1,1-dicyano-2-methoxy-2-(1′-naphtylmethyl)-ethylene 9.175g (36.95 mmol) and t-Bu-hydrazine hydrochloride 4.65g (37.3 mmol) was suspended in absolute ethanol 0.25L and triethylamine 5.3mL was added dropwise over 7 min period. After stirring at RT for extra 10 min, the mixture was placed on oil bath (90C) and refluxed overnight (18 hours). The cooled reaction mix was evaporated and the residue was portioned between DCM 150mL and water 100mL. The aqueous phase was re-extracted twice with DCM (2x100mL), the combined extracts were dried (Na2SO4) and evaporated. The residue was purified on a column of silica (250g) in DCM, eluted with straight DCM 0.3L and then 20:1 DCM+EtOAc (v/v; 2L).
The obtained 5-amino-1-tert-butyl-4-cyano-3-(1′-naphtylmethy)-pyrazole (cream-colored crystalline solid, 7.15g, 63.5%Y) was flushed with Ar in a 1L flask, formamide 100mL was added, the flask was equipped with a straight glass tube as air-cooled condenser and the mixture was deoxygenated by a highvac/Ar purge. The mixture was stirred on a 180C oil bath under Ar for 7 hours. The mixture was allowed to cool to R.T., the formed slurry was gradually diluted with water (60mL) and the mix was stirred for additional 30 min. The precipitated product was collected by filtration, thoroughly washed with water, dried by suction and on highvac. The crude product (7.05g) was dissolved in ethanol 0.5L at reflux. One spoon of charcoal was added, the mix was stirred at reflux for additional 10 min then filtered while still warm (the charcoal was washed with additional ethanol) and the filtrate was evaporated to dryness. The obtained foamy residue was re-crystallized from a mix of benzene 30mL and cyclohexane 20mL (RT, overnight). The crystallized product was collected by filtration, washed with 1:1 benzene-cyclohexane mix and then with hexanes, dried by suction and on highvac.
Y=7.788g (57% overall Y) of a cream-colored crystalline solid as a 2:1 co-crystal with benzene.
1H(d6-DMSO, 400MHz): 8.905(very br s, 2H), 8.473(s, 1H), 8.249(m, 1H), 7.936(m, 1H), 7.816(d, 8.2Hz, 1H), 7.555(m, 2H), 7.395(dd, 8.1Hz, 7.2Hz, 1H), 7.153(d, 7.0Hz, 1H), 4.873(s, 2H), 1.654(s, 9H); LC/MS(+ESI): 332(M+1)
Note 1: 1NMPP1 is commercially available but very dear
Note 2: To remove the benzene trace (the compound is intended for biology use) the purified material was re-dissolved in ethanol 150mL, the solution was carefully concentrated on rotovap from a 50C bath down to about 1/3 volume and the remaining solution was slowly diluted down with water – about 200mL – until cloudy, the crystallization was then induced mechanically (by scratching the solution against the flask joint). The resulting slurry was stirred on ice bath for 1 hour. The precipitate was collected by filtration, washed with ice water, dried by suction and on highvac. This provided 6.012g of pure product free of benzene (Y=49% overall). 1H(d6-DMSO, 400MHz): 8.319(m, 1H), 8.141 (s, 1H), 7.921(m, 1H), 7.793(d, 8.2Hz, 1H), 7.541(m, 2H), 7.391(dd, 8.1Hz, 7.3Hz, 1H), 7.145(d, 7.0Hz, 1H), 7.027(very br s, 2H), 4.875(s, 2H), 1.662(s, 9H)