A series of six pyrazoles was synthesized by Michael-type addition reaction. The molecules 5- amino-1- aryl-1H- pyrazole-4- carbonitrile (3a-f) were synthesized from (ethoxymethylene)malo-nonitrile (1) and fluorinated and non-fluorinated aryl hydrazines (2a-f) using ethanol and fluorinated ethanol as solvents at reflux. An excellent regio-selectivity was found when pyrazole derivatives were formed as an exclusive product. No other regioisomer or uncyclised hydrazide was observed. Their structures were confirmed by spectroscopy data ( 1H, 13C, 19F, COSY (correlation spectroscopy), HSQC (heteronuclear single-quantum correlation spectroscopy) and HMBC (heteronuclear multiple-bond correlation spectroscopy); MS (mass-spectrometry). The yields ranged from good to excellent (47% - 93%) under mild reaction conditions. It would indicate a high selectivity in the one-step work procedure. These products (3a-f) and derivatives have a potential academic and industrial use as key intermediates, in special, for application in crop protection.
Heterocyclic compounds containing nitrogen have played a major role in modern pesticide industry; it has been reported that more than 85% of pesticides with high activity and low toxicity contain nitrogen heterocyclic com- pounds [
Several compounds of this type can be directly applied as pest-control agents, in particular as acaricides and nematicides [
Pyrazole compounds prepared by chemists and biologists have gained widespread attention as they have become fairly accessible and show diverse properties [
As a pharmacophore, the 1-alkyl or aryl-1H-pyrazole unit has been patented and widely reported in previous studies [
Experiments on aryl pyrazole insecticides began in 1985 [
In previous papers, our group reported the synthesis of a series of fluorinated pyrazole-5-carboxamide de- rivatives structurally related to the commercial acaricide Tebufenpyrad (
All the reagents were commercially available and used as received from the supplier. The solvents were analyt-
iccal-grade and were purified according to standard methods. The purity and chemical structure of the synthesized compounds were checked by TLC, CG, UPLC-MS, HRMS (in case 2b and 2e), NMR spectra, and melting point.
Analytical TLC was performed on a Merck precoated TLC plate (Silica Gel 60 F254). Gas chromathographic (GC) analyses were performed on a DANI Master GC chromatograph equipped with a 5% diphenyl, 95% dimethylpolysiloxane, low bleed capillary column (30 m × 0.53 mm, 0.5 mm film thickness) and a flame ionization detector. Column Chromatography was performed on silica gel (70 - 230 mesh ASTM). High-purity grade, pore size 60 Å. Isolated and authentic compounds were used as internal standards to perform quantitative GC analyses. Ultra performance liquid chromatography and mass-spectrometry (UPLC-MS) analyses were performed on a H-CLASS SQD2 Detector (Waters). HRMS were obtained on a Bruker micro QTOF-Q11 mass spectrometer equipped with an electrospray ionization (ESI). 1H NMR (300 MHz), 13C NMR (75 MHz). 19F NMR (300 MHz), COSY (Correlation spectroscopy), HSQC (heteronuclear single-quantum correlation spectroscopy) and HMBC (heteronuclear multiple-bond correlation spectroscopy) experiments were recorded on a Bruker Avance 300 spectrometer in CDCl3 using TMS as internal standard. Coupling constants are given in Hz and chemical shifts are reported in δ values in ppm. Data are reported as follows: chemical shift, multiplicity (s = singlet, s br = broad singlet, d = doublet, t = triplet, m = multiplet), coupling constants (Hz), and integration. Melting points (Mp) were recorded on a Büchi b-540 micro melting point apparatus and were uncorrected.
To a solution of aryl hydrazine (2a-f) [phenylhydrazine 2a, 4-fluorophenylhydrazine hydrochloride 2b, (per- fluorophenyl)hydrazine 2c, 4-(trifluoromethyl)phenylhydrazine 2d, [2,6-dichloro-4-(trifluoromethyl)phenyl] hy- drazine 2e, and 4-methoxyphenylhydrazine hydrochloride 2f]; i.e., (1.2 mmol) in absolute ethanol (or trifluoro- ethanol) (2 mL) with stirring, (ethoxymethylene)malononitrile (1) was added slowly. Once the addition was complete, the solution was carefully brought to reflux keeping nitrogen atmosphere.
