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Synlett 2008(16): 2479-2482  
DOI: 10.1055/s-2008-1078056
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Stable Synthetic Equivalent of 2,3-Dihydropyridine

Stephen Born, Yoshihisa Kobayashi*
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, Mail Code 0343, La Jolla, CA 92093-0343, USA
e-Mail: ykoba@ucsd.edu;
Further Information

Publication History

Received 16 June 2008
Publication Date:
12 September 2008 (online)

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Abstract

We introduce a synthetic procedure of 2,3-dihydropyridine derivative from its stable synthetic equivalent. The synthesis of a chiral 2,3-dihydropyridine derivative in a high yield and the unique mechanism of the unmasking step are described.

Key words

dihydropyridine - synthetic equivalent - enamine - imine - enone

    References and Notes

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7

Under thermal (>100 ˚C), Brønsted/Lewis acid (TfOH, TFA, CSA-TsOH, BF3˙OEt, MeAlCl2, Et2AlCl, EtAlCl2, etc.), basic (NaOEt, NaOH, LDA, etc.), or nucleophilic conditions (dimedone, piperidine, NaSEt, etc.).

8

Experimental Procedure for Preparation of Compound 2
To a 50 mL round-bottom flask at 25 ˚C was added 6
(1.23 g, 3.38 mmol) and benzene (34 mL). Pyridinium p-toluenesulfonate (PPTS, 85 mg, 0.34 mmol, 10 mol%) was then added and the solution allowed stirring under reflux while monitoring by TLC. After 1 h, the reaction was quenched by the addition of sat. NaHCO3, and separated. The aqueous layer was extracted twice with EtOAc, the combined organics washed with brine, and dried over Na2SO4. Concentration in vacuo yielded crude material which was then purified on SiO2 (hexane-EtOAc, 5:1) to yield compound 2 (1:1 mixture of diastereomers 2 and 2′, 1.07 g, 95%) as a clear oil. ¹H NMR (400 MHz, CDCl3): δ = 7.28-7.20 (m, 2 H and 2 H′), 7.18-7.08 (m, 3 H and 3 H′), 6.00-5.90 (m, 1 H and 1 H′), 5.32 (d, J = 17.2 Hz, 1 H and 1 H′), 5.23 (d, J = 10.0 Hz, 1 H and 1 H′), 4.95 (d, J = 
4.4 Hz, 1 H), 4.90 (d, J = 3.6 Hz, 1 H′), 4.63 (d, J = 5.6 Hz, 2 H and 2 H′), 3.73 (dd, J = 2.4, 12.8 Hz, 1 H), 3.67 (dd, J = 2.8, 12.8 Hz, 1 H′), 3.34 (dd, J = 7.2, 12.8 Hz, 1 H′), 3.31 (app. t, J = 4.8 Hz, 1 H′), 3.14 (dd, J = 9.2, 12.4 Hz, 1 H), 2.99 (m, 1 H), 2.89-2.65 (m, 4 H and 4 H′), 2.45 (q, J = 7.6 Hz, 2 H), 2.43 (q, J = 7.2 Hz, 2 H′), 2.14-2.10 (m, 1 H), 1.95-1.90 (m, 1 H′), 1.20 (t, J = 7.2 Hz, 3 H′), 1.18 (t, J = 7.2 Hz, 3 H), 1.06 (d, J = 6.8 Hz, 3 H), 0.99 (d, J = 6.8 Hz, 3 H′). 3C NMR (100 MHz, CDCl3): δ = 154.0 (C and C′), 141.5 (C′), 141.5, 139.9, 138.8 (C′), 132.5 (C and C′), 128.5 (2C′), 128.5 (2C), 128.2 (2 C and 2 C′), 125.8 (C and C′), 118.1 (C and C′), 112.7 (C and C′), 66.42 (C′), 66.38, 49.0, 48.5 (C′), 45.7, 45.1 (C′), 37.0 (C′), 36.8, 34.7 (C′), 34.4, 33.5 (C′), 26.5 (C′), 24.0, 16.9, 15.2 (C′), 14.89 (C′), 14.85. HRMS: m/z calcd for C20H27NO2S: 345.1757; found: 345.1755.

9

Experimental Procedure for Preparation of Compound 1
To a 10 mL round-bottom flask at 25 ˚C was added 2 (70 mg, 0.20 mmol) in THF (0.4 mL), and placed under a blanket of nitrogen. Then, Pd2dba3˙CHCl3 (5.2 mg, 0.005 mmol,
5 mol%) and 1,4-bis(diphenylphosphino)butane (dppb,
8.6 mg, 0.020 mmol, 10 mol%) were added and the solution allowed stirring while monitoring by TLC. Upon completion after 2 h, the solution was diluted with THF, filtered over Celite, and concentrated in vacuo to yield compound 1 as a viscous oil. ¹H NMR (400 MHz, CDCl3): δ = 7.28-7.23 (m, 2 H), 7.20-7.14 (m, 3 H), 6.21 (dd, J = 3.5, 9.5 Hz, 1 H), 5.86 (dd, J = 2.5, 10.0 Hz, 1 H), 3.66 (dd, J = 7.0, 15.5 Hz, 1 H), 3.16 (dd, J = 12.0, 16.0 Hz, 1 H), 2.86 (t, J = 7.5 Hz, 2 H), 2.56 (t, J = 8.5 Hz, 2 H), 2.27 (m, 1 H), 0.98 (d, J = 7.5 Hz, 3 H). 13C NMR (100 MHz, CDCl3): d = 165.3, 142.7, 141.5, 128.6 (2 C), 128.3 (2 C), 125.9, 121.7, 53.4, 35.7, 32.6, 30.4, 17.3. HRMS: m/z calcd for C14H19N: 199.1356; found: 199.1357.