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

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New Synthesis of Pyrazolyl-1,3,4-Oxadiazole and 1,3,4-Oxadiazoline Derivatives

Bertrand Cottineau, Stphanie Renaux, Jacques Chenault and Grald Guillaumet*
Institut de Chimie Organique et Analytique, UMR CNRS 6005, Universit dOrlans, BP 6759, 45067 Orlans 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 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, 80C, 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, Universit dOrlans, BP 6759, 45067 Orlans 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 Eatons 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
2005 Bentham Science Publishers Ltd.

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Letters in Organic Chemistry, 2005, Vol. 2, No. 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.

5a-e

Scheme 2. Reagents and conditions: (a) R1 COR2 , EtOH-H2 O, rt, 8h. (b) Ac2 O, reflux, 6h.

disulfide, an excess of this reagent was periodically (every 6 hours) added to the reaction (Scheme 1, Table 1). Thus, 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. The synthesis of the pyrazolyloxadiazolines 5a-e was achieved using the methodology described by H.L Yale et al. [10] through a cyclization of a pyrazolylhydrazone in acetic anhydride. The proposed mechanism for this reaction consists in the addition of the anhydride to the hydrazone followed by the elimination of acetic acid. The pyrazoles 4a-e [11] were obtained by condensation of the hydrazide 2 with an aldehyde or a ketone, respectively, in good to excellent yields ranging from 74% to 99%. 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, Table 2).
Table 2.
R1 Me Me Ph p-ClPh cyclohexyl
a isolated yield.

[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, we have successfully achieved the synthesis of a series of pyrazolyl-1,3,4-oxadiazole and 1,3,4oxadiazoline derivatives, in one or two steps from the readily available hydrazide 2. The biological activity of these compounds is currently under investigation. REFERENCES
[1] [2] [3] Rostom, S. A. F.; Shahaby, M. A. F.; El Demellawy, M. A. Eur. J. Med. Chem. 2003, 38, 959. Abadi, A. H.; Eeissa, A. A. H.; Hassan, G. S. Chem. Pharm. Bull. 2003, 51, 838. (a) Cottineau, B.; Chenault, J. Synlett, 2002, 769. (b) Cottineau, B.; Toto, P.; Marot, C.; Pipaud, A.; Chenault, J. Bioorg. Med. Chem. Lett., 2002, 12, 2105 (c) Cottineau, B.; Chenault, J.; Guillaumet, G. Tetrahedron Lett., in press. Synthesis of compound 2: A solution of pyrazole 1 (4g, 21.7mmol) in 40mL of hydrazine hydrate is stirred at rt during 5h. After concentration under vacuum, the residue was triturated in ethanol [9]

[4]

