A Stable Synthetic Equivalent of 2,3-Dihydropyridine

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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• 2 Jones G. In Comprehensive Heterocyclic Chemistry II   Vol. 5:  Katritzky A. Rees CW. Scriven EFV. Pergamon; Oxford: 1996.  p.167 
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• 6 Born S. Olson EE. Kobayashi Y. Synthetic Studies towards (+)-Symbioimine, In Abstracts of Papers   232nd National Meeting of the American Chemical Society; San Francisco CA: Sept 10-14, 2006. American Chemical Society: Washington D. C., 2006; ORGN-748

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.