Asymmetric Synthesis of 4-Aryl-3,4-dihydrocoumarins by N-Heterocyclic Carbene Catalyzed Annulation of Phenols with Enals

Article abstract of DOI:10.1021/acs.orglett.7b00088

The highly enantioselective synthesis of 4-aryl-3,4-dihydrocoumarins was realized through direct annulation of phenols with enals catalyzed by dihydroisoquinoline-type NHC (DHIQ-NHC), an N-heterocyclic carbene derived from l-phenylalanine. The catalytic reaction proceeds with a wide scope of electron-rich phenols and enals providing structurally diverse 4-aryl-3,4-dihydrocoumarins in good to excellent yields and enantioselectivity. This method was useful in the synthesis of natural products and biologically relevant compounds from readily available starting materials.

Full text of DOI:10.1021/acs.orglett.7b00088

Letter
pubs.acs.org/OrgLett
Asymmetric Synthesis of 4‑Aryl-3,4-dihydrocoumarins by
N‑Heterocyclic Carbene Catalyzed Annulation of Phenols with Enals
Guo-Tai Li, Zhi-Ke Li, Qing Gu, and Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Lu, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: The highly enantioselective synthesis of 4-aryl-3,4-
dihydrocoumarins was realized through direct annulation of
phenols with enals catalyzed by dihydroisoquinoline-type NHC
(DHIQ-NHC), an N-heterocyclic carbene derived from L-phenyl-
alanine. The catalytic reaction proceeds with a wide scope of
electron-rich phenols and enals providing structurally diverse
4-aryl-3,4-dihydrocoumarins in good to excellent yields and
enantioselectivity. This method was useful in the synthesis of
natural products and biologically relevant compounds from readily
available starting materials.
oumarin derivatives are found in numerous natural
products, pharmaceuticals, and biologically active com-
indolin-3-ones,16 and pyrazolones,17 have been successfully
explored as suitable reaction partners.18 However, phenols have
been rarely utilized as the nucleophiles despite the fact that
such a reaction provides direct access to 4-aryl-3,4-dihydro-
coumarins.19 As a part of our continuing interest in chiral NHC
catalysis, we recently realized an NHC-catalyzed annulation
reaction of 2-naphthols with α,β-unsaturated aldehydes.13
In this paper, we report a straightforward synthesis of 4-aryl-
3,4-dihydrocoumarins by NHC-catalyzed annulation reaction of
enals with substituted phenols (Scheme 1).
C
pounds.1 In particular, 4-aryl-3,4-dihydrocoumarins exist
extensively as naturally occurring compounds from various
plants (Figure 1), such as Polygonum perfoliatum,2a Dorstenia
Scheme 1. α,β-Unsaturated Acyl Azolium Involved
Annulation Reactions
Figure 1. Selected natural products containing 4-aryl-3,4-dihydrocou-
marin core.
poinsettifolia,2b Pityrogramma calomelanos,2c and Gnetum mon-
tanum Markgr. f. megalocarpum Markgr.2d Of particular note,
these compounds have been found to possess interesting
biological activities, such as antibacterial,3a antioxidant,3b
antiherpetic,3c antiplasmodial,3d and hepatoprotective.3e In
addition, 4-aryl-3,4-dihydrocoumarins are important synthetic
intermediates.4 As such, various synthetic methods toward
4-aryl-3,4-dihydrocoumarins have been developed;5−10 how-
ever, most reported methods involve racemic syntheses. There
have been only a handful of examples on the asymmetric
synthesis of 4-aryl-3,4-dihydrocoumarins.6−9 Therefore, the
catalytic asymmetric syntheses of 4-aryl-3,4-dihydrocoumarins
remain highly desirable.
N-Heterocyclic carbenes (NHCs) have been demonstrated
as useful catalysts for the synthesis of substituted dihydrocou-
marin compounds.11 Since the introduction of α,β-unsaturated
acyl azolium intermediates by the reaction of NHC with
α,β-unsaturated aldehydes, various nucleophiles, such as enols,12
naphthols,13 heterocyclic C−H acids,14 1,3-dicarbonyls,15
At the outset, we tested the reaction of 3,5-dimethoxyphenol
(1a) with 4-methoxycinnamaldehyde (2a) in the presence of
3,3′,5,5′-tetra-tert-butyldiphenoquinone (5)20 with NHCs
derived from readily available triazolium salts (Table 1).
To our delight, in most cases, the annulation product 3a could
be obtained. The reaction catalyzed by triazolium salt A derived
NHC proceeded well to give annulation product 3a in 40%
yield and 63% ee (entry 1). Of particular note, DHIQ-NHC
derived from triazolium salt D gave results similar to those of
Received: January 17, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00088
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of the Reaction Conditions
Table 2. Substrate Scope
b
c
d
entry triazolium salt time (h) yield of 3a (%) ee (%)
3a/4a
1
2
3
4
5
6
7
8
A
B
C
D
E
F
5
5
40
44
63
1/1.27
1/1.09
1/4.11
1/1.56
1/1.54
1/0.98
1/1.33
1/0.39
−5
24
8
<20
32
60
49
87
56
