Cu-Catalyzed Enantioselective Ring Opening of Cyclic Diaryliodoniums toward the Synthesis of Chiral Diarylmethanes

Article abstract of DOI:10.1021/jacs.8b05743

A Cu-catalyzed enantioselective desymmetrizing ring-opening reaction of six-membered cyclic diaryliodonium salts with carboxylic acids or thioacids is reported for the facile access to chiral diarylmethanes. A Cu/[cyclopropyl bis(oxazoline)] catalyst well

Full text of DOI:10.1021/jacs.8b05743

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Communication
Cu-Catalyzed Enantioselective Ring-Opening of Cyclic
Diaryliodoniums towards the Synthesis of Chiral Diarylmethanes
Bin Li, Zengyin Chao, Chunyu Li, and Zhenhua Gu
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 17 Jul 2018
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Cu-Catalyzed Enantioselective Ring-Opening of Cyclic Diaryliodoni-
ums towards the Synthesis of Chiral Diarylmethanes
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Bin Li, Zengyin Chao, Chunyu Li and Zhenhua Gu*
Department of Chemistry, Center for Excellence in Molecular Synthesis, and Hefei National Laboratory for Physical
Sciences at the Microscale, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026,
P.R. China
Supporting Information Placeholder
low yield (38%) and enantioselectivity (28% ee) were ob-
ABSTRACT: A Cu-catalyzed enantioselective desymmetriz-
tained after careful optimization in this report (Scheme 1a).
Recently, we reported a Cu/bis(oxazolinyl)pyridine-catalyzed
enantioselective ring-opening reaction of cyclic diaryliodoni-
um salts with amines to give ortho tetra-substituted biaryl
atropisomers with very high enantiomeric excesses (Scheme
1b).6-7
ing ring-opening reaction of six-membered cyclic diarylio-
donium salts with carboxylic acids or thioacids is reported
for the facile access to chiral diarylmethanes.
A
Cu/[cyclopropyl bis(oxazoline)] catalyst well discriminates
two C-I bonds of prochiral cyclic diaryliodonium salts. A
stereochemical model was proposed to rationalize the stere-
ochemical outcome on the basis of the crystal structure of
cyclic diaryliodonium salt.
Scheme 1. Asymmetric Ring-Opening of Cyclic Dia-
ryliodoniuma
a) Atropisomer Synthesis via Pd-Catalyzed Ring-Opening Reaction
Pd(OAc)2 (3 mol%)
(R)-BINAP (6 mol%)
Et3N, DMF, 60 oC, 3 h
-
)
4
Diaryliodonium salts, also known as diaryl-λ3-iodanes, rep-
resent an important class of compounds that are widely used
in organic synthesis and molecule assembly chemistry.1-2 The
high electron-deficient nature of diaryliodonium salts, in
combination with the excellent leaving propensity of Ar-I
renders these compounds powerful arylation reagents in
synthetic organic chemistry. Generally, diaryliodonium salts
demonstrate higher reactivity profiles than the correspond-
ing aryl iodides in transition metal-catalyzed arylation reac-
tion. Many elegant transformations of diaryliodonium salts
have been developed, including some elegant enantioselec-
tive arylations reported by Gaunt and others.3 However, the-
se reactions typically involve acyclic diaryliodonium salts as
arylation reagents, which would produce one equivalent of
aryl iodide as the byproduct, reducing their atom-economy.
Examples where the aryl iodides “byproduct” could be used
in situ as the second arylation reagents are very limited.4a
However, this drawback has been avoided with the use of
cyclic diaryliodoniums, which have been successfully applied
in the synthesis of a serial of functionalized biaryls.4b-d
CO2Me
B(ArF
I
+
CO
+
MeOH
I
38%, 28% ee
b) Atropisomer Synthesis via Cu-Catalyzed Ring-Opening Reaction
R2
R1
R2
R1
R2
R1
I
Cu(CH3CN)4PF6, PyBox
NH2
TfO-
I
TfO-
I
NHR
R
up to 99% yield, > 99% ee
c) THIS WORK
Center Chiral Molecular Synthesis via Asymmetric Ring-Opening Reaction
Prochiral
Center
R
R
transition metal
chiral liagnd
H
Nu
R1
+
R1
Nu
H
R1
I
I
TfO-
R1
Catalytic asymmetric synthesis of chiral diarylmethane,
important motifs found in many pharmaceuticals or biologi-
cally active compounds,8 has attracted significant attentions.
