Stepwise Suzuki?Miyaura Cross-Coupling of Triborylalkenes Derived from Alkynyl?B(dan)s: Regioselective and Flexible Synthesis of Tetrasubstituted Alkenes

Article abstract of DOI:10.1002/adsc.202001116

Alkenes with three boryl groups of differing reactivities were synthesized and subsequently cross-coupled regioselectively with aryl halides in a stepwise manner to afford tetrasubstituted alkenes. The key triborylalkene is derived from the platinum-catalyzed diboration of alkynyl?B(dan)s with B₂(pin)₂. Due to excellent regioselectivity and reaction efficiency of each step starting with alkynyl?B(dan)s, tetrasubstituted alkenes with desired carbon frameworks at desired positions can be prepared in high yields. For example, an alkene with four distinct aryl groups, p-MeOC₆H₄, p-CF₃C₆H₄, p-MeC₆H₄, and p-NCC₆H₄, was obtained in 71% overall yield via six steps, starting with the dehydrogenative borylation of p-MeC₆H₄C≡CH with HB(dan). Moreover, a variety of tetrasubstituted alkenes, including regio- and stereoisomers of the above tetraarylalkene, AIE-active TPTPE and derivatives thereof, and (Z)-tamoxifen, a well-known breast cancer drug, were accessed via the developed strategy. (Figure presented.).

Full text of DOI:10.1002/adsc.202001116

Title: Stepwise Suzuki–Miyaura Cross-Coupling of Triborylalkenes
Derived from Alkynyl–B(dan)s: Regioselective and Flexible
Synthesis of Tetrasubstituted Alkenes
Authors: Tomohiro Tani, Naomi Takahashi, Yuuki Sawatsugawa, Mana
Osano, and Teruhisa Tsuchimoto
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202001116
Link to VoR: https://doi.org/10.1002/adsc.202001116

10.1002/adsc.202001116
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Stepwise Suzuki–Miyaura Cross-Coupling of Triborylalkenes
Derived from Alkynyl–B(dan)s: Regioselective and Flexible
Synthesis of Tetrasubstituted Alkenes
Tomohiro Tani,a Naomi Takahashi,a Yuuki Sawatsugawa,a Mana Osano,a and Teruhisa
Tsuchimotoa,*
a
Department of Applied Chemistry, School of Science and Technology, Meiji University, 1-1-1 Higashimita, Tama-ku,
Kawasaki 214-8571, Japan
Fax: (+81)-44-934-7228
E-mail: tsuchimo@meiji.ac.jp
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Alkenes with three boryl groups of differing was obtained in 71% overall yield via six steps, starting
reactivities were synthesized and subsequently cross-coupled with the dehydrogenative borylation of p-MeC6H4CCH
regioselectively with aryl halides in a stepwise manner to with HB(dan). Moreover, a variety of tetrasubstituted
afford tetrasubstituted alkenes. The key triborylalkene is alkenes, including regio- and stereoisomers of the latter,
derived from the platinum-catalyzed diboration of alkynyl– AIE-active TPTPE and derivatives thereof, and (Z)-
B(dan)s with B2(pin)2. Due to excellent regioselectivity and tamoxifen, a well-known breast cancer drug, were accessed
reaction efficiency of each step starting with alkynyl– via the developed strategy.
B(dan)s, tetrasubstituted alkenes with desired carbon
frameworks at desired positions can be prepared in high
yields. For example, an alkene with four distinct aryl groups,
namely p-MeOC6H4, p-CF3C6H4, p-MeC6H4, and p-NCC6H4,
Keywords: Alkynes; Boron; C–C coupling; Conjugation;
Homogeneous catalysis; Materials science
monometalated alkenes prepared via the first stages
of Schemes 1a and 1b have been utilized as reagents
for the assembly of tetrasubstituted alkenes (Schemes
1a and 1b),[9a,10,13] which can also be derived from
dimetalated alkenes with two different or identical
carbon–metal bonds via two-step cross-coupling
reactions (Schemes 1c and 1d).[12,14] In contrast to
remarkable development of strategies depicted in
Schemes 1a–1d, significantly fewer studies exist
regarding stepwise cross-coupling reactions of
trimetalated alkenes, probably due to the difficulty in
discriminating between the three carbon–metal bonds
to achieve regioselective cross-coupling reactions
(Scheme 1e). To the best of our knowledge, only two
groups have achieved the synthesis of tetrasubstituted
alkenes via three-step cross-coupling reactions. The
Nishihara group utilized diborylsilylalkenes.[15] The
Ito group employed alkenes with boron, silicon, and
copper atoms in such an approach;[16] therein, a non-
cross-coupling transformation to convert the C–Si
bond to a C–halide bond, which in turn participates in
the cross-coupling reaction, is included. A major
advantage of conducting stepwise cross-coupling
reactions is the broad scope of carbon units that can
be installed on the C=C core in a pre-determined
order, allowing for the assembly of structurally
diverse tetrasubstituted alkenes. Related to the two
precedents, two types of triborylalkenes with all of
Introduction
Tetrasubstituted alkenes are important structural
motifs in various functional molecules, including
optoelectronic materials and bioprobes based on
aggregation-induced emission (AIE) fluorogens,[1] as
well as bioactive compounds and pharmaceuticals.[2]
To date, a variety of strategies for the preparation of
tetrasubstituted alkenes have emerged in the
literature;[3] among them, cross-coupling-based
derivatization of metalloid- and metal-substituted
alkenes [metal(loid) = B,[4] Si,[5] and Sn,[6] among
others[7]] has become a practical and reliable
approach, in terms of high functional group tolerance
and stereoselectivity.[8] Hereinafter, "metalloid and
metal" are collectively referred to as "metal". In this
context, carbometalation of alkynes is among the
most straightforward methods for the preparation of
monometalated alkenes (first stage in Scheme 1a).[9]
In addition, ligand-controlled stereodivergent
diarylation
of
alkynylborates
leading
to
monoborylalkenes has been reported (first stage in
Scheme 1b).[10] Regarding dimetalated alkenes, either
dimetalation of alkynes[11] or carbometalation of
alkynylmetals[12] has been successfully employed
(first stage in Scheme 1c or 1d). In fact,
1
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10.1002/adsc.202001116
Advanced Synthesis & Catalysis
carbometalation
stepwise
Nishihara, 2014
SMCC reactions
[a]
R1
syn or anti
cross-coupling
reaction
R3
R1
M
R3
R1
R4
R2
X–Ar2
cat. Pd
addition
Ar2
R1
B(pin)
Ar2
R1
Ar3
Ar4
R2
(pin)B
R1
B(pin)
R2
B(mida)
B(mida)
diarylation
[b]
R1
syn or anti
Ar2 Ar3
Ar2 Ar3
addition
SMCC reaction
Ozerov, 2015
Marder, 2020
stepwise
SMCC reactions
B
R1
B
R1
Ar4
X–Ar2
cat. Pd
(pin)B
Ar1
B(pin)
(pin)B
Ar1
Ar2
Ar3
Ar1
Ar2
Ar4
stepwise
cross-coupling
dimetalation
syn or anti
addition
[c]
R1
M
M' reactions
R3
R1
R4
R2
B(pin)
B(pin)
R2
R1
R2
double SMCC reaction
O
O
N
stepwise
cross-coupling
O
O
carbometalation
X–Ar3, X–Ar3
cat. Pd
B
O
B
[d]
R1
Ar3
Ar1
Ar2
Ar3
R2
R1
M' reactions
R2
R1
R3
R4
O
syn addition
M
B(pin)
B(mida)
M
Stang/Zhao, 2020
stepwise
cross-coupling
reactions
dimetalation
[e]
R1
Scheme 2. Previous reports on SMCC reaction of
triborylalkenes.
M'
M"
M
R4(3) R2
R1 R3(4)
syn addition
M
R1
R1
B(dan) 1
Scheme 1. Preceding approaches from metal-substituted
alkenes to tetrasubstituted alkenes.
H
N
B(dan):
B
diboration (pin)B B(pin)
N
H
the same C–B bonds have been prepared on a
preparative scale: the first contains two B(pin)s and
one B(mida) (mida = N-methyliminodiacetate),[17]
and the other consists of three B(pin)s (pin =
pinacolate) (Scheme 2).[18] However, the three C–B
bonds of these triborylalkenes have not been utilized
in stepwise Suzuki–Miyaura cross-coupling (SMCC)
reactions. Attempts by the Nishihara, Ozerov, and
Marder research groups have accomplished only the
first SMCC reaction:[17,19] the triborylalkene prepared
by the Nishihara group cross-couples with X–Ar2 at
the different site of the C–B(pin) bond, unlike those
reported by other research groups. Very recently, the
Stang and Zhao groups synthesized tetraarylalkenes
from the triborylalkene with three B(pin)s. However,
stepwise SMCC reactions of two C–B(pin) bonds that
remained after the first SMCC reaction have yet to be
attained.[20] These precedents indicate the difficulty in
the stepwise execution of the regioselective cross-
coupling reactions of trimetalated alkenes with
identical carbon–metal bonds.
