4-hydroxyphenylacetic acid methyl ester 99.98g (601.6mmol) solid was gradualy added with cooling on ambient water bath to a solution of anhydrous hydrazine 80mL (79.25g, 2.47mol) in methanol 400mL over 10 minutes. The mixture was stirred at RT for 1 day. The precipitated product (88.926g) was collected by filtration, compressed on Buchner funnel, washed with methanol (4x25mL) and dried on highvac. A second crop (8.120g) precipitated from supernatants at -20C (freezer) overnight. The combined yield was 94.046g (94%) of pure hydrazide as a white crystalline solid.
1H(d6-DMSO, 400MHz): 9.182(br s, 1H), 9.108(br s, 1H), 7.035(app d, 8.6Hz, 2H), 6.666 (app d, 8.6Hz, 2H), 4.176(br d, 3.1Hz, 2H), 3.207(s, 2H) [minor rotamer signals 8.25, 7.2, 6.8, 6.5, 4.4, 3.6 are present in the 1H spectra]. 13C(d6-DMSO, 100MHz): 170.66, 156.45, 130.47(2C), 127.00, 115.63(2C), 40.48
A suspension of 4-hydroxyphenacetyl hydrazide 23.78g (143.1mmol) and KHCO3 15.76g (157.4mmol) in methanol 200mL was cooled to 0C. With vigorous stirring, solid cyanogen bromide 16.07g (151.7 mmol) was added in a single portion, followed by additional methanol 20mL (to wash the funnel and flask walls). The reaction mixture was stirred at 0 to 5C for 2 hours, the cooling bath was allowed to warm up to ambient temperature over a 2 hour period, and the reaction was continued for extra 1 hour at RT. The reaction mixture was diluted with water 230mL and the reaction mixture was stirred in an open flask for 1 hour. The precipitated product (17.215g) was collected by filtration, washed with water and dried on highvac. A second crop (9.400g) of pure product was obtained by concentrating the supernatants (to remove all methanol) from a 40C bath and letting the concentrated supernatants crystallize at RT overnight. The combined yield was 26.615g (97%) of a white crystalline solid.
1H(d6-DMSO, 400MHz) 9.334(s, 1H), 7.040(app d, 9.0Hz, 2H), 6.839(br s, 2H), 6.706(app d, 8.6Hz, 2H), 3.879(s, 2H)
Cyanogen bromide is a nasty irritant - it could “bleach” the sense of smell. BrCN-burned nose (or hands) could take days to recover. Weighing the solid BrCN is best done in fume hood, with gloves, into a closed container (pre-weighted test-tube with a septa, for example) . Few rounds of walk - with a closed tube – between hood and balances are preferable to gassing the lab with BrCN vapors.
Using the same reaction sequence, p-fluorophenylacetic acid methyl ester 25.66g (152.5 mmol) and anhydrous hydrazine 20mL in MeOH 120mL was heated to 60C (under reflux condenser) for 2 hours. The reaction mixture was evaporated to dryness and the residue was re-crystallized from 1-propanol 100mL (overnight to RT). Evaporating the supernatants and re-crystallizing the residue from benzene provided a second crop. The combined Y=24.855g (97%) of pure hydrazide as a white flakes. 1H(d6-DMSO, 400MHz): 9.194(br s, 1H), 7.272(m, 2H), 7.107(m, 2H), 4.202(br d, 4.3Hz, 2H), 3.329(s, 2H); 19F(d6-DMSO, 376.5Mhz): -116.96(m, 1F). A suspension of the p-F-phenacetyl hydrazide 19.85g(118mmol) and KHCO3 14.77g(147.5gmmol) in methanol 150mL at 0C was treated with BrCN 13.77g (130mmol) with stirring the mixture on ice for 1 hour and then at RT for 17h. The reaction mixture was diluted with water 200mL and allowed to crystallize at 0C for 1 hour. The precipitated product was collected by filtration, a second fraction was obtained by concentrating supernatants. Combined Y=20.836g (91.5%) of pure 2-amino 5-(p-F-benzyl)-oxadiazole as a white crystalline solid. 1H(d6-DMSO, 400MHz): 7.289(m, 2H), 7.148(m, 2H), 6.873(br s, 2H), 4.014(s, 2H); 19F(d6-DMSO, 376.5MHz): -116.01(m, 1F)