Thus, a number of useful protocols have been developed for
construction of these molecules, including asymmetric hy-
drogenation,9 direct benzylic C-H arylation,10 aryl-benzyl
cross-coupling,11 Barbier-type addition and conjugate addi-
tion.12 Recently, catalytic asymmetric C-H functionalization
of prochiral diarylmethane derivatives has emerged as a
highly promising strategy. In 2008, Yu and co-workers de-
scribed a pyridine-directed Pd(II)/(chiral amino acids)-
catalyzed alkylation for the synthesis of chiral pyridin-2-yl
diarylmethanes.13 Subsequently, this strategy was applied in
synthesis of other functionalized chiral diarylmethanes with
carboxylic acid and amides as the direction groups.14-15 De-
spite these remarkable advances, the development of new
Cyclic diaryliodonium salts are tricyclic derivatives with an
iodonium center, whereby two aryl rings bonding to the io-
dine atom are bridged. The cyclic diaryliodonium salts exhib-
it compromised reactivity compared to their acyclic counter-
parts;1c however, the released aryl iodide moieties still remain
within the products and can be used for further elaboration.
Until Hayashi and co-workers described
a palladium-
catalyzed carboxylation reaction of dinaphtho[2,1-b:1',2'-
d]iodol-7-ium in 2004, there had been no study of asymmet-
ric arylation with cyclic diaryliodonium salts.5 However, only
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Journal of the American Chemical Society
Page 2 of 6
methods to access highly functionalized chiral diarylmethane
is still desirable, yet challenging. We reasoned that asymmet-
ric ring-opening of the six-membered prochiral cyclic dia-
ryliodonium salts would give highly functionalized diarylme-
thane analogous. The products bear one aryl ring attached to
the nucleophiles and the other containing a synthetically
versatile C(sp2)-I bond (Scheme 1c).
9
Cu(OTf)2/L8
CuTC/L8
83
85
79
85
89
93
91
94
94
93
93
93
93
92
14:1
10:1
7:1
1
2
3
4
5
6
7
8
10
11
12
13b
14b,c
15
Cu(OAc)2/L8
CuI/L8
13:1
11:1
11:1
13:1
Cu(OTf)2/L8
Cu(OTf)2/L8
Cu(OTf)2/L9
We started our studies with six-membered cyclic diarylio-
donium salt 1a and potassium thioacetate 2a. Initially,
Cu(CH3CN)4PF6 was chosen as the catalyst and various of
oxazoline type ligands were screened. The phenyl substituted
bisoxazoline L1 gave the expected product 3a in 28% ee,
along with the formation small amount of O-arylation 4a
(3a:4a = 17:1) (Table 1, entry 1). Replacing the phenyl group
with tert-butyl or benzyl groups did not improve the stere-
oinduction, albeit the O-arylation reaction was suppressed
(entries 2-3). Surprisingly, bis(oxazolinyl)pyridine ligand L4
effected no stereoinduction (entry 4). Further optimization
focused on the effects of some spirobis(oxazoline) ligands L5-
L7 (entries 5-7). The enantioselectivities jumped from 3% to
51% when the ring size was reduced from cyclohexane to
cyclopentane structure, though the regioisomeric ratio de-
creased to 10:1. The enantioselectivity was improved to 86%
with cyclopropane derivative L7 as the ligand, whose ana-
logues L8 and L9 afforded product 4a in 92-93% ee (entries 8
and 15). The dramatic increment of enantioselectivity from
dimethyl to cyclopropyl based bis(oxazoline) may attribute
to the increased bite angle of two oxazoline moieties.16 The
sources of copper salts were screened and found to have
marginal effect on the enantioselectivity (entries 9-12). Fur-
ther tuning the molar ratio of 1a:2a and the concentration of
the reaction improved the yield of this asymmetric ring-
opening reaction (entries 13-14). Thus, we established the
optimal catalyst system: Cu(OTf)2/L8 with 1.2 equiv of 2a in
dichloroethane with the concentration of 1a being 0.10 mol/L.
9
10
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13
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60
a
Unless stated otherwise, the reaction was conducted with 1a (0.10
mmol), 2a (0.10 mmol), Cu salt (5 mol%), ligand (6 mol%) in dichloro-
ethane (DCE) (2.0 mL) at 60 C for 10 h. 1.2 equiv of 2a was used. 1a
(0.20 mmol), 2a (0.20 mmol) and 2.0 mL of DCE were used.
