Silicon-tethered strategy for copper(I)-catalyzed stereo- and regioselective alkylboration of alkynes

Article abstract of DOI:10.1021/ol503620n

Stereoselective silicon-tethered alkylboration of alkynes in the presence of a copper(I) catalyst and a diboron reagent provided the corresponding cyclic alkenylboronates in high yields (up to 99% yield) with excellent regio- and syn-selectivities (E/Z =

Full text of DOI:10.1021/ol503620n

Letter
pubs.acs.org/OrgLett
Silicon-Tethered Strategy for Copper(I)-Catalyzed Stereo- and
Regioselective Alkylboration of Alkynes
Koji Kubota, Hiroaki Iwamoto, Eiji Yamamoto, and Hajime Ito*
Division of Chemical Process Engineering, Graduate School of Engineering, Hokkaido University, Sapporo, Hokkaido 060-8628,
Japan
S
* Supporting Information
ABSTRACT: Stereoselective silicon-tethered alkylboration of
alkynes in the presence of a copper(I) catalyst and a diboron
reagent provided the corresponding cyclic alkenylboronates in
high yields (up to 99% yield) with excellent regio- and syn-
selectivities (E/Z = <1:99). The products, which can be
considered as the formal alkyne intermolecular alkylboration
products, undergo subsequent selective derivatization, including
ring opening, to give functionalized trans-stilbene derivatives.
lkenylboronates are useful and versatile intermediates for
the synthesis of multisubstituted alkenes because they
Scheme 2. Copper(I)-Catalyzed Formal Alkyne
Intermolecular Alkylboration Using Silicon-Tethered
Strategy
A
undergo stereospecific C−C bond forming reactions.1−3 In
recent years, much effort has been devoted to the development of
efficient methods for boryl addition across alkynes.4−9 Copper-
(I)-catalyzed carboboration of alkynes is a particularly useful
method for the preparation of multisubstituted alkenylboron
compounds.10−13 In this procedure, the alkenylcopper(I)
intermediate generated by addition of a borylcopper(I) species
to an alkyne subsequently reacts with a carbon electrophile
(Scheme 1). However, this method has some limitations:
Scheme 1. Copper(I)-Catalyzed 1,2-Carboboration of
Alkynes
can be considered as formal alkyne intermolecular alkylboration
products, which undergo subsequent selective derivatization,
including ring opening via tethered Si−C bond cleavage, to give
functionalized multisubstituted alkenes.
We initially focused on the efficient preparation of silicon-
tethered alkyne derivatives. The desired silicon-tethered alkynes
3a can be easily synthesized in three steps through iridium-
catalyzed regioselective hydrosilylation of an allyl bromide with
an alkynylhydrosilane 2, derived from terminal alkyne 1, as
recently reported by Rahaim and co-workers (Scheme 3).17
reactions using unactivated alkyl electrophiles required long
reaction times (up to 51 h), and the yields were moderate (36−
60%).10b This is probably because of the low reactivity of such
electrophiles in substitutions by an alkenylcopper(I) nucleophile.
Furthermore, the regioselectivity of borylcupration to C−C
triple bonds was poor in reactions with unsymmetrical diaryl and
aliphatic alkynes, so this process is not widely applicable.10
To achieve highly reactive and regioselective alkylboration of
alkynes, we designed a silicon-tethered carboboration reaction
(Scheme 2).14 This novel strategy has the following advantages.
The low reactivity of unactivated alkyl electrophile substitution
by alkenylcopper(I) can be improved by changing from an
intermolecular to an intramolecular reaction mode.15,16 More-
over, the regioselectivity of the addition of the borylcopper(I)
intermediate to the alkyne moiety can be controlled by the
electronic effect of a silyl group.9g The products in this strategy
Scheme 3. Preparation of Silicon-Tethered Alkyne 3a
Received: December 17, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ol503620n
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
With an efficient route for the synthesis of silylalkyne 3a in
hand, we then investigated the intramolecular alkylboration in
the presence of a CuCl/phosphine ligand complex catalyst (5
mol %), bis(pinacolato)diboron 4 (1.2 equiv), and a
stoichiometric amount of K(O-t-Bu) base (1.2 equiv) in THF
at 50 °C (Table 1). Phosphine ligand screening (entries 1−6,
silicon-tethered alkynes, using unactivated alkyl electrophiles,
were investigated under the optimized conditions (Scheme 4).
