Trans -diborylation of alkynes: Pseudo -intramolecular strategy utilizing a propargylic alcohol unit

Article abstract of DOI:10.1021/ja5036754

We present the first trans-selective diborylation reaction of alkynes. By means of theoretical calculation-assisted reaction analysis, we designed a pseudo-intramolecular reaction of diboron, propargyl alcohol, and a base to facilitate B-B bond activation and C-B bond formation with high efficiency. This approach provides synthetically versatile and densely functionalized 4-borylated 1,2-oxaborol-2(5H)-oles (vinyldiboronates) in a straightforward manner. Detailed computational analysis showed that the directing alkoxide functionality markedly lowers the activation energy of B-C bond formation.

Full text of DOI:10.1021/ja5036754

Communication
pubs.acs.org/JACS
Trans-Diborylation of Alkynes: Pseudo-Intramolecular Strategy
Utilizing a Propargylic Alcohol Unit
Yuki Nagashima,† Keiichi Hirano,*,† Ryo Takita,‡ and Masanobu Uchiyama*,†,‡
†Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
‡Advanced Elements Chemistry Research Team, RIKEN Center for Sustainable Resource Science, and Elements Chemistry
Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
S
* Supporting Information
Scheme 1. DFT Calculation on Intermolecular Diborylation
ABSTRACT: We present the first trans-selective dibor-
of 2-Butyne at the B3LYP/6-31+G* Level (ΔG in kcal/mol)
ylation reaction of alkynes. By means of theoretical
calculation-assisted reaction analysis, we designed a
pseudo-intramolecular reaction of diboron, propargyl
alcohol, and a base to facilitate B−B bond activation and
C−B bond formation with high efficiency. This approach
provides synthetically versatile and densely functionalized
4-borylated 1,2-oxaborol-2(5H)-oles (vinyldiboronates) in
a straightforward manner. Detailed computational analysis
showed that the directing alkoxide functionality markedly
lowers the activation energy of B−C bond formation.
inylboronates are widely used in organic synthesis as
Vbuilding blocks for regio-/stereoselective construction of
multisubstituted olefins. They are readily storable and easy to
handle, and their C−B bonds can be easily transformed into
C−C and C−heteroatom bonds by means of various synthetic
methods, as represented by the Suzuki−Miyaura cross-coupling
reaction.1,2 Hydroborations,3 haloborations4 and diborylations5
of alkynes are excellent methods for synthesis of vinylboronates
or vinyldiboronates. However, in all cases, the reactions are
triggered by interaction between a vacant orbital of a transition
metal (or boron atom) and a π-orbital of acetylene, and
therefore cis-addition is predominant. Finding a means to
obtain trans-selectivity in borylation reactions remains an
important challenge. We anticipated that trans-addition should
be accomplished by addition of a boryl anion equivalent to
acetylene.6−8 To examine the feasibility of this idea, we
performed a model calculation using butyne, bis(pinacolato)-
diboron, and LiOMe (Scheme 1). The results indicated that
trans-borylation would proceed selectively (CP2inter) through
an anionic mechanism with 11.1 kcal/mol exothermicity, but it
would be necessary to overcome a very high activation energy
(+51.9 kcal/mol). In order to achieve this, we adopted a
pseudo-intramolecular reaction strategy,9 which enabled us to
achieve regioselective trans-diborylation of alkynes for the first
time. We show that this reaction provides versatile access to
trans-vinyldiboronates and oxaborololes (Scheme 2).
Scheme 2. Our Strategy (Working Hypothesis)
experimentation, we found that the combination of propargyl
alkoxide, prepared from propargylic alcohol (1a) and base, and
2a promoted the C−C triple bond without any catalyst (Table
1). Unexpectedly, the present trans-diborylation gave an
oxaborole ring as a partial structure of the product. The
reaction temperature and countercation of the base played
crucial roles in determining the yield of this diborylation. The
reaction progress was sluggish at room temperature, and only a
trace amount of the desired product 3a was obtained (entry 1).
A higher yield of product 3a was obtained at 50 °C, and the
yield was further increased to 77% at 75 °C (entries 2 and 3).
