Dichloromethane → N-[(1-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)methyl]-4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzamide

HRID 2090109Notes

Reaction equation

HRID 2090109 reaction equation
[NH2:1][CH2:2][CH:3]1[CH2:9][CH2:8][C:7]2=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=[C:6]2[CH2:5][CH2:4]1.[NH2:15]CC1CCC2C=C(N)C=CC=2CC1.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:72]([C:74]1[CH:75]=[C:76]([CH:92]([CH3:94])[CH3:93])[C:77]2[O:81][C:80]([C:82]3[CH:90]=[CH:89][C:85]([C:86](O)=[O:87])=[CH:84][CH:83]=3)=[N:79][C:78]=2[CH:91]=1)#[N:73].ClCCl>>[NH2:14][C:10]1[C:7]2[CH2:8][CH2:9][CH:3]([CH2:2][NH:1][C:86](=[O:87])[C:85]3[CH:84]=[CH:83][C:82]([C:80]4[O:81][C:77]5[C:76]([CH:92]([CH3:94])[CH3:93])=[CH:75][C:74]([C:72]#[N:73])=[CH:91][C:78]=5[N:79]=4)=[CH:90][CH:89]=3)[CH2:4][CH2:5][C:6]=2[CH:13]=[CH:12][CH:11]=1.[NH2:15][C:12]1[CH:11]=[CH:10][C:7]2[CH2:8][CH2:9][CH:3]([CH2:2][NH2:1])[CH2:4][CH2:5][C:6]=2[CH:13]=1

Participants

9

Reactant 7

HCID 6344DichloromethaneHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 573699454-(5-Cyano-7-isopropylbenzo[d]oxazol-2-yl)benzoic acid2×HCID 684101847-(aminomethyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-amineHCID 684114377-(aminomethyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-1-amine

Product 2

HCID 59435939N-[(1-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)methyl]-4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzamideYield 11.93%HCID 684101847-(aminomethyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-amineYield 7.42%

Conditions

Temperature
25 °C

Procedure

To a suspension of a mixture of 7-(aminomethyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-1-amine and 7-(aminomethyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-amine (300 mg, 1.577 mmol) in dichloromethane (5 ml) were added o-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (1315 mg, 3.47 mmol), 1-hydroxybenzotriazole (320 mg, 2.365 mmol), diisopropylethylamine (0.67 ml, 3.84 mmol), and 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoic acid (435 mg, 1.419 mmol, INTERMEDIATE 2), and the mixture was stirred overnight at 25° C. The residue was purified by flash chromatography on a Biotage Horizon, 40M column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes. The resulting mixture was repurified under the same conditions to provide the two diastereomers N-[(1-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)methyl]-4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzamide (90 mg, 0.188 mmol, 11.93% yield) and 1-(2-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)methanamine (56 mg, 0.117 mmol, 7.42% yield). Mass spectrum for N-[(1-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)methanamine (ESI) 479.2 (M+1). Mass spectrum for 1-(2-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)methanamine (ESI) 479.0 (M+1). 1H NMR data for the mixture (500 MHz, CDCl3): δ 8.32 (d, J=8.5 Hz, 2H), 7.90-8.96 (m, 4H), 7.51 (s, 1H), 7.49 (d, J=11 Hz, 1H), 7.49 (d, J=8.0 Hz, 2H), 7.32 (d, J=7.5 Hz, 2H), 7.25 (d, J=8.5 Hz, 1H), 7.20 (t, J=7.5 Hz, 1H), 6.42 (br s, 1H), 3.30-3.52 (m, 4H), 3.14 (dd, J=8.0, 14.0 Hz, 1H), 2.86-3.02 (m, 4H), 2.67 (dd, J=11.5, 14.5 Hz, 1H), 2.06-2.20 (m, 4H), 1.45 (d, J=7.5 Hz, 6H), 1.40-1.50 (m, 2H), 1.14-1.36 (m, 5H).

Workup

  1. customThe residue was purified by flash chromatography on a Biotage Horizon, 40M column
  2. washeluting with 1 column volume of 100% dichloromethane
  3. customThe resulting mixture was repurified under the same conditions

Sources & evidence

ORD record
ord-13a547c51b12488f885a86fce3f597d9
Source dataset
uspto-grants-2013_05
Patent number
US08436028B2

Reaction notes

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