and filter off to give a white solid (3.2g, 92%). mp: 177C. 1 H NMR (250 MHz, CDCl3 ) 3.65 (3H, s); 3.80 (3H, s); 4.30 (2H, s); 7.9 (1H, s); 8.1 (1H, s). 13 C NMR (63 MHz, CDCl3 ) 39.0; 58.6; 102.7; 136.6; 161.8; 163.9. MS: 171 [M+H]+. IR (KBr) 1630, 3207, 3307cm-1. (a) Somoghyi, L. Tetrahedron, 1985, 41, 5190. (b) Charisto, D. A.; Vagenas, G. V.; Tzavellas, L. C.; Tsoleridis, C. A.; Rodios, N. A. J. Heterocyclic Chem., 1994, 31, 1593. (c) Rigo, B.; Couturier, D. J. Heterocyclic Chem., 1986, 23, 253. Synthesis of compound 3a: To a stirred solution of compound 2 (0.4g, 2.3mmol) in 10mL of ethanol is added cyanogen bromide (1g, 9.4mmol). The resulting mixture was refluxed during 6h, cooled to rt, neutralized with NaHCO 3 and extracted with CH2 Cl2 . Organic layer was dried over MgSO4 and concentrated under vacuum. Residue was triturated in a mixture of ethyl acetate and acetonitrile and filtered off. Then, filtrate was concentrated under vacuum to give a white solid (230mg, 50%). mp: 210C. 1 H NMR (250 MHz, CDCl3 ) 3.75 (3H, s); 3.87 (3H, s); 6.98 (2H, s); 8.02 (1H, s). 13 C NMR (63 MHz, CDCl 3 ) 39.7; 56.5; 91.7; 132.1; 152.2; 159.6; 163.0. MS: 196 [M+H] +. IR (KBr) 1628, 1672cm-1. Synthesis of compound 3b: To a stirred solution of compound 2 (0.4g, 2.3mmol) in 5mL of DMF, is added acetic anhydride (2.2mL, 23mmol). The resulting mixture was stirred 24h at rt and concentrated under vacuum. The residue was triturated with a mixture of ethanol and isopropylether (9/1) and filtered off. The resulting solid was added to a solution of P2 O5 (0.9g, 6.3mmol) in 4.5mL of MeSO3 H, the reaction mixture was stirred at 80C during 5h, cooled and neutralized with Na2 CO3 . After extraction with CH2 Cl2 , the organic layer was separated, dried over MgSO4 and concentrated under vacuum to give a white solid (260mg, 74%). mp: 170C. 1 H NMR (250 MHz, CDCl3 ) 2.53 (3H, s); 3.78 (3H, s); 4.00 (3H, s); 7.70 (1H, s). 13 C NMR (63 MHz, CDCl3 ) 11.0; 39.5; 56.8; 92.2; 125.9; 131.7; 160.8; 162.0. MS: 195 [M+H]+. IR (KBr) 1628, 1663cm-1. Synthesis of compound 3c : To 25mL of acetic anhydride is added slowly, at 0C, 10mL of formic acid, the resulting solution was warmed to 50C during 30min and cooled to 0C. Pyrazole 2 (3g, 14.6mmol) was added to the solution and reaction mixture was refluxed during 5h. After concentration under vacuum. K2 CO3 solution and CH2 Cl2 were added to the residue, the organic layer was separated, dried over MgSO4 and concentrated under vacuum to give a white solid (1.6g, 50%). mp: 216C. 1 H NMR (250 MHz, CDCl3 ) 3.78 (3H, s); 4.00 (3H, s); 7.77 (1H, s); 8.30 (1H, s). 13 C NMR (63 MHz, CDCl3 ) 39.9; 57.2; 98.3; 132.5; 151.6; 158.9; 160.0. MS: 181 [M+H]+. IR (KBr) 1672cm-1. Synthesis of compound 3d: To a stirred solution of compound 2 (0.5g, 3mmol) in 10mL of a mixture ethanol/water (1/1) is added KOH (168mg, 3mmol). Reaction mixture was stirred 30min at rt and carbon disulfide is added (0.5mL, 9mmol). then, the resulting mixture was refluxed during 48h, adding every 6h 0.5mL of carbone disulfide. After concentration under vacuum, the residue was triturated in 10%HCl, filtered off and washed with water to give a white solid (610mg, 96%). mp>260C. 1 H NMR (250 MHz, CDCl3 ) 3.71 (3H, s); 3.84 (3H, s); 8.20 (1H, s). 13 C NMR (63 MHz, CDCl3 ) 39.9; 57.2; 88.9; 132.4; 154.9; 159.0; 175.3. MS: 213 [M+H]+. IR (KBr) 1635, 1653, 2700cm-1.

New Synthesis of Pyrazolyl-1,3,4-Oxadiazole [10] [11] Yale, H. L.; Losee, K.; Martins, J.; Holsing, M.; Perry, F. M.; Bernstein, J. J. Am. Chem. Soc., 1953, 75, 1933. (a) Synthesis of compound 4a: A solution of compound 2 (2g, 11.2mmol) in 30mL of acetone is refluxed during 6h. After cooling to 0C, the precipitate was filtered off to give a white solid (2.4, 99%). Synthesis of compounds 4b-e , general procedure: A solution of compound 2 (1g, 5.9mmol) and the carbonyl derivative (11.8mmol) in 30mL of a mixture of ethanol and water (1/2) is refluxed during 8h. After concentration under vacuum, the residue was triturated with ether and filtered off to give a white solid. (b) Spectral data for compounds 4a-4e . 4a mp: 152C. 1 H NMR (250 MHz, CDCl3 ) 1.95 (3H, s); 2.15 (3H, s); 3.75 (3H, s); 4.05 (3H, s); 7.85 (1H, s); 9.55 (1H, s). 13 C NMR (63 MHz, CDCl3 ) 16.8; 25.8; 39.9; 57.5; 101.9; 135.6; 153.3; 158.6; 160.0. MS: 211 [M+H] +. IR (KBr) 1671, 3343cm-1. 4b mp: 195C. 1 H NMR (250 MHz, CDCl3 ) 1.33 (3H, t, J =7.2 Hz); 2.10 (3H, s); 3.75 (3H, s); 4.04 (3H, s); 4.29 (2H, q, J =7,2 Hz); 7.86 (1H, s); 9.78 (1H, s). 13 C NMR (63 MHz, CDCl ) 11.9; 14.6; 40.0; 57.7; 62.4; 105.6; 3 107.6; 136.1; 157.0; 165.2; 169.0. MS: 269 [M+H]+. IR (KBr) 1650, 1696, 3326cm-1. 4c mp: 155C. 1 H NMR (250 MHz, CDCl3 ) 3.72 (3H, s); 4.03 (3H, s); 7.28-7.35 (3H, m); 7.70-7.74 (2H, m); 7.82 (1H, s); 8.10 (1H, s); 9.67 (1H, s). 13 C NMR (63 MHz, CDCl3 ) 41.9; 59.4; 103.7; 128.3; 131.0; 132.5; 136.3; 137.8; 149.2; 161.0; 162.0. MS: 259 [M+H]+. IR (KBr) 1668, 3314cm-1. 4d mp: 170C. 1 H NMR (250 MHz, CDCl3 ) 3.69 (3H, s); 3.99 (3H, s); 7.26 (2H, d, J =7,0 Hz); 7.61 (2H, d, J =7,0 Hz); 7.77 (1H, s); 8.05 (1H, s); 9.68 (1H, s). 13 C NMR (63 MHz, CDCl3 ) 40.4; 57.9; 103.7; 129.6; 130.6; 133.4; 136.3; 136.8; 146.3; 159.5; 160.5. MS: 292-294 [M+H]+. IR (KBr) 1668, 3314.cm-1. 4e mp<40C. 1 H NMR (250 MHz, CDCl3 ) 1.56-1.70 (6H, m); 2.27-2.33 (4H, m); 3.67 (3H, s); 3.96 (3H, s); 7.77 (1H,

