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Synlett 2008(17): 2601-2604  
DOI: 10.1055/s-0028-1083522
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Diastereoselective Synthesis of Substituted 4-Piperidones and 4-Piperidols Using a Double Mannich Reaction

Yinman Chan, Holger Guthmann, Margaret A. Brimble, David Barker*
Department of Chemistry, The University of Auckland, 23 Symonds St, Auckland, New Zealand
Fax: +64(9)3737422; e-Mail: d.barker@auckland.ac.nz;
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Publication History

Received 21 July 2008
Publication Date:
01 October 2008 (online)

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Abstract

A simple and efficient synthesis of polysubstituted 4-piperidones was achieved from the double Mannich reaction of β-keto esters and bisaminol ethers. The reaction is highly diastereoselective, as is the subsequent hydride reduction, to give polysubstituted 4-piperidols.

Key words

4-piperidones - Mannich reaction - multicomponent reaction

19

General Procedure for the Synthesis of 4-Piperidones 5 Methyltrichlorosilane (1.5 mmol) was added dropwise to a mixture of β-keto ester 4 (1 mmol) and bisaminol ether 3 (1.2 mmol) in dry MeCN (3 mL) then stirred at r.t. for 20 h. The reaction was then quenched with aq sat. NaHCO3 until basic, extracted with EtOAc (3 × 3 mL), dried (MgSO4), and concentrated in vacuo to give the crude product, which was purified by flash chromatography to afford the 4-piperidones 5 in 51-90% yields.
General Procedure for the Synthesis of 4-Piperidols 6 A solution of piperidone 5 (1 mmol) in THF (4 mL) was added to a solution of NaBH4 (0.5 mmol) in THF (4 mL) and deionized H2O (4 mL). The mixture was stirred for 30 min at 0 ˚C, then stirred for 3 h at r.t. The reaction was quenched with 2 M NaOH and extracted with Et2O (3 × 10 mL). The combined organic extracts were washed with brine, dried (MgSO4), and concentrated in vacuo to give the crude product, which was purified by flash chromatography to afford the 4-piperidol 6.
