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.