Enantioselective Synthesis of Axially Chiral Benzothiophene/Benzofuran-Fused Biaryls by N-Heterocyclic Carbene Catalyzed Arene Formation

Article abstract of DOI:10.1002/anie.202103415

Axially chiral biaryl scaffolds are prevalent in natural products, chiral ligands, and organocatalysts. However, N-heterocyclic carbene (NHC) catalyzed de novo construction of an aromatic ring with concomitant axial chirality induction for the synthesis o

Full text of DOI:10.1002/anie.202103415

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International Edition: doi.org/10.1002/anie.202103415
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Organocatalysis
Hot Paper
Enantioselective Synthesis of Axially Chiral Benzothiophene/
Benzofuran-Fused Biaryls by N-Heterocyclic Carbene Catalyzed
Arene Formation
Chun-Lin Zhang,* Yuan-Yuan Gao, Hai-Ying Wang, Bang-An Zhou, and Song Ye*
Abstract: Axially chiral biaryl scaffolds are prevalent in
natural products, chiral ligands, and organocatalysts. However,
N-heterocyclic carbene (NHC) catalyzed de novo construction
of an aromatic ring with concomitant axial chirality induction
for the synthesis of biaryl atropisomers is far less developed,
and the efficient synthesis of axially chiral tetra-ortho-substi-
tuted biaryls remains an unsolved problem under NHC
catalysis. Reported here is an NHC-catalyzed de novo synthesis
of axially chiral benzothiophene/benzofuran-fused biaryls
from enals and 2-benzyl-benzothiophene/benzofuran-3-car-
baldehydes through a [2+4] annulation, decarboxylation, and
oxidative aromatization cascade with central-to-axial chirality
conversion. The developed method provides efficient and
general access to novel axially chiral benzothiophene/benzo-
furan-fused biaryls in high enantioselectivities and works well
for the synthesis of tetra-ortho-substituted biaryls.
chiral biaryls via organocatalytic benzene formation is much
less explored. In 2014, Sparr and co-workers pioneered the
synthesis of axially chiral biaryls by an elegant secondary
amine organocatalyzed intramolecular atroposelective aldol
condensation.[12] Despite these contributions, the limitation of
structural diversity and the substituents on the aromatic rings
hampered the application of axially chiral compounds. Thus,
the development of new methods for organocatalytic enan-
tioselective construction of axially chiral biaryls, especially
the sterically hindered tetra-ortho-substituted ones, is still
highly desirable.
In the past few decades, N-heterocyclic carbene (NHC)
catalysis has emerged as a powerful tool for the construction
of various carbo- and heterocycles.[13] The NHC-catalyzed
synthesis of achiral benzenes has been well established
(Scheme 1a). In 2011, Lupton et al. reported an elegant
NHC-catalyzed [4+2] cycloaddition of a,b-unsaturated acid
fluorides and silyl dienol ethers, followed by the oxidative
aromatizations for the synthesis of (tetrahydro)naptha-
A
xially chiral biaryls are important motifs present in natural
products,[1] bioactive molecules,[2] and advanced materials.[3]
They are also privileged scaffolds in chiral ligands and
organocatalysts in enantioselective catalysis.[4] Thus, the
development of novel methods for their enantioselective
and structurally diverse synthesis is of great value. Classically,
axially chiral biaryls were prepared by the enantioselective
aryl–aryl cross coupling.[5] In addition, various enantioselec-
tive transformations of racemic or prochiral biaryls have been
reported, such as kinetic resolution,[6] desymmetrization,[7]
ring-opening of cyclic compounds,[8] functionalization of
aromatic rings,[9] and others.[10]
In contrast, de novo construction of the aromatic ring with
concomitant axially chiral induction has attracted much less
attention. As a conceptually new pathway to the axially chiral
biaryls, this protocol was well exemplified by enantioselective
transition-metal-catalyzed benzene formation via [2+2+2]
cycloadditions of alkynes.[11] However, the synthesis of axially
[*] C.-L. Zhang, Y.-Y. Gao, H.-Y. Wang, B.-A. Zhou, Prof. Dr. S. Ye
Beijing National Laboratory for Molecular Sciences, CAS Key
Laboratory of Molecular Recognition and Function, CAS Research/
Education Center for Excellence in Molecular Sciences, Institute of
Chemistry, Chinese Academy of Sciences
Beijing 100190 (China)
E-mail: zhangchunlin@iccas.ac.cn
songye@iccas.ac.cn
Y.-Y. Gao, H.-Y. Wang, B.-A. Zhou, Prof. Dr. S. Ye
University of Chinese Academy of Sciences
Beijing 100049 (China)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202103415.
Scheme 1. NHC-catalyzed synthesis of benzenes and axially chiral
biaryls.
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lenes.[14] In 2014, Chi et al. developed the NHC-catalyzed
benzene formation via [3+3] annulation of b-methyl enals
with enones.[15] Subsequently, they disclosed NHC-catalyzed
[4+2] annulation of dienals and 1,3-diketones for the syn-
thesis of benzene ring.[16] In 2016, Wang and we independently
reported the NHC-catalyzed benzene formation via the [2+4]
annulation of enals with b-methyl enones.[17] Later the
benzene formations from bromoenals, a,b-unsaturated car-
boxylic acids were also developed.[18] In comparison, the
development of NHC-catalyzed enantioselective synthesis of
axially chiral biaryls via benzene formation is relatively rare
(Scheme 1b). In 2015, Lupton et al. reported the first NHC-
catalyzed enantioselective cycloisomerization of triene, pro-
viding tri-ortho-substituted axially chiral biaryls in moderate
yields and enantioselectivities via central-to-axial chirality
conversion.[19] Very recently, Zhu et al. developed an efficient
approach for the synthesis of tri-ortho-substituted axially
chiral biaryls via NHC-catalyzed enantioselective benzannu-
lation of dienals with benzyl ketones.[20] To the best of our
knowledge, the synthesis of sterically hindered tetra-ortho-
substituted biaryls is still a challenging but unsolved issue
under NHC catalysis. In this communication, we report an
enantioselective NHC-catalyzed synthesis of tri- and tetra-
ortho-substituted axially chiral benzothiophene or benzo-
furan-fused biaryls from 2-benzyl-benzothiophene/benzo-
furan-3-carbaldehydes and enals (Scheme 1c).
Table 1: Synthesis of axially chiral tri-ortho-substituted benzothiophene-
fused biaryls.
Considering the wide application of thiophene-fused
biaryl in materials[21] and bioactive compounds,[22] 2-benzyl-
benzothiophene-3-carbaldehydes were chosen as the poten-
tial dienolate precursors to react with enals under NHC
catalysis. After optimization (see Table S1 in the Supporting
Information), we were pleased to find that the desired axially
chiral benzothiophene-fused biaryl 3a was obtained in 70%
yield and 94% ee when the model reaction of enal 1a and 2-
(2-bromobenzyl)benzothiophene-3-carbaldehyde (2a) was
carried out using aminoindanol-derived NHC precursor A
as the catalyst in the presence of DQ as the oxidant, DBU as
the base and DDQ as the second oxidant for oxidative
aromatization.
A series of enals 1 were then investigated for the reaction
(Table 1). It was found that the reaction of enals with various
para-substituted aryls (R = C6H5, 4-MeC6H4, 4-PhC6H4, 4-
FC6H4, 4-ClC6H4, 4-BrC6H4) went smoothly to give the
desired biaryls (3b–3g) in good yields and high enantiose-
lectivities. The enals with meta- and ortho-substituted aryl
(R = 3-MeOC6H4, 3-FC6H4, 3-BrC6H4, 2-MeOC6H4, 2-
BrC6H4) were also tolerated affording the products (3h–3l)
with moderate to good yields and good to high enantiose-
lectivities. In addition, the enals with multiple substituents on
the aryl or ring-fused ones also worked well to give the
products (3m–3r) in moderate to good yields with high ee
values. It should be noted that the reaction of b-alkyl enals
gave no or trace desired products under current conditions.