Use of MeLi gave 3a in comparable yield to that obtained with
nBuLi (entry 3 vs 4), whereas MeMgBr and NaH each gave
only a small amount of 3a (entries 5 and 6), indicating that the
lithium cation most efficiently promotes the borylation. To our
All initial attempts at intermolecular reaction using various
acetylenes and bis(pinacolato)diboron (2a) under various
conditions were unsuccessful, as expected from the computa-
tional results. Thus, we focused on installing a heteroatom(s)
on the acetylene skeleton to coordinate/activate diboron in
order to lower the activation energy. After extensive
Received: April 16, 2014
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
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Table 1. Optimization of Reaction Conditions
Table 2. Scope and Limitations of trans-Diborylation of
Propargylic Alcohols
a
entry
base
temp (°C)
yield (%)
1
2
3
4
5
6
nBuLi
nBuLi
nBuLi
MeLi
rt
trace
66
50
75
75
75
75
77
72
MeMgBr
NaH
trace
27
a
1
Determined by H NMR analysis.
knowledge, this is the first example of diborylation of alkynes
giving the trans-product as the major product,5j,k though trans-
hydroboration of alkynes,3h,10,11 Pd-catalyzed trans-silaboration
of terminal alkynes,12 and classical trans-carbometalation of
propargyl alcohols6a,b have been reported.
Next, we examined the scope and limitations of the trans-
diborylation of propargylic alcohols (Table 2). The electronic
effect at acetylene carbons showed little influence on the
regioselectivity/reactivity and various phenyl propargylic
alcohols with an electron-donating group (o/p-MeO and
NH2) as well as an electron-withdrawing group (Cl, CF3,
ester, and CN) on the phenyl ring were efficiently converted to
the corresponding vinyldiboronates in high yields without
formation of detectable amounts of isomers (entries 1−8). In
addition, base/nucleophile-sensitive moieties such as ester and
CN groups were compatible with the reaction conditions
(entries 6 and 7). The acidic proton of aniline derivative 1h was
not deleterious to the reaction, and 3h was obtained in 85%
yield. Other aromatic rings and heterocycles such as pyridine,
thiophene, and naphthalene rings caused no problem (entries
9−11). This reaction is not limited to aryl-substituted alkynes.
Primary (entries 12 and 13) and secondary aliphatic
substituents (entry 13) afforded the product in high yield.
On the other hand, a tertiary alkyl group significantly slowed
down the reaction, probably due to steric hindrance (entry 15).
Distal multiple bonds were untouched in the cases of the
conjugate enyne 1p and diyne 1q affording products 3p and 3q
chemoselectively in good yields (entries 16 and 17). However,
an acetylenic C−Br bond did not survive under these
conditions (entry 18). We confirmed that this reaction could
be conducted on a gram scale: pure 3a was obtained in 87%
yield (1.37 g) just by triturating the crude solid in cold hexane
after workup.
This reaction also shows a wide scope for propargylic
substituents and diborons (Table 3). A cyclic tertiary alcohol
(1s) and secondary alcohols (1t, 1u, 1v, 1w, and 1x) were
converted to the desired products (entries 1−6). In particular,
chemoselective diborylation of the triple bond of 1u was
achieved even in the presence of the double bond, presumably
because a transition-metal-free ionic reaction is involved (entry
5). The desired product was not formed with 3-phenyl-2-
propyn-1-ol, where R2 and R3 are hydrogen, indicating the
importance of the Thorpe−Ingold effect for this trans-
formation. Bis(neopentylglycolato)diboron (2b) gave the
corresponding vinylboronate 3y in modest yield (entry 7).
The unsymmetrical diboron 2c5g underwent diborylation in a
a
b
Isolated yield. Yield in 1,4-dioxane as a solvent in parentheses.
5
c
d
n
mmol scale. MeLi was used instead of BuLi as a base. Determined
by H NMR analysis.
1
stereo-/chemoselective manner (entry 8). Homopropargylic
alcohols were not reactive under these reaction conditions.
We have demonstrated that the trans-diborylated products
can be obtained from terminal acetylenes via sequential
reactions in one pot (Scheme 3). Starting with acetone and
4-methoxyphenylacetylene, the trans-diborylated product 3b
was obtained in comparable yield to that of the two-pot
procedure (vide supra). This method provides operationally
more facile access to vinyldiboronates.
