A facile one-pot synthesis of aryl-substituted fused pyrimidinones

Article abstract of DOI:10.1515/hc-2015-0262

The convenient synthesis of a series of 3-phenylpyrido[1,2-A]pyrimidinones 4, 3-phenylpyrimido[1,2-c]quinazolinones 7 and 3-phenylpyrazino[1,2-A]pyrimidinones 10 with promising biological activity is presented.

Full text of DOI:10.1515/hc-2015-0262

Heterocycl. Commun. 2016; 22(2): 59–62
Preliminary Communication
HAyufcak JcooilLeee aondnYean-gp-Hoeotn Ssoyngn* thesis of aryl-substituted
fused pyrimidinones
DOI 10.1515/hc-2015-0262
Received January 11, 2016; accepted February 5, 2016; previously
published online March 26, 2016
or persistently activated in most tumors [14], effective
IL-6/STAT3 inhibitors could be useful candidates for
development of new anticancer and anti-inflammatory
drugs [15].
In this communication we report synthesis new fused
pyrimidinone compounds, 3-phenylpyrido[1,2-a]pyrimi-
dinones 4, 3-phenylpyrimido[1,2-c]quinazolinones 7 and
3-phenylpyrazino[1,2-a]pyrimidinones 10 by reactions
Abstract: The convenient synthesis of
a series of
3-phenylpyrido[1,2-a]pyrimidinones 4, 3-phenylpyrimido-
[1,2-c]quinazolinones 7 and 3-phenylpyrazino[1,2-a]pyrimi-
dinones 10 with promising biological activity is presented.
Keywords: cyclization; pyrazino[1,2-a]pyrimidinones; of heteroaryl formamidines with phenylacetyl chlorides
pyrido[1,2-a]pyrimidinones; pyrimido[1,2-c]quinazolinones. (Scheme 1).
The heterocyclic substrates 2a–b [16], 6 [17] and 9 [18]
were easily prepared in quantitative yield by treatment
Fused pyrimidinone systems have been important in
of fused heterocyclic amines 1a–b, 5 and 8 with dimeth-
drug design over many years due to diverse biologi-
ylformamide dimethyl acetal (DMF-DMA), and they were
cal properties including antimicrobial, antiviral, anti-
used without isolation for the next reaction. The cycliza-
oxidant and antitumor activities [1–4]. In particular,
tion of 2a–b with various 2-phenylacetyl chlorides 3 in
C3-arylated pyrido[1,2-a]pyrimidin-4-ones have been
dichloromethane in the presence of a catalytic amount of
exploited in the design of pharmaceutically active com-
triethylamine at room temperature gave 4a–f within 3 h
pounds such as phosphoinositide 3-kinase (pi3k) inhibi-
in good to excellent yields. The reaction of 6 or 9 with 3
tors, endothelial cell dysfunction inhibitors, and CXCR3
under similar conditions was also successfully carried
antagonists [5–7]. The conventional methods previously
out to afford corresponding 7a–e or 10a–e in good yields.
reported for the synthesis (Gould-Jacob type reaction)
The crude solid products obtained were easily isolated
[8–10] and the functionalization (Suzuki-Miyaura reac-
by filtration, washing and drying, and then purified by
tion) [11] of fused pyrimidinones have limitations in that
crystallization from ethanol. All products were fully char-
they are multi-step reactions and require harsh reaction
acterized by spectral data and elemental analysis. The
conditions. Recently, Guchhait showed a novel method
preliminary biological tests of IL-6/STAT3 inhibition for
for the synthesis of 3-aryl-pyrido[1,2-a]pyrimidin-4-ones
some synthesized compounds (4b, 7c, 10d) exhibited
by Pd-catalyzed Ag(I)-promoted activation-arylation of
IC
50 values ranging from 1.5 μm to 5.8 μm [19], and further
pharmacological studies are still in progress.