o
b
c
Scheme 2. Substrate Scope with Thioatesa
R
O
R
I
Cu(OTf)2 (5.0 mol%)
L8 (5.0 mol%)
O
H
S
R'
R1
+
R1
DCE, 60 oC, 10 h
R1
R'
SK
I
TfO-
R1
O
1
2
3
O
O
CO2Et
CO2Et
CO2Et
PhS
H
H
S
H
S
Cy
S
Ph(CH2)2
I
I
I
3b, 78%, 95% ee, rr >20:1
3c, 75%, 97% ee, rr >20:1
3d, 97%, 97% ee, rr >20:1
O
O
CO2Et
CO2Et
O
CO2R
H
H
Me
S
Cy
S
H
Me
S
Me
OMe
I
I
I
Me
MeO
3e, R = Me, 94%, 93% ee, rr 14:1
3f, R = iPr, 78%, 91% ee, rr 10:1
3g, 99%, 93% ee, rr >20:1
3h, 93%, 94% ee, rr >20:1
O
O
O
CO2Et
CO2Et
CO2Et
H
H
H
R
S
Me
S
Me
S
Br
F
Cl
I
Table 1. Optimization of Reaction Conditionsa
I
I
Br
F
Cl
3k, R = Me, 93%, 90% ee, rr 9:1
3l, R = Cy, 93%, 90% ee, rr >20:1
3i, 98%, 91% ee, rr 15:1
3j, 91%, 93% ee, rr 10:1
O
CO2Et
MeO
H
N
Me
S
R
Me
O
O
R
H
S
Me
Me
I
Me
I
3m, R = H, 99%, 96% ee, rr 8:1
3n, R = Me, 96%, 94% ee, rr >20:1
(50 oC, 15 h)
3o, 99%, 97% ee, rr >20:1
Structure of (S)-3o
MeO
N
MeO
N
Ph
Me
X
O
O
N
Me
O
O
Me
O
O
H
S
Me
X
H
H
S
S
Me
I
X
I
I
entry
Cu/L
Yield
61
ee/%
28
7
3a:4a
17:1
3p, X = OMe, 92%, 91% ee, rr >20:1 3r, X = H, 99%, 94% ee, rr >20:1
3q, X = F, 91%, 97% ee, rr 18:1 3s, X = Me, 99%, 95% ee, rr >20:1
3t, 99%, 97% ee, rr >20:1
a Unless stated otherwise, the reaction was conducted with 1 (0.20 mmol),
2 (0.24 mmol), Cu(OTf)2 (5.0 mol%), L8 (5.0 mol%) in dichloroethane
(2.0 mL) at 60 oC for 10 h. rr = regioisomeric ratio.
1
2
3
4
5
6
7
8
Cu(MeCN)4PF6/L1
Cu(MeCN)4PF6/L2
Cu(MeCN)4PF6/L3
Cu(MeCN)4PF6/L4
Cu(MeCN)4PF6/L5
Cu(MeCN)4PF6/L6
Cu(MeCN)4PF6/L7
Cu(MeCN)4PF6/L8
70
>20:1
>20:1
>20:1
15:1
With the optimal conditions in hand, we examined the
scope of this enantioselective ring-opening reaction (Scheme
2). Substituted potassium thioacetates, such as 3-
phenylpropanoic thioacid, 2-(phenylthio)acetic thioacid,
cyclohexanecarboxylic thioacid, improved the enantioselec-
tivity to 95-97% (3b-3d). Steric properties of the carboxylic
ester did not affect the stereoinduction (3e and 3f); Introduc-
ing methyl or methoxyl groups to the para position of the C-I
bond has marginally affect the enantioselectivity (3g and 3h).
55
0
87
0
47
3
45
51
86
93
10:1
88
11:1
81
14:1
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To our delight, the C-F, C-Cl and C-Br bonds are also com-
dimethylphenyl group of bisoxazoline L8 and the alkyl chain
{CH2CO2Et]} would be generated in stereochemical model IV
than that in III. Thus, breaking of the left C(sp2)-I bond in I
is favored to deliver the product with S-configuration.
1
2
3
4
5
6
7
8
patible, with a very slight decrease in enantioselectivity (3i-
3l). meta-Substituent to the C-I bond had slightly negative
impact on the enantioselectivity; for these substrates the
reactions were performed at a lower temperature (50 ºC)
with prolonged reaction time (3m and 3n). Generally, the
enantioselection is better for Weinreb amide or N-
methylphenyl amide as compared to carboxylic esters, and
up to 97% ee was achieved (3o-3t). The structure and abso-
lute (S)-configuration of the ring-opening products were
unambiguously established by single crystal X-ray diffraction
analysis of compound 3o.17
(a)
9
10
11
12
13
14
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This asymmetric ring-opening reaction was also applied to
the oxygen nucleophiles, such as potassium carboxylates
(Scheme 3). Generally, the rate with carboxylates as nucleo-
philes was much slower than those with S-nucleophiles in
this Cu-catalyzed ring-opening reaction, which is consist
with the observed ratio of S/O-arylation with thioacetates as
nucleophiles. Regardless the substituents on the phenyl rings,
excellent enantioselectivity were achieved (6a-6d). The func-
tional groups in the aliphatic chain, such as Weinreb amide,
ester or amide had slight effects on the ee values (6e and 6f).
