Letters in Organic Chemistry, 2005, 2, 599-601

599

New Synthesis of Pyrazolyl-1,3,4-Oxadiazole and 1,3,4-Oxadiazoline Derivatives
Bertrand Cottineau, Stéphanie Renaux, Jacques Chenault and Gérald Guillaumet*
Institut de Chimie Organique et Analytique, UMR CNRS 6005, Université d’Orléans, BP 6759, 45067 Orléans Cedex 2, France
Received June 07, 2005: Accepted July 24, 2005

Abstract: The synthesis of hitherto unknown (pyrazol-4-yl)-1,3,4-oxadiazoles described. They were all synthesized in one or two steps from the hydrazide 2.

and

1,3,4-oxadiazolines

is

Keywords: Pyrazolyl-1,3,4-oxadiazoles, pyrazolyl-1,3,4-oxadiazolines. Recently, much attention has focused on the pyrazoles as they have been considered as interesting components in terms of biological activity. For instance, it was demonstrated, last year, that the combination of pyrazole with an oxadiazole (such as compound A) or an oxadiazoline moiety (such as compound B ) could result in the formation of compounds with good anticancer activity (Fig 1). Compound A is cytotoxic [1] meanwhile B exhibits an antiangiogenic [2] activity.
NO2 Cl N Ph N N Ph A N N O O OAc N N B R NH 2 Me H SH
a isolated yield.

pyrazole 1 [3]. In order to get a cleaner reaction, this was carried out at room temperature during five hours (Scheme 1).
Me Me N MeO COOEt 1 N a MeO O CONHNH2 2 R N N 3a-d N N b Me MeO N N

N

N Ac

Scheme 1 . Reagents and conditions: (a) NH2 -NH2 , H2 O, rt, 5h, 92%. (b) Method A (R=NH2 ): BrCN, EtOH, reflux, 6h, 50%. Method B (R=CH3 ): 1) Ac2 O, DMF, 24h. 2) P2 O5 , MeSO3 H, 80°C, 5h, 74%. Method C (R=H): HCOOH, Ac2 O, reflux 5h, 50%. Method D (R=SH): CS2 , KOH, EtOH-H2 O, reflux, 48h, 99%. Table 1. Synthesis of Pyrazolyloxadiazoles 3a-d
Method A B C D 3 3a 3b 3c 3d Yield (%) a 50 74 50 99

Fig. (1). Biologically active pyrazolyloxadiazoles.

In the last few years, we have reported on the reactivity and biological activity of ethyl 3-hydroxy-1H-pyrazole-4carboxylate and especially on the reactions at their N -1, O-3, and C-5 positions. Their in vivo hypoglycemic activities were also disclosed [3]. We now report a new and efficient synthesis of pyrazolyloxadiazoles such as (3-methoxy-1methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazole and 1,3,4-oxadiazoline bearing different substituents at the C-2 position of the oxadiazole. In order to develop a convenient synthetic strategy, we decided to synthesize these compounds starting from the known key intermediate, the 3-methoxy-1-methyl-1Hpyrazol-4-carboxylic acid hydrazide 2 [4]. This compound was obtained by the condensation of hydrazine hydrate, acting also as the solvent, with the ester function of the
*Address correspondence to this author at the Institut de Chimie Organique et Analytique, UMR CNRS 6005, Université d’Orléans, BP 6759, 45067 Orléans Cedex 2, France; E-mail: gerald.guillaumet@univorleans.fr 1570-1786/05 $50.00+.00