pyrido[1,2-a]pyrimidin-4-one [12]. We have also reported
convenient synthesis of novel 3-phenylpyrimido[1,2-c]
thienopyrimidinones as potent inhibitors of interlukin-6/
signal transducer and activator of transcription 3 (IL-6/
STAT3) by the one-pot reaction of formamidine deriva- Experimental
tives of 4-aminothienopyrimidine with phenylacetyl
Melting points were measured using capillary tubes on a Büchi
chlorides [13]. Since STAT3 is frequently over-expressed
apparatus and are uncorrected. The reactions were monitored by
thin-layer chromatography on Merck kieselgel 60F254 plates and the
products were purified by column chromatography using Merck sil-
ica gel (70–230 mesh). The 1H NMR spectra were recorded on a Unity
Inova 400NB FT NMR spectrometer at 400 MHz in DMSO-d6. Mass
spectra were recorded on a HP 59580 B spectrometer with electro-
spray ionization in a positive ion mode. Elemental analyses were per-
formed on a Carlo Erba 1106 elemental analyzer.
*Corresponding author: Yang-Heon Song, Department of Chemistry,
Mokwon University, Daejeon 35349, South Korea,
e-mail: yhsong@mokwon.ac.kr
Hyuck Joo Lee: Department of Chemistry, Mokwon University,
Daejeon 35349, South Korea
Unauthenticated
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ꢀꢀꢀꢁ
60ꢀ
ꢀH.J. Lee and Y.-H. Song: Synthesis of fused pyrimidinones
N
NH2
N
N
X
Cl
3
N
X
DMF-DMA
DMF-DMA
O
N
N
O
R
R
R
CH2CI2, cat. Et3N
4a–f
1a,b
2a,b
N
N
X
N
Cl
3
NH2
N
X
O
N
O
N
CH2CI2, cat. Et3N
N
N
N
5
7a–e
6
N
X
NH2
N
Cl
3
N
N
X
O
DMF-DMA
N
N
O
CH2CI2, cat. Et3N
N
N
N
10a–e
8
9
1a, 2a: R = H; 1b, 2b: R = 5-Cl; 4a: X = 3-Cl, R = H; 4b: X = 4-Cl, R = H;
4c: X = 4-Br, R = H; 4d: X = 4-NO2, R = H; 4e: X = 4-OMe, R = H;
4f: X = 4-Cl, R = 7-Cl; 7a: X = 2-Cl; 7b: X = 3-Cl; 7c: X = 4-Cl; 7d: X = 4-Br;
7e: X = 4-NO2; 10a: X = H; 10b: X = 2-Cl; 10c: X = 3-Cl; 10d: X = 4-Cl;
10e: X = 4-OMe
Scheme 1ꢀOne-pot synthesis of compounds 4a–f, 7a–e and 10a–e.
1
chloride; yield: 82%; mp 200–202°C; H NMR: δ 9.07 (d, 1H, J ꢁ=ꢁ
7.5 Hz), 8.57 (s, 1H), 7.98 (t, 1H, J ꢁ=ꢁ 7.5 Hz), 7.79 (d, 2H, J ꢁ=ꢁ 8.0 Hz), 7.73
(d, 1H, J ꢁ=ꢁ 7.5 Hz), 7.60 (d, 2H, J ꢁ=ꢁ 8.0 Hz), 7.41 (t, 1H, J ꢁ=ꢁ 7.5 Hz), MS
General procedure for the preparation of compounds
4a–f, 7a–e and 10a–e
+
(ESI): m/z 301.22 (M ). Anal. Calcd for C14H9BrN2O: C, 55.84; H, 3.01; N,
A mixture of heterocyclic amine 1a,b, 5 or 8 (5 mmol) and DMF-DMA
(6 mmol) was heated under reflux for 3 h and then stirred at room
temperature for 10 h and concentrated. The residue was treated
with a solution of the appropriate acyl chloride 3 (5 mmol) in dichlo-
romethane (10 mL) containing a catalytic amount of triethylamine.