On the other hand, we have reported that terminal
alkynes dehydrogenatively couple with HB(dan) (dan
= 1,8-diaminonaphthyl) to give alkynyl–B(dan)s
under zinc–pyridine catalysis in a nitrile solvent.[21]
We envisioned that triborylalkenes, potentially
accessed by diboration of alkynyl–B(dan)s, could
lead to the first successful tetrasubstituted alkene via
three-step cross-coupling reactions. Our working
hypothesis is depicted in Scheme 3. The first step
entails the addition of (pin)B–B(pin) to alkynyl–
B(dan) 1 to afford triborylalkene 2. The C(sp2)–
B(dan) bond of 2 has generally been recognized to be
inactive under conditions of the SMCC reaction; this
unique concept as a masked boryl group of the
B(dan) was introduced by Suginome and colleagues
in 2007.[22,23] Therefore, the achievement of the
regioselective SMCC reaction at the two C–B(pin)
bonds is required. As previously reported, B(pin) and
2nd
1st
stepwise SMCC reactions
X–R2
(pin)B
B(pin)
R3
R1
R2
R4
X–R3
X–R4
R1
B(dan)
2
final
Scheme 3. A working hypothesis for the synthesis of
tetrasubstituted alkenes via stepwise SMCC reactions of
triborylalkenes derived from alkynyl–B(dan)s.
B(dan) groups having a B(sp2) atom show strong
electron-withdrawing properties, in contrast to a
B(sp3)-based B(mida) group, which acts as a very
weak electron-withdrawing group and thus scarcely
affects electronically.[24] This involves that 2 and all-
B(pin)-based triborylalkenes consist of only a B(sp2)-
based boryl group, in contrast to the Nishihara's
triborylalkene. We therefore predicted that the C–
B(pin) at the right side of 2 should be more reactive
towards the first SMCC reaction, as similar to the
case of the all-B(pin)-based triborylalkene. Iterative
SMCC reactions of 2 were thus expected to proceed
in the order shown in Scheme 3. We herein present
the first example to construct tetrasubstituted alkenes
in a stepwise manner from trimetalated alkenes with
identical carbon–metal bonds.[25]
Results and Discussion
We began this study by exploring the diboration of
alkynyl–B(dan)s 1 to obtain triborylalkenes 2.
Among a variety of options for the diboration of
alkynes,[11] the copper-catalyzed protocol reported by
the Yoshida group was initially examined (Scheme
4).[26] Thus, upon treatment of B2(pin)2 with
2
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10.1002/adsc.202001116
Advanced Synthesis & Catalysis
(pin)B
Hex
B(pin)
Table 1. Platinum-catalyzed diboration reaction of
alkynyl–B(dan)s.[a]
B(dan)
(pin)B–B(pin)
2k
(pin)B
B(pin)
Pt(PPh3)4 (0.5 mol%)
Cu(OAc)2 (2.7 mol%)
PCy3 (9.5 mol%)
(pin)B–B(pin)
20% yield
+
toluene, T ºC, t h
+
+
R
B(dan)
R
B(dan)
toluene, 80 ºC, 24 h
(pin)B
Hex
H
2
Hex
B(dan)
1
B2(pin)2/1k = 1.3/1
1k
B(dan)
2a (R' = H);[b] 98% yield, T = 90, t = 24
2b (R' = 2-Me); 99% yield, T = 90, t = 15
2c (R' = 4-Me);[b] 99% yield, T = 80, t = 48
2d (R' = 4-OMe);[c] 98% yield, T = 80, t = 48
2e (R' = 4-CF3);[d] 96% yield, T = 100, t = 48
2f (R' = 4-CN); 96% yield, T = 90, t = 24
2g (R' = 4-Br); 96% yield, T = 90, t = 24
3k
62% yield
(pin)B
B(pin)
B(dan)
(pin)B–B(pin)
(pin)B
Ph
B(pin)
B(dan)
Pt(PPh3)4 (0.5 mol%)
+
R'
toluene, 90 ºC, 24 h
Ph
B(dan)
2a
99% yield
B2(pin)2/1a = 1.01/1
1a
(dan)B
(pin)B
B(pin)
(pin)B
B(pin)
(pin)B
B(pin)
B(pin)
Scheme 4. Copper- or platinum-catalyzed diboration
reaction of alkynyl–B(dan)s with B2(pin)2. Yields were
determined by 1H NMR spectroscopy.
B(dan)
B(dan)
(pin)B
B(dan)
S
N
2h;[d,e] 92% yield
T = 80, t = 24
2i; 99% yield
T = 80, t = 48
2j;[f] 88% yield
T = 50, t = 48
HexC≡CB(dan) (1k) in the presence of catalytic
Cu(OAc)2 and PCy3 (Cy = cyclohexyl), the desired
triborylalkene 2k was produced in 20% yield, but the
hydroboration reaction of 1k was dominant, giving
3k in a moderate yield.[27] In contrast to this reaction,
the platinum method, originally reported by the
(pin)B
B(pin)
(pin)B
B(pin)
(pin)B
B(pin)
B(dan)
B(dan)
B(dan)
Cl
2k;[d] 92% yield
T = 90, t = 24
2l; 93% yield
T = 90, t = 24
2m; 90% yield
T = 100, t = 24
Ishiyama–Miyaura–Suzuki
group,[28]
and
subsequently modified by the Srebnik group,[18a]
proved to be the method of choice for the diboration
of 1 (Scheme 4). With 1a as a substrate, the
diboration reaction proceeded smoothly, thereby
giving triborylalkene 2a almost quantitatively. This
reaction has several practical advantages: 1) only 0.5
mol% of the catalyst Pt(PPh3)4 is sufficient; 2) the use
of B2(pin)2 and 1a in near equimolar amounts avoids
the wasteful use of substrates; 3) the quantitative
formation of 2a enables its purification by only
simple filtration through silica gel impregnated with
boric acid [B(OH)3]: the B(OH)3-impregnated SiO2 is
effective for the purification of B(pin)-containing
compounds due to suppressing over-absorption to
silica gel.[29]
With the platinum method in hand, the scope of the
diboration was examined (Table 1). Besides 1a, a
range of sterically and electronically different
aromatic alkynyl–B(dan)s reacted successfully with
B2(pin)2 to provide 2b–2g in ≥ 96% yields.[30]
Alkynyl–B(dan) 1h with two C≡CB(dan) units in a
single molecule underwent double diboration, giving
2h with six boryl groups. Triborylalkenes 2i and 2j
with thienyl and pyridyl rings, respectively, were also
obtained. In addition to these (hetero)aromatic
alkynyl–B(dan)s, a series of 1 bearing linear and
branched alkyl groups, with or without a functional
group, participated favorably in this diboration
reaction, delivering 2k–2p in high yields. The
compatibility of various functionalities, including
CF3, CN, Br–C(sp2), pyridyl, Cl–C(sp3), ester, SO2,
and amino groups, with this protocol allows for the
access to a diverse range of 2. However, the
diboration of 1q and 1r was unsuccessful, due to low
and no conversions, respectively (Figure 1). As with
2a, purification by simple filtration through B(OH)3-
(pin)B
B(pin)
(pin)B
B(pin)
B(dan)
(pin)B
B(pin)
B(dan)
B(dan)
N
CN
O
O
S
O
O
2n; 95% yield
T = 90, t = 24
2o; 92% yield
T = 90, t = 24
2p; 85% yield
T = 90, t = 24
[a]
Reagents: B2(pin)2 (0.101 mmol), 1 (0.100 mmol),
Pt(PPh3)4 (0.500 mol), toluene (0.80 mL). Yields of
isolated 2 based on 1 are shown here.
10.0 mmol scale.
Performed on a 0.200 mmol scale.
mmol) and Pt(PPh3)4 (6.00 mol) were used. Performed
with B2(pin)2 (0.110 mmol) in THF (0.80 mL) instead of
toluene.
[b]
Performed on a
[c]
[d]
Performed on a 2.50 mmol scale.
[e]
B2(pin)2 (0.404
[f]
O
PhS
B(dan)
B(dan)
1q
1r
Figure 1. Incompatible alkynyl–B(dan)s with platinum-
catalyzed diboration reaction.
impregnated SiO2 was applicable to the other
products, except for 2h, 2j, and 2p. The purification
of 2j required recycling gel permeation
chromatography. In contrast, 2h and 2p were purified
by only washing with hot hexane. Rapid and simple
purification is crucially beneficial when scaling up. In
fact, we confirmed that, for instance, 2c and 2d could
be prepared on 10 and 2.5 mmol scales, respectively,
as shown in Table 1, thereby delivering 5.31 g of 2c
and 1.35 g of 2d.
3
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10.1002/adsc.202001116
Advanced Synthesis & Catalysis
Table 2. Palladium-catalyzed SMCC reaction of
triborylalkene 2c with 4-iodobenzotrifluoride.[a]
Having obtained 2c with three boryl groups, we
next explored the regioselective SMCC reaction
thereof (Table 2). When a mixture of 2c and 4-
iodobenzotrifluoride (4a) was treated with 5 mol% of
external-ligand-free PdCl2 in an aqueous (aq.)/THF
solution of K3PO4 at 70 ºC for 3 h, we were pleased
to find that 5a, formed by cross-coupling at the site
expected in advance, was obtained in 92% yield with
92% regioselectivity (entry 1). We have reported this
result previously,[21b] but have since endeavored to
improve it. Table 2 depicts the structure of desired
product 5a, as well as those of byproducts, including
regioisomer 6a, double arylated product 7a, and
others probably resulting from protodeborylation of
2c, 5a, and 6a. Although the protodeborylated
byproducts could not be isolated in pure form, their
(pin)B
B(pin)
+
I
CF3
B(dan)
4a
2c
PdCl2 (5 mol%) THF
base (3 equiv.) 70 ºC, 3 h
CF3 F3C
F3C
CF3
(pin)B
B(pin)
B(dan)
+
+
B(dan)
B(dan)
5a
6a
7a
1
formation was confirmed by H NMR, GC-MS, and
others:
(pin)B
CF3 F3C
HRMS analyses (see Supporting Information for
details). Using aq. K2CO3, Cs2CO3, LiOH, and KOH
increased yields of the protodeborylation products
(entries 2–4, and 6). In contrast, the choice of aq.
NaOH effectively suppressed the protodeborylation
reaction and improved the selectivity of 5a (entry 5).
However, the yield of 7a increased in this case, likely
due to the stronger basicity of NaOH, which may
accelerate the transmetalation. This trend was also
observed when aq. KOH with even stronger basicity
was used (entries 5 and 6). Due to favorable
performances of aq. K3PO4 and NaOH, these dried
bases were tested. With dried K3PO4, interestingly,
the SMCC reaction gave opposite isomer 6a over 5a,
albeit moderately (entry 7). The use of dried NaOH
was effective for enhancing the selectivity of 5a, but
again resulted in the formation of a significant
amount of 7a (entry 8). However, it was found that
lowering both the reaction temperature and NaOH
loading reduced the double arylation (entries 9 and
10). The excellent yield and selectivity shown in
entry 10 was finally accomplished when using 2.5
molar equivalents of dried NaOH at 50 ºC. It should
be noted that the reaction with equimolar amounts of
2c and 4a can be performed.
H
H
H
B(dan)
B(dan)
B(dan)
Yield [%] of
5a + 6a (5a/6a) 7a others
Entry Base
1
2
3
4
5
6
7
1.5 M K3PO4 aq.
1.5 M K2CO3 aq.
1.5 M Cs2CO3 aq. 62 (68:32)
1.5 M LiOH aq.
1.5 M NaOH aq.
1.5 M KOH aq.
K3PO4 dried
92[b] (92:8)
49 (69:31)
4
4
4
4
11
4
39
33
41
4
46 (98:2)
85 (95:5)
54 (89:11)
84 (30:70)
81 (97:3)
84 (97:3)
94 (97:3)
15 12
9
15
8
1
4
8
2
8
NaOH dried
NaOH dried
9[c]
10[c,d] NaOH dried
4
[a]
Reagents: 2c (0.10 mmol), 4a (0.10 mmol), PdCl2 (5.0
mol), base (0.30 mmol), THF (1.0 mL). Yields of
products and ratios of 5a/6a were determined by 1H NMR.
[b]
[c]
[d]
Isolated yield.
Performed at 50 ºC.
Dried NaOH
(0.25 mmol) was used.
For a mechanistic understanding, we analyzed a
residue of the B(pin) group after the SMCC reaction.
Upon the addition of H2O followed by the extraction
with Et2O, as similar to the usual workup of the
reaction mixture (see Experimental Section), no
pinacol, which is possibly formed by the hydrolysis
of the B(pin) during the reaction, was detected from
the organic phase; it is separately confirmed that
pinacol in aq. NaOH can be extracted with Et2O.
Moreover, the generation of (pin)BOB(pin)[31] was
confirmed when aq. NH4Cl instead of H2O was used
for quenching: note that (pin)BOB(pin) cannot be
extracted from an aq. base. These results reveal that
the SMCC reaction proceeds through a borate
intermediate, C(sp2)–[B(pin)OH]–, not a hydrolysis of
the B(pin), and would thus be informative for further
mechanistic studies.
reaction conditions established in Table 2 were also
well suited to unsubstituted aryl iodide 4c, as well as
to those bearing CN (4b) and OMe groups (4d, 4e).
However, fine-tuning of conditions was necessary,
depending on the electronic and steric nature of 4.
Thus, when using electron-rich aryl iodide 4d,
lowering the reaction temperature from 50 to 40 °C
was beneficial for avoiding double arylation and
protodeborylation of 2c (cf. yields of 5d: 63%,
double arylation: 15%, and protodeborylation: 10%
under the standard reaction conditions). The reaction
of sterically congested aryl iodide 4e required a
higher loading of 4e (1.3 molar equivalents) and a
higher temperature of 70 ºC (cf. yield of 5e: 45%
under the standard reaction conditions).
When the reaction conditions used for iodide 4a
were applied to the corresponding bromide, p-
BrC6H4CF3 (4’a), the yield of 5a + 6a was low,
whereas the high selectivity for 5a was maintained
Our attention then turned to explore the scope of
the first SMCC reaction (Table 3). Gratifyingly, the
4
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10.1002/adsc.202001116
Advanced Synthesis & Catalysis
Table 3. Palladium-catalyzed SMCC reaction of triborylalkenes with aryl halides.[a]
(pin)B
B(pin)
(pin)B
Ar
Ar
R
B(pin)
PdCl2 (5 mol%)
X
Ar
+
+
NaOH (2.5 equiv.)
THF, T ºC, t h
R
B(dan)
R
B(dan)
B(dan)
2
4
6
5
yield of 5 + 6 (5/6)
scope of I–Ar 4:
CF3
CN
scope of R in 2:
(pin)B
(pin)B
(pin)B
(pin)B
B(dan)
B(dan)
B(dan)
B(dan)
MeO
5a (2c + 4a)
94% (96:4)
T = 50, t = 3
5b (2c + 4b)
90% (96:4)
T = 50, t = 3
5f (2d + 4c)
87% (99:<1)
T = 40, t = 16
5g (2a + 4c)
90% (96:4)
T = 50, t = 6
O
O
(pin)B
(pin)B
(pin)B
(pin)B
(pin)B
B(dan)
B(dan)
B(dan)
B(dan)
B(dan)
F3C
5c (2c + 4c)
90% (96:4)
T = 50, t = 3
5d (2c + 4d)
90% (99:1)
T = 40, t = 3
5e (2c + 4e)[b]
75% (99:<1)
T = 70, t = 4
5h (2e + 4c)
83% (97:3)
T = rt, t = 30
5i (2b + 4c)
90% (99:<1)
T = 50, t = 24
scope of Br–Ar 4':
CF3
O
(pin)B
(pin)B
(pin)B
(pin)B
Cl
(pin)B
B(dan)
B(dan)
B(dan)
B(dan)
B(dan)
CN
5a (2c + 4'a)[c]
85% (97:3)
T = 50, t = 3
5d (2c + 4'd)[c]
70% (99:1)
T = 50, t = 3
5j (2k + 4c)[d]
85% (99:<1)
T = rt, t = 48
5k (2m + 4c)
92% (99:<1)
T = rt, t = 48
5l (2n + 4c)[e]
78% (99:<1)
T = rt, t = 48
[a] Reagents: 2 (0.10 mmol), 4 (0.10 mmol), PdCl2 (5.0 mol), dried NaOH (0.25 mmol), THF (1.0 mL). Yields of isolated
1
[b]
[c]
5 are shown here. Ratios of 5/6 were determined by H NMR.
