References
1 Present address: Merck Frosst Canada & Co., 16711 Trans Canada Hwy, Kirkland, Quebec, H9H 3L1, Canada.
2 For reductive amination see review: Hutchins RO.
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6 This method seems to require prior hydrolysis of acetals or enol ethers to carbonyl compounds catalyzed by B10H14: Park ES.
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9 For the preparation of N-methylpiperidine enol ether, see: Wanner K.
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Few examples of preclinical drugs containing N-isopropyl aromatic amines:
10a HCV NS-3 protease inhibitor, BILN-2061
10b 5-HT-4 receptor antagonists, LY353433
10c 5-HT-4 agonists, BIMU 8.
11 All new compounds were fully characterized (1H NMR,
13C NMR and HRMS) and exhibited spectroscopic data consistent with their structures. Yields refer to isolated and chromatographically pure compounds.
Typical Experimental Procedure.
To a stirred solution of anilines (2.0 mmol) in DCE (6.0 mL) under nitrogen was added sequentially 2-methoxypropene (0.287 mL, 3.0 mmol), HOAc (0.114 mL, 2.0 mmol) and NaBH(OAc)3 (636 mg, 3.0 mmol). After stirring at r.t. for required time, then reaction mixture was quenched with aq 1 N NaOH solution and extracted with CH2Cl2 (3 × 10 mL). The combined organic extracts were washed with brine and dried (Na2SO4). Concentration of the extracts gave essentially pure product. However, the crude product was purified on small plug of silica gel using EtOAc-hexane mixture (1:20) as an eluent produced N-isopropylaromatic amine derivatives.
N
-Isopropyl-aniline:12
1H NMR (400 MHz, CDCl3): δ = 7.16 (t, J = 8.2 Hz, 2 H), 6.66 (t, J = 7.2 Hz, 1 H), 6.58 (d, J = 8.2 Hz, 2 H), 3.90 (br s, 1 H), 3.63 (m, 1 H), 1.21 (d, J = 6.3 Hz, 6 H).
N
,
N
-Diisopropylaniline:13
2-(Isopropylamino)benzo-nitrile:14
1H NMR (400 MHz, CDCl3): δ = 7.38-7.34 (m, 1 H), 7.37 (d, J = 7.5, 1 H), 6.68-6.60 (m, 2 H), 4.40 (br s, 1 H), 3.72 (m, 1 H), 1.26 (d, J = 6.4 Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ = 149.7, 134.4, 133.1, 118.3, 116.3, 111.2, 95.8, 44.3, 22.9.
N
-Isopropyl-2-nitroaniline:15
1H NMR (400 MHz, CDCl3): δ = 8.17 (d, J = 8.6 Hz, 1 H), 8.02 (br s, 1 H), 7.42 (t, J = 8.5 Hz, 1 H), 6.86 (d, J = 8.9 Hz, 1 H), 6.61 (d, J = 8.2 Hz, 1 H), 3.84 (m, 1 H), 1.34 (d, J = 6.3 Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ = 145.0, 136.4, 132.0, 127.3, 115.1, 114.4, 44.1, 22.9.
Ethyl 2-(isopropylamino)benzoate:
1H NMR (400 MHz, CDCl3): δ = 7.93 (d, J = 8.1 Hz, 1 H), 7.76 (br s, 1 H), 7.35 (t, J = 8.5 Hz, 1 H), 6.74 (d, J = 8.6 Hz, 1 H), 6.58 (t, J = 7.5 Hz, 1 H), 4.31 (q, J = 7.2 Hz, 2 H), 3.72 (br s, 1 H), 1.38 (t, J = 7.0 Hz, 3 H), 1.28 (d, J = 6.3 Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ = 169.0, 150.7, 134.7, 132.0, 114.2, 111.9, 110.1, 60.4, 43.5, 23.0, 14.6. HRMS (FAB+): m/z calcd for C12H17NO2 [M + H]+: 208.1338; found: 208.1324.
N
-Isopropyl-2-methylaniline: 1H NMR (400 MHz, CDCl3): δ = 7.12 (dt, J = 1.6, 7.2 Hz, 1 H), 7.05 (d, J = 7.6 Hz, 1 H), 6.64-6.60 (m, 2 H), 3.70-3.66 (m, 1 H), 3.30 (br s, 1 H), 2.12 (s, 3 H), 1.25 (d, J = 6.3 Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ = 145.6, 130.5, 127.3, 121.9, 116.6, 110.5, 44.2, 23.5, 17.8. HRMS (FAB+): m/z calcd for C10H15N [M + H]+: 150.1283; found: 150.1283.
