All-Carbon Quaternary Stereocenters α to Azaarenes via Radical-Based Asymmetric Olefin Difunctionalization

Article abstract of DOI:10.1021/jacs.0c08329

A radical-based asymmetric olefin difunctionalization strategy for rapidly forging all-carbon quaternary stereocenters α to diverse azaarenes is reported. Under cooperative photoredox and chiral Br?nsted acid catalysis, cyclopropylamines with α-branched 2-vinylazaarenes can undergo a sequential two-step radical process, furnishing various valuable chiral azaarene-substituted cyclopentanes. The use of the rigid and confined C2-symmetric imidodiphosphoric acid catalysts achieves high enantio- and diastereo-selectivities for these asymmetric [3 + 2] cycloadditions.

Full text of DOI:10.1021/jacs.0c08329

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All-Carbon Quaternary Stereocenters α to Azaarenes via Radical-
Based Asymmetric Olefin Difunctionalization
§
§
́
Yanli Yin, Yunqiang Li, Theo P. Gonca̧ lves, Qiangqiang Zhan, Guanghui Wang, Xiaowei Zhao,
Baokun Qiao, Kuo-Wei Huang,* and Zhiyong Jiang*
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ABSTRACT: A radical-based asymmetric olefin difunctionalization strategy for rapidly forging all-carbon quaternary stereocenters
α to diverse azaarenes is reported. Under cooperative photoredox and chiral Brønsted acid catalysis, cyclopropylamines with α-
branched 2-vinylazaarenes can undergo a sequential two-step radical process, furnishing various valuable chiral azaarene-substituted
cyclopentanes. The use of the rigid and confined C2-symmetric imidodiphosphoric acid catalysts achieves high enantio- and
diastereo-selectivities for these asymmetric [3 + 2] cycloadditions.
Scheme 1. Enantioselective Construction of All-Carbon
Quaternary Stereocenters α to Azaarenes
zaarenes are important structural motifs that are diverse
and ubiquitous in bioactive natural and non-natural
A
products, drugs, ligands, and functional materials. The
synthesis of azaarene-containing compounds, especially the
development of enantioselective variants, continues to be an
attractive task in synthetic chemistry. In recent years, the direct
exploitation of the electronic properties of the azaarene itself to
trigger catalytic asymmetric transformations of azaarene-based
prochiral substrates has been recognized as an effective and
efficient strategy.1−21 Among such reactions, many elegant
methods for accessing imine-bearing azaarene-based chiral
compounds with different stereocenters at distinct positions
have been established.3−21 To construct an all-carbon
quaternary stereocenter at the α-position of azaarenes, the
Palomo group developed 2-(cyanomethyl)azaarene oxides as
the nucleophiles, in which using a strongly electron-with-
drawing cyano group and the prepared azaarene N-oxide as the
substituents can tremendously increase the acidity of the C−H
bond, resulting in efficient deprotonation (Scheme 1a).8
However, the formation of such a challenging stereogenic
center without introducing an activating functional group as a
more general and direct synthetic approach has not been
reported. The fact that these azaarenes are less able than
carbonyl moieties to activate functional groups makes the
development of new and highly reactive protocols of great
importance.
Visible-light-driven photoredox catalysis,22,23 a powerful tool
in organic synthesis, has recently been employed to construct
azaarene-based variants by enabling radical-based trans-
formations.5−7,18,20,24−30 Specifically, radical conjugate addi-
tions to alkenylazaarenes have been revealed as a promising
and fruitful synthetic approach due to the high reactivity and
diversity of radical species.6,18,20,24−30 Among such reactions, a
radical conjugate−enantioselective protonation strategy has
been developed to build azaarene-substituted tertiary carbon
stereocenters.6 The reduction of the α-azaarene radical species,
which is generated from the conjugate addition of radical
species to alkenes, furnishes anions, allowing the enantiose-
Received: August 3, 2020
https://dx.doi.org/10.1021/jacs.0c08329
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
© XXXX American Chemical Society
A

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a
lective protonation. We wondered if such radical intermediates
could subsequently add to an unsaturated double bond,
thereby affording the desired all-carbon quaternary stereo-
center α to azaarenes. In consideration of the high reactivity of
radicals in additions to imines,31,32 we were fascinated by the
possibility of an enantioselective [3 + 2] cycloaddition between
cyclopropylamines33−36 and α-branched 2-vinylazaarenes
under cooperative photoredox and chiral Brønsted acid
catalysis (Scheme 1b).5−7,18,20,31,32 The envisaged bimolecular
chemical transformation might involve a sequential two-step
radical process, namely, a radical conjugate addition of distonic
