Catalytic Reductive Cross Coupling and Enantioselective Protonation of Olefins to Construct Remote Stereocenters for Azaarenes

Article abstract of DOI:10.1021/jacs.1c01073

A novel enantioselective protonation protocol that is triggered by reductive cross coupling of olefins is reported. When under cooperative photoredox and chiral hydrogen-bonding catalytic conditions and using a terminal reductant, various α-branched vinyl

Full text of DOI:10.1021/jacs.1c01073

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Catalytic Reductive Cross Coupling and Enantioselective
Protonation of Olefins to Construct Remote Stereocenters for
Azaarenes
Manman Kong,∥ Yaqi Tan,∥ Xiaowei Zhao, Baokun Qiao, Choon-Hong Tan, Shanshan Cao,*
and Zhiyong Jiang*
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ABSTRACT: A novel enantioselective protonation protocol that is triggered by
reductive cross coupling of olefins is reported. When under cooperative photoredox
and chiral hydrogen-bonding catalytic conditions and using a terminal reductant, various
α-branched vinylketones with diverse vinylazaarenes could provide important
enantioenriched azaarene derivatives containing tertiary stereocenters at their remote
δ-position with high yields and enantioselectivities. This reaction system is also suitable
for α-branched vinylazaarenes, thus successfully assembling elusive 1,4-stereocenters. The convenient late-stage modifications of
products, especially the formation of remote ε-tertiary and ε-heteroquaternary carbon stereocenters, further highlight the important
synthetic value of this method. Control experiments and density functional theory (DFT) calculations were conducted to elucidate
the plausible reaction mechanism and origins of regioselectivity and stereoselectivity.
Scheme 1. Enantioselective Construction of δ-Stereocenters
for Azaarenes
INTRODUCTION
■
Structurally diverse azaarenes exist widely in numerous natural
products, pharmaceuticals, and agrochemicals as well as ligands
and catalysts in catalysis. The prominent importance has
inspired continuous pursuits for developing efficient catalytic
synthetic protocols to access azaarene derivatives, especially in
an enantioselective fashion.1,2 Among them, exploiting the
inherent electronic properties of azaarenes to directly trigger
transformations has been appreciated as an expedient and
practical strategy owing to the potential advantages of using
simple and readily accessible feedstocks and avoiding tedious
operations in the late-stage modifications of products. For
instance, with respect to imine-containing azaarenes that
feature an electron-withdrawing ability, a variety of catalytic
asymmetric methods using 2-alkylazaarenes as pronucleophiles
and 2-alkenylazaarenes as electrophiles have been establish-
ed;1c,3−6 substantial enantioenriched azaarene derivatives
bearing various α-,3 α,β-,4 β-,5 and γ-stereocenters6 were
obtained. By contrast, directly constructing relatively remote δ-
stereocenters remains underdeveloped. As the only strategy,
unstable 2-allylazaarenes have been devised to perform
enantioselective γ-selective addition to ketones (Scheme
1A).7 Given the prevalence of such structural motifs in
bioactive molecules,8 exploring new, convenient, and general
synthetic methods is always highly desirable.
(HAT)/protonation process.3b,4e,5i,6b,10 Furthermore, by merg-
ing extrinsic, chiral Brønsted acid catalysis,11 our group
reported an efficient method to construct tertiary carbon
stereocenters α to azaarenes through radical addition−
enantioselective protonation of N-aryl glycines with α-
branched 2-vinylazaarenes,3b in which prochiral anion
intermediates were formed on the electrophilic olefins
(Scheme 1B1). This work provided us with an important
hypothesis that if prochiral anions could be generated on
Received: January 28, 2021
Published: March 2, 2021
Due to the weaker electron-withdrawing ability of azaarenes
as compared to that of carbonyls, in recent years, photoredox
catalysis9 has been extensively used in the synthesis of azaarene
derivatives.2 In particular, the high reactivity of radicals has
enabled various radical species to be successfully embedded on
2-alkyenylazaarenes via an addition−hydrogen atom transfer
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nucleophilic radical species, then the desired remote stereo-
genic centers could be achieved (Scheme 1B2). To this end,
we conceived that α-branched vinylketones might be viable
precursors of desired radicals, given the proven capability of
vinyl ketones to produce α-enolate radicals via single-electron
reduction.12
Herein, we report the development of reductive cross
coupling−enantioselective protonation of α-branched vinyl-
ketones to 2-vinylazaarenes (Scheme 1C). By establishing a
dual catalyst system involving a dicyanopyrazine-derived
chromophore (DPZ) photosensitizer and a SPINOL-based
chiral phosphoric acid (CPA) and using Hantzsch ester (HE)
as the terminal reductant, a variety of enantioenriched azaarene
variants bearing δ-tertiary carbon stereocenters on acyclic or
cyclic frameworks were obtained in high yields with good to
excellent enantiomeric excesses (ee’s). α-Branched 2-vinyl-
azaarenes were also compatible, leading to products containing
nonadjacent 1,4-stereocenters with satisfactory results.
satisfactory given that the homocoupling product of the α-
enolate radical was observed (vide infra), leading to the use of
2.0 equiv of 1a. Using 10 mol % diphenyl phosphate as a
racemic Brønsted acid catalyst afforded 3a in the same yield
(entry 2, Table S1).
Nevertheless, we still engaged in developing the enantiose-
lective manifold by using CPAs as chiral Brønsted acid
catalysts given their robust ability in asymmetric photoredox-
catalyzed synthesis of azaarene-based compounds.3b,6a,11e It is
worth mentioning that, in addition to the inherent challenge
originating from the very small volume and high mobility of
protons, the arguably strong racemic background reaction
would further increase the difficulty of attaining high
enantioselectivity for this unprecedented enantioselective
protonation reaction.14 After careful examinations of diverse
CPAs, HEs, and reaction parameters (Tables S1−S4), to our
delight, product 3a was obtained in 73% yield with 90% ee
when using 20 mol % SPINOL-CPA C1, HE-1, and (tert-
butyl)-3,5-dimethylbenzene as the solvent (entry 1, Table 1).
Both the ee and yield were highly sensitive to the substituents
at the 6,6′-position of the SPINOL (entries 2 and 3); for
instance, when the substituents were 2,6-dimethyl-4-tert-butyl
phenyl, roughly no 3a was achieved (entry 3). The ester
groups of HEs also affected the enantioselective result (entries
4 and 5). When iPr2NEt instead of HE was used as the
reductant, no reaction was observed (entry 6). Several viable
photoredox catalysts were also evaluated, but the yield of 3a
deteriorated, accompanied by decreased ee (entries 7 and 8).
Interestingly, transformation could not proceed when in the
absence of CPA C1, suggesting that the current solvent could
effectively suppress the racemic background reaction.15 Other
control experiments indicated that DPZ, visible light, and the
oxygen-free environment are indispensable to the success of
the reaction (entries 10−12).
Substrate Scope and Synthetic Applications. With the
optimal reaction conditions, a variety of α-branched vinyl-
ketones 1 and vinylazaarenes 2 were examined to evaluate the
substrate scope of this reductive cross coupling−enantiose-
lective protonation strategy (Scheme 2). Reactions of α-phenyl
vinylketones featuring diverse substituents on the ketones with
vinylpyridines 2a were first carried out (Scheme 2A). With
respect to aryl groups, it was found that the corresponding
products 3a−3q could be obtained in 53−81% yields with 62−
92% ee’s within 60 h. Distinct electron-withdrawing and
electron-donating groups at the para- and meta-positions of
aromatic rings always presented excellent ee’s, while moderate
ee’s were obtained when the substituent was introduced on the
ortho-position. Ketones with fused aromatic (3p) and
heteroaromatic (3q) rings as the substituents were also well
tolerated. For a benzyl-substituted α-phenyl vinylketone, the
transformation became sluggish, leading to product 3r in 46%
yield with 68% ee. 2-Aryl acrylophenones were subsequently
tested (Scheme 2B); regardless of the electronic properties and
substitution patterns of the aryls, products 3s−3z could be
achieved with excellent ee’s. Notably, the reactions of 2-benzyl
and 2-alkyl acrylophenones with 2a afforded products in
moderate yields and ee’s.15 Transformations of various 2-
vinylazaarenes with 2-phenyl acrylophenone 1a were then
examined (Scheme 2C). 2-Vinylpyridines containing diverse
electron-deficient and electron-rich substituents on the 3-, 4-,
and 5-positions of pyridine rings generated products 3aa−3ai
in 35−63% yields and 82−93% ee’s. The reaction did not
occur for 6-substituted pyridine-derived olefins, likely because
RESULTS AND DISCUSSION
Reaction Optimization. We began our study by selecting
2-phenyl acrylophenone (1a) and 2-vinylpyridine (2a) as
■
a
Table 1. Optimization of the Reaction Conditions
b
c
entry
variation from the standard conditions
yield (%) ee (%)
1
none
73
90
2
3
4
5
6
7
8
9
C2 instead of C1
C3 instead of C1
HE-2 instead of HE-1
HE-3 instead of HE-1
iPr2NEt instead of HE-1
[Ir(ppy)2(dtbbpy)]PF6 instead of DPZ
eosin Y instead of DPZ
no C1
51
trace
63
60
N.R.
41
52
N.A.
86
88
N.A.
57
d
e
29
88
N.R.
N.A.
N.A.
N.A.
N.A.
f
10
11
12
no DPZ
no light
air
0
N.R.
f
0
a
Reaction conditions: 1a (0.2 mmol), 2a (0.1 mmol), solvent (8.0
b
c
mL). Yield of isolated product. ee’s were determined by HPLC
d
e
f
analysis. N.A. = not available. N.R. = no reaction. 1a was
transformed to 4a via a Diels−Alder reaction.12
model substrates (Table 1 and Table S1 in the Supporting
Information [SI]). The transformation was first tested in the
presence of 1.0 mol % DPZ and 1.2 equiv of HE (HE-3) in
CH2Cl2 as the solvent at 25 °C and under irradiation with a 3
W blue LED (entry 1, Table S1). It was found that the reaction
proceeded smoothly, providing desired racemic product 3a in
82% yield within 24 h. Notably, after single-electron reduction
and protonation of 1a, a neutral ketyl radical intermediate
would first be generated; in addition to experiencing
tautomerization to form the desired α-enolate radical,13 the
neutral ketyl radical intermediate could undergo addition to
activated olefins.10f Accordingly, in addition to the high
reactivity, the result also suggests satisfactory regioselectivity
of this intermolecular reaction. The chemoselectivity is not so
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a
Scheme 2. Substrate Scope to Access Chiral Azaarenes Containing δ-Stereocenters
a
b
c
d
e
f
g
0.1 mmol scale. 10 °C, adding 1.0 equiv of NH3SO3. Adding 1.0 equiv of NH3SO3. 15 °C. 10 °C, adding 0.5 equiv of NH3SO3. 10 °C. 1/2 =
h
i
1:1, 2 mL of solvent. 15 °C, adding 1.0 equiv of NH3SO3. C5 instead of C4 was used and at 15 °C in 7.0 mL of solvent.
Scheme 3. Substrate Scope with Respect to α-Branched 2-
Vinylazaarenes
Scheme 4. Synthetic Applications
a
the steric hindrance inhibits the hydrogen-bonding interaction
between catalyst C1 and the pyridine rings. Transformations of
3-vinylpyridines and 4-vinylpyridines with 1a only afforded the
homocoupling product of 1a (vide infra), suggesting their
poorer reactivity as compared to 2-vinylpyridines.15 Gratify-
ingly, 2-vinylbenzimidazole was compatible, leading to product
3aj with satisfactory results. Next, we turned our attention to
vinylketones generated from cyclic ketones (5, Scheme 2D). It
was observed that, under the modified reaction conditions,
enantioenriched pyridine derivatives 6a−6c were obtained
with good ee’s, wherein tertiary carbon stereocenters on the
cyclic skeletons of α-tetralone, chromanone, and benzosuber-
one were successfully formed at the δ-position of pyridine.
To further demonstrate the practicality and generality of this
strategy, we next attempted transformations of α-branched
vinylketones 1 with α-branched vinylazaarenes 7 to simulta-
neously construct attractive but challenging nonadjacent 1,4-
stereocenters. As depicted in Scheme 3, under the slightly
modified reaction conditions, the reactions succeeded
a
b
0.1 mmol scale in 4.0 mL of solvent. 0.1 mol % DPZ was used.
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Figure 3. Gibbs free energy profiles (ΔGsol, in kcal/mol) for the
radical addition step.
Figure 1. Control experiments.
smoothly, leading to a large array of desired products 8a−8s in
63−95% yields with 85−99% ee’s and 1:1 to 16:1 dr.16 In
addition to the extensive substituent patterns for the aromatic
rings of α-branched vinylketones 1, diverse α-aryl vinyl-
pyridines 7 were well tolerated. Furthermore, α-alkyl vinyl-
pyridine (8p) and 2-benzyl acrylophenone (8q) were
compatible. Notably, benzimidazolyl (8r) and benzothiazolyl
(8s) were also revealed as viable azaarene groups for substrates
7.
With respect to this developed strategy, in addition to
providing access to constructing ketone-substituted δ-tertiary
stereogenic centers for azaarenes, the ketone moiety of
products, as a versatile functional group, offers important
opportunities to synthesize various optically pure azaarene
derivatives with potential bioactivities. For example, reduction
of 3a by using DIBAL-H furnished product 9 in 98% yield with
90% ee and >20:1 dr (Scheme 4). In this regard, this work
accomplished the formation of ε-stereocenters for azaarenes.
The hydroxy group of 9 was then readily transformed to azide
(10) under the Mitsunobu reaction conditions, further
expanding the synthetic utility owing to the robust ability of
azide for convenient and diverse modifications. Moreover, by
treatment of PdCl2 and Et3SiH,17 hydrogenation of 9 was
accomplished, producing an enantioenriched pyridine deriva-
tive 11 bearing an attractive δ-stereocenter that is substituted
by a phenyl and a benzyl group. Importantly, the reaction of 3a
with allylmagnesium chloride could generate 12 with
satisfactory results; in addition to embedding a readily
modified allyl group into the molecule, a heteroquaternary
carbon stereocenter ε to pyridine was successfully assembled.
Mechanistic Studies. We next investigated the plausible
mechanism of the reactions. Stern−Volmer experiments were
first conducted,15 and no measurable luminescence quenching
of *DPZ by 2-phenyl acrylophenone (1a) or 2-vinylpyridine
(2a) was observed.18 Based on previous works,6b,10f,19
accordingly, the reduction of α-branched vinylketones 1 by
DPZ•− may undergo an exothermic proton-coupled electron
transfer (PCET) process enabled by CPA and PyH+, which
was generated from the oxidation of HE• by *DPZ.
Subsequently, the transformation of 1a with 2a was performed
under standard conditions and in the presence of D2O or using
4,4-D2-HE-1 as the reductant (Figure 1A). The results suggest
that protonation is a viable pathway to construct C−H bonds
of α-ketones, and HAT is responsible for the formation of C−
H bonds of α-azaarenes. Similar outcomes were observed for
reactions using α-branched vinylazaarenes as partners.15
Therefore, the construction of tertiary stereocenters α to
azaarenes of products 8 should experience enantioselective
HAT, which is an unprecedented example of the asymmetric
photoredox synthesis of enantioenriched azaarene variants.
Figure 2. Proposed catalytic cycle.
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Figure 4. Calculated energy profiles for processes of enantioselective HAT and enantioselective protonation. All energies relative to the radical
complex II. M06-2X/6-31+G(d,p)/SMD(Mesitylene)//B3LYP-D3/6-31G(d,p).
reaction conditions and in the presence of pyridine-substituted
olefin 15, 2-bromo-1,2-diphenylpropan-1-one 14 afforded the
reductive debrominative protonation product 16 with 12%
ee,20 of which the absolute configuration of the stereocenter
was determined to be S but not R.21 The results suggest that
the enantioselective protonation of enolates is most likely after
radical addition to vinylazaarenes. From the above, a plausible
mechanism is proposed as shown in Figure 2.15
To gain further insights into the mechanism and origins of
selectivity, we performed DFT calculations on the reaction of
2-phenyl acrylophenone (1a) and 2-(1-phenylvinyl)pyridine
(7a) with CPA C1 as catalyst.15 In the initial step, a neutral
ketyl radical 1a• is generated from 1a through a PCET
process. Then, CPA C1 interacts with 1a• and 7a through two
H-bonding interactions, leading to a relatively stable complex I
(Figure 3). Complex I will undergo radical addition via TS1
(9.64 kcal/mol) and TS1-1 (15.93 kcal/mol), which occurs at
the C1 and C2 position on radical 1a•, respectively. The
results show that transition state TS1 is highly favored due to
the less distortion of radical 1a• in TS1 than that in TS1-1,
perfectly validating the good regioselectivity of the radical
addition process.
Subsequently, the HAT from HE to the radical intermediate
Figure 5. DFT-optimized enantiodetermining transition states for SR-
II occurs via R-TS2 (0.62 kcal/mol) and S-TS2 (6.17 kcal/
TS3, RS-TS3, RR-TS3, and SS-TS3.
mol) to afford intermediates R-III and S-III (Figure 4). The
lower-energy pathway was calculated to be R-TS2, which is
lower in energy by 5.55 kcal/mol relative to S-TS2. Herein, the
possibility of the protonation process for intermediate II was
also considered, but the energy barrier is too high to proceed
under this reaction conditions (see Figure S11 in the SI). From
intermediates R-III and S-III, the subsequent intermolecular
proton transfer process occurs through four possible
diastereomeric transition states S,R-TS3, S,S-TS3, R,R-TS3,
The relationship between the ee of CPA C1 and the ee of
product 3a was also evaluated (Figure 1B); the linear
correlation result strongly suggests that only a single molecule
of the chiral phosphate is included in the C−H bond-forming
step. Notably, in the reaction between 1a and 2a, molecule 13,
which was generated from two molecules of 1a, was obtained
with 29% ee (Figure 1C). Moreover, under the established
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Figure 6. Noncovalent interaction (NCI) plots for the key transition states SR-TS3, RR-TS3, and RS-TS3. The blue, green, and red regions
represent strong, weak, and repulsive interactions, respectively.
and R,S-TS3 (Figure 5). The results suggest that both the rate-
determining and enantiodetermining step for this reaction are
the protonation step. The geometries of transition states S,R-
TS3, S,S-TS3, R,R-TS3, and R,S-TS3 were explored. As
shown in Figure 4, S,R-TS3 possesses the most stabilized
structure, followed by R,R-TS3 and R,S-TS3, and the energy
differences between S,R-TS3, R,R-TS3, and R,S-TS3 are 1.57
and 5.77 kcal/mol, respectively, in good accord with the
experimentally obtained 99% ee and 12:1 dr.
Further, the enantioselectivity seems to be provided by the
subtle combination of steric and hydrogen bonding inter-
actions. As depicted in Figure 6, noncovalent interaction
(NCI) analysis indicates that there are more noncovalent C−
H···π interactions between tertiary butyl groups on the
substituents of C1 and the phenyl (or pyridine) groups on
the substrate fragment, as well as the π···π interactions between
the two phenyl groups on substrate fragment. Compared with
the transition state S,R-TS3, there are fewer C−H···π
interactions and no π···π interaction present in the transition
sate R,R-TS3 and R,S-TS3, and the weak steric interaction
between the tertiary butyl group on C1 and methylene group
was also found in R,S-TS3. This is the key contribution to the
preference for the formation of the major product.
protonation reactions via highly reactive radical-based
asymmetric photoredox catalysis.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c01073.
General information, optimization of reaction condi-
tions, general experimental procedures, mechanistic
studies, characterization data, X-ray of product 8g, and
NMR spectra (PDF)
Accession Codes
CCDC 2020078 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
Shanshan Cao − Henan Key Laboratory of Organic
Functional Molecule and Drug Innovation, School of
Chemistry and Chemical Engineering, Henan Normal
University, Xinxiang, Henan 453007, P. R. China;
Email: caoshanshan@htu.edu.cn
Zhiyong Jiang − International Scientific and Technological
Cooperation Base of Chiral Chemistry, Henan University,
Kaifeng, Henan 475004, P. R. China; Henan Key Laboratory
of Organic Functional Molecule and Drug Innovation, 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
CONCLUSIONS
■
In summary, we developed a reductive cross coupling−
enantioselective protonation of α-branched vinylketones to
vinylazaarenes via visible-light-mediated cooperative photo-
redox and chiral hydrogen-bonding catalysis. This method
offers highly efficient access to valuable enantioenriched
azaarene derivatives featuring diverse tertiary stereocenters δ
to azaarenes in high yields and ee’s. It is also effective for α-
branched vinylazaarenes, thus successfully assembling elusive
1,4-stereocenters. In addition, the ketone moiety of products
offers versatile approaches to constructing remote ε-tertiary
and ε-heteroquaternary carbon stereocenters for azaarenes.
Control experiments and theoretical studies via DFT
calculations suggested that the reactions should experience a
tandem radical addition, (enantioselective) HAT, and
enantioselective protonation process. This work represents
an unprecedented enantioselective protonation strategy, which
will further inspire the pursuit of novel enantioselective
Authors
Manman Kong − International Scientific and Technological
Cooperation Base of Chiral Chemistry, Henan University,
Kaifeng, Henan 475004, P. R. China
Yaqi Tan − International Scientific and Technological
Cooperation Base of Chiral Chemistry, Henan University,
Kaifeng, Henan 475004, P. R. China
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Using Asymmetric Protonation: Method Development and Mecha-
nistic Study. Chem. - Eur. J. 2020, 26, 12249−12255.
Xiaowei Zhao − International Scientific and Technological
Cooperation Base of Chiral Chemistry, Henan University,
Kaifeng, Henan 475004, P. R. China
Baokun Qiao − International Scientific and Technological
Cooperation Base of Chiral Chemistry, Henan University,
Kaifeng, Henan 475004, P. R. China
Choon-Hong Tan − International Scientific and Technological
Cooperation Base of Chiral Chemistry, Henan University,
Kaifeng, Henan 475004, P. R. China; Division of Chemistry
and Biological Chemistry, Nanyang Technological University,
Singapore 637371; orcid.org/0000-0003-3190-7855
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H. W. Diastereo- and Enantioselective Pd(II)-Catalyzed Additions of
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Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c01073
(e) Yin, Y.; Li, Y.; Gonca̧ lves; Zhan, Q.; Wang, G.; Zhao, X.; Qiao, B.;
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Author Contributions
∥M.K. and Y.T. contributed equally.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Grants from the National Natural Science Foundation of
China (21925103 and 21901062), Key Technologies R&D
Program of Henan (202102310005), Henan Normal Uni-
versity, and Henan University are gratefully acknowledged.
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1
thin layer chromatography (TLC) analysis, and it is difficult for H
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