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. 2024 Oct 18;14(45):32944-32957.
doi: 10.1039/d4ra06449f. eCollection 2024 Oct 17.

Domino dehydration/intermolecular (enantioselective) ketone-ene reactions catalysed by a simple solid in batch and in flow

Miguel Espinosa  1 , Antonio Leyva-Pérez  1
Affiliations

Domino dehydration/intermolecular (enantioselective) ketone-ene reactions catalysed by a simple solid in batch and in flow

Miguel Espinosa et al. RSC Adv. .

Abstract

The intermolecular carbonyl-ene reaction of ketones is still considered a challenge in organic chemistry, particularly with reusable solid catalysts, and implemented in a domino reaction. Herein, we show that the extremely cheap and non-toxic solid salt MgCl2 catalyzes the reaction of trifluoromethyl pyruvates not only during the conventional carbonyl-ene reaction with various aromatic and alkyl alkenes (in very high yields, up to >99%) but also in a domino reaction with the corresponding alcohols (precursors to the alkenes) in similar good yields. The solid can be reused in both cases without any erosion of the catalytic activity and can be employed in an in-flow process to maximize the reaction throughput. Besides, the reaction can be performed under solventless reaction conditions. Addition of a catalytic amount of chiral binaphthyl hydrogen phosphate allows carrying out the reaction with a reasonable enantiomeric excess (up to >70%) and in flow, in a rare example of enantioselective solid-catalyzed domino carbonyl-ene reaction using a cheap, simple, readily available and physically mixed catalytic solid. The MgCl2-catalytic system is also active in the industrially relevant citronellal-to-isopulegol carbonyl-ene reaction. These results pave the way to design sustainable domino carbonyl-ene reactions with extremely cheap solid catalysts.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. Overall view of the catalytic maturity during the intermolecular carbonyl-ene reaction of the different reactive carbonyl groups and the envisioned domino reaction with ketones. ✓✓ well-resolved, ✓ several examples, ✗ few examples, ✗✗ rare examples or none.
Fig. 2
Fig. 2. Kinetic plot of the intermolecular ketone-ene reaction between α-methyl styrene 1 and methyl pyruvate 2 (1 equivalent) catalyzed by MgCl2 (5 mol%, black line) or none (blue line) in a DCM (0.5 M) solvent at room temperature. Lines are a guide to the eye. GC yields. Error bars account for 5% uncertainty.
Fig. 3
Fig. 3. Scope of the carbonyl-ene reaction of different alkenes and pyruvates catalyzed by MgCl2 (5 mol%), at room temperature for 18 h, without any solvent or DCM (0.5 M). The results from left to right indicate: GC yield for the solventless reaction, isolated yield (between parentheses) and GC yield in DCM. Reactions were performed twice, showing very good reproducibility.
Fig. 4
Fig. 4. Enantioselective catalytic results for the intermolecular ketone-ene reaction between α-methyl styrene 1 and methyl pyruvate 2 (1 equivalent) catalyzed by MgCl2 (5 mol%) and the chiral (R) ligands 21–26 (6 mol%), in DCM (0.5 M) at room temperature. Yields calculated by GC and enantiomeric excess (ee) calculated by chiral HPLC resolution.
Fig. 5
Fig. 5. In-flow reaction with MgCl2 + chiral ligand 21 as a catalyst (111 mg in total, 5 : 2 wt% ratio) for the intermolecular ketone-ene reaction between α-methyl styrene 1 and methyl pyruvate 2 (1 equivalent) in DCM (0.5 M) at room temperature. The feed flow rate is 2 mL h−1. GC yields and HPLC ees.
Fig. 6
Fig. 6. Results of the intramolecular carbonyl-ene reaction of citronellal 27 (0.25 mmol) with MgCl2 as a catalyst (20 wt%) in DCM (0.5 M) at 40 °C. Isolated yield.
Fig. 7
Fig. 7. Results of the domino dehydration/intermolecular carbonyl-ene reaction of alcohol 29 with trifluoromethyl pyruvate 2 (1 equiv.) catalysed by MgCl2 (5 mol%) without any solvent, at 50 °C for 18 h, after recovering the MgCl2 catalyst by decantation and reuse. GC yields, mass balances are complete with unreacted starting material 29.
Fig. 8
Fig. 8. In-flow reaction with MgCl2 + chiral ligand 21 as a catalyst (111 mg in total, 5 : 2 wt% ratio) for the domino reaction, in DCE (0.5 M) at room temperature. The feed flow rate is 0.7 mL h−1. GC yields and chiral GC ees. Error bars account for a 5% uncertainty.
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