Copper-Catalyzed Intramolecular Desymmetric Aryl C-O Coupling for the Enantioselective Construction of Chiral Dihydrobenzofurans and Dihydrobenzopyrans

Article abstract of DOI:10.1002/anie.201503882

O-Heterocyclic structures such as 2,3-dihydrobenzofurans are key motifs in many natural compounds and pharmaceuticals. Enantioselective formation of chiral dihydrobenzofurans and analogues was achieved through a copper-catalyzed desymmetrization strategy with a chiral cyclic 1,2-diamine. A broad range of substrates are compatible with this Cu^I-diamine catalytic system and afford the desired coupling products with chiral tertiary or quaternary carbon centers in high yields and good to excellent enantioselectivities under mild conditions. O-Heterocyclic structures such as chiral dihydrobenzofurans can be formed enantioselectively through a copper-catalyzed desymmetrization strategy with a chiral cyclic 1,2-diamine ligand. A broad range of substrates is compatible with this Cu^I-diamine catalytic system and afford the desired coupling products with chiral tertiary or quaternary carbon centers in high yields and good to excellent enantioselectivities under mild conditions.

Full text of DOI:10.1002/anie.201503882

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201503882
German Edition: DOI: 10.1002/ange.201503882
Asymmetric Catalysis
À
Copper-Catalyzed Intramolecular Desymmetric Aryl C O Coupling
for the Enantioselective Construction of Chiral Dihydrobenzofurans
and Dihydrobenzopyrans**
Wenqiang Yang, Yangyuan Liu, Shasha Zhang, and Qian Cai*
Abstract: O-Heterocyclic structures such as 2,3-dihydroben-
zofurans are key motifs in many natural compounds and
pharmaceuticals. Enantioselective formation of chiral dihy-
drobenzofurans and analogues was achieved through
a copper-catalyzed desymmetrization strategy with a chiral
cyclic 1,2-diamine. A broad range of substrates are compatible
with this CuI-diamine catalytic system and afford the desired
coupling products with chiral tertiary or quaternary carbon
centers in high yields and good to excellent enantioselectivities
under mild conditions.
been developed for the synthesis of such structures, asym-
metric synthesis in this area is still a challenge.[2,8,9]
In 2013, we reported the first Pd-catalyzed enantioselec-
tive aryl C O coupling reaction[9a] for the formation of central
À
chirality in chromans through an asymmetric desymmetriza-
tion strategy,[10–12] which differentiates the two symmetric
hydroxy groups of 2-(2-haloaryl)1,3-diols[13] by intramolecu-
larly reacting with one aryl halide. However, such a method
has the following limits to its practical applications: 1) only
low to moderate yields were obtained in most cases due to b-
H elimination and dehalogenation side reactions; 2) only
moderate enantioselectivity was obtained due to the limited
availability of chiral ligands; 3) substrates were restricted to
those forming six-membered ring chromans. Asymmetric 5-
membered cyclization afforded dihydrobenzofurans with only
50% yield and 50% ee. Furthermore, substrates were limited
to those with tertiary prochiral centers. Substrates with
a quaternary prochiral carbon center showed very low
reactivity and poor enantioselectivity; and 4) the reaction
conditions were relatively harsh.
O
xygen-heterocycles such as 2,3-dihydrobenzofurans and
chromans are common structures in a variety of naturally
occurring and medicinally relevant compounds (Figure 1).[1–3]
Although many catalytic systems employing transition-metal-
catalyzed coupling reactions, such as couplings of aryl halides
with oxygen nucleophiles catalyzed by Pd[4,5] and Cu[6,7], have
Although an improved Pd catalytic system was later
developed for the asymmetric desymmetrization of 2-(2-
halophenoxyl)1,3-diols by employing a SDP(O) ligand,[9b] the
efficiency of the system was limited to a narrow range of
substrates and still only tertiary chiral carbon centers were
formed in these reactions. Thus, it is highly desirable to
develop a new catalytic system with a broader substrate scope
and with high yield and enantioselectivity.
Copper catalysts have been complementary to Pd cata-
lysts in cross-coupling reactions[14] and copper-catalyzed
coupling reactions of aryl halides with alcohols or phenols
are important methods for the formation of aryl alkyl ethers
or diaryl ethers. Improved protocols for such reactions have
been developed in recent years by using appropriate ligands
to promote them under relatively mild conditions.[6,7] More
importantly, dehalogenation in copper-catalyzed coupling
reactions is not as prevalent as in palladium-catalyzed
reactions, and this may offer an opportunity to improve the
reaction efficiency. However, to the best of our knowledge,
only one example of copper-catalyzed enantioselective aryl
Figure 1. Examples of bioactive natural products or pharmaceuticals
with 2,3-dihydrobenzofuran frameworks.
[*] W. Yang, S. Zhang, Prof. Dr. Q. Cai
Guangzhou Institutes of Biomedicine and Health
Chinese Academy of Sciences
No.190 Kaiyuan Avenue, Guangzhou Science Park
Guangzhou, 510530 (China)
E-mail: cai_qian@gibh.ac.cn
Y. Liu
College of Chemistry and Chemical Engineering
Hunan Normal University
No. 36 Lushan Road, Changsha, 410081 (China)
À
C O coupling, generating axial chirality in the intramolecular
diaryl ether formation, has been reported[15] and no copper-
À
catalyzed aryl C O coupling for the enantioselective forma-
[**] We are grateful to the National Natural Science Foundation (Grant
21272234) for their financial support. We also thank Prof. Dr.
Jinsong Liu and Yongzhi Lu from Guangzhou Institutes of
Biomedicine and Health, Chinese Academy of Sciences, for the X-
ray experiments.
