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21st March 2012 @ 06:36
Product obtained in 96% yield overall.

===

Synthesis of pyrazole analogue core from ethyl acetoacetate, dimethylformamide dimethyl acetal and phenylhydrazine.



Reaction Start Time: 08.35 22/03/12
Ethyl acetoacetate (2.0 mL, 15.7 mmol, 1 equiv.) and dimethylformamide dimethyl acetal (2.2 mL, 16.6 mmol, 1.06 equiv.) were mixed then heated to 100 °C. The mixture turns yellow to orange. After 20 minutes, the reaction is a red solution, refluxing at <80 °C, indicating possible evolution of MeOH. After 50 minutes (<=90 °C) reaction is a bright red oil, TLC shows consumption of ethyl acetoacetate. Reaction cooled to room temperature and concentrated under reduced pressure. The red oil was dissolved in EtOH (20 mL). Phenylhydrazine (1.5 mL, 15.7 mmol, 1 equiv.) in EtOH (20 mL) was added dropwise to the reaction over 5 minutes. The reaction was then heated to reflux. After 2 hours TLC shows formation of new product and consumption of phenylhydrazine, the reaction was allowed to cool to room temperature. The mixture was concentrated under reduced pressure. The resulting oil was dissolved in DCM (40 mL) and washed with water (20 mL), 10% NaHCO3 (20 mL), brine then dried (MgSO4) and concentrated under reduced pressure to a brown oil (3.46 g, 96% over 2 steps).

TLC (20% EtOAc/hexane) visualised with UV and vanillin:
TLC 50 minutes
TLC stage 2, 2 hours


NMR:
1H NMR intermediate
1H NMR crude
1H NMR crude PDF


Risk and Hazard Assessment:
RA


Reference:
doi:10.1002/jhet.5570240634

InChi:
Starting materials: InChI=1S/C6H10O3/c1-3-9-6(8)4-5(2)7/h3-4H2,1-2H3 AND InChI=1S/C5H13NO2/c1-6(2)5(7-3)8-4/h5H,1-4H3
Product: InChI=1S/C13H14N2O2/c1-3-17-13(16)12-9-14-15(10(12)2)11-7-5-4-6-8-11/h4-9H,3H2,1-2H3
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Scheme
RA
TLC 50 minutes
TLC stage 2, 2 hours
1H NMR intermediate
1H NMR crude
1H NMR crude PDF