The reaction mixture was refluxed for 4 hours except for 3a (0.5 hours). The reaction crude was purified by column chromatography on silica gel adsorption with a hexane/ethyl acetate gradient mixture as eluants. The above mentioned general procedure gave 3a-f in 84%, 47%, 63%, 67%, 47%, and 68% yields, respectively. Once purified, the pyrazole was characterized by NMR (1H, 13C, 19F, COSY, HSQC and HMBC).
For aryl hydrazines hydrochlorides 2b, 2f (1.2 mmol), a previous step of neutralization with Et3N (1.0 mmol) at 0˚C in ethanol (2 mL) was needed. Then, (ethoxymethylene)malononitrile (1) was added as described in the methodology above. In this case, the reaction crude was diluted with ethyl acetate (50 mL) and washed with water (30 mL). The organic phase obtained was dried over Na2SO4, filtered, and the organic solvent was eva- porated under reduced pressure. The workup and purification of the crude product was identical with that described above.
a) 5-Amino-1-phenyl-1H-pyrazole-4-carbonitrile (3a)
Compound 3a was obtained according to the general procedure. The product was purified by column chroma- tography on silica gel eluting with hexane/ethyl acetate gradient (5:1 → 3:1) and was isolated as white crystals (84%); Mp = 138.5˚C - 139.6˚C (140.0˚C - 140.5˚C) [
b) 5-Amino-1-(4-fluorophenyl)-1H-pyrazole-4-carbonitrile (3b)
Compound 3b was obtained according to the general procedure. The product was purified by column chroma- tography on silica gel eluting with hexane/ethyl acetate gradient (6:1 → 4:1) and was isolated as white powder (47 %); Mp = 178.5˚C - 179.8˚C (177.0˚C - 178.0˚C) [
c) 5-Amino-1-(perfluorophenyl)-1H-pyrazole-4-carbonitrile (3c)
Compound 3c was obtained according to the general procedure. The product was purified by column chroma- tography on silica gel eluting with hexane/ethyl acetate gradient (7:1 → 5:1) and was isolated as a white solid (63 %); Mp = 135.4˚C - 136.4˚C; 1H NMR [300 MHz (CDCl3)] δ = 4.69 (s br, 2H, NH2); 7.73 (s, 1H, CH); 19F NMR [300 MHz] δ = −158.95 (t, 2F); −148.58 (t, 1F); −143.24 (d, 2F).13C NMR [75 MHz]: δ = 76.4(C); 113.1 (C); 143.4 (CH); 152.1 (C). It was not possible to assign the other carbons corresponding to this molecule. 1H-1H COSY NMR (300 MHz, CDCl3) δH/δH 7.76/7.76, 4.72/4.72. 1H-13C HSQC NMR (300 MHz, CDCl3) δH/δC 7.75/143.4.1H-13C HMBC NMR δH/δC 7.76/76.4, 7.76/112.1, 7.76/152.1. HRMS (ESI−): Anal.Calcd. for C10H3F5N4−: 273.0194; found: 273.0206.
d) 5-Amino-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-4-carbonitrile (3d)
Compound 3d was obtained according to the general procedure. The product was purified by column chroma- tography on silica gel eluting with hexane/ethyl acetate gradient (6:1 → 4:1) and was isolated as yellow solid (67 %); Mp = 156.9˚C - 158.3˚C (170.0˚C - 171.0˚C) [
e) 5-Amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-1H-pyrazole-4-carbonitrile (3e)
Compound 3e was obtained according to the general procedure. The product was purified by column chroma- tography on silica gel eluting with hexane/ethyl acetate gradient (6:1 → 3:1) and was isolated as white solid (47%); Mp = 163.5˚C - 164.8˚C; 1H NMR [300 MHz (CDCl3)] δ = 4.70 (s br, 2H, NH2); 7.72 (s, 1H, CH); 7.77 (s, 2H, CH). 19F NMR [300 MHz] δ = −63.22 (s, 2F).13C NMR [75 MHz]: δ = 75.4 (C); 113.4 (C); (116.5, 120.1, 123.7, 127.3, q, 1J = 273.58Hz -CF3); 126.2 (CH); (133.8, 134.2, 134.7, 134.9,q, 2J = 34.59Hz-CF3); 136.7(C); 142.9 (CH); 151.4(C). 1H-1H COSY NMR (300 MHz, CDCl3) δH/δH 7.77/7.77, 7.72/7.72, 4.69/4.69. 1H-13C HSQC NMR (300 MHz, CDCl3) δH/δC 7.77/126.2, 7.72/142.9.1H-13C HMBC NMR δH/δC 7.77/75.4, 7.77/134.7, 7.77/136.7. HRMS (ESI+): Anal. Calcd. for C11H5Cl2F3N4Na+: 342.9736.; found: 342.9731.
