A Novel and Efficient Oxidation of 1,2-Amino Alcohols to Dialkylamides

Abstract

The oxidation of 1,2-amino alcohols and α-amino ketones can be efficiently performed using potassium hydroxide in the presence of air. This novel procedure affords carboxylic derivatives in excellent yields and high purity.

1,2-amino alcohols - α-amino ketones - oxidations - potassium hydroxide - radical reactions

References

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For oxidations under air in strongly basic solutions, see:

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9

Typical experimental procedure: The amino alcohol (1a-k) (0.1 g) was added to a stirred suspension of KOH (1.0 g) in diethyl ether (20 mL). The stirring was continued for the proper time (Table [1] ) at room temperature. The solid was filtered off and washed with ether. The solvent was removed to yield the amide. The solid was dissolved in water and the solution acidified with HCl and extracted with ether. The organic layer was dried and the solvent was removed to yield the corresponding carboxylic acid.

The starting amino alcohols were purchased from the usual suppliers (1e: 1-dimethylamino-2-propanol, 1f: N-methylephedrine, 1j: 2-dimethylamino-2-methyl-1-propanol, 1k: 1-methyl-2-piperidinemethanol) or synthesized by literature procedures:

10a 1a (2-dimethylamino-1-propanol): Rosnati V. Gazz. Chim. Ital.  1950,  80:  663 

10b 1b (2-Dibenzylamino-1-propanol) and 1i (2-Dibenzylamino-2-methyl-1-propanol): Kerwin JF. Ullyot GE. Fuson RC. Zirkle CL. J. Am. Chem. Soc.  1947,  69:  2961 

10c 1c (2-Dimethylamino-1-butanol): Halverstadt IF. Hardie WR. Willians AR. J. Am. Chem. Soc.  1959,  81:  3618 

10d 1d (2-Dimethylamino-2-phenylethanol): Miyano S. Lu LD.-L. Viti SM. Sharpless KB. J. Org. Chem.  1985,  50:  4350 

10e 1g (2-Dibenzylamino-1-phenyl-1-propanol): Schwan TJ. Lougheed GS. Burrous SE. J. Heterocyclic Chem.  1974,  11:  807 

10f 1h (2-Butylamino-1-phenyl-1-propanol): Soai K. Yokoyama S. Hayasaka T. J. Org. Chem.  1991,  56:  4264 

11 The resulting amides 2a, 2f (dimethylacetamide); 2b, 2g (dibenzylacetamide); 2h (dibutylacetamide); 2c (dimethyl-propanamide); 2d (dimethylbenzamide); 2e (dimethyl-formamide); 2k (1-methyl-2-piperidone) are commercial products or described in literature; 2l (1-acetylpyrrol-idine): Al-Sehemi AG. Atkinson RS. Fawcett J. J. Chem. Soc., Perkin Trans 1  2002,  257 

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13a The starting amino ketones were purchased from the usual suppliers (4e: 1-dimethylamino-2-propanone); synthesized by literature procedures. 4f (2-dimethylamino-1-phenyl-1-propanone): Welle F. Verevkin SP. Keller M. Beckhaus H.-D. Ruechardt C. Chem. Ber.  1994,  127:  697 

13b 4l (α-Phenyl-α-pyrrolidinoacetophenone): Heinzelman RV. Aspergren BD. J. Am. Chem. Soc.  1953,  75:  3409 ; or synthesized by known methods

13c

4h: (2-Dibutylamino-1-phenyl-1-propanone): Pyridinium chlorochromate (1.29 g, 6 mmol) was added in small portions to a stirred solution of amino alcohol 1h (0.39 g, 1.5 mmol) in CH₂Cl₂ (30 mL) over 4 Å sieves. The resulting mixture was stirred at r.t. for 6 h and filtered. The solvent was evaporated under reduced pressure. The residue was dissolved in an aqueous solution of NaOH (15% w/v, 10 mL) and extracted with ether. The organic layer was separated, washed with brine and dried (Na₂SO₄). Removal of the solvent left a residue, which was purified by column chromatography (hexane/EtOAc, 6:1) to yield amino ketone 4h (67%). Colorless liquid. bp 82-84 (0.2 mmHg). IR (neat, cm^-1): 1685. ¹H NMR (CDCl₃, 200 MHz): 0.79 (t, 6 H, J = 12 Hz); 1.04-1.21 (m, 7 H), 1.22-1.38 (m, 4 H); 2.40 (t, 4 H, J = 12 Hz); 4.31 (q, 1 H, J = 9.0 Hz); 7.22-7.50 (m, 3 H); 7.94-8.00 (m, 2 H). ¹³C NMR (CDCl₃, 50 MHz): 9.2 (CH₃); 14.0 (CH₃); 20.4 (CH₂); 30.7 (CH₂); 50.7 (CH₂); 60.4 (CH); 128.1 (CH_Ar);128.9 (CH_Ar); 132.4 (CH_Ar); 137.0 (C_Ar); 201.8 (CO). MS (m/z, %): 260 (M⁺ - 1, 1), 156(100). Anal. Calcd for C₁₇H₂₇NO: C, 78.11; H, 10.41; N, 5.36. Found: C, 78.22; H, 10.63; N, 5.27.