Scheme 4. Attempted 1,2-Carboboration of Non-Silicon-
Tethered Alkyne Substrates Using Unactivated Alkyl
Bromides
Table 1. Copper(I)-Catalyzed Alkylboration of Silicon-
a
Tethered Alkynes under Various Conditions
b
c
entry
ligand
PPh3
base
E/Z
yield (%)
1
2
3
4
5
6
K(O-t-Bu)
K(O-t-Bu)
K(O-t-Bu)
K(O-t-Bu)
K(O-t-Bu)
K(O-t-Bu)
K(O-t-Bu)
K(O-t-Bu)
K(O-t-Bu)
K(O-t-Bu)
Na(O-t-Bu)
NaOMe
<1:99
<1:99
<1:99
<1:99
<1:99
<1:99
<1:99
<1:99
<1:99
<1:99
<1:99
<1:99
<1:99
<1:99
61
18
93
27
14
72
99
94
97
34
98
95
54
95
The intermolecular carboboration of nontethered alkynylsilane
6, using 2-phenylethyl bromide as an alkyl electrophile, did not
provide a carboboration product, while the hydroboration
product 7 was detected (3% GC yield) (Scheme 4a). This result
indicates that the intermolecular halide substitution of
alkenylcopper(I) derived from the insertion of borylcopper(I)
to the alkyne is very slow (see Supporting Information, p S21).
The intramolecular carboboration of alkynyl bromide 8 also
failed to provide any alkylboration products (Scheme 4b). These
results clearly show that the present silicon-tethered borylation
strategy has a significant effect on the reactivity in the
carboboration of alkynes using unactivated alkyl electrophiles.
Next, various silicon-tethered alkynes were subjected to the
intramolecular alkylboration reaction in the presence of the
CuCl/IMes complex catalyst system (Table 2). The reactions
proceeded with complete syn-selectivities. Alkenylboronates
bearing alkyl substituents [R = n-Bu (5a), CH2CH2Ph (5b),
and CH2Cy (5c)] were successfully obtained in good yields (92−
98%) from the corresponding silicon-tethered alkynes (entries
1−3, Table 2). The reaction exhibited high functional group
tolerance and afforded the corresponding alkylboration products
containing silyl ether (5d), alkyl chloride (5e), acetal (5f), and
ether (5g) moieties in high yields (entries 4−7, Table 2). The
alkylborations of aromatic alkynes also proceeded to provide the
products 5h and 5i with high regioselectivities in the presence of
a CuCl/dppp catalyst (entries 8 and 9, Table 2). Furthermore,
we found that this catalytic system was also effective for the
synthesis of the six-membered ring product (Z)-10 from the
corresponding silicon-tethered alkyne 9 (entry 10, Table 2).
π-Conjugated systems are challenging substrates for boryla-
tion reactions, because of multiborylation, and regio- and
stereoselectivity problems.18 We found that the reaction of 3j
under the optimized conditions produced the desired 2-boryl-
1,3-butadiene (Z)-5j in good yield, with perfect regioselectivity,
and without any side products such as diborylated compounds
(Scheme 5). The Diels−Alder reaction of (Z)-5j with maleimide
gave the desired cycloaddition product 11 as a single isomer in
good yield (79%). The structure of 11 was confirmed by single-
crystal X-ray crystallography and NOE experiments.19
dppe
dppp
dppb
dppf
Xantphos
IMes·HCl
SIMes·HCl
ICy·HCl
IPr·HCl
IMes
d
7
e
8
f
9
g
10
11
12
13
IMes
IMes
KOAc
h
14
IMes
K(O-t-Bu)
a
Conditions: CuCl (0.025 mmol), ligand (0.025 mmol), 3a (0.5
mmol), bis(pinacolato)diboron 4 (0.6 mmol), and K(O-t-Bu) (0.6
b
mmol) in THF (1.0 mL). Determined by GC and NMR analysis.
c
Determined by GC analysis of the crude reaction mixture with an
d
internal standard. IMes·HCl: 1,3-bis(2,4,6-trimethylphenyl)-
imidazolium chloride. SIMes·HCl: 1,3-bis(2,4,6-trimethylphenyl)-
imidazolinium chloride. ICy·HCl: 1,3-dicylohexylimidazolium chlor-
e
f
g
ide. IPr·HCl: 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride.
h
Toluene was used as a solvent instead of THF.
