Versatile synthesis of 1,1-diaryl-1-alkenes using vinylboronate ester as a platform

Article abstract of DOI:10.1055/s-2005-871539

A sequence of double Mizoroki-Heck reaction of vinylboronate pinacol ester with aryl halides followed by Suzuki-Miyaura coupling of thus-generated β,β-diarylvinylboronate esters with alkyl halides produces pharmaceutically important 1,1-diaryl-1-alkenes v

Full text of DOI:10.1055/s-2005-871539

1802
CLUSTER
Versatile Synthesis of 1,1-Diaryl-1-alkenes Using Vinylboronate Ester as a
Platform
Versatile
S
ynthesis
e
of 1,1-Dia
i
ryl-1-a
s
lkenes uke Tonogaki,a Kazuya Soga,a Kenichiro Itami,*b Jun-ichi Yoshida*a
a
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Nishikyo-ku,
Kyoto 615-8510, Japan
Fax +81(75)3832727; E-mail: yoshida@sbchem.kyoto-u.ac.jp
b
Research Center for Materials Science, Nagoya University, Nagoya 464-8602, Japan
E-mail: itami@chem.nagoya-u.ac.jp
Received 6 April 2005
Abstract: A sequence of double Mizoroki–Heck reaction of vinyl-
boronate pinacol ester with aryl halides followed by Suzuki–
Miyaura coupling of thus-generated b,b-diarylvinylboronate esters
with alkyl halides produces pharmaceutically important 1,1-diaryl-
1-alkenes very efficiently. In the Pd-catalyzed Suzuki–Miyaura
coupling step, the use of bulky electron-rich ligands such as
P(t-Bu)2Me and PCy2(t-Bu) were found to be very effective.
Key words: palladium catalyst, Mizoroki–Heck reaction, Suzuki–
Scheme 1 Multisubstituted olefin synthesis using vinyl-element
compounds as a platform
Miyaura coupling, vinylboronate ester, alkyl halides
and straightforward synthesis of 1,1-diaryl-1-alkenes 3
The regio- and stereoselective synthesis of multisubstitut- using vinylboronate ester 1 as a platform.
ed olefins is one of the most important subjects in organic
Since we have already established an efficient procedure
synthesis. In view of its synthetic challenge as well as
potential application as functional materials and pharma-
ceuticals, we have been pursuing the chemistry (synthesis
and property) of multisubstituted olefins during the last
several years.1–4 In particular, we have developed a num-
ber of programmable synthesis of multisubstituted olefins
based on a sequential installation of substituents on a C=C
core of an appropriate vinyl-element compound (plat-
form, Scheme 1).1–3
for the synthesis of b,b-diarylvinylboronate esters 2 (dou-
ble Mizoroki–Heck reaction of vinylboronate ester 1 and
aryl halides),2 the cross-coupling of 2 with alkyl halides
was the initial focal point of this research program. In this
regard, an efficient Suzuki–Miyaura cross-coupling of
alkyl electrophiles with boronic acids reported recently by
Fu and coworkers attracted much interest.10 Thus, we be-
gan by simply applying the Fu’s conditions [Pd(OAc)2,
P(t-Bu)2Me, t-BuOK, tert-amyl alcohol] to the cross-cou-
For example, we have developed a rapid synthesis of pling of b,b-diarylvinylboronate ester 2a with 4-phenyl-
triarylethenes through the Pd-catalyzed sequential triaryl- butyl bromide. Unfortunately, however, the expected 1,1-
ation using vinylboronate ester as a platform.2 Thus, Pd- diaryl-1-alkene 3aa was obtained only in 52% yield under
catalyzed double Mizoroki–Heck reaction5,6 of vinylbor- their conditions (Table 1, entry 1). Therefore, we investi-
onate ester 1 and aryl halides produces various b,b-di- gated various parameters of the reaction conditions for
arylvinylboronate esters 2 very efficiently. The thus- Pd-catalyzed cross-coupling of b,b-diarylvinylboronate
obtained boronate esters 2 can further undergo Suzuki– esters with alkyl bromides.
Miyaura coupling7 with aryl halides to afford triaryl-
ethenes very rapidly (Scheme 2). From the triarylethene-
Ar1
X
(2.0 equiv)
Ar1
Ar2
X
based extended p-system library, we were able to find a
number of interesting fluorescent materials as well as
interesting photophysical properties.1,2
Ar1
O
O
B
Ar2
B
Ar1
O
O
Ar1
(one-pot)
Pd[P(t-Bu)3]2
i-Pr2NH
NaOH, H2O
1
2
During these investigations targeting multisubstituted ole-
fins, we became aware that pharmaceutically important
1,1-diaryl-1-alkenes 3 (Figure 1)8,9 would be obtained
straightforwardly if an efficient cross-coupling reaction of
b,b-diarylvinylboronate esters 2 with alkyl halides could
be developed (Scheme 2). Herein we describe an efficient
platform
Double Mizoroki–Heck reaction
Suzuki–Miyaura cross-coupling
Alkyl-X
Ar1
Alkyl
Ar1
3
1,1-diaryl-1-alkene
SYNLETT 2005, No. 11, pp 1802–1804
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7
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7
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0
0
5
Advanced online publication: 14.06.2005
DOI: 10.1055/s-2005-871539; Art ID: Y00805ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Synthetic strategy for 1,1-diaryl-1-alkenes using vinyl-
boronate ester as a platform