N,
2-Diisopropylaniline: 1H NMR (400 MHz, CDCl3): δ = 7.16-7.08 (m, 2 H), 6.70 (t, J = 7.3 Hz, 1 H), 6.66 (d, J = 7.9 Hz, 1 H), 3.72-3.66 (m, 1 H), 3.48 (br s, 1 H), 2.87-2.80 (m, 1 H), 1.25 (d, J = 6.7 Hz, 6 H), 1.24 (d, J = 6.3 Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ = 144.4, 132.2, 127.0, 125.3, 117.0, 111.4, 44.4, 27.4, 23.5, 22.6. HRMS (FAB+): m/z calcd for C12H19N [M + H]+: 178.1596; found: 178.1596.
(2-Fluorophenyl)-isopropylamine: 1H NMR (400 MHz, CDCl3): δ = 7.02-6.92 (m, 2 H), 6.70 (dt, J = 8.4, 1.6 Hz, 1 H), 6.62-6.56 (m, 1 H), 3.70 (br s, 1 H), 3.67-3.61 (m, 1 H), 1.24 (d, J = 6.2 Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ = 151.8 (d, J = 239 Hz), 136.2, 124.8, 116.3 (d, J = 7.6 Hz), 114.7 (d, J = 19.1 Hz), 112.8, 44.3, 23.2. HRMS (FAB+): m/z calcd for C9H12NF [M + H]+: 154.1032; found: 154.1032.
(2-Iodophenyl)-isopropylamine: 1H NMR (400 MHz, CDCl3): δ = 7.65 (d, J = 7.8 Hz, 1 H), 7.19 (t, J = 8.2 Hz, 1 H), 6.60 (d, J = 8.1 Hz, 1 H), 6.42 (t, J = 7.5 Hz, 1 H), 3.68-3.65 (m, 1 H), 1.26 (d, J = 6.3 Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ = 146.8, 139.4, 129.6, 118.4, 111.4, 86.1, 44.9, 23.2. HRMS (FAB+): m/z calcd for C9H12NI [M + H]+: 262.0094; found: 262.0093.
N
-Isopropyl-2-methoxyaniline:16
1H NMR (400 MHz, CDCl3, 8:1): δ = 6.86 (dt, J = 7.6, 1.5 Hz, 1 H), 6.76 (dd, J = 7.8, 1.3 Hz, 1 H), 6.66-6.60 (m, 2 H), 4.05 (br s, 1 H), 3.84 (s, 3 H), 3.65-6.59 (m, 1 H), 1.24 (d, J = 6.3 Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ = 147.0, 137.6, 121.5, 116.1, 110.5, 109.7, 55.6, 44.0, 23.3.
1-[3-(Isopropylamino)phenyl]-ethanone: 1H NMR (400 MHz, CDCl3): δ = 7.27-7.22 (m, 2 H), 7.21-7.18 (m, 1 H), 6.83-6.79 (m, 1 H), 3.72-3.66 (m, 1 H), 2.56 (s, 3 H), 1.23 (d, J = 6.3 Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ = 199.0, 147.9, 138.4, 129.6, 118.2, 117.6, 112.2, 44.4, 27.0, 23.1. HRMS (FAB+): m/z calcd for C11H15NO [M + H]+: 178.1231; found: 178.1232.
N
-Isopropyl-4-nitroaniline:12
1H NMR (400 MHz, CDCl3): δ = 8.08 (d, J = 9.1 Hz, 2 H), 6.50 (d, J = 8.8 Hz, 2 H), 4.40 (br s, 1 H), 3.74-3.71 (m, 1 H), 1.27 (d, J = 6.3 Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ = 152.9, 137.6, 126.8, 111.5, 44.5, 22.7.
(2,4-Dichlorophenyl)-isopropylamine: 1H NMR (400 MHz, CDCl3): δ = 7.25 (m, 1 H), 7.09 (m, 1 H), 6.61 (d, J = 8.8 Hz, 1 H), 3.64-3.61 (m, 1 H), 1.25 (d, J = 6.3 Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ = 141.0, 127.9, 126.7, 119.6, 118.4, 111.3, 43.4, 21.8. HRMS (FAB+): m/z calcd for C9H11NCl2 [M + H]+: 204.0348; found: 204.0347.