Table 1) showed that the reaction using dppp as the ligand
afforded the desired cyclic alkenylboronate (Z)-5a in high yield
with perfect regioselectivity and excellent syn selectivity (93%, E/
Z = <1:99, entry 4, Table 1). We found that the reaction using
electron-donating N-heterocyclic carbene ligands also provided
the desired product (Z)-5a (entries 7−10, Table 1). The IMes
(IMes·HCl: 1,3-bis(2,4,6-trimethylphenyl)imidazolium chlor-
ide) ligand gave the best result (99%, E/Z = <1:99, entry 7,
Table 1). We then investigated the base effects, using a CuCl/
IMes complex catalyst system (entries 11−13, Table 1). The use
of other alkoxide bases such as Na(O-t-Bu) and NaOMe instead
of K(O-t-Bu) did not affect the product yield or stereoselectivity,
and gave good results (98% and 95%, E/Z = <1:99, entries 11 and
12, Table 1, respectively). The weaker base KOAc gave a lower
yield (entry 13). The reaction using toluene as the solvent also
gave good results (95%, E/Z = <1:99, entry 14, Table 1).
To confirm the effectiveness of the silicon-tethered strategy,
inter- and intramolecular 1,2-carboboration reactions of non-
The obtained cyclic alkenylboronates can be considered as the
formal alkyne intermolecular alkylboration products, because
they undergo ring opening of the cyclic silicon functional group
B
DOI: 10.1021/ol503620n
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Substrate Scope for Intramolecular Alkylboration of
Silicon-Tethered Alkynes
Scheme 5. Alkylboration of Conjugated Enyne 3j and
Subsequent Diels−Alder Reaction
a
Scheme 6. Selective Transformation of Silicon-Tethered
Alkylboration Product
oxidation using H2O2 and tetra-n-butylammonium fluoride
(TBAF).
A proposed reaction mechanism for the intramolecular
alkylboration is shown in Figure 1. First, Cu(O-t-Bu) A,
generated via the reaction between CuCl and K(O-t-Bu) base,
reacts with a diboron compound to form the borylcopper(I)
active species B. Subsequent regioselective insertion of B into
silylalkyne 3 affords the alkenylcopper(I) intermediate C, which
would be stabilized by the electronic effect of the silyl group,9g
a
Conditions: CuCl (0.025 mmol), IMes/HCl (0.025 mmol), 3 (0.5
mmol), 4 (0.6 mmol), and K(O-t-Bu) (0.6 mmol) in THF (1.0 mL).
b
c
d
Isolated yield. THP: 2-Tetrahydropyranyl group. dppp was used
instead of IMes ligand and reaction temperature was 40 °C.
(Scheme 6). The Suzuki−Miyaura cross-coupling reaction of
alkylboration product (Z)-5a with 1-bromo-4-trifluoromethyl-
benzene proceeded in the presence of the Pd[P(t-Bu)3]2 catalyst
to give the arylation product (E)-12 in high yield (96%).
Treatment with bromine and NaOMe cleaved the Si−C bond to
produce the alkenyl bromide (E)-13, with retention of the
stereochemistry.20 Subsequent Suzuki−Miyaura cross-coupling
of (E)-13 afforded the trans-stilbene (E)-14 with complete
stereospecificity. Furthermore, the resulting silyl ether (E)-14
was converted to the corresponding alcohol (E)-15 via Tamao
Figure 1. Proposed reaction mechanism.
C
DOI: 10.1021/ol503620n
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Organic Letters
Letter
Ed. 2005, 44, 2380. (b) Daini, M.; Suginome, M. Chem. Commun. 2008,
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Nagao, K.; Ohmiya, H.; Sawamura, M. J. Am. Chem. Soc. 2014, 136,
10605.
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see: (a) Suginome, M.; Nakamura, H.; Ito, Y. Chem. Commun. 1996,
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alkynes, see: (a) Kim, H. R.; Jung, G.; Yoo, K.; Jang, K.; Lee, E. S.;
Yun, J.; Son, S. U. Chem. Commun. 2010, 46, 758. (b) Jang, H.;
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followed by formation of an ate complex D through coordination
of the alkoxide to the copper center. Oxidative addition and
elimination of the bromide moiety then produce the cyclic
copper(III) intermediate E, in a manner similar to the
nucleophilic substitution of alkyl electrophiles by cuprates.
