Reductive Alkylation of Aromatic Amines with Enol Ethers

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  
• 3a Gribble GW. Lord PD. Skotnicki J. Dietz SE. Eaton JT. Johnson JL. J. Am. Chem. Soc.  1974,  96:  7812 
• 3b Abdel-Magid AF. Carson KG. Harris BD. Maryanoff CA. Shah RD. J. Org. Chem.  1996,  61:  3849 ; and references cited therein
• 4 Apodaca R. Xiao W. Org. Lett.  2001,  3:  1745 
• For combination of Ti(OPr)₄ with NaBH₄ or PMHS:
• 5a

  see ref.^3b

• 5b Chandrasekhar S. Reddy CR. Ahmed M. Synlett  2000,  1655 
• 5c Bhattacharya S. Neidigh KA. Avery MA. Williamson JS. Synlett  1999,  1781 
• 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 
• 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 
• 7b

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

• 7c

  There were only two methods available when we carried out our first experiment, see ref. 3.

• 8a Tapia I. Alonso-Cires L. Lopez-Tudanca PL. Mosquera R. Labeaga L. Innerarity A. Orjales A. J. Med. Chem.  1999,  42:  2870 
• 8b Schaus JM. Thompson DC. Bloomquist WE. Susemichel AD. Calligaro DO. Cohen ML. J. Med. Chem.  1998,  41:  1943 
• 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 
• 13 Bhaskar JV. Periasamy M. J. Org. Chem.  1993,  58:  3156 
• 14 Couture A. Deniau E. Gimbert Y. Grandclaudon P. Tetrahedron  1993,  49:  1431 
• 15 Figge A. Altenbach HJ. Brauer DJ. Tielmann P. Tetrahedron: Asymmetry  2002,  13:  137 
• 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 
• 17 Gasc MB. Perie J. Lattes A. Tetrahedron  1978,  34:  1943 
• 18 Kawakami T. Sugimoto T. Shibata I. Baba A. Matsuda H. Sonoda N. J. Org. Chem.  1995,  60:  2677 

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 1}H 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 1}H 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 1}H 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 1}H 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 1}H 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 1}H 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 1}H 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