Sodium Cyanide → 4-[(1-Cyanocyclobutyl)amino]-2-fluoro-N-methylbenzamide

HRID 1051124Notes

Reaction equation

[C-:1]#[N:2].[Na+].[CH3:4][NH:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[F:14].[C:16]1(=O)[CH2:19][CH2:18][CH2:17]1>C(O)(=O)C>[CH3:4][NH:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:16]2([C:1]#[N:2])[CH2:19][CH2:18][CH2:17]2)=[CH:9][C:8]=1[F:14]

Participants

Conditions

Temperature: 80 °C

Procedure

Sodium cyanide (1.47 g, 30 mmol) was added to a mixture of N-methyl 4-amino-2-fluorobenzamide (1.68 g, 10 mmol) and cyclobutanone (1.4 g, 20 mmol) in 90% acetic acid (20 ml). The reaction mixture was stirred at 80° C. for 24 hours. The mixture was washed with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to dryness under vacuum. The solid was washed with a 50:50 mixture of ethyl ether and hexane (10 ml) to remove cyclobutanone cyanohydrin to afford after filtration B2 (2.19 g, 8.87 mmol, 89%). 1H NMR (CDCl3, 400 MHz) δ 1.87-1.95 (m, 1H), 2.16-2.27 (m, 1H), 2.35-2.41 (m, 2H), 2.76-2.83 (m, 2H), 2.97 (d, J=4.4 Hz, 3H), 4.68 (bs, 1H), 6.29 (dd, J=14.3, 1.8 Hz, 1H), 6.48 (dd, J=8.3, 1.8 Hz, 1H), 6.75 (q, J=4.4 Hz, 1H), 7.90 (dd, J=8.3, 8.3 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 15.7, 26.7, 33.9, 49.4, 100.2 (d, J=29.5 Hz), 110.6, 111.0 (d, J=11.8 Hz), 133.1 (d, J=4.2 Hz), 148.4 (d, J=12.0 Hz), 162.0 (d, J=244.1 Hz), 164.4 (d, J=3.6 Hz).

Workup

washThe mixture was washed with water
extractionextracted with ethyl acetate
dry with materialThe organic layer was dried over magnesium sulfate
concentrationconcentrated to dryness under vacuum
washThe solid was washed with a 50:50 mixture of ethyl ether and hexane (10 ml)
customto remove cyclobutanone cyanohydrin
customto afford

Sources & evidence

ORD record: ord-9ea34004f5db483c87fd18e67b196f4b
Source dataset: uspto-grants-2016_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09388159B2

Reaction notes

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