Enhanced Reactivity by Torsional Strain of Cyclic Diaryliodonium in Cu-Catalyzed Enantioselective Ring-Opening Reaction

Article abstract of DOI:10.1016/j.chempr.2018.01.017

Atropisomers are stereoisomers arising from the restricted rotation around a single bond. In particular, biaryl atropisomers represent an important class of compounds, as they are widely present in natural products, ligands and pharmaceutical molecules. However, the preparation of structurally diverse biaryl atropisomers under mild conditions is a significant challenge. Here, we describe a Cu-bis(oxazolinyl)pyridine-catalyzed asymmetric ring-opening amination reaction of cyclic diaryliodoniums. Increasing the torsional strain of these cyclic compounds significantly improved the reactivity of cyclic diaryliodoniums. Computational investigation indicated that the two conformers of the cyclic diaryliodoniums had a low rotational barrier, and generally the reaction achieved high yields and high enantioselectivity (up to >99% ee). Furthermore, this ring-opening amination reaction also featured high atom economy in comparison with traditional reactions involving diaryliodonium. Finally, we propose a catalytic cycle and a mechanistic model that accounts for the observed enantioselectivity. Axially chiral biaryls represent an important class of stereoisomers that arise from restricted rotation around a single bond. They can be found among natural products, ligands, and pharmaceutical molecules. Divergent and atom-economic synthetic approaches toward optically active biaryl atropisomers, in particular ones generating little to no waste, constitute a significant challenge. Here, we describe a highly enantioselective copper-catalyzed ring-opening reaction of cyclic diaryliodoniums where increasing the torsional strain of the diaryliodonium salts improved the relative poor reactivity of the cyclic diaryliodoniums. This method enabled us to access enantio-enriched amino aryliodides with higher atom economy than traditional reactions involving diaryliodonium. These axially chiral molecules are important precursors for divergent synthesis of axially chiral compounds, which are potentially useful catalysts or ligands in industry. An efficient method is developed for preparing functionalized axially chiral compounds via the ring-opening reaction of cyclic diaryliodonium salts. Two conformers of the cyclic diaryliodonium salt observed in the crystal structure underwent quick equilibration. The distortion of the diaryliodonium salts significantly increased reactivity toward the chiral copper catalyst, which enabled the reaction to take place in mild conditions to furnish the products in enantioselectivities up to 99.5:0.5 (R:S).

Full text of DOI:10.1016/j.chempr.2018.01.017

Article
Enhanced Reactivity by Torsional Strain of
Cyclic Diaryliodonium in Cu-Catalyzed
Enantioselective Ring-Opening Reaction
Kun Zhao, Longhui Duan, Shibo
Xu, Julong Jiang, Yao Fu,
Zhenhua Gu
fuyao@ustc.edu.cn (Y.F.)
zhgu@ustc.edu.cn (Z.G.)
HIGHLIGHTS
Significant reactivity improvement
by torsional strain of cyclic
diaryliodoniums
Rapid access to optically active
amino aryliodide atropisomers
Highly atom-economic synthesis
of aryliodide atropisomers via
ring-opening reaction
An efficient method is developed for preparing functionalized axially chiral
compounds via the ring-opening reaction of cyclic diaryliodonium salts. Two
conformers of the cyclic diaryliodonium salt observed in the crystal structure
underwent quick equilibration. The distortion of the diaryliodonium salts
significantly increased reactivity toward the chiral copper catalyst, which enabled
the reaction to take place in mild conditions to furnish the products in
enantioselectivities up to 99.5:0.5 (R:S).
Zhao et al., Chem 4, 1–14
March 8, 2018 ª 2018 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2018.01.017

Please cite this article in press as: Zhao et al., Enhanced Reactivity by Torsional Strain of Cyclic Diaryliodonium in Cu-Catalyzed Enantioselective
Ring-Opening Reaction, Chem (2018), https://doi.org/10.1016/j.chempr.2018.01.017
Article
Enhanced Reactivity by Torsional Strain
of Cyclic Diaryliodonium in Cu-Catalyzed
Enantioselective Ring-Opening Reaction
1,3,
Kun Zhao,1,2 Longhui Duan,1,2 Shibo Xu,1 Julong Jiang,1 Yao Fu,1, and Zhenhua Gu
*
*
SUMMARY
The Bigger Picture
Axially chiral biaryls represent an
important class of stereoisomers
that arise from restricted rotation
around a single bond. They can be
found among natural products,
ligands, and pharmaceutical
molecules. Divergent and atom-
economic synthetic approaches
toward optically active biaryl
atropisomers, in particular ones
generating little to no waste,
constitute a significant challenge.
Here, we describe a highly
Atropisomers are stereoisomers arising from the restricted rotation around a
single bond. In particular, biaryl atropisomers represent an important class of
compounds, as they are widely present in natural products, ligands and pharma-
ceutical molecules. However, the preparation of structurally diverse biaryl atro-
pisomers under mild conditions is a significant challenge. Here, we describe a
Cu-bis(oxazolinyl)pyridine-catalyzed asymmetric ring-opening amination reac-
tion of cyclic diaryliodoniums. Increasing the torsional strain of these cyclic
compounds significantly improved the reactivity of cyclic diaryliodoniums.
Computational investigation indicated that the two conformers of the cyclic di-
aryliodoniums had a low rotational barrier, and generally the reaction achieved
high yields and high enantioselectivity (up to >99% ee). Furthermore, this
ring-opening amination reaction also featured high atom economy in compari-
son with traditional reactions involving diaryliodonium. Finally, we propose
a catalytic cycle and a mechanistic model that accounts for the observed
enantioselectivity.
enantioselective copper-
catalyzed ring-opening reaction
of cyclic diaryliodoniums where
increasing the torsional strain of
the diaryliodonium salts improved
the relative poor reactivity of the
cyclic diaryliodoniums. This
method enabled us to access
enantio-enriched amino
INTRODUCTION
Atropisomerism is a type of stereoisomerism where rotation via a single bond is
restricted. Atropisomers are frequently seen in amides, biaryls, and diaryl ethers.1,2
In some cases, the atropisomeric architecture is the key feature in bioactive natural
products, pharmaceuticals (i.e., vancomycin) (Scheme 1B), and privileged ligands or
catalysts (i.e., [1,10-binaphthalene]-2,20-diol [BINOL] and KenPhos) (Scheme 1C).3–6
In contrast to stereogenic sp3 carbons bearing four distinct substituents, biaryl atro-
pisomerism requires two conditions: (1) a restricted rotation around a stable axis,
typically a bond, and (2) different substituents on both sides of the axis (A s B
and C s D; Scheme 1A). Thus, the axis of a stable biaryl atropisomer is usually ste-
rically congested, and its construction is challenging. Because of their importance
and widespread applications in both medicinal and synthetic chemistry, a number
of strategies for the construction of biaryl atropisomers have been developed,
aryliodides with higher atom
economy than traditional
reactions involving
diaryliodonium. These axially
chiral molecules are important
precursors for divergent synthesis
of axially chiral compounds, which
are potentially useful catalysts or
ligands in industry.
including
metal-catalyzed
asymmetric
cross-coupling,7–11
asymmetric
‘‘aromatic substitution,’’12 and de novo aromatic ring formation (such as asymmetric
[2 + 2 + 2] cycloaddition).13–15 In addition, modification of the existing biaryl struc-
tures enables access to enantio-enriched atropisomers via either a desymmetriza-
tion reaction or (dynamic) kinetic resolution (Scheme 1D).16–25 Furthermore, the
construction of benzylic center chirality, followed by center-to-axial chirality transfer
aromatization is also an effective approach to access enantio-enriched biaryl atro-
pisomers.26,27 Recently, there have been a number of reports on organocatalyzed
asymmetric atropisomer synthesis.28–36 Ring opening of strained biaryl compounds
Chem 4, 1–14, March 8, 2018 ª 2018 Elsevier Inc.
1

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Ring-Opening Reaction, Chem (2018), https://doi.org/10.1016/j.chempr.2018.01.017
is a powerful method for the construction of functionalized biaryl atropisomers.
Bringmann and co-workers reported the asymmetric reduction of biaryl lactones
to form a series of axially chiral 20-(hydroxymethyl)-[1,10-biphenyl]-2-ol analogs,
and a number of atropisomeric natural products have been efficiently synthesized
by this protocol.3,4 Nickel-catalyzed ring opening of dinaphthothiophene to afford
axially chiral 1,10-binaphthyls was described by Hayashi and colleagues.37 In addi-
tion, the same group reported an elegant palladium-catalyzed asymmetric carbon-
ylation reaction of dinaphthaleneiodonium, albeit with low enantioselectivity.38 It is
of significance to develop synthetic methods to access atropisomers that can serve
as ‘‘platform molecules’’, i.e., compounds that can be readily converted to structur-
ally diverse atropisomers. Recently, copper-catalyzed aminations of diaryliodonium
have emerged as important methods for the synthesis of aniline derivatives.39–45 Di-
aryliodoniums act as powerful reagents for arylation of nucleophiles in both asym-
metric and non-asymmetric reactions, most notably in contributions from the Gaunt
group.46–53 We reasoned that the ring-opening reaction of cyclic diaryl iodoniums
would give atropisomeric aryl iodides, which represent an ideal class of precursors
for the divergent synthesis of biaryl atropisomers (Scheme 1E).54–59 The key chal-
lenges, however, are (1) how to increase the reactivity, because cyclic diaryliodo-
niums showed significantly lower activity than noncyclic reagents,57 and (2) how to
avoid the formation of diamination products or carbazoles. These requirements
prompted us to establish proper reaction conditions that are mild enough to keep
the aryl-iodine bonds in the products intact. Here, we report on the realization of
this ring-opening amination process that directly converts cyclic iodonium salts to
valuable atropisomeric products with very high enantiocontrol. The merits of this
transformation include (1) a very high level of enantiocontrol, (2) high atom econ-
omy, and (3) high synthetic utility. The resulting aryl iodides are not only precursors
for further diverse elaboration but also possible catalysts in hypervalent iodine
oxidation reactions.59
RESULTS AND DISCUSSION
As a result of the extreme importance of the C–N bond formation reaction in chem-
istry,60 our initial trials started with the ring-opening reaction between cyclic diary-
liodonium 1a (Figures S9–S13) and p-methylaniline with a copper salt as catalyst.
X-ray single-crystal analysis found that iodonium 1a has two atropisomeric con-
formers (Figure 1; also see Data S1). Computational calculations indicated that the
two conformers have a very low rotation barrier (Dsr Gmq = 36.1 kJ molꢀ1) and are
thus configurationally dynamic with a half-life around 1.2 3 10ꢀ7 s under ambient
conditions (Figures S2–S4). The ring-opening product 2a bearing four ortho substit-
uents exhibits a much higher rotation barrier and should be configurationally stable.
Our preliminary survey focused on identifying a class of suitable chiral ligands for
asymmetric induction. The reactions with picolinamide derivative L1, PHOX (L2),
and (R)-BINAP (L3) as ligands gave no atropselectivity, albeit virtually quantitative
yields of 2a were obtained (Scheme 2, entries 1–3). The reaction with bis(oxazoline)
1Department of Chemistry, Center for Excellence
L4 as ligand gave a complex mixture (entry 4). The Cu(OAc)2/(ligand L5) combination
in Molecular Synthesis and Hefei National
delivered 2a in only 10% yield with 37% enantiomeric excess (ee) (entry 5). Displac-
ing bis(oxazoline) ligand with tri-dentated bis(oxazolinyl)pyridine L6 boosted the
yield, and the enantioselectivity was also increased to 54% (entry 6). Phenyl-
substituted ligand L7 further improved the enantiomeric excess (entry 7). The use
of a cationic copper source Cu(OTf)2 or CuOTf$0.5PhH boosted the enantioselectiv-
ity to 85%, but the valence of the copper pre-catalysts had no influence on either
reactivity or selectivity (entries 8 and 9). A decrease in loading of the ligand L7
(Cu(OTf)2/L7 = 1:1) did not result in deterioration of the yield, whereas the
Laboratory for Physical Sciences at the
Microscale, University of Science and Technology
of China, 96 Jinzhai Road, Hefei, Anhui 230026,
P.R. China
2These authors contributed equally
3Lead Contact
*Correspondence: fuyao@ustc.edu.cn (Y.F.),
zhgu@ustc.edu.cn (Z.G.)
https://doi.org/10.1016/j.chempr.2018.01.017
2
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Please cite this article in press as: Zhao et al., Enhanced Reactivity by Torsional Strain of Cyclic Diaryliodonium in Cu-Catalyzed Enantioselective
Ring-Opening Reaction, Chem (2018), https://doi.org/10.1016/j.chempr.2018.01.017
OH
OH
A
B
C
OH
H2N
HO
O
OH
OH
O
O
O
O
Me
Atropisomerism
in diaryl ethers
Me
Cl
O
O
A
B
Cl
HO
OH
O
(S)-BINOL
C
D
O
H
N
H
N
H
NH
N
N
H
N
H
H
O
O
O
O
NH
NMe2
PCy2
HO2C
NH2
Atropisomerism
in biaryls
OH
OH
HO
vancomycin
(S)-KenPhos
D
R
R3
R1
R4
R2
Asymmetric
R3
R1
R4
R2
De Novo Synthesis
Desymmetrization
Cross-coupling
X
+
Y
R1
R2
R
Dynamic Kinetic
Resolution
R
R'
R
R
x
R1
R2
R1
R2
R1
R2
non-symetric molecule
high rotation barrier
free rotation
(low rotation barrier)
symetric molecule
E: This Work: Ring-opening Reaction of Cyclic Diaryliodonium Salts
Enantioselective
R2
R1
R2
R1
R2
R1
I
Ring-opening Reaction
TfO-
I
TfO-
I
NHR
Cu(I)/PyBox, amine
up to 99% yield, > 99% ee
high yields and excellent enantioselectivity
high atom economy
readily elaboration
Scheme 1. Strategies in Biaryl Atropisomer Synthesis
(A) Model structure of biaryl atropisomers.
(B) Structure of vancomycin.
(C) Ligands with a biaryl atropisomeric skeleton.
(D) Strategies for the synthesis of asymmetric biaryl atropisomers.
(E) This work.
enantioselectivity was significantly reduced (entry 10). Further screening of the
ligands revealed that benzyl- or 2,3-dihydro-1H-indene-derived ligands L8 and L9
improved the enantiomeric excess to 99% with almost quantitative yields (entries
11 and 12). Copper(I) complexes A1 or A2 with a composition of Cu:ligand = 1:2
Chem 4, 1–14, March 8, 2018
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Ring-Opening Reaction, Chem (2018), https://doi.org/10.1016/j.chempr.2018.01.017
Me
C2
C5
C1
H
H
C6
C7
Tf2N-
I
TfO-
I
H
Me
C8
C12
1b
1c
Structure of 1c
Me
Me
I
TfO-
1a
Structure of 1a (a pair of conformers)
1b
1c
1a
Angle
125.0
125.9 °
128.0
128.3
127.9
129.7
C5-C6-C7
C6-C7-C12
Distortion
C5-C6/C7-C12
0.3 °
31.0 °
3.6 °
0oC, 24 hr: 5%
40oC, 5 hr: 97%
40oC, 5 hr: 30%
0oC, 24 hr: 98%
high
Reactivity
low
Distortion
low
Reactivity
high
Figure 1. Structure and Reactivity Properties of Cyclic Diaryliodoniums
Reaction conditions: the reaction was catalyzed by Cu(Bn-PyBox)2PF6 (A1) in the presence of
BnNH2 and Na2CO3 in dichloromethane.
prepared independently according to the literature61 gave more consistent results
for the reactions wherein (sub)milligrams of catalyst was used. In addition, the
loading of the catalyst A1 or A2 could be decreased to 5 mol % without compro-
mising the yield or enantioselectivity of 2a (entries 13 and 14) (Figures S98, S99,
and S188–S189).
A
single crystal of 1a was obtained by slow evaporation of the solvent
(methanol/H2O = 10:1) at room temperature. The crystal structure of 1a revealed
that the distortion of C5-C6/C7-C12 was over 30ꢁ, and both (S) and (R) conformers
were found in the crystal packing (Figure 1; also see Data S1). However, the corre-
sponding structures without ortho methyl (1b)62 or with one ortho methyl group
(1c) barely have distortion (0.3ꢁ and 3.6ꢁ, respectively) (Figure 1; also see Data S2),
and all the atoms of the biaryl moiety are in approximately the same plane (Figures
S14–S18). In sharp contrast to compound 1a, there are no stereoisomers ((R) or (S)
conformers) in the crystal structures of 1b or 1c (Figure 1). Furthermore, the angles
of C5–C6–C7 and C6–C7–C12 of 1a were slightly larger than those of 1b. It was re-
ported that the five-membered cyclic diaryliodonium showed much lower reactivity
than noncyclic [Ar2I]+ for aromatic nucleophilic substitution reactions.57,63 Our
studies found that the reactivity of these cyclic diaryliodonium depended signifi-
cantly on their structural properties. Substrates with more distorted structure
exhibited higher reactivity (Figure 1). Specifically, under the optimized catalytic sys-
tem, the reaction of compound 1b and benzylamine gave 5% yield of the corre-
sponding product at 0ꢁC after 24 hr and 97% yield at 40ꢁC after 5 hr. However,
4
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Ring-Opening Reaction, Chem (2018), https://doi.org/10.1016/j.chempr.2018.01.017
NH2
Copper, Ligand
Na2CO3, CH2Cl2, 12 hr
Me
Me
I
Me
Me
Me
Me
TfO-
I
TfO-
H
N
I
+
Me
Me
TS_rs +36.1 kJ mol-1
(R)-conformer
(R)-1a
(S)-conformer
(S)-1a
2a
O
O
O
O
PPh2
PPh2
O
NH HN
N
N
PPh2
N
R
R
N
N
iPr
R = iPr, Box-Pr, L4
R = Ph, Box-Ph, L5
(R)-BINAP, L3
L1
L2
PF6
PF6
O
O
O
O
N
N
O
H
O
H
H
N
N
O
N
O
N
N
N
N
N
Bn
Bn
Bn
N
N
N
Cu
Cu
H
R
R
Bn
R = iPr, PyBox-Pr, L6
R = Ph, PyBox-Ph, L7
R = Bn, PyBox-Bn, L8
N
O
N
N
PyBox-In, L9
N
O
N
O
O
A1
A2
Entry
1
Cu source
Ligand/mol%
L1, 40 mol%
L2, 40 mol%
L3, 40 mol%
L4, 40 mol%
L5, 40 mol%
L6, 40 mol%
L7, 40 mol%
L7, 40 mol%
L7, 40 mol%
L7, 20 mol%
L8, 40 mol%
L9, 40 mol%
-
Temp./oC Yield/%
ee%
Cu(OAc)2, 20 mol%
Cu(OAc)2, 20 mol%
Cu(OAc)2, 20 mol%
Cu(OAc)2, 20 mol%
Cu(OAc)2, 20 mol%
Cu(OAc)2, 20 mol%
Cu(OAc)2, 20 mol%
Cu(OTf)2, 20 mol%
40
40
40
40
40
40
40
40
40
40
0
99
0
2
99
0
3
99
0
4
complex
10
-
5
37
54
60
85
85
26
99
99
98
98
6
99
7
99
8
99
9
CuOTf·0.5PhH, 20 mol%
Cu(OTf)2, 20 mol%
Cu(OTf)2, 20 mol%
Cu(OTf)2, 20 mol%
A1, 5 mol%
99
10
11
12
13
14
99
99
0
99
0
99
-
0
99
A2, 5 mol%
Scheme 2. Optimization of the Reaction Conditions
The enantiomeric excess (ee) was determined by chiral high-performance liquid chromatography analysis.
Chem 4, 1–14, March 8, 2018
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Ring-Opening Reaction, Chem (2018), https://doi.org/10.1016/j.chempr.2018.01.017
A1 or A2 (5 mol%)
Na2CO3, DCM, 0oC, 24 hr
Me
Me
I
Me
Me
Me
Me
TfO-
H
N
I
TfO-
H2N
R
+
I
R
Me
Me
I
Me
Me
I
Me
Me
I
Me
Me
I
Me
Me
I
H
N
H
N
H
N
H
N
H
N
N
OMe
tBu
Me
Ac
2b, 99%, >99% ee
2c, 99%, 98% ee
2a, 99%, 98% ee
(99%, 98% ee at 1.14 g, 2.50
mmol)
2d, 99%, 97% ee
2e, 96%, 98% ee
Me
Me
I
Me
Me
I
Me
Me
I
Me
Me
I
Me
Me
I
H
N
H
N
H
N
H
N
H
N
Br
Cl
2g, 69%, 99% ee (48 hr)
2j, 70% (77% conv.), >99% ee
(60 hr)ಳ
2f, 72% (75% conv.), 99% ee
2i, 72% (80% con.), 95% ee
2h, 97%, 99% ee
(48 hr)
(48 hr)
Me
Me
I
Me
Me
I
Me
Me
I
OMe
Me
F
H
N
H
N
H
N
Me
Me
I
H
N
2l, 90%, 96% ee
2m, 79% (88% con.), >99% ee (48 hr)
2k, 98%, 99% ee
(at 35 oC, 24 hr)
N
H
I
2q, 92%, dr 50:1, >99% ee‡
Me
Me
I
Me
Me
I
Me
Me
I
H
N
H
N
H
N
NH2
Me
CF3
NH2
Cl
S
O
O
2p, 55% (89% brsm), 90% ee
2o, 96%, 96% ee
2n, 95%, 98% ee (48 hr)
(-20 oC, 48 hr)
CF3
CN
Cl
Me
Me
I
Me
Me
I
Me
Me
I
Me
Me
I
H
N
H
N
H
N
H
N
Ph
Cl
2r, 99%, 95% ee (-5oC)#
2u
o
2s, 63% 90% ee (-5oC)
2t, 99% 95% ee (0oC)
, 99% 97% ee (-5 C)
(24 hr)
(72 hr)
(24 hr)
Me
Me
I
Me
Me
I
Me
Me
I
H
N
H
N
H
N
Cl
Cl
2v, 96% 90% ee (-5 oC)
2w, 86%, dr 20:1 (-5 oC)
2x, 93%, dr 1:13 (-5 oC)
Structure of (R)-2v
(36 hr)
(48 hr)
(48 hr)
6
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Scheme 3. Substrate Scope with Various Amines
Reaction conditions: cyclic diaryliodonium 1a (1.0 equiv), amine (1.2 equiv), copper catalyst (5.0 mol %) (A1 for anilines, A2 for benzylamines), and
Na2CO3 (3.0 equiv) in dichloromethane (0.050 mol Lꢀ1) at 0ꢁC or indicated otherwise. yent-A1 was used; zbenzidine (0.5 equiv) was used; #benzylamine
was used as a limiting reagent.
the reaction of 1c only produced the desired product in 30% yield after 5 hr at 40ꢁC,
possibly as a result of enhanced steric hindrance. Pleasingly, the ring-opening reac-
tion of the more torsionally strained substrate 1a proceeded uneventfully at 0ꢁC and
afforded the corresponding product in 98% yield after 24 hr.
With the optimal conditions for asymmetric ring-opening reaction in hand, we
examined the scope for the substrate (Scheme 3). First, a panel of substituted
aniline derivatives were tested (2a–2x) (Figures S98–S148 and S188–S231). Alkyl
substituents had a negligible effect on either the yield or enantioselectivity
(2a–2c, 2h). Electron-donating groups on the aniline ring diminished the enantiose-
lectivity slightly (2d and 2e). Electron-withdrawing groups significantly decreased
the reactivity of this ring-opening reaction, although almost perfect enantioselec-
tivity could still be achieved (2f, 2g, and 2m). The bulkiness of ortho substituents
on the aniline had significant effects on the reactivity (2j–2m). For instance, with
naphthalen-1-amine and 2-methylaniline as the substrates, the reaction became
sluggish and either increased reaction temperature or prolonged reaction time
was necessary to get satisfactory conversion (2l and 2j). Taking advantage of this
ortho-substituent effect, the catalyst was able to differentiate two amino groups
with different steric environments. Compounds 2n and 2o were formed as
the key products with attractive yields and enantioselectivity. In addition, trifluoro-
methanesulfonamide was also amenable to the copper-catalyzed ring-opening
reaction, and a lower reaction temperature was applied to get satisfactory enantio-
selectivity (2p). Starting from benzidine, double ring-opening product 2q was
formed with 50:1 dr and fantastic selectivity. Benzylamines displayed higher reac-
tivity than anilines, and the reactions of benzylamines were conducted at a slightly
lower reaction temperature to gain satisfactory ee values (2r–2x). The structure of
the products was confirmed by single-crystal X-ray diffraction analysis of 2v, and
the absolute configuration of the major enantiomer was determined to be R
(Data S3). The extant chirality in 1-phenylethanamine imparted negligible effects
on the yield or selectivity. With optically pure (R)- and (S)-1-phenylethanamine as
the amination reagents, compounds 2w and 2x were formed with excellent diaster-
eoselectivities regardless of the existed center chirality, underlining the high
catalyst-directed stereocontrol. Finally, to demonstrate the practicability, the cop-
per-catalyzed asymmetric ring-opening reaction was facilely performed on a gram
scale of 1a (1.14 g, 2.50 mmol) with p-methylaniline, and product 2a was obtained
in 99% yield with 98% ee (see Scheme 3, 2a).
Subsequently, a study was initiated to further explore the substrate scope regarding
the diaryliodonium salts (Scheme 4; Figures S19–S97). The reaction smoothly deliv-
ered the corresponding products with enantiomeric excesses ranging from 95% to
97% when additional methyl groups were introduced to the meta or para positions
(2y–2cc) (Figures S149–S158 and S232–S241). Pleasingly, the asymmetric ring-open-
ing reaction was applicable to the 2,20-diethyl-1,10-biphenyl-derived cyclic iodonium
salt, and the reaction proceeded uneventfully with minimal reduction in stereocon-
trol (2dd and 2ee) (Figures S159–S162 and S242–S245). For non-symmetric cyclic di-
aryliodoniums, a group adjacent to the iodine atom was introduced to accomplish
exclusive regioselectivity (2ff–2nn) (Figures S163–S181 and S246–S263). Further-
more, the reaction was not limited to 1,10-biphenyl substrates, and compound 2jj
Chem 4, 1–14, March 8, 2018
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R'
R
R'
R
R'
A1 or A2 (5 mol %)
Na2CO3, DCM, 0oC, 24 hr
R2
R1
R2
R1
R2
R1
I
TfO-
I
TfO-
I
+
H2N
R
H
N
R
R
Me
Me
Me
Me
Me
Me
Me
I
Me
Me
I
Cl
Me
Me
I
Me
Me
I
Me
Me
I
H
N
H
N
H
N
H
N
H
N
Me
Me
Cl
Me
OMe
Me
Me
OMe
Me
Me
Me
Me
2y, 98%, 97% ee
2z, 97%, 95% ee
2aa, 98%, 96% ee
2bb, 98%, 97% ee
2cc, 98%, 98% ee
Me
Me
Me
Me
Me
Me
I
I
Me
Me
Me
Me
I
H
I
H
N
H
N
N
Me
H
N
Me
OMe
OMe
Me
Me
2dd, 98%, 94% ee
2ee, 97%, 97% ee
2ff, 99%, 95% ee
2gg, 98%, 97% ee
Me
Me
Me
Me
X
Me
Me
Me
I
Me
Me
I
Me
I
H
N
H
N
Me
I
H
N
Me
Me
H
N
Me
OMe
OMe
Me
Me
2kk, X = F, 86%, 88% ee (48 hr)
2hh, 98%, 94% ee
2ii, 97%, 97% ee
2jj, 97%, 93% ee
2ll, X = Cl, 85%, 94% ee (25oC, 48 hr)
Cl
2mm, X = OMe, 84%, 83% ee (40oC)
Me
Me
Me
Me
Me
Me
I
TsO
TsO
I
I
I
H
N
H
N
H
H
N
H
Me
Me
N
Me
Me
Me
Me
Me
Me
2pp, 72%, >99% ee (25oC, 48 hr)
Me
2qq, 82%, 88% ee (40oC, 36 hr)
2oo, 60%, >99% ee (40oC, 48 hr)
2nn, 88%, 99% ee (48 hr)
Scheme 4. Substrate Scope with Cyclic Diaryliodoniums
Reaction conditions: cyclic diaryliodonium 1a (1.0 equiv), amine (1.2 equiv), copper catalyst (5.0 mol %) (A1 for anilines and A2 for benzylamines), and
Na2CO3 (3.0 equiv) in dichloromethane (0.05 mol Lꢀ1) at 0ꢁC or indicated otherwise.
bearing a naphthyl-phenyl skeleton was isolated in 97% yield with excellent stereo-
induction. Incorporation of a fluorine or chlorine atom, or a methoxyl group adjacent
to the iodine atom resulted in a decrease of enantioselectivity, and the correspond-
ing products 2kk–2mm were delivered in 84%–86% yields and synthetically valuable
enantioselectivity. High enantiocontrol could still be achieved when the substrate
had an electron-withdrawing group at the meta position of the iodine atom
(compare 2nn with 2gg). Notwithstanding the sluggish reaction rate of the 2,2-bi-
phenol derivative, the high ee value of 2oo still showcased the high potential
of this reaction to apply in ortho oxygenated biaryls (Figures S182–S183 and
8
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A
B
C
Figure 2. Mechanistic Studies
(A) Enantiomeric excess of 2a versus the ratio of Ph-PyBox/Cu(OTf)2.
(B) Correlation between the enantiomeric excesses of 2a and the ee values of Bn-PyBox.
(C) Plot of the initial rate versus the concentration of A1.
S264–S265). The reaction of diaryliodonium with the 1,10-binaphthalene skeleton
also proceeded uneventfully to afford high enantioselectivity (2pp) (Figures S184–
S185 and S266–S267). However, introducing an iso-propyl group at the 6-position
resulted in a decrease in enantioselectivity (88% ee) of the corresponding aminoio-
dide (2qq) (Figures S186–S187 and S268–S269).
To get preliminary mechanistic insights of this copper-catalyzed ring-opening reac-
tion, we examined the effect of the ratio of L7/Cu(OTf)2 on the enantioselectivity.
The enantiomeric excess gradually increased when the ratio of L7/Cu(OTf)2 was
increased before reaching the highest value when L7/Cu(OTf)2 was 2:1 (Figure 2A).
Further increasing the loading of ligand L7 did not improve the ee values. Analysis of
the ee values of the product 2a produced by Pybox-Bn ligand L8 with various de-
grees of reduced enantiomeric excess revealed a linear correlation between the
ee values of the product and the ligand (Figure 2B), suggesting that monomeric
CuL* (L* = Pybox-Bn) might be the active species. Catalysts containing one copper
bearing two bis(oxazolinyl)pyridine ligands (i.e., complex A1), dimeric forms, or
higher-order aggregates were not supposed to be active species. These results
corroborate the requirement of excess ligand for high enantiocontrol, which allows
effective suppression of the dissociation of bis(oxazolinyl)pyridine ligand from the
metal center.
Although a precise understanding of the catalytic rationale is beyond reach at this
point, a plausible reaction pathway was proposed on the basis of the above
studies (Scheme 5). Disproportionation of copper species occurred in a solution
of pre-catalyst A1 and amine in dichloromethane. The catalyst A1 is an inactive
species, which would quickly dissociate to give A3. Species A3 was postulated
as the real catalytically active species in this reaction. On the basis of the results
presented in Figure 2B, the dissociation of A1 to A3 was much faster than the
rate of the A3-catalyzed ring-opening reaction. The fast dissociation of A1 to A3
was further confirmed by the first-order dependence of the reaction rate on the
concentration of catalyst A1, which was measured by monitoring the initial reaction
rates at various catalyst loadings (Figure 2C) (Tables S1–S4; Figure S1). In addition,
in the presence of amines, the copper complex A3 undergoes ligand displacement
to form an amino-copper complex, which, because of the lack of chiral ligand, cat-
alyzes the reaction to give products with no stereoinduction. The independent re-
actions of Cu(OTf)2 or CuOTf$0.5PhH in the absence of bis(oxazolinyl)pyridine
Chem 4, 1–14, March 8, 2018
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+
O
O
O
O
N
+
N
N
N
N
Bn
Bn
Bn
Bn
amines
- PyBox
+ PyBox
Cu/amine
complex
active species
background reaction
no enantioselectivity
CuI
O
O
-
-
PF6
PF6
N
CuI
N
N
N
Bn
Bn
2a
1a
active species
A3
reductive
elimination
A1
replusion
inactive species
2+
Ph
2+
Ph
+
Bn
O
O
N
N
O
N
O
N
N
N
I
N
CuI
CuI
N
I
I
CuIII
NH
Ph
N
O
O
Ph
Ph
Bn
replusion
less sterically hindered
A7
sterically hindered
A4
A4'
NaHCO3
Na2CO3
2+
2+
Bn
Bn
O
O
ent-2a
minor enantiomer
N
N
I
N
N
I
CuIII
NH2
Ph
N
CuIII
N
O
O
Bn
Bn
A6
PhNH2
A5
Scheme 5. The Rationale of the Copper-Catalyzed Ring-Opening Reaction
ligand proceeded faster than the reactions with ligands. The amount of
amino-copper complex may decrease significantly via coordination-dissociation
equilibrium upon increasing the loading of bis(oxazolinyl)pyridine. The interaction
between A3 and cyclic iodonium would give A4 and A40, where the two con-
formers of iodonium moieties should rapidly interconvert. However, A40 is steri-
cally disfavored because of steric repulsion between the benzyl group of
bis(oxazolinyl)pyridine and the methyl in cyclic diaryliodonium, which would
quickly invert to A4 and undergo a ring-opening reaction to give A5 to establish
axial chirality. Subsequently, the coordination of aniline to the Cu(III) center would
give intermediate A6. Deprotonation of the amine moiety of A6 followed by reduc-
tive elimination delivers the major enantiomer (R)-2a and regenerates the catalyst
A3 to complete the catalytic cycle.
Computational calculations on the ring-opening step with A3 as the catalyst were
performed (Figures S4–S8). It was found that (1) the two diastereomers of the ring-
opening copper complexes have significant energy differences (30.4 kJ/mol for
1b-derived complexes and 18.8 kJ/mol for 1a-derived complexes) (Scheme 6A),
and (2) the oxidation addition is a fast step. The reaction of Cu(I)/PyBox with 1a pro-
ceeds much faster than the reaction of Cu(I)/PyBox with 1b (3.7 kJ/mol versus
19.3 kJ/mol) (Schemes 6B and 6C), but oxidative addition could not be the rate-
determining step. The computational activation energies are consistent with the
results reported by Canty and Sanford and their co-workers, who found that the
oxidative addition of Cu(I) with [(Mes)PhI]+ had a very low activation energy.64,65
10
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Chem 4, 1–14, March 8, 2018
11

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Ring-Opening Reaction, Chem (2018), https://doi.org/10.1016/j.chempr.2018.01.017
Scheme 6. Computational Results
(A) Energies for copper complexes.
(B) Energy changes of the oxidative addition step with 1b.
(C) Energy changes of the oxidative addition step with 1a.
Conclusion
A catalytic enantioselective synthesis of atropisomeric 20-iodo-[1,10-biphenyl]-2-
amines by a highly efficient ring-opening amination reaction of cyclic diaryliodo-
niums was developed. The relatively low reactivity of cyclic diaryliodoniums was
overcome by increasing the distortion of the cyclic substrates. In this reaction, the
chiral Cu-bis(oxazolinyl)pyridine complex likely discriminated the two conformers
of cyclic diaryliodonium salts to give products with very high enantiomeric excess.
A linear correlation between ee values of 2a and the ee values of Pybox-Bn was
observed, indicating that monomeric Cu(Pybox-Bn)+ was more likely to be the actual
catalyst in this reaction. The protocol offers a general method for the construction of
axially chiral biaryliodides under mild conditions, which are expected to be useful
precursors for further elaboration to structurally diverse biaryl atropisomers.
EXPERIMENTAL PROCEDURES
Full experimental procedures are provided in the Supplemental Information.
DATA AND SOFTWARE AVAILABILITY
The crystallography data have been deposited at the Cambridge Crystallographic
Data Center (CCDC) under accession numbers CCDC: 1565987 (1a), CCDC:
1565988 (1c), and CCDC: 1565989 (2v) and can be obtained free of charge from
www.ccdc.cam.ac.uk/getstructures.
SUPPLEMENTAL INFORMATION
Supplemental Information includes Supplemental Experimental Procedures, 269 fig-
ures, 4 tables, and 3 data files and can be found with this article online at https://doi.
org/10.1016/j.chempr.2018.01.017.
ACKNOWLEDGMENTS
We are grateful for financial supported from the National Natural Science Founda-
tion of China (21622206 and 21472179), the 973 project from the Chinese Ministry
of Science and Technology (2015CB856600), and the Strategic Priority Research
Program of the Chinese Academy of Sciences (XDB20000000). We thank Professor
Zakarian (University of California, Santa Barbara) for language editing our
manuscript.
AUTHOR CONTRIBUTIONS
K.Z. initiated this project. K.Z., L.D., and S.X. performed the experiments and
analyzed data for all compounds. Z.G. designed and directed the project. Z.G. wrote
the manuscript. J.J. and Y.F. performed the computational calculation.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: September 6, 2017
Revised: November 27, 2017
Accepted: January 25, 2018
Published: February 22, 2018
12
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