Various substituted 2-benzylbenzothiophene-3-carbalde-
hydes 2 were then evaluated under the optimized reaction
conditions. It was found that the 2-benzyl with various ortho-
substituent beyond bromide (Ar’ = 2-ClC6H4, 2-IC6H4, 2-
CF3C6H4, 2-NO2C6H4, 2-POPh2C6H4) worked well to give
the expected products in good yields and high enantioselec-
Yields are those of isolated products. The ee values were determined by
HPLC.
tivities (3s–3w). The one with ortho-methoxy (Ar’ = 2-
MeOC6H4,) gave the product 3x in some decreased yield
and enantioselectivity. The ortho-methoxy may decrease the
acidity of the g-proton of compound 2 and increase the barrier
for the formation of dienoate, while its less steric property
may cause the decreased enantioselectivity. The (aR)-config-
2
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uration of compound 3t was established by X-ray structure
(POPh2)-6-FC6H3) were all tolerated under the optimized
analysis of its single crystal.[23] The reaction of aldehyde 2 with
a-naphthyl (Ar’ = a-naphthyl) gave the corresponding axially
chiral compound 3y in 84% yield and 85% ee. The aldehydes
2 with 2,4-disubstituted or 2,5-disubstituted benzyl worked
well to provide the corresponding products 3z–3ai in good
yields with high enantioselectivities. Notably, the reaction of
aldehydes 2 with a-bromonaphthyl (Ar’ = b-(a-Br-naphthyl))
and with 1,3-dioxolane-fused benzyl proceeded well to give
products 3aj and 3ak.
reaction conditions giving the corresponding axially chiral
tetra-ortho-substituted products 4a–4 f in good yields with
very good enantioselectivities. The reaction of 2-(2-bromo/
iodo-6-fluorobenzyl)benzothiophene-3-carbaldehydes with
various enals all worked well and afforded the products
(4g–4r) in moderate to good yields with high enantioselec-
tivities. The meta-substituents on the benzyl ring had no
negative impact on the results with respect to the yields and
enantioselectivities (4s–4t).
Tetra-ortho-substituted biaryl motif is a common feature
of many axially chiral natural products, metal ligands, and
organocatalysts.[24] However, in comparison of the well-
established approaches to the axially chiral tri-ortho-substi-
tuted biaryls, the enantioselective construction of the more
sterically hindered tetra-ortho-substituted biaryls through
organocatalyzed arene formation is still a challenging issue
to be solved,[12b] especially in NHC catalysis. We envision that
substrates equipped with different substituents on the ortho-
positions of the aromatic ring may yield the tetra-ortho-
substituted biaryls (Table 2). To our delight, 2-benzyl with the
sterically different substituents (Ar’ = 2-Cl-6-FC6H3, 2-Br-6-
FC6H3, 2-I-6-FC6H3, 2-F-6-CF3C6H3, 2-F-6-NO2C6H3, 2-
Dibenzofurans are commonly found in many bioactive
natural products, and have a wide application in material
sciences.[25] Thus, 2-benzylbenzofuran-3-carbaldehydes were
also investigated as the dienolate precursors for the reaction
(Table 3). It was found that 2-(2-bromobenzyl)benzofuran-3-
Table 3: Synthesis of axially chiral benzofuran-fused biaryls.
Table 2: Synthesis of axially chiral tetra-ortho-substituted benzothio-
phene-fused biaryls.
