Remarkable Diastereoselectivity of the Thia-Michael Reaction on α,α′-Di[(E)-benzylidene]alkanones: Exclusive Formation of a meso Product

Abstract

Thia-Michael addition of thiophenol to α,α′-di[(E)-benzyl­idene]alkanones of both cyclic (six-membered) and acyclic varieties using anhydrous K₂CO₃ or amberlyst-15 as catalyst has been found to be highly diastereoselective at 15 °C. A one-pot protocol was developed for such reactions by a tandem aldol-thia-Michael process. The stereochemistry of the products was confirmed by X-ray crystallographic studies and in all cases formation of a meso product was observed.

Key words

diastereoselective process - thia-Michael reaction - α,α′-di[(E)-benzylidene]alkanones - thiophenol - DFT calculations

• References and Notes

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• 10 General Procedure for the Synthesis of Bis-β-aryl-β-mercaptoalkanones (3/5/8/10): α,α′-Di[(E)-benzylidene]alkanones (1/4/9, 1 mmol) were thoroughly mixed with neutral alumina (4 g) with added anhydrous K₂CO₃ (2 mmol) or amberlyst-15 (80 mg). The mass was cooled to 15 °C and thiophenol (2, 2 mmol) was added to keep the temperature constant. The resulting mixture was kept at 15 °C for 4 h under closed conditions. The solid was then washed thoroughly with CH₂Cl₂. The washings were collected, concentrated and subjected to column chromatography through silica gel using PE–EtOAc mixtures as eluents to get the bis-β-aryl-β-mercaptoalkanones (3/5/8/10). General Procedure for One-Pot Synthesis of Bis-β-aryl-β-mercaptocyclohexanones (5/8) from Cyclohexanones: A mixture of a cyclohexanone (6, 1 mmol) and aromatic aldehyde (7, 2 mmol) was thoroughly ground over neutral alumina (4 g) with added anhydrous K₂CO₃ (2 mmol) or amberlyst-15 (80 mg) and the resulting powder was subjected to microwave irradiation at 540 W for 5 min (120–125 °C). After cooling the mass to 15 °C, thiophenol (2, 2 mmol) was added to keep the temperature constant and the components were thoroughly mixed. The mixture was kept at 15 °C for 4 h under closed conditions. The solid was then washed thoroughly with CH₂Cl₂ and the concentrate of the washings was subjected to column chromatography over silica gel using PE–EtOAc mixtures as eluents to get the bis-β-aryl-β-mercaptocyclohexanone (5/8) in pure state as a single diastereomer.
• 11 Physical and spectral data of representative compounds of the series 3, 5 and 8: Compound 3b: colourless crystals; mp 72–74 °C. IR (KBr): 1678 (C=O), 1492, 1325, 1226, 1015, 815 cm^–1.¹H NMR (300 MHz, CDCl₃): δ = 2.28 (s, 6 H, 2 × ArMe), 2.89–2.92 (m, 4 H, 2 × CH₂), 4.59 (dd, J = 8.0, 6.8 Hz, 2 H, 2 × CH), 6.97–7.02 (m, 2 × 4 H, ArH), 7.19–7.24 (m, 2 × 5 H, ArH). ¹³C NMR (75 MHz, CDCl₃): δ = 21.1, 47.5, 49.6, 127.4, 127.5, 128.8, 129.1, 132.7, 134.2, 137.0, 137.6, 204.8. HRMS: m/z [M + Na]⁺ calcd for C₃₁H₃₀NaOS₂: 505.1636; found: 505.1637. Compound 5b: colourless crystals; mp 124–126 °C. IR (KBr): 1678 (C=O), 1514, 1344, 1219, 998, 986, 822 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 1.66–1.69 (m, 3 H, cyclohexanone H_A-3, H_A-4, H_A-5), 2.00 (br s, 1 H, cyclohexanone H_B-4), 2.28 (s, 6 H, 2 × ArMe), 2.61 (br s, 2 H, cyclohexanone H_B-3, H_B-5), 2.86 (t, J = 4.5 Hz, 2 H, 2 × H_α), 4.62 (d, J = 7.5 Hz, 2 H, 2 × H_β), 6.89 (d, J = 8.1 Hz, 4 H, ArH), 7.00 (d, J = 8.1 Hz, H, ArH), 7.12–7.23 (m, 10 H, ArH). ¹³C NMR (75 MHz, CDCl₃): δ = 21.0, 25.4, 32.8, 52.3, 57.5, 126.8, 127.8, 128.6, 128.7, 132.1, 135.1, 136.0, 139.0, 208.4. HRMS: m/z [M + Na]⁺ calcd for C₃₄H₃₄NaOS₂: 545.1933; found: 545.1949. Compound 8a: colourless crystals; mp142–144 °C. IR (KBr): 1673 (C=O), 1515, 1333, 1215, 977, 818, 782 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 1.08 (d, J = 6.3 Hz, 3 H, Me), 1.45–1.57 (m, 2 H, cyclohexanone H_A-3, H_A-5), 1.99 (br s, 1 H, cyclohexanone H-4), 2.49–2.54 (m, 2 H, cyclohexanone H_Β-3, H_Β-5), 2.91–2.96 (m, 2 H, 2 × H_α), 4.69 (d, J = 6.9 Hz, 2 H, 2 × H_β), 7.07–7.28 (m, 20 H, ArH). ¹³C NMR (75 MHz, CDCl₃): δ = 21.3, 32.0, 39.8, 52.6, 56.0, 126.6, 127.0, 128.0, 128.04, 128.6, 132.2, 134.8, 141.9, 208.2. HRMS: m/z [M + Na]⁺ calcd for C₃₃H₃₂NaOS₂: 531.1692; found: 531.1564.