tion of central chirality has been reported to date. In this
communication, we would like to report a copper-catalyzed
À
enantioselective aryl C O coupling reaction, useful for the
formation of 2,3-dihydrobenzofurans and analogues with
tertiary and all-carbon quaternary stereochemical centers
based on a desymmetrization strategy.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201503882.
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Table 1: Screening reaction conditions.
Table 2: Substrate scope for the enantioselective formation of dihydro-
benzofurans and chromans with tertiary stereocenters.[a,b,c]
Entry
L*
Solvent
Base
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
L8
L8
L8
L8
L8
L8
L8
L8
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
DMSO
tBuOH
toluene
1,4-dioxane
acetone
acetone
acetone
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
13
17
92
91
81
74
91
83
86
80
72
15
76
93
37
6
33
11
80
79
68
79
83
89
90
80
80
35
85
92
85
81
9
10
11
12
13
14
15
16
[a] Reagents and reaction conditions: 1 (0.3 mmol, 1.0 equiv), CuI
(0.03 mmol, 10 mol%), L8 (0.045 mmol, 15 mol%), Cs2CO3, (0.6 mmol,
2.0 equiv), solvent (1.5 mL), X=I, rt for n=1, 508C for n=2, 15 h.
[b] Yield of isolated products. [c] Determined by HPLC analysis.
[d] X=Br.
K2CO3
[a] Reagents and reaction conditions: 1a (0.3 mmol, 1.0 equiv), CuI
(0.03 mmol, 10 mol%), ligand (0.045 mmol, 15 mol%), Cs2CO3,
(0.6 mmol, 2.0 equiv), solvent (1.5 mL), rt, 15 h. [b] Yield of isolated
products. [c] Determined by HPLC analysis (Chira AD-H column).
With the optimized conditions in hand, we explored the
substrate scope. As shown in Table 2, a variety of 2-iodoaryl
1,3-diols delivered the corresponding coupling products with
tertiary chiral centers in high yields and with excellent
enantioselectivity. Both electron-donating and electron-with-
drawing substituents on the aryl ring were well tolerated. In
one example, the bromide substrate 1a’ was tested at room
temperature and it produced the desired coupling product in
87% yield and 88% ee. Furthermore, the asymmetric
cyclization of a class of 1,5-diol substrates also proceeded
well at the slightly higher temperature of 508C to afford the
desired six-membered chromans bearing tertiary chiral
carbon centers at the 4-position (2i–m) in high yields and
with excellent enantioselectivity. It should be noted that no
dehalogenated by-products were detected in these reactions.
The absolute configurations of 2,3-dihydrobenzofurans were
assigned by analogy to that of 2a, whereas the configurations
of 2i–m were assigned by comparison with that of 2k, whose S
configuration was confirmed unambiguously by X-ray crys-
tallography.[16]
Our research was initiated with the model case of the
reaction of 2-(2-iodophenyl)propane-1,3-diol (1a). As shown
in Table 1, three types of chiral ligands, including an N,O-
ligand [l-proline (L1)], an O,O-ligand [(R)-binol (L2)], and
an N,N-ligand [N1,N2-dimethyl-cyclohexamine (L3)], were
first screened (Table 1, entries 1–3) and L3 showed much
better results than L1 or L2 in both the yield and the
enantioselectivity. The desired coupling product was obtained
in 92% yield and 80% ee in MeCN at room temperature with
Cs2CO3 as the base (Table 1, entry 3).[12] Several other chiral
diamine ligands (L4–L6) were also screened and all led to
enantioselectivity that was slightly inferior (Table 1,
entries 4–6). The cyclic chiral diamine ligands L7 and L8
showed better results in enantioselectivity. L8 gave the best
result with 83% yield and 89% ee (Table 1, entry 8). Screen-
ing of solvents with the CuI/L8 catalytic system revealed that
a slight improvement of both yield and ee value was obtained
in DMF and acetone (Table 1, entries 9 and 14). The best
results of 93% yield and 92% ee were obtained in acetone
(Table 1, entry 14). Two other bases K3PO4 and K2CO3 were
also tested but gave inferior results (Table 1, entries 15 and
16). The absolute configuration of 2a was assigned to be S by
comparison with reported data.[13]
We next turned our attention to the enantioselective
formation of quaternary stereochemical centers, especially
all-carbon quaternary stereochemical centers, a field which is
known to be one of the most challenging in asymmetric
synthesis.[17,18] With this copper-catalyzed protocol, various
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Table 3: Substrate scope for the enantioselective formation of 2,3-
In summary, we have discovered a copper-catalyzed,
dihydrobenzofurans with quaternary stereocenters.[a,b,c]
À
highly enantioselective, intramolecular aryl C O coupling
reaction for the formation of chiral 2,3-dihydrobenzofurans
and analogues based on an asymmetric desymmetrization
strategy. A wide range of substrates work well with this CuI/
cyclic diamine ligand catalytic system under mild reaction
conditions and afford the O-heterocyclic products in high
yields and with high enantioselectivity. All-carbon quaternary
stereocenters were also constructed through this strategy and
the products were used for the synthesis of some spirocyclic
compounds. Further exploration and application of this
method in organic synthesis is in progress in our laboratory.
Keywords: asymmetric catalysis · copper · desymmetrization ·
2,3-dihydrobenzofuran · O-arylation
How to cite: Angew. Chem. Int. Ed. 2015, 54, 8805–8808
Angew. Chem. 2015, 127, 8929–8932
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[a] Reagents and reaction conditions: 3 (0.3 mmol, 1.0 equiv), CuI
(0.03 mmol, 10 mol%), ligand (0.045 mmol, 15 mol%), Cs2CO3,
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Received: April 28, 2015
Published online: June 8, 2015
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