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

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.

asymmetric organocatalysis - Brønsted acid - thiourea - 1,4-dihydropyridines - β-enamino esters - α,β-unsaturated aldehydes

References and Notes

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<A NAME="RU02810ST-15">15</A>

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.

<A NAME="RU02810ST-16">16</A>

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).

<A NAME="RU02810ST-17">17</A>

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.

<A NAME="RU02810ST-18">18</A>

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^-¹. ^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).