Sustainable Organocatalyzed Enantioselective Catalytic Michael Additions in Betaine-Derived Deep Eutectic Solvents

Abstract

The organocatalyst cinchonidine-squaramide was immobilized within three different deep eutectic solvents (DESs): betaine:d-sorbitol:water, betaine: d-xylitol:water, and betaine:d-mannitol:water and evaluated in a well-known asymmetric Michael addition. These reactions provided excellent yields (up to 99%) and enantioselectivities (up to 98%) using only 1 mol% of organocatalyst. It was also possible to achieve 9 cycles in reactions with DES (betaine:d-sorbitol:water), proving the high recyclability of this system. In the reactions realized with only 0.5 mol% of organocatalyst, it was possible to achieve 5 cycles, and the products were obtained with high yields (up to 95%) and excellent enantioselectivities (up to 94%), using DES (betaine:d-sorbitol:water).

Keywords

cinchonidine-squaramide - betaine - deep eutectic solvent (DES) - immobilization - organocatalysis

Publication History

Received: 23 March 2023

Accepted after revision: 26 June 2023

Accepted Manuscript online:
26 June 2023

Article published online:
17 August 2023

• References and Notes

• 1 Current address: Faculty Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal; e-mail: [e-mail].
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• 18 General Procedure for Producing DESs In general, DESs result from the mixture of several components in the appropriate amounts to obtain the DES in the desired ratios. The conditions presented were optimized for each DES. The specific DES resulted from mixing 1 equiv of betaine with 1 equiv of the desired sugar and 3 equiv of water, in the case of DESs produced in the ratio 1:1:3.
• 19 General Procedure for Asymmetric Catalytic Michael Additions 2 mL of DES solvent was added to a 25 mL round-bottom flask containing a magnetic stirring bar. 1 equiv of trans-β-nitrostyrene (2, 0.25 mmol) and 1.1 equiv of acetylacetone (1) or methyl 2-oxocyclopentane-1-carboxylate (4, 0.275 mmol) were added to the DES. Finally, 5, 1, or 0.5 mol% of cinchonidine-squaramide (catalyst A in the Supporting Information) were added to the mixture and allowed to react for 24 h at 40 °C under sufficient stirring (this is very important as the DES by nature is viscous). The reaction was monitored by TLC and after total consumption of the starting material, extraction was performed with Hex:AcOEt (1:1, 2 × 2 mL). The crude products 3 (yellowish solid) or 5 (colorless opaque oil) isolated from the reaction mixture were directly analyzed by ¹H NMR spectroscopy and HPLC without further purification. The previously described procedure was repeated for several reaction cycles until the catalyst no longer showed catalytic activity.
• 20 Product 3 Yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.35–7.16 (m, 5 H, ArH), 4.65 (m, 2 H, CH₂), 4.38 (m, 1 H, CH), 4.27 (m, 1 H, CH), 2.29 (s, 3 H, CH₃), 1.94 (s, 3 H, CH₃) ppm. ¹³C APT-NMR (100 MHz, CDCl₃): δ = 201.80 (C), 201.03 (C), 135.99 (CH), 129.36 (2 × CH), 128.58 (CH), 127.95 (2 × CH), 78.20 (CH₂), 70.74 (CH), 42.80 (CH), 30.45 (CH₃), 29.55 (CH₃) ppm.
• 21 Product 5 ¹H NMR (400 MHz, CDCl₃): δ = 1.81–2.07 (m, 4 H, 2 CH₂), 2.31–3.39 (m, 2 H, CH₂), 3.75 (s, 3 H, CH₃), 4.08 (dd, J = 4, 12 Hz, 1 H, CH), 4.98–5.04 (m, 1 H, CH₂), 5.14–5.18 (m, 1 H, CH₂), 7.23–7.33 (m, 5 H, ArH) ppm.¹² HPLC: Daicel Chiralpak OD-H column, n-hexane/i-propanol = 95/5, 1 mL/min, 220 nm. Retention times: t _major = 15.747 min, t _minor = 26.280 min (minor diastereomer); t _major (S,R) = 19.040 min, t _minor = 27.487 min (major diastereomer).¹²