f) 5-Amino-1-(4-methoxyphenyl)-1H-pyrazole-4-carbonitrile (3f)
Compound 3f was obtained according to the general procedure. The product was purified by column chroma- tography on silica gel eluting with hexane/ethyl acetate gradient (6:1 → 3:1) and was isolated as a dark yellow powder (68%); Mp = 148.4˚C - 148.8˚C (144.9˚C - 145.9˚C) [
It is known that (ethoxymethylene)malononitrile can undergo not only 1,3-dipolar cycloadditions but also nu- cleophilic addition with hydrazines to selectively produce aminopyrazoles or hydrazides [
Scheme 1. Synthesis of 5-amino-1-aryl-1H-pyrazole-4-carbonitriles (3a-f).3a Ar = C6H5; 3b Ar = 4-F-C6H4; 3c Ar = C6F5; 3d Ar = 4-CF3-C6H5; 3e Ar = 2,6-Cl2-4-CF3-C6H2; 3f Ar = 4- CH3O-C6H4.
Initially, it was showen the effectiveness of TFE as a solvent in the preparation of 5-amino-1-phenyl-1H-pyra- zole-4-carbonitrile 3a. (Ethoxymethylene)malononitrile 1 was treated with phenylhydrazine 2a at reflux in various solvents (TFE, EtOH, MeOH and THF) (
In order to show the generalities of this reaction, different substituted pyrazoles were synthesized using a variety of aryl hydrazines in TFE as a solvent, chosen for its great yield in the first assays (
The low to moderate yields obtained from TFE in the synthesis of different aryl pyrazoles were compared with the results obtained from the synthesis carried out under the same reaction conditions with EtOH as a solvent (
The synthesis of the compounds 3a-f was accomplished in a one-step reaction. Yields ranged from good to excellent (46% - 93%), though no attempt was made to optimize the conditions for each reaction.
A detailed study of different aryl hidrazines was performed toward the formation of aryl pyrazole derivatives (
It was found that the yield is high (93%) when there are no substituents in the hydrazine ring 3a, (
Entry | Solventsa | Time (h) | Product | Yieldsb (%) |
---|---|---|---|---|
1 | TFE | 0.5 | 3a | (100)c |
2 | EtOH | 0.5 | 3a | 84 (93)c |
3 | THF | 0.5 | 3a | (33)c |
4 | MeOH | 0.5 | 3a | (60)c |
a. TFE: Trifluoroethanol; EtOH: Ethanol; THF: Tetrahydrofuran; MeOH: Methanol.b. Isolated yields.c. Quantified by GC (internal standard method).
Entry | Time (h) | Products | Yieldsa (%) |
---|---|---|---|
1 | 0.5 | 3a | (100)b |
2 | 4 | 3b | 29 (30)b |
3 | 4 | 3c | (20)b |
4 | 4 | 3d | 28 (30)b |
5 | 4 | 3f | 46 (43)b |
a. Isolated yields.b. Quantified by GC (internal standard method).
Entry | Ar | Productsa | Time (h) | Yieldsb (%) | ||
---|---|---|---|---|---|---|
Found | Reported | Ref. | ||||
1 | 0.5 | 84 (93)c | 69 | [ | ||
2 | 4 | (66)c | 97 | [ | ||
3 | 4 | 63 (65)c | [ | |||
4 | 4 | 67 (80)c | 71 | [ | ||
5 | 4 | 47 (46)c | [ | |||
6 | 4 | 68 | 69 | [ |
a. All the products were characterized by 1H NMR, 13C NMR, 19F NMR, COSY, HSQC, HMBC and MS spectral data. b. Isolated yields. c. Quantified by GC (internal standard method).
After reviewing the literature, a plausible mechanism for the formation of the 5-amino-1-aryl-1H-pyrazole-4- carbonitriles (3a-f) may be explained by the initial Michael type addition [
Scheme 2. A plausible mechanism for the formation of 3a-f.
