Olefin cross-metathesis/Suzuki-Miyaura reactions on vinylphenylboronic acid pinacol esters

Article abstract of DOI:10.1016/j.tetlet.2012.12.081

A series of alkenyl phenylboronic acid pinacol esters has been synthesized via an olefin cross-metathesis reaction of vinylphenylboronic acid pinacol ester derivatives. After catalytic hydrogenation, the resulting boronates were coupled via a microwave-mediated Suzuki-Miyaura reaction to afford a library of biarylethyl aryl and biarylethyl cycloalkyl derivatives. A complementary reaction sequence involved an initial Suzuki-Miyaura coupling.

Full text of DOI:10.1016/j.tetlet.2012.12.081

Tetrahedron Letters 54 (2013) 1211–1217
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Olefin cross-metathesis/Suzuki–Miyaura reactions on vinylphenylboronic acid
pinacol esters
Christine B. Baltus a, Irina S. Chuckowree a, Neil J. Press b, Iain J. Day c, Simon J. Coles d, Graham J. Tizzard d,
John Spencer a,c,
⇑
a School of Science at Medway, University of Greenwich, Chatham ME4 4TB, UK
b Novartis Pharmaceuticals UK, Horsham, Sussex RH12 5AB, UK
c Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QJ, UK
d EPSRC National Crystallography Service, School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of alkenyl phenylboronic acid pinacol esters has been synthesized via an olefin cross-metathesis
reaction of vinylphenylboronic acid pinacol ester derivatives. After catalytic hydrogenation, the resulting
boronates were coupled via a microwave-mediated Suzuki–Miyaura reaction to afford a library of biaryl-
ethyl aryl and biarylethyl cycloalkyl derivatives. A complementary reaction sequence involved an initial
Suzuki–Miyaura coupling.
Received 1 October 2012
Revised 28 November 2012
Accepted 18 December 2012
Available online 28 December 2012
Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
Keywords:
Arylboronic esters
Cross-metathesis
Suzuki–Miyaura coupling
C–C bond formation
Microwaves
A number of diarylethane derivatives display biological activity.
For example, 1a is a potent Helicobacter pylori urease inhibitor1 and
1b is an estrogen receptor (ERb) agonist (Fig. 1).2 Relatively few
examples of bioactive biarylethyl aryl compounds appear in the lit-
erature; 2a is an interleukin-4 antagonist3 and 2b is an effective
bombesin receptor subtype-3 (BRS-3) agonist for the treatment
of obesity4 (Fig. 1).
as a desiccant. Initial CM reaction optimizations were attempted
on 4a (4-vinylphenylboronic acid pinacol ester) with styrene (5a)
using a catalytic amount of Grubbs’ catalysts, 6b or 6c (Table 1).
The ester 4a and styrene (5a) are considered to be type I olefins
which imply that they are able to undergo a rapid homodimeriza-
tion and whose homodimers can participate in competing CM reac-
tions. An excess of 5a (up to 5 equiv) was used in order to obtain
the cross-coupled product 7a in good yield and to minimize homo-
coupling.10 In our case, this still led to a large amount of E-stilbene
(styrene homodimerization product) which, in most cases, was dif-
ficult to separate from the expected product, 7a, by chromatogra-
phy, probably also impacting on the final isolated yield of the
latter. A number of pertinent observations can be made regarding
this reaction:
Retrosynthetic analysis reveals a cross-metathesis5 reaction
(CM) (Scheme 1) and a hydrogenation sequence with a supplemen-
tary Suzuki–Miyaura (SM) reaction to furnish 10 via the useful
substituted ethylarylboronate synthon 8 (Scheme 1). We present
herein our studies on a series of reactions leading to a library of bia-
rylethyl arenes and precursors, with the crucial CM chemistry med-
iated by catalysts 6.
Schmalz et al. previously investigated the synthesis of biologi-
cally important trans-stilbenes via Ru-catalyzed cross-metathesis
reactions.6 Indeed, olefin metathesis followed by hydrogenation
reactions are vital in the synthesis of alkyl-bridges or chains,7 or ali-
phatic rings or macrocycles,8 and in diversity-oriented synthesis.9
Vinylphenylboronic acid pinacol esters 4 were readily synthe-
sized in good yields from their boronic acid precursors 3 by reac-
tion with pinacol, in the presence of magnesium sulfate (MgSO4)
(i) The reaction time appears to affect the yields obtained.
When the reaction was stopped after 2.5 h a moderate yield
of 55% was obtained (Table 1, entry 1) and better yields were
obtained after 16 h or 24 h, that is, 58% and 60%, respectively
(Table 1, entries 3 and 4). However, the best yield was
obtained after 6 h reaction time (76%).
(ii) A decrease in the molar percentage of catalyst led to a
decrease in the yields (e.g., 76% yield with 5 mol % of 6b,
Table 1, entry 2; 65% yield with 3 mol % of 6b, entry 6; 52%
yield with 1 mol % of 6b, entry 9).
⇑
Corresponding author.
E-mail address: j.spencer@sussex.ac.uk (J. Spencer).
0040-4039/$ - see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.081