Performed with 4e (0.13 mmol).
Performed with
PdCl2(dppf) (5.0 mol) instead of PdCl2, and with a 1.5 M KOH aq. solution (0.17 mL, 0.25 mmol of KOH) instead of
dried NaOH. [d] Performed with 4c (0.11 mmol). [e] PdCl2(CH3CN)2 (5.0 mol) was used instead of PdCl2.
(Table 4, entry 1). Switching the base to aq. KOH
increased the yield, but diminished the selectivity
(entry 2). However, the participation of a phosphine
ligand proved beneficial for increasing both the yield
and selectivity. After a brief screening of palladium–
phosphine complexes, the yield and regioselectivity
were improved to 86% and 96%, respectively, with
the use of the catalyst PdCl2(dppf) (entries 3–5); the
results of entry 5 after isolation are given in Table 3.
Under the modified reaction conditions, electron-rich
p-BrC6H4OMe (4’d) also underwent the SMCC
reaction with 2c to give 5d almost exclusively.
The scope of the R group in 2 was likewise broad,
as shown on the right side of Table 3, where I–Ph
(4c) was used as the other coupling partner. Similar
to 2c with the p-tolyl group (see the left side of Table
3), 2 with electronically and sterically different aryl
groups reacted with 4c in a highly regioselective
manner to afford 5f–5i in high yields, though a lower
reaction temperature and/or prolonged reaction time
was necessary. Furthermore, 2 derived from alkynyl–
B(dan)s with linear and functionalized alkyl groups
reacted smoothly. Worthy of note is that 5j, 5k, and
5l were obtained as single regioisomers. Note that,
under the standard reaction conditions using
phosphine-free PdCl2 as a catalyst, the reaction of 2n
provided 5l contaminated with a significant amount
of 6l in an 80:20 ratio. This might be ascribed to
complexation of the good-coordinating cyano group
in 2n with a palladium intermediate,[32] which in turn
is possibly directed toward the B(pin) group geminal
to the (CH2)4CN group to form 6l. On the basis of this
assumption, the acetonitrile-precoordinated palladium
complex, PdCl2(CH3CN)2, was tested in an attempt to
avoid the undesired in situ complexation.
Gratifyingly, this led to the exclusive generation of 5l
in a good yield.
As stated above, the first SMCC reaction of 2 was
successfully achieved in a regioselective manner. The
level of difficulty in controlling the regioselectivity of
the ensuing SMCC reaction of 5, having one B(pin)
and one B(dan) groups with distinctly different
5
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10.1002/adsc.202001116
Advanced Synthesis & Catalysis
Table 4. Palladium-catalyzed SMCC reaction of
triborylalkene 2c with 4-bromobenzotrifluoride.[a]
utilize this strategy, the consideration of certain
factors is crucial. For example, upon the second
SMCC reaction of 5b with the strongly electron-
withdrawing cyano group under the standard reaction
conditions, significant protodeborylation of the
C(sp2)–B(dan) bond was observed, likely due in part
to the enhanced Lewis acidity of the B(dan) moiety:
7c, and a protodeborylated product where the B(dan)
of 7c is protonated, were formed in 58% and 32%
yields, respectively. This can be avoided by
decreasing the concentration of aq. KOH and
equivalents of KOH, as shown in Table 5.
(pin)B
B(pin)
+
Br
CF3
B(dan)
PPh2
PPh2
4'a
Fe
2c
Pd (5 mol%)
THF
dppf
base (2.5 equiv.) 50 ºC, 3 h
CF3 F3C
PCy2
OMe
MeO
(pin)B
B(pin)
A salient feature of this strategy is the high overall
yields of tetraarylalkenes 9, despite requiring six
steps from the terminal alkyne, p-tolylCCH, as a
starting substrate (Scheme 5). This is owing to the
high reaction efficiency of ≥ 90% of each step, thus
reaching 71%, 60%, and 70% overall yields of 9a, 9b,
and 9c, respectively. Accordingly, this protocol will
be one of the practical and reliable choices among
various repertoires in a synthetic toolbox when
tetraarylalkenes having desired aryl units at desired
positions are needed.
To expand the applicability of this strategy, we
turned our attention to the assemble of novel AIE-
based molecules. The concept of AIE was first
proposed by Tang's group in 2001.[34] AIE molecules
intensely emit in the aggregate or solid state, in
contrast to most conventional organic dyes exhibiting
aggregation-caused quenching due to the strong
intermolecular - stacking interaction.[1] Organic
molecules with a tetraarylalkene structure have thus
attracted much attention owing to their prominent
+
B(dan)
B(dan)
SPhos
5a
6a
Yield [%] of
Entry Pd
Base
5a + 6a (5a/6a)
1
2
PdCl2
PdCl2
NaOH dried
1.5 M KOH aq.
21 (97:3)
49 (74:26)
65 (98:2)
67 (98:2)
86 (96:4)
3[b]
4
PdCl2/SPhos 1.5 M KOH aq.
Pd(PPh3)4
1.5 M KOH aq.
1.5 M KOH aq.
5
PdCl2(dppf)
[a]
Reagents: 2c (0.10 mmol), 4’a (0.10 mmol), Pd (5.0
mol), base (0.25 mmol), THF (1.0 mL). Yields of
products and ratios of 5a/6a were determined by 1H NMR.
[b] SPhos (10 mol) was used as an external ligand.
reactivities, was expected to be much lower than that
of the first SMCC reaction. Results of the second
SMCC reaction as well as those of subsequent
transformations, specifically the unmasking of the
B(dan) group followed by the final SMCC reaction,
are summarized in Table 5.
A brief screening of the reaction conditions for the
second SMCC reaction was conducted, resulting in
the following set: cat. Pd(OAc)2/SPhos in aq. 1.5 M
KOH/THF at 70 °C for 24 h. Here, a higher
temperature and longer reaction time were required
compared to those for the first SMCC reaction. The
difference is likely to reveal the lower reactivity of
the C(sp2)–B(pin) participating in the second SMCC
reaction than that of the C(sp2)–B(pin) consumed in
the first SMCC reaction. This will thus be an
important objective fact to recognize reactivities of
the two C(sp2)–B(pin)s in triborylalkenes 2.
In fact, the second SMCC reaction of 5a with 4-
iodoanisole (4d) was conducted; it was found to
occur exclusively on the B(pin)-substituted carbon
atom, thereby giving 7b in 93% yield. The ensuing
acid-mediated unmasking of the B(dan) moiety
yielded 8a with a B(pin) group.[33] This was followed
by the final SMCC reaction conducted under the
same reaction conditions as those used for the second
SMCC reaction, affording tetraarylalkene 9a, having
four different aryl groups, quantitatively. Moreover,
by simply altering the order of the aryl units
introduced onto the C=C core, we obtained 9b and 9c,
stereo- and regioisomers of 9a, respectively, in high
to excellent yields of each step, thus demonstrating
the flexibility of this strategy. However, to effectively
MeAr
H
yields of each step
dehydrogenative
borylation
step 1
Ar3
MeAr
Ar2
Ar4
HB(dan)
9a; 99%
9b; 92%
9c; 96%
MeAr
step 2
B(dan) 1c; 91%
diboration
final SMCC
I–Ar4
step 6
B2(pin)2
(pin)B
MeAr
B(pin)
Ar3
Ar2
8a; 95%
8b; 90%
B(dan)
MeAr
B(pin) 8c; 95%
2c; 99%
1st SMCC
I–Ar2
unmasking
step 3
step 5
pinacol
2nd SMCC
I–Ar3
(pin)B
MeAr
Ar2
Ar3
Ar2
MeAr
B(dan)
step 4
B(dan)
5a; 94% (5a/6a = 96:4)
5b; 90% (5b/6b = 96:4)
5d; 90% (5d/6d = 99:1)
7b; 93%
7c; 93%
7d; 96%
MeOAr
ArCF
MeOAr
MeAr
ArCN
ArCF
F CAr
ArOMe
ArCN
3
3
MeAr
ArCN
MeAr
3
9a
71% overall yield
9b
60% overall yield
9c
70% overall yield
Scheme 5. Summary on yields of each step and on overall
yields from p-tolylCCH to tetraarylalkenes. MeAr = 4-
Me–C6H4 (p-tolyl). ArCF = 4-F3C–C6H4. ArCN = 4-NC–
3
C6H4. ArOMe = 4-MeO–C6H4.
6
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10.1002/adsc.202001116
Advanced Synthesis & Catalysis
Table 5. Synthesis of unsymmetrical tetraarylalkenes from diaryldiborylalkenes via the second SMCC, unmasking, and
final SMCC reactions.
2nd SMCC
unmasking
final SMCC
I–Ar3 4 (1.2 equiv.)
Pd(OAc)2 (5 mol%)
SPhos (10 mol%)
I–Ar4 4 (1.2 equiv.)
Pd(OAc)2 (5 mol%)
SPhos (10 mol%)
(pin)B
MeAr
Ar2
Ar3
MeAr
Ar2
Ar3
MeAr
Ar2
Ar3
MeAr
Ar2
Ar4
pinacol (8 equiv.)
1.5 M KOH aq. (3 equiv.)
THF, 70 ºC, 24 h
3 M H2SO4 aq. (10 equiv.)
THF, 70 ºC, 24 h
1.5 M KOH aq. (3 equiv.)
THF, 70 ºC, 24 h
B(dan)
B(dan)
B(pin)
5
7
8
9
2nd SMCC
unmasking
final SMCC
O
CF3
O
CF3
O
CF3
B(dan)
B(pin)
CN
CN
7b (5a + 4d)
93% yield
8a
95% yield
9a (8a + 4b)
99% yield
O
CN
O
CN
O
B(dan)
B(pin)
CF3
7c (5b + 4d)[b,c]
8b
9b (8b + 4a)
93% yield
90% yield
92% yield
regioisomer of 9a
F3C
O
F3C
O
F3C
O
B(dan)
B(pin)
CN
7d (5d + 4a)[b]
8c
9c (8c + 4b)
96% yield
95% yield
96% yield
[a] Reagents for the second SMCC reaction: 5 (0.10 mmol), 4 (0.12 mmol), Pd(OAc)2 (5.0 mol), SPhos (10 mol), 1.5 M
KOH aq. solution (0.20 mL, 0.30 mmol of KOH), THF (0.30 mL). Reagents for unmasking: 7 (0.10 mmol), pinacol (0.80
mmol), 3 M H2SO4 aq. solution (0.33 mL, 1.0 mmol of H2SO4), THF (2.0 mL). Reagents for the final SMCC reaction: 8
(0.10 mmol), 4 (0.12 mmol), Pd(OAc)2 (5.0 mol), SPhos (10 mol), 1.5 M KOH aq. solution (0.20 mL, 0.30 mmol of
KOH), THF (0.30 mL). Yields of isolated 7 based on 5, 8 based on 7, and 9 based on 8 are shown here. MeAr = 4-Me–C6H4.
[b] 4 (0.15 mmol) was used. [c] Performed with a 1 M KOH aq. solution (0.25 mL, 0.25 mmol of KOH) for 32 h.
AIE performance. Therefore, by employing the
methodology developed herein, we synthesized
extended -systems 10 with a C6H4 core sandwiched
by two triarylalkenyl frameworks, as shown in Table
6, and investigated their AIE properties. The
compound with the simplest structure, 10a, being
abbreviated in general as TPTPE, has been found to
emit blue light in a THF/H2O (1/9) solution, based on
the AIE phenomenon.[35] However, little is known
about the AIE properties of TPTPE derivatives.[35b,36]
Unlike in the SMCC reaction of 2 detailed in Table
3, we first examined whether the SMCC reaction of
the two C–B(pin) bonds in 2 could be carried out in a
single step. When using Pd(PPh3)4 as a catalyst in aq.
KOH/THF, the double phenylation of 2a with I–Ph
(4c) occurred smoothly, providing 7e in a high yield
of 91%, whereas no detailed examination of the
reaction conditions was attempted here. With the
reaction conditions established in Table 5, replacing
the "dan" on the boryl atom of 7e with the "pin" in
the unmasking step, followed by a double SMCC
reaction with 1,4-C6H4I2 (4f), gave TPTPE (10a) in
85% overall yield via 3 steps from 2a. Electronically
distinct TPTPE derivatives were analogously
obtained, specifically the pull–pull type 10b with four
CN groups, neutral type 10c, and push–push type 10e
with four OMe groups. In the case of the push–pull
type 10d, the stepwise SMCC reaction was successful.
The SMCC reaction of p-IC6H4Br (4g) with 8g (Ar1 =
ArMe, Ar2 = ArOMe) entailed the I-site selective
coupling to give 9d, and the ensuing SMCC reaction
occurred between the remaining C–Br bond in 9d and
the C–B(pin) bond in 8e having two ArCN units.
With TPTPE (10a) and its derivatives (10b–10e) in
7
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10.1002/adsc.202001116
Advanced Synthesis & Catalysis
Table 6. Synthesis of TPTPE and derivatives thereof from triborylalkenes.[a]
I
I 4f
Ar2
Ar1
Ar2
(0.5 equiv.)
Pd(OAc)2 (5 mol%)
SPhos (10 mol%)
I–Ar2 4 (2.5 equiv.)
Pd(PPh3)4 (5 mol%)
(pin)B
Ar1
B(pin)
Ar2
Ar1
Ar2
Ar2
Ar1
Ar2
pinacol (8 equiv.)
1.5 M KOH aq. (6 equiv.)
THF, 70 ºC, 48 h
3 M H2SO4 aq.
(10 equiv.)
THF, 70 ºC, 24 h
1.5 M KOH aq.
(3 equiv.)
THF, 70 ºC, 24 h
Ar1
Ar2
B(dan)
B(dan)
B(pin)
2
7
8
10
Ar2
(pin)B
ArMe
ArCN
8e
Ar1 = ArMe
Ar2 = ArOMe
for 8g
NCAr
(1 equiv.)
Pd(OAc)2 (5 mol%)
SPhos (10 mol%)
iPr
MeOAr
MeAr
ArOMe
MeOAr
MeAr
ArOMe
I
Br 4g
4b: I–ArCN
4c: I–Ph
(1.5 equiv.)
Pd(PPh3)4 (5 mol%)
iPr
4d: I–ArOMe
1.5 M K2CO3 aq.
(3 equiv.)
THF, 70 ºC, 24 h
1.5 M KOH aq. (3 equiv.)
1,4-dioxane, 90 ºC, 40 h
iPr PtBu2
tBuXPhos
ArMe
ArCN
10d
9d
Br
NCAr
NC
CN
NC
CN
10a
10b
85% overall yield (3 steps)
58% overall yield (3 steps)
O
O
O
O
7e (2a + 4c); 91% yield
8d; 96% yield
7f (2c + 4b);[b] 75% yield
8e; 96% yield
10a (8d + 4f); 98% yield
10b (8e + 4f); 81% yield
NC
CN
O
O
10c
10d
53% overall yield (6 steps)
10e
84% overall yield (3 steps)
81% overall yield (3 steps)
7g (2c + 4c); 96% yield
8f; 96% yield
7f (2c + 4b);[b] 75% yield
8e; 96% yield
7h (2c + 4d); 90% yield
8g; 92% yield
7h (2c + 4d); 90% yield
8g; 92% yield
10c (8f + 4f); 92% yield
9d (8g + 4g); 98% yield
10d (9d + 8e); 92% yield
10e (8g + 4f); 98% yield
[a] Reagents for the synthesis of 7: 2 (0.10 mmol), 4 (0.25 mmol), Pd(PPh3)4 (5.0 mol), 1.5 M KOH aq. solution (0.40 mL,
0.60 mmol of KOH), THF (0.50 mL). Reagents for unmasking (synthesis of 8): refer to Table 5. Reagents for the synthesis
of 10a, 10b, 10c, and 10e: 8 (0.10 mmol), 4f (0.050 mmol), Pd(OAc)2 (5.0 mol), SPhos (10 mol), 1.5 M KOH aq.
solution (0.20 mL, 0.30 mmol of KOH), THF (0.30 mL). Reagents for the synthesis of 9d: 8g (0.10 mmol), 4g (0.15
mmol), Pd(PPh3)4 (5.0 mol), 1.5 M KOH aq. solution (0.20 mL, 0.30 mmol of KOH), 1,4-dioxane (0.30 mL). Reagents
for the synthesis of 10d: 8e (0.10 mmol), 9d (0.10 mmol), Pd(OAc)2 (5.0 mol), SPhos (10 mol), 1.5 M K2CO3 aq.
