Copper-Catalyzed Synthesis of Tetrasubstituted Alkenes via Regio- and anti-Selective Addition of Silylboronates to Internal Alkynes

Article abstract of DOI:10.1002/chem.202100933

As a new and complementary method for the synthesis of structurally defined tetrasubstituted alkenes, a copper-catalyzed regio- and anti-selective addition of silylboronates to unsymmetric internal alkynes has been developed. A variety of unactivated alky

Full text of DOI:10.1002/chem.202100933

Communication
doi.org/10.1002/chem.202100933
Chemistry—A European Journal
Copper-Catalyzed Synthesis of Tetrasubstituted Alkenes via
Regio- and anti-Selective Addition of Silylboronates to
Internal Alkynes
[a]
[a]
Hirokazu Moniwa and Ryo Shintani*
Abstract: As a new and complementary method for the
synthesis of structurally defined tetrasubstituted alkenes, a
copper-catalyzed regio- and anti-selective addition of
silylboronates to unsymmetric internal alkynes has been
developed. A variety of unactivated alkynes can be
employed with high selectivity under simple and mild
conditions, and the resulting products have been further
functionalized by utilizing silyl and boryl groups on the
alkene.
Alkenes constitute a fundamental structural component in
various organic molecules and widely appear in biologically
active compounds as well as functional organic materials. It is
therefore highly important to develop efficient synthetic
methods of alkenes with precise control of the regio- and
stereochemistry. In particular, synthesis of tetrasubstituted
alkenes can be quite challenging because of the steric
congestion and the number of isomers that need to be
distinguished when the substituents are different with one
Scheme 1. Silylboration of alkynes for the synthesis of silicon- and boron-
substituted alkenes.
[1]
[6]
another. Among the possible synthetic strategies to tetrasub-
stituted alkenes, 1,2-difunctionalization of internal alkynes is
one of the most straightforward approaches, and addition of
silylboronates would be highly attractive in view of the
substituted alkynes as substrates (Scheme 1b). In this context,
herein we describe a copper-catalyzed regio- and anti-selective
addition of silylboronates to unactivated unsymmetric internal
alkynes to give the corresponding tetrasubstituted alkenes
under simple and mild conditions (Scheme 1c).
[2]
synthetic utility of silyl and boryl groups. Indeed, silylboration
of alkynes have been extensively investigated since pioneering
work by Suginome, Nakamura, and Ito under palladium and
Initially, we employed 1-phenyl-1-propyne (1a) as the
substrate and conducted a reaction with silylboronate 2a in the
presence of CuI (10 mol%) and LiOtBu (40 mol%) in THF at
40°C (Table 1, entry 1). Under these conditions, silylboration
[3a]
platinum catalysis, and several effective catalyst systems have
[3]
been developed to date. However, most of the existing
methods employ either terminal alkynes or symmetric internal
alkynes as substrates, and silicon and boron are introduced syn-
selectively across the CÀ C triple bond (Scheme 1a). With regard
to the anti-selective addition of silylboronates to internal
alkynes, only two approaches have been reported to date: a
product 3aa was obtained in 81% yield with 96% selectivity via
[7]
regio- and anti-selective addition. We subsequently found that
the use of NaOtBu in place of LiOtBu improved the selectivity to
>99% in 79% yield (entry 2), but the use of KOtBu led to a
significant decrease of the yield while keeping the high
selectivity (29% yield, >99% selectivity; entry 3). On the other
hand, no reaction took place by using NaOMe (entry 4), and the
reaction using NaOtBu in the absence of CuI gave only 9% yield
of the product with much lower selectivity (72% selectivity;
entry 5). The present reaction also proceeded with similar
efficiency and high regio- and anti-stereoselectivity by using
several ligands for copper such as PPh , PCy , Xantphos, and IPr
tributylphosphine-catalyzed
addition
to
3-substituted
[4]
propiolates and a PhLi/12-crown-4-mediated addition to 3-
[5]
substituted propiolamides, both of which require carbonyl
[a] H. Moniwa, Prof. Dr. R. Shintani
Division of Chemistry, Department of Materials Engineering Science
Graduate School of Engineering Science
Osaka University, Toyonaka, Osaka 560-8531 (Japan)
E-mail: shintani@chem.es.osaka-u.ac.jp
3
3
(
(
entries 6–9), but no reaction occurred in the presence of Phen
entry 10).
Under the conditions in Table 1, entry 2, the scope of alkyl
aryl alkynes 1 was found to be fairly broad in the addition of
Supporting information for this article is available on the WWW under
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Table 1. Copper-catalyzed reaction of 1a with 2a: effect of base and
ligand.
[a]
[a]
Entry
Ligand
MOR
Yield [%]
3aa/other isomers
1
2
3
4
5
6
7
8
9
1
None
None
None
None
None
LiOtBu
NaOtBu
KOtBu
NaOMe
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
81
79
29
0
96/4
>99/1
>99/1
–
72/28
96/4
99/1
>99/1
99/1
–
[
b]
9
PPh
PCy
Xantphos
3
71
78
75
75
0
3
[
c]
[
c,d]
IPr
Phen
[
c]
0
1
[
a] Determined by H NMR against internal standard (dimethyl terephtha-
late). [b] No CuI was used. [c] 10 mol% of ligand was used. [d] (IPr)CuCl was
used instead of CuI/ligand.
2
a, giving products 3 with high regio- and anti-selectivity as
summarized in Scheme 2 (typically �96% selectivity). For
example, in addition to compound 3aa having a methyl group,
primary, secondary, and even tertiary alkyl group-substituted
compounds 3ba–ea could be synthesized in 77–86% yield with
�
94% selectivity. Several functional groups such as alkene,
ether, silyl ether, and carbazole on the alkyl chain were
tolerated as shown for the synthesis of compounds 3fa–ia.
Regarding the substituents on the aromatic rings, various
[8]
Scheme 2. Scope of copper-catalyzed silylboration of unsymmetric internal
alkynes. [a] The reaction was conducted using 2a (2.0 equiv), CuI (20 mol%),
and NaOtBu (80 mol%) at 10°C for 70 h. [b] Selectivity=94/6. [c]
groups including ether (3ka, 3qa, 3sa), halide (3ja, 3ma,
na), ester (3oa), and acetal (3pa) could be introduced at
3
either para-, meta-, or ortho-position without affecting the
regio- and anti-stereoselectivity. Heteroaryl groups as well as an
alkenyl group could also be used in place of an aryl group to
give the corresponding products 3ua–wa with similarly high
selectivity.
Selectivity=93/7. [d] The reaction was conducted at 60°C. [e] The reaction
was conducted using 1o (1.2 equiv) and 2a (1.0 equiv).
[8]
The present anti-selective silylboration reaction is also
applicable to symmetric diarylalkynes 4 as briefly examined in
Scheme 3. In addition to (dimethylphenylsilyl)boronate 2a,
(triethylsilyl)boronate 2b could be used for the reaction of
diphenylacetylene (4a) to give the corresponding products
[9]
5
aa–ab with high selectivity. Several substituted diphenylace-
tylenes including a sterically congested one underwent silylbo-
[10]
ration with 2a to give compounds 5ba–ea as well.
The tetrasubstituted alkenes obtained in the present
catalysis can be further transformed into various other com-
pounds by utilizing the silyl and/or boryl groups installed into
the molecules. For example, alkylation of the alkenylboronate
of 3ha could be achieved by a rhodium-catalyzed 1,4-addition
to a vinyl ketone to give stereochemically defined γ,δ-
Scheme 3. Scope of copper-catalyzed silylboration of symmetric diary-
lalkynes. [a] The reaction was conducted at 60°C.
