Ruthenium-Catalyzed (Z)-Selective Hydroboration of Terminal Alkynes with Naphthalene-1,8-diaminatoborane

Article abstract of DOI:10.1021/jacs.9b06910

The metal-catalyzed (Z)-selective hydroboration of terminal alkynes is synthetically challenging due to the usually (E)-selective nature of the hydroboration and the formation of the thermodynamically unstable (Z)-isomer. Herein, we report that N-heterocyclic-carbene-ligated ruthenium complexes catalyze the (Z)-selective hydroboration of terminal alkynes with H-B(dan) (dan = naphthalene-1,8-diaminato), which generates a diverse range of synthetically valuable (Z)-alkenylboranes. Mechanistic studies, particularly the isolation of a catalytically relevant borylruthenium complex, revealed a mechanism that involves the insertion of the alkyne into a Ru-B bond, which provides a catalytic cycle that is distinctly different from that of previously reported (Z)-selective hydroborations. The direct cross-coupling of the obtained (Z)-alkenyl-B(dan) enables the rapid synthesis of biologically active Combretastatin A-4 analogues.

Full text of DOI:10.1021/jacs.9b06910

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Communication
Ruthenium-Catalyzed (Z)-Selective Hydroboration of
Terminal Alkynes with Naphthalene-1,8-diaminatoborane
Kensuke Yamamoto, Yusei Mohara, Yuichiro Mutoh, and Shinichi Saito
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b06910 • Publication Date (Web): 14 Sep 2019
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Ruthenium-Catalyzed (Z)-Selective Hydroboration of Terminal
Alkynes with Naphthalene-1,8-diaminatoborane
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Kensuke Yamamoto, Yusei Mohara, Yuichiro Mutoh,* and Shinichi Saito*
Department of Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601.
Supporting Information Placeholder
metal-catalyzed (Z)-selective hydroboration of terminal
alkynes, which generates synthetically valuable (Z)-
ABSTRACT:
The
metal-catalyzed
(Z)-selective
hydroboration of terminal alkynes is synthetically challenging
due to the usually (E)-selective nature of the hydroboration
and the formation of the thermodynamically unstable (Z)-
isomer. Herein, we report that N-heterocyclic-carbene-ligated
ruthenium complexes catalyze the (Z)-selective
hydroboration of terminal alkynes with H–B(dan) (dan =
naphthalene-1,8-diaminato), which generates a diverse range
of synthetically valuable (Z)-alkenylboranes. Mechanistic
studies, particularly the isolation of a catalytically relevant
borylruthenium complex, revealed a mechanism that involves
the insertion of the alkyne into a Ru–B bond, which provides
a catalytic cycle that is distinctly different from that of
previously reported (Z)-selective hydroborations. The direct
cross-coupling of the obtained (Z)-alkenyl-B(dan) enables the
rapid synthesis of biologically active Combretastatin A-4
analogues.
alkenylboranes.
A
palladium-catalyzed (Z)-selective
hydroboration using 1,3-enynes has also been reported,7a and
an outer-sphere mechanism was proposed based on a
computational study.7b
We have recently discovered that the N-heterocyclic-
carbene-(NHC)-ligated
[RuHCl(CO)(H2IMes)(PCy3)] (1a; H2IMes
ruthenium
complex
1,3-
=
dimesitylimidazolin-2-ylidene) exhibits high catalytic activity
for the (Z)-selective hydrosilylation of terminal alkynes with
HSiMe(OSiMe3)2.10 The NHC ligand is essential for
increased catalytic activity and high (Z)-selectivity. We
envisioned that [Ru(NHC)] complexes could also catalyze
the (Z)-selective 1,2-hydroboration of terminal alkynes.
Herein, we report the (Z)-selective 1,2-hydroboration of
terminal alkynes, which leads to various (Z)-alkenylboranes,
catalyzed by air-stable [Ru(NHC)] complexes (Scheme 1c).