14a Turaeva DA. Kurbatov YV. Russ. J. Org. Chem.  1999,  1092 

14b Turaeva DA. Kurbatov YV. Kurbatova AS. Russ. J. Org. Chem.  1995,  739 

15

The EPR studies were made on the reaction mixtures without filtration. Moreover, the evolution of the EPR spectra taken at different reaction times showed the presence of mixtures of radicals as intermediates in these reactions.

16a Neelakantan L. J. Org. Chem.  1971,  36:  2256 

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17

NOESY experiments showed that the angular oxazolidine proton at C-7a was trans to the proton at C-6, indicating an S configuration at this carbon. (2S,3R,6S,7aR)-6-Benzyl-2-phenyl-3-methyl-5-oxo-2,3,5,6,7,7a-hexahydro-pyrrolo-[2,1-b]-oxazole (5). White solid, mp 101-103 ºC. [α]²³ _D +34.6 (c 1.6, CHCl₃). IR (neat, cm^-1) 1700. ¹H NMR (CDCl₃, 300 MHz): 1.00 (d, J = 6.8 Hz, 3 H), 2.19-2.23 (m, 2 H), 2.88 (dd, J = 13.2 Hz, 8.2 Hz, 1 H), 3.06-3.18 (m, 2 H), 3.95 (qd, J = 6.9 Hz, 6.8 Hz, 1 H), 4.95 (t, J = 5.4 Hz, 1 H), 5.19 (d, J = 7.1 Hz, 1 H), 7.20-7.37 (m, 5 H, H_Ar). ¹³C NMR (CDCl₃, 75 MHz): 13.4 (CH₃), 30.7 (CH₂), 37.6 (CH₂), 48.6 (CH), 54.7 (CH), 85.3(CH), 91.2 (CH), 126.6 (CH_Ar), 128.0 (CH_Ar), 128.3 (CH_Ar), 128.5 (CH_Ar), 129.1 (CH_Ar), 136.3 (C_Ar), 138.5 (C_Ar), 175.5 (CO). Anal.calcd for C₂₀H₂₁NO₂: C, 78.15; H, 6.89; N, 4.56. Found: C, 77.77; H, 7.08; N, 4.35.

18

Two isomers were observed at room temperature. (R)-1-Acetyl-2-benzyl pyrrolidine (2m). Colorless oil. [α]_D ²³ +25.54 (c 1.1, CHCl₃), IR (neat, cm^-1) 1650. MS (m/z, %): 203 (M⁺, 32), 91(28), 43(100). ¹H NMR (CDCl₃, 300 MHz): 1.53-1.75 (m, 2 H), 1.95-2.05 (m, 8 H), 2.41-2.52 (m, 2 H), 2.62-2.69 (m, 4 H), 3.03-3.12 (m, 2 H), 3.33-3.58 (m, 4 H), 3.61-3.68 (m, 2 H), 7.14-7.33 (m, 5 H, H_Ar). ¹³C NMR (CDCl₃, 75 Mz): 22.2 (CH₃), 22.4 (CH₃), 30.4 (CH₂), 31.7 (CH₂), 39.0 (CH₂), 39.6 (CH), 41.1 (CH), 45.1 (CH₂), 46.9 (CH₂), 50.7 (CH₂), 52.5 (CH₂), 126.2 (CH_Ar), 126.3 (CH_Ar), 128.4 (CH_Ar), 128.5 (CH_Ar), 128.6 (CH_Ar), 139.9 (C_Ar), 169.2 (CO). Anal. Calcd for C₁₃H₁₇NO: C, 76.81; H, 8.43; N, 6.89. Found: C, 76.70; H, 8.62; N, 6.76.