solution (0.20 mL, 0.30 mmol of K2CO3), THF (0.30 mL). Yields of isolated 7 based on 2, 8 based on 7, 9d based on 8g,
[b]
and 10 based on 8 are shown here. Performed with 4b (0.30 mmol), a 1 M KOH aq. solution (0.40 mL, 0.40 mmol of
KOH), and also Pd(OAc)2/tBuXPhos (5.0/10 mol) instead of Pd(PPh3)4 for 40 h.
hand, the photophysical properties thereof were
investigated. As shown in Figure 2, the absorption
spectra of 10a–10e in THF, a good solvent for these
compounds, were measured at room temperature, and
the corresponding data are listed in Table 7. All of the
compounds exhibit low-intensity absorption bands in
the range of 300–360 nm. Electronically comparable
two compounds, 10a and 10c, display similar
absorption trends. The peak gently observed at
approximately 386 nm in the absorption spectrum of
10d could be assigned to intramolecular charge
transfer (ICT) from the electron-rich p-MeOC6H4
moiety to electron-poor p-NCC6H4.[37]
The emission images of 10a–10e in THF and in
THF/H2O (1/9) as well as in the solid state under UV
light irradiation are shown in Figure 3. Analogously
8
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10.1002/adsc.202001116
Advanced Synthesis & Catalysis
10a
10b
1.0
0.8
0.6
0.4
0.2
10d; 302, 323, 386 nm
10b; 304, 339 nm
10e; 317, 347 nm
10c
10d
10e
10a; 312, 334 nm
10c; 315, 337 nm
Figure 3. Photographs of 10a–10e in THF (left), in
THF/H2O (v/v = 1/9, middle), and in the solid state (right)
under irradiation at 365 nm with a UV lamp.
0.0
250
300
350
400
450
Figure 2. Absorption spectra of 10a–10e in THF (1.5 ×
10–5 M). a.u. = arbitrary units.
[a]
1.0
10a; 489 nm
10c; 497 nm
10e; 509 nm
10b; 522 nm
10d; 571 nm
0.8
0.6
0.4
0.2
0.0
Table 7. Photophysical properties of TPTPE and
derivatives thereof.[a]
abs
em, aggr

em, solid

Comp. [nm]
[nm]
F, aggr

[nm]
F, solid
312, 334 489
304, 339 522
315, 337 497
302, 323, 571
386
0.18
0.56
0.19
0.38
457
529
447
554
0.87
0.13
0.91
0.63
10a
10b
10c
10d
350
450
550
650
750
317, 347 509
0.39
458
0.96
10e
wavelength [nm]
[a]
Abbreviations, conditions: Comp. = compound. abs
=
[b]
1.0
0.8
0.6
0.4
0.2
0.0
absorption maximum, measured in THF (1.5 × 10–5 M).
em, = emission maximum in the aggregate state,
aggr
excited at 350 nm and measured in THF/H2O (v/v = 1/9,
1.5 × 10–6 M). F, aggr = FL quantum yield in the aggregate
state, determined with reference to the quantum yield of
9,10-diphenylanthracene. em, solid = emission maximum in
the solid state, excited at 350 nm. F, solid = FL quantum
yield in the solid state, measured by a calibrated
integrating sphere.
10c; 447 nm
10a; 457 nm 10b; 529 nm
10e; 458 nm 10d; 554 nm
to 10a,[35] novel TPTPE derivatives, 10b–10e, exhibit
notable AIE properties; thus negligible emissions are
observed for their dilute THF solutions [fluorescence
(FL) quantum yields (F): < 0.2% in all the cases],
while considerably more intense emissions are noted
when they are in the aggregate state. Moreover, 10b–
10e emit blue, green, and yellow light of high
intensity in the solid state. Photoluminescence (PL)
spectra were also measured in the aggregate and solid
states (Figures 4a and 4b), and the data, along with
corresponding FL quantum yields, are summarized in
Table 7. Compared to the emission spectrum of 10c,
being electronically neutral among 10b–10e, those of
NC- and/or MeO-bearing derivatives appear in the
longer-wavelength regions, irrespective of their states.
In particular, 10d, with the push–pull characteristic,
is the most red-shifted.[38] Although 10b emits at
similar wavelength regions in both the aggregate and
solid states, emission spectra of the other compounds
are considerably blue-shifted in the solid state
350
450
550
650
750
wavelength [nm]
Figure 4. Photoluminescence spectra of 10a–10e [a] in
THF/H2O (v/v = 1/9, 1.5 × 10–6 M) and [b] in the solid
state when excited at 350 nm. a.u. = arbitrary units.
compared to when aggregated. With regard to FL
quantum yields, much higher values are obtained in
solid states than as THF/H2O solutions, except for
10b. This result would be favorable in terms of
device applications. The lower F, solid value of 10b
may be attributed to excimer formation in the solid
state, as previously observed in the AIE-active
molecule with the same C=C unit, which is vicinally
diarylated with p-NCC6H4.[39]
Breast cancer is the most prevalent cancer in
women worldwide, and (Z)-tamoxifen has been used
9
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001116
Advanced Synthesis & Catalysis
(pin)B
B(pin)
for over 40 years in the treatment thereof. Due to the
importance of (Z)-tamoxifen as an anticancer drug,
which works by blocking estrogen receptors in breast
cancer cells,[2b] the utility of this methodology was
further validated by the synthesis of (Z)-tamoxifen
(Scheme 6).[12a,12b,14f,14g,40] As already presented in
Table 3, the first SMCC reaction of 2a with I–Ph (4c)
yielded 5g, which then led to 7i via the second SMCC
reaction with vinyl bromide (4h). The regioselective
hydrogenation of the terminal C=C bond in 7i with
Wilkinson’s catalyst,[41] followed by unmasking of
B(dan) in 7j gave 8h. Notably, high reaction
efficiencies of ≥ 90% in each step from 2a to 8h were
once again achieved. By way of the final SMCC
reaction of 8h to (Z)-tamoxifen (9e) according to a
previously reported method,[12b,42] we attained the
formal total synthesis of (Z)-tamoxifen.
+
NaOH
B(dan)
1/0–3
2c
THF/H2O
rt, 10 min
OH
OH
OH OH
(pin)B B(pin)
(pin)B
B(pin)
(pin)B
B(pin)
B(dan)
B(dan)
B(dan)
11
12
13
H
O
OH OH
(pin)B
B(pin)
(pin)B
B(pin)
B(dan)
B(dan)
OH
14
15
A possible explanation for the regioselectivity of
the first SMCC reaction can come from the results of
11B NMR
[a]
11
some B NMR experiments. As shown in Figure 5a,
d 30.4
d 30.4
the three boryl groups of 2c appeared as one signal at
30.4 ppm. Upon treatment with an equimolar amount
of NaOH, a new signal integrated for one boron atom
was observed at 9.2 ppm, which is in a typical range
of B(sp3) species (Figure 5b); due to poor solubility
of NaOH in THF, the minimum quantity of H2O
required to dissolve NaOH was used here. This result
may exclude the possibility of 14, the two B(pin)s of
which might appear in an upper-field region than 30.4
ppm. Moreover, the following two interpretations are
possible: one is the selective formation of 11 due to
the selective formation of 5 from 2 (see Table 3), and
the other is the formation of a mixture of 11 and 12.
Adding one more equivalent of NaOH led to the
upfield-shift of two boryl groups (Figure 5c).
However, no further change occurred in the use of
2c
[b]
[c]
[d]
d 9.2
2c/NaOH = 1/1
2c/NaOH = 1/2
0.998
1.992
2.000
d 9.7
d 9.3
d 30.4
1.000
d 30.5
1.000
2c/NaOH = 1/3
1.988
0
60
50
40
30
20
10
–10 –20 –30
ppm
Figure 5. Observation of 11B NMR of 2c with NaOH in
THF/H2O. [a] was measured in THF without adding H2O.
Na+ in 11–15 is omitted.
[b]
Br
cat. Pd
[a] I–Ph 4c
cat. Pd
4h
(pin)B
Ph
B(pin)
(pin)B
Ph
Ph
B(dan)
B(dan)
2a
5g; 90% yield
(5g/6g = 96:4)
three equivalents of NaOH (Figure 5d). No B(dan)-
based borate has been reportedly formed when using
bases other than t-BuOK.[23] Similar to the precedents,
Figure 5d reveals that the formation of 15 should be
unlikely in the presence of NaOH. Since 2.5 molar
equivalents of NaOH to 2c are used for the first
SMCC reaction, a plausible form of an intermediate
would be 13, thus suggesting that 11 does not exist, at
least mainly, under the SMCC reaction conditions.