Spectral Data for Selected ProductsEthyl (3 R *,5 R *)-1-Butyl-3,5-dimethyl-4-oxopiperidine-3-carboxylate (5e) ¹H NMR (300 MHz, CDCl3): δ = 0.90 (3 H, t, J = 7.2 Hz, NCH2CH2CH2CH 3), 1.00 (3 H, d, J = 6.5 Hz, 5-CH3), 1.20 (3 H, s, 3-CH3), 1.23 (3 H, t, J = 6.0 Hz, OCH2CH 3), 1.28-1.39 (2 H, m, NCH2CH2CH 2CH3), 1.41-1.51 (2 H, m, NCH2CH 2CH2CH3), 1.95 (1 H, d, J = 11.5 Hz, 2A-H), 1.97 (1 H, dd, J = 10.9, 10.9 Hz, 6A-H), 2.26-2.47 (2 H, m, NCH 2CH2CH2CH3), 2.89-3.01 (1 H, m, 5-H), 3.03-3.10 (1 H, m, 6B-H), 3.54 (1 H, dd, J = 11.5, 3.1 Hz, 2B-H), 4.17 (2 H, q, J = 7.11 Hz, OCH 2CH3). ¹³C NMR (75 MHz, CDCl3): δ = 11.6 (CH3, 5-CH3), 13.9 [CH3, N(CH2)3 CH3], 14.0 (CH3, OCH2 CH3), 17.9 (CH3, 3-CH3), 20.4 (CH2, NCH2CH2 CH2CH3), 29.2 (CH2, NCH2 CH2CH2CH3), 43.2 (CH, C-5), 56.8 (CH2, NCH2CH2CH2CH3), 56.8 (q, C-3), 61.2 (CH2, OCH2CH3), 62.2 (CH2, C-6), 63.2 (CH2, C-2), 173.1 (q, COO), 208.1 (q, C-4).
Ethyl (3 R *,5 R *)-1-Butyl-5-ethyl-3-methyl-4-oxopiperi-dine-3-carboxylate (5f) ¹H NMR (400 MHz, CDCl3): δ = 0.88-0.95 (6 H, m,
5-CH2CH 3, NCH2CH2CH2CH 3), 1.12-1.19 (1 H, m, 1 ×  5-CH2CH 3), 1.21 (3 H, s, 3-CH3), 1.24-1.29 (3 H, m, OCH2CH 3), 1.31-1.38 (2 H, m, NCH2CH2CH 2CH3), 1.45-1.53 (2 H, m, NCH2CH 2CH2CH3), 1.86 (1 H, p, J = 5.4 Hz, 1 × 5-CH 2CH3), 1.95 (1 H, dd, J = 8.6, 1.0 Hz, 2A-H), 1.98 (1 H, dd, J = 11.0, 8.5 Hz, 6A-H), 2.29-2.50 (2 H, m, NCH 2CH2CH2CH3), 2.73-2.81 (1 H, m, 5-H), 3.10-3.15 (1 H, m, 6B-H), 3.57 (1 H, dd, J = 8.6, 2.2 Hz, 2B-H), 4.15-4.25 (2 H, m, OCH 2CH3). ¹³C NMR (100 MHz, CDCl3): δ = 11.6 (CH3, 5-CH2 CH3), 13.9 (2 × CH3, OCH2 CH3, NCH2CH2CH2 CH3), 17.8 (CH3, 3-CH3), 19.7 (CH2,
5-CH2CH3), 20.4 (CH2, NCH2CH2 CH2CH3), 29.2 (CH2, NCH2 CH2CH2CH3), 50.1 (CH, C-5), 56.8 (q, C-3), 56.9 (CH2, NCH2CH2CH2CH3), 60.4 (CH2, C-6), 61.1 (OCH2CH3), 63.0 (CH2, C-2), 173.0 (q, COO), 207.62
(q, C-4).
Ethyl 1-Butyl-3,5,5-trimethyl-4-oxopiperidine-3-carboxylate (5h) ¹H NMR (300 MHz, CDCl3): δ = 0.85 (3 H, t, J = 7.2 Hz, NCH2CH2CH2CH 3), 1.03 and 1.05 [2 × 3 H, d, J = 6.7 Hz,
5-(CH3)2], 1.24 (3 H, t, J = 7.1 Hz, OCH2CH 3), 1.22-1.40 (4 H, m, NCH2CH 2CH2CH3, NCH2CH2CH 2CH3), 1.38 (3 H, s, 3-CH3), 2.53 (2 H, t, J = 6.9 Hz, NCH 2CH2CH2CH3), 2.86 (2 H, d, J = 6.7 Hz, 6-H), 2.91 (2 H, d, J = 1.5 Hz, 2-H), 4.16 (2 H, q, J = 10.7 Hz, OCH 2CH3). ¹³C NMR (75 MHz, CDCl3): δ = 13.9 (CH3, NCH2CH2CH2 CH3), 14.0 (CH3, OCH2 CH3), 18.4 (CH3, 3-CH3), 19.9 [CH3, 1 × 5-(CH3)2], 20.1 (q, C-3), 20.2 (CH2, NCH2CH2 CH2CH3), 20.3 [CH3, 1 × 5-(CH3)2], 32.0 (CH2, NCH2 CH2CH2CH3), 37.0 (CH2, C-6), 50.2 (CH2, NCH2CH2CH2CH3), 54.2 (q, C-5), 54.2 (CH2, C-2), 61.1 (CH2, OCH2CH3), 172.7 (q, COO), 212.9 (q, C-4).