97
40
10
40
24
39
49
G
F
43
e
71
a
Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), triazolium salt
́
́
(0.02 mmol), K3PO4 (0.04 mmol), 3,3,5,5-tetra-tert-butyldiphenoqui-
b
none 5 (0.24 mmol) in toluene (2.0 mL) at rt. Isolated yield of 3a.
c
d
Determined by HPLC analysis. Determined by 1H NMR of the
e
crude reaction mixture. 20 mol % of LiHMDS was used as base, and a
mixed solvent of BuOH/toluene (1/4) was used.
t
triazolium salt A, while the triazolium salt F, featuring a free
hydroxyl group, gave 3a in 87% ee (Table 1, entries 1, 4, and
6). The key role of the free hydroxyl group is also supported
by the fact that triazolium salt G is superior to E (Table 1,
entries 5 and 7). However, in general, the yields of 3a are
moderate due to the formation of byproduct 4a.
With triazolium salt F as the NHC precursor, further
optimization of the reaction conditions (bases, solvents, and
additives) was carried out (Tables S1−S4).21 The best results (3a,
71% yield, 97% ee) were obtained in a mixed solvent of tBuOH/
toluene (1/4) and with 20 mol % of LiHMDS as base (entry 8).
The conjugate addition of phenol to acyl azolium intermediate is
more favorable presumably due to the existence of a hydrogen-
t
bond interaction between BuOH and the carbonyl group.
It should be noted that the significantly increased yield of
annulation product 3a is more attributed to the use of LiHMDS.
In the presence of 10 mol % of triazolium salt F, 20 mol % of
LiHMDS, and 120 mol % of oxidant 5 in tBuOH/toluene (1/4)
at room temperature (Table 1, entry 8), the reactions of various
α,β-unsaturated aldehydes with substituted phenols have been
tested to investigate the generality of the reaction. The results
are summarized in Table 2. When 3,5-dimethoxyphenol was
used, substituted cinnamaldehydes bearing either an electron-
donating or electron-withdrawing group were examined. In all
cases, the reaction proceeded smoothly, affording their corre-
sponding products in excellent enantioselectivity and yields
(85−97% ee for 3, entries 1−13). In the case of a strong
electron-withdrawing group incorporated substrate such as
4-nitrocinnamaldehyde, a slight decrease of enantioselectivity
was observed (85% ee, entry 9). Notably, (E)-3-(furan-2-
yl)acrylaldehyde was found to be a suitable substrate, yielding
3m in excellent enantioselectivity (entry 13, 52% yield, 96% ee).
a
Reaction conditions: 1 (0.3 mmol), 2 (0.36−0.6 mmol, 1.2−2.0 equiv),
F (0.03 mmol), LiHMDS (0.06 mmol), 5 (0.36−0.6 mmol, 1.2−
b
2.0 equiv) in toluene/tBuOH (3.0 mL) at rt. Isolated yield.
c
d
1
Determined by HPLC. Determined by H NMR.
However, the reaction of phenol 1a with crotonaldehyde (R2 =
methyl) was slugglish, and only a trace amount of prod-
uct was observed. Then different substituted phenols were also
investigated. When 3-(dimethylamino)phenol and sesamol
were used, the annulation products were obtained in 92−94%
ee (3n,o) together with a significant amount of side products 4.
Substituents such as ethyl, styryl, and bromo at the 2-position
of 3,5-dimethoxyphenol could be well tolerated (3p−r), and
B
DOI: 10.1021/acs.orglett.7b00088
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
their corresponding annulation products were obtained in 37−
81% yields and 92−96% ee. A substrate derived from chrysin22
could also be utilized in this reaction to afford the annulation
product 3s, an analogue of natural product calomelanol C, in
47% yield and 85% ee. However, in all cases, byproduct 4 was
inevitable under the reaction conditions. In order to determine
the absolute configuration of the product, a single-crystal X-ray
analysis of enantiopure 3a was carried out, and the configuration
was determioned to be R.
The enantioenriched products obtained here could undergo
diverse transformations and could be utilized as key intermediates
for highly efficient syntheses of natural products and bioactive
compounds. As depicted in Scheme 2, demethylation of 3a
Shu-Li You: 0000-0003-4586-8359
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Basic Research Program of China from
MOST (2016YFA0202900, 2015CB856600), the National
Natural Science Foundation of China (21332009, 21421091),
and the Strategic Priority Research Program of the Chinese
Academy of Sciences (XDB20000000) for generous financial
support. We thank Mr. Can-Can Bao for carrying out a 1 mmol
scale reaction.
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Scheme 2. Transformations of 3a and 3l into Natural
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AUTHOR INFORMATION
Corresponding Author
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ORCID
Qing Gu: 0000-0003-4963-2271
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