Simple and Efficient Three Component One-pot Synthesis of Pyrazolo[1,5, a ]pyrimidines

A series of novel 5-(2-bromophenyl)-N-cyclohexyl-2-(methylthio)-6-nitro-7-phenyl-4,7-dihydropyrazolo[1,5- a ]pyrimidine-3-carboxamides were synthesized by a one-pot reaction of 5-amino-N-cyclohexyl-3-(methylthio)-1H-pyrazole-4-carboxamide, 1-(2-bromophenyl)-2-nitroethanone and aryl aldehydes in the presence of boric acid in water at refluxing temperature. Structures of compounds were demonstrated by Fourier transform infrared, 1 H NMR, 13 C NMR and elemental analysis. The advantages of this method are mild reaction condition, good yields, and operational simplicity.


EXPERIMENTAL
Thin-layer chromatography was accomplished on 0.2 mm precoated plates of silica gel G60 F254 (Merck). Visualization was made with UV light (254 and 365 nm) or with an iodine vapor. IR spectra were recorded on a FTIR-8400 spectrophotometer using DRS prob. 1 H (400 MHz), 13 C (100 MHz) NMR spectra were recorded on a Bruker AVANCE II spectrometer in CDCl 3 and DMSO. Chemical shifts are expressed in δ ppm downfield from TMS as an internal standard. Mass spectra were determined using direct inlet probe on a GCMS-QP 2010 mass spectrometer (Shimadzu). Solvents were evaporated with a BUCHI rotary evaporator. Melting points were measured in open capillaries and are uncorrected.

Synthesis of 1-(2-bromophenyl)-2-nitroethanol (Int-a).
A mixture of 2-bromobenzaldehyde (0.1 mol), nitromethane (0.1 mol) and sodium acetate (0.2 mol) was stirred at RT for 24 h. The reaction was monitored by TLC. After completion of reaction, the solvent was removed under reduced pressure. The residue was poured in water and extracted with ethylacetate. The organic layer was dried and evaporated to afford Int-a in form of viscous oil. This oil was forwarded to next step without further purification.

Synthesis of 1-(2-bromophenyl)-2-nitroethanone (Int-b).
To the suspension of K 2 Cr 2 O 7 (24.8 mmol) in 15ml water, Int-a was added drop wise at 0 °C. This mixture was allowed to stir for 30 min and then solution of sulphuric acid (10 ml con H 2 SO 4 and 6 ml water) was drop wise added at same temperature. Here the exothermicity was controlled by keeping addition rate very slow. After completion of addition reaction mixture was stirred for 15 min at the same temp. Color of the reaction mixture turns dark green then it was poured over crushed ice. Separated solid was immediately filtered before temperature rise and was dissolved in saturated NaHCO 3 solution. Filtration was again carried out to separate non-dissolved matter. Filtrate was acidified with con HCl. Precipitated solid was filtered and wash with distilled water. Crystallization was carried out from methanol to afford pure Int-b.

Synthesis of 2-cyano-N-cyclohexylacetamide (Int-1).
In a 250 mL round bottom flask equipped with magnetic stirrer and thermometer was placed ethyl 2-cyanoacetate (0.25 mol), cyclohexaylamine (0.25 mol) and toluene (100 mL). The reaction mixture was heated up to 110-115 °C for 8 h. The progress of reaction was monitored by thin layer chromatography. The reaction mixture was cooled to room temperature and the solid product was filtered, washed with toluene to afford 90% yield.

Synthesis of 2-cyano-N-cyclohexyl-3,3-bis(methylthio)acrylamide (Int-2).
A 100 mL conical flask equipped with magnetic stirrer and septum was charged with a solution of 2-cyano-N-cyclohexylacetamide (1), (10 mmol) in DMF (10 mL). Dry K 2 CO 3 (10 mmol) was added and the mixture was stirred at RT for 2 h. CS 2 (30 mmol) was added and the mixture was stirred for an additional 2 h at room temperature. Then, methyl iodide (20 mmol) was added at 0-5 °C and the mixture was stirred for 4 h at room temperature. The progress of the reaction was monitored by thin layer chromatography. After completion of the 74 ILCPA Volume 41 reaction, it was poured into 50ml cold water. The precipitated crude product was purified by filtration followed by crystallization from EtOH.
In 50 ml RBF Int-b (2.5 mmol), Int-3 (2.5 mmol) and substituted aldehyde were suspended in 20 ml water under stirring on magnetic stirrer. H 3 BO 3 (2.5 mmol) was added in to the reaction mixture and reaction mixture was refluxed for 10 to 12 h. The reaction was monitored by TLC. After the completion of reaction, water was decanted and solid residue was triturated with methanol to afford pure compound.

CONCLUSION
In summary, we have described the water mediated synthesis of nitro substituted triazolopyrimidine derivatives in moderate to good yield. The reaction of various substituted aldehydes with 1-(2-bromophenyl)-2-nitroethanone and 5-amino-N-cyclohexyl-3-(methylthio)-1H-pyrazole-4-carboxamide afforded the triazolo pyrimidine derivatives in the presence boric acid and water as a solvent. We have confirmed the structure on the basis of spectroscopic technique.