ions to alkenes and radical addition to iminium ions. The
method would provide the first access to the biologically
important highly enantioenriched molecular architectures that
are azaarene-substituted cyclopentanes featuring an all-carbon
quaternary stereocenter.37−40
The implementation of this reaction scenario will inarguably
face two significant challenges. (a) Chemoselectivity. Because
α-azaarene radicals can act as oxidants,6,18,41,42 the high steric
hindrance is likely to make the competitive single-electron
reduction and protonation more favorable. (b) Enantioselec-
tivity. Through H-bonding interactions with the N atom of
azaarenes, a chiral Brønsted acid catalyst can provide a chiral
environment for the formation of stereocenters by activating
the system for the radical conjugate addition.6,20 However, this
interaction will decrease the electron density on the α-azaarene
radical species, which disfavors the subsequent radical addition
to the iminium. To overcome this deactivation, the H-bonding
interaction tends to dissociate, which weakens the stereo-
controlling effect of the chiral Brønsted acid in the
simultaneous formation of the two stereocenters. In addition,
the highly enantioselective construction of all-carbon quater-
nary stereocenters is always a formidable challenge in radical
chemistry.32,43−45
Table 1. Optimization of the Reaction Conditions
b
c
d
entry
cat
solvent
T (°C) yield (%)
ee (%)
dr
1:1.5
>19:1
1
2
3
4
5
6
7
8
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
benzene
Et2O
25
25
25
25
25
25
25
25
25
25
25
25
25
25
−40
−60
33
76
79
78
74
77
78
79
79
78
60
63
76
80
80
83
N.A.
11
21
16
22
31
50
50
60
68
65
47
61
63
79
91
4a
4b
5a
5b
6a
6b
6c
6d
6d
6d
6d
6d
6d
6d
6d
>19:1
>19:1
>19:1
2:1
>19:1
>19:1
>19:1
15:1
9
10
11
12
13
14
15
15:1
THF
CPME
>19:1
>19:1
>19:1
>19:1
>19:1
e
m.s.
m.s.
m.s.
e
f
e
16
a
0.05 mmol scale: 1a:2a = 2.0:1, 1.0 mL solvent, irradiation distance
= 3.0 cm. Entries 1−14, t = 12 h. Entry 15, t = 48 h. Entry 16, t = 60
b
c
h. Yield of isolated product. Determined by HPLC analysis on a
d
e
chiral stationary phase. Determined by crude 1H NMR analysis. m.s.
f
= mixed solvent: Et2O/CPME/benzene = 1/1/1 (3.0 mL). 20 mol %
We began our investigation by selecting cyclopropylaniline
(1a) and 2-(1-phenylvinyl)pyridine (2a) as the model
substrates (Table 1). Our developed dicyanopyrazine-derived
chromophore (DPZ, for *DPZ, Et(S*/S•−) = +1.42 V vs SCE
in CH3CN)46 was chosen as the photoredox catalyst because
its excited state is theoretically able to perform the single-
electron oxidation of 1a (E1/2red = +0.92 V, +1.30 V vs SCE in
CH3CN). We first evaluated the reaction using 0.5 mol % DPZ
in toluene as the solvent at 25 °C with irradiation by a 3 W
blue LED (entry 1). It was found that racemic [3 + 2]
cycloaddition adduct 3a, the desired product, was obtained in a
33% yield with a 1:1.5 dr. The result shows an enantiocontrol
challenge due to the occurrence of the background reaction.
We then tested a series of (S)-BINOL-based chiral phosphoric
acids (CPAs), such as 4a−b (entries 2−3), and (S)-SPINOL-
based CPAs, such as 5a−b (entries 4−5) (for more details, see
Table S1 in the Supporting Information), which led to
enantioenriched product 3a with unsatisfactory ee values.
Importantly, the diastereoselectivity was reversed and became
excellent. The results indicate the suitability of chiral Brønsted
acids as catalysts. We wondered if the highly rigid and confined
C2-symmetric imidodiphosphoric acids could achieve better
enantioselectivity since they can provide extremely sterically
demanding chiral environments, geometrically restraining the
α-pyridine radical intermediate.47−50 In addition, the greater
distance between the catalytically active bifunctional acid/base
pair might increase the probability of interacting with the
iminium, which can weaken the negative influence of the
racemic background reaction by lowering the energy barrier to
of 6d was used, and irradiation distance = 6.0 cm. N.A. = not
available.
the radical addition. As such, we screened a range of
imidodiphosphoric acids based on the BINOL backbone,
such as 6a−d, with different substituents at the 3,3′-positions
(entries 6−9). To our delight, 3a could be obtained in 60% ee
with a > 19:1 dr when 6d was used (entry 9). A solvent
screening revealed that benzene, Et2O, and cyclopentyl methyl
ether (CPME) gave higher enantioselectivities (entries 10−
13). However, benzene has a higher freezing point (5.5 °C),
and neither Et2O nor CPME as the medium could provide
sufficient enantioselectivity even when the temperature was
decreased (see Table S1). This dilemma prompted us to test
mixed solvents involving on the most suitable solvent
(benzene) to decrease the freezing point. As a result, 3a was
obtained with a promising 63% ee when using the mixed Et2O/
CPME/benzene in a 1:1:1 ratio as the solvent (entry 14).
When the reaction was conducted at −40 °C, the ee of 3a was
improved to 78% (entry 15). Finally, 3a was obtained in 83%
yield with 91% ee and >19:1 dr after 60 h, when using 20 mol
% of 6d at −60 °C and increasing the distance to the radiation
source from 3.0 to 6.0 cm (entry 16). Several control
experiments supported that DPZ, chiral Brønsted acid, visible
light, and an oxygen-free environment were essential to this
transformation (see Table S2).
With the optimal reaction conditions in hand, the scope of
this asymmetric [3 + 2] cycloaddition protocol was examined
(Table 2). A wide range of 2-(1-arylvinyl)pyridines (2)
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a
Table 2. Substrate Scope of α-Branched 2-Vinylpyridines
Table 3. Substrate Scope of Other α-Branched
Vinylazaarenes
a
a
b
c
0.1 mmol scale. 3.0 mmol scale, t = 72 h, yield = 90%, ee = 93%. 6e
d
as the catalyst, and Et2O/toluene/benzene = 1:1:1 as the solvent. 6f
a
b
c
as the catalyst, MTBE/CPME/benzene = 1:1:1 as the solvent and at
0.1 mmol scale. Et2O as the solvent and at −65 °C. 6f as the
e
f
d
−25 °C. Et2O as the solvent and at −65 °C. 6f as the catalyst,
catalyst, and MTBE/CPME/benzene = 1:1:1 as the solvent. 6e as
the catalyst, and Et2O/toluene/benzene = 1:1:1 as the solvent. t =
100 h. 4m as the catalyst, THF as the solvent, at −60 °C for 120 h.
g
e
CPME as the solvent and at −70 °C. 6f as the catalyst, MTBE/
f
CPME/benzene = 1:1:1 as the solvent and irradiation distance = 2.0
h
cm. 5q as the catalyst, tBuPh as the solvent and at −45 °C within 60
h.
containing diverse substituents on either the aromatic or
pyridyl ring were first evaluated in the reaction with 1a. All the
tested substrates were well tolerated regardless of their
electronic properties or substitution patterns, and correspond-
ing products 3a−u were obtained in 57−98% yields with 80−
96% ee and 4:1 to >19:1 dr, and in most cases, the
diastereoselectivity was excellent. Notably, when there was a
methoxy group present on the aromatic ring, the enantiose-
lectivity was poor even after the careful examination of the
reaction conditions (<30% ee). We reasoned that its strong
electron-donating ability caused the α-pyridine radical
intermediate to be highly nucleophilic, which made enantio-
control more difficult. Accordingly, we suggested using an
oxygen-derived electron-withdrawing group instead of methoxy
to solve this problem. As a result, products 3j−l with OTf and
OTs as the substituent were obtained with satisfactory results.
An α-methyl-substituted terminal alkene was then examined,
and it provided product 3v in 54% yield with 63% ee and 1.2:1
dr; the moderate yield was due to poor reactivity. On the other
hand, distinct N-cyclopropyl arylamines reacted with 2a to
provide products 3w−z with a high yield and stereoselectivity.
The success encouraged us to evaluate this method for the
formation of other azaarene-substituted chiral cyclopentane
variants. As depicted in Table 3, a variety of α-branched 2-
vinylazaarenes with various important azaarenes, such as
benzimidazole (8a−m), quinoline (8n), isoquinoline (8o),
imidazole (8p−q), thiazole (8r), and benzothiazole (8s), are
compatible with the catalytic system, leading to products 8a−s
in 62 to >99% yields with a 77−96% ee and >19:1 dr. In
addition, α-phenyl 3-vinylpyridine afforded product 8t in 83%
yield with excellent enantioselectivity but poor diastereose-
lectivity. The broad substrate scope, the satisfactory results for
constructing azaarene-substituted all-carbon quaternary stereo-
centers and the bioactive potential of the products highlight
the generality and importance of this strategy.
To further reveal the synthetic utility of this method, 8a was
synthesized on a 3.0 mmol scale, and a similar yield and
stereoselectivity were achieved (footnote b, Table 3). More-
over, 3y could be oxidized by m-chloroperbenzoic acid
(mCPBA), leading to ketone 9 in 80% yield and without
compromising the ee (eq 1). After a single recrystallization, 9
was obtained with 99% ee, and its pyridine N-oxide could be
reduced by PCl3, resulting in α,α-diaryl-substituted ketone 10
in 82% yield with 98% ee. Inarguably, the formation of
carbonyl group tremendously enriches the application
potentials of this method.
C
https://dx.doi.org/10.1021/jacs.0c08329
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General information, optimization of reaction condi-
tions, general experimental procedures, mechanistic
studies, synthetic transformations, determination of the
absolute configurations, characterization data, and
HPLC and NMR spectra (PDF)
Crystallographic information for C21H22N3Br (CCDC
1959655, compound 8q, file: YZ21030) (CIF)
Crystallographic information for C16H15NO2 (CCDC
1959654, compound 9, file: wgh0188) (CIF)
With regard to a plausible mechanism of this enantiose-
lective [3 + 2] cycloaddition, Stern−Volmer experiments
suggested that the transformations are triggered by the
reductive quenching of *DPZ with cyclopropylamines (see
the SI), with a quantum yield (Φ) of 0.079. Furthermore, the
relationship between the ee of chiral Brønsted acid 6d and the
ee of product 3a was evaluated (see the SI), and a linear
correlation was identified, indicating that a single molecule of
the chiral imidodiphosphoric acid is involved in the stereo-
center-forming step. Given the remarkable difference in the
enantioselectivities observed with electron-withdrawing and
electron-donating substituents on the aromatic ring of the 2-
(1-arylvinyl)pyridine, a ternary transition state with the chiral
Brønsted acid acting as a bifunctional catalyst was proposed
and plausible pathways of the cyclization reactions were
calculated at the wB97X-D/6-31G(d) level of theory with
ONIOM approach (see the SI for details). Two key transition
states were located for the cyclization step leading to both
enantiomers (Figure 1). Consistent with the experimental
AUTHOR INFORMATION
Corresponding Authors
■
Zhiyong Jiang − Henan University, Kaifeng, Henan 475004,
P. R. China; School of Chemistry and Chemical Engineering,
Henan Normal University, Xinxiang, Henan 453007, P. R.
China; orcid.org/0000-0002-6350-7429;
Email: jiangzhiyong@htu.edu.cn
Kuo-Wei Huang − KAUST Catalysis Center and Division of
Physical Sciences and Engineering, King Abdullah University
of Science and Technology (KAUST), Thuwal 23955-6900,
Saudi Arabia; Email: hkw@kaust.edu.sa
Authors
Yanli Yin − Henan University, Kaifeng, Henan 475004, P. R.
China; College of Bioengineering, Henan University of
Technology, Zhengzhou, Henan 450001, P. R. of China;
School of Chemistry and Chemical Engineering, Henan
Normal University, Xinxiang, Henan 453007, P. R. China
Yunqiang Li − Henan University, Kaifeng, Henan 475004, P.
R. China
́
Theo P. Gonca̧ lves − KAUST Catalysis Center and Division
of Physical Sciences and Engineering, King Abdullah
University of Science and Technology (KAUST), Thuwal
23955-6900, Saudi Arabia
Qiangqiang Zhan − Henan University, Kaifeng, Henan
475004, P. R. China
Guanghui Wang − School of Chemistry and Chemical
Engineering, Henan Normal University, Xinxiang, Henan
453007, P. R. China
Xiaowei Zhao − Henan University, Kaifeng, Henan 475004,
P. R. China
Baokun Qiao − Henan University, Kaifeng, Henan 475004, P.
R. China
Figure 1. Stereoselectivity model.
observations, TS3-a+· was found to be more favorable than
TS3-b+·. The steric interactions between the iminium
substituent (Ph) originated from cyclopropylaniline and the
3,3′-aryl groups (Ar) of the chiral Brønsted acid are crucial for
the radical addition-based cyclization to attain high enantio-
selectivity.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c08329
In summary, these studies reveal the robust ability of radical
chemistry to achieve the formation of all-carbon quaternary
stereocenters for azaarenes. Under cooperative photoredox and
Brønsted acid catalysis, readily accessible cyclopropylamines
and α-branched 2-vinylazaarenes can efficiently undergo a
tandem two-step radical addition process, accomplishing a
formal [3 + 2] cycloaddition. A series of azaarene-substituted
cyclopentane derivatives featuring all-carbon quaternary stereo-
centers at the α-position of the azaarenes have been
synthesized in high yields with good to excellent enantio-
and diastereo-selectivities. The substrate scope is extremely
broad, and the excellent compatibility for diverse azaarenes is
especially notable.
Author Contributions
§These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Grants from NSFC (21672052, 21925103) and the PhD
Research Foundation of Henan University of Technology
(2019BS003) are gratefully acknowledged.
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ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c08329.
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