Arylboration of internal alkynes by cooperative palladium/copper catalysis

Article abstract of DOI:10.1246/bcsj.20170226

A versatile method for the arylboration of internal alkynes with aryl chlorides or bromides and bis(pinacolato)diboron has been developed. This method tolerates various functional groups, including acetyl, methoxycarbonyl, cyano, and fluoro substituents, and affords a range of tri-substituted vinylboronates, which are highly useful intermediates for the synthesis of tetra-substituted ethenes, in high yield and regioselectivity.

Full text of DOI:10.1246/bcsj.20170226

Selected Paper
Arylboration of Internal Alkynes by Cooperative Palladium/Copper
Catalysis
Kazuhiko Semba,* Megumi Yoshizawa, Yasuhiro Ohtagaki, and Yoshiaki Nakao*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510
E-mail: semba.kazuhiko.5n@kyoto-u.ac.jp, nakao.yoshiaki.8n@kyoto-u.ac.jp
Received: July 13, 2017; Accepted: September 15, 2017; Web Released: September 28, 2017
Kazuhiko Semba
Kazuhiko Semba received his Ph.D. from Kyoto University in 2013 under the supervision Prof. Yasushi Tsuji.
During his Ph.D. study, he worked with Prof. Cathleen M. Crudden at Queen’s University in Canada. Just
after his graduation, he joined the Department of Material Chemistry, Graduate School of Engineering, Kyoto
University, as an Assistant Professor.
Yoshiaki Nakao
Dr. Yoshiaki Nakao was educated in chemistry at Kyoto University (Ph.D. with Profs. Tamejiro Hiyama and
Eiji Shirakawa in 2005), Yale University (with Prof. John F. Hartwig), and Max-Planck-Institut für
Kohlenforschung (with Prof. Manfred T. Reetz). He has been faculty at Kyoto University since 2002.
Abstract
cyanoborations, alkylborations, arylborations, alkenylbora-
tions, alkynylborations, and boracarboxylations have been
accomplished.6 For the intermolecular arylboration of alkynes,
palladium-catalyzed arylborations based on chloroboranes and
arylzirconiums, as well as copper-catalyzed arylborations based
on bis(pinacolato)diboron [B2(pin)2] and aryl iodides have
been developed (Scheme 1a, 1b).6f,6g Recently, phosphine-
catalyzed arylborations of alkynoates with aryl-9BBN have
A versatile method for the arylboration of internal alkynes
with aryl chlorides or bromides and bis(pinacolato)diboron
has been developed. This method tolerates various functional
groups, including acetyl, methoxycarbonyl, cyano, and fluoro
substituents, and affords a range of tri-substituted vinylboro-
nates, which are highly useful intermediates for the synthesis of
tetra-substituted ethenes, in high yield and regioselectivity.
a)
R1
10 equiv
Cl
R1
Ar
R2
N
1) Pd cat.
2) pinacol
B
R2
Ar
+
+
R
+
ZrCp2Cl
N
1. Introduction
B(pin)
1.0 equiv
1.5 equiv
Substituted vinylboronic acids and esters are useful interme-
diates for the synthesis of various alkenes via diverse transfor-
mations of carbon-boron to carbon-carbon,1 carbon-nitrogen,2
and carbon-oxygen2a,3 bonds. Such acids and esters are usually
prepared by the hydroboration of alkynes,4 or the nucleophilic
substitution of boron-electrophiles with alkenylmagnesium or
alkenyllithium reagents.1a However, the synthesis of multi-
substituted vinylboronates (especially tri-substituted ones) via
such conventional methods is nontrivial, due to the diffi-
culties associated with preparing stereochemically defined tri-
substituted vinyl halides. An alternative to these conventional
methods is the carboboration5 of alkynes, which may afford
multi-substituted vinylboronates from readily available alky-
nes.5g,5h,6 To date, various carboborations of alkynes including
b)
R1
Ar
R2
Cu cat.
base
R1
R2
Ar
I
B2(pin)2
+
B(pin)
1.0 equiv
1.5 equiv
1.5 equiv
c)
RO2C
Ar
9BBN
R
PBu3 cat.
Ar
B
+
RO2C
Ar–9BBN
1.0 equiv
1.0 equiv
d)
Ph
Ar
Ph
Pd/Cu cat.
base
+
B2(pin)2
+
Ph
Ph
Ar Br
B(pin)
Ar = p-MeOC6H4
1.0 equiv
1.5 equiv
1.5 equiv
Scheme 1.
1340 | Bull. Chem. Soc. Jpn. 2017, 90, 1340–1343 | doi:10.1246/bcsj.20170226
© 2017 The Chemical Society of Japan

been reported (Scheme 1c).6n In this context, our group has
developed an arylboration of diphenylacetylene with B2(pin)2
and p-bromoanisole by cooperative palladium/copper catalysis
(Scheme 1d).5h,7 The advantages of this protocol are that it:
i) does not require a large excess of alkynes; ii) can be carried
out using moisture-stable B2(pin)2 instead of chloroboranes or
aryl-9BBNs; iii) can be carried out using readily available aryl
chlorides or bromides rather than aryl iodides. Shortly after
the publication of our work, Cazin reported the arylboration of
alkynes employing a similar strategy.6m However, alkynes are
limited to alkyl(aryl)acetylenes. Herein, we report the arylbo-
ration of alkynes including diarylacetylenes, alkyl(aryl)acetyl-
enes, and dialkylacetylenes with aryl chlorides or bromides and
B2(pin)2 by cooperative palladium/copper catalysis.
Table 1. Optimization of the arylboration of diphenylacety-
lene (1a) with p-chlorotoluene (2a) and B2(pin)2
Ph
Ph
Pd(OAc)2 (1.0 mol %)
CuCl (1.0 mol %)
RuPhos (3.0 mol %)
1a
0.50 mmol
+
Ph
Ph
Ph
H
Ph
+
NaOtBu (1.0 mmol)
B2(pin)2 (1.0 mmol)
PhMe, 80 °C, 3 h
p-tol
B(pin)
B(pin)
p-tol Cl
3aa
4a
2a
0.75 mmol
standard conditions
Yield (%)a)
Deviation from the
standard conditions
Entry
p-tol-B
(pin)c)
3aab)
4ab)
1
2
3
4
5
6
7
8
9
®
88
0
2
<1
57
62
61
0
5
14
28
<1
13
12
9
10
13
2
34
0
PPh3 instead of RuPhos
PCy3 instead of RuPhos
PtBu3 instead of RuPhos
XPhos instead of RuPhos
KOtBu instead of NaOtBu
NaOMe instead of NaOtBu
Cs2CO3 instead of NaOtBu
w/o Pd(OAc)2
<1
<1
20
33
33
0
2. Experimental
Crystallographic data reported in this manuscript have been
deposited with Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC-1558119. Copies of the
data can be obtained free of charge via CCDC Website.
General Procedures for Table 2. In a glove box, a vial was
charged with 2 (0.75 mmol) and a solution of Pd(OAc)2 (1.1 mg,
5.0 ¯mol) and RuPhos (4.7 mg, 10 ¯mol) in toluene (1.0 mL).
The resulting solution (solution A) was stirred for 10 min at
room temperature. Another vial was consecutively charged with
CuCl (0.50 mg, 5.0 ¯mol), RuPhos (2.3 mg, 5.0 ¯mol), NaOtBu
(96 mg, 1.0 mmol), B2(pin)2 (254 mg, 1.0 mmol), toluene (1.0
mL), 1 (0.50 mmol), and solution A. The resulting mixture
was stirred for 3 h at 80 °C. After cooling to room temperature,
the mixture was filtered through a pad of silica gel, before all
volatiles were removed in vacuo. The product was purified by
MPLC on silica gel to afford the corresponding products.
0
12
0
15
10
w/o CuCl
a) Determined by GC analysis using n-tridecane as an internal
standard. b) Yield based on 1a. c) Yield based on 2a.
Cy
Cy
Cy
Cy
P
P
OiPr
OiPr
iPr
iPr
iPr
RuPhos
XPhos
3. Results and Discussion
Table 2. Substrate scope of the arylboration of 1 with 2 and
B2(pin)2 by cooperative palladium/copper catalysis
The reaction conditions were optimized using diphenylacet-
ylene (1a), p-chlorotoluene (2a), and B2(pin)2. After screening
various parameters, 3aa was obtained in 88% yield in toluene
(T = 80 °C, t = 2 h) in the presence of Pd(OAc)2 (1.0 mol%),
CuCl (1.0 mol%), RuPhos (3.0 mol%), and NaOtBu (1.0 mmol),
under concomitant formation of small amounts of the hydro-
boration8 product 4a and p-tol-B(pin)9 (Entry 1, Table 1). The
impact of the phosphine was examined using Pd(OAc)2 (1.0
mol%) and CuCl (1.0 mol%). While PPh3, PCy3, and PtBu3
were ineffective, dicyclohexyl(o-biphenyl)phosphines such as
XPhos and especially RuPhos were effective (Entries 1-5).
Although other alkoxide bases such as KOtBu and NaOMe
afforded 3aa in moderate yield, Cs2CO3 did not furnish any 3aa
(Entries 6-8). In the absence of Pd(OAc)2 or CuCl, the yield
of 3aa was dramatically decreased (Entries 9 and 10). These
results clearly show that the cooperative palladium/copper cata-
lysis is indispensable to promote the reaction in high efficiency.
Using the optimized reaction conditions, electron-rich
and electron-poor aryl chlorides afforded the corresponding
arylboration products in moderate to good yield, although
higher catalyst loadings were necessary to obtain the products
in good yield when using electron-deficient aryl chlorides
(Entries 1-5). Even o-chloroanisole (2f) engages in the present
reaction, and 2- or 3-thienyl bromides generate the desired
products in good yield (Entries 6-8). Conversely, the corre-
Pd(OAc)2 (1.0 mol %)
CuCl (1.0 mol %)
G
R
RuPhos (3.0 mol %)
+
R
Ar–X
2
0.75 mmol
G
NaOtBu (1.0 mmol)
B2(pin)2 (1.0 mmol)
PhMe, 80 °C, 2 h
Ar
B(pin)
1
3
0.50 mmol
Yield of
3 (%)a)
Entry
1
2
1
2
1a
1a
2a
82 (3aa)
67 (3ab)
Cl
MeO
2b
3b) 1a
4b) 1a
5c) 1a
54 (3ac)
54 (3ad)
58 (3ae)
Cl
Ac
2c
Cl
MeO2C
2d
Cl
NC
2e
Continued on next page:
Bull. Chem. Soc. Jpn. 2017, 90, 1340–1343 | doi:10.1246/bcsj.20170226
© 2017 The Chemical Society of Japan | 1341