Based on the isolation of a catalytically relevant
borylruthenium complex, we propose a mechanism that
involves a formal anti-borylmetalation of the alkynes, which
provides a pathway that is distinctly different from that of the
Alkenylboranes are attractive building blocks in organic
synthesis due to their low toxicity and broad functional-group
compatibility.1 The hydroboration of alkynes using transition-
metal catalysts represents a reliable and straightforward
synthetic route to alkenylboranes.1d,f Compared to readily
available (E)-alkenylboranes, which can be obtained from the
hydroboration of terminal alkynes, the selective synthesis of
(Z)-alkenylboranes is challenging due to the syn-selective
nature of the hydroboration and the thermodynamic
instability of the obtained (Z)-isomer. It is thus hardly
surprising that only few examples of transition-metal-
catalyzed (Z)-selective hydroborations, e.g., 1,1-2–5 and formal
trans-1,2-hydroborations6 of terminal alkynes, have been
reported.1d,7–9 The 1,1-hydroborations involve the formation
of a vinylidene intermediate of rhodium,2 iridium,2 or
ruthenium,3 whereas a syn-hydrometalation of the in-situ-
generated alkynylboranes is involved in the cobalt-4 or iron-5
catalyzed reactions (Scheme 1a). The formal 1,2-trans-
hydroboration has been achieved via a hydrometalation of
alkynes using a copper complex, even though the
corresponding overreduction products were also formed
(Scheme 1b).6 The development of other 1,2-trans-
hydroborations is desirable to further the understanding of the
previously
reported
metal-catalyzed
(Z)-selective
hydroborations of alkynes.2–8
Scheme 1. Transition-metal-catalyzed (Z)-Selective
Hydroborations of Terminal Alkynes
a) 1,1-Hydroboration (vinylidene formation and syn-hydrometalation)
H
H
H
[M]
H
H
H
H
B
•
R
R
H
H
[M]
[Rh], [Ir]
[Ru]
R
B
R
B
R
B
[Co]
H
H
R
H
[Co]
H
R
H
H
B
[Co], [Fe]
R
B
R
B
B
b) 1,2-trans-Hydroboration (via formal anti-hydrometalation)
H
H
H
R
H
H
[Cu]
R
R
B
B
H
B
H B
R
H
+
[Cu]
R
H
[Cu]
B
c) This work: 1,2-trans-Hydroboration (via formal anti-borylmetalation)
[Ru]
B
[Ru]
R
H
H
R
H
H
B
H B
R
H
R
H
[Ru(NHC)]
B
B
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Initially, we screened a suitable borane reagent for the (Z)-
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hydroboration of phenylacetylene (2a) in the presence of 1a
(1 mol %) at 70 °C in toluene (Table 1). When H–B(dan) (dan
= naphthalene-1,8-diaminato) was used, styrylborane 3a was
obtained in 98% yield (Z/E = 98:2) together with trace
amounts of 1,1-diborylalkene 3′ (entry 1). In contrast,
catecholborane and pinacolborane were not suitable reagents
for this (Z)-selective hydroboration in terms of the yields of
the products and the Z/E ratio (entries 2 and 3).
9
Table 1. Screening of Borans for the (Z)-Selective
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Hydroboration of 2aa
N
N
CO
B
Ph
B
(Z)-3
Ph
Ph
Ru
H
Ph
(E)-3
Cl
PCy3
time 3, yield Z/E
2a (1.1 equiv)
B
B
+
entry
2
1
NHC
1a (1.0 mol %)
(h)
(%)b
3a, 98
3a, 94
3a, 93
3a, 95
3b, 89
3b, 88
3b, 96
3b, 95
ratioc
98:2
+
toluene (0.1 M)
H
B
Ph
α-3
B
1d
2
3
4
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7
8
2a
2a
2a
2a
2b
2b
2b
2b
1a H2IMes
1b IMes
2
70 o
C
(1.0 equiv)
3
4
88:12
83:17
78:22
76:24
76:24
89:11
94:6
ratioc
time yield
1c H2IPr
1d IPr
3
entry
B
(h)
(%)b
α-3
0
(Z)-3 (E)-3
3′
<1
0
4
1
2d
B(dan)
2
98
60
34
98
75
45
2
1a H2IMes
1e H2IMes
2
B(cat) 20
B(pin) 24
25
54
0
2
3
3
0
1f
H2IMesOMe
3
aGeneral reaction conditions: 1a (1.0 mol %), 2a (1.1 equiv), H–
1g H2IMest-Bu
2
B (1.0 equiv), toluene ([2a]0 = 0.1 M). bIsolated yields relative to
aGeneral reaction conditions: 1 (1.0 mol %), 2a (1.1 equiv), H–
c
1
the borane. The product ratio was estimated based on the H
NMR analysis of the unpurified product mixture. dThe
catecholate moiety was replaced by 1,8-diaminatonaphthalene
before purification.
b
B(dan) (1.0 equiv), toluene ([2]0 = 0.1 M). Isolated yields
relative to H–B(dan). cThe Z/E ratio was estimated based on the
1H NMR analysis of the unpurified product mixture. dTaken from
entry 1 in Table 1.
Next, we studied the impact of the structure of the NHC
ligand on the (Z)-selectivity in the hydroboration of 2a and 4-
bromophenylacetylene (2b) with H–B(dan) (Table 2). When
other ruthenium complexes with unsaturated and/or bulkier
NHC ligands (1b–d) were used as the precatalysts, the (Z)-
selectivity toward 3a decreased (entries 1–4). In the reaction
of 2b, 1a was less effective (entry 5). To develop a catalyst with
a wider scope in the (Z)-selective hydroboration, we
examined the reaction of 2b with several [Ru(NHC)]
complexes (1e–g; entries 6–8). The catalytic activity of the
styryl complex [RuCl(CH=CHPh)(CO)(H2IMes)(PCy3)]
(1e), which we discovered to be air-stable in the solid state and
in solution, exhibited comparable activity to that of 1a (entry
6). When a methoxy group was introduced at the para-
position of the N-aryl moiety in the NHC ligand, the yield and
(Z)-selectivity toward 3b increased (entry 7). Assuming that
the steric effect of the substituent in the NHC ligand on the
Subsequently, we investigated the scope of this
hydroboration with respect to alkyne substrates, testing
various aryl, heteroaryl, and aliphatic terminal alkynes 2
(Table 3). Generally, the products (3) were isolated in > 90%
yields under the established optimal conditions, and the
isomers can be separated by column chromatography. 4-
Substituted (Z)-styrylboranes 3a–f were obtained with high
(Z)-selectivity from the corresponding arylacetylenes,
regardless of the substituents. The (Z)-selectivity of the
products should be affected by not only the substrates but also
the ruthenium complexes. Moreover, the reaction of 2a could
be carried out i) on the gram-scale and ii) with 0.01 mol % of
1e, which indicates that the turnover number of the
[Ru(NHC)] complex reached ca. 9800. The hydroboration of
the alkynyl moiety in 4-vinylphenylacetylene (2f) proceeded
selectively to afford 3f in a 93:7 Z/E ratio, and the
hydroboration of the vinyl group was not observed. Although
the Z/E ratio of 3g was low in the reaction of 3-
bromophenylacetylene (2g) in the presence of 1e, the ratio
increased to 94:6 when 1g was employed as the precatalyst. In
contrast, the (Z)-selective hydroboration of 3-
methoxyphenylacetylene (2h) using 1e afforded 3h in a 94:6
reaction
would
be
significant,
we
tested
[RuCl(CH=CHPh)(CO)(H2IMest-Bu)(PCy3)] (1g) as a
precatalyst. The reaction of 2b with H–B(dan) furnished 3b in
a 94:6 Z/E ratio (entry 8).
Table 2. Impact of the Structure of the Ruthenium Complex on
the (Z)-Selective Hydroborationa
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Z/E ratio. The meta-substituent appears to be the main factor
examples of a metal-catalyzed (Z)-selective hydroboration of
ethynylthiophenes, particularly when using 2-
ethynylthiophene (2o). The hydroboration of 1-hexyne (2q)
afforded 3q in high yield, albeit that the Z/E ratio was lower
compared to other examples.
1
2
3
4
5
6
7
8
that determines the (Z)-selectivity in these reactions.
Although the observed (Z)-selectivity was low for the reaction
of 2-bromophenylacetylene (2i) in the presence of 1e, the
Z/E ratio of 3i increased to 70:30 when the bulkier H2IMest-
Bu-ligated complex 1g was employed.
Moreover, we found that the current catalytic system can be
applied to hydroboration of an internal alkyne. Thus,
diphenylacetylene (2r) was treated with H–B(dan) in the
presence of 1g to furnish 1,2-addition product 3r in 96% yield
(E/Z = 30:70) (Scheme 2). This result reveals promising
potential for the development of metal-catalyzed trans-
hydroborations of diarylalkynes that would complement the
existing trans-hydroborations of internal alkynes.7a,11–13
Table 3. Scope and Limitations Regarding the Terminal Alkynes
a
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Scheme 2. Hydroboration of Diphenylacetylene with H–
B(dan)a
1
aThe E/Z ratio was estimated based on the H NMR analysis of
the unpurified product mixture.