Ethyl (3 R *,4 S *,5 R *)-1-Butyl-3,5-dimethyl-4-hydroxy-piperidine-3-carboxylate (6b) ¹H NMR (300 MHz, CDCl3): δ = 0.86 (3 H, t, J = 7.1 Hz, NCH2CH2CH2CH 3), 0.97 (3 H, d, J = 6.5 Hz, 5-CH3), 1.22-1.28 (8H, m, 3-CH3, OCH2CH 3, NCH2CH2CH 2CH3), 1.30-1.44 (2 H, m, NCH2CH 2CH2CH3), 1.61 (1 H, d, J = 11.5 Hz, 2A-H), 1.64 (1 H, t, J = 11.1, 6A-H), 1.90-2.01 (1 H, m, 5-H), 2.08-2.31 (2 H, m, NCH 2CH2CH2CH3), 2.69 (1 H, t, J = 11.2 Hz, 4-H), 2.73-2.79 (1 H, m, 6B-H), 3.26 (1 H, dd, J = 11.5, 5.2 Hz, 2B-H), 3.36 (1 H, d, J = 11.8 Hz, OH), 4.14 (2 H, q, J = 7.1 Hz, OCH 2CH3). ¹³C NMR (75 MHz, CDCl3): δ = 13.9 (CH3, NCH2CH2CH2 CH3), 14.0 (CH3, OCH2 CH3), 20.4 (CH2, NCH2CH2 CH2CH3), 21.3 (CH3, 3-CH3), 29.2 (CH2, NCH2 CH2CH2CH3), 36.3 (CH, C-5), 47.9 (q, C-3), 57.4 (CH2, NCH2CH2CH2CH3), 60.4 (CH2, OCH2CH3), 61.7 (CH2, C-6), 62.1 (CH2, C-2), 81.9 (CH, C-4), 177.4 (q, COO).
Ethyl (3 R *,4 S *,5 R *)-1-Butyl-4-hydroxy-5-isopropyl-3-methylpiperidine-3-carboxylate (6d) ¹H NMR (300 MHz, CDCl3): δ = 0.83 [3 H, d, J = 7.1 Hz, 1 × CH(CH 3)2], 0.87 (3 H, t, J = 7.2 Hz, NCH2CH2CH2CH 3), 0.88-0.97 (2 H, m, NCH2CH2CH 2CH3), 0.93 [3 H, d, J = 7.2 Hz, 1 × CH(CH 3)2], 1.25 (3 H, t, J = 7.1 Hz, OCH2CH 3), 1.26 (3 H, s, 3-CH3), 1.32-1.45 (2 H, m, NCH2CH 2CH2CH3), 1.54 (1 H, d, J = 11.5 Hz, 2A-H), 1.70 (1 H, d, J = 11.3 Hz, 6A-H), 1.79-1.88 (1 H, m, 5-H), 2.03-2.34 [3H, m, CH(CH3)2, NCH 2CH2CH2CH3], 2.70-2.75 (1 H, m, 6B-H), 3.00 (1 H, d, J = 10.5 Hz, 4-H), 3.26 (1 H, dd, J = 12.3, 3.3 Hz, 2B-H), 3.72-3.74 (1 H, m, OH), 4.14 (2 H, qd, J = 7.1, 1.7 Hz, OCH 2CH3). ¹³C NMR (100 MHz, CDCl3): δ = 14.0 (2 × CH3, OCH2 CH3, NCH2CH2CH2 CH3), 16.8 [CH3, 1 × CH(CH3)2], 20.5 (CH2, NCH2CH2 CH2CH3), 20.9 (CH3, 3-CH3), 21.5 [CH3, 1 × CH(CH3)2], 25.6 [CH, CH(CH3)2], 29.2 (CH2, NCH2 CH2CH2CH3), 45.6 (CH, C-5), 47.8 (q, C-3), 54.4 (CH2, C-6), 57.8 (CH2, NCH2CH2CH2CH3), 60.4 (CH2, OCH2CH3), 61.7 (CH2,
C-2), 77.6 (CH, C-4), 177.5 (q, COO).