Yields are those of isolated products. The ee values were determined by
HPLC.
carbaldehyde reacted well with a variety of b-aryl enals to
afford the corresponding benzofuran-fused biaryls 6a–6h in
moderate yields and high enantioselectivities. The reaction of
5- or 6-substituted 2-(2-bromobenzyl)benzofuran-3-carbalde-
hydes gave the desired products 6i–6l in moderate yields with
good enantioselectivities. It is worth noting that 2-benzylben-
zofuran-3-carbaldehyde with chloride as the ortho-substituent
showed similar result as that with bromide, giving the chiral
biaryl 6m in 46% yield with 86% ee.
To investigate the stereochemical stability of these axially
chiral products, the racemization experiments were carried
out. The biaryl 3a bearing 2-bromo group showed excellent
stability with DG° = 162 kJmolÀ1 (463 K in polyethylene
Yields are those of isolated products. The ee values were determined by
HPLC.
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glycol 400) and half-life time t1/2 = 29 million years at 258C
(see Supporting information for details).
enantioselectivities, respectively (Scheme 2c). In addition,
compound 3w could be reduced by HSiCl3 to afford the
axially chiral phosphine 11, which is a potential chiral
monophosphorus ligand for palladium-catalyzed enantiose-
lective reaction, in 96% yield without deterioration of the
enantioselectivity (Scheme 2d).
To verify the practicality of this protocol, gram-scale
synthesis of axially chiral biaryls 3t, 3v and 3w was carried
out under the optimized reaction conditions, which afforded
the products in high yields and high enantioselectivities
(Scheme 2a). After recrystallization from chloroform/ace-
In summary, the NHC-catalyzed enantioselective de novo
synthesis of axially chiral benzothiophene/benzofuran-fused
biaryls from enals and 2-benzylbenzothiophene/benzofuran-
3-carbaldehydes was developed through a cascade strategy of
[2+4] annulation, decarboxylation, and oxidative aromatiza-
tion with central-to-axial chirality conversion. The reaction
features mild reaction conditions, broad substrate scope,
exclusive chemoselectivity, and high enantioselectivity. Fur-
thermore, the reaction worked well for the synthesis of
challenging tetra-ortho-substituted axially chiral biaryls. This
approach provides an efficient route to axially chiral benzo-
thiophene/benzofuran-fused biaryls which are potentially
useful in enantioselective catalysis, drug discovery and
material sciences. Other related NHC-catalyzed synthesis of
axially chiral compounds is under way in our laboratory.
Acknowledgements
Financial support from the National Natural Science Foun-
dation of China (Nos 21801245, 21831008, 21521002), the
Beijing Natural Science Foundation (2192063), Beijing
National Laboratory for Molecular Science (BNLMS-
CXXM-202003) and the Ministry of Science and Technology
of China is greatly acknowledged.
Conflict of interest
The authors declare no conflict of interest.
Keywords: arenes · atropisomerism · chirality ·
N-heterocyclic carbenes · organocatalysis
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Manuscript received: March 9, 2021
Accepted manuscript online: April 14, 2021
Version of record online: && &&, &&&&
Angew. Chem. Int. Ed. 2021, 60, 1 – 6
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5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Organocatalysis
C.-L. Zhang,* Y.-Y. Gao, H.-Y. Wang,
B.-A. Zhou, S. Ye*
&&&& — &&&&
Enantioselective Synthesis of Axially
Chiral Benzothiophene/Benzofuran-
Fused Biaryls by N-Heterocyclic Carbene
Catalyzed Arene Formation
The N-heterocyclic carbene catalyzed
enantioselective de novo synthesis of
axially chiral benzothiophene/benzo-
furan-fused biaryls from enals and 2-
benzylbenzothiophene/benzofuran-3-car-
baldehydes has been developed. This
cascade process comprises a [2+4]
annulation, decarboxylation, and oxida-
tive aromatization with central-to-axial
chirality conversion, allowing rapid
access to atropoisomeric tri- and tetra-
ortho-substituted biaryls with high enan-
tioselectivities.
6
www.angewandte.org
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 1 – 6
These are not the final page numbers!