The resulting solution was stirred at room temperature for 3 h and the
precipitated crude product was filtered, washed with ethyl acetate,
and crystallized from ethanol.
9.30. Found: C, 55.70; H, 3.18; N, 9.18.
3-(4-Nitrophenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (4d)ꢀThis
compound was obtained from 1a and 2-(4-nitrophenyl)acetyl chlo-
ride; yield 88%; mp 166–168°C; 1H NMR: δ 9.14 (d, 1H, J ꢁ=ꢁ 7.5 Hz), 8.78
(s, 1H), 8.27 (d, 2H, J ꢁ=ꢁ 8.0 Hz), 8.18 (d, 2H, J ꢁ=ꢁ 8.0 Hz), 8.06 (t, 1H, J ꢁ=ꢁ
7.5 Hz), 7.80 (d, 1H, J ꢁ=ꢁ 7.5 Hz), 7.66 (t, 1H, J ꢁ=ꢁ 7.5 Hz); MS: m/z 267.80
+
(M ). Anal. Calcd for C14H9N3O3: C, 62.92; H, 3.39; N, 15.72. Found: C,
62.80; H, 3.49; N, 15.88.
3-(3-Chlorophenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (4a)ꢀThis
compound was obtained from 1a and 2-(3-chlorophenyl)acetyl chlo-
ride; yield 80%; mp 177–179°C; 1H NMR: δ 9.09 (d, 1H, J ꢁ=ꢁ 7.6 Hz), 8.66
(s, 1H), 8.00 (t, 1H, J ꢁ=ꢁ 7.6 Hz), 7.94 (s, 1H), 7.79 (d, 1H, J ꢁ=ꢁ 7.6 Hz), 7.75
(d, 1H, J ꢁ=ꢁ 7.6 Hz), 7.45 (m, 2H), 7.38 (d, 1H, J ꢁ=ꢁ 7.6 Hz); MS: m/z 256.67
3-(4-Methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one
(4e)ꢀThis compound was obtained from 1a and 2-(4-methoxyphe-
nyl)acetyl chloride; yield: 65%; mp 142–143°C (Lit. [11] mp 142–144°C);
1H NMR: δ 9.06 (d, 1H, J ꢁ=ꢁ 7.5 Hz), 8.54 (s, 1H), 7.93 (t, 1H, J ꢁ=ꢁ 7.5 Hz),
7.76 (d, 2H, J ꢁ=ꢁ 7.5 Hz), 7.69 (d, 1H, J ꢁ=ꢁ 7.5 Hz), 7.38 (t, 1H, J ꢁ=ꢁ 7.5 Hz),
+
(M ). Anal. Calcd for C14H9ClN2O: C, 65.51; H, 3.53; N, 10.91. Found: C,
65.82; H, 3.80; N, 10.60.
+
6.98 (d, 2H, J ꢁ=ꢁ 7.5 Hz), 3.75 (s, 3H); MS: m/z 252.69 (M ). Anal. Calcd
for C15H12N2O2: C, 71.42; H, 4.79; N, 11.10. Found: C, 71.66; H, 4.88; N,
10.91.
3-(4-Chlorophenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (4b)ꢀThis
compound was obtained from 1a and 2-(4-chlorophenyl)acetyl chlo-
1
ride; yield 85%; mp 198–199°C (Lit. [12] mp 198–200°C); H NMR: δ
9.07 (d, 1H, J ꢁ=ꢁ 7.6 Hz), 8.61 (s, 1H), 7.97 (t, 1H, J ꢁ=ꢁ 7.6 Hz), 7.85 (d, 2H, 7-Chloro-3-(4-chlorophenyl)-4H-pyrido[1,2-a]pyrimidin-4-one
J ꢁ=ꢁ 8.0 Hz), 7.72 (d, 1H, J ꢁ=ꢁ 7.6 Hz), 7.46 (d, 2H, J ꢁ=ꢁ 8.0 Hz), 7.41 (t, 1H, (4f)ꢀThis compound was obtained from 1b and 2-(4-chlorophenyl)
+
1
J ꢁ=ꢁ 7.6 Hz); MS: m/z 256.80 (M ). Anal. Calcd for C14H9ClN2O: C, 65.51; acetyl chloride; yield: 68%; mp 198–200°C; H NMR: δ 9.04 (s, 1H),
H, 3.53; N, 10.91. Found: C, 65.77; H, 3.20; N, 10.69.
