Stereoselective Synthesis of 2,4-Disubstituted Thiochromans Using the ­Supported Reagent System ‘Na₂CO₃/SiO₂-PPA/SiO₂’

Abstract

A simple and efficient method has been developed for the stereoselective synthesis of 2,4-disubstituted thiochromans from arylthiols and α,β-unsaturated aldehydes by using an acid- and a base-supported reagent system, Na₂CO₃/SiO₂-PPA/SiO₂. Michael addition of arylthiol to α,β-unsaturated aldehydes was promoted by Na₂CO₃/SiO₂, and then the product was cyclized in the presence of PPA/SiO₂.

stereoselective synthesis - thiochroman - supported ­reagents

References and Notes

<A NAME="RU12906ST-1">1</A> Advances in Heterocyclic Chemistry   Vol. 18:  Katrizky AR. Boulton AJ. Academic Press; New York: 1975.  p.76 

<A NAME="RU12906ST-2">2</A> Meyers CY. Rinaldi C. Bonoli L. J. Org. Chem.  1963,  28:  2440 

<A NAME="RU12906ST-3">3</A> Nakazawa T. Sato K. Itabashi K. Nihon Kagaku Kaishi  1990,  119 

<A NAME="RU12906ST-4">4</A> Jafarzadeh M. Amani K. Nikpour F. Tetrahedron Lett.  2005,  46:  7567 

<A NAME="RU12906ST-5">5</A> Ishino Y. Mihara M. Kawai H. Synlett  2001,  1317 

<A NAME="RU12906ST-6">6</A> Aoyama T. Takido T. Kodomari M. Synlett  2004,  2307 

<A NAME="RU12906ST-7">7</A> Aoyama T. Takido T. Kodomari M. Synlett  2005,  2739 

<A NAME="RU12906ST-8A">8a</A> Mckillop A. Young DW. Synthesis  1979,  401 

<A NAME="RU12906ST-8B">8b</A> Posner GH. Angew. Chem., Int. Ed. Engl.  1978,  17:  487 

<A NAME="RU12906ST-8C">8c</A> Cornelis A. Laszlo P. Synthesis  1985,  909 

<A NAME="RU12906ST-9">9</A>

Preparation of PPA/SiO ₂ .
PPA (4.0 g) and CHCl₃ (100 mL) were placed in the round-bottomed flask, and the mixture was stirred at 50 °C for 1 h. Then, SiO₂ [Wakogel C-200 (Wako Pure Chemical Ind. Ltd.), 16.0 g], which was dried in vacuo (10 mmHg) at
160 °C for 2 h, was added to the mixture, and the mixture was stirred for another 1 h. The CHCl₃ was removed with rotary evaporator and the resulting solid was dried in vacuo (10 mmHg) at r.t. for 3 h.

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Preparation of Na ₂ CO ₃ /SiO ₂ . Silica gel [Wakogel C-200 (Wako Pure Chemical Ind. LTD.), 16.82 g] was added to a solution of Na₂CO₃ (30 mmol, 3.18 g) in distilled H₂O (100 mL), and the mixture was stirred at r.t. for 0.5 h. Then, H₂O was removed by rotary evaporator under reduced pressure, and the resulting reagent was dried in vacuo (10 mmHg) at 160 °C for 5 h.

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Typical Procedure. A mixture of arylthiols (4.20 mmol), α,β-unsaturated aldehydes (2.00 mmol), Na₂CO₃/SiO₂ (1.88 mmol, 1.25 g) and PPA/SiO₂ (20 wt%, 3.00 g) was stirred in PhCl (15 mL) at 80 °C for 4 h, and then the used supported reagents were removed by filtration. The filtrate was evaporated to leave crude product, which was purified by column chromatography eluted with hexane-EtOAc (300:1).