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Versatile Synthesis of 1,1-Diaryl-1-alkenes
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Table 2 Examination of Pd Precursor and Ligand
Pd cat. (5%)
ligand (10%)
CO2H
N
Me
Ph
( )4
Ar
Ar
Ph
Br
B(pin)
+
( )4
(2 equiv)
NaOH (3 equiv)
dioxane, 60 °C
Ar
2a
Ar
3aa
HCl
CO2H
S
N
Ar = 4-CH3C6H4
Me
S
GABA uptake inhibitor
(SKF 89976A)
HCl
Entry
Pd
Ligand
Yield (%)
GABA uptake inhibitor
anticonvulsant drug (tiagabine)
Br
1
2
3
4
5
6
7
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
P(t-Bu)2Me
BiPhPCy2
BiPhP(t-Bu)2
Ad2PBn
80
N.d.
8
MeO
CO2Me
MeO2C
18
78
13
76
Br
CO2Me
PCy2(t-Bu)
PCy(t-Bu)2
PCy2(t-Bu)
OMe
non-nucleoside HIV-1 reverse
transcriptase inhibitors (NMRTIs)
Figure 1 Examples of pharmaceutically important 1,1-diaryl-1-
alkenes
With improved conditions for the Pd-catalyzed Suzuki–
Miyaura cross-coupling of b,b-diarylvinylboronate
esters with alkyl bromides in hand, we subsequently
applied these conditions to the synthesis of various 1,1-di-
aryl-1-alkenes (Scheme 3). Although three systems we
found (Table 2, entries 1, 5, and 7) might be equally effec-
tive, we applied one of these conditions [Pd(OAc)2,
P(t-Bu)2Me, NaOH, dioxane, 60 °C] in these syntheses.
We initially screened various base additives (t-BuOK,
NaOH, K2CO3, Cs2CO3) and solvents (tert-amyl alcohol,
toluene, dioxane; Table 1). Among various combinations
examined, we found that the combination of NaOH and
dioxane leads to an efficient cross-coupling of 2a with 4-
phenylbutyl bromide giving 3aa in 80% yield (Table 1,
entry 4).
Next, we investigated Pd precursor and phosphine ligand
using NaOH as an additive and dioxane as solvent that
were optimized above (Table 2). When Pd(OAc)2 was
used as a catalyst precursor, P(t-Bu)2Me and PCy2(t-Bu)
were the best among those that we examined (entries 1
and 5). It was also found that PdCl2/PCy2(t-Bu) system is
equally effective in the cross-coupling of 2a with alkyl
bromide (entry 7).
Pd(OAc)2 (5%)
P(t-Bu)2Me (10%)
Ar
Ar
alkyl
B(pin)
alkyl–Br
(2 equiv)
+
NaOH (3 equiv)
dioxane, 60 °C
Ar
Ar
2
3
OPiv
( )6
SiMe3
OH
( )6
Table 1 Examination of Additive and Solvent
Pd(OAc)2 (5%)
3bc, 59%
3bb, 70%
3bd, 78%
Ph
( )4
Ar
P(t-Bu)2Me (10%)
Ar
Ph
Br
+
B(pin)
( )4
(2 equiv)
MeO
MeO
MeO
additive (3 equiv)
solvent, 60 °C
Ar
2a
Ar
3aa
OTES
CN
( )6
( )3
( )6
Ar = 4-CH3C6H4
Entry
Additive
t-BuOK
NaOH
Solvent
Yield (%)
52
OMe
OMe
3ce, 85%
OMe
1
2
3
4
5
6
7
tert-Amyl alcohol
tert-Amyl alcohol
Toluene
3cf, 61%
3cg, 94%
66
O
F
F
NaOH
71
N
( )4
( )4
NaOH
Dioxane
80
O
( )3
t-BuOK
K2CO3
Cs2CO3
Dioxane
42
F
F
Dioxane
N.d.
N.d.
3dh, 59%
3di, 52%
3eg, 58%
Dioxane
Scheme 3 Synthesis of various 1,1-diaryl-1-alkenes
Synlett 2005, No. 11, 1802–1804 © Thieme Stuttgart · New York