Continued:
Yield of
3 (%)a)
Entry
6
1
2
1a
74 (3af)
Cl
B
O
OMe
Br
O
2f
7
8
1a
1a
66 (3ag)
66 (3ah)
O
S
O
2g
Br
Figure 1. Molecular structure of 3fd in the crystalline state;
thermal ellipsoids set at 30% probability; H atoms omitted
for clarity.
S
2h
Ar1
Ar2
1b
1c
Ar
B(pin)
Ar1 = Ar2
=
LPd0
9
2a
2a
73 (3ba)
76 (3ca)
R
Ar-Cl
2
5
R
3
10
Ar1 = Ar2
Ar1 = Ph
=
F
step a
step c
11
2a
55 (3da)
(71:29)d)
Cycle Pd
LPd Ar
R
Ar
Cl
B(pin)
Ar2
=
LPdII
R
6
7
1d
step b
12
2a
63 (3ea)
(52:48)e)
Ar1
Ar2
=
=
OMe
CF3
LCu
R
B(pin)
LCu-Cl
9
R
1e
Me
8
13
2a
2d
2a
Ph
1f
Ph
Pr
67 (3fa)
(96:4)d)
82 (3fd)
(97:3)d)
80 (3ga)
(93:7)d)
54 (3hi)
NaOtBu
1f
step e
Cycle Cu
step d
R
14f)
15
NaCl
R
1
LCu-OtBu
LCu-B(pin)
Et
Pr
1g
10
11
step f
16g)
Br
1h
MeO
(pin)B-B(pin)
(pin)B-OtBu
2i
Scheme 2. A plausible mechanism for the arylboration of
internal alkynes by cooperative palladium/copper catalysis.
17
2b
0
Ph
H
1i
a) Yield of the isolated products. b) CuCl (5.0 mol%), RuPhos
(7.0 mol%), T = 40 °C, t = 3 h. c) CuCl (5.0 mol%), RuPhos
(7.0 mol%), T = 40 °C, t = 6 h. d) Regioselectivity determined
by GC analysis of the crude mixture. e) Regioselectivity deter-
mined by H NMR analysis of the crude mixture. f) CuCl (10
mol%) and RuPhos (12 mol%). g) (IMes)CuCl (2.5 mol%) and
PPh3 (2.0 mol%) instead of CuCl and RuPhos; t = 3 h.
The arylboration of alkyl(aryl)alkynes such as 1-phenyl-1-
propyne (1f) or 1-phenyl-1-butyne (1g) proceeded in a highly
regioselective manner to give the corresponding products (3fa,
3fd, and 3ga), which contain the boryl group at the carbon
atom attached to the alkyl substituent, in good yield (Entries
13-15). The molecular structure of 3fd in the crystal was deter-
mined by single-crystal X-ray diffraction analysis (Figure 1).
In the case of 4-octyne (1h), an arylborylation product was
obtained in 54% yield when PPh3 (2.0 mol%) and (IMes)CuCl
(2.5 mol%) were used instead of RuPhos and CuCl (Entry 16).
Under standard conditions, phenylacetylene (1i) did not afford
the corresponding product (Entry 17).
1
sponding heteroaryl chlorides did not furnish the arylboration
products. Symmetrical diarylacetylenes with electron-donating
or -withdrawing substituents at the para-position of the ben-
zene ring showed good reactivity (Entries 9 and 10). When
mesityl(phenyl)acetylene (1d) was used, the boryl group was
preferentially introduced at the carbon atom attached to the
mesityl group (Entry 11). In the case of diarylacetylene 1e,
the reaction proceeded in low regioselectivity (Entry 12).
A plausible mechanism for the present arylboration is shown
in Scheme 2. The oxidative addition of aryl chlorides to LPd(0)
(5) should afford arylpalladium(II) 6 (step a in Cycle Pd).
Transmetallation of 6 and alkenylcopper 8, which should be
1342 | Bull. Chem. Soc. Jpn. 2017, 90, 1340–1343 | doi:10.1246/bcsj.20170226
© 2017 The Chemical Society of Japan