(b)
(c)
Scheme 3. Substrate Scope with Carboxylatesa
Figure 1. Crystal Structure of 1n. (a) Dihedral Angle of the
Two Phenyl Rings (CF3SO3 was omitted) (b) Top View. (c)
Side View.
-
R
O
R
I
Cu(OTf)2 (5.0 mol%)
L8 (5.0 mol%)
H
O
O
R'
R1
R1
+
R1
H3C
OK
DCE, 60 oC, 48 h
I
Scheme 4. Plausible Catalytic Cycle and Stereoinduc-
tion Models
TfO-
R1
1
5a
6
O
O
CO2Et
CO2Et
O
EtO
CO2Et
EtO
O
H
O
O
H
H
O
O
H
Me
Me
H
O
Me
O
N
N
Me
OMe
CuI
Me
Me
Ar
Me
Me
Ar
Me
Me
I
I
Me
Me
I
Me
A
OMe
I
I
TfO-
S
6a, 99%, 97% ee
6b, 71%, 93% ee
6c, 81%, 94% ee
1n
R
O
3
MeO
N
Ph
N
O
CO2Et
Me
Me
EtO
O
O
O
O
EtO
O
H
H
O
Me
Me
O
H
H
O
Me
Me
Me
O
Me
H
Me
Me
Me
Me
I
Me
Me
Me
Me
Me
I
I
I
[CuIII
S
]
I
[CuIII
]
6d, 86%, 97% ee
6e, 82%, 98% ee
6f, 90%, 97% ee
O
a
B
The reaction was conducted with 1 (0.20 mmol), 5a (0.24 mmol),
C
R
O
Cu(OTf)2 (5.0 mol%), L8 (5.0 mol%) in DCE (2.0 mL) at 60 oC for 48 h.
(2)
KS
R
O
To gain some insight regarding the stereoinduction of this
Cu-catalyzed asymmetric ring-opening reaction, single crys-
tal of cyclic diaryliodonium salt 1n was obtained by slow
evaporation of the solvent [petroleum ether/ethyl acetate]
and its structure solved (Figure 1).18 The compound has a “Λ”-
shape structure in solid state, with the dihedral angle of the
two phenyl rings being 124 º (Figure 1a). The six-membered
iodonium heterocycle adopts a boat-like conformation (Fig-
ure 1b and 1c), where the alkyl chain locates at the equatorial
position and the hydrogen atom is at the axial position. A
plausible catalytic cycle, as well as the chemical structure of
1n and the possible stereochemical models were shown in
Scheme 4. On the basis of previous computational studies,19
the Cu(I)/bis(oxazoline) A was regarded as the active catalyst,
which underwent oxidative addition with cyclic iodonoium
salt 1n to deliver B. The coordination of potassium thioates 2
to Cu(III) center gave C, which would give the final products
3 via reductive elimination. To rationalize the result of stere-
oinduction, the Cu catalyst would interact with 1n from the
convex side, while approach to the concave side is sterically
disfavored [Scheme 4, I (top view) and II (side view)]. In this
scenario, stronger steric repulsion between the 3,5-
EtO
convex side
I
convex side
O
O
H
O
O
OO
Ar
EtO
O
H
N
EtO
N
Me
Me
EtO
N
N
CuI
CuI
Ar
I
Ar
Me
Me
I
Ar
I
TfO-
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
concave side
(Schielded)
[top view]
concave side
(Schielded)
[side view]
favored
disfavored
I
II
III
IV
Finally a brief synthetic application of the obtained thioe-
sters was demonstrated (Scheme 5). Hydrolysis of thioester
and carboxylic ester of 3g, followed by cyclization would give
thioester 7 in 68% overall yield. The Sonogashira coupling of
7 gave alkyne 8 uneventfully with 91% ee.
Scheme 5. Synthetic Application
O
O
O
CO2Et
S
S
1) NaOH, EtOH/THF
2) DCC, DMAP, DCM
Pd(PPh2)Cl2
CuI, Et3N
H
Me
Me
Me
S
Me
H
H
I
I
Ph
Me
Me
Me
Ph
3g
prepared at 3.0 mmol scale
(99%, 92% ee)
7
, 68% (two steps)
8
, 75%, 91% ee
In conclusion, we have disclosed an asymmetric ring-
opening reaction of diaryliodoniums to access molecules
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ASSOCIATED CONTENT
Supporting Information
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The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures, spectroscopic data (PDF)
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AUTHOR INFORMATION
Corresponding Author
zhgu@ustc.edu.cn
Notes
The authors declare no competing financial interests.
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ACKNOWLEDGMENT
We are grateful for financial supported from NSFC
(21622206, 21472179), the '973' project from the MOST of
China (2015CB856600), Strategic Priority Research Program
of the Chinese Academy of Sciences (XDB20000000), and
Fundamental Research Funds for the Central Universities
(WK2060190086).
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