Asymmetric Cyclizative Dimerization of (ortho-Alkynyl Phenyl) (Methoxymethyl) Sulfides with Palladium(II) Bisoxazoline Catalyst

Article abstract of DOI:10.1002/chem.201804779

The first example of an asymmetric cyclization–dimerization of (ortho-alkynyl phenyl) (methoxymethyl) sulfides with a palladium(II) bisoxazoline (box) catalyst has been developed. The box ligand enhances the alkynophilicity of benzothienyl palladium(II) intermediate A and thus promotes coordination of the second alkyne substrate, leading to the dimerization. The characteristic properties of the box ligand were supported by density functional theory (DFT) calculations of the intermediate. Axially chiral bibenzothiophenes were obtained in good yields with good enantioselectivities.

Full text of DOI:10.1002/chem.201804779

A Journal of
Accepted Article
Title: Asymmetric Cyclizative Dimerization of (ortho-Alkynyl Phenyl)
(Methoxymethyl) Sulfides with Palladium(II) Bisoxazoline Catalyst
Authors: Cheng Peng Peng, Taichi Kusakabe, Shoko Kikkawa,
Tomoyuki Mochida, Isao Azumaya, Yogesh Daulat Dhage,
Keisuke Takahashi, Hiroaki Sasai, and Keisuke Kato
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To be cited as: Chem. Eur. J. 10.1002/chem.201804779
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COMMUNICATION
Asymmetric Cyclizative Dimerization of (ortho-Alkynyl Phenyl)
Methoxymethyl) Sulfides with Palladium(II) Bisoxazoline Catalyst
(
[
a]
[a]
[a]
[b]
[a]
Cheng Peng, Taichi Kusakabe, Shoko Kikkawa, Tomoyuki Mochida, Isao Azumaya, Yogesh
[
a]
[a]
[c]
[a]
Daulat Dhage, Keisuke Takahashi, Hiroaki Sasai, and Keisuke Kato*
Dedicated to Professor Dr. Kiyoshi Sakai on the occasion of his 88th birthday
Abstract: The first example of an asymmetric cyclizative
dimerization of (ortho-alkynylphenyl) (methoxymethyl) sulfides with a
palladium(II) bisoxazoline (box) catalyst has been developed. The
box ligand enhances the alkynophilicity of benzothienyl palladium(II)
intermediate A and thus promotes coordination of the second alkyne
substrate, leading to the dimerization. The characteristic properties
of the box ligand were supported by density functional theory (DFT)
calculations of the intermediate. Axially chiral bibenzothiophenes
were obtained in good yields with good enantioselectivities.
were obtained in a one-step procedure. We believe that the box
ligand enhances the alkynophilicity of the acyl palladium
intermediate A‘,[ and thus promotes coordination of the second
8]
Axially chiral biaryl scaffolds are important structural motifs in
natural products, pharmaceuticals, functional materials, and
chiral ligands.[1] Although a number of synthetic strategies have
been developed, the catalytic asymmetric synthesis of axially
[
2]
chiral C-C bonded bi-heteroaryls is still challenging.
[
3]
Benzothiophenes are present in several drug candidates, and
are widespread in materials chemistry.[4] Among them,
bibenzothiophenes are also an important class of compounds in
functional
materials[5a,b,g,j-n]
and
ligands.[5h,i]
However,
conventional methods for the synthesis of axially chiral
bibenzothiophenes have been restricted to the optical resolution
of racemates and diastereselective Stille coupling reactions
Scheme 1. Previous work and this work.
using chiral auxiliaries.[5g-n]
Cyclizative dimerization of
synthetically efficient
nucleophile-bearing alkynes is
a
triple bond, leading to the dimerization. If this characteristic
property of the box ligand could be applied to the benzothienyl
transformation for the synthesis of bi-heteroaryls, because the
construction of two heteroaryls and the coupling reaction occur
in a one-step procedure.[6,7] A few examples of cyclizative
dimerization of alkynyl ketones,[6a] o-alkynylanilines,[6i,l,m,o] o-
alkynylphenols[6e] and homopropargylic amines[6p] have been
reported, affording bifurans, bisindoles, bibenzofurans and
bipyrroles in good to low yields in racemic form. If the cyclizative
dimerization could be expanded to the synthesis of axially chiral
biaryls, the process would be more valuable.
palladium
intermediate
A,
enantioselective
cyclizative
dimerization of 1 can be realized (Scheme 1, this work).
Consequently, we report herein the first example of the
palladium(II) box complex catalyzed asymmetric cyclizative
dimerization of (ortho-alkynylphenyl) (methoxymethyl) sulfides 1.
Initially, we screened several kinds of bidentate ligands such
as diamine L1, phosphine L2, sulfoxide L3, phox L4, bipyridine
L5 and box L6 for the cyclizative dimerization of 1a[ (Table 1,
entries 1-6). Interestingly, N-coordinate ligands bearing C=N L5
and L6 were effective for this reaction, affording dimer 2a (41-
9]
Previously, we reported the cyclization-carbonylation-
cyclization-coupling reaction (CCC-coupling reaction) of (o-
alkynylphenyl) (methoxymethyl) sulfides
1
catalyzed by
5
4%) along with 3a (26-32%) (entries 5 and 6). Next, optically
active box analogues L7-L12 were tested in the reaction (entries
-13). Higher reaction temperature caused an increased yield of
palladium(II) bisoxazoline (box) complexes (Scheme 1, previous
work).[8b] Symmetrical ketones bearing two benzothiophenes
7
the monomer 3a (entries 7 and 8). Among them, L11 and L12
gave good enantioselectivities, but not satisfactory yields.
Although we investigated the protecting groups and counter ions
of palladium, better results could not be obtained.[10] The use of
increased amounts of catalyst (10-14 mol%) gave good yields
and enantioselectivities (entries 14 and 15). Recently, we
reported the CCC-coupling reaction of 1 using molecular oxygen
as the terminal oxidant.[8e] Thus, we investigated the reaction of
[
a]
Mr. C. Peng, Dr. T. Kusakabe, Prof. Dr. I. Azumaya, Ms. S. Kikkawa,
Dr. Y. D. Dhage, Dr. K. Takashi, Prof. Dr. K. Kato
Faculty of Pharmaceutical Sciences, Toho University
2-2-1 Miyama, Funabashi, Chiba 274-8510, (Japan)
Fax: (+81)474-721-805
E-mail: kkk@phar.toho-u.ac.jp
Prof. Dr. T. Mochida
Department of Chemistry, Faculty of Sciences, Kobe University,
Rokkodai, Nada, Kobe 657-8501, (Japan)
Prof. Dr. H. Sasai
The Institute of Scientific and Industrial Research (ISIR), Osaka
University, Mihogaoka, Ibaraki-shi, Osaka 567-0047, (Japan)
[
[
b]
c]
1a using the [Pd(L11)(tfa)
2
] (14 mol%) / p-benzoquinone (10
mol%) / CuCl (10 mol%) catalytic system under an oxygen
2
atmosphere (balloon) (Table 1, entry 16). Although 2a was
obtained in 74% yield (84% ee), the reaction time was quite long.
Supporting information for this article is given via a link at the end of
the document.
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COMMUNICATION
With the optimal conditions in hand, we investigated the
substrate scope (Table 2). Both aryl-substituted alkynes 1a-1c
and alkyl-substituted alkynes 1d, 1e gave good yields and high
enantioselectivities (entries 1-5). A thienyl group was well
tolerated (entry 6). The reaction of 1g-1n bearing additional
Me group as a substituent in the R2 position shortened the
reaction time (entries 7-11). On the other hand, halogen
substituents slowed down the reaction (entries 15-17). The
products 2o-2q were obtained in low yields but good
enantioselectivities, along with benzothiophenes 3o-3q (5-18%)
and recovery of starting materials (15-65%). Interestingly,
2
3
substituents (R and R ) provided the desired products in good
yields and enantioselectivities (entries 7-14). Introduction of a
2
introduction of a methyl group (R ) into the substrates 1r and 1s
improved the reaction, producing 2r and 2s in good yields and
enantioselectivities (entries 18 and 19). The absolute
configurations of 2a and 2q were determined by X-ray
crystallographic analysis.[10]
Table 1. Optimization of the reaction conditions.
Table 2. Substrate scope.
R1
R2
R3
Time (h)
Yield %
Entry
SM
(
ee %)
1
2
3
4
5
6
7
8
9
1a
Ph
4-MeOPh
4-MePh
Phenethyl
Cyclopropyl
3-Thienyl
Ph
H
H
H
H
72
96
96
96
72
96
24
16
48
17
16
72
42
96
96
96
96
96
96
81 (90)
86 (84)
90 (85)
79 (98)
83 (90)
90 (85)
90 (93)
91 (88)
92 (85)
92 (86)
90 (87)
83 (98)
95 (82)
88 (86)
47 (91)
47 (92)
25 (82)
95 (93)
92 (95)
Yield % of
Yield % of
Entry
Catalyst
Conditions
1b
2a (ee %)
3a
1[a]
1c
1d
1e
1f
H
H
Pd(tfa)
2
2
2
2
/ L1
0ºC, 3days
0ºC, 3days
0ºC, 3days
0ºC, 3days
0ºC, 3days
0ºC, 4days
5ºC, 3days
20ºC ~ -10ºC,
-
7
H
H
2
3
4
5
6
7
Pd(tfa)
Pd(tfa)
Pd(tfa)
/ L2
/ L3
/ L4
-
-
82
87
74
32
26
22
H
H
H
H
trace
41
/ L5[b]
2
1g
1h
1i
Me
Me
Me
Me
Me
Me
Me
H
H
PdCl
4-MeOPh
3-Thienyl
4-tBuPh
Cyclopropyl
Phenethyl
Ph
H
Pd(tfa)
2
2
/ L6
/ L7
54
H
Pd(tfa)
64 (46)
10
11
12
13
14
1j
H
-
8
9
Pd(tfa)
2
/ L7
85 (56)
24 (48)
6
5days
1k
1l
H
Pd(tfa)
2
2
/ L8
/ L9
5ºC, 4days
5ºC, 2days
66
45
5
H
10
11
12
Pd(tfa)
40 (-43)
73 (-63)
61 (87)
1m
1n
1o
1p
1q
1r
Me
Me
H
Pd(tfa)
2
2
/ L10
/ L11
-20ºC, 5days
-20ºC, 4days
20ºC ~ -10ºC,
Ph
Pd(tfa)
7
1 [
5
a]
4-BrPh
4-ClPh
H
-
13
Pd(tfa)
2
/ L12
68 (91)
6
16[b]
17[c]
18
4days
H
H
1
4[c]
Pd(tfa)
2
2
/ L11
/ L11
-20ºC, 4days
78 (90)
81 (90)
5
5
Ph
Br
Me
Me
H
1
5[d]
Pd(tfa)
-20ºC , 3days
-5ºC ~ -0ºC,
4-BrPh
4-ClPh
H
6d,e]
19
1s
H
1
Pd(tfa)
2
/ L11
74 (84)
16
7days
[
a] 3o (9%), recovery (24%). [b] 3p (18%), recovery (15%). [c] 3q (5%),
a] Recovery 75%. [b] Commercially available complex was employed. [c] [Pd recovery (60%).
tfa) (L11)] (10 mol%). [d] [Pd(tfa) (L11)] (14 mol%), [e] p-benzoquinone (10
mol%), CuCl (10 mol%), O balloon.
[
(
2
2
2
2
To gain mechanistic insights into this transformation, we
conducted control experiments. When the reaction was
performed under an argon atmosphere, it gave similar results to
those above. When the benzothiophene 3a was subjected to the
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COMMUNICATION
reaction conditions, no reaction occurred, and 3a was recovered
quantitatively, indicating that oxidative coupling of the
benzothiophene 3 does not occur. In our previous work, the
CCC-coupling reaction of 1o and 1p proceeded well, affording
the corresponding ketones bearing two benzothiophene rings in
good yields (Scheme 1). [8b,10] We wondered why the present
reactions of 1o-1q were slow (Table 2, entries 15-17) given that
the reaction conditions of the CCC-coupling reaction were
almost the same as that of the present reaction with the
exception of the CO atmosphere. Thus, a crossover experiment
was performed using 1b and 1q as substrates (Table 3). The
reaction of a 1 : 1 mixture of 1b and 1q afforded three kinds of
dimers: 2t (cross: 37% yield), 2b (homo: 42% yield) and 2q
To understand the role of the box ligand, DFT calculations
were performed on complexes with box and other ligands (L1,
L2, L3, L5 and L6). The calculations revealed that the affinity for
the second substrate was significantly higher for the complexes
with L5 and L6 that stabilized intermediate A. These results
account for the formation of dimers when using L5 and L6. The
stabilization of intermediate A is ascribed to the -conjugation of
these ligands, which accept the electron density from the
heteroaryl ring formed by the first substrate, which is a strong
sigma donor ligand. [10]
As a working hypothesis, a tentative model for the observed
stereochemical outcome of the cyclizative dimerization is
proposed as shown in Scheme 2. It is assumed that: (1) the
sulfur atom attacks from underneath the palladium complex to
avoid the phenyl group of the box ligand, leading to intermediate
A; (2) the phenyl group of the benzothiophene moiety is situated
over the palladium, such that the second cyclization should
occur from the underside of intermediate A to avoid steric
hindrance on the upper side; and (3) the product (R)-2 is formed
by reductive elimination and clockwise rotations of the Pd-C
(
2
homo: 27% yield). Compared with the results of entry 17 (Table
), the conversion of 1q was slightly increased (Table 3, entry 1).
