N-(Pyridin-4-yl)pivalamide

Light yellow solid

Preparation of 2, 2-Dimethyl-N-pyridinyl-propionamides 1A : 2, 2-Dimethyl-N-pyridin-4-yl-propionamide [081] Following procedures generally taught in J. A. Turner, J. Org. Chem. 1983, 48, 3401- 3408, a solution of pivaloyl chloride (13.5 mL, 110 mmol) in CH2C12 (20 mL) was slowly added to an ice-cold solution of 4-aminopyridine (9.41 g, 100 mmol) and triethylamine (17.4 mL, 125 mmol) in CH2C12 (150 mL). After addition was complete, the resulting mixture was warmed to room temperature and stirred for 2 h. The solution was poured into water, the CH2C12 layer was washed with dilute NaHC03, dried over Na2SO4, and evaporated to leave a light brown solid. Recrystallization from EtOAc/hexanes afforded the product as a white crystal, which was collected by vacuum filtration (13.03 g, 73percent). 1H NMR (400 MHz, CDC13) 8 8. 50 (d, J= 4.8 Hz, 2 H), 7.50 (d, J= 4.8 Hz, 2 H), 7.44 (br s, 1 H), 1. 33 (s, 9 H). MS (LR-APCI) calcd. for CloH1sN20 (M+H) 179.1 ; found 179.1.To a stirred solution of 4-amino pyridine (A; 5 g, 53.12 mmol) in CHCITo a solution of 1 .88 g (20.0 mmol, 1 eq.) of 4-aminopyridine and 3.6 mL (26.0 mmol, 1 .3 eq.) of triethylamine in 30 mL of DCM, cooled to 0°C, were added 2.7 mL (22.0 mmol, 1 .1 eq.) of trimethylacetyl chloride in 4 mL of DCM. After 2 hours, the mixture was stirred one hour at room temperature. Then, 40 mL of water were added. The aqueous layer was extracted with 20 mL of dichloromethane. The organic phase was washed with 20 mL of aqueous NaHC0To a solution of 1.88 g (20.0 mmol, 1 eq.) of 4-aminopyridine and 3.6 mL (26.0 mmol, 1 .3 eq.) of triethylamine in 30 mL of DCM, cooled to 0°C, were added 2.7 mL (22.0 mmol, 1 .1 eq.) of trimethylacetyl chloride in 4 mL of DCM. After 2 hours, the mixture was stirred one hour at room temperature. Then, 40 mL of water were added. The aqueous layer was extracted with 20 mL of dichloromethane. The organic phase was washed with 20 mL of aqueous NaHC0A solution of trimethyl acetyl chloride (32.5 mL, 0.264 mol) in dry dichloromethane (50 mL) was added drop wise over 1 h to a stirred suspension of 4-aminopyridine (22.60 g, EPO Step 1: A solution of trimethylacetylcholride (423 mg, 3.51 mmol, 1.1 eq) in dichloromethane was slowly added to an ice cooled solution of pyridin-4-amine (300 mg, 3.19 mmol) and triethylamine (0.56 mL, 3.98 mmol, 1.25 eq) of dichloromethane. The resulting mixture was stirred in and ice bath for 15 min and then at room temperature for 2 h and poured into water. The reaction mixture was washed with dilute NaHC0Step 1: A solution of pivaloyl chloride (13.4 g, 1 1 1 mmol) in DCM (20 mL) was slowly added to a cooled (0 °C) solution of pyridin-4-amine (10 g, 106 mmol) and triethylamine (26.7 g, 265 mmol) in DCM (80 mL). After addition, the icebath was removed and the resulting mixture was stirred at 20 °C for 6 hours. The mixture was poured into water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic extract was washed with saturated NaHC0To a cooled (-78 °C) solution of N-(pyridin-4-yl)pivalamide (2.50 g, 14.0 mmol) in anhydrous THF (100 mL) was added BuLi (2.5 M in hexanes, 12 mL, 29.4 mmol). The mixture was allowed to warm rapidly to 0 °C and stirred at this temperature for 1.5 hours. The resulting mixture was cooled to -78 °C again and a solution of tetraisopropylthiuram disulfide (4.93 g, 14.0 mmol) in anhydrous THF (20 mL) was slowly added. After addition, the mixture was allowed to warm to room temperature, and then water (200 mL) and EtO Ac (200 mL) were added sequentially. The organic layer was separated, washed with water (2 x 200 mL), dried over Na2S04, and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography, eluting with EtO Ac/petroleum ether (1 :8) to give the desired product as a yellow solid (2.46 g, 50percent yield). 3/4 NMR (500 MHz, CDC13): delta 8.60 (d, J = 7.5 Hz, 1H), 8.50-8.45 (m, 2H), 8.40 (d, J = 6.5 Hz, 1H), 1.60-1.11 (m, 14H), 1.29 (s, 9H). LCMS (ESI) m/z: 354.2 [M+H+].Step 1 To a solution of 4-pivaloylaminopyridine (7.0 g, 39 mmol) in tetrahydrofuran (100 ml) was added n-butyllithium (39.3 ml, 98 mmol, 2.5 M solution in tetrahydrofuran) at -78° C. under a N2 atmosphere. The reaction mixture was stirred at 0° C. for 5 h, re-cooled to -78° C. and quenched with a solution of N-methoxy-N-methyl-4-fluorobenzamide (7.9 g, 43 mmol) in 100 ml tetrahydrofuran. The reaction mixture was warmed to room temperature and poured into water. The product was extracted into ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography (10percent ethyl acetate/hexanes gradient) to afford N-[3-(4-fluorobenzoyl)pyridin-4-yl]-2, 2-dimethylpropanamide (10 g).

Molecular Weight:178.23
XLogP3:1.9
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:2
Exact Mass:178.110613074
Monoisotopic Mass:178.110613074
Topological Polar Surface Area:42
Heavy Atom Count:13
Complexity:178
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes