A solution of 4-bromo-2-fluoronitrobenzene 1.300 g (5.909 mmol) and 1,3-propanediol 5.0mL (69mmol) in anhydrous dioxane 20mL in a 100mL 14/20 joint flask was placed on ambient water bath and a solution of sodium tert-butoxide 1.00 g (10.8 mmol) in anh dioxane 40mL was added dropwise from an addition funnel over 15 min with vigorous stirring. The resulting deep-orange reaction mix was stirred under Ar for additional 2 hours. A solution of potassium carbonate 2.80 g (20mmol) in water 30 mL was added into the flask and the mixture was deoxygenated by argon sparge (long needle through the septa) on ultrasonic bath for 15 min. A solid mix of pinacolate ester of 4-pyrazolylboronic acid 1.50 g (7.73mmol) and Pd(PPh3)4 600mg (0.519mmol; 8.8mol%) was added in one portion and the mixture was sparge-deoxygentaed with Ar for additional 10 min on ultrasonic bath, then vigorously stirred under Ar on a 95C oil bath for 150 minutes. The reaction mix was cooled and portioned between saturated aqueous ammonium chloride 200mL and ethyl acetate 200mL. The aqueos phase was re-extracted with EtOAc (200mL). The organic extracts were washed with additional sat ammonium chloride (200mL) and then combined, dried (MgSO4) and evaporated. The obtained solid yellow residue was suspended in benzene 20mL, heated briefly to reflux and then allowed to sit at RT for 1 hour. The precipitated product (1.248g) was collected by filtration, washed with additional benzene (2x10mL) and dried on highvac. Concentrating the supernatants and re-crystallizing the oily residue from benzene (5mL) overnight provided additional small fraction of the product (47mg, 95% pure). The combined yield was 1.295g (83% th) of a pale yellow solid, >98% by HPLC.
1H(d6-DMSO, 400MHz): 13.165(br s, 1H), 8.455(s, 1H), 8.124(s, 1H), 7.891(d, 8.5Hz, 1H), 7.529(d, 1.5Hz, 1H), 7.344(dd, 8.5Hz, 1.5Hz, 1H), 4.577(t, 5.1Hz, 1H), 4.301(t, 6.1Hz, 2H), 3.594(q, 5.4Hz, 2H), 1.899(quint, 6.2Hz, 2H); LC/MS(+ESI): 264(M+1)
Org Prep Daily 