Letters in Organic Chemistry, 2005, Vol. 2, No. 7

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[12]

s); 9.47 (1H, s). 13 C NMR (63 MHz, CDCl3 ) 25.9; 26.2; 27.1; 35.7; 39.8; 57.5; 102.0; 135.6; 158.9; 159.8; 160.0. MS: 251 [M+H] +. IR (KBr) 1694, 3304.cm-1. (a) Synthesis of compounds 5a-e , general procedure: A solution of compound 4 (2.4mmol) in 5mL of acetic anhydride is refluxed during 6h. After concentration under vacuum, the residue was purified by flash chromatography on silica gel to give a white solid. (b) Spectral data for compounds 5a-e . 5a mp: 128C. 1 H NMR (250 MHz, CDCl3 ) 1.77 (6H, s); 2.25 (3H, s); 3.74 (3H, s); 3.97 (3H, s); 7.49 (1H, s). 13 C NMR (63 MHz, CDCl3 ) 22.8; 24.9; 31.4; 39.8; 57.2; 99.1; 132.7; 149.8; 161.0; 166.5. MS: 253 [M+H] +. IR (KBr) 1638cm-1. 5b mp: 98C. 1 H NMR (250 MHz, CDCl3 ) 1.20 (3H, t, J =7,0 Hz); 1.83 (3H, s); 2.24 (3H, s); 3.71 (3H, s); 3.95 (3H, s); 4.18 (2H, q, J =7,0 Hz); 7.48 (1H, s). 13 C NMR (63 MHz, CDCl3 ) 12.9; 19.3; 20.4; 38.4; 55.7; 61.4; 90.8; 93.4; 131.4; 148.2; 159.9; 165.1; 166.1. MS: 311 [M+H]+. IR (KBr) 1659, 1744cm-1. 5c mp: 149C. 1 H NMR (250 MHz, CDCl3 ) 2.30 (3H, s); 3.72 (3H, s); 3.98 (3H, s); 6.91 (1H, s); 7.32-7.44 (5H, m); 7,52 (1H, s). 13 C NMR (63 MHz, CDCl3 ) 22.7; 40.7; 58.1; 92.0; 93.5; 127.8; 130.0; 131.0; 133.9; 137.8; 152.3; 162.4; 168.8. MS: 301 [M+H]+. IR (KBr) 1648cm-1. 5d mp: 220C. 1 H NMR (250 MHz, CDCl3 ) 2.28 (3H, s); 3.72 (3H, s); 3.98 (3H, s); 6.88 (1H, s); 7.26-7.38 (4H, m); 7.52 (1H, s). 13 C NMR (63 MHz, CDCl3 ) 33.6; 42.2; 59.4; 94.6; 125.2; 130.6; 131.9; 134.6; 140.1; 137.8; 152.5; 163.7; 165.0. MS: 334-336 [M+H] +. IR (KBr) 1624.cm-1. 5e mp: 155C. 1 H NMR (250 MHz, CDCl 3 ) 1.55 (2H, m); 1.75 (6H, m); 2.18 (3H, s); 2.55 (2H, m); 3.70 (3H, s); 3.92 (3H, s); 7.48 (1H, s). 13 C NMR (63 MHz, CDCl 3 ) 23.1; 23.2; 24.6; 32.7; 39.7; 57.1; 93.3; 100.7; 132.6; 149.4; 163.1; 167.0. MS: 293 [M+H]+. IR (KBr) 1653.cm-1.