N
-Isopropyl-
N
-phenylaniline: 1H NMR (400 MHz, CDCl3): δ = 7.30-7.24 (m, 4 H), 6.99 (t, J = 7.3 Hz, 2 H), 6.87-6.85 (m, 4 H), 4.37-4.30 (m, 1 H), 1.16 (d, J = 6.6 Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ = 146.4, 129.4, 123.1, 121.8, 48.0, 21.3. HRMS (FAB+): m/z calcd for C15H17N [M + H]+: 212.1440; found: 212.1439.
N
-Cyclohexylaniline:17
1H NMR (400 MHz, CDCl3): δ = 7.15 (t, J = 8.4 Hz, 2 H), 6.67 (t, J = 7.5 Hz, 1 H), 6.61 (d, J = 8.1 Hz, 2 H), 3.28-3.23 (m, 1 H), 2.07-2.04 (m, 2 H), 1.80-1.10 (m, 8 H). 13C NMR (100 MHz, CDCl3): δ = 148.0, 129.5, 117.2, 113.5, 52.0, 33.7, 26.2, 25.3.
N
-Cyclopentylaniline: 1H NMR (400 MHz, CDCl3): δ = 7.17 (m, 2 H), 6.68 (t, J = 2.1 Hz, 1 H), 6.61 (dd, J = 8.6, 1.0 Hz, 2 H), 3.82-3.67 (m, 2 H), 2.06-1.98 (m, 2 H), 1.76-1.43 (m, 6 H). 13C NMR (100 MHz, CDCl3): δ = 148.3, 129.4, 117.1, 113.4, 54.9, 33.8, 24.3. HRMS (FAB+): m/z calcd for C11H15N [M + H]+: 162.1283; found: 162.1283.
N
-(1-Phenylethyl)aniline:18
1H NMR (400 MHz, CDCl3): δ = 7.38-7.21 (m, 5 H), 7.11-7.07 (m, 2 H), 6.66 (t, J = 7.5 Hz, 1 H), 6.53 (d, J = 7.9 Hz, 2 H), 4.49 (q, J = 6.7 Hz, 1 H), 1.53 (d, J = 6.7 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 147.6, 145.6, 129.4, 129.0, 127.2, 126.2, 117.6, 113.6, 53.8, 25.4.
1-Methyl-
N
-phenylpiperidin-4-amine: 1H NMR (400 MHz, CDCl3): δ = 7.18-7.14 (m, 2 H), 6.68 (dt, J = 7.3, 1.0 Hz, 1 H), 6.61-6.58 (m, 2 H), 3.49 (br s, 1 H), 3.29 (br s, 1 H), 2.82 (m, 2 H), 2.31 (s, 3 H), 2.17-2.05 (m, 4 H), 1.54-1.46 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 146.5, 129.5, 117.5, 113.5, 55.0, 47.5, 33.5. HRMS (FAB+): m/z calcd for C12H18N2 [M + H]+: 191.1548; found: 191.1548.
Methyl 3-(Isopropyl-amino)-5-phenylthiophene-2-carboxylate: 1H NMR (400 MHz, CDCl3): δ = 7.64-7.61 (m, 2 H), 7.43-7.34 (m, 3 H), 6.86 (s, 1 H), 6.71 (br s, 1 H), 3.83 (s, 3 H), 3.78-3.74 (m, 1 H), 1.29 (d, J = 6.4 Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ = 165.4, 155.8, 149.8, 133.7, 129.0, 126.1, 112.2, 97.4, 51.0, 46.3, 43.5, 23.5. HRMS (FAB+): m/z calcd for C15H17NO2S [M + H]+: 276.1059; found: 276.1059.
Methyl 3-(Isopropyl-amino)thiophene-2-carboxylate: 1H NMR (400 MHz, CDCl3): δ = 7.37 (d, J = 5.6 Hz, 1 H), 6.69 (d, J = 5.4 Hz, 1 H), 3.84 (s, 3 H), 3.73-3.67 (m, 1 H), 1.28 (d, J = 6.3 Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ = 165.5, 155.5, 98.0, 132.4, 116.4, 51.0, 46.3, 23.5. HRMS (FAB+): m/z calcd for C9H13NO2S [M + H]+: 200.0745; found: 200.0745
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