The pyrazolyloxadiazoles 3a-d were firstly synthesized using known methodologies [5]. The 2-amino-1,3,4oxadiazole derivative 3a [6] was obtained by condensation of cyanogen bromide on the hydrazide 2, in refluxing ethanol (method A). The methyl substituted oxadiazole was synthesized in two steps. The hydrazide 2 was first acetylated using acetic anhydride in DMF at room temperature, then a dehydration with the Eaton’s reagent produced 3b [7] in 74% overall yield (method B). These conditions were not suitable for the synthesis of nonsubstituted oxadiazole 3c [8]; this was thus achieved in one step by refluxing 2 in formic and acetic anhydride (method C). Finally, the pyrazolyloxadiazole 3d [9] was synthesized in quantitative yield by condensation of an excess of carbon disulfide with the hydrazide 2 in the presence of potassium hydroxide (method D). Due to the volatility of carbon
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CDCl 3 ) 39.600 Letters in Organic Chemistry. 161. The residue was triturated with a mixture of ethanol and isopropylether (9/1) and filtered off. 838.. H.4g. the residue was triturated in 10%HCl. 13 C NMR (63 MHz. 175. 3mmol). 151. 6h.00 (3H. 8.98 (2H. 1 H NMR (250 MHz. 13 C NMR (63 MHz. The resulting solid was added to a solution of P2 O5 (0. s). J. A. s). Abadi. Toto. 6. 2003. 96%).9. rt. MS: 195 [M+H]+. Chem.77 (1H. s). 2005. s).3mmol) in 4. K2 CO3 solution and CH2 Cl2 were added to the residue. Chenault. in one or two steps from the readily available hydrazide 2. 1653. Residue was triturated in a mixture of ethyl acetate and acetonitrile and filtered off.3. 3307cm-1.20 (1H. in good to excellent yields ranging from 74% to 99%. 56. CDCl3 ) 39. 8.0. A. dried over MgSO4 and concentrated under vacuum to give a white solid (260mg. (a) Somoghyi. 58. the reaction mixture was stirred at 80°C during 5h. 131. 1 H NMR (250 MHz.. disulfide. 13 C NMR (63 MHz.6g. is added acetic anhydride (2. El Demellawy. 4. IR (KBr) 1628. 2002. Heterocyclic Chem. 163. Marot. the resulting mixture was refluxed during 48h.. Chem. IR (KBr) 1672cm-1. s). 9mmol).2. The biological activity of these compounds is currently under investigation. 21. s). 160.8. 3. at 0°C.. Synthesis of compound 3a: To a stirred solution of compound 2 (0..5g.84 (3H.9.9. mp: 170°C. 163.. C. 158. CDCl3 ) 3. Table 2. G.1. 38. Synthesis of compound 3d: To a stirred solution of compound 2 (0. 7. 160. s). 10mL of formic acid.65 (3H.3. 14. 9.. Synthesis of compound 3b: To a stirred solution of compound 2 (0. s). adding every 6h 0. 1986. Reaction mixture was stirred 30min at rt and carbon disulfide is added (0. L. reflux. Thus.0. After concentration under vacuum. dried over MgSO4 and concentrated under vacuum to give a white solid (1. 1 H NMR (250 MHz. 92.0. M. Heterocyclic Chem. . (b) Charisto. L. A. we have successfully achieved the synthesis of a series of pyrazolyl-1. 23mmol). s). 3. 23.1 (1H. 125. an excess of this reagent was periodically (every 6 hours) added to the reaction (Scheme 1. 4. Synlett. EtOH-H2 O. CDCl3 ) 2. B. Guillaumet. The reaction of these compounds with acetic acid anhydride resulted in the formation of the desired oxadiazolines 5a-e [12] in moderate to good yields (Scheme 2. (c) Rigo. Couturier. J. 3mmol) in 10mL of a mixture ethanol/water (1/1) is added KOH (168mg.2. s). 2.70 (1H. s).5mL. s). Bioorg. A... 56.9. REFERENCES [1] [2] [3] Rostom. 1672cm-1. 7. 50%).8. The resulting mixture was refluxed during 6h. 12. neutralized with NaHCO 3 and extracted with CH2 Cl2 . Eeissa. [5] [6] [7] Synthesis of Pyrazolyloxadiazolines 5a-e R2 Me COOEt H H 4 4a 4b 4c 4d 4e Yield (%) a 99 89 96 93 74 5 5a 5b 5c 5d 5e Yield (%) a 76 65 37 51 34 [8] In summary.9.4g. R1 Me Me Ph p-ClPh cyclohexyl a isolated yield. Vagenas. 74%). J.4mmol). 2002.30 (1H. 132.2. F. Rodios. the organic layer was separated. Pharm. Pipaud.5.3mmol) in 10mL of ethanol is added cyanogen bromide (1g. 50%). 2700cm-1.. Med. 6. MS: 171 [M+H]+. Organic layer was dried over MgSO4 and concentrated under vacuum.71 (3H. F. G. 2003.9g. D. mp: 216°C. Chenault.6. 39. Shahaby. A. Med. A.0.3mmol) in 5mL of DMF. 8h. CDCl3 ) 3. 2. B. Synthesis of compound 2: A solution of pyrazole 1 (4g. A. mp>260°C. s).7mmol) in 40mL of hydrazine hydrate is stirred at rt during 5h.. 162. 13 C NMR (63 MHz.5. Tetrahedron.7. s).7.8. Table 2).9.02 (1H.78 (3H. Tsoleridis.6mmol) was added to the solution and reaction mixture was refluxed during 5h.00 (3H. s). IR (KBr) 1635. these procedures produced the desired pyrazolyloxadiazoles 3a-d in one or two steps from the hydrazide 2 with yields ranging from 50% to 99% and in a good diversity on the oxadiazole ring.6. 132. C. 4. D.6. filtrate was concentrated under vacuum to give a white solid (230mg. 154. 91. P.80 (3H.75 (3H.5mL of carbone disulfide. A. 159. 1985.6. C. J. 102.5mL of MeSO3 H. 57.. After concentration under vacuum. S. 31. J. The synthesis of the pyrazolyloxadiazolines 5a-e was achieved using the methodology described by H. 8.0. 253.4oxadiazoline derivatives. 3. Vol. 769. IR (KBr) 1630. MS: 213 [M+H]+. 88. 159. The proposed mechanism for this reaction consists in the addition of the anhydride to the hydrazone followed by the elimination of acetic acid.78 (3H.. s). filtered off and washed with water to give a white solid (610mg.. 1994. [10] through a cyclization of a pyrazolylhydrazone in acetic anhydride.L Yale et al. 8. (b) Cottineau. The pyrazoles 4a-e [11] were obtained by condensation of the hydrazide 2 with an aldehyde or a ketone. 3207.7. Reagents and conditions: (a) R1 COR2 . 1593. H. A. s). G. 51. 1 H NMR (250 MHz... Lett. 13 C NMR (63 MHz.. 1 H NMR (250 MHz.9. the residue was triturated in ethanol [9] [4] and filter off to give a white solid (3.9 (1H. Eur.53 (3H. s). 1663cm-1.2g. The resulting mixture was stirred 24h at rt and concentrated under vacuum. Chenault.4. Bull.. s). s). MS: 196 [M+H] +. mp: 177°C. MS: 181 [M+H]+. V. 132. 136. (a) Cottineau. IR (KBr) 1628. CDCl3 ) 11.7. Tetrahedron Lett. 2. cooled to rt. No. 57. 5a-e Scheme 2. 7 Me Me Me N MeO CONHNH2 2 N a MeO O 4a-e N H N R1 R2 R2 R1 N N b O N N Ac MeO N N Cottineau et al.3. A.5. 98. mp: 210°C. cooled and neutralized with Na2 CO3 . then.. Pyrazole 2 (3g. CDCl3 ) 39. After concentration under vacuum. the organic layer was separated. the resulting solution was warmed to 50°C during 30min and cooled to 0°C. Table 1).87 (3H. CDCl3 ) 3. B. M.. 2105 (c) Cottineau. respectively. Tzavellas.4-oxadiazole and 1. CDCl3 ) 3. CDCl3 ) 39. 41. 5190.3. J. 152. After extraction with CH2 Cl2 . Hassan. N. 7. Chem. Then. in press. B.2mL. 959. 3.30 (2H. (b) Ac2 O. 92%).0. Synthesis of compound 3c : To 25mL of acetic anhydride is added slowly. S.2.

05 (3H..5.0 Hz).96 (3H. 159.33 (3H.4. s). 103. 3. 99%).72 (3H.1.3.5. 75.4. 165.3. 2.95 (3H.0. CDCl3 ) 1. s). s). 94. 1 H NMR (250 MHz.3. 93. s). s). CDCl3 ) 33. q.91 (1H. 160. 7. 57.67 (3H.4. J =7. 2.75 (3H.48 (1H. 57.5. MS: 334-336 [M+H] +. CDCl3 ) 1. Am. After cooling to 0°C. 1. s).04 (3H. 2. 4. 131. 165.2. 3. 9. 6. t. d. Perry.72 (3H. general procedure: A solution of compound 2 (1g. 3.3. 3. MS: 251 [M+H] +. s). (b) Spectral data for compounds 4a-4e . 137. 13 C NMR (63 MHz.98 (3H. 152.. 3304. 3. 102. 4. 57.1. Synthesis of compounds 4b-e . 40. 161.7.9. 1 H NMR (250 MHz.7. After concentration under vacuum. Chem. s).67 (1H.1. s).6. 4b mp: 195°C.7.cm-1.30 (3H. the residue was purified by flash chromatography on silica gel to give a white solid.2. 23. 135.28 (3H. 158.8. 5.29 (2H. J. CDCl 3 ) 1. 100.4. 7. 61. 19. 1 H NMR (250 MHz. 162. MS: 293 [M+H]+. 152.0 Hz). H. IR (KBr) 1638cm-1. J =7. 167.92 (3H. CDCl3 ) 1.25 (3H.0. m). Martins.4mmol) in 5mL of acetic anhydride is refluxed during 6h. MS: 269 [M+H]+. 146.88 (1H.2. F. 3.44 (5H. 13 C NMR (63 MHz. 3326cm-1. 1933.69 (3H. IR (KBr) 1650. 5d mp: 220°C. 24. 7.0.68 (1H. 162. 93. 130. J =7. s). 26.8. m). IR (KBr) 1624.20 (3H. 58.4.55 (2H. 140. 168. 136. 131.15 (3H. IR (KBr) 1648cm-1. 134.38 (4H.03 (3H.2.3.6. CDCl3 ) 2. 14. 13 C NMR (63 MHz.. m). CDCl3 ) 1. CDCl3 ) 16. CDCl ) 11. s).56-1. After concentration under vacuum.6. s).0.8. 136. 148. 165. 90. s). 39. s). m). 132. 131. s). s). s).0.6. 129. s). 39.cm-1. 132. Losee. 7. s).35 (3H. CDCl3 ) 25.7. Soc. s). 13 C NMR (63 MHz..9. 3. 13 C NMR (63 MHz. 3.8. d.8. s). s). s). m).55 (1H.28-7. J. 1696. 38. (b) Spectral data for compounds 5a-e .4.9.0.8. CDCl3 ) 1.7.3.4.0. J =7.. J =7. 59.1.4. s). 128. 13 C NMR (63 MHz. CDCl3 ) 2.8. J =7. 163. MS: 292-294 [M+H]+. 3. 3314cm-1.48 (1H. 62. 149. 4. 131.74 (3H.9mmol) and the carbonyl derivative (11. 7. 1 H NMR (250 MHz. 4.8. 7 601 [12] s).26-7. s).05 (1H.75 (6H.83 (3H. 160. 136. 11. 35. 8. MS: 211 [M+H] +. IR (KBr) 1668.61 (2H.4. J.9. 159. q. 5b mp: 98°C.7.10 (3H. the precipitate was filtered off to give a white solid (2.1. CDCl3 ) 12. 25.78 (1H.0. 4d mp: 170°C.52 (1H. MS: 259 [M+H]+.0. s).98 (3H. Holsing. 5a mp: 128°C. s).82 (1H.26 (2H. 1 H NMR (250 MHz.86 (1H.1.7. 101. 103. m). 149. 39. 2. s). IR (KBr) 1653. s).6. s).0.2. 55. 166. 105..85 (1H. s). m).9. 163.9. the residue was triturated with ether and filtered off to give a white solid.95 (3H. 24. 149. s).1. s).8. 4c mp: 155°C. 5c mp: 149°C.5. s). 133. s).3. 4a mp: 152°C.9.10 (1H. s). M. 9. 2.4. 158.5. 6. (a) Synthesis of compounds 5a-e .70 (6H.8. s). 1744cm-1.75 (3H. 7.9. 161. 13 C NMR (63 MHz. 9.8.2mmol) in 30mL of acetone is refluxed during 6h. (a) Synthesis of compound 4a: A solution of compound 2 (2g. 5e mp: 155°C.32-7. 7. 7.77 (1H. 2. IR (KBr) 1659.0 Hz). 127. Bernstein.4. 132. 153.99 (3H.7. 3.4-Oxadiazole [10] [11] Yale.2.27-2. 2005.0.2. 130. 2. 1 H NMR (250 MHz. 160. general procedure: A solution of compound 4 (2. CDCl3 ) 22. 4. 57. 7. 3. 13 C NMR (63 MHz. 3.6. 13 C NMR (63 MHz. Letters in Organic Chemistry.9.6. 57. 3.8. M. 42. 3314. 157. 3343cm-1. 7.70 (3H. MS: 253 [M+H] +.3.0.0.2 Hz). s). CDCl3 ) 22. 133.9. s).70-7. s).7.6. 159.1.24 (3H. 7. s). 9. CDCl 3 ) 23. 3 107. t.72 (3H. 7. 7. m). s).6. s).6. m).4. 9. No. 1953.8. 135.52 (1H. 169. 1 H NMR (250 MHz. CDCl3 ) 41. s).8mmol) in 30mL of a mixture of ethanol and water (1/2) is refluxed during 8h.1.5. 166.18 (3H. 130.2 Hz).1. 3. 32. 125. 7.6. 8.71 (3H.7. 93.33 (4H.6.97 (3H. 4e mp<40°C.0. 99. 1. 1 H NMR (250 MHz.47 (1H. MS: 301 [M+H]+.18 (2H. s).49 (1H. s). . 27. 136.7.cm-1. 59.9. 39. CDCl3 ) 3. 2.2. 1 H NMR (250 MHz.6. CDCl3 ) 40.5.3. L. s). 31. 40. 92.77 (1H. 1 H NMR (250 MHz. IR (KBr) 1668. Vol.0.4. MS: 311 [M+H]+. 7. 13 C NMR (63 MHz. 57.9.6.New Synthesis of Pyrazolyl-1. IR (KBr) 1671.55 (2H. 20.8. s).0 Hz).cm-1. 137. 3.7. CDCl3 ) 3.74 (2H.77 (6H. 7. 137.4. IR (KBr) 1694. K.5.

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