This study has clearly demonstrated that 5-amino-1-aryl-1H-pyrazole-4-carbonitriles can be synthesized and used as predecessors―key intermediates―of a wide variety of heterocycles for academic interest and agroche- mical applications. We have shown that it is possible to synthesize a series of six pyrazoles by a one-step reaction involving the refluxing of the reactants in ethanol as the most suitable solvent. A plausible mechanism was proposed to explain the regioselectivity observed for the reaction. In general, the yields of pyrazoles obtained under the experimental conditions with aromatic hydrazines and (ethoxymethylene)malononitrile ranged from good to excellent, with a simple and efficient methodology. The aryl pyrazoles 3a-f were obtained and characterized by NMR and MS spectroscopy. It is worth mentioning that the functional groups (i.e. cyano, amine and fluor) in the pyrazole moiety could have interesting applications in the crop protection. Currently, we are working with these key intermediaries to the development of new agrochemicals.
The present work is partially supported by National Ministry of Science and Technology (MINCyT), CONICET, and UNL of Argentina. We also acknowledge to Dr. Javier Fernando Guastavino for his contribution in the pre- paration of this paper and for obtaining the NMR analyses data.
Experimental Section
1) General
All the reagents were commercially available and used as received from the supplier. The solvents were analytical-grade and were purified according to standard methods. The purity and chemical structure of the synthesized compounds were checked by TLC, CG, UPLC-MS, HRMS (in case 2b and 2e), NMR spectra, and melting point.
Analytical TLC was performed on a Merck precoated TLC plate (Silica Gel 60 F254). Gas chromathographic (GC) analyses were performed on a DANI Master GC chromatograph equipped with a 5% diphenyl, 95% dimethylpolysiloxane, low bleed capillary column (30 m × 0.53 mm, 0.5 µm film thickness) and a flame ionization detector. Column Chromatography was performed on silica gel (70 - 230 mesh ASTM). High-purity grade, pore size 60 Å. Isolated and authentic compounds were used as internal standards to perform quantitative GC analyses. Ultra performance liquid chromatography and mass-spectrometry (UPLC-MS) analyses were performed on a H-CLASS SQD2 Detector (Waters). HRMS were obtained on a Bruker micro QTOF-Q11 mass spectrometer equipped with an electrospray ionization (ESI). 1H NMR (300 MHz), 13C NMR (75 MHz). 19F NMR (300 MHz), COSY, HSQC and HMBC experiments were recorded on a Bruker Avance 300 spectrometer in CDCl3 using TMS as internal standard. Coupling constants are given in Hz and chemical shifts are reported in δ values in ppm. Data are reported as follows: chemical shift, multiplicity (s = singlet, s br = broad singlet, d = doublet, t = triplet, m = multiplet), coupling constants (Hz), and integration. Melting points were recorded on a Büchi b-540 micro melting point apparatus and were uncorrected.
2) General Procedure for the Synthesis of 5-amino-1-aryl-1H-pyrazole-4-carbonitriles (3af)
To a solution of aryl hydrazine (2a-f) [phenylhydrazine 2a, 4-fluorophenylhydrazine hydrochloride 2b, (per- fluorophenyl)hydrazine 2c, 4-(trifluoromethyl)phenylhydrazine 2d, [2,6-dichloro-4-(trifluoromethyl) phenyl] hydrazine 2e, and 4-methoxyphenylhydrazine hydrochloride 2f]; i.e., (1.2 mmol) in absolute ethanol (or trifle- oroethanol) (2 ml) with stirring, (ethoxymethylene)malononitrile (1) was added slowly. Once the addition was complete, the solution was carefully brought to reflux keeping nitrogen atmosphere.
The reaction mixture was refluxed for 4 hours except for 3a (0.5 hours). The reaction crude was purified by column chromatography on silica gel adsorption with a hexane/ethyl acetate gradient mixture as eluants. The above mentioned general procedure gave 3a-f in 84%, 47%, 63%, 67%, 47%, and 68% yields, respectively. Once purified, the pyrazole was characterized by NMR (1H, 13C, 19F, COSY, HSQC and HMBC).
For aryl hydrazines hydrochlorides 2b, 2f (1.2 mmol), a previous step of neutralization with Et3N (1.0 mmol) at 0˚C in ethanol (2 ml) was needed. Then, (ethoxymethylene)malononitrile (1) was added as described in the methodology above. In this case, the reaction crude was diluted with ethyl acetate (50 ml) and washed with water (30 ml). The organic phase obtained was dried over Na2SO4, filtered, and the organic solvent was evaporated under reduced pressure. The workup and purification of the crude product was identical with that described above.
