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Letters in Organic Chemistry, 2005,2, 599-601 599
New Synthesis of Pyrazolyl-1,3,4-Oxadiazole and 1,3,4-OxadiazolineDerivatives
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 and 1,3,4-oxadiazolines is
described. They were all synthesized in one or two steps from the hydrazide 2.
Keywords: Pyrazolyl-1,3,4-oxadiazoles, pyrazolyl-1,3,4-oxadiazolines.
Recently, much attention has focused on the pyrazoles asthey have been considered as interesting components interms of biological activity. For instance, it wasdemonstrated, last year, that the combination of pyrazolewith an oxadiazole (such as compoundA) or an oxadiazolinemoiety (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 anantiangiogenic [2] activity.
pyrazole 1 [3]. In order to get a cleaner reaction, this wascarried out at room temperature during five hours (Scheme1).
NN
Me
MeO
COOEt
NN
Me
MeO
CONHNH2
NN
O
N
N
MeO
Me
R
a b
12 3a-d
NNN
N
OPh OAc
Cl
A
NN
Ph
O
N
NAc
N
NO2
B
Scheme 1 . Reagents and conditions: (a) NH2-NH2, H2O, rt, 5h
92%. (b) Method A (R=NH2): BrCN, EtOH, reflux, 6h, 50%
Method B (R=CH3): 1) Ac2O, DMF, 24h. 2) P2O5, MeSO3H
80C, 5h, 74%. Method C (R=H): HCOOH, Ac2O, reflux 5h, 50%
Method D (R=SH): CS2, KOH, EtOH-H2O, reflux, 48h, 99%.
Table 1. Synthesis of Pyrazolyloxadiazoles 3a-d
R Method 3 Yield (%)a
NH2 A 3a 50
Fig. (1). Biologically active pyrazolyloxadiazoles.Me B 3b 74
In the last few years, we have reported on the reactivityand biological activity of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate and especially on the reactions at theirN-1, O-3,and C-5 positions. Their in vivo hypoglycemic activitieswere also disclosed [3]. We now report a new and efficientsynthesis of pyrazolyloxadiazoles such as (3-methoxy-1-methyl-1H-pyrazol-4-yl)-1,3,4-oxadiazole and 1,3,4-oxa-diazoline bearing different substituents at the C-2 position ofthe oxadiazole.
H C 3c 50
SH D 3d 99
aisolated yield.
The pyrazolyloxadiazoles 3a-d were firstly synthesizedusing known methodologies [5]. The 2-amino-1,3,4-oxadiazole derivative 3a [6] was obtained by condensation ofcyanogen bromide on the hydrazide 2, in refluxing ethanol(method A). The methyl substituted oxadiazole wassynthesized in two steps. The hydrazide 2 was firsacetylated using acetic anhydride in DMF at roomtemperature, then a dehydration with the Eatons reagent
produced3b [7] in 74% overall yield (method B). Theseconditions were not suitable for the synthesis of non-substituted oxadiazole 3c [8]; this was thus achieved in onestep by refluxing 2 in formic and acetic anhydride (methodC). Finally, the pyrazolyloxadiazole 3d [9] was synthesizedin quantitative yield by condensation of an excess of carbondisulfide with the hydrazide 2 in the presence of potassiumhydroxide (method D). Due to the volatility of carbon
In order to develop a convenient synthetic strategy, wedecided to synthesize these compounds starting from theknown key intermediate, the 3-methoxy-1-methyl-1H-
pyrazol-4-carboxylic acid hydrazide 2 [4]. This compoundwas 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 ChimieOrganique et Analytique, UMR CNRS 6005, Universit dOrlans, BP6759, 45067 Orlans Cedex 2, France; E-mail: [email protected]
1570-1786/05 $50.00+.00 2005 Bentham Science Publishers Ltd.
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600 Letters in Organic Chemistry, 2005, Vol. 2, No. 7 Cottineau et al
NN
Me
MeO
CONHNH2
NN
Me
MeO
NON R2
R1H
NN
O
N
N
MeO
Me
AcR1
R2
25a-e
ab
4a-e
Scheme 2. Reagents and conditions: (a) R1COR2, EtOH-H2O, rt, 8h. (b) Ac2O, reflux, 6h.
disulfide, an excess of this reagent was periodically (every 6hours) added to the reaction (Scheme 1, Table 1).
and filter off to give a white solid (3.2g, 92%). mp: 177C. 1HNMR (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.
Thus, these procedures produced the desiredpyrazolyloxadiazoles 3a-d in one or two steps from thehydrazide 2 with yields ranging from 50% to 99% and in agood diversity on the oxadiazole ring.
[5] (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, DJ. Heterocyclic Chem., 1986, 23, 253.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 inacetic anhydride. The proposed mechanism for this reactionconsists in the addition of the anhydride to the hydrazonefollowed by the elimination of acetic acid.
[6] Synthesis of compound3a: 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 6hcooled to rt, neutralized with NaHCO3 and extracted with
CH2Cl2. Organic layer was dried over MgSO4 and concentrated
under vacuum. Residue was triturated in a mixture of ethyacetate and acetonitrile and filtered off. Then, filtrate wasconcentrated under vacuum to give a white solid (230mg, 50%)
mp: 210C. 1H 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, CDCl3) 39.7
56.5; 91.7; 132.1; 152.2; 159.6; 163.0. MS: 196 [M+H]+. IR (KBr
1628, 1672cm-1.