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Compound 3aa (trans:cis = 1.0:0.1): yellow solid; mp 59.4-60.1 °C (hexane-EtOAc). Anal. Calcd for C₁₈H₂₀S₂: C, 71.95; H, 6.71. Found: C, 71.91; H, 6.79. HRMS (EI): m/z calcd for C₁₈H₂₀S₂ [M⁺]: 300.1006; found: 300.0999. IR (neat): 3015, 1489, 1479, 818, 780 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.29 (0.27 H, d, J = 6.8 Hz), 1.31 (2.73 H, d, J = 6.8 Hz), 1.85 (0.91 H, ddd, J = 14.1, 11.7, 3.1 Hz), 1.99 (0.09 H, dt, J = 13.7, 10.7 Hz), 2.19 (0.91 H, dt, J = 14.1, 3.1 Hz), 2.22 (2.73 H, s), 2.27 (0.27 H, s), 2.32 (0.27 H, s), 2.35 (2.73 H, s), 2.50 (0.09 H, ddd, J = 13.7, 5.6, 2.9 Hz), 3.23-3.32 (0.09 H, m), 3.94-4.03 (0.91 H, m), 4.36 (0.09 H, dd, J = 10.7, 5.6 Hz), 4.47 (0.91 H, t, J = 3.1 Hz), 6.89-7.37 (7 H, m).
Compound 3ab (trans:cis = 1.0:0.04): white solid; mp 77-78 °C (EtOH). Anal. Calcd for C₂₀H₂₄S₂: C, 73.12; H, 7.39. Found: C, 73.03; H, 7.36. HRMS (EI): m/z calcd for C₂₀H₂₄S₂ [M⁺]: 328.1319; found: 328.1320. IR (neat): 3019, 1493, 1479, 814, 799 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.90 (0.12 H, t, J = 7.3 Hz), 0.95 (2.88 H, t, J = 7.3 Hz), 1.40-1.50 (2.00 H, m), 1.55-1.62 (2.00 H, m), 1.85 (0.96 H, ddd, J = 14.1, 11.7, 3.2 Hz), 1.99 (0.04 H, dt, J = 13.7, 11.0 Hz), 2.23 (0.96 H, dt, J = 14.1, 3.2 Hz), 2.23 (2.88 H, s), 2.27 (0.12 H, s), 2.33 (0.12 H, s), 2.36 (2.88 H, s), 2.53 (0.04 H, ddd, J = 13.7, 5.6, 3.7 Hz), 3.18-3.25 (0.04 H, m), 3.88-3.95 (0.96 H, m), 4.35 (0.04 H, dd, J = 11.0, 5.6 Hz), 4.46 (0.96 H, t, J = 3.3 Hz), 6.89-7.38 (7 H, m).
Compound 3ac (trans:cis = 1.0:0): white solid; mp 100-102 °C (acetone-hexane). Anal. Calcd for C₂₃H₂₂S₂: C, 76.24; H, 6.19. Found: C, 76.19; H, 6.12. HRMS (EI): m/z calcd for C₂₃H₂₂S₂ [M⁺]: 362.1163; found: 362.1163. IR (neat): 3034, 1598, 1492, 1479, 807 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 2.26 (3 H, s), 2.31 (3 H, s), 2.34-2.37 (2 H, m), 4.57 (1 H, t, J = 3.0 Hz), 5.10 (1 H, dd, J = 9.3, 5.4 Hz), 6.93-7.42 (12 H, m).
Compound 3ad: oil. HRMS (EI): m/z calcd for C₁₇H₁₈S₂ [M⁺]: 286.0850; found: 286.0851. IR (neat): 3016, 1597, 1491, 1482, 810 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 2.07 (1 H, ddt, J = 14.1, 12.4, 3.2 Hz), 2.22 (3 H, s), 2.22-2.29 (1 H, m), 2.32 (3 H, s), 2.69-2.75 (1 H, m), 3.68 (1 H, td, J = 12.4, 3.2 Hz), 4.44 (1 H, t, J = 3.2 Hz), 6.87-7.36 (7 H, m).
Compound 3ae: oil. HRMS (EI): m/z calcd for C₁₉H₂₂S₂ [M⁺]: 314.1163; found: 314.1164. IR (neat): 3018, 1597, 1491, 1475, 810 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.33 (3 H, s), 1.38 (3 H, s), 2.14-2.25 (2 H, m), 2.30 (3 H, s), 2.33 (3 H, s), 4.42 (1 H, dd, J = 10.0, 6.4 Hz), 6.92-6.99 (2 H, m), 7.09 (2 H, d, J = 7.8 Hz), 7.26-7.29 (2 H, m), 7.65 (1 H, s).