Accordingly, the regioselective SMCC reaction of 2c
might be ascribed to the higher nucleophilicity of the
highlighted C(sp2) atom in 13, rather than the
selective formation of 11 over 12 based on different
Lewis acidities of the two B(pin)s.
Ph
Ph
[c] H2, cat. Rh
[d] pinacol, H+
Ph
B(dan)
Ph
B(dan)
7j; 98% yield
7i; 95% yield
references
12b and 42
Ph
Ph
B(pin)
8h; 98% yield
N
9e
O
(Z)-tamoxifen
Scheme 6. Formal total synthesis of (Z)-tamoxifen from
triborylalkene 2a. Reagents and conditions: [a] refer to
Table 3; [b] vinyl bromide (4h) (5 equiv.) in THF,
Pd(OAc)2 (5 mol%), SPhos (10 mol%), 1.5 M KOH aq.
solution (3 equiv. of KOH), THF, 70 ºC, 24 h; [c]
RhCl(PPh3)3 (3 mol%), toluene, H2 (balloon), 100 ºC, 3 h;
[d] pinacol (8 equiv.), 3 M H2SO4 aq. solution (10 equiv.
of H2SO4), THF, 70 ºC, 24 h.
Conclusion
Triborylalkenes with two B(pin) and one B(dan)
groups were used for the construction of extended -
10
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10.1002/adsc.202001116
Advanced Synthesis & Catalysis
(0.100 mmol), a 1.5 M KOH aqueous solution (0.170 mL,
0.250 mmol of KOH), and THF (1.0 mL). After degassing
by three freeze-pump-thaw cycles, to this was added
PdCl2(dppf) (3.66 mg, 5.00 μmol), and the resulting
mixture was stirred at 50 ºC for 3 h. H2O (1 mL) was
added to the mixture, and the aqueous phase was extracted
with Et2O (2 mL × 3). The combined organic layer was
washed with brine (1 mL) and then dried over anhydrous
sodium sulfate. Filtration through a pad of Celite and
evaporation of the solvent followed by purification gave
product 5.
conjugated molecules including a C=C core. This is
the first example of triborylalkenes wherein the three
C–B bonds were successfully subjected to iterative
SMCC reactions. A range of aryl and alkyl units with
or without functional groups were tolerated in this
system. Because of the excellent regioselectivity (≥
96%) of each step, four different aryl units can be
installed at targeted positions of the C=C moiety in
the desired order, thereby enabling the assembly of
diverse tetraarylalkenes. This methodology was
applied to the synthesis of AIE-active light-emitting
molecules, and (Z)-tamoxifen, used in anti-breast
cancer therapy. Of importance to note is that the
successful performance of triborylalkenes, accessible
via dehydrogenative alkynylation of HB(dan)
developed by us, would be dependent on both the
existence and position of the B(dan) group. We
anticipate that the utility of this new triborylalkene
will be extended in the near future, and continuous
efforts toward this realization are thus underway in
our laboratory.
Synthesis of Unsymmetrical Tetraarylalkenes from
Diaryldiborylalkenes via
the Second SMCC,
Unmasking, and Final SMCC Reactions: General
Procedures for Table 5
Second SMCC Reaction of 5 with Aryl Iodides
Under an argon atmosphere, a 20 mL Schlenk tube was
charged with 5 (0.100 mmol), 4 (0.120 or 0.150 mmol), a
KOH aqueous solution [(1.5 M, 0.200 mL, 0.300 mmol of
KOH) or (1 M, 0.250 mL, 0.250 mmol of KOH)], and THF
(0.30 mL). After degassing by three freeze-pump-thaw
cycles, to this were added Pd(OAc)2 (1.12 mg, 5.00 μmol)
and SPhos (4.11 mg, 10.0 μmol), and the resulting mixture
was stirred at 70 ºC for 24 or 32 h. H2O (1 mL) was added
to the mixture, and the aqueous phase was extracted with
Et2O (2 mL × 3). The combined organic layer was washed
with brine (1 mL) and then dried over anhydrous sodium
sulfate. Filtration through a cotton plug and evaporation of
the solvent followed by purification gave product 7.
Experimental Section
Platinum-Catalyzed Diboration Reaction of Alkynyl–
B(dan)s: A General Procedure for Table 1
Unmasking of the B(dan) Group in 7
This diboration reaction was conducted according to a
modified literature procedure.[18a] Under an argon
atmosphere, a flame-dried 20 mL Schlenk tube was
charged with toluene (0.80 mL), which was degassed by
three freeze-pump-thaw cycles. To this were added
bis(pinacolato)diboron (25.6 mg, 0.101 mmol), alkynyl–
B(dan) 1 (0.100 mmol), and Pt(PPh3)4 (0.622 mg, 0.500
µmol) in that order, and the resulting solution was
degassed again by two freeze-pump-thaw cycles. After
stirring at 50, 80, 90 or 100 ºC for the time specified in
Table 1, H2O (1 mL) was added to the mixture, and the
aqueous phase was extracted with Et2O or CH2Cl2 (2 mL ×
3). The combined organic layer was washed with brine (1
mL) and then dried over anhydrous sodium sulfate.
Filtration through a cotton plug and evaporation of the
solvent followed by purification gave triborylalkene 2.
Under an air atmosphere, a 20 mL Schlenk tube was
charged with 7 (0.100 mmol), pinacol (94.5 mg, 0.800
mmol) and THF (2.0 mL), and the resulting mixture was
stirred at rt for 3 min. To this was added a 3 M H2SO4
aqueous solution (0.330 mL, 1.00 mmol of H2SO4), and the
resulting solution was stirred at 70 °C for 24 h. After
cooling down to rt, Et2O (5 mL) was added to the mixture.
The organic phase was washed with H2O (2 mL × 5) and
brine (1 mL), and then dried over anhydrous sodium
sulfate. Filtration through a cotton plug and evaporation of
the solvent followed by purification gave product 8.
Final SMCC Reaction of 8 with Aryl Iodides
Under an argon atmosphere, a 20 mL Schlenk tube was
charged with 8 (0.100 mmol), 4 (0.120 mmol), a 1.5 M
KOH aqueous solution (0.200 mL, 0.300 mmol of KOH),
and THF (0.30 mL). After degassing by three freeze-
pump-thaw cycles, to this were added Pd(OAc)2 (1.12 mg,
5.00 μmol) and SPhos (4.11 mg, 10.0 μmol), and the
resulting mixture was stirred at 70 ºC for 24 h. H2O (1 mL)
was added to the mixture, and the aqueous phase was
extracted with Et2O (2 mL × 3). The combined organic
layer was washed with brine (1 mL) and then dried over
anhydrous sodium sulfate. Filtration through a cotton plug
and evaporation of the solvent followed by purification
gave product 9.
Palladium-Catalyzed
SMCC
Reaction
of
Triborylalkenes with Aryl Halides:
Procedure for Aryl Iodides in Table 3
A
General
PdCl2 (0.887 mg, 5.00 μmol) and NaOH (10.0 mg, 0.250
mmol) were placed in a 20 mL Schlenk tube, which was
dried in vacuo at room temperature (rt) for 1 h and filled
with argon. To this were added THF (1.0 mL), which had
been degassed by three freeze-pump-thaw cycles just prior
to use, triborylalkene 2 (0.100 mmol) and aryl iodide 4
(0.100, 0.110 or 0.130 mmol), and the resulting mixture
was stirred at rt, 40, 50, or 70 ºC. After the time specified
in Table 3, H2O (1 mL) was added to the mixture, and the
aqueous phase was extracted with Et2O (2 mL × 3). The
combined organic layer was washed with brine (1 mL) and
then dried over anhydrous sodium sulfate. Filtration
through a pad of Celite and evaporation of the solvent,
followed by purification, gave product 5. Minor isomer 6
was also isolated in some cases.
Synthesis of TPTPE and Derivatives Thereof from
Triborylalkenes: General Procedures for Table 6
Double SMCC Reaction of Triborylalkenes with Aryl
Iodides
Under an argon atmosphere, a 20 mL Schlenk tube was
charged with 2 (0.100 mmol), 4 (0.250 or 0.300 mmol), a
KOH aqueous solution [(1.5 M, 0.400 mL, 0.600 mmol of
KOH) or (1 M, 0.400 mL, 0.400 mmol of KOH)], and THF
(0.50 mL). After degassing by three freeze-pump-thaw
cycles, to this was added Pd(PPh3)4 (5.78 mg, 5.00 μmol)
or Pd(OAc)2/tBuXPhos (1.12 mg, 5.00 μmol)/(4.25 mg,
10.0 μmol), and the resulting mixture was stirred at 70 ºC
Palladium-Catalyzed
SMCC
Reaction
of
Triborylalkenes with Aryl Halides:
Procedure for Aryl Bromides in Table 3
A
General
Under an argon atmosphere, a 20 mL Schlenk tube was
charged with 2c (53.6 mg, 0.100 mmol), aryl bromide 4’
11
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001116
Advanced Synthesis & Catalysis
for 40 or 48 h. H2O (1 mL) was added to the mixture, and
the aqueous phase was extracted with Et2O (2 mL × 3).
