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Synlett 2005(4): 583-586  
DOI: 10.1055/s-2005-863704
LETTER
© Georg Thieme Verlag Stuttgart · New York

Reductive Alkylation of Aromatic Amines with Enol Ethers

T. Jagadeeswar Reddy*, Michael Leclair, Melanie Proulx
Virochem Pharma Inc., 275 Armand-Frappier Blvd, Laval, Quebec, H7V 4A7, Canada
Fax: +1(514)4284900; e-Mail: thumkunta_reddy@merck.com;
Further Information

Publication History

Received 21 July 2004
Publication Date:
22 February 2005 (online)

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Abstract

Reductive alkylation of aromatic amines with 2-meth­oxypropene using 1.0 equivalent of HOAc and NaBH(OAc)3 in 1,2-dichloroethane (DCE) at room temperature furnished N-isopropyl amines in 50-98% yields. This method was successfully extended to trimethylsilyl enol ethers. The mild reaction conditions provide a new alternative procedure for the reductive amination of electron deficient aromatic amines.

Key words

reductive alkylation - aromatic amines - 2-methoxypropene - trimethylsilylenol ethers - sodium triacetoxyborohydride

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1

Present address: Merck Frosst Canada & Co., 16711 Trans Canada Hwy, Kirkland, Quebec, H9H 3L1, Canada.

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