Synlett 2010(12): 1865-1869  
DOI: 10.1055/s-0030-1258090
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Brønsted Acid-Thiourea Co-catalysis: Asymmetric Synthesis of Function­alized 1,4-Dihydropyridines from β-Enamino Esters and α,β-Unsaturated ­Aldehydes

Kohzo Yoshida, Tsubasa Inokuma, Kiyosei Takasu, Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Fax: +81(75)7534569; e-Mail: takemoto@pharm.kyoto-u.ac.jp;
Further Information

Publication History

Received 12 April 2010
Publication Date:
11 June 2010 (online)

Abstract

A Brønsted acid and a novel thiourea derivative co-catalyze the addition of β-enamino esters to α,β-unsaturated aldehydes leading to functionalized 1,4-dihydropyridines with moderate to good enantioselectivity. A regioselective synthesis of 1,2-dihydropyridines from α,β-unsaturated aldehydes is also described.

    References and Notes

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15

When 2a (E/Z = 25:75) was reacted with 3a in the presence of DFA-(S,S)-1c, 4aa was obtained in 50% ee (compared
to entry 8 in Table  [¹] ). Therefore we concluded that the stereochemistry of the enamino esters would not effect to the enantioselectivities.

16

The absolute configuration of the thiourea catalysts described has been assigned based on the known configuration of the starting 1,2-diaminocyclohexane or has been established by X-ray-analysis (CCDC768496).

17

In addition to toluene, we tested a chlorinated solvent (CH2Cl2) and ethers (THF, Et2O). Lower temperature (0 ˚C) led to a decrease in yield (<5%), while higher temperatures (50 ˚C) and catalyst loading (20 mol%) led to an increased yield but lower ee (28%, 55% ee). The addition of molecular sieves (3 Å, 4 Å) inhibited the reaction, while other additives (NaSO4, MgSO4) led to a decrease in enantioselectivity without improving the yield.

18

Typical Procedure for the Reaction of 2j and 3a Catalyzed by Thiourea 1g - DFA To a solution of cinnamaldehyde (3a, 17.7 mg, 0.10 mmol) in toluene (0.40 mL) were added thiourea 1f (5.4 mg, 0.010 mmol) and 0.1 M difluoroacetic acid in toluene solution (100 µL, 0.010 mmol) at r.t. To this mixture was added dropwise (50 µL/30 min) a solution of 2j (22.0 mg, 0.10 mmol) in toluene (0.50 mL) at r.t. After being stirred at the same temperature for 12 h the reaction mixture was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (hexane-EtOAc = 5:1) to give 4ja (30.8 mg, 81%) as a yellow oil.
( R )-Ethyl 1-Benzyl-2-methyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3-carboxylate (4ja) IR (ATR): 2979, 2925, 1684, 1516 cm. ¹H NMR (400 MHz, CDCl3): δ = 8.13 (d, J = 8.8 Hz, 2 H), 7.39 (d, J = 8.8 Hz, 2 H), 7.38-7.31 (m, 3 H), 7.22-7.20 (m, 2 H), 6.02 (d, J = 7.6 Hz, 1 H), 4.93 (dd, J = 7.6, 5.5 Hz, 1 H), 4.78 (d, J = 5.5 Hz, 1 H), 4.69 (d, J = 16.8 Hz, 1 H), 4.59 (d, J = 16.8 Hz, 1 H), 3.99 (q, J = 7.1 Hz, 2 H), 2.46 (s, 3 H), 1.09 (t, J = 7.1 Hz, 3 H) ppm. ¹³C NMR (125 MHz, CDCl3): δ = 168.3, 155.9, 149.8, 146.3, 137.6, 130.3, 129.0, 128.1, 127.7, 126.2, 123.6, 106.6, 99.3, 59.5, 53.8, 40.5, 16.0, 14.2. MS (FAB+): m/z (%) = 378 (100) [M+]. HRMS (FAB+):
m/z calcd for C22H22N2O4 [M+]: 378.1580; found: 378.1578. HPLC (CHIRALCEL AD-H, hexane-2-PrOH = 90:10, flow rate 1.0 mL/min, 254 nm): t r(minor) = 12.0 min, t r(major) = 15.3 min. A sample with 80% ee gave [α]D ²³ +309.8 (c 1.36, CHCl3).