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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

    References

  • 2 For reductive amination see review: Hutchins RO. Hutchins MK. Comprehensive Organic Synthesis   1st ed., Vol. 8:  Trost BM. Pergamon Press; Oxford: 1991.  p.25-78  
    Search in Google Scholar
  • 3a Gribble GW. Lord PD. Skotnicki J. Dietz SE. Eaton JT. Johnson JL. J. Am. Chem. Soc.  1974,  96:  7812 
    CrossrefPubMedSearch in Google Scholar
  • 3b Abdel-Magid AF. Carson KG. Harris BD. Maryanoff CA. Shah RD. J. Org. Chem.  1996,  61:  3849 ; and references cited therein
    CrossrefPubMedSearch in Google Scholar
  • 4 Apodaca R. Xiao W. Org. Lett.  2001,  3:  1745 
    CrossrefPubMedSearch in Google Scholar
  • For combination of Ti(OPr)4 with NaBH4 or PMHS:
  • 5a

    see ref.3b

    Thieme Connect
  • 5b Chandrasekhar S. Reddy CR. Ahmed M. Synlett  2000,  1655 
    Thieme Connect
  • 5c Bhattacharya S. Neidigh KA. Avery MA. Williamson JS. Synlett  1999,  1781 
    Thieme Connect
  • 6 This method seems to require prior hydrolysis of acetals or enol ethers to carbonyl compounds catalyzed by B10H14: Park ES. Lee JH. Kim SJ. Yoon CM. Synth. Commun.  2003,  33:  3387 
    CrossrefSearch in Google Scholar
  • 7a Chan L. Pereira O. Reddy TJ. Das SK. Poisson C. Courchesne M. Proulx M. Siddiqui A. Yannopoulos CG. Nguyen-Ba N. Roy C. Nasturica D. Moinet C. Bethell R. Hamel M. L’Heureux L. David M. Nicolas O. Courtemanche-Asselin P. Brunette S. Bilimoria D. Bédard J. Bioorg. Med. Chem. Lett.  2004,  14:  797 
    CrossrefSearch in Google Scholar
  • 7b

    For preliminary presentation see: Reddy, T. J.; Leclair, M.; Proulx, M.; Quebec and Ontario Mini Symposium in Organic Synthesis November, 2002.

    Crossref
  • 7c

    There were only two methods available when we carried out our first experiment, see ref. 3.
    Crossref
  • 8a Tapia I. Alonso-Cires L. Lopez-Tudanca PL. Mosquera R. Labeaga L. Innerarity A. Orjales A. J. Med. Chem.  1999,  42:  2870 
    CrossrefSearch in Google Scholar
  • 8b Schaus JM. Thompson DC. Bloomquist WE. Susemichel AD. Calligaro DO. Cohen ML. J. Med. Chem.  1998,  41:  1943 
    CrossrefSearch in Google Scholar
  • 9 For the preparation of N-methylpiperidine enol ether, see: Wanner K. Liebigs Ann. Chem.  1984,  1103 
  • 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.

  • 12 Verardo G. Giumanini AG. Strazzolini P. Poiana M. Synthesis  1993,  121 
    Thieme Connect
  • 13 Bhaskar JV. Periasamy M. J. Org. Chem.  1993,  58:  3156 
    CrossrefSearch in Google Scholar
  • 14 Couture A. Deniau E. Gimbert Y. Grandclaudon P. Tetrahedron  1993,  49:  1431 
    CrossrefSearch in Google Scholar
  • 15 Figge A. Altenbach HJ. Brauer DJ. Tielmann P. Tetrahedron: Asymmetry  2002,  13:  137 
    CrossrefSearch in Google Scholar
  • 16 Henke BR. Aquino CJ. Birkemo LS. Croom DK. Dougherty RW. Ervin GN. Grizzle MK. Hirst GC. James MK. Johnson MF. Queen KL. Sherrill RG. Sugg EE. Suh EM. Szewczyk JW. Unwalla RJ. Yingling J. Willson TM. J. Med. Chem.  1997,  40:  2706 
    CrossrefSearch in Google Scholar
  • 17 Gasc MB. Perie J. Lattes A. Tetrahedron  1978,  34:  1943 
    CrossrefSearch in Google Scholar
  • 18 Kawakami T. Sugimoto T. Shibata I. Baba A. Matsuda H. Sonoda N. J. Org. Chem.  1995,  60:  2677 
    CrossrefSearch in Google Scholar
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