To gain insight into the mechanism underlying this (Z)-
selective hydroboration, we carried out a deuterium-labeling
experiment and stoichiometric reactions (Scheme 3). The
hydroboration of 1-phenylacetylene-2-d (2a-d) with H–
B(dan) in the presence of 1e furnished the deuterium-
retention product 3a-d (Scheme 3a). This result indicates that
the present ruthenium-catalyzed (Z)-selective hydroboration
with H–B(dan) involves a formal 1,2-anti-addition of H–
B(dan) to the terminal alkynes and proceeds via a pathway that
is distinctly different from previously reported metal-
catalyzed (Z)-selective hydroboration reactions that shown in
Scheme 1a.2–5,7
A reaction between hydrido complex 1a and H–B(dan) was
not observed at 70 °C,14 but the reaction of 1a and 2a
proceeded at room temperature to afford styryl complex 1e in
94% yield (Scheme 3b).15 The treatment of 1e with H–B(dan)
for 2 h at 70 °C resulted in the formation of the boryl complex
[RuCl{B(dan)}(CO)(H2IMes)(PCy3)] (1h) in 54% isolated
yield (Scheme 3b).16 When 1h was employed as the
precatalyst, 3a was obtained in yield and Z/E ratio comparable
to those when using 1a and 1e, albeit a higher temperature was
required (Scheme 3c).17
aGeneral reaction conditions: 1 (1.0 mol %), 2 (1.1 equiv), H–
b
B(dan) (1.0 equiv), toluene ([2]0 = 0.1 M). Isolated yields
relative to H–B(dan). cThe Z/E ratio was estimated based on the
d
1H NMR analysis of the unpurified product mixtures. Isolated
yields of the (Z)-isomers after chromatographic separation are
shown in parenthesis.
The high functional-group tolerance was demonstrated by
employing disubstituted phenylacetylenes 2j–m, 2-
ethynylnaphthalene (2n), as well as heteroarylalkynes 2o and
2p as substrates. The reactions of 2j–m in the presence of 1g
produced 3j–m with high (Z)-selectivity, even when hydroxy
and amino groups were introduced at the benzene ring, albeit
longer reaction time and/or higher temperature were required
for the reactions of 2j–k. The compatibility of the thiophene
ring is noteworthy (cf. 3o and 3p), as it provides two very rare
Scheme 3. Mechanistic Studies
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concomitant regeneration of borylruthenium D. The E-to-F
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isomerization should be the critical step to achieve high (Z)-
selectivity in this reaction. The presence of a bulky substituent
at the para-position of the N-aryl group bound to the NHC
ligand and/or the use of a bulky H–B(dan) would accelerate
the isomerization and the (Z)-isomer would be generated as
the major product.
Scheme 4. Proposed Catalytic Cycle
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On the basis of the aforementioned experiments, a
modified Chalk-Harrod-type mechanism, which has been
proposed for transition-metal-catalyzed hydrosilylation
reactions of alkynes and alkenes,18,19 should be operative in the
present ruthenium-catalyzed (Z)-selective hydroboration of
terminal alkynes with H–B(dan) (Scheme 4). A migratory
insertion of the terminal alkyne into the Ru–H bond of
hydrido complex A generates styryl complex B,15 which
should undergo σ-bond metathesis with H–B(dan) after
liberation of PCy3 to yield boryl complex D and styrene.16
Subsequently, the migratory insertion of 2 into the Ru–B bond
of D would afford borylethenyl complex E.20 Due to the steric
repulsion between the NHC ligand in the ruthenium complex
and the B(dan) group, the rapid isomerization from E to F
should proceed through a zwitterionic species21 or a
Finally, we demonstrated the synthetic utility of the
obtained (Z)-alkenyl-B(dan) 3 by synthesizing analogues of
Combretastatin A-4.25 Although Suzuki–Miyaura cross-
coupling reactions of alkenyl-B(dan) derivatives usually
require the removal of the dan moiety under acidic conditions,
which generates the corresponding reactive boronic acids,26
we accomplished the first Suzuki–Miyaura cross-coupling of 3
without removing the dan group (Table 4). 27 Thus, when (Z)-
3, which was obtained by chromatographic separation, was
treated at 70 °C with 3,4,5-trimethoxyiodobenzene in toluene
in the presence of [Pd2(dba)3]×CHCl3, PPh3, and KOt-Bu, the
corresponding (Z)-diarylethenes (4a–d) were obtained in
high yields under retention of the stereochemistry. These
compounds represent prospective inhibitors of tubulin
polymerization and exhibit antifeedant activity.28–31 This
hydroboration–cross-coupling sequence thus enables the
rapid synthesis of sterically demanding (Z)-diarylethenes.
