
-4.00
-4.00
-4.07
-4.00
-4.49
-4.00
-4.30
-5.48
-6.39
-4.00
-4.00
-4.00
-4.00
-4.00
-4.00
-4.00
-4.00
-4.30
-5.11
-6.14
-4.11 -4.00 -4.07 -4.31 -4.00 -4.10
-4.00 -4.00 -4.00 -4.00 -4.00 -4.00
-4.00 -4.00 -4.00 -4.00 -4.00 -4.00
-4.37 -4.02 -4.03 -4.17 -4.00 -4.08
-4.00 -4.00 -4.00 -4.00 -4.00 -4.01
-4.00 -4.00 -4.00 -4.00 -4.00 -4.00
-4.10 -4.01 -4.02 -4.07 -4.00 -4.10
-4.01 -4.00 -4.00 -4.00 -4.00 -4.00
-4.62 -4.37 -4.42 -4.44 -4.30 -4.51
-5.12 -5.08 -5.18 -4.99 -4.49 -4.79
-6.18 -6.08 -6.45 -6.17 -6.41 -6.05
B
A: Melphalan, B: Cisplatin
Results and discussion
Chemistry
In this study, the fourth method mentioned above was used for the formation of an imidazo[1,2-a]pyrazine
ring system. To obtain 4,5-diarylimidazoles, Ia−d , benzoyls were taken as starting materials and reacted with
urotropine and ammonium acetate in acetic acid. Imidazole derivatives were reacted with suitable benzoylchlo-
rides in pyridine and triethylamine to give 2-aryloyl-4,5-diarylimidazole derivatives, IIa−l . Those were then
21

˙
˘ ˙
˙
Synthesis of some 2,3,6,8-tetraarylimidazo[1,2-a]pyrazine derivatives..., I. KAYAGIL, S¸. DEMIRAYAK
reacted with suitable 2-bromoacetophenones to give 1-(2-aryl-2-oxoethyl)-2-aryloyl-4,5-diarylimidazoles 1-36.
To obtain the target compounds, 2,3,6,8-tetraarylimidazo[1,2-a]pyrazines 37-72, the diketo compounds 1-36
were reacted with ammonium acetate in acetic acid. The reaction was carried out by using either the clas-
sical reflux or microwave irradiation method as a facile synthetic method.2,17 The synthetic sequences of the
compounds are outlined in Figure 2, and some of their characteristics are given in Table 1.
R
R
R'
N
O
O
N
N
b
a
+
+
Cl
R
N
N
N
O
H
R
R
Ia - d
R'
R'
R
N
N
R''
N
N
c
O
+
O
Br
O
R
H
O
R
IIa - l
1-36
R'
R
R''
N
d
N
N
R
37-72
R''
Reagents: a: CH3COONH4, CH3COOH; b: triethylamine, pyridine;
c: K2CO3, CH3COCH3; d: CH3COONH4, CH3COOH
Figure 2. Synthesis of the compounds.
It was demonstrated that many organic reactions can be conducted very rapidly under microwave
irradiation. This method has been preferred due to high reaction rates, cleaner products, and operational
simplicity. In this alternative reaction condition, no product could be obtained in the absence of solvent.
Thus, a small amount of acetic acid was used for solving the substrates and microwave energy transfer. The
22

˙
˘ ˙
˙
Synthesis of some 2,3,6,8-tetraarylimidazo[1,2-a]pyrazine derivatives..., I. KAYAGIL, S¸. DEMIRAYAK
combination of solvent-free procedures with microwave irradiation is an interesting and well-accepted approach
within the concepts of green chemistry. This combination takes advantage of both the absence of solvent and
of microwave technology under economical, efficient, and safe conditions with a minimization of waste and
pollution.20 In this case, to use a small amount of solvent in any reaction is suitable in terms of environmental
pollution. In this sense, it can be reported that microwave synthetic methods are environmentally safe.
The structural elucidation of the compounds was achieved by using spectral data. In the IR spectra,
the carbonyl stretching bands, which were characteristic for compounds 1-36, were observed at about the 1700
cm−1 and 1640 cm−1 regions. These 2 groups of carbonyl stretching bands were not observed after cyclization
to give the imidazopyrazine ring system.
In the NMR spectra, methylene protons resonated in the aliphatic area at about 6 ppm for 1-36. After
cyclization, however, the corresponding proton resonances were shifted to the aromatic area at about 9.2 ppm
as singlets for compounds 37-72. Other characteristic peaks due to the aromatic protons were observed as
expected.
Anticancer activity
According to the test method, it can be stated that the compounds having log10 GI50 (GI50 : growth inhibition
of 50%) values greater than -4 are considered inactive. Therefore, we may conclude that compounds 55 and
70 provide a notable activity level. The highest activity value (i.e. -4.62) was obtained for compound 70
against CNSC. The other higher values were -4.52 and -4.50, due to compounds 70 and 55 against BC and L,
respectively. Melphalan and cisplatin (cis-diaminodichloroplatinum), 2 of the commonly used chemotherapeutic
agents, were used as standard compounds. When the mean graph midpoint (MG-MID) values of the compounds
melphalan and cisplatin, i.e. -5.09 and -6.20, respectively, were considered, it was observed that compound 70
provided an acceptable activity level (MG-MID -4.42). With regard to all of these data, in the 2 groups of
newly synthesized compounds, no significant difference was observed among substituents.
Acknowledgements
The authors present their thanks to the National Cancer Institute (NCI), USA, and Anadolu University BIBAM,
Turkey, for anticancer test results and some of the NMR spectra, respectively.
References
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24

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