Moreover, the use of a 2 : 1 (1b : 1q) mixture of substrates gave
the cross coupling product 2t in 75% yield with 88% ee.
Eventually, 80% of 1q was converted to the dimers (Table 3,
entry 2). In these reactions, two kinds of benzothienyl palladium
complexes Bb and Bq should be produced (Figure 1). In the
case of the complex Bb, coordination of the triple bond of the
second substrate induces the second cyclization leading to the
dimers 2t and 2b. On the other hand, coordination of a second
substrate 1q to the complex Bq may be unfavorable. These
results suggest that electronic effects of the initially constructed
benzothiophene moiety in the intermediates Bb and Bq play an
important role in the coordination of the second substrate (and
second cyclization).
(
aryl) bonds, which is favored over counterclockwise rotations
due to steric reasons. DFT calculations supported our working
model. [10]
Table 3. Crossover experiment.
Ratio of
Yield % of
t (ee %)
Yield % of
2b (ee %)
Yield % of
2q (ee %)
Entry
2
1b : 1q
Scheme 2. Working model of the cyclizative dimerization.
1
2
1 : 1
37 (91)
42 (77)
48 (85)
27 (94)
5 (94)
2 : 1
75[a] (88)
In conclusion, we have developed an asymmetric cyclizative
dimerization of (ortho-alkynylphenyl) (methoxymethyl) sulfides
with a palladium(II) bisoxazoline (box) catalyst. The construction
of two benzothiophenes and the coupling reaction occurred in a
one-step procedure with control of axial chirality. The products
were obtained in good yields and optical purities. DFT
calculations indicated that the box ligand enhances the
alkynophilicity of benzothienyl palladium(II) intermediate A and
thus promotes coordination of the second alkyne substrate,
leading to the dimerization. Detailed investigations of the
reaction and the extension of this process are currently
underway in our laboratories.
[
a] Calculated based on 1q.
Figure 1. Coordination of the triple bond of a second substrate to the
palladium intermediate Bb or Bq..
Experimental Section
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COMMUNICATION
Typical experimental procedure: A solution of 1a (76.3 mg, 0.30 mmol)
and p-benzoquinone (48.6 mg, 0.45 mmol) in MeOH (3 mL) was cooled
to -20 ºC. A MeOH solution (1 mL) of [Pd(tfa) (L11)] (32.7 mg, 0.042
2
Spencer, M. C. O’Reilly, K. A. Brown, Robert R. Lavieri, C.l-H. Cho, D.-I.
Jung, R. C. Larock, H. A. Brown, C. W. Lindsley, ACS Chem. Biol. 2015,
10, 421-432.
mmol) was added to the stirred solution. The remaining complex was
washed in MeOH (1 mL) twice. After stirring for 72h at -20ºC, the mixture
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was diluted with CH
The aqueous layer was extracted with CH
combined organic layers were dried over MgSO
2
Cl
2
(40 mL) and washed with 3% NaOH (40 mL).
Cl (20 mL) twice, and the
and concentrated in
2
2
4
vacuo. The crude product was purified by column chromatography on
silica gel. The fraction eluted with hexane / ethyl acetate (100/1) afforded
dimer 2a as colorless needles.
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This research was supported by JSPS KAKENHI Grant Number
JP15K07871.
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Keywords: bisoxazoline • palladium •bibenzothiophene •
cyclization • dimerization
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[10] See the Supporting Information.
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Title
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Cheng Peng, Taichi Kusakabe, Shoko
Kikkawa, Tomoyuki Mochida, Isao
Azumaya, Yogesh Daulat Dhage,
Keisuke Takahashi, Hiroaki Sasai,
Keisuke Kato*
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The first example of an asymmetric cyclizative dimerization of (ortho-alkynylphenyl)
methoxymethyl) sulfides with a palladium(II) bisoxazoline (box) catalyst has been
Title
(
developed. Axially chiral bibenzothiophenes were obtained in good yields and
enantioselectivities. (20 examples, 25-95% yield (84-98% ee))
Asymmetric Cyclizative Dimerization
of (ortho-Alkynylphenyl)
(
Methoxymethyl) Sulfides with
Palladium(II) Bisoxazoline Catalyst
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