Cu-Catalyzed Site-Selective and Enantioselective Ring Opening of Cyclic Diaryliodoniums with 1,2,3-Triazoles

Article abstract of DOI:10.1021/acs.orglett.0c02256

A Cu-catalyzed enantioselective ring-opening/triazolylation reaction is reported. The reaction shows excellent chemoselectivity regarding the three different nitrogen atoms of 1,2,3-triazoles. The optically enriched axially chiral aryl iodides thus obtained were readily derivatized to different types of chiral phosphine ligands and their corresponding copper or palladium complexes.

Full text of DOI:10.1021/acs.orglett.0c02256

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Letter
Cu-Catalyzed Site-Selective and Enantioselective Ring Opening of
Cyclic Diaryliodoniums with 1,2,3-Triazoles
Zengyin Chao, Mingming Ma,* and Zhenhua Gu*
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ABSTRACT: A Cu-catalyzed enantioselective ring-opening/triazo-
lylation reaction is reported. The reaction shows excellent chemo-
selectivity regarding the three different nitrogen atoms of 1,2,3-
triazoles. The optically enriched axially chiral aryl iodides thus
obtained were readily derivatized to different types of chiral
phosphine ligands and their corresponding copper or palladium
complexes.
xial biaryls are a class of unique atropisomers whose
chirality arises from restricted rotation of single bonds
was reported, where only one example of enantioselective
carbonylation with 38% yield and 28% ee was shown (Scheme
2, A).14 With Cu(I)/(R,R)-Bn-PyBox as the catalyst, we
realized a high enantioselectivity amination/ring-opening
reaction of cyclic diaryliodoniums (Scheme 2, B). Sub-
sequently, by taking advantage of the remarkably high
reactivity of diaryliodoniums, asymmetric ring-opening reac-
tions with various nucleophiles were developed, wherein
A
that link the two aryl units. The axially chiral biaryls widely
occur in bioactive compounds1 and ligands or catalysts.2 It is
challenging to construct these sterically hindered molecules.
The past two decades have witnessed great advances in
catalytic asymmetric synthesis of biaryl atropisomers.3−8
A
notable method is the “lactone asymmetric ring-opening
strategy”, which has been extensively studied by Bringmann
and co-workers (Scheme 1). It provides a convenient approach
Scheme 2. Atropisomer Synthesis from Cyclic Iodoniums
Scheme 1. Atropisomer Synthesis via Ring Opening
for the synthesis of bioactive natural products.9,10 In 2018, the
catalytic asymmetric hydrogenation of “Bringmann Lactone”
was realized via iridium catalysis.9c Alternatively, biaryl N,O-
acetal has a similar role in lactone functionality. Through the
dynamic equilibrium of N,O-acetal, atroposelective amination
was realized via the catalysis of a chiral phosphoric acid or
iridium complex.11 Recently, the ring-opening reactions have
been extended to the breaking of carbon−carbon bonds via
palladium-catalyzed enantioselective β-carbon elimination.12
In 2002, Hayashi and co-workers realized an asymmetric
ring-opening reaction of dinaphtho[2,1-b:1′,2′-d]thiophene via
nickel-catalyzed Kumada-type cross-coupling (Scheme 1).13
Later, a ring-opening/Heck reaction of cyclic diaryliodoniums
Received: July 8, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02256
© XXXX American Chemical Society
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A