8.62 (s, 1H), 8.02 (d, 1H, J ꢁ=ꢁ 7.5 Hz), 7.85 (d, 2H, J ꢁ=ꢁ 7.5 Hz), 7.75 (d,
+
1H, J ꢁ=ꢁ 7.5 Hz), 7.48 (d, 2H, J ꢁ=ꢁ 7.5 Hz); MS: m/z 291.45 (M ). Anal.
3-(4-Bromophenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (4c)ꢀThis Calcd for C14H8Cl2N2O: C, 57.76; H, 2.77; N, 9.62. Found: C, 57.90; H,
compound was obtained from 1a and 2-(4-bromophenyl)acetyl 2.69; N, 9.77.
Unauthenticated
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ꢁꢀꢀꢀ
H.J. Lee and Y.-H. Song: Synthesis of fused pyrimidinonesꢂ
ꢂ61
3-(2-Chlorophenyl)-4H-pyrimido[1,2-c]quinazolin-4-one 3-(4-Chlorophenyl)-4H-pyrazino[1,2-a]pyrimidin-4-one
(7a)ꢀThis compounds was obtained from 5 and 2-(2-chlorophenyl) (10d)ꢀThis compound was obtained from 8 and 2-(4-chlorophenyl)
acetyl chloride; yield 85%; mp 237–239°C; 1H NMR: δ 9.46 (s, 1H), 8.75 acetyl chloride; yield 81%; mp 224–226°C; 1H NMR: δ 9.16 (s, 1H), 8.77
(d, 1H, J ꢁ=ꢁ 7.6 Hz), 8.41 (s, 1H), 8.00 (t, 1H, J ꢁ=ꢁ 7.6 Hz), 7.96 (d, 1H, J ꢁ=ꢁ (d, 1H, J ꢁ=ꢁ 7.6 Hz), 8.75 (s, 1H), 8.26 (d, 1H, J ꢁ=ꢁ 7.6 Hz), 7.90 (d, 2H, J ꢁ=ꢁ
+
7.6 Hz), 7.82 (t, 1H, J ꢁ=ꢁ 7.6 Hz), 7.76 (d, 1H, J ꢁ=ꢁ 7.6 Hz), 7.45 (m, 3H); MS: 8.0 Hz), 7.52 (d, 1H, J ꢁ=ꢁ 8.0 Hz); MS: m/z 257.64 (M ). Anal. Calcd for
+
m/z 307.44 (M ). Anal. Calcd for C17H10ClN3O: C, 66.35; H, 3.28; N, 13.65. C13H8ClN3O: C, 60.60; H, 3.13; N, 16.31. Found: C, 60.44; H, 3.01; N,
Found: C, 66.74; H, 3.39; N, 13.40.
16.22.