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K. Tonogaki et al.
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Gratifyingly, a wide range of functional groups was found
to be intact in this cross-coupling. The use of 3-phenylpro-
pyl bromide produced desired cross-coupling products
3cg and 3eg in good yields. When alkyl bromides having
free hydroxyl group or triethylsilylether group were used,
desired 1,1-diaryl-1-alkenes 3bb and 3cf were also ob-
tained in good yields. Functional groups such as ester,
nitrile, and imide were also tolerated (3bc, 3ce, and 3di).
When alkyl bromide having olefinic moiety was used, de-
sired 1,1-diaryl-1-alkene 3dh was also obtained efficient-
ly. When 2-(trimethylsilyl)ethyl bromide was used, the
desired product 3bd was also obtained in good yield.
Moreover, various electronically and structurally diverse
b,b-diarylvinylboronate esters 2b–e can be applied in this
reaction system to give 1,1-diaryl-1-alkenes 3 efficiently.
Acknowledgment
This work was financially supported in part by a Grant-in-Aid for
Scientific Research from the Japan Society for the Promotion of
Science. K.T. is a recipient of the JSPS Predoctoral Fellowships for
Young Scientists.
References
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2 with alkyl bromides. When combined with the double
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becomes extremely versatile and flexible as a whole. All
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Typical Procedure for the Suzuki–Miyaura Coupling of b,b-Di-
arylvinylboronate Esters with Alkyl Bromides
A mixture of Pd(OAc)2 (3.4 mg, 15 mmol, 5 mol%), P(t-Bu)2Me
(4.8 mg, 30 mmol, 10 mol%), NaOH (36.0 mg, 0.90 mmol), 2c (0.30
mol, 109.9 mg), and 3-phenylpropyl bromide (0.60 mmol, 119.5
mg) in dry dioxane (1.5 mL) was stirred vigorously at 60 °C for 24
h. After cooling the reaction mixture to r.t., catalyst and salts were
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filtrate was evaporated, and the residue was subjected to silica gel
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1
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127.6, 128.1, 128.2, 128.3, 130.9, 132.6, 135.8, 140.8, 142.3, 158.2,
158.5. HRMS (EI): m/z calcd for C25H26O2: 358.1933; found:
358.1931.
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Synlett 2005, No. 11, 1802–1804 © Thieme Stuttgart · New York