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Letter
a
generally excellent enantioselectivities were obtained (Scheme
2, C−D).15,16
Table 1. Reaction Conditions Optimization
1,2,3-Triazoles have wide applications in material science,
synthetic chemistry, and chemical biology,17 i.e. yellow-light
emitting compound I,18 triazole-based ligands (i.e., II and
III),19 and carbene precursors (IV) (Figure 1). 1,2,3-Triazoles
Figure 1. Triazole-based material, ligands, and carbene precursor
are good σ-donor and π-receptor ligands, and their gold
complexes were extensively studied by Shi and co-workers.20
We became interested in the development of a Cu-catalyzed
enantioselective ring-opening reaction of cyclic diaryliodo-
niums with 1,2,3-triazoles. Besides enantioselectivity control, a
foreseeable challenge is the issue of chemoselectivity caused by
three different nitrogen atoms in the substituted 1,2,3-triazole
ring (Scheme 2). It was reported that simple 1,2,3-triazole has
two tautomers of 1-NH and 2-NH with a ratio of 0.34:0.66 in
CDCl3.21
entry
ligand
temp/°C
3a/%
3a:4a
ee/% of 3a
1
b
L1
L2
L3
L4
L5
L1
L1
L6
L7
L1
L1
L1
40
40
40
40
40
0
0
−20
−20
−20
−20
−20
79
53
57
74
77
81
82
77
90
79
91
93
9.6:1
1.4:1
3.7:1
3.9:1
9.4:1
8.7:1
12.9:1
>30:1
8.1:1
14.8:1
>30:1
30:1
93
−
0
2
3
4
5
6
7
8
9
19
82
95
97
90
71
93
96
94
c
c
c
cd
,
In the presence of diaryliodonium salt 1a, 4-phenyl-1H-
1,2,3-triazole 2a, and Cu(MeCN)4PF6, a series of bis-
(oxazoline) ligands were screened (Table 1).22 The bis-
(oxazoline) L1 smoothly induced this ring-opening reaction to
give 3a in 79% yield and promising stereoselectivity at 40 °C,
along with a small amount of regioisomer 4a.23,24 When 1,10-
phenanthroline L2 was used as the ligand, the reaction also
showed good reactivity, but poor regioselectivity (3a/4a) was
observed (entry 2). The PyBox ligand L3 did not display any
stereoinduction, and the regioselectivity decreased to 3.7:1
(entry 3). The modification of bis(oxazoline) ligands (L4−L7)
offered no improvement in stereoselectivity (entries 4−5 and
8−9). Decreasing the reaction temperature to 0 °C improved
the ee value of 3a to 95% without affecting the isolated yield
(entry 6). Use of 1,2-dichloroethane as solvent slightly
improved the efficacy and stereoselection (entry 7). Decreasing
the loading of copper catalyst Cu(MeCN)4PF6 to 5 mol % had
a slightly deleterious effect on the yield and ee value (entry
10). However, this disadvantage was overcome by the use of
10
11
12
cde
,
,
e f
,
a
Unless otherwise stated, the reaction was conducted under a
nitrogen atmosphere with 1a (0.10 mmol), 2a (0.12 mmol, 1.2 equiv),
Cu(MeCN)4PF6 (0.01 mmol, 10 mol %), ligand (0.02 mmol, 20 mol
%), and Na2CO3 (0.30 mmol, 3.0 equiv) in CH2Cl2 (1.0 mL, 0.10
mol/L) for 5 h. The reaction was performed on 1.0 mmol scale of
1a, with PF6 as the counteranion of the iodonium. 1,2-Dichloro-
ethane was used. 5.0 mol % of Cu(MeCN)4PF6 was used. The
counteranion is PF6 . 1,2-Dichloroethane (0.04 mol/L) was used.
The reaction was performed on 2.90 mmol scale (1.31 g of 1a).
b
c
−
d
e
−
f
Scheme 3. Anion Effect
−
PF6 as the counteranion of the iodonium salt under more
diluted conditions (entry 11). To highlight the practicability of
this reaction, a reaction at 2.90 mmol scale of 1a (1.31 g)
under the optimal conditions was performed, which proceeded
uneventfully to give 3a in 93% yield and 94% ee (entry 12).
Another notable aspect is the strong anion effect. By
replacing PF6− with BF4 , the regioselectivity was reversed and
−
compound 4a was formed as the major product. Furthermore,
both the yields and enantiomeric excesses dropped dramati-
cally (Scheme 3). Poor regioselectivity was also observed when
bromide was employed.
With the optimal conditions in hand, the substrate scope of
this asymmetric ring-opening reaction was explored (Scheme
4). In most cases excellent enantioselectivity was achieved,
except the reaction of simple 1H-1,2,3-triazole, which gave 3v
in 48% yield and 74% ee. The reactions with 4-(4′-
ethylphenyl)- or 4-(4′-methoxyphenyl)-1H-1,2,3-triazole fac-
ilely gave the products 3b and 3c in excellent enantioselec-
tivity. The reaction of 4-formylphenyl 1H-1,2,3-triazole
delivered product 3d in a slightly lower ee value, while an
ester-substituted analogue was obtained with high stereo-
selectivity (3e). The aryl-halogen bonds were also well-
accommodated at either the para- or ortho- position (3f−3h,
and 3l−3n). Furthermore, the ortho-substituents, such as
methyl, methoxy, or isoproxy groups, have marginal effect on
either reactivity or selectivity (3i−3j). The yield was reduced
for sterically bulky triazoles, such as 4-(naphthalen-1-yl)- or 4-
(naphthalen-2-yl)-1H-1,2,3-triazole. Triazoles bearing hetero-
cyclic units, such as 2- or 3-furyl and 2- or 3-thiophenyl,
underwent this ring-opening reaction smoothly with high
stereoselectivity (3q−3t). Particularly, the reaction with 4-(n-
B
https://dx.doi.org/10.1021/acs.orglett.0c02256
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a
Finally, other N-heterocyclic compounds as coupling
partners were tested for this asymmetric N-arylation reaction.
Imidazole and benzo[d]imidazole showed moderate reactivity.
Furthermore, very low stereoinduction was observed in these
reactions (Scheme 5). The corresponding reaction with
pyrazole as the nucleophile gave a 71% yield of 5c with
excellent enantioselectivity.
Scheme 4. Substrate Scope
Scheme 5. Ring-Opening Reactions with other N-
Heterocycles
To demonstrate the utility of these axially chiral triazole-
containing compounds, chiral phosphine ligands were
prepared. In Balakrishna’s work a temperature-dependent
deprotonation process between triazole and aryllithium was
observed. Treatment of 1-(2-bromophenyl)-4-phenyl-1H-
1,2,3-triazole with n-BuLi at −78 °C gave phenyllithium
intermediate V, which kinetically delivered phosphine VI by
the addition of Ph2PCl at −78 °C (Scheme 6).19b
Scheme 6. Temperature-Controlled Deprotonation between
Triazoles and Aryllithiums
a
The reaction was conducted with 1 (0.20 mmol, 1.0 equiv), 2 (0.24
mmol, 1.2 equiv), Cu(MeCN)4PF6 (0.01 mmol, 5 mol %), L1 (0.02
mmol, 10 mol %), and Na2CO3 (0.60 mmol, 3.0 equiv) in (CH2Cl)2
b
(5.0 mL, 0.040 mol/L) for 5 h; rr is the ratio of 3:4. The reactions
were performed by using 10 mol % of Cu(MeCN)4PF6 and 20 mol %
of L1 at −30 °C for 7 h.
butyl)-1H-1,2,3-triazole as the coupling partner proceeded
efficiently to furnish 3u in 96% ee.
Cyclic diaryliodoniums bearing p-methyl or m-methyl were
synthesized, which displayed comparable reactivity and
enantioselectivity as the model compound (3w−3y and 3F).
In cases where regioisomers were possible for the unsym-
metrical diaryliodoniums, the C−I bond cleavage occurred
solely at the less hindered site. When the methyl group was
introduced to the adjacent position of C−I bond, the reaction
yielded 3z−3A with high ee values. However, the chloro atom
adjacent to the C−I bond dramatically decreased the
enantioselectivity. For example, a moderate ee value (79%)
of compound 3B was detected. The binaphthyl iodonium
underwent ring opening smoothly to deliver 3D in 96% ee.
Furthermore, the dichloro substituted iodonium underwent
ring opening/triazolylation uneventfully to give the product 3E
in 78% yield and 95% ee, though the regioselectivity decreased
to 7:1.
Alternatively, upon warming to room temperature for 5 h,
the phenyllithium intermediate V undergoes deprotonation to
VII, which, upon treatment with Ph2PCl, gave thermodynamic
product VIII. In our case, this deprotonation process was
controlled by steric effects. Treatment of 3a with t-BuLi at −78
°C, followed by the addition of CuI and then Cy2PCl at the
same temperature, gave an oxygen- and moisture-stable
copper−phosphine dimer 6a, which could be purified by
column chromatography on silica gel (Scheme 7).25 Treatment
of the copper complex with aqueous NH4OH gave free
phosphine 7a in 84% yield. Furthermore, product 3k that bears
an ortho isopropyl group can be similarly converted to produce
phosphine 8a, whose structure was confirmed by its palladium
complex 9a by single crystal X-ray analysis.26 The crystal
structure of 9a clearly shows 8a as a P,N-bidentate ligand, and
the triazole moiety works as one of the coordinative arms.27
C
https://dx.doi.org/10.1021/acs.orglett.0c02256
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Letter
University of Science and Technology of China, Hefei, Anhui
230026, P. R. China; orcid.org/0000-0002-7967-8927;
Email: mma@ustc.edu.cn
Scheme 7. Synthetic Applications
Zhenhua Gu − Hefei National Laboratory for Physical Sciences
at the Microscale, and Department of Chemistry, University of
Science and Technology of China, Hefei, Anhui 230026, P. R.
China; Center for Excellence in Molecular Synthesis of CAS,
Hefei, Anhui 230026, P. R. China; orcid.org/0000-0001-
8168-2012; Email: zhgu@ustc.edu.cn
Author
Zengyin Chao − Hefei National Laboratory for Physical
Sciences at the Microscale, and Department of Chemistry,
University of Science and Technology of China, Hefei, Anhui
230026, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02256
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by National Natural
Science Foundation of China (21871241, 21722/406),
Strategic Priority Research Program of the Chinese Academy
of Sciences (XDB20000000), and the Fundamental Research
Funds for the Central Universities (WK2060190086,
WK2060190098, WK2060190102).
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ASSOCIATED CONTENT
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