The combined organic layer was washed with brine (1 mL)
and then dried over anhydrous sodium sulfate. Filtration
through a cotton plug and evaporation of the solvent
followed by purification gave product 7.
for the synthesis of 5g, "Palladium-Catalyzed SMCC
Reaction of Triborylalkenes with Aryl Halides: A
General Procedure for Aryl Iodides in Table 3" (vide
supra).
Second Step: SMCC Reaction of 5g with Vinyl Bromide
Unmasking of the B(dan) Group in 7
Under an argon atmosphere, a 20 mL Schlenk tube was
charged with Pd(OAc)2 (1.12 mg, 5.00 μmol), SPhos (4.11
mg, 10.0 μmol), 5g (47.2 mg, 0.100 mmol), a 1 M THF
solution of 4h (0.500 mL, 0.500 mmol) and a 1.5 M KOH
aqueous solution (0.200 mL, 0.300 mmol of KOH), and the
resulting mixture was stirred at 70 ºC for 24 h. H2O (1 mL)
was added to the mixture, and the aqueous phase was
extracted with Et2O (2 mL × 3). The combined organic
layer was washed with brine (1 mL) and then dried over
anhydrous sodium sulfate. Filtration through a cotton plug
and evaporation of the solvent followed by column
chromatography on silica gel (n-hexane/EtOAc = 20/1)
gave 2-[(1E)-1,2-diphenyl-1,3-butadien-1-yl]-2,3-dihydro-
1H-naphtho[1,8-de]-1,3,2-diazaborine (7i) in 95% yield
(35.4 mg).
Synthesis of 8 in this section was carried out in a manner
similar to the procedure described in the same heading,
"Unmasking of the B(dan) Group in 7" (vide supra).
SMCC Reaction of 8 with 1,4-Diiodobenzene
Under an argon atmosphere, a 20 mL Schlenk tube was
charged with 8 (0.100 mmol), 4f (16.5 mg, 0.0500 mmol),
a 1.5 M KOH aqueous solution (0.200 mL, 0.300 mmol of
KOH), and THF (0.30 mL). After degassing by three
freeze-pump-thaw cycles, to this were added Pd(OAc)2
(1.12 mg, 5.00 μmol) and SPhos (4.11 mg, 10.0 μmol), and
the resulting mixture was stirred at 70 ºC for 24 h. H2O (1
mL) was added to the mixture, and the aqueous phase was
extracted with Et2O or CH2Cl2 (2 mL × 3). The combined
organic layer was washed with brine (1 mL) and then dried
over anhydrous sodium sulfate. Filtration through a cotton
plug and evaporation of the solvent followed by
purification gave product 10.
Third Step: Hydrogenation of the Terminal C=C bond in
7i
Under an argon atmosphere, a flame-dried 20 mL Schlenk
tube was charged with toluene (1.0 mL), which was
degassed by three freeze-pump-thaw cycles. To this were
added 7i (37.2 mg, 0.100 mmol) and Rh(PPh3)3Cl (2.78 mg,
3.00 μmol), and the resulting solution was again degassed
by two freeze-pump-thaw cycles, followed by introducing
hydrogen gas filled in a balloon. The resulting mixture in
the tube connected with the balloon was stirred at 100 ºC
for 3 h. H2O (1 mL) was added to the mixture, and the
aqueous phase was extracted with Et2O (2 mL × 3). The
combined organic layer was washed with brine (1 mL) and
then dried over anhydrous sodium sulfate. Filtration
through a cotton plug and evaporation of the solvent
followed by column chromatography on silica gel (n-
hexane/EtOAc = 20/1) gave 2-[(E)-1,2-diphenyl-1-buten-
1-yl]-2,3-dihydro-1H-naphtho[1,8-de]-1,3,2-diazaborine
(7j) in 98% yield (36.7 mg).
SMCC Reaction of 8g with 1-Bromo-4-iodobenzene
Under an argon atmosphere, a 20 mL Schlenk tube was
charged with 8g (45.6 mg, 0.100 mmol), 4g (42.4 mg,
0.150 mmol), a 1.5 M KOH aqueous solution (0.200 mL,
0.300 mmol of KOH), and 1,4-dioxane (0.30 mL). After
degassing by three freeze-pump-thaw cycles, to this was
added Pd(PPh3)4 (5.78 mg, 5.00 μmol), and the resulting
mixture was stirred at 90 ºC for 40 h. H2O (1 mL) was
added to the mixture, and the aqueous phase was extracted
with Et2O (2 mL × 3). The combined organic layer was
washed with brine (1 mL) and then dried over anhydrous
sodium sulfate. Filtration through a cotton plug and
evaporation of the solvent followed by column
chromatography on silica gel (n-hexane/EtOAc = 5/1) gave
4-[(E)-1,2-bis(4-methoxyphenyl)-2-(4-
Fourth Step: Unmasking of the B(dan) Group in 7j
methylphenyl)ethenyl]bromobenzene (9d) in 98% yield
(47.6 mg).
Synthesis of 4,4,5,5-tetramethyl-2-[(E)-1,2-diphenyl-1-
buten-1-yl]-1,3,2-dioxaborolane (8h) was carried out in a
manner similar to the procedure described in the following
section, "Unmasking of the B(dan) Group in 7" (vide
supra). Product 8h was isolated by column
chromatography on silica gel (n-hexane/EtOAc = 20/1) in
98% yield (32.8 mg).
SMCC Reaction of 9d with 8e
Under an argon atmosphere, a 20 mL Schlenk tube was
charged with 8e (44.6 mg, 0.100 mmol), 9d (48.5 mg,
0.100 mmol), a 1.5 M K2CO3 aqueous solution (0.200 mL,
0.300 mmol of K2CO3), and THF (0.30 mL). After
degassing by three freeze-pump-thaw cycles, to this were
added Pd(OAc)2 (1.12 mg, 5.00 μmol) and SPhos (4.11 mg,
10.0 μmol), and the resulting mixture was stirred at 70 ºC
for 24 h. H2O (1 mL) was added to the mixture, and the
aqueous phase was extracted with CH2Cl2 (2 mL × 3). The
combined organic layer was washed with brine (1 mL) and
then dried over anhydrous sodium sulfate. Filtration
through a cotton plug and evaporation of the solvent
followed by column chromatography on silica gel (n-
hexane/EtOAc = 5/1) gave 1-[(Z)-1,2-bis(4-cyanophenyl)-
2-(4-methylphenyl)ethenyl]-4-[(Z)-1,2-bis(4-
Characterization data of and NMR spectra of products
are collected in the Supporting Information.
Acknowledgements
Financial support by KAKENHI (Grants-in-Aid for Scientific
Research) No. 19K05484 from Japan Society for the Promotion
of Science is highly acknowledged. We thank Ms. Hitomi
Kawahara for experimental assistance.
methoxyphenyl)-2-(4-methylphenyl)ethenyl]benzene (10d)
in 92% yield (66.7 mg).
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Scheme 6
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12
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10.1002/adsc.202001116
Advanced Synthesis & Catalysis
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10.1002/adsc.202001116
Advanced Synthesis & Catalysis
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groups such as 3k are expected to be good scaffolds for
constructing trisubstituted alkenes in a regioselective
manner. Accordingly, studies on the synthetic
14
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Advanced Synthesis & Catalysis
[41] For example, see: a) P. N. Carlsen, T. J. Mann, A. H.
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15
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Advanced Synthesis & Catalysis
FULL PAPER
Stepwise Suzuki–Miyaura Cross-Coupling of
Triborylalkenes Derived from Alkynyl–B(dan)s:
Regioselective and Flexible Synthesis of
Tetrasubstituted Alkenes
R1
B(dan)
cat. Pt
X
R2
B2(pin)2
X
R3
R4
Adv. Synth. Catal. Year, Volume, Page – Page
X
(pin)B
R1
B(pin)
R3
R1
R2
R4
cat. Pd
B(dan)
Tomohiro Tani, Naomi Takahashi, Yuuki
Sawatsugawa, Mana Osano, Teruhisa Tsuchimoto*
16
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