Synthesis of Substituted Pyrazole N -Oxides and Pyrazoles from Propargylamines
CH 3 CN CHCl 3
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The compound 46 was reacted with excess of zinc and ammonium formate to form a tricyclic compound pyrazoloquinoline 47 in 68% yield via a reductive coupling procedure.38 Similarly, reduction of 42k with zinc and ammonium formate furnished an amino compound 48, which after diazotization followed by cyclization gave pyrazolo-cinnoline 49 in 75% yield. (Scheme 3.4.1).36
Conclusions
In conclusion, we have developed a mild and efficient method for the synthesis of substituted pyrazole N-oxides from propargylamines in excellent yields. The reaction is compatible with a wide range of functional groups such as ester, ether, nitrile, -NO2, and halides. The pyrazole N-oxide can be converted to pyrazole and chlorinated pyrazole under different reaction conditions. Nitroaryl substituted pyrazole can be converted to pyrazolo-N-oxide-cinnoline 45, pyrazolo-quinoline 47 and pyrazolo-cinnoline 49.
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acetylenes 37 (4 mmol) were added by dissolving in 3 mL of dry toluene and the reaction mixture was stirred at 110 oC for 2-4 h time. After completion of the reaction, the reaction was cooled; the solvent was removed under rotary evaporator, diluted with saturated ammonium chloride and then extracted with ethyl acetate. The organic layer was further washed with water for 3 times. The combined organic layers were dried over Na2SO4 and concentrated in rotary evaporator. The crude was subjected to column chromatography over silica gel to give the desired product.
3.5.3. General procedure for the synthesis of pyrazole N-oxides (39):
Propargylamine 38 (0.3 mmol), NaNO2 (0.9 mmol) and Ag(OTf) (0.03 mmol) in anhydrous CHCl3 (1 mL) was stirred at 0 oC followed by slow addition of Acetic acid (0.6 mL). Then reaction mixture stirred at room temperature for 2-4 h. After completion of the reaction the mixture was poured into water (10 ml) and diluted with saturated NaHCO3 solution and extracted with dichloromethane (3 x 10 mL). The combined organic layers were dried over Na2SO4 and concentrated in rotary evaporator. The crude was subjected to column chromatography over silica gel to give the corresponding product 39.
3.5.4. Typical procedure for the reduction of pyrazole N-oxide with PCl3 (42):
To a stirred solution of pyrazole N-oxide 39 (0.15 mmol) in CHCl3 (1.5 mL) was added phosphorus trichloride (0.9 mmol) and the reaction mixture was heated to 60 oC. The reaction was monitored by TLC. After completion of reaction, the reaction mixture was poured into ice-cold water. The aqueous layer basified with NaOH and the product was extracted with DCM. The organic layer was dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography by elution with hexane/ EtOAc to give the desired product 42.
3.5.5. Typical procedure for the synthesis of 4-chloropyrazoles (43):
To a mixture of compound 39 (0.3 mmol), in anhydrous DMF (1.0 mL), added phosphoryl chloride (2.4 mmol) drop by drop at 0 oC under N2 atmospheric condition, then the reaction mixture was stirred at room temperature for 1 h. Further, the reaction mixture was heated to 100 °C for 3.5 h, the reaction mixture was poured into ice cold water and treated with saturated bicarbonate solution, and extracted with dichloromethane (3 x 5 mL). The combined organic layers were dried over Na2SO4 and concentrated in rotary evaporator. The crude was subjected to column chromatography over silica gel to achieve the resultent product 43.
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3.5.6. Experimental procedure for the reduction of nitro group:
Under N2 atmosphere compound 39k (0.3 mmol) in anhydrous ethanol (4 mL) was added to SnCl2.2H2O (1.5 mmol) and the reaction mixture was stirred at 80 °C for 5 h. After completion of the reaction (monitored by TLC), the mixture was filtered through celite, and washed with saturated NaHCO3 solution. The layers were separated and the aqueous layer was further extracted with ethyl acetate. The combined organic layers was dried over Na2SO4 and concentrated in rotary evaporator. The crude was subjected to column chromatography over silica gel to give the corresponding product 44.
3.5.7. Experimental procedure for the synthesis of pyrazolo-N-oxide-cinnoline 45:
To a mixture of compound 44 (0.15 mmol) and NaNO2 (0.45 mmol) in DCM (1.0 mL) was slowly added AcOH (0.5 ml) at 0 oC. Then the reaction mixture was stirred at room temperature. Upon completion of the reaction (monitored by TLC), the reaction mixture was poured into ice cold water, diluted with saturated NaHCO3 and the organic layer was extracted with DCM (3x5 mL) washed with brine solution for 2-3 times. The combined organic layers were dried over Na2SO4 and concentrated in rotary evaporator. The crude was subjected to column chromatography over silica gel to accomplish the resultant product 45.
3.5.8. Typical procedure for the formylation of pyrazole:
To a mixture of compound 42k (0.3 mmol), in anhydrous DMF (1.0 mL), added phosphoryl chloride (3.0 mmol) drop by drop at 0 oC under N2 atmospheric condition, then the reaction mixture was stirred at room temperature for 1 h. Further, the reaction mixture was heated to 100 °C for 6 h, the reaction mixture was poured into ice cold water and treated with saturated bicarbonate solution, and extracted with DCM (3 x 5 mL). The combined organic layers were dried over Na2SO4 and concentrated in rotary evaporator. The crude was subjected to column chromatography over silica gel to form the desired product 46.
3.5.9. Experimental procedure for the synthesis of pyrazolo-quinoline 47:
To a stirred mixture of ammonium formate (1.5 mmol) in anhydrous MeOH and THF (2:1) were added nitro compound 46 (0.15 mmol) and Zn dust (1.5 mmol) and the reaction mixture stirred for 15 h, at room temperature and the mixture was filtered off. The organic layer was evaporated and the residue dissolved in DCM, washed with brine solution for 2-3 times. The combined organic layers were dried over Na2SO4 and concentrated in rotary evaporator. The TH-1731_126122030
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crude was subjected to column chromatography over silica gel to give the consequent product 47.
3.5.10. Experimental procedure for the reduction of nitro group:
To a stirred mixture of ammonium formate (3.0 mmol) in anhydrous MeOH:THF (2:1) were added nitro compound 42k (0.30 mmol) and Zn dust (3.0 mmol) and the reaction mixture stirred for 45 minutes at room temperature, the mixture was filtered off. The organic layer was evaporated and the residue dissolved in DCM, and washed with brine solution for 2-3 times.
The combined organic layers were dried over Na2SO4 and concentrated in rotary evaporator.
The crude was subjected to column chromatography over silica gel to give the subsequent product 48.
3.5.11. Experimental procedure for the synthesis of pyrazolo-cinnoline (49):
To a mixture of compound 48 (0.15 mmol) and NaNO2 (0.45 mmol) in DCM (1.0 mL), AcOH (0.5 ml) was slowly added at 0 oC. Then the reaction mixture was stirred at room temperature.
Upon completion of the reaction (monitored by TLC), the reaction mixture was poured into ice cold water, diluted with saturated NaHCO3 and the organic layer was extracted with DCM (3x5 mL) and washed with brine solution for 2-3 times. The combined organic layers were dried over Na2SO4 and concentrated in rotary evaporator. The crude was subjected to column chromatography over silica gel to afford the resultant product 49.
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