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A one-step synthesis of pyrazolone

A one-step synthesis of pyrazolone Molbank 2004 http://www.mdpi.org/molbank/molbank2006/m464.htm Molbank 2006, M464 http://www.mdpi.net/molbank/ Gernot A. Eller* and Wolfgang Holzer Department of Drug Synthesis, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria Phone: +43-1-4277-55634, e-mail: gernot.eller@univie.ac.at *Author to whom correspondence should be addressed Received: 3 January 2006 / Accepted: 4 January 2006 / Published: 22 January 2006 Keywords: Pyrazolone, cyclization, NMR spectroscopy, tautomerism. Abstract: The fully unsubstituted pyrazolone (= 2-pyrazolin-5-one, which is tautomer to 1H-pyrazol-3-ol and 1H-pyrazol-5-ol) was prepared from hydrazine hydrate and methyl (2E)-3- 1 13 15 methoxyacrylate in almost quantitative yield. Detailed spectroscopic data ( H NMR, C NMR, N NMR, MS) for this compound are presented. Substituted 2-pyrazolin-5-ones play an important role as substructures of numerous pharmaceuticals, agrochemicals, dyes, pigments, as well as chelating agents and thus attract remarkable attention [1,2]. Recently, we investigated the synthesis of some N1-unsubstituted pyrazolones by use of the PMB (p-methoxybenzyl) protecting group [3,4]. Although this substituent proved to be conveniently removable from various 4-substituted pyrazolones upon treatment with refluxing trifluoroacetic acid only poor results were obtained when the parent 1-PMB-pyrazolone (= 2-(4-methoxybenzyl)-2,4-dihydro- 3H-pyrazol-3-one [3]) was subjected to these conditions. Even prolonged heating (1 week instead of 1 day) did not effect full deprotection (1 day ~ 15%, 2 days ~ 35%, 7 days ~ 75%; monitored by mean of H NMR). Hence, there is need for other and more suitable methods for the synthesis of the unsubstituted pyrazolone 1. With respect to the fact that other hitherto described syntheses of 1 are characterized by multi-step procedures and/or low yields [5,6], we report here an almost quantitative one-step preparation of the fully unsubstituted pyrazolone system from hydrazine hydrate and methyl (2E)-3-methoxyacrylate following an already known procedure for the synthesis of 1-alkyl pyrazolones [7] (Scheme 1). Scheme 1. One-step procedure for the preparation of ‘pyrazolone’ 1. A considerable number of studies deal with the prototropic tautomerism of pyrazolones [8]. Determination of the tautomeric composition of compound 1 is quite challenging as eight possible tautomeric forms have to be considered. This may also be a reason why in the Chemical Abstracts Service (CAS) references are cited for all possible tautomeric forms of compound 1 (Figure 1) except for form E. From the signal multiplicities in the carbon NMR spectra tautomeric forms B, C, F, G, and H can be excluded. Moreover, the N NMR chemical shifts found for compound 1 (–126.5 ppm and –192.0 ppm) rule out form A, as for this tautomer a much smaller chemical shift for the =CH–NH– atom has to be expected (for instance, in phenazone – 1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one – which is structurally related to form A this atom exhibits a chemical shift of –245.1 ppm [9]). The differentiation 1 von 3 24.02.2009 12:54 Molbank 2004 http://www.mdpi.org/molbank/molbank2006/m464.htm between forms D and E is not a trivial task. However, from comparison of the C chemical shifts, the 15 3 13 1 N chemical shifts, the J(H,H) coupling constants, and the different C, H-coupling constants of 1 with those of the corresponding N-phenyl analogues (1-phenyl-1H-pyrazol-3-ol, 1-phenyl-1H-pyrazol-5-ol) [10,11] we assume that form D is predominating in DMSO-d solution. Nevertheless an additional contribution of other isomers (in minor amounts) can not be ruled out. Figure 1. Possible tautomeric forms of ‘pyrazolone’ 1. Compound 1: Under stirring, to a solution of 5.81 g (50 mmol) of methyl (2E)-3-methoxyacrylate in methanol (5 mL) was hydrazine hydrate (2.75 g, 55 mmol) added and the mixture was refluxed for 1h. Evaporation under reduced pressure to dryness gave 4.13 g (98%) of a slightly yellowish powder, pure according to H NMR spectroscopy. Melting point: 160–162 °C, crystal modifications starting at ~140 °C, (lit. [12] 162–164 °C). H-NMR (300 MHz, DMSO-d , 28 °C, numbering for 1H-pyrazol-3-ol = form D) [13]: δ= 9.82 (br s, 2H, 3 3 XH); 7.33 (d, J = 2.3 Hz, 1H, H5); 5.43 (d, J = 2.3 Hz, 1H, H4). (H5,H4) (H4,H5) C-NMR (75 MHz, DMSO-d , 28 °C, numbering for 1H-pyrazol-3-ol = form D) [13]: δ= 161.0 (C3, 2 3 1 2 1 J = 3.4 Hz, J = 9.2 Hz); 130.1 (C5, J = 184.0 Hz, J = 8.2 Hz); 89.3 (C4, J = 175.6 (C3,H4) (C3,H5) (C5,H4) Hz, J = 8.7 Hz). (C4,H5) N-NMR (50 MHz, DMSO-d , 294 K) [14]: δ= –126.5; –192.0. MS (m/z, %) [15]: 84 (M , 100); 55 (24). Elemental Analysis: Calculated for C H N O (84.08): C, 42.86%; H, 4.80%; N, 33.32%. Found: C, 3 4 2 42.75%; H, 4.65%; N, 33.15%. References and /otes: 1. J. Elguero, In 'Comprehensive Heterocyclic Chemistry: Pyrazoles and their Benzo Derivatives', Vol. 5; A. R. Katritzky and C. W. Rees, Eds., Pergamon Press, Oxford, 1984, 167–303. 2. Stanovnik, B.; Svete, J. Product class 1: Pyrazoles. Science of Synthesis 2002, 12, 15–225. 3. Eller, G. A.; Holzer, W. Heterocycles 2004, 63, 2537–2555. 4. Becker, W.; Eller, G. A.; Holzer, W. Synthesis 2005, 2583–2589. 5. Testa, E.; Fontanella, L. Farmaco 1971, 26, 1017–35. 6. Dorn, H.; Zubek, A. J. Prakt. Chem. 1971, 313, 1118–24. 7. Maywald, V.; Steinmetz, A.; Rack, M.; Gotz, N.; Gotz, R.; Henkelmann, J.; Becker, H.; Aiscar Bayeto, PCT Int. Appl. WO 0031042 A2 2000 (Chem. Abstr., 2000, 133, 4655). 8. Holzer, W.; Hallak, L. Heterocycles 2004, 63, 1311–1334, and references cited therein. 9. Cizmarik, J.; Lycka, A. Pharmazie 1988, 43, 794–795. 10. Holzer, W.; Kautsch, C.; Laggner, C.; Claramunt, R. M.; Perez-Torralba, M.; Alkorta, I.; Elguero, J. 2 von 3 24.02.2009 12:54 Molbank 2004 http://www.mdpi.org/molbank/molbank2006/m464.htm Tetrahedron 2004, 60, 6791–6805. 11. Sackus, A.; Holzer, W. manuscript in preparation. 12. Lingens, F.; Schneider-Bernloehr, H. Liebigs Ann. Chem. 1965, 686, 134–144. 13. The spectrum was obtained on a Varian UnityPlus 300 spectrometer (299.95 MHz for H, 75.43 MHz for C). The center of the solvent signal was used as an internal standard which was related to TMS with 1 13 δ 2.49 ppm ( H NMR) and δ 39.5 ppm ( C NMR). 14. The spectrum was obtained on a Bruker Avance 500 spectrometer and was referenced against neat, external nitromethane (coaxial capillary). The signals were not unequivocally assigned to the N atoms. 15. The spectrum was obtained on a Shimadzu QP 1000 instrument (EI, 70eV). Sample Availability: Available from MDPI. © 2006 MDPI. All rights reserved. 3 von 3 24.02.2009 12:54 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Molbank Multidisciplinary Digital Publishing Institute

A one-step synthesis of pyrazolone

Eller, Gernot A.; Holzer, Wolfgang
Molbank , Volume 2006 (1) – Jan 22, 2006
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10.3390/M464
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Abstract

Molbank 2004 http://www.mdpi.org/molbank/molbank2006/m464.htm Molbank 2006, M464 http://www.mdpi.net/molbank/ Gernot A. Eller* and Wolfgang Holzer Department of Drug Synthesis, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria Phone: +43-1-4277-55634, e-mail: gernot.eller@univie.ac.at *Author to whom correspondence should be addressed Received: 3 January 2006 / Accepted: 4 January 2006 / Published: 22 January 2006 Keywords: Pyrazolone, cyclization, NMR spectroscopy, tautomerism. Abstract: The fully unsubstituted pyrazolone (= 2-pyrazolin-5-one, which is tautomer to 1H-pyrazol-3-ol and 1H-pyrazol-5-ol) was prepared from hydrazine hydrate and methyl (2E)-3- 1 13 15 methoxyacrylate in almost quantitative yield. Detailed spectroscopic data ( H NMR, C NMR, N NMR, MS) for this compound are presented. Substituted 2-pyrazolin-5-ones play an important role as substructures of numerous pharmaceuticals, agrochemicals, dyes, pigments, as well as chelating agents and thus attract remarkable attention [1,2]. Recently, we investigated the synthesis of some N1-unsubstituted pyrazolones by use of the PMB (p-methoxybenzyl) protecting group [3,4]. Although this substituent proved to be conveniently removable from various 4-substituted pyrazolones upon treatment with refluxing trifluoroacetic acid only poor results were obtained when the parent 1-PMB-pyrazolone (= 2-(4-methoxybenzyl)-2,4-dihydro- 3H-pyrazol-3-one [3]) was subjected to these conditions. Even prolonged heating (1 week instead of 1 day) did not effect full deprotection (1 day ~ 15%, 2 days ~ 35%, 7 days ~ 75%; monitored by mean of H NMR). Hence, there is need for other and more suitable methods for the synthesis of the unsubstituted pyrazolone 1. With respect to the fact that other hitherto described syntheses of 1 are characterized by multi-step procedures and/or low yields [5,6], we report here an almost quantitative one-step preparation of the fully unsubstituted pyrazolone system from hydrazine hydrate and methyl (2E)-3-methoxyacrylate following an already known procedure for the synthesis of 1-alkyl pyrazolones [7] (Scheme 1). Scheme 1. One-step procedure for the preparation of ‘pyrazolone’ 1. A considerable number of studies deal with the prototropic tautomerism of pyrazolones [8]. Determination of the tautomeric composition of compound 1 is quite challenging as eight possible tautomeric forms have to be considered. This may also be a reason why in the Chemical Abstracts Service (CAS) references are cited for all possible tautomeric forms of compound 1 (Figure 1) except for form E. From the signal multiplicities in the carbon NMR spectra tautomeric forms B, C, F, G, and H can be excluded. Moreover, the N NMR chemical shifts found for compound 1 (–126.5 ppm and –192.0 ppm) rule out form A, as for this tautomer a much smaller chemical shift for the =CH–NH– atom has to be expected (for instance, in phenazone – 1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one – which is structurally related to form A this atom exhibits a chemical shift of –245.1 ppm [9]). The differentiation 1 von 3 24.02.2009 12:54 Molbank 2004 http://www.mdpi.org/molbank/molbank2006/m464.htm between forms D and E is not a trivial task. However, from comparison of the C chemical shifts, the 15 3 13 1 N chemical shifts, the J(H,H) coupling constants, and the different C, H-coupling constants of 1 with those of the corresponding N-phenyl analogues (1-phenyl-1H-pyrazol-3-ol, 1-phenyl-1H-pyrazol-5-ol) [10,11] we assume that form D is predominating in DMSO-d solution. Nevertheless an additional contribution of other isomers (in minor amounts) can not be ruled out. Figure 1. Possible tautomeric forms of ‘pyrazolone’ 1. Compound 1: Under stirring, to a solution of 5.81 g (50 mmol) of methyl (2E)-3-methoxyacrylate in methanol (5 mL) was hydrazine hydrate (2.75 g, 55 mmol) added and the mixture was refluxed for 1h. Evaporation under reduced pressure to dryness gave 4.13 g (98%) of a slightly yellowish powder, pure according to H NMR spectroscopy. Melting point: 160–162 °C, crystal modifications starting at ~140 °C, (lit. [12] 162–164 °C). H-NMR (300 MHz, DMSO-d , 28 °C, numbering for 1H-pyrazol-3-ol = form D) [13]: δ= 9.82 (br s, 2H, 3 3 XH); 7.33 (d, J = 2.3 Hz, 1H, H5); 5.43 (d, J = 2.3 Hz, 1H, H4). (H5,H4) (H4,H5) C-NMR (75 MHz, DMSO-d , 28 °C, numbering for 1H-pyrazol-3-ol = form D) [13]: δ= 161.0 (C3, 2 3 1 2 1 J = 3.4 Hz, J = 9.2 Hz); 130.1 (C5, J = 184.0 Hz, J = 8.2 Hz); 89.3 (C4, J = 175.6 (C3,H4) (C3,H5) (C5,H4) Hz, J = 8.7 Hz). (C4,H5) N-NMR (50 MHz, DMSO-d , 294 K) [14]: δ= –126.5; –192.0. MS (m/z, %) [15]: 84 (M , 100); 55 (24). Elemental Analysis: Calculated for C H N O (84.08): C, 42.86%; H, 4.80%; N, 33.32%. Found: C, 3 4 2 42.75%; H, 4.65%; N, 33.15%. References and /otes: 1. J. Elguero, In 'Comprehensive Heterocyclic Chemistry: Pyrazoles and their Benzo Derivatives', Vol. 5; A. R. Katritzky and C. W. Rees, Eds., Pergamon Press, Oxford, 1984, 167–303. 2. Stanovnik, B.; Svete, J. Product class 1: Pyrazoles. Science of Synthesis 2002, 12, 15–225. 3. Eller, G. A.; Holzer, W. Heterocycles 2004, 63, 2537–2555. 4. Becker, W.; Eller, G. A.; Holzer, W. Synthesis 2005, 2583–2589. 5. Testa, E.; Fontanella, L. Farmaco 1971, 26, 1017–35. 6. Dorn, H.; Zubek, A. J. Prakt. Chem. 1971, 313, 1118–24. 7. Maywald, V.; Steinmetz, A.; Rack, M.; Gotz, N.; Gotz, R.; Henkelmann, J.; Becker, H.; Aiscar Bayeto, PCT Int. Appl. WO 0031042 A2 2000 (Chem. Abstr., 2000, 133, 4655). 8. Holzer, W.; Hallak, L. Heterocycles 2004, 63, 1311–1334, and references cited therein. 9. Cizmarik, J.; Lycka, A. Pharmazie 1988, 43, 794–795. 10. Holzer, W.; Kautsch, C.; Laggner, C.; Claramunt, R. M.; Perez-Torralba, M.; Alkorta, I.; Elguero, J. 2 von 3 24.02.2009 12:54 Molbank 2004 http://www.mdpi.org/molbank/molbank2006/m464.htm Tetrahedron 2004, 60, 6791–6805. 11. Sackus, A.; Holzer, W. manuscript in preparation. 12. Lingens, F.; Schneider-Bernloehr, H. Liebigs Ann. Chem. 1965, 686, 134–144. 13. The spectrum was obtained on a Varian UnityPlus 300 spectrometer (299.95 MHz for H, 75.43 MHz for C). The center of the solvent signal was used as an internal standard which was related to TMS with 1 13 δ 2.49 ppm ( H NMR) and δ 39.5 ppm ( C NMR). 14. The spectrum was obtained on a Bruker Avance 500 spectrometer and was referenced against neat, external nitromethane (coaxial capillary). The signals were not unequivocally assigned to the N atoms. 15. The spectrum was obtained on a Shimadzu QP 1000 instrument (EI, 70eV). Sample Availability: Available from MDPI. © 2006 MDPI. All rights reserved. 3 von 3 24.02.2009 12:54

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