generated via the borylcupration of alkynes,6h,10 followed by a
reductive elimination should afford 5, arylboration product 3,
and LCuCl (9) (steps b and c in Cycle Pd). Borylcopper 1111
would then be regenerated from B2(pin)2 and LCuOtBu (10),
which would be generated from 9 and NaOtBu (steps e and f in
Cycle Cu).
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4. Conclusion
6
For selected examples on the carboboration of alkynes, see:
We have developed a versatile method for the arylboration of
internal alkynes with aryl chlorides or bromides and B2(pin)2
by cooperative palladium/copper catalysis that affords tri-
substituted vinylboronates in a highly regioselective manner.
Due to the diverse reactivity of organoboron compounds, the
thus obtained products represent potent intermediates for the
synthesis of tetra-substituted ethenes.
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This research was supported by a Grant-in-Aid for Young
Scientists (B) (26810058) from MEXT and the CREST
program “Establishment of Molecular Technology towards
the Creation of New Functions” (JPMJCR14L3) from the JST.
Supporting Information
Detailed experimental procedures, spectroscopic data for
the products, and crystallographic data for 3fd are described.
This material is available on http://dx.doi.org/10.1246/bcsj.
20170226.
7
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Bull. Chem. Soc. Jpn. 2017, 90, 1340–1343 | doi:10.1246/bcsj.20170226
© 2017 The Chemical Society of Japan | 1343