3-(3-Chlorophenyl)-4H-pyrimido[1,2-c]quinazolin-4-one 3-(4-Methoxyphenyl)-4H-pyrazino[1,2-a]pyrimidin-4-one
(7b)ꢀThis compounds was obtained from 5 and 2-(3-chlorophenyl) (10e)ꢀThis compound was obtained from 8 and 2-(4-methoxyphe-
acetyl chloride; yield 80%; mp 259–261°C; 1H NMR: δ 9.64 (s, 1H), 8.75 nyl)acetyl chloride; yield 62%; mp 233–235°C; 1H NMR: δ 9.12 (s, 1H),
(d, 1H, J ꢁ=ꢁ 7.5 Hz), 8.68 (s, 1H), 8.00 (m, 2H), 7.92 (s, 1H), 7.83 (d, 1H, 8.75 (d, 1H, J ꢁ=ꢁ 7.3 Hz), 8.69 (s, 1H), 8.21 (d, 1H, J ꢁ=ꢁ 7.3 Hz), 7.83 (d, 2H,
+
J ꢁ=ꢁ 7.5 Hz), 7.79 (d, 1H, J ꢁ=ꢁ 7.5 Hz), 7.49 (t, 1H, J ꢁ=ꢁ 7.5 Hz), 7.45 (d, 1H, J ꢁ=ꢁ J ꢁ=ꢁ 8.0 Hz), 7.02 (d, 2H, J ꢁ=ꢁ 8.0 Hz), 3.77 (s, 3H); MS: m/z 253.38 (M ).
+
7.5 Hz); MS: m/z 307.60 (M ). Anal. Calcd for C17H10ClN3O: C, 66.35; H, Anal. Calcd for C14H11N3O2: C, 60.40; H, 4.38; N, 16.59. Found: C, 60.65;
3.28; N, 13.65. Found: C, 66.58; H, 3.11; N, 13.72.
H, 4.22; N, 16.47.
3-(4-Chlorophenyl)-4H-pyrimido[1,2-c]quinazolin-4-one
(7c)ꢀThis compound was obtained from 5 and 2-(4-chlorophenyl)
Acknowledgments: This work was supported by the Korea
Research Foundation (project number 2010-0021038).
1
acetyl chloride; yield: 90%; mp 262–264°C; H NMR: δ 9.50 (s, 1H),
8.74 (d, 1H, J ꢁ=ꢁ 7.5 Hz), 8.65 (s, 1H), 7.98 (m, 2H), 7.87 (d, 2H, J ꢁ=ꢁ
8.0 Hz), 7.82 (d, 1H, J ꢁ=ꢁ 7.5 Hz), 7.53 (d, 2H, J ꢁ=ꢁ 8.0 Hz); MS: m/z 307.90
+
(M ). Anal. Calcd for C17H10ClN3O: C, 66.35; H, 3.28; N, 13.65. Found: C,
66.50; H, 3.39; N, 13.80.
References
3-(4-Bromophenyl)-4H-pyrimido[1,2-c]quinazolin-4-one [1] Guo, C.; Linton, A.; Jalaie, M.; Kephart, S.; Ornelas, M.;
(7d)ꢀThis compound was obtained from 5 and 2-(4-bromophenyl)
acetyl chloride; yield 80%; mp 268–270°C; 1H NMR: δ 9.50 (s, 1H), 8.74
(d, 1H, J ꢁ=ꢁ 7.5 Hz), 8.66 (s, 1H), 7.98 (m, 2H), 7.80 (d, 2H, J ꢁ=ꢁ 8.0 Hz),
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4H-pyrido[1,2-a]pyrimidi-4-one as novel PKM2 activators.
Bioorg. Med. Chem. Lett. 2013, 23, 3358–3363.
+
7.80 (d, 1H, J ꢁ=ꢁ 7.5 Hz), 7.67 (d, 2H, J ꢁ=ꢁ 8.0 Hz); MS: m/z 352.44 (M ).
Anal. Calcd for C17H10BrN3O: C, 57.98; H, 2.86; N, 11.93. Found: C, 58.22; [2] Bakavoli, M.; Bagherzadeh, G.; Vaseghifar, M.; Shiri, A.;
H, 2.77; N, 11.77.
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3-(4-Nitrophenyl)-4H-pyrimido[1,2-c]quinazolin-4-one (7e)ꢀThis
compound was obtained from 5 and 2-(4-nitrophenyl)acetyl chloride;
1
yield 85%; mp 231–233°C; H NMR: δ 9.50 (s, 1H), 8.75 (d, 1H, J ꢁ=ꢁ 7.6 [3] Januszczyk, P.; Fogt, J.; Boryski, J.; Izawa, K.; Onishi, T.; Neyts, J.;
Hz), 8.65 (s, 1H), 8.00–7.98 (m, 2H), 7.87 (d, 2H, J ꢁ=ꢁ 8.0 Hz), 7.82 (d, 1H,
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+
J ꢁ=ꢁ 7.6 Hz), 7.53 (d, 2H, J ꢁ=ꢁ 8.0 Hz); MS: m/z 318.53 (M ). Anal. Calcd for
C17H10N4O3: C, 64.15; H, 3.17; N, 17.60. Found: C, 63.90; H, 3.28; N, 17.88.
3-Phenyl-4H-pyrazino[1,2-a]pyrimidin-4-one (10a)ꢀThis com- [4] Gouda, M. A. Synthesis and antioxidant activity of a novel series
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mp 221–223°C; 1H NMR: δ 9.13 (s, 1H), 8.76 (d, 1H, J ꢁ=ꢁ 7.6 Hz), 8.70 (s,
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+
MS: m/z 223.44 (M ). Anal. Calcd for C13H9N3O: C, 69.95; H, 4.06; N,
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(10b)ꢀThis compound was obtained from 8 and 2-(2-chlorophenyl)
acetyl chloride; yield 84%; mp 173–175°C; 1H NMR: δ 9.17 (s, 1H), 8.74
(d, 1H, J ꢁ=ꢁ 7.6 Hz), 8.47 (s, 1H), 8.25 (d, 1H, J ꢁ=ꢁ 7.6 Hz), 7.56 (d, 1H, J ꢁ=ꢁ 7.6 [7] Li, A.-R.; John, M. G.; Liu, J.; Chen, X.; Du, X.; Mihalic, J. T.;
+
Hz), 7.45–7.42 (m, 3H); MS: m/z 257.60 (M ). Anal. Calcd for C13H8ClN3O:
Deignan, J.; Gustin, D. J.; Duquette, J.; Fu, Z.; et al. Optimization
of the heterocyclic core of the quinazolinone-derived CXCR3
antagonists. Bioorg. Med. Chem. Lett. 2008, 18, 688–693.
C, 60.60; H, 3.13; N, 16.31. Found: C, 60.48; H, 3.01; N, 16.50.
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(10c)ꢀThis compound was obtained from 8 and 2-(3-chlorophenyl)
acetyl chloride; yield 79%; mp 252–254°C; 1H NMR: δ 9.16 (s, 1H), 8.79
(s, 1H), 8.76 (d, 1H, J ꢁ=ꢁ 7.6 Hz), 8.27 (d, 1H, J ꢁ=ꢁ 7.6 Hz), 7.95 (s, 1H), 7.81
cyclic phenols: 9-hydroxy-pyrido[1,2-a]pyrimidine-4-one and
9-hydroxy-pyrimidio[1,6-a]pyrimidine-4-one. Tetrahedron Lett.
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(d, 1H, J ꢁ=ꢁ 7.6 Hz), 7.50 (t, 1H, J ꢁ=ꢁ 7.6 Hz), 7.44 (d, 1H, J ꢁ=ꢁ 7.6 Hz); MS: [9] Cassis, R.; Tapia, R.; Valderrama, J. A. Synthesis of 4(1H)-
+
m/z 257.66 (M ). Anal. Calcd for C13H8ClN3O: C, 60.60; H, 3.13; N, 16.31.
quinolones by thermolysis of arylaminoethylene Meldrum’s acid
derivatives. Synth. Commun. 1985, 15, 125–133.
Found: C, 60.85; H, 3.19; N, 16.48.
Unauthenticated
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62ꢀ ꢀH.J. Lee and Y.-H. Song: Synthesis of fused pyrimidinones
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