metallacyclopropene intermediate (G).22,23
A
similar
metallacyclopropene intermediate has been proposed in the
ruthenium-catalyzed trans-hydroboration of internal
alkynes,11b,c albeit the overall process is significantly different
from that shown in Scheme 4. We assume that the E-to-F
isomerization is fast and reversible, and that F, which should
be in equilibrium between a potential catalytic resting state
H,24 is the major isomer in most examples. When the E-to-F
isomerization does not proceed smoothly, or when the E/F
ratio is high, (E)-alkenylboranes could be formed via the σ-
bond metathesis of E with H–B(dan). Finally, F could react
with H–B(dan) to afford (Z)-alkenylboranes 3 under
In conclusion, we have developed a (Z)-selective
hydroboration of terminal alkynes with H–B(dan) using well-
defined [Ru(NHC)] complexes. Mechanistic studies provide
a new rationale for the (Z)-selective hydroboration of terminal
alkynes based on the borylmetalation of the alkynes followed
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(1) (a) Organoboranes for Syntheses, ACS Symposium Series 783;
by the rapid isomerization. The obtained (Z)-alkenyl-B(dan)
derivatives are useful substrates for Suzuki–Miyaura cross-
coupling reactions that afford potentially bioactive (Z)-
diarylethene substances.
Ramachandran, P. V.; Brown, H. C., Eds.; American Chemical Society:
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Probes for Site-Selective Labeling of Proteins. Angew. Chem., Int. Ed. 2018,
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1
2
3
4
5
6
7
8
Table 4. Direct Cross-Coupling of (Z)-Alkenyl-B(dan) 3a
Ar
B(dan)
3 (Z/E = >99:1)
(1.25 equiv)
[Pd2(dba)3]•CHCl3 (2.0 mol %)
PPh3 (4.0 mol %)
1.0 M KOt-Bu/THF (2.5 equiv)
Ar
9
+
I
OMe
OMe
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toluene (0.05 M)
70 °C, 24 h
OMe
OMe
MeO
4 (Z/E = >99:1)
MeO
(1.0 equiv)
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5207.
OMe
OMe
F
OMe
MeO
MeO
MeO
MeO
OMe
4a: 90%
4b: 85%
OMe
OMe
OMe
S
O
O
MeO
MeO
OMe
4e: 88%
4f: 89%
aGeneral reaction conditions:
3
(1.25 equiv), 3,4,5-
trimethoxyiodobenzene (1.0 equiv), [Pd2(dba)3]·CHCl3 (2.0
mol %), PPh3 (4.0 mol %), KOt-Bu (2.5 equiv), toluene
([aryliodide]0 = 0.05 M). The Z/E ratio (> 99:1) was estimated
1
based on the H NMR analysis of the unpurified product
mixtures. Isolated yields are shown.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures and characterization data (PDF)
X-ray crystallographic data (CIF)
AUTHOR INFORMATION
Corresponding Author
* E-mail: ymutoh@rs.tus.ac.jp (Y.M.).
* E-mail: ssaito@rs.kagu.tus.ac.jp (S.S.).
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This research was supported by the Foundation for Interaction in
Science and Technology (FIST), Japan. We would also like to
thank Mr. Shotaro Ito, Dr. Takuya Kuwabara, and Prof. Youichi
Ishii at Chuo University ( Japan) for elemental analysis
measurements.
(11) (a) Fürstner, A. trans-Hydrogenation, gem-Hydrogenation, and
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Chung, L. W.; Wu, Y.-D. A Combined DFT/IM-MS Study on the Reaction
Mechanism of Cationic Ru(II)-Catalyzed Hydroboration of Alkynes. ACS
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