A Facile One-pot Synthesis of 1-Arylpyrazolo[3,4-d]Pyrimidin- 4-ones
1
Oujiang College, Wenzhou Universtity, Wenzhou 325035, China
2
College of Chemistry and Materials Engineering, Wenzhou Universtity, Wenzhou 325035, China
*
Author to whom correspondence should be addressed.
Molecules 2010, 15(5), 3079-3086; https://doi.org/10.3390/molecules15053079
Submission received: 19 March 2010
/
Revised: 9 April 2010
/
Accepted: 21 April 2010
/
Published: 27 April 2010
Abstract
:One pot synthesis of 1-arylpyrazolo[3,4-d]pyrimidin-4-ones by the reaction of 5-amino-N-substituted-1H-pyrazole-4-carbonitrile with different lower aliphatic acids in the presence of POCl3 has been developed. The structures of all the title compounds have been confirmed by IR, 1H-NMR, 13C-NMR, and elemental analyses. Moreover, the structures of one of these compounds, 2c, was confirmed by single-crystal X-ray diffraction.
1. Introduction
Pyrazolopyrimidinone derivatives have attracted the attention of numerous researchers over many years due to their important biological activities [1,2,3,4]. Structural analogs of pyrazolo[3,4-d]- pyrimidines have displayed good activities as inhibitors of cyclin-dependent kinase 2 [5] and PI3 kinase-A [6], anticancer and radioprotective activity [7], antimicrobial [8] and other biology activity [9]. The importance of pyrazolo[3, 4-d]pyrimidines had resulted in the development of several synthetic methods for their construction [10,11]. The traditional transformation utilizes two steps to assemble aminopyrazolo[3, 4-d] pyrimidin-4-ones, as illustrated in Scheme 1 and Scheme 2. However, the transformation of compounds 2 requires two steps and sufferes from several disadvantages such as vigorous conditions, long reaction times and low yields [12,13]. The development of one-step and efficient syntheses of aminopyrazolo[3,4-d]pyrimidin-4-ones under mild conditions remained a work in progress.
Scheme 1.
Synthesis of pyrazolo [3, 4-d] pyrimidin-4-ones by the reaction of esters.
Scheme 2.
Synthesis of pyrazolo [3, 4-d] pyrimidin-4-ones by the reaction of acyl chlorides.
Here, we report a simple and efficient method for the synthesis of usefully functionalized pyrazolo[3,4-d] pyrimidins-4-ones 2 by heteroannulation under mild conditions using POCl3.
2. Result and Discussion
The 5-amino-N-substituted-1H-pyrazole-4-carbonitrile starting materials 1, synthesized by a one–pot synthesis literature procedure [14], was then reacted with lower aliphatic acids in the presence of POCl3 to give the target N-substituted pyrazolo[3,4-d]pyrimidin-4-ones 2 (Scheme 3).
Scheme 3.
Synthesis of pyrazolo[3, 4-d]pyrimidin-4-ones by the reaction of carboxylic acid in the presence of POCl3.
Scheme 3.
Synthesis of pyrazolo[3, 4-d]pyrimidin-4-ones by the reaction of carboxylic acid in the presence of POCl3.
A number of works about POCl3-catalyzed reactions, especially intramolecular condensations [15] have been reported. In our reaction system POCl3 acted not only as a chlorinating reagent, but also an oxidant. Thus, we concluded that the 5-amino-N-substituted-1H-pyrazole-4-carbonitrile were first oxidized to give the corresponding N-substituted-5-amino-pyrazole-4-carboxamide, which immediately reacted with the acyl chloride which might be generated in situ from the reaction of the carboxylic acid with POCl3. Followed by cyclization and condensation of the intermediate, the target products were formed. The reaction went smoothly by controlling the amount of POCl3, and the products were obtained in good yields. The results were presented in Table 1.
Table 1.
N-substituted prazolo[3, 4-d]pyrimidin-4-one 2a-j via Scheme 3.
| Entry | R2 | R1 | Yield a | Time(h) |
|---|---|---|---|---|
| 2 a | H | 2,6-Cl2-4-CF3-C6H2- | 90 | 1.5 |
| 2 b | CH3 | 2,6-Cl2-4-CF3-C6H2- | 87 | 2 |
| 2 c | CH2CH3 | 2,6-Cl2-4-CF3-C6H2- | 90 | 2.5 |
| 2 d | CCl3 | 2,6-Cl2-4-CF3-C6H2- | 89 | 2 |
| 2 e | CH3 | 4-OCH3-C6H4- | 83 | 1 |
| 2 f | CH3 | 2,4-(NO2)2-C6H3- | 90 | 1.5 |
| 2 g | CH3 | 2,4,6-Cl3-C6H2- | 97 | 1.5 |
| 2h | CH3 | 2-Cl-C6H4- | 82 | 2 |
| 2 i | CH3 | H | 75 | 2.5 |
| 2 j | CH3 | n-Bu | 70 | 2.5 |
| a isolated yields based on compound 2 | ||||
The structures of compounds 2a-j were deduced from their elemental analyses and their IR, 1H- NMR, 13C-NMR and mass spectra and all elemental and spectral data of compounds 2a-j were in accord with the suggested structures. The 1H-NMR spectrum of 2c, as an example, consisted of a singlet at δ 11.06 from the NH function, a singlet at δ 8.27 is from the H-3 proton, a singlet at δ 8.11 due to the phenyl ring (two protons), a multiplet at δ 2.74 (two protons) from the CH2 and a triplet at δ 1.23 due to the methyl group (three protons). Moreover the structure of 2c was confirmed via X-ray crystallographic analysis (Figure 1).
Figure 1.
Single crystal X-ray crystal structure of 2c.
3. Experimental
3.1. General
All the melting points were uncorrected. 1H-, 13C-, and 19F-NMR spectra were recorded on a FT-Bruker AT-300 instrument using CDCl3 or CD3COCD3 as a solvent with tetramethylsilane (TMS) as the internal standard. J-values are given in Hz. Compounds were properly characterized by elemental analyses using a Carlo-Erba EA-1112 instrument. IR spectra were measured on a Bruker VECTOR55 instrument. Silica gel 60 GF254 was used for analytical and preparative TLC.
3.2. General procedure for the preparation of the pyrazolo[3,4-d]pyrimidines 2a-2j: preparation of 2c
5-Amino-1-[2,6-dichloro-4-(trifloromethyl)phenyl]-1H-pyrazole-4-carbonitrile (0.321 g, 1 mmol) was dissolved in propanoic acid (3 mL). Then POCl3 (0.2 mL) was added quickly. The mixture was refluxed for 2 h (the reaction system was carefully observed by TLC). After the mixture was cooled, added ice water (50 mL). A mass of white precipitate was produced. K2CO3 was added to neutralize the acid till no bubble occurs. The reaction mixture was filtered, and washed with a small amount of ethanol, dried. A 90% yield of the compound was obtained. Crystals of 2c suitable for X-ray diffraction were obtained by slow evaporation of ethanol-acetone mixture solution. The other compounds were also synthesized according to this method.
1-(2,6-Dichloro-4-(trifluoromethyphenyl]-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one (2a): White solid; mp 271-273 ºC, IR (KBr, cm-1): 3849, 3749, 2924, 1699, 1592, 681; 1H-NMR (CD3COCD3, 300 MHz): δ 11.32 (s, 1H), 8.36 (s, 1H), 8.15 (s, 1H), 8.12 (s, 2H); 13C-NMR (CD3COCD3, 75 MHz): δ 106.3 (1C), 122.4 (q, J = 272 Hz, 1C), 126.4 (1C), 132.7 (q, J = 33.75 Hz, 1C), 135.5 (2C), 136.1 (1C), 137.8 (2C), 149.8 (1C), 153.8 (1C), 157.0 (1C); MS: m/z (%) = 348 (100, [M+]). Anal. Calcd. for C12H5Cl2F3N4O: C, 41.29; H, 1.44; N, 16.05. Found: C, 41.20; H, 1.45; N, 16.00%.
6-Methyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one (2b): White solid; mp 259-260 ºC, IR (KBr, cm-1): 3772, 3105, 2896, 1598, 1392, 1317, 1131; 1H-NMR (DMSO-d6, 300 MHz): δ 12.42 (s, 1H), 8.40 (s, 1H), 8.27 (s, 2H), 2.31 (s, 3H); 13C-NMR (DMSO-d6, 75 MHz): δ 21.2 (1C), 104.3 (1C), 122.2 (q, J = 272 Hz, 1C), 126.4 (1C), 132.6 (q, J = 33.70 Hz, 1C), 135.6 (2C), 136.3 (1C), 137.6 (2C), 154.5 (1C), 157.6 (1C), 159.8 (1C); MS: m/z (%) = 361 (100, [M+ - 1]); Anal. Calcd for C13H7Cl2F3N4O: C, 43.00; H, 1.94; N, 15.43. Found: C, 42.91; H, 1.90, N, 15.38.
6-Ethyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one (2c): White solid; mp 232-233 ºC, IR (KBr, cm-1): 3094, 2989, 1681, 1598, 1531, 1319, 1173, 1124, 1H-NMR (CD3COCD3, 300 MHz): δ 11.16 (s, 1H), 8.27 (s, 1H), 8.11 (s, 2H), 2.74 (q, J = 7.5 Hz, 2H), 1.23 (t, J = 7.5 Hz, 3H); 13C-NMR (DMSO-d6, 75 MHz): δ 11.8 (1C), 27.8 (1C), 104.6 (1C), 122.4 (q, J = 272 Hz, 1C), 126.5 (1C), 132.7 (q, J= 33.75 Hz, 1C), 135.7 (2C), 136.5 (1C), 137.7 (2C), 154.6 (1C), 158.0 (1C), 164.1 (1C); MS: m/z (%) = 375 (100, [M+ - 1]); Anal. Calcd for C14H9Cl2F3N4O: C, 44.59; H, 2.41; N, 14.86. Found: C, 44.51; H, 2.36, N, 14.83.
6-Trichloromethyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-4,5-dihydro-1H-pyrazolo[3,4-d]- pyrimid- in-4-one (2d): White solid; mp 238-239 ºC, IR (KBr, cm-1): 3013, 2920, 1683, 1589, 1333, 1317, 1124, 663, 1H-NMR (DMSO-d6, 300 MHz): δ 12.50 (s, 1H), 8.45 (s, 1H), 8.24 (s, 2H); 13C-NMR (DMSO-d6, 75 MHz): 79.0 (1C), 105.6 (1C), 122.6 (q, J = 273 Hz, 1C), 126.8 (1C), 132.9 (q, J = 33.75 Hz, 1C), 136.0 (2C), 137.0 (1C), 138.1 (2C), 155.3 (1C), 159.0 (1C), 164.7 (1C); MS: m/z (%) = 463 (100, [M+ - 1]); Anal. Calcd for C13H4Cl5F3N4O: C, 33.47; H, 0.86; N, 12.01. Found: C, 33.451; H, 0.85, N, 12.05.
6-Methyl-1-(4-methyloxyphenyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one (2e): White solid, mp 258-260 ºC; IR (KBr, cm-1): 3850, 3745, 3618, 2926, 1690 (s), 1518, 1463, 675 ; 1H-NMR (DMSO-d6, 300 MHz): δ 12.23 (s, 1H), 8.19, (s, 1H), 7.86 (d, J = 7.5 Hz, 2H), 7.08 (d, J = 7.5 Hz, 2H), 3.80 (s, 3H), 2.37 (s, 3H); 13C-NMR (DMSO-d6, 75 MHz): δ 21.5 (1C), 55.5 (1C), 105.2 (1C), 114.3 (2C), 123.5 (2C), 131.5 (1C), 135.3 (1C), 152.1 (1C), 157.9 (1C), 158.1 (1C), 158.3 (1C); MS: m/z (%) = 255 (100, [M+ - 1]); Anal. Calcd for C13H12N4O2: C, 60.93; H, 4.72; N, 21.86. Found: C, 60.88; H, 4.68, N, 21.76.
6-Methyl-1-(2,4-dinitrophenyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one (2f): Yellow solid, mp 229-230ºC; IR (KBr, cm-1): 3749, 2921, 1695(s), 1605, 1533, 1348 ; 1H-NMR (DMSO-d6, 300 MHz): δ 12.52 (s, 1H), 8.85 (s, 1H), 8.70 (d, J = 9 Hz, 1H), 8.37 (s, 1H), 8.19 (d, J = 9 Hz, 1H), 2.44 (s, 3H); 13C-NMR (DMSO-d6, 75 MHz): δ 21.5 (1C), 105.6 (1C), 121.3 (1C), 128.5 (1C), 128.8 (1C), 134.1 (1C), 138.4 (1C), 143.3 (1C), 146.1 (1C), 153.9 (1C), 157.5 (1C), 160.1 (1C); MS: m/z (%) = 315 (100, [M+ - 1]); Anal. Calcd for C12H8N6O5: C, 45.58; H, 2.55; N, 26.58. Found: C, 45.45; H, 2.50, N, 26.46.
6-Methyl-1-(2,4,6-trichlorophenyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one (2g): White solid, mp 236-237 ºC; IR (KBr, cm-1): 3432, 1685, 1599, 1536, 1386, 667; 1H-NMR (DMSO-d6, 300 MHz): δ 12.4 (s, 1H), 8.3 (s, 1H), 8.0 (s, 2H), 2.3 (s, 3H); 13C-NMR (DMSO-d6, 75 MHz): δ 21.4 (1C), 104.4 (1C), 129.2 (2C), 132.2 (1C), 135.4 (2C), 136.4 (1C), 137.4 (1C), 154.6 (1C), 1587.9 (1C), 159.7 (1C); MS: m/z (%) = 327 (100, [M+ - 1]); Anal. Calcd for C12H7Cl3N4O: C, 43.73; H, 2.14; N, 17.00. Found: C, 43.67; H, 2.10, N, 16.88.
6-Methyl-1-(2-chlorophenyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one (2h): White solid, mp 217-219 ºC; IR (KBr, cm-1): 3840, 3745, 2929, 1693, 1602, 1520; 1H-NMR (DMSO-d6, 300 MHz): δ 12.3 (s, 1H), 8.2 (s, 1H), 7.6 (m, 4H), 2.3 (s, 3H); 13C-NMR (DMSO-d6, 75 MHz): δ 21.2 (1C), 104.2 (1C), 128.1 (1C), 130.2 (2C), 131.2 (1C), 131.4 (1C), 134.9 (1C), 136.0 (1C), 153.9 (1C), 157.9 (1C), 158.8 (1C); MS: m/z (%) = 259 (100, [M+ - 1]); Anal. Calcd for C12H9ClN4O: C, 55.29; H, 3.84; N, 21.49. Found: C, 55.12; H, 3.80, N, 21.36.
6-Methyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one (2i): White solid, mp 264-265 ºC; IR (KBr, cm-1): 3842, 2925, 2272, 1741, 1645, 1518, 1461, 1391, 1121, 669; 1H-NMR (DMSO-d6, 300 MHz): δ12.03 (s, 1H), 10.36 (s,1H), 8.33 (s, 1H), 2.36 (s, 3H); 13C-NMR (DMSO-d6, 75 MHz): 22.0(1C), 105.00 (1C), 135.17 (1C), 153.70 (1C), 158.78 (1C), 159.20 (1C); MS: m/z (%) = 149 (100, [M+ - 1]); Anal. Calcd for C6H6N4O: C, 48.00; H, 4.03; N, 37.32. Found: C, 47.95; H, 4.00, N, 37.28.
6-Methyl-1-n-butyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one (2j), White solid, mp 144-145 ºC; IR (KBr, cm-1):2925, 2855, 1387, 1120, 676; 1H-NMR (CD3COCD3): δ 11.60 (s, 1H), 8.44 (s, 1H), 4.20 (t, J = 6.8 Hz, 2H), 2.26 (s, 3H), 1.78 (m, J = 10.6 Hz, 2H), 1.20 (m, J = 7.41Hz, 2H), 0.86 (t, J = 7.4 Hz, 3H); 13C-NMR (CD3COCD3): 13.36 (1C), 19.09 (1C), 21.43 (1C), 31.50 (1C), 52.1 (1C), 104.73 (1C), 128.46 (1C), 155.52 (1C), 159.24 (1C), 159.32 (1C); MS: m/z (%) = 205 (100, [M+ - 1]); Anal. Calcd for C10H14N4O: C, 58.24; H, 6.84; N, 27.16. Found: C, 58.20; H, 6.80, N, 27.10.
3.3. X-ray crystallography
Compound 2c was subjected to single crystal X-ray crystallography and intensity data were collected at 298(2)K on an Siemens P4 diffractometer and use graphite Monochromated MoKa adiation (λ = 0.71073Å). The structure was solved by a direct method using the SHELXL-97 program [16] and refined with the SHELXL-97 program. All H atoms bonded to the C atoms were placed geometrically at the distances of 0.93–0.96Å and included in the refinementin riding motion approximation with Uiso (H) = 1.2 or 1.5Ueq of the carrier atom. The thermal ellipsoids were plotted with the SHELXL-97 program at 50% probability. The molecular structure is shown in Figure 1. Selected crystal data and structure refinement details are presented in Table 2. Selected bond distances and angles are listed in Table 3.
CCDC 774536 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge, CB2 1EZ, UK; E-mail: [email protected].
| Empirical formula | C14 H9 Cl2 F3 N4 O |
| Formula weight | 377.15 |
| Temperature | 298(2) K |
| Wavelength | 0.71073 A |
| Crystal system | Monoclinic |
| space group | P 2/n |
| Unit cell dimensions | a = 13.468(4) A alpha = 90 deg. |
| b = 8.234(3) A beta = 112.056(6) deg. | |
| c = 15.047(5) A gamma = 90 deg | |
| Volume | 1546.4(9)A3 |
| Z | 4 |
| Absorption coefficient | 0.463 mm-1 |
| F(000) | 760 |
| Theta range for data collection | 2.47° to 25.02° |
| Limiting indices | -16<=h<=15, -9<=k<=9, -17<=l<=14 |
| Reflections collected / unique | 7730 / 2740 [R(int) = 0.0213] |
| Completeness to theta = 25.02 | 99.6% |
| Absorption correction | Semi-empirical from equivalents |
| Max. and min. transmission | 0.9214 and 0.8154 |
| Refinement method | Full-matrix least-squares on F2 |
| Data / restraints / parameters | 2740 / 0 / 218 |
| Goodness-of-fit on F^2 | 1.142 |
| Final R indices [I>2sigma(I)] | R1 = 0.0866, wR2 = 0.2087 |
| R indices (all data) | R1 = 0.0945, wR2 = 0.2142 |
| Largest diff. peak and hole | 0.660 and -0.897 e.A-3 |
| F(1)-C(1) | 1.341(6) | O(1)-C(10) | 1.236(5) | N(1)-C(11) | 1.369(6) |
| N(2)-C(12) | 1.355(6) | N(3)-C(8) | 1.310(6) | N(4)-C(8) | 1.368(6) |
| C(1)-C(2) | 1.504(7) | C(2)-C(7) | 1.360(7) | C(4)-C(5) | 1.388(6) |
| C(6)-C(7) | 1.377(7) | C(9)-C(10) | 1.436(6) | C(9)-C(12) | 1.388(6) |
| C(11)-N(1)-C(10) | 125.1(4) | C(8)-N(3)-C(9) | 110.2(4) | C(12)-N(4)-C(5) | 127.9(4) |
| C(8)-N(4)-C(5) | 120.2(3) | C(7)-C(2)-C(3) | 120.3(4) | C(3)-C(2)-C(1) | 119.3(4) |
| C(4)-C(3)-C(2) | 119.8(4) | C(6)-C(5)-C(4) | 117.3(4) | C(6)-C(5)-N(4) | 120.3(4) |
| N(3)-C(8)-N(4) | 106.8(4) | C(12)-C(9)-C(10) | 117.6(4) | N(1)-C(10)-C(9) | 112.1(4) |
| N(2)-C(11)-N(1) | 123.9(4) | N(1)-C(11)-C(13) | 115.3(4) | N(2)-C(12)-C(9) | 127.9(4) |
4. Conclusions
In summary, we have successfully developed a simple and efficient method for the synthesis of variously functionalized pyrazolo[3,4-d]pyrimidin-4-ones by heteroannulation under mild conditions using POCl3. This works has been patented [17]. Further heteroannulation studies are underway in our laboratory.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (grant No. 20972114), the Natural Science Foundation of Zhejiang Province (grant No. Y407079 and Y4080027), and the Foundation of Science and Technology Department of Zhejiang Province (No. 2007C21116).
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Zhang, X.; Lin, Q.; Zhong, P. A Facile One-pot Synthesis of 1-Arylpyrazolo[3,4-d]Pyrimidin- 4-ones. Molecules 2010, 15, 3079-3086. https://doi.org/10.3390/molecules15053079
AMA Style
Zhang X, Lin Q, Zhong P. A Facile One-pot Synthesis of 1-Arylpyrazolo[3,4-d]Pyrimidin- 4-ones. Molecules. 2010; 15(5):3079-3086. https://doi.org/10.3390/molecules15053079
Chicago/Turabian StyleZhang, Xiaohong, Qiulian Lin, and Ping Zhong. 2010. "A Facile One-pot Synthesis of 1-Arylpyrazolo[3,4-d]Pyrimidin- 4-ones" Molecules 15, no. 5: 3079-3086. https://doi.org/10.3390/molecules15053079