3) Characterization of Products
5-amino-1-phenyl-1H-pyrazole-4-carbonitrile (3a): Compound 3a was obtained according to the general pro- cedure. The product was purified by column chromatography on silica gel eluting with hexane/ethyl acetate gradient (5:1 → 3:1) and was isolated as white crystals. (84%); M.p. 138.5˚C - 139.6˚C (140.0˚C - 140.5˚C) [
1H NMR, 13C NMR, COSY, HSQC, HMBC and MS Spectra:
5-amino-1-(4-fluorophenyl)-1H-pyrazole-4-carbonitrile (3b): Compound 3b was obtained according to the general procedure. The product was purified by column chromatography on silica gel eluting with hexane /ethyl acetate gradient (6:1 → 4:1) and was isolated as white powder. (47%); M.p. 178.5˚C - 179.8˚C (177.0˚C - 178.0˚C) [
1H NMR, 13C NMR, COSY, HSQC, HMBC and MS Spectra:
5-amino-1-(perfluorophenyl)-1H-pyrazole-4-carbonitrile (3c): Compound 3c was obtained according to the general procedure. The product was purified by column chromatography on silica gel eluting with hexane/ethyl acetate gradient (7:1 → 5:1) and was isolated as white solid. (63 %); M.p. 135.4˚C - 136.4˚C; 1H RMN [300 MHz (CDCl3)] δ = 4.69 (s br, 2H, NH2); 7.73 (s, 1H, CH); 19F RMN [300 MHz] δ = −158.95 (t, 2F); −148.58 (t, 1F); −143.24 (d, 2F). 13C NMR [75 MHz]: δ = 76.4(C); 113.1 (C); 143.4 (CH); 152.1 (C). It was not possible to assign the other carbons corresponding to this molecule. 1H-1H COSY NMR (300 MHz, CDCl3) δH/δH 7.76/ 7.76, 4.72/4.72. 1H-13C HSQC NMR (300 MHz, CDCl3) δH/δC 7.75/143.4. 1H-13C HMBC NMR δH/δC 7.76/76.4, 7.76/112.1, 7.76/152.1. HRMS (ESI−): Anal.Calcd. for C10H3F5N4−: 273.0194; found: 273.0206.
1H NMR, 19F, 13C NMR, COSY, HSQC, HMBC and HRMS Spectra:
5-amino-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-4-carbonitrile (3d): Compound 3d was obtained accord- ing to the general procedure. The product was purified by column chromatography on silica gel eluting with hexane/ethyl acetate gradient (6:1 → 4:1) and was isolated as yellow solid. (67%); M.p. 156.9˚C - 158.3˚C (170.0˚C - 171.0˚C) [
1H NMR, 19F, 13C NMR, COSY, HSQC, HMBC and MS:
5-amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-1H-pyrazole-4-carbonitrile (3e): Compound 3e was ob- tained according to the general procedure. The product was purified by column chromatography on silica gel eluting with hexane /ethyl acetate gradient (6:1 → 3:1) and was isolated as white solid. (47%); M.p. 163.5˚C - 164.8˚C; 1H RMN [300 MHz (CDCl3)] δ = 4.70 (s br, 2H, NH2); 7.72 (s, 1H, CH); 7.77 (s, 2H, CH). 19F RMN [300 MHz] δ = −63.22 (s, 2F). 13C NMR [75 MHz]: δ = 75.4 (C); 113.4 (C ); (116.5, 120.1, 123.7, 127.3, q, 1J = 273.58 Hz - CF3); 126.2 (CH); (133.8, 134.2, 134.7, 134.9, q, 2J = 34.59 Hz - CF3); 136.7(C); 142.9 (CH); 151.4(C). 1H-1H COSY NMR (300 MHz, CDCl3) δH/δH 7.77/7.77, 7.72/7.72, 4.69/4.69. 1H-13C HSQC NMR (300 MHz, CDCl3) δH/δC 7.77/126.2, 7.72/142.9. 1H-13C HMBC NMR δH/δC 7.77/75.4, 7.77/134.7, 7.77/ 136.7. HRMS (ESI+): Anal. Calcd. for C11H5Cl2F3N4Na+: 342.9736; found: 342.9731.
1H NMR, 19F, 13C NMR, COSY, HSQC, HMBC and HRMS Spectra:
5-amino-1-(4-methoxyphenyl)-1H-pyrazole-4-carbonitrile (3f): Compound 3f was obtained according to the general procedure. The product was purified by column chromatography on silica gel eluting with hexane/ethyl acetate gradient (6:1 → 3:1) and was isolated as dark yellow poder. (68%); M.p. 148.4˚C - 148.8˚C (144.9˚C - 145.9˚C) [
1H NMR, 13C NMR, COSY, HSQC, HMBC and MS Spectra: