Michael Reaction Inspired Atroposelective Construction of Axially Chiral Biaryls

Article abstract of DOI:10.1021/jacs.0c01963

The first copper-catalyzed atroposelective Michael-type addition between azonaphthalenes and arylboronic acids for the construction of biaryl atropisomers was established using a novel BINOL-derived phosphoramidite as a chiral ligand. A broad range of atropisomeric biaryls were obtained with good efficiency, and the practicality of this approach was verified by versatile transformations toward axially chiral ligands, catalysts, and other functional atropisomers. This set of catalytic systems successfully inhibited the routine 1,2-addition and promoted the formation of an aryl-aryl chiral axis. Meanwhile, this strategy bypassed the use of an oxidant as well as the harsh conditions normally necessary for transition-metal-mediated arene C-H coupling with arylboronic acids as an arylation counterpart, offering a straightforward alternative to access optically active biaryls.

Full text of DOI:10.1021/jacs.0c01963

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Communication
Michael Reaction Inspired Atroposelective
Construction of Axially Chiral Biaryls
Shengyi Yan, Shaoyu Li, Qiuling Song, Bin Tan, Wang Xia, and Shao-Hua Xiang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c01963 • Publication Date (Web): 08 Apr 2020
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Journal of the American Chemical Society
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Michael Reaction Inspired Atroposelective Construction of Axially
Chiral Biaryls
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Shengyi Yan,† Wang Xia,† Shaoyu Li,†,§ Qiuling Song*,‡ Shao-Hua Xiang†,§and Bin Tan*,†
†Shenzhen Grubbs Institute and Department of Chemistry, Guangdong Key laboratory of Catalysis, Southern
University of Science and Technology, Shenzhen, 518055, China
‡Institute of Next Generation Matter Transformation, College of Material Sciences Engineering, Huaqiao University,
Xiamen, Fujian, 361021, China
§Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen, 518055,
China
ABSTRACT: The first copper-catalyzed atroposelective Michael type addition between azonaphthalenes and arylboronic
acids for the construction of biaryl atropisomers was established using a novel BINOL-derived phosphoramidite as chiral
ligand. A broad range of atropisomeric biaryls were obtained in good efficiency and the practicality of this approach was
verified by versatile transformations towards axially chiral ligands, catalysts, and other functional atropisomers. This set of
catalytic systems successfully inhibited the routine 1,2 addition and promoted the formation of aryl-aryl chiral axis.
Meanwhile, this strategy bypassed the use of oxidant as well as the harsh conditions normally necessary for transition-
metal mediated arene C-H coupling with arylboronic acids as arylation counterpart, offering a straightforward alternative to
access optically active biaryls.
Axially chiral biaryl frameworks are ubiquitous in
biologically active natural products, drugs and advanced
materials.1-3 They also constitute the essential chiral
element in a variety of privileged chiral ligands and
catalysts within asymmetric catalysis.4 Therefore, the
catalytic and enantioselective establishment of optically
active biaryl skeletons has gained tremendous attentions
over the past couple of decades5 to accomplish a suite of
highly atroposelective and efficient synthetic strategies,
including the formation of a chiral axis through aryl-aryl
coupling,6 de novo construction of an aromatic ring,7
functionalization of a biaryl,8 and traceless point-to-axial
chirality transfer.9 Among these developed strategies,
palladium-catalyzed asymmetric Suzuki-Miyaura coupling
reactions10 with arylboronic acids have been widely
employed for constructing non-C2-symmetric biaryl
atropisomers since the pioneering works from
Buchwald10a and Cammidge10b (Figure 1a). Transition
metal catalyzed C−H arylation of arene with arylboronic
acid featuring improved atom-economy due to obviation of
pre-functionalization was then established as a promising
alternative to construct the biaryls (Figure 1b).11 In spite of
seminal attempts through palladium-catalyzed cross-
coupling between thiophenes and arylboronic acids by
Yamaguchi, Itami and coworkers,12 the exploitation of
asymmetric variation for this tactic remains in its infancy.
This coupling method necessitates exogenous oxidant
indispensable in conventional Suzuki-type couplings as
well as elevated reaction temperature due to the low
reactivity of arenes; both of which could imperil
enantiocontrol of the stereogenic axis. Accordingly, a more
efficient and enantioselective route for this strategy is
extremely desirable to unravel its potential.
a)
Asymmetric Suzuki-Miyaura cross-coupling
Ar
B(OH)2
Palladium catalyst
Chiral ligand
Ar
X
+
*
Ar
Ar
well-developed strategy with pre-functionalizations of both arenes
b)
Atroposelective C-H arylation of arenes with ArB(OH)2
B(OH)2
Ar
[Pd]/Ligand
Ar
+
*
Ar
Oxidant
H
Ar
improved strategy with functionalization of only one arene
external stoichiometric oxidant elevated temperature
poor enantiocontrol
c)
This work: Cu-catalyzed Atroposelective Michael Reaction with ArB(OH)2
H
Ar
B(OH)2
Ar
N
Copper catalyst
Chiral ligand
Ar
N
R
N
+
R
H
*
3
N
1
4
2
Ar
Michael reaction inspired aryl C-H arylation
no oxidant
mild conditions
novel BINOL based chiral phosphoramidite ligand
excellent enantiocontrol
Figure 1. Representative strategies for metal-catalyzed
enantioselective construction of axially chiral biaryls with
arylboronic acids.
Building on seminal work of Hayashi,13d catalytic
enantioselective Michael addition of organoboron to α,β-
unsaturated compounds mediated by transition metal
catalysts has been widely employed to assemble centrally
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chiral compounds by several groups.13 As these Michael
Page 2 of 7
catalyst, BINOL-derived chiral phosphoramidite L115 as the
ligand and KHCO3 as base could give the desired product
3a in 30% yield with 71:29 enantiomeric ratio (er) in
CH2Cl2 at room temperature after 16 hours (Table 1).
Encouraged by these results, a range of ligands with BINOL
backbone were evaluated (L1-L10). Interestingly, the
ligand bearing trifluoromethyl group (L8) was superior to
other commonly used aryl substituents and afforded 3a
with a moderate enantioselectivity (80:20 er). The
employment of bromine-substituted ligand L9 further
improved the reaction outcome. To our delight, L10
possessing iodine atom on 3,3’-position proved to be the
best basic framework in terms of both yield and
1
2
3
4
5
6
7
8
acceptors are derived from different conjugated olefins,
the unexampled participation of an aromatic Michael
acceptor is reckoned to be vastly attributed to the high
energy barrier during dearomatization process. Our recent
discovery of acid-promoted enantioselective Michael type
reactions between azonaphthalenes and a group of
reactive C-nucleophiles to enable the rare nucleophilic
aromatic substitution prompted us to investigate
applicability of this aromatic Michael acceptor for C(sp2)−H
arene arylation under transition metal catalysis.14 The
success of this design would provide a unified solution to
the above-mentioned issues in typical Suzuki type C−H
oxidative couplings with boronic acid counterparts,
favorably without exogenous oxidants, as a novel synthetic
tool to assemble two arenes in an atroposelective manner
(Figure 1c).
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enantioselectivity.
Subsequently,
a
series
of
phosphoramidite ligands were prepared with different
amines based on this beneficial framework and the
influence of the amine groups on the phosphoramidite was
investigated in detail. As displayed in Table 1, L11 with
two n-butyl groups on the nitrogen gave a similar reaction
result (73% yield, 85:15 er). When pyrrolidine, indoline
and carbazole were used, relative lower er values were
achieved (L12-L14). To our delight, most 2-substituted
cyclic piperidine containing ligands slightly improved the
enantiocontrol (L15-L18). It should be noted that chirality
in piperidine ring has a significant influence on the
stereoselectivity. We can see clearly from the results that
R-configuration of ethylpiperidine in L18 proved to be
much better than S-enantiomer L17. Finally, optically pure
ligand L19 carrying iso-propyl group on C2 position was
found to furnish the best enantioselectivity (92.5:7.5 er).
With L19 as the ligand, further optimization through the
screening of other reaction parameters concluded a set of
optimized conditions as follows: 1a (0.10 mmol), 2a (0.20
mmol), Cu(TFA)2 (15 mol%), L19 (20 mol%), KHCO3 (2.0
equiv) in CH2Cl2 (5 mL) at 15 °C for 24 hours, affording the
atropisomeric biaryl 3a in 79% yield with 96:4 er (see
supporting information for details). The absolute
configuration of ligand L19 was unambiguously confirmed
by X-ray crystallographic analysis.16
Based on the previous reports on copper-mediated
enantioselective conjugate addition with arylboronic
acids13e-g and our continuous understandings of catalytic
asymmetric construction of atropisomeric biaryls,5g,14
a
plausible reaction process was rationalized as follows: the
catalytic cycle commences from the transmetallation
between arylboronic acid 2 and chirally active Cu species,
giving rise to A. The following coordination of this aryl-
copper species with azonaphthalene
1
generates
intermediate B. Activation effect of azo group and
coordination with metal center cooperatively enhances the
electrophilicity of 1 to effect the atroposelective Michael
type reaction. The central chirality in intermediate C was
determined by the stereoinduction from chiral
phosphoramidite ligand. Finally, a rapid central-to-axial
chirality transfer produces enantioenriched biaryl
atropisomer 3 along with the regeneration of Cu-
phosphoramidite complex (Scheme 1).
CuX2 + L*
B(OH)2
H
N
R
N
H
L*CuIIX2
*
O
Table 1. Representative chiral ligands screening.
2
transmetall
point-to-axial
chirality transfer
3
H
N
Cu(OTf)2 (10 mol%)
B(OH)2
ation
L
(13 mol%)
N
CO2Me
+
H
N
KHCO3 (1.5 equiv)
CH2Cl2 (2 mL), r.t., 16 h
N
CO2Me
3a
1a
2a
(0.15 mmol)
(0.10 mmol)
H
N
R
II L*X
*
Cu
N
L1, R = C6H5; 30%, 71:29 er
H
L2
L3
L4
L5
L6
L7
L8
L9
, R = 4-PhC6H4; 51%, 74:26 er
, R = 4-NO2C6H4; trace
, R = 3,5-(CF3 2C6H3; trace
R
I
I
O
A
CuIIL*X2
)
Et
Et
nBu
nBu
O
O
O
O
O
P
, R = 2,4,6-iPr3C6H2; 34%, 64:36 er
, R = 2-naphthyl; 15%, 74.5:25.5 er
, R = 9-anthryl; 40%, 48:52 er
, R = CF3; 49%, 80:20 er
C
P
N
P
N
N
O
unprecedented
asymmetric
Michael Reaction
R
I
I
, R = Br; 63%, 82:18 er
, R = I; 74%, 85:15 er
L10
L11
, 73%, 85:15 er
L12
, 64%, 77.5:22.5 er
N
R
I
I
I
I
N
Me
Et
2
N
4
N
R
1
O
O
O
O
O
O
3
1
P
N
P
N
P
N
P N
O
O
O
O
CuII
L*
I
I
I
I
L15
L16
, 71%, 87.5:12.5 er
L13
L14
, 68%, 86:14 er
I
, 58%, 77.5:22.5 er
, 49%, 79:21 er
B
I
I
Et
Et
O
O
O
P
N
P N
P
N
Scheme 1. Process hypothesis for the designed reaction.
O
O
O
I
I
I
To validate the feasibility of this hypothesis,
azonaphthalene derivative 1a was chosen as the model
substrate for enantioselective arylation with 1-
naphthylboronic acid 2a. After some initial trials, we were
pleased to find that the reaction with Cu(OTf)2 as the
L17
L18
L19
Optimal conditions: 79%, 96:4 era
, 63%, 92.5:7.5 er;
, 84%, 79.5:20.5 er
, 70%, 91:9 er
aCu(TFA)2 (15 mol%) and L19 (20 mol%) was stirred in CH2Cl2 (5
mL) for 1.5 hours, 1a (0.1 mmol), 2a (0.2 mmol), KHCO3 (2.0
equiv) were added and stirred at 15 °C for 24 hours. Isolated yield
was provided and other yields in this table were determined by
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1H NMR using CH2Br2 as internal standard. Enantiomeric ratio (er)
value was determined by chiral HPLC.
with an er of 91.5:8.5. When ortho-isopropyl substituted
phenylboronic 2l was utilized, the corresponding axially
chiral phenyl-naphthyl 3w was obtained in 65% yield and
90:10 er with L18 as the ligand. Although compound 3x
could be synthesized in 84% yield with L18, significantly
compromised enantiomeric ratios were observed for both
catalysts. The reaction failed to give any product when 4-
isoquinolinylboronic acid was evaluated with the
established conditions. Meanwhile, the ortho-substituted
1-naphthalenylboronic acids were also tested for this
transformation, however, no reaction occurred in these
cases probably due to the low activity resulting from
strong steric hindrance.
1
2
3
4
5
6
7
8
After the establishment of the optimal reaction conditions,
the substrate generality for this atroposelective cross-
coupling was evaluated. First, a group of azonaphthalenes
were examined and the results were summarized in Table
2. All substrates with different ester groups gave the
expected product 3b-3e in similar enantiocontrol. As
compared to the methyl ester, the replacement with an
ethyl or iso-propyl ester resulted in a higher yield, while
relative lower efficiency was observed with benzyl and
Fmoc esters. Notably, substrates with bromo substitutions
which were commonly incompatible for conventional
palladium-catalyzed asymmetric Suzuki-Miyaura cross-
couplings could be well tolerated for this transformation to
furnish the desired atropisomers 3f and 3i in synthetically
useful yields with about 90% enantiomeric excess. In
addition, the retained bromine atom in the products
offered an effective functional handle for the downstream
functionalization. Next, the electronic effect of substituents
was probed and generally, the reactions with substrates
bearing electron-donating group produced the biaryl
compounds in higher yields (3g, 3j-3k). Moderate yield
was obtained for axailly chiral biaryl molecule 3h formed
from azonaphthalene with an electron-withdrawing ester
group on C6 position of the aromatic ring.
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Table 3. Substrate generality of arylboronic acids 2.a
H
Cu(TFA)2 (15 mol%)
or (20 mol%)
L18 L19
B(OH)2
N
N
CO2Me
+
H
N
R
KHCO3 (2.0 equiv)
N
CO2Me
CO2Me
CH2Cl2 (5 mL), 15 °C, 24 h
R
1a
2
3m-x
H
H
N
H
N
H
N
N
N
N
CO2Me
N
CO2Me
N
CO2Me
H
H
H
H
F
Me
MeO
Ph
3m
3n
3o
3p
L19: 50%, 94:6 er
L18: 56%, 92:8 er
L19: 62%, 94:6 erb,c
L18: 70%, 93:7 erb,c
L19: 44%, 92:8 er
L18: 40%, 94:6 er
L19: 53%, 93:7 er
L18: 55%, 92.5:7.5 er
H
N
H
N
H
N
H
N
N
CO2Me
N
CO2Me
N
CO2Me
N
CO2Me
H
H
H
H
3q
3r
3s
Me
L19: < 30%, n.d.
L18: 69%, 93:7 er
3t
F
F
L19: 72%, 94.5:5.5 er
L18: 73%, 94.:6 er
L19: 60%, 94:6 erb
L18: 56%, 91:9 erb
L19: 53%, 91.5:8.5 erd
L18: 57%, 92:8 erd
Table 2. Substrate scope of azonaphthalene derivatives 1.a
H
N
H
N
H
N
H
N
N
H
CO2Me
N
CO2Me
N
CO2Me
N
CO2Me
R2
H
H
H
H
B(OH)2
Cu(TFA)2 (15 mol%)
L19 (20 mol%)
iPr
Cl
N
N
CO2R1
R2
+
H
N
N
CO2R1
KHCO3 (2.0 equiv)
Me
F3C
CH2Cl2 (5 mL), 15 °C
3u
3v
3w
3x
Br
3a-l
1
2a
L19: 30%, 90:10 erb
L18: 68%, 92:8 erb
L19: 71%, 88:12 er
L18: 80%, 91:9 er
L19: 51%, 90:10 erb
L18: 65%, 90:10 erb
L19: 41%, 68:32 erb
L18: 84%, 64:36 erb
H
N
H
H
H
N
N
N
CO2iPr
N
CO2Me
N
CO2Et
N
N
CO2Bn
H
H
H
H
a1a (0.1 mmol), 2a (0.2 mmol), Cu(TFA)2 (15 mol%), L18 or L19
(20 mol%), KHCO3 (2.0 equiv) in CH2Cl2 (5 mL) at 15 °C for 24
hours. Isolated yields were provided and er values were
3a, 79%, 96:4 er
3b, 85%, 95:5 er
3c, 89%, 95:5 er
3d, 67%, 95:5 er
Br
MeO
MeO2
C
b
determined by chiral HPLC. The reaction proceeded for 2 days.
H
N
H
N
H
N
H
N
cPPh3 (2.0 equiv) was added and stirred for 4 hours after the
completion of the reaction. d The reaction proceeded for 5 days.
N
H
CO2Fmoc
N
H
CO2Me
N
CO2Me
N
H
CO2Me
H
3e, 72%, 96:4 er
3f, 68%, 94.5:5.5 er
3g, 87%, 92.5:7.5 er
3h, 65%, 94:6 erb
To demonstrate the synthetic practicality of this approach,
a gram-scale synthesis of biaryl atropisomer 3a was
performed and the reaction proceeded smoothly to give
the corresponding product in identical enantioselectivity
with slight loss of chemical yield (Figure 2a, 75% yield,
96:4 er). Moreover, a useful chiral 2-aminobinaphthyl 4
was yielded in excellent efficiency without erosion of
stereochemical integrity after reductive cleavage of N–N
bond in compound 3a in the presence of Raney-nickel and
hydrogen atmosphere under ultrasound (Figure 2b). The
absolute configuration of 4 was confirmed by comparison
with the reported compound,17 and the corresponding
absolute configuration of other products was assigned by
analogy.
H
N
H
N
H
N
H
N
Br
N
H
CO2MeMe
N
CO2MeMeO
N
CO2MePh
N
H
CO2Me
H
H
3i, 57%, 95:5 er
3j, 90%, 95.5:4.5 er
3k, 75%, 94:6 er
3l, 76%, 95:5 er
a1a (0.1 mmol), 2a (0.2 mmol), Cu(TFA)2 (15 mol%), L19 (20
mol%), KHCO3 (2.0 equiv) in CH2Cl2 (5 mL) at 15 °C for 24 hours.
Isolated yields were provided and er values were determined by
chiral HPLC. bL18 (20 mol%) was used.
Encouraged by the above results, we then set out to
investigate the substrate scope of arylboronic acids 2. As
displayed in Table 3, a group of substrates 2 bearing
different substituents and substitution patterns were
treated under the standard conditions where most
furnished the corresponding biaryl atropisomers (3m-3v)
in lower yields with slightly diminished enantiocontrol. To
further improve the experimental results for these
substrates, the other promising ligand L18 was employed
to re-evaluate this transformation. To our delight, better
results were obtained for 3s, 3u and 3v when respective
naphthylboronic acids were used as Michael donor. It
should be noted that this reaction was also amenable to 1-
pyrenylboronic acid, delivering product 3t in 53% yield
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Journal of the American Chemical Society
Page 4 of 7
a)
highly enantioenriched products without the loss of
b)
H
N
2a
Raney-Ni, H2
(8 mmol)
N
CO2Me
3a
75%, 96:4 er
NH2
1
enantiopurity. It is expected that the further exploitation of
this strategy will bring about a useful and universal
alternative for the synthesis of atropisomeric biaryl
structures.
H
N
standard conditions
MeOH, ultrasound, 6 h
85%, 96:4 er
N
CO2Me
2
1a
(4 mmol)
4
3
CO2Et
c)
4
a, b
NHAc
e, f, g
PPh2
CO2Et
57%, 95.5:4.5 er
62%, 96:4 er
5
6
5
8
ASSOCIATED CONTENT
O
Supporting information for this article is given via a link at the
end of the document. Experimental procedures, additional
figures and tables, compound characterization data, NMR and
chiral HPLC spectra.
7
8
9
NH2
Ar
N
c
e, h
N
H
CO2H
H
58%, 96:4 er
85%, 96:4 er
6
9
4
, 96:4 er
Ar = 3,5-(CF3)2C6H3
S
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Ar
e, i
d
N
H
N
H
Ph
74%, 96:4 er
92%, 96:4 er
AUTHOR INFORMATION
Corresponding Author
*tanb@sustech.edu.cn
*qsong@hqu.edu.cn
10
7
Figure 2. Gram-scale synthesis of 3, preparation and
transformations of 4. Reagents and conditions: a) AcCl, Et3N,
CH2Cl2, 0 °C to r.t.; b) Pd(OAc)2, K2S2O8, TFA/CH2Cl2 (v/v =
4/1),
r.t.;
c)
1-isothiocyanato-3,5-
Notes
bis(trifluoromethyl)benzene, THF, r.t.; d) 1-isocyanato-3,5-
bis(trifluoromethyl)benzene, THF, r.t.; e) NaNO2, KI, con.
HCl/H2O/THF; f) Pd(OAc)2, diphenylphosphine oxide, dppb,
DIPEA, DMSO, 120 °C; g) HSiCl3, Et3N, toluene, 115 °C; h) n-
BuLi, CO2, -78 °C to 0 °C; i) Pd(PPh3)2Cl2, CuI, Et3N, N2, 60 °C.
The authors declare that they have no conflict of interest.
ACKNOWLEDGMENT
We are grateful for financial support from the National
Natural Science Foundation of China (Nos. 21702092,
21825105, 21901102 and 21901105), Shenzhen Nobel Prize
Scientists Laboratory Project (C17213101), and Shenzhen
Special Funds for the Development of Biomedicine, Internet,
To further expand the utility of this reaction, axially chiral
2-aminobinaphthyl 4 was facilely transformed to a series
of biaryl-scaffold-based ligands, catalysts as well as other
functional molecules (Figure 2c). First, a tetra-ortho-
substituted atropisomeric biaryl
constructed by sequential acetyl protection of amine and
C–H olefination reaction (57%, 95.5:4.5 er). Furthermore,
New
Energy,
and
New
Material
Industries
5
was efficiently
(JCYJ20170412151701379).
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the reaction of
4
with isocyanatoarene or
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isothiocyanatoarene underwent smoothly to afford axially
chiral urea 6 and thiourea 7 respectively in excellent yields
with retention of optical purity. More importantly, chiral
phosphine 8 which could serve as a chiral mono-
phosphorus ligand for palladium-catalyzed asymmetric
hydrosilylation
process
was
provided
without
deterioration of enantioselectivity.18 Following C–H
functionalization of the mono-phosphorus ligand might
further broaden the applicability of the obtained biaryl
structures.19 Compound 9 was also accessible in moderate
yield with 96:4 er through conversion of the amino group
to a carboxylic acid. Finally, an alkynyl-substituted
atropisomer 10 with the same enantiopurity was
synthesized by successive diazotization, iodination and
palladium-catalyzed Sonogashira cross-coupling.
In conclusion, we have described the first copper-catalyzed
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arylboronic acids under mild conditions, delivering the
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Ar
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chiral ligand
B(OH)2
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Michael addition inspired C(sp2)-H arylation no oxidant
excellent enantiocontrol novel phosphoramidite ligand
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