a All the reactions were run with 0.1 mmol of 1a in 2 ml DCE at 130 oC for 20 h.b Determined by1H NMR using 1,1,2,2-tetrachloroethane as the internal standard. Abbreviations: DCE, Dichloroethane. DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene. TMP, 2,2,6,6-Tetramethylpiperidine
(78% ee) (Table 1, entry 2). Similarly, other chiral phosphoramidite ligands, such as L3 and L9 , also yielded favorable results (Table 1, entries 3 and 9). Building upon these initial findings, we directed our attention towards optimizing the choice of base and solvent parameters. It was observed that the use of the inorganic base K2CO3 resulted in the production of 2a with good enantioselectivity (83% ee) and outstanding NMR yield (75%). Furthermore, 1,2-Dichloroethane (DCE) has been emerged as the most advantageous solvent for this reaction. Subsequent efforts to refine the experimental conditions did not yield significant improvements (see more details in the Supporting Information).
Unless otherwise noted, all reactions were carried out with 0.2 mmol of1 in 4 mL DCE at 130 oC for 20 h.
Figure 1 The scope of substrate 1
With the optimal conditions in hand, the substrate scope of this intramolecular enantioselective tandem reaction was examined as illustrated in Figure 1. A variety of substituted 2-(3-hydroxy-1-phenylprop-1-en-1-yl)phenols with diverse aryl groups demonstrated a smooth progression through the tandem process, affording the desired lactones with moderate yields and a good level of enantioselectivity. However, the 2-(tert -butyl) or 2,4-di-tert -butyl-6-(3-hydroxy-1-phenylprop-1-en-1-yl)phenol was subjected into the reaction conditions, delivering reduced enantioselectivity with 68% and 49% ee respectively (2g and2h ). The introduction of various substituents on another aryl group was well-tolerated, yielding the corresponding lactones in good yields and enantioselectivities (2i -2q ). Notably, product 2q holds significant promise as it can undergo further transformations, ultimately leading to the formation of a chiral β,β-diaryl carboxylic acid that serves as a potent agonist for GPR40, rendering it a prospective drug candidate for diabetes treatment. Encouragingly, even a heterocyclic substituent, such as the thiophene group, proved compatible with the reaction conditions, providing the desired product 2r in a 60% isolated yield, albeit with 77% ee. Furthermore, the reaction consistently demonstrated its efficiency, delivering the desired dihydrocoumarins with various substituents on the two aryl groups (2s -2x ). Remarkably, when the aryl substituents at the β-position of the primary allylic alcohol were replaced with alkyl substituents, the reaction still proceeded efficiently, yielding the desired dihydrocoumarins in good efficiency (4a -4h ). We were delighted to confirm that electron-neutral, electron-rich, and electron-deficient substituents on the aromatic ring were well tolerated, resulting in the corresponding products with excellent yields. The presence of tert-butyl group substituents in the aromatic ring also led to good yield and enantioselectivity (4e ). Unfortunately, when the R4 group was replaced with the bulkier ethyl group (4h ) instead of the methyl group (4a ), it led to lower enantioselectivity.
Unless otherwise noted, all reactions were carried out with 0.2 mmol of1 in 4 mL DCE at 130 oC for 20 h.
Figure 2 The scope of substrate 3 .
To gain deeper insights into the mechanics of this reaction, particularly concerning the isomerization of primary allylic alcohols and the formation of the new C−O bond, isotopic labeling studies were conducted, as depicted in Figure 3. Deuterium labeling experiments were executed using 1x -d2 to elucidate on the plausible mechanism. The analysis by1H NMR revealed that deuterium in dihydrocoumarin2x -d 2 was integrated at both C1 (0.51D) and C2 (0.14D), providing evidence that the hydrogen transfer during the reaction followed a chain-walking process involving iterative β-H elimination and reinsertion steps. Furthermore, a hydrogen signal was detected via gas chromatography during the reaction of1y , indicating that a dehydrogenative process was incorporated into this transformation process.
Based on the experimental findings and previous research on Ru-catalyzed alkene double bond isomerization,[8] we propose a specific reaction mechanism. The plausible catalytic cycle is illustrated in Figure 3c, encompassing the isomerization of alkenyl alcohol and the subsequent coupling processes for lactone formation. The reaction commences with the activation of the reactant through a deprotonation step in the presence of the base, leading to the formation of alkoxide I . Subsequently, a β-hydride elimination event occurs, resulting in the generation of aldehyde intermediate IIinto complex III . Tautomerization then leads to the formation of intermediate IV . Swift protonation and subsequent esterification processes yield VI , which can further release H2 gas to produce the desired chiral 3,4-dihydrocoumarins while regenerating the ruthenium catalyst for subsequent reactions.
Figure 3 Mechanism exploration.
Conclusions
In summary, we have successfully developed a ruthenium catalytic system for the enantioselective isomerization of alkenyl alcohols, followed by a tandem coupling reaction that enables the synthesis of diverse chiral dihydrocoumarins. This protocol demonstrates a wide substrate applicability, excellent tolerance for various functional groups, and good enantioselectivities, and presents its potential for the construction of GPR40 agonists. Ongoing efforts are dedicated to further elucidating the underlying reaction mechanism.
Experimental
General procedure for the synthesis of 2
A flame–dried 15 mL cylindrical pressure vessel was charged with1 (0.2 mmol, 1.0 equiv.). The cylindrical pressure vessel was directly transferred into a nitrogen-filled glovebox without caps. Then, RuCl2(cod) (2.8 mg, 0.01 mmol, 5 mol%), L2(5.1 mg, 0.012 mmol, 6 mol%), K2CO3(55.3 mg, 0.4 mmol, 2.0 equiv.) and 4.0 mL dry DCE were added. Then the cylindrical pressure vessel was tightly sealed, transferred out of the glovebox and stirred at 130 °C for 20 h. After the completion of the reaction, the solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel to give the desired 4-aryldihydrocoumarin compounds.