The pyrazoles 4a-e [11] were obtained by condensation ofthe hydrazide 2 with an aldehyde or a ketone, respectively,in good to excellent yields ranging from 74% to 99%. Thereaction of these compounds with acetic acid anhydrideresulted in the formation of the desired oxadiazolines 5a-e[12] in moderate to good yields (Scheme 2, Table 2). [7] Synthesis of compound3b: 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 andconcentrated under vacuum. The residue was triturated with amixture of ethanol and isopropylether (9/1) and filtered off. Theresulting solid was added to a solution of P2O5 (0.9g, 6.3mmol) in
4.5mL of MeSO3H, the reaction mixture was stirred at 80Cduring 5h, cooled and neutralized with Na2CO3. After extraction
with CH2Cl2, the organic layer was separated, dried over MgSO4and concentrated under vacuum to give a white solid (260mg
74%). mp: 170C. 1H NMR (250 MHz, CDCl3) 2.53 (3H, s)
3.78 (3H, s); 4.00 (3H, s); 7.70 (1H, s). 13 C NMR (63 MHzCDCl3) 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.
Table 2. Synthesis of Pyrazolyloxadiazolines 5a-e
R1 R2 4 Yield (%)a 5 Yield (%)a
Me Me 4a 99 5a 76
Me COOEt 4b 89 5b 65
Ph H 4c 96 5c 37
p-ClPh H 4d 93 5d 51
cyclohexyl 4e 74 5e 34[8] Synthesis of compound3c: To 25mL of acetic anhydride is added
slowly, at 0C, 10mL of formic acid, the resulting solution waswarmed to 50C during 30min and cooled to 0C. Pyrazole 2 (3g14.6mmol) was added to the solution and reaction mixture wasrefluxed during 5h. After concentration under vacuum. K2CO3solution and CH2Cl2 were added to the residue, the organic laye
was separated, dried over MgSO4 and concentrated unde
vacuum to give a white solid (1.6g, 50%). mp: 216C. 1H 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.
aisolated yield.
In summary, we have successfully achieved the synthesisof a series of pyrazolyl-1,3,4-oxadiazole and 1,3,4-oxadiazoline derivatives, in one or two steps from thereadily available hydrazide 2. The biological activity of thesecompounds is currently under investigation.
REFERENCES[9] Synthesis of compound3d: To a stirred solution of compound 2
(0.5g, 3mmol) in 10mL of a mixture ethanol/water (1/1) is addedKOH (168mg, 3mmol). Reaction mixture was stirred 30min at rand carbon disulfide is added (0.5mL, 9mmol). then, the resultingmixture was refluxed during 48h, adding every 6h 0.5mL ofcarbone disulfide. After concentration under vacuum, the residuewas triturated in 10%HCl, filtered off and washed with water to
give a white solid (610mg, 96%). mp>260C. 1H 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.
[1] Rostom, S. A. F.; Shahaby, M. A. F.; El Demellawy, M. A. Eur. J.Med. Chem. 2003, 38, 959.
[2] Abadi, A. H.; Eeissa, A. A. H.; Hassan, G. S. Chem. Pharm. Bull.2003, 51, 838.
[3] (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.
[4] Synthesis of compound2: A solution of pyrazole 1 (4g, 21.7mmol)in 40mL of hydrazine hydrate is stirred at rt during 5h. Afterconcentration under vacuum, the residue was triturated in ethanol
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New Synthesis of Pyrazolyl-1,3,4-Oxadiazole Letters in Organic Chemistry, 2005, Vol. 2, No. 7 601
[10] Yale, H. L.; Losee, K.; Martins, J.; Holsing, M.; Perry, F. M.;Bernstein, J.J. Am. Chem. Soc., 1953, 75, 1933.
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.[11] (a) Synthesis of compound 4a: A solution of compound 2 (2g,11.2mmol) in 30mL of acetone is refluxed during 6h. Aftercooling to 0C, the precipitate was filtered off to give a white solid(2.4, 99%). Synthesis of compounds 4b-e, general procedure: Asolution of compound2 (1g, 5.9mmol) and the carbonyl derivative(11.8mmol) in 30mL of a mixture of ethanol and water (1/2) isrefluxed during 8h. After concentration under vacuum, theresidue was triturated with ether and filtered off to give a white
solid.
[12] (a) Synthesis of compounds 5a-e , general procedure: A solutionof compound4 (2.4mmol) in 5mL of acetic anhydride is refluxedduring 6h. After concentration under vacuum, the residue wa
purified by flash chromatography on silica gel to give a whitesolid.
(b) Spectral data for compounds 5a-e . 5a mp: 128C. 1H 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. 1H NMR (250 MHzCDCl3) 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 CNMR (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. 1H NMR (250 MHzCDCl3) 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. 1H 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 CNMR (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. 1H NMR (250MHz, CDCl3) 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 (63MHz, CDCl3) 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
(b) Spectral data for compounds 4a-4e. 4a mp: 152C. 1H 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). 13C 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. 1H NMR (250MHz, 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, CDCl3) 11.9; 14.6; 40.0; 57.7; 62.4; 105.6;
107.6; 136.1; 157.0; 165.2; 169.0. MS: 269 [M+H]+. IR (KBr)
1650, 1696, 3326cm-1. 4c mp: 155C. 1H 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 (63MHz, 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. 1H 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