[11]
unsaturated ketone 6 in 72% yield (Scheme 4a). In addition,
Suzuki coupling of 3pa with iodobenzene efficiently proceeded
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the aromatic ring, rather than desilylative bromination on the
[
13]
alkene, by the reaction with NBS/NaBr to give compound 11,
and this could be converted to benzosilole 12 by treating it
with tBuLi (Scheme 4c).
With regard to the mechanism of the present catalysis,
although we do not have full understanding at this stage, the
following observations have been made so far. The reaction of
1
2
f having 3-buten-1-yl group on the alkyne with silylboronate
a under the standard conditions gave the corresponding
silylboration product 3fa with no formation of a cyclized
product through a 5-exo-trig process, indicating that the
present reaction does not involve a radical mechanism [Eq. (1)].
In addition, the amount of NaOtBu used in the present catalysis
showed a significant impact on the reaction outcome (Table 2).
Thus, in the presence of 10 mol% of CuI, no reaction took place
when the amount of NaOtBu was 0–30 mol% (entry 1). In
contrast, high yields of 3aa were realized with 40–50 mol%
(
entries 2 and 3), and the yield became gradually lower by
further increasing the amount to 100–200 mol% (entries 4 and
). Because alkoxides are known to displace halogens on
copper(I) and can form cuprate complexes when an excess
5
[14]
amount is used with respect to copper, alkoxycuprates could
be the key catalytically active species, considering that the
amount of NaOtBu needs to be sufficiently high (�40 mol%) to
promote the present reaction. In addition, alkoxides are also
[15]
known to coordinate to the boron of silylboronates and the
resulting species become less electrophilic at boron, which
could lead to lower efficiency of the borylation process. This is
probably why the yields become lower when a stoichiometric
amount of NaOtBu is used in the present reaction.
Scheme 4. Functionalization of silylborated tetrasubstituted alkenes 3.
Table 2. Effect of the amount of base in the copper-catalyzed reaction of
1
a with 2a.
On the basis of the above information as well as the related
[a]
[a]
Entry
x
Yield [%]
3aa/other isomers
literature reports on the anti-selective addition to alkynes under
[16]
transition metal catalysis, a possible catalytic cycle for the
1
2
3
4
5
0–30
40
50
100
200
0
–
79
74
66
50
>99/1
99/1
99/1
>99/1
reaction of 1-phenyl-1-propyne (1a) with silylboronate 2a is
illustrated in Scheme 5. Thus, the reaction of CuI, NaOtBu, and
[2]
2
a generates catalytically active silylcuprate species A. This
then undergoes regioselective syn-insertion of alkyne 1a to
give alkenylcuprate B, which presumably isomerizes to D via C.
Subsequent transmetalation with 2a gives anti-addition prod-
1
[a] Determined by H NMR against internal standard (dimethyl terephtha-
late).
[17]
uct 3aa along with regeneration of A. The isomerization from
B to D would be facilitated by electron-rich cuprates and by α-
[18]
to give alkenylsilane 7 and this could be readily transformed
into the corresponding bromoalkene 8 by reacting it with N-
bromosuccinimide (NBS) (Scheme 4b). Subsequent deprotection
of the MOM group of 8 led to compound 9, a known precursor
for the synthesis of (Z)-tamoxifen. On the other hand, similarly
cross-coupled compound 10 obtained from 3sa having 3-tert-
butoxyphenyl group preferentially underwent bromination on
carbanion stabilization effect of the silyl group. Once D is
formed, this could be more reactive toward borylation with 2a
due to the electron-donating nature of the silyl group at the β-
[19]
anti-position.
[12]
In summary, we developed a copper-catalyzed regio- and
anti-selective addition of silylboronates to unsymmetric internal
alkynes to give the corresponding tetrasubstituted alkenes
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Support has been provided in part by JSPS KAKENHI Grant
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Conflict of Interest
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Keywords: anti-addition · copper · regio-control · silylboration ·
tetrasubstituted alkenes
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Manuscript received: March 15, 2021
Accepted manuscript online: March 26, 2021
Version of record online: April 14, 2021
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