Finally, reductive elimination generates the intramolecular
alkylboration products (Z)-5 (n = 1) or (Z)-10 (n = 2) and
Cu(O-t-Bu) A.
In summary, we have developed a novel strategy for the
copper(I)-catalyzed carboboration of alkynes using unactivated
alkyl electrophiles, based on a silicon-tethered reaction. The
alkylboration of silicon-tethered alkynes gave excellent yields (up
to 99%) with high regioselectivities and complete syn selectivities
(E/Z = <1:99), even in the presence of various functional groups.
The low reactivity of unactivated alkyl electrophile substitution
by an alkenylcopper(I) intermediate was improved by changing
from an intermolecular to an intramolecular reaction mode
through silicon tethering. The products can be considered as
formal alkyne intermolecular alkylboration products, which
undergo subsequent selective derivatization, including ring
opening via tethered Si−C bond cleavage, to give the
functionalized trans-stilbene derivatives. The synthesis of
products with various ring sizes and functional groups will be
investigated; we believe that this will increase the use of silicon-
tethered alkylboration reactions.
́ ́
(d) Moure, A. L.; Arrayas, R. G.; Cardenas, D. J.; Alonso, I.; Carretero, J.
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(10) For copper(I)-catalyzed intermolecular carboboration of alkynes
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
́
using alkyl halides, see: (a) Alfaro, R.; Parra, A.; Aleman, J.; Ruano, J. L.
G.; Tortosa, M. J. Am. Chem. Soc. 2012, 134, 15165. (b) Yoshida, H.;
Kageyuki, I.; Takaki, K. Org. Lett. 2013, 15, 952.
(11) For copper(I)-catalyzed intermolecular carboboration of alkynes
using carbon dioxide, see: Zhang, L.; Cheng, J.; Carry, B.; Hou, Z. J. Am.
Chem. Soc. 2012, 134, 14314.
(12) Copper(I)-catalyzed intramolecular carboboration of 1,6-enynes,
see: Liu, P.; Fukui, Y.; Tian, P.; He, Z.; Sun, C.; Wu, N.; Lin, G. J. Am.
Chem. Soc. 2013, 135, 11700.
(13) For noncatalytic carboboration of alkynes, see: Okuno, Y.;
Yamashita, M.; Nozaki, K. Angew. Chem., Int. Ed. 2011, 50, 920.
(14) For review of silicon-tethered reactions, see: Bols, M.; Skrydstrup,
T. Chem. Rev. 1995, 95, 1253.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: hajito@eng.hokudai.ac.jp.
Notes
The authors declare no competing financial interest.
(15) For our copper(I)-catalyzed intramolecular alkylboration of
silicon-substituted alkenes, see: (a) Ito, H.; Kosaka, Y.; Nonoyama, K.;
Sasaki, Y.; Sawamura, M. Angew. Chem., Int. Ed. 2008, 47, 7424. (b) Ito,
H.; Toyoda; Sawamura, M. J. Am. Chem. Soc. 2010, 132, 5990.
(16) For our copper(I)-catalyzed intramolecular alkylboration of
alkenes, see: (a) Zhong, C.; Kunii, S.; Kosaka, Y.; Sawamura, M.; Ito, H.
J. Am. Chem. Soc. 2010, 132, 11440. (b) Kubota, K.; Yamamoto, E.; Ito,
H. J. Am. Chem. Soc. 2013, 135, 2635.
(17) Muchnij, J. A.; Kwaramba, F. B.; Rahaim, R. J. Org. Lett. 2014, 16,
1330.
(18) Sasaki, Y.; Horita, Y.; Zhong, C.; Sawamura, M.; Ito, H. Angew.
Chem., Int. Ed. 2011, 50, 2778.
(19) Details have been described in the Supporting Information.
(20) Inversion of the stereochemistry was reported in the bromination
of vinylsilanes in the literature (see ref 8e). The constrained structure of
(E)-12 would cause this retention stereochemistry. The structures of
(E)-13−15 were determined by NOE analysis. The details have been
described in the Supporting Information.
ACKNOWLEDGMENTS
■
This work was financially supported by the MEXT (Japan)
program “Strategic Molecular and Materials Chemistry through
Innovative Coupling Reactions” of Hokkaido University. K.K.
thanks JSPS for scholarship support.
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D
DOI: 10.1021/ol503620n
Org. Lett. XXXX, XXX, XXX−XXX