B
dx.doi.org/10.1021/ja5036754 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
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Table 3. Substrate Scope of Propargylic Alcohols and
Diborons
Scheme 4. Sequential Trans-Diborylation/Suzuki−Miyaura
Cross-Coupling Processes in One Pot
a
Scheme 5. DFT Calculation on Trans-Diborylation of
Lithium 2-Methylpent-3-yn-2-olate at the B3LYP/6-31+G*
Level (ΔG in kcal/mol)
a
B2(OR)4 = bis(pinacolato)diboron (2a) (entries 1−6), bis-
(neopentylglycolato)diboron 2b (entry 7), and unsymmetrical diboron
(pin)B−B(dan) 2c5g (entry 8) were used as diborons 2. Isolated
b
yield.
Scheme 3. One-Pot Trans-Diborylation from Terminal
Alkynes
(−8.5 kcal/mol), and then borylation via B−B bond activation
occurs with a significantly lowered activation energy (+23.2
kcal/mol) compared with the intermolecular case (Scheme 1).
The second borylation contributes to a large energy gain
(−32.6 kcal/mol), and the thermodynamically stable trans-
product is formed. Aqueous workup hydrolyzes the borate part
of PD (trans) to form the oxaborolole moiety. A possible
equilibrium/pathway between the cis- and trans-diborylated
products via rotation of the C−C bond was computed to
require an extremely high activation energy (+62.0 kcal/mol)
and is unlikely to occur under the present reaction conditions.13
In summary, we have developed an unprecedented trans-
diborylation of alkynes by designing a pseudo-intramolecular
reaction, such that the activation barrier of addition of boryl
anion to the triple bond was significantly lowered. This
methodology opens up facile access to synthetically versatile
unsymmetrical vinyldiboronates with high functional group
compatibility. The method provides a simple and direct route
for the synthesis of regio-controlled tetrasubstituted olefins
from various functionalized terminal alkyne precursors. In
addition, the oxaborole skeleton and its analogues have recently
been recognized as key structural platforms and potent
pharmacophores in materials and pharmaceutical sciences.14
Further work to expand the scope of the reaction and to study
applications of the products, multiply substituted olefins/
oxaborololes, for the synthesis of biologically active and
functional molecules is in progress.
We also succeeded in the synthesis of a tetrasubstituted
olefin via sequential diborylation/Suzuki−Miyaura cross-
coupling processes in one pot (Scheme 4). The putative
borate intermediate 4 generated by diborylation of 1u was
directly subjected to the coupling reaction with 4-iodotoluene
without workup to give the desired olefin 5 in 64% yield. This
result demonstrates the potential applicability of this method-
ology for regio-controlled synthesis of densely functionalized
alkenes, such as tamoxifen derivatives.
Finally, DFT calculation was performed in order to shed light
on the mechanism of this unprecedented trans-diborylation
reaction. The calculated potential energy profiles are
summarized in Scheme 5. Initial complexation of diboron and
lithium propargyl alkoxide releases a small amount of energy
C
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Journal of the American Chemical Society
Communication
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ASSOCIATED CONTENT
* Supporting Information
Experimental details and NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
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AUTHOR INFORMATION
Corresponding Authors
k1hirano@mol.f.u-tokyo.ac.jp
uchiyama@mol.f.u-tokyo.ac.jp
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partly supported by JSPS KAKENHI (S) (No.
24229011), Takeda Science Foundation, The Asahi Glass
Foundation, Daiichi-Sankyo Foundation of Life Sciences,
Mochida Memorial Foundation, Tokyo Biochemical Research
Foundation, Foundation NAGASE Science Technology Devel-
opment, Yamada Science Foundation and Sumitomo Founda-
tion (to M.U.), JSPS Grant-in-Aid for Young Scientists (Start-
up) (No. 24850005) and JSPS Grant-in-Aid for Young
Scientists (B) (No. 26860010) (to K.H.), and JSPS Grant-in-
Aid for Young Scientists (A) (to R.T.) (No. 25713001). The
calculations were performed on the Riken Integrated Cluster of
Clusters (RICC). We gratefully acknowledge the Advanced
Center for Computing and Communication (RIKEN) for
providing computational resources. Dr. Daisuke Hashizume
(RIKEN) was gratefully acknowledged for single X-ray
crystallographic analysis of 3a.
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