1212
C. B. Baltus et al. / Tetrahedron Letters 54 (2013) 1211–1217
OH
OH
HO
HO
CN
HO
1a
1b
MeO
OH
N
OH
N
N
H
2a
2b
Figure 1. Biologically active diarylethanes and biarylethyl arenes.
R1
R1
O
O
O
HO
OH
5
B(OH)2
B
B
CM reaction
O
6
3
4
7
E / Z
H2
Pd (cat.)
Br Ar1
R1
R1
O
O
9
Ar1
B
SM reaction
10
8
PCy3
Ru
N
Cl
Cl
N
Cl
Cl
N
N
Cl
Cl
Ru
O
Ph
Ru
PCy3
Ph
PCy3
Grubbs' catalyst
1st generation
Grubbs' catalyst
2nd generation
Hoveyda-Grubbs' catalyst
2nd generation
6a
6b
6c
Scheme 1. Synthesis of biarylethyl arenes or cycloalkanes via a CM/SM reaction sequence.
(iii) Product yields do not appear to be affected by the number of
A few non-aromatic vinyl derivatives were reacted with 4a. The
cyclohexane derivative 7k was obtained in a reasonable 58% yield
(Table 2, entry 10), while none of the expected product was
observed for the CM reaction with vinyl acetate 5l (Table 2, entry
11), possibly due to the high volatility of this compound.
For the reactions leading to 7b and 7g, the expected products
were obtained as mixtures with the homodimerization products
of 5b and 5g, respectively, and could not be separated by chroma-
tography. The yield could not be calculated by 1H NMR spectros-
copy due to overlapping signals (Table 2, entries 1 and 6). Hence,
these products were used as mixtures for the next steps.
The CM reaction was also attempted with heterocyclic deriva-
tives 5h–j, but only the starting materials were observed after
6 h (Table 2, entries 7–9) in line with previous findings.11,12
Although Schrock’s catalyst has been shown to be successful for
some of these substrates, we did not attempt to use it for these
reactions.
equivalents of 5a used. Very similar yields were obtained
when changing the number of equivalents (65%, 58%, and
63% yields obtained with 5, 2, and 1.6 equiv of 5a, Table 1,
entries 6–8, respectively).
(iv) With catalyst 6c the expected product was formed in a mod-
erate yield, 51% (Table 1, entry 11).
(v) The reaction was also attempted under microwave irradia-
tion but gave lower yields (Table 1, entries 12 and 13).
Next, other 2-, 3-, and 4-substituted styrene derivatives 5 were
selected as reaction partners with 4a, using 6b as the catalyst
(3 mol %), in order to broaden the CM reaction scope (Table 2).
The products 7 were obtained in poor to moderate yields (Table 2)
although the 2-substituted styrene 5o did not react, probably due
to steric reasons. Crystals of the anisole-substituted product 7d
were grown and analyzed by X-ray crystallography (Fig. S1), which
confirmed the presence of the olefin and boronate moieties, in the
(E)-configuration.
Related symmetrical (E)-stilbenes have previously been pre-
pared via the homocoupling of 1,3-dibenzylbenzotriazolium

C. B. Baltus et al. / Tetrahedron Letters 54 (2013) 1211–1217
1213
bromides13 and styrylboronates 7 are also accessible via Wittig
reactions.14,15
Table 1
CM reaction of 4a with 5a
The homodimerization products 7m and 7s, from 4a and 4b,
respectively, were deliberately synthesized, moreover in excellent
yields, (Table 2, entries 12 and 18). Crystals of 7m were grown and
analyzed by X-ray diffraction (Fig. S1) and this confirmed its (E)-
configuration. Compounds 7m and 7s promise to be useful syn-
thons for the synthesis of symmetrical stilbenes (vide infra) as does
the orthogonally-protected MIDA-analogue 7f,16 which is a poten-
tial precursor to unsymmetrical stilbenes (MIDA: methyliminodi-
acetic acid). 11B NMR spectroscopic studies were able to
distinguish the distinct boron [sp2 (pinacol) or sp3 (MIDA)] envi-
ronments in the boron-containing metathesis products (Table 3
and Supplementary data).
Next, catalytic hydrogenations were performed on compounds
7 to afford the reduced products 8 in very good yields (Table S1,
Supplementary data). Crystals of 8b were grown and analyzed by
X-ray crystallography, which, along with its NMR spectra, con-
firmed that both the nitro group and vinylic bond had been re-
duced (Fig. S1).
O
O
O
B
O
6
B
CH2Cl2
43 °C
N2
5a
E-7a
4a
Entry
5a (equiv)
6 (mol %)
Time (h)
Yielda (%)
1
2
3
4
5
5
5
5
5
5
6b (5)
6b (5)
6b (5)
6b (5)
6b (5)
2.5
6
16
24
16
55
76b
58b
60b
42b,c
6
7
8
5
2
1.6
6b (3)
6b (3)
6b (3)
6
6
6
65
58
63
9
10
5
2
6b (1)
6b (1)
24
24
52b
65b
11
5
6c (3)
6
51
46b,d
26b,d
12
13
5
5
6b (5)
6b (5)
0.5
2
The boronic esters 8 were then coupled with a range of aryl ha-
lides 9 in Suzuki–Miyaura (SM) reactions in the presence of tetra-
kis(triphenylphosphine)palladium(0) using microwave conditions.
The corresponding biarylethyl arenes 10 were obtained in moder-
ate to very good yields (Table 4). Crystals of 10e were grown and
analyzed by X-ray crystallography (Fig. S1). The symmetrical prod-
uct 10f is a very interesting compound (Table 4, entry 6) since it
contains indole moieties, which are privileged scaffolds in medici-
Only the (E)-isomer was observed by 1H NMR.
a
Isolated yields.
b
Yield calculated by 1H NMR spectroscopy; mixture of expected product + traces
of starting material 4a.
c
Reaction achieved at room temperature.
Reaction under microwave irradiation in a sealed vial at 40 °C (Power max.,300
d
W, in a CEM Explorer).
Power max is a special cooling feature which enables microwave irradiation with
concomitant cooling.
Table 2
CM reactions of 4
O
B
O
6b (3 mol%)
R1
O
O
B
R1
CH2Cl2
43 °C
N2
4
5
7
Entry
4
5 (equiv)
Time (h)
Product (7)
Yielda (%)

1214
C. B. Baltus et al. / Tetrahedron Letters 54 (2013) 1211–1217
Table 2 (Continued)
Entry
4
5 (equiv)
Time (h)
Product (7)
Yielda (%)
Only the (E)-isomer was observed by 1H NMR.
bYield undetermined because the product is in a mixture with the homodimerization product of 5 and could not be separated by chromatography.
cPercentage yield in parentheses, calculated from the crude 1H NMR.
dYield calculated by 1H NMR, a mixture of the expected product and traces of the homodimerization product of 5d were obtained.
eBy-product of entry 5.
a
Isolated yields.
nal chemistry. Such analogues could be potential ligands for, for
example, dimeric GPCRs (G-protein coupled receptors).17
A complementary route toward the synthesis of biarylethyl aryl
and biarylethyl cycloalkyl derivatives was undertaken via an initial
SM coupling, followed by a CM reaction. 4-Vinylphenylboronic acid
(3a) was coupled with aryl halides 9 using McCluskey’s conditions,
with Pd(DIPHOS)2 as the catalyst [DIPHOS = 1,2-bis(diphenylphos-
phino)ethane].18 In our hands, the SM coupling under these condi-
tions was effective for electron-rich and electron-poor aryl
bromides (Table 5, entries 2 and 6), but no expected product was
observed when using an ortho-substituted aryl bromide (Table 5,
entry 5), although we did not investigate this extensively.

C. B. Baltus et al. / Tetrahedron Letters 54 (2013) 1211–1217
1215
Table 3
More examples of related biarylethyl aryl analogues were ob-
tained through reduction of the nitro group in 10b, affording ami-
nopyridine 13a, which was subsequently functionalized by
reaction with isovaleryl chloride to give 15a (Scheme 2). Both the
olefin and nitro group in compound 12b were reduced by catalytic
hydrogenation to afford the aryl product 13b in 75% yield
(Scheme 2).
11B chemical shifts of homo- and cross-metathesis boron-containing stilbenesa
Compound
11B chemical shift
4a
5f
7f
7m
7t
30.7b
15.8c
28.7, 10.4c
30.8b
14.1b
In conclusion, we have demonstrated that 3- and 4-vinyl-
phenylboronic acid pinacol esters are able to undergo CM reactions
allowing the synthesis of ethylenic phenylboronic acid pinacol es-
ter derivatives. The latter can be reduced, coupled via an SM reac-
tion and functionalized leading to a library of highly substituted
biarylethyl aryl and biarylethyl cycloalkyl compounds. A comple-
mentary and equally useful approach, employing an initial SM cou-
pling, was also achieved. This highlights the synthetic potential of
arylboronic esters, in furnishing libraries of compounds with drug-
like properties or synthetically challenging architectures.19,20 Com-
pounds 7m/8f, and regiosiomers, for example, 7s, as well as the
orthogonally protected boronic ester 7f, may have applications as
linkers or staplers in, for example, supramolecular chemistry or
as synthons in organic synthesis and medicinal chemistry, and this
is actively being pursued.21,22 Moreover, although somewhat lim-
ited commercially, vinylaryl boronic acids should be readily syn-
a
Shifts are quoted at the peak center, relative to BF3ÁEt2O, recorded on a Varian
VNMRS 600 spectrometer at 192 MHz.
b
Recorded in CDCl3.
Recorded in DMSO-d6.
c
Three ruthenium-based catalysts were tested in the CM reac-
tion of 11b: 6a was found to be inefficient (Table 6, entry 1), how-
ever, catalysts 6b and 6c were both suitable for this reaction since
the expected product 12a was obtained in moderate yields (e.g.,
54% yield with 6b, Table 6, entry 2 and 62% yield with 6c, Table 6,
entry 4). The CM reaction was also attempted on 11c with olefin
5d, catalyzed by 6b, which gave the expected product 12b in 75%
yield (Table 6, entry 5). E/Z ratios were generally high.
Table 4
SM reactions of compounds 8
Pd(PPh3)4
O
Na2CO3
B
Br Ar
Ar
R3
O
R3
toluene
EtOH
8
9
10
H2O
µw, 150 °C, 10 min
Entry
8
9
Product (10)
Yielda (%)
Conditions: 9 (1.1 equiv), Pd(PPh3)4 (3 mol %), Na2CO3 (3 equiv), toluene/ethanol/water 1:1:1, microwave irradiation (Power max., 300 W, CEