A facile one-pot synthesis of aryl-substituted fused pyrimidinones
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Hyuck Joo Lee
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]pyrimidinones 10 with promising biological activity is presented.
Fused pyrimidinone systems have been important in drug design over many years due to diverse biological properties including antimicrobial, antiviral, antioxidant and antitumor activities [1–4]. In particular, C3-arylated pyrido[1,2-a]pyrimidin-4-ones have been exploited in the design of pharmaceutically active compounds such as phosphoinositide 3-kinase (pi3k) inhibitors, endothelial cell dysfunction inhibitors, and CXCR3 antagonists [5–7]. The conventional methods previously reported for the synthesis (Gould-Jacob type reaction) [8–10] and the functionalization (Suzuki-Miyaura reaction) [11] of fused pyrimidinones have limitations in that they are multi-step reactions and require harsh reaction conditions. Recently, Guchhait showed a novel method for the synthesis of 3-aryl-pyrido[1,2-a]pyrimidin-4-ones by Pd-catalyzed Ag(I)-promoted activation-arylation of 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 derivatives of 4-aminothienopyrimidine with phenylacetyl chlorides [13]. Since STAT3 is frequently over-expressed 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]pyrimidinones 4, 3-phenylpyrimido[1,2-c]quinazolinones 7 and 3-phenylpyrazino[1,2-a]pyrimidinones 10 by reactions of heteroaryl formamidines with phenylacetyl chlorides (Scheme 1).
One-pot synthesis of compounds 4a–f, 7a–e and 10a–e.
The heterocyclic substrates 2a–b [16], 6 [17] and 9 [18] were easily prepared in quantitative yield by treatment of fused heterocyclic amines 1a–b, 5 and 8 with dimethylformamide dimethyl acetal (DMF-DMA), and they were used without isolation for the next reaction. The cyclization of 2a–b with various 2-phenylacetyl chlorides 3 in dichloromethane in the presence of a catalytic amount of triethylamine at room temperature gave 4a–f within 3 h in good to excellent yields. The reaction of 6 or 9 with 3 under similar conditions was also successfully carried out to afford corresponding 7a–e or 10a–e in good yields. The crude solid products obtained were easily isolated by filtration, washing and drying, and then purified by crystallization from ethanol. All products were fully characterized by spectral data and elemental analysis. The preliminary biological tests of IL-6/STAT3 inhibition for some synthesized compounds (4b, 7c, 10d) exhibited IC50 values ranging from 1.5 μm to 5.8 μm [19], and further pharmacological studies are still in progress.
Experimental
Melting points were measured using capillary tubes on a Büchi 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 silica 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 electrospray ionization in a positive ion mode. Elemental analyses were performed on a Carlo Erba 1106 elemental analyzer.
General procedure for the preparation of compounds 4a–f, 7a–e and 10a–e
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 dichloromethane (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.
3-(3-Chlorophenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (4a)
This compound was obtained from 1a and 2-(3-chlorophenyl)acetyl chloride; 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 (M+). Anal. Calcd for C14H9ClN2O: C, 65.51; H, 3.53; N, 10.91. Found: C, 65.82; H, 3.80; N, 10.60.
3-(4-Chlorophenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (4b)
This compound was obtained from 1a and 2-(4-chlorophenyl)acetyl chloride; yield 85%; mp 198–199°C (Lit. [12] mp 198–200°C); 1H 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, J = 8.0 Hz), 7.72 (d, 1H, J = 7.6 Hz), 7.46 (d, 2H, J = 8.0 Hz), 7.41 (t, 1H, J = 7.6 Hz); MS: m/z 256.80 (M+). Anal. Calcd for C14H9ClN2O: C, 65.51; H, 3.53; N, 10.91. Found: C, 65.77; H, 3.20; N, 10.69.
3-(4-Bromophenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (4c)
This compound was obtained from 1a and 2-(4-bromophenyl)acetyl chloride; yield: 82%; mp 200–202°C; 1H 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 (ESI): m/z 301.22 (M+). Anal. Calcd for C14H9BrN2O: C, 55.84; H, 3.01; N, 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 chloride; 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-(4-Methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (4e)
This compound was obtained from 1a and 2-(4-methoxyphenyl)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), 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.
7-Chloro-3-(4-chlorophenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (4f)
This compound was obtained from 1b and 2-(4-chlorophenyl)acetyl chloride; yield: 68%; mp 198–200°C; 1H NMR: δ 9.04 (s, 1H), 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. Calcd for C14H8Cl2N2O: C, 57.76; H, 2.77; N, 9.62. Found: C, 57.90; H, 2.69; N, 9.77.
3-(2-Chlorophenyl)-4H-pyrimido[1,2-c]quinazolin-4-one (7a)
This compounds was obtained from 5 and 2-(2-chlorophenyl)acetyl chloride; yield 85%; mp 237–239°C; 1H NMR: δ 9.46 (s, 1H), 8.75 (d, 1H, J = 7.6 Hz), 8.41 (s, 1H), 8.00 (t, 1H, J = 7.6 Hz), 7.96 (d, 1H, 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: m/z 307.44 (M+). Anal. Calcd for C17H10ClN3O: C, 66.35; H, 3.28; N, 13.65. Found: C, 66.74; H, 3.39; N, 13.40.
3-(3-Chlorophenyl)-4H-pyrimido[1,2-c]quinazolin-4-one (7b)
This compounds was obtained from 5 and 2-(3-chlorophenyl)acetyl chloride; yield 80%; mp 259–261°C; 1H NMR: δ 9.64 (s, 1H), 8.75 (d, 1H, J = 7.5 Hz), 8.68 (s, 1H), 8.00 (m, 2H), 7.92 (s, 1H), 7.83 (d, 1H, 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 = 7.5 Hz); MS: m/z 307.60 (M+). Anal. Calcd for C17H10ClN3O: C, 66.35; H, 3.28; N, 13.65. Found: C, 66.58; H, 3.11; N, 13.72.
3-(4-Chlorophenyl)-4H-pyrimido[1,2-c]quinazolin-4-one (7c)
This compound was obtained from 5 and 2-(4-chlorophenyl)acetyl chloride; yield: 90%; mp 262–264°C; 1H 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.
3-(4-Bromophenyl)-4H-pyrimido[1,2-c]quinazolin-4-one (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), 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; H, 2.77; N, 11.77.
3-(4-Nitrophenyl)-4H-pyrimido[1,2-c]quinazolin-4-one (7e)
This compound was obtained from 5 and 2-(4-nitrophenyl)acetyl chloride; yield 85%; mp 231–233°C; 1H NMR: δ 9.50 (s, 1H), 8.75 (d, 1H, J = 7.6 Hz), 8.65 (s, 1H), 8.00–7.98 (m, 2H), 7.87 (d, 2H, J = 8.0 Hz), 7.82 (d, 1H, 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 compound was obtained from 8 and 2-phenylacetyl chloride; yield 77%; mp 221–223°C; 1H NMR: δ 9.13 (s, 1H), 8.76 (d, 1H, J = 7.6 Hz), 8.70 (s, 1H), 8.23 (d, 1H, J = 7.6 Hz), 7.82 (d, 2H, J = 7.6 Hz), 7.46–7.42 (m, 3H); MS: m/z 223.44 (M+). Anal. Calcd for C13H9N3O: C, 69.95; H, 4.06; N, 18.82. Found: C, 69.72; H, 3.90; N, 19.03.
3-(2-Chlorophenyl)-4H-pyrazino[1,2-a]pyrimidin-4-one (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 Hz), 7.45–7.42 (m, 3H); MS: m/z 257.60 (M+). Anal. Calcd for C13H8ClN3O: C, 60.60; H, 3.13; N, 16.31. Found: C, 60.48; H, 3.01; N, 16.50.
3-(3-Chlorophenyl)-4H-pyrazino[1,2-a]pyrimidin-4-one (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 (d, 1H, J = 7.6 Hz), 7.50 (t, 1H, J = 7.6 Hz), 7.44 (d, 1H, J = 7.6 Hz); MS: m/z 257.66 (M+). Anal. Calcd for C13H8ClN3O: C, 60.60; H, 3.13; N, 16.31. Found: C, 60.85; H, 3.19; N, 16.48.
3-(4-Chlorophenyl)-4H-pyrazino[1,2-a]pyrimidin-4-one (10d)
This compound was obtained from 8 and 2-(4-chlorophenyl)acetyl chloride; yield 81%; mp 224–226°C; 1H NMR: δ 9.16 (s, 1H), 8.77 (d, 1H, J = 7.6 Hz), 8.75 (s, 1H), 8.26 (d, 1H, J = 7.6 Hz), 7.90 (d, 2H, J = 8.0 Hz), 7.52 (d, 1H, J = 8.0 Hz); MS: m/z 257.64 (M+). Anal. Calcd for C13H8ClN3O: C, 60.60; H, 3.13; N, 16.31. Found: C, 60.44; H, 3.01; N, 16.22.
3-(4-Methoxyphenyl)-4H-pyrazino[1,2-a]pyrimidin-4-one (10e)
This compound was obtained from 8 and 2-(4-methoxyphenyl)acetyl chloride; yield 62%; mp 233–235°C; 1H NMR: δ 9.12 (s, 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 = 8.0 Hz), 7.02 (d, 2H, J = 8.0 Hz), 3.77 (s, 3H); MS: m/z 253.38 (M+). Anal. Calcd for C14H11N3O2: C, 60.40; H, 4.38; N, 16.59. Found: C, 60.65; H, 4.22; N, 16.47.
Acknowledgments:
This work was supported by the Korea Research Foundation (project number 2010-0021038).
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Articles in the same Issue
- Frontmatter
- Preliminary Communication
- A facile one-pot synthesis of aryl-substituted fused pyrimidinones
- Research Articles
- Three-component synthesis of new o-hydroxyphenyl-substituted pyrazolo[3,4-b]pyridines promoted by FeCl3
- Reactions of ferrocenyl chalcones with hydrazines and active methylene compounds
- Synthesis of 3-alkyl-5-allylamino-2-benzoylimino-1,3,4-thiadiazoles via Dimroth rearrangement
- Chiral oxazoline ligands with two different six-membered azaheteroaromatic rings – synthesis and application in the Cu-catalyzed nitroaldol reaction
- Stereoselective Michael addition of O-nucleophiles to carbohydrate-based nitro-olefin
- The synthesis of hydrophobic 1-alkyl-1H,1′H-2,2′-bibenzo[d]imidazoles
- Novel synthesis and reactions of pyrazolyl-substituted tetrahydrothieno[2,3-c]isoquinoline derivatives
- Acid-base properties and keto-enol equilibrium of a 5-substituted derivative of 1,3-diethyl-2-thiobarbituric acid
Articles in the same Issue
- Frontmatter
- Preliminary Communication
- A facile one-pot synthesis of aryl-substituted fused pyrimidinones
- Research Articles
- Three-component synthesis of new o-hydroxyphenyl-substituted pyrazolo[3,4-b]pyridines promoted by FeCl3
- Reactions of ferrocenyl chalcones with hydrazines and active methylene compounds
- Synthesis of 3-alkyl-5-allylamino-2-benzoylimino-1,3,4-thiadiazoles via Dimroth rearrangement
- Chiral oxazoline ligands with two different six-membered azaheteroaromatic rings – synthesis and application in the Cu-catalyzed nitroaldol reaction
- Stereoselective Michael addition of O-nucleophiles to carbohydrate-based nitro-olefin
- The synthesis of hydrophobic 1-alkyl-1H,1′H-2,2′-bibenzo[d]imidazoles
- Novel synthesis and reactions of pyrazolyl-substituted tetrahydrothieno[2,3-c]isoquinoline derivatives
- Acid-base properties and keto-enol equilibrium of a 5-substituted derivative of 1,3-diethyl-2-thiobarbituric acid