Ethyl (3 R *,4 S *)-1-Butyl-4-hydroxy-3,5,5-trimethyl-piperidine-3-carboxylate and Ethyl (3 R *,4 R *)-1-Butyl-4-hydroxy-3,5,5-trimethylpiperidine-3-carboxylate (6e) ¹H NMR (300 MHz, CDCl3): δ (* denotes signals from the second diastereomer) = 0.82-0.96 [18 H, m, 2 × C(CH 3)2, 2 × C(CH 3)2*, NCH2CH2CH2CH 3, NCH2CH2CH2CH 3*], 1.08 (3 H, s, 3-CH3*), 1.20 (3 H, s, 3-CH3), 1.23 (3 H, t, J = 7.13 Hz, OCH2CH 3), 1.24 (3 H, t, J = 6.3 Hz, OCH2CH 3*), 1.28-1.34 (2 × 2H, m, NCH2CH2CH 2CH3, NCH2CH2CH 2CH3*), 1.35-1.43 (4 H, m, NCH2CH 2CH2CH3, NCH2CH 2CH2CH3*), 2.58-2.48 (4 H, m, NCH 2CH2CH2CH3, NCH 2CH2CH2CH3*), 2.64 (1 H, d, J = 10.5 Hz, 6-H*), 2.78 (1 H, d, J = 12.4 Hz, 6-H), 2.97
(2 H, d, J = 9.8 Hz, 2-H*), 3.01 (2 H, d, J = 8.13 Hz, 2-H), 3.49 (1 H, d, J = 4.0 Hz, 4-H*), 3.81 (1 H, d, J = 5.5 Hz,
4-H), 4.06-4.16 (6 H, m, OCH 2CH3, OCH 2CH3*, OH, OH*). ¹³C NMR (75 MHz, CDCl3): δ (* denotes signals from the second diastereomer) = 13.8-14.1 (4 × CH3, OCH2 CH3, OCH2 CH3*, NCH2CH2CH2 CH3, NCH2CH2CH2 CH3*), 16.8 (CH3, 3-CH3*), 16.9 [CH3, 1 × 
5-(CH3)2*], 18.5 [CH3, 1 × 5-(CH3)2], 20.2 (CH3, NCH2CH2 CH2CH3*), 20.36 (CH3, 3-CH3), 21.32 [CH3, 1 × 5-(CH3)2*], 21.99 [CH3, 1 × 5-(CH3)2], 29.61 (q, C-3*), 30.91 (q, C-3), 31.78 (CH2, NCH2 CH2CH2CH3*), 31.85 (CH2, NCH2 CH2CH2CH3), 48.74 (q, C-5*), 49.68 (CH2, NCH2CH2CH2CH3*), 49.98 (q, C-5), 50.07 (CH2, NCH2CH2CH2CH3), 56.30 (2 × CH2, C-2*, C-6*), 56.66 (2 × CH2, C-2, C-6), 60.46 (CH2, OCH2CH3*), 60.57 (CH2, OCH2CH3), 80.95 (CH, C-4*), 82.27 (CH, C-4), 175.91 (q, COO*), 176.32 (q, COO).
(3 S *,4 S *,5 R *)-(1-Butyl-5-ethyl-4-hydroxy-3-methylpiperidin-3-yl)methanol (7) ¹H NMR (300 MHz, CDCl3): δ = 0.84 (3 H, s, 3-CH3), 0.87 (3 H, t, J = 7.2 Hz, 5-CH2CH 3), 0.94 (3 H, d, J = 6.4 Hz, NCH2CH2CH2CH 3), 1.22-1.34 (4 H, m, 5-CH 2CH3, NCH2CH2CH 2CH3), 1.37-1.44 (2 H, m, NCH2CH 2CH2CH3), 1.57 (1 H, t, J = 11.4 Hz, 6A-H), 1.91
(1 H, dd, J = 11.9, 1.9 Hz, 2A-H), 2.20 (2 H, td, J = 14.4, 2.0 Hz, NCH 2CH2CH2CH3), 2.28-2.40 (1 H, m, 5-H), 2.53 (1 H, m, 4-H), 2.79-2.84 (2 H, m, 2B-H, 6B-H), 3.52 (1 H, br,
4-OH), 3.60 (1 H, d, J = 10.8 Hz, 1 × CH AOH), 3.81 (1 H, dd, J = 10.8, 1.9 Hz, 1 × CH BOH), 5.48 (1 H, s, CH2OH). ¹³C NMR (75 MHz, CDCl3): δ = 13.9 (CH3, NCH2CH2CH2 CH3), 16.8 (CH3, 5-CH2 CH3), 20.5 (CH2, NCH2CH2 CH2CH3), 22.5 (CH3, 3-CH3), 29.1 (CH2, NCH2 CH2CH2CH3), 29.7 (CH2, 5-CH2CH3), 35.2 (CH, C-5), 39.7 (q, C-3), 57.5 (CH2, NCH2CH2CH2CH3), 60.7 (CH2, C-6), 64.7 (CH2, C-2), 68.9 (CH2, CH2OH), 87.0 (CH, C-4).