Design and Atroposelective Construction of IAN analogues by Organocatalytic Asymmetric Heteroannulation of Alkynes

Article abstract of DOI:10.1002/anie.202010598

An organocatalytic atroposelective strategy for accessing enantioenriched axially chiral IAN analogues was developed for the first time. A class of novel atropisomeric C2-arylquinoline skeletons were synthesized with high enantiocontrol via chiral phosphoric-acid-catalyzed heteroannulation of in situ generated vinylidene ortho-quinone methide (VQM) intermediates with ortho-aminophenones. The strategy tolerated a broad substrate scope, providing a facile organocatalytic approach to IAN analogues in good yields and excellent enantioselectivities under mild reaction conditions. Moreover, the synthetic utility of this methodology was illustrated through further transformations into IAN-type ligand and axially chiral thiourea.

Full text of DOI:10.1002/anie.202010598

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Accepted Article
Title: Design and Atroposelective Construction of IAN analogues via
Organocatalytic Asymmetric Heteroannulation of Alkynes
Authors: Bin Tan, Lei Zhang, Jiahua Shen, San Wu, Guofu Zhong, and
Yong-Bin Wang
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Design and Atroposelective Construction of IAN analogues by
Organocatalytic Asymmetric Heteroannulation of Alkynes
Lei Zhang,*[a],[b] Jiahua Shen,[a] San Wu,[b] Guofu Zhong,*[a] Yong-Bin Wang[b] and Bin Tan*[b]
Abstract: The organocatalytic atroposelective strategy for accessing
enantioenriched axially chiral IAN analogues was developed for the
first time. A class of novel atropisomeric C2-arylquinoline skeletons
were synthesized with high enantiocontrol via chiral phosphoric-acid-
catalyzed heteroannulation of in-situ generated vinylidene ortho-
quinone methide (VQM) intermediates with ortho-aminophenones.
The strategy tolerated a broad substrate scope, providing a facile
organocatalytic approach to IAN analogues in good yields and
excellent enantioselectivities under mild reaction conditions.
Moreover, the synthetic utility of this methodology was illustrated
through further transformations into IAN-type ligand and axially chiral
thiourea.
of a (hetero)aromatic ring.[6c,6e-f] However, as the number of this
type of axially chiral ligands and catalysts in asymmetric
catalysis grows, a highly efficient organocatalytic approach to
corresponding axially chiral heterobiaryl skeletons becomes an
urgent need.
The research on axially chiral biaryls have developed rapidly
and gained considerable momentum in recent years because of
their widespread appearance in natural products,[1] bioactive
molecules,[2] and privileged chiral ligands and catalysts.[3] In
sharp contrast, the asymmetric construction of axially chiral
heterobiaryls was still underdeveloped,[4] even though it is
scientifically important and of great significance in practical
application.[5] For instance, the effective approaches to access
axially chiral 2-arylpyridines (isoquinolines) are especially scanty,
while they have emerged as essential backbone of numerous
chiral catalysts and ligands in asymmetric catalysis (Figure 1).[6]
This type of heteroaryl atropisomers ordinarily formed a chelate
ring with metal atom through the coordination of nitrogen and
other donor atoms, such as phosphorus, nitrogen, oxygen, and
sulfur, providing the asymmetric induction in various metal-
catalyzed enantioselective transformations (Figure 2a).[7]
Conventionally, synthetic approaches for enantioenriched 2-
arylpyridine/isoquinoline skeletons depend mainly on transition-
metal mediated patterns, such as cross-coupling,[6i,r] (dynamic)
kinetic resolution/transformation[6a,6g-h,6j-q,6s] and de novo construction
Figure 2. Previous work and our strategy.
Quinolines are one of the prominent classes of heterocyclic
systems and exist in many biologically active compounds.[8]
Although many significant achievements have been achieved in
developing efficient and practical approach for the construction
of quinolines,[9] novel atropisomeric quinoline-containing ligands
or catalysts have scarcely been explored, in sharp contrast to
the isoquinoline analogues. A plausible explanation is that the
current reports about quinoline-derived axially chiral frameworks
mostly focused on aryl-C4-, C5- or C8-quinoline skeletons[6r],[10]
and the dicisive nitrogen atom for coordination with metal center
in such structures was always distant from the chiral axis, thus
leading to the difficulty in stereoinduction (Figure 2b). To the
best of our knowledge, there was no approach to access axially
chiral C2-arylquinoline skeletons, in spite of their predictable
catalytic and bioactive potentials. Consequently, we designed a
new atropisomeric quinoline-containing skeleton like IAN, but
how to assemble this structure in an atroposelective manner and
control the stability of chiral axis remains a tough challenge.
Figure 1. a) Current status of asymmetric synthesis of biaryl atropisomers; b)
Selected ligands/catalysts with 2-arylpyridines/isoquinolines skeleton.
Motivated by elegant studies from Yan group and our recent
work involving the atroposelective vinylidene ortho-quinone
methide (VQM) chemistry,[11] as well as our continuous interest
in developing novel axially chiral scaffolds,[12] we envisaged that
chiral phosphoric acid (CPA) catalyzed[13] enantioselective
heteroannulation by trapping in-situ generated VQMs
intermediates could afford the desired axially chiral C2-
arylquinoline skeletons (Figure 2c). Nevertheless, the
unprecedented organocatalytic atroposelective synthesis of IAN
analogues is a particularly challenging attempt, and some
[a] L. Zhang, J. Shen, Prof. Dr. G. Zhong
College of Materials, Chemistry and Chemical Engineering
Hangzhou Normal University, Hangzhou 311121 (China)
E-mail: zhanglei0109@hznu.edu.cn; zgf@hznu.edu.cn
[b] L. Zhang, S. Wu, Y.-B. Wang, Prof. Dr. B. Tan
Shenzhen Grubbs Institute and Department of Chemistry, Southern
University of Science and Technology, Shenzhen, 518055 (China)
E-mail: tanb@sustech.edu.cn
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.202010598
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fundamental issues need to be solved. First, the selection of
competent reactants should not only guarantee the final
intramolecular cyclization, delivering the new quinoline ring, but
also generate steric hindrance to ensure the configurational
stability of products; second, the choice of a proper CPA which
is capable of activating alkynes to afford VQMs intermediates
and offering an effective interaction with reactants to control the
atroposelectivity.
reaction conditions, we have failed to obtain satisfactory yields
and enantioselectivities. Fortunately, the dilemma has been
solved significantly by introducing a CF3-group into the aniline
substrates (Scheme 1, R2 = CF3; 90% yield, 88% ee). Herein we
report the first organocatalytic approach to access novel axially
chiral C2-arylquinoline skeletons in high yields with excellent
enantioselectivities, affording a practical metal-free avenue for
the synthesis of enantioenriched IAN analogues.
Scheme 2. Substrate scope with respect to variation of 1-
Scheme 1. Initial investigations.
alkyne-2-naphthylamine.[a]
To overcome the above-mentioned challenges, we initiated
our studies by identifying suitable reactants. As is well known,
ortho-carbonyl-substituted anilines have proven to be versatile
reactants for diverse annulation reactions.[14] Then a preliminary
study was conducted in the presence of C1 to evaluate the
effect of different types of reactants on the reactivity and
stereoselectivity of the reaction (Scheme 1), and the results
demonstrated that ortho-alkynyl-naphthylamines 1 bearing a
bulky R1 group were unfavorable for the formation of axially
chiral IAN analogues (for details, see Supporting Information).
Moreover, the R2 group on the anilines derivatives has great
influence on both the yields and enantioselectivities. The
strategy can be carried out smoothly to give the expected axially
chiral skeletons no matter the R2 is phenyl, methyl or hydrogen
atom. Despite making great efforts toward optimization of the
Table 1. Screening results of reaction conditions.[a]
entry
CPA
solvent
T (°C) time (h) yield (%)[b] ee (%)[c]
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
3
6
90
85
83
82
80
77
86
87
84
77
74
82
82
84
86
88
91
91
1
2
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C1
C1
C1
C1
C1
C1
C1
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
CHCl3
toluene
THF
88
83
18
14
52
70
36
48
53
3
[a] Unless otherwise stated, all reactions were carried out with 1 (0.18 mmol),
2 (0.15 mmol), C1 (10 mol%) and Na2SO4 (50 mg) in 8.0 mL of DCE. Isolated
yields were provided. Ee values were determined by HPLC analysis using a
chiral stationary phase.
3
3
48
48
4
4
5
6
Based on our initial discovery, we utilized N-benzyl-1-
(phenylethynyl)naphthalen-2-amine (1a) and ortho-trifluoroacetyl
aniline (2a) as the model substrates to further optimize the
reaction conditions in the presence of diversified CPA catalysts.
Firstly, we set out to evaluate the electronic and steric effects of
the substituents and axially chiral backbone on the CPA (Table 1,
entries 1-11). C1 with 9-anthryl at the 3,3’-position was found to
be the best catalyst with respect to enantioselectivity for the
model reaction (Table 1, entry 1). With the optimum catalyst
identified, the influences of different solvents were then
investigated (Table 1, entries 12-15). In addition, the
enantioselectivity was also affected by the reaction temperature,
different additives and concentration of reactants (Table 1,
entries 16-18; for details, see Supporting Information). Based on
24
17
4
7
8
9
24
24
5
10
11
12
13
14
15
16
17[d]
18[d,e]
45
82
77
81
59
86
90
92
5
5
24
22
5
DCE
DCE
DCE
r.t.
r.t.
5
[a] Unless otherwise stated, all reactions were carried out with 1a (0.12 mmol),
ortho-trifluoroacetyl aniline 2a (0.10 mmol), and CPA (10 mol%) in 3.0 mL of
solvent. [b] Yields of isolated products. [c] Determined by HPLC analysis using
a chiral stationary phase. [d] Na2SO4 (33 mg) was added. [e] 5.4 mL of DCE.
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10.1002/anie.202010598
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the above results, we identified the optimal conditions as follows:
when 2a was treated with 1.2 equivalent of 1a in 1,2-
dichloroethane at room temperature in the presence of 10 mol%
of C1, the desired axially chiral arylquinoline 3a was obtained in
91% isolated yield with 92% ee (Table 1, entry 18).
with CF2Cl. The absolute configuration of 4c (CCDC 2011655)
has been determined by X-ray crystallographic analysis (see
Supplementary Figure) and those of other products were
assigned by analogy.
To gain further insight into the reaction mechanism, we
performed control experiments to isolate the key intermediate of
the process. After a lot of explorations, fortunately, when 1a and
2-acetylaniline (2l) were tested under the optimal conditions, the
key intermediate 4ad was obtained in 53% yield and
accompanied with formation of the final product 3ad in 29% yield
with 15% ee. Prolonging the reaction time or increasing the
reaction temperature, the final axially chiral arylquinoline 3ad
was obtained as the principal product with approximately 20%
ee (Scheme 4a). In addition, by treating the intermediate 4ad
with 10 mol% of C1 at room temperature or 60 °C, the desired
product 3ad could be formed smoothly in excellent yields with
the same enantioselectivities (Scheme 4b). Worthy of note is
that the intermediate 4ad was demonstrated to be the enamine
structure by the analysis of NMR and mass spectrometry (for
details, see Supporting Inforamtion).
With the optimal reaction conditions in hand, we then explored
the scope of substrates for this transformation. Firstly, the
generality of 1-alkyne-2-naphthylamine derivatives
1 was
evaluated. As summarized in Scheme 2, an array of 1-alkyne-2-
naphthylamines bearing different R1 were investigated. To our
delight, the electronic and steric effects of the substituents at
different positions of the aromatic rings has little impact on the
reaction, affording the corresponding products in 89-96% yield
with 88-92% ee (3a-3n). Moreover, no detrimental effects to the
high catalytic efficiency and stereoselectivity of this process
were detected with substrates bearing heteroaryl (3o-3p) or
naphthyl (3q). Subsequently, the effect of the substituents on the
R2 was examined (3r-3t). Finally, 1-alkynyl-2-naphthylamine
substrates with diverse R3 substituents were also tested. The
positions and the electronic properties of the substituents on the
R3 had
a negligible impact on the chemical yields and
Scheme 4. Control experiments and isolation of intermediate.
enantioselectivities (3u-3ac). In addition, 1,6- and 1,7-bisalkynyl
2-naphthylamines (3x and 3ac) proved to be efficiently
transformed into the expected products, while the side products
from the annulation of the 6- and 7-alkynyl groups were not
detected.
To further expand the applicability of this transformation,
various ortho-aminoacetophenone derivatives 2 were evaluated
for this atroposelective annulation reaction. As shown in scheme
3, substrates 2b-2i bearing either electron-rich or electron-
deficient aromatic rings reacted smoothly with 1a to afford the
desired axially chiral products (4a-4h) in excellent chemical
yields (90-95%) with high enantioselectivities (85-93% ee). It
should be noted that the corresponding product 4e was also
obtained in 90% yield and 86% ee when replacing the CF3 group
Based on the results of control experiments and literature
precedent,[11g],[15] a possible reaction pathway of this asymmetric
heteroannulation reaction has been proposed in Scheme 5. The
dual hydrogen-bonding between ortho-alkynyl-naphthylamine 1a
and CPA was the pivotal interaction to form the complex I. The
π−π interaction according to a recent report efficiently assists
the formation of this intermediate.[16] Next, the activated alkyne
Scheme 3. Substrates scope in terms of variation of fluorinated
ortho-aminophenones.[a]
Scheme 5. Proposed reaction mechanism.
[a] Unless otherwise stated, all reactions were carried out with 1a (0.144
mmol), fluorinated ortho-aminophenones 2 (0.12 mmol), C1 (10 mol%) and
Na2SO4 (40 mg) in 10.0 mL of solvent. Isolated yields were provided. Ee
values were determined by HPLC analysis using a chiral stationary phase. [b]
The corresponding product 4i was obtained in 91% yield with 61% ee when
CF2Cl group was replaced with C2F5.
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undergoes a concerted 1,5-H transfer to form the key VQM
intermediate II. Association with ortho-trifluoroacetyl aniline 2a
results in a stabilized complex III, which features an additional
hydrogen-bonding between the substrates and CPA.
Subsequently, the attack of ortho-trifluoroacetyl aniline 2a to the
VQM intermediate results in the formation of the enamine
intermediate IV. The intramolecular aldol reaction, followed by
dehydration affords the desired axially chiral product 3a.
Obviously, CPA plays an important role in the asymmetric
induction by creating an appropriate chiral environment in the
final cyclization process.
sulfonamide. Further applications of the axially chiral C2-
arylquinoline skeletons in asymmetric catalysis are currently
underway in our laboratory.
Acknowledgements
We gratefully acknowledge the National Natural Science
Foundation of China (NSFC) (No. 21373073, 21672048,
21825105) and Hangzhou Normal University for financial
support. G.Z. acknowledges a Qianjiang Scholar award from
Zhejiang Province, China.
To demonstrate the practicality of this method, a preparative
scale synthesis of product 3a was carried out under the optimal
reaction conditions and there was almost no deterioration in
chemical yield (90%) and enantioselectivity (91% ee), thus
Conflict of interest
The authors declare no conflict of interest.
indicating
that
large-scale
chemical
production
of
enantioenriched IAN analogues could be achieved (Scheme 6).
Subsequently, a variety of synthetic transformations were then
performed based on the generated products 3a. Axially chiral
IAN analogue 5, bearing a free amine group on the naphthalene
ring, was obtained without loss of stereochemical integrity
through the debenzylation of 3a. Furthermore, treatment of 5
with bis(trifluoromethyl)phenyl isothiocyanate led to an
atropisomeric thiourea 6 with complete retention of enantiopurity,
which could potentially serve as an efficient organocatalyst in
asymmetric transformations. Apart from that, upon treatment of
3a with methanesulfonyl chloride in dichloromethane from -20 °C
to 50 °C for 10 hours, the corresponding atropisomeric
sulfonamide 7 was obtained in 88% yield without any erosion of
the enantioselectivity.
Keywords: chiral phosphoric acid
•
atroposelective
•
arylquinolines • heteroannulation • axial chirality
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In summary, we have developed the first organocatalytic
enantioselective construction of axially chiral IAN analogues
through the asymmetric heteroannulation of alkynes with ortho-
aminophenones via an active VQM intermediate. This
transformation accommodated broad substrate scope with
excellent yields and enantioselectivities (up to 96% yield, 93%
ee) in the presence of CPA. Moreover, the reaction could be
scaled up without any loss of yield and enantioselectivity. On the
whole, the strategy not only offered a new type of axially chiral
C2-arylquinoline skeletons, but also provided an efficient metal-
free approach to the atroposelective synthesis of IAN-type N,N-
ligands. The synthetic utility of this methodology was illustrated
through further transformations into atropisomeric thiourea and
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This article is protected by copyright. All rights reserved.

10.1002/anie.202010598
Angewandte Chemie International Edition
COMMUNICATION
The first organocatalytic strategy
for accessing enantioenriched
axially chiral IAN analogues has
been developed. A class of novel
L. Zhang*, J. Shen, S. Wu, G. Zhong*,
Y.-B. Wang, B. Tan*
Page No. – Page No.
atropisomeric
C2-arylquinoline
Design
Construction of IAN analogues by
Organocatalytic Asymmetric
Heteroannulation of alkynes
and
Atroposelective
skeletons were synthesized with
high enantiocontrol via chiral
phosphoric-acid-catalyzed
heteroannulation of alkynes. The
synthetic
methodology
utility
was
of
this
illustrated
through further transformations
into IAN-type ligand and axially
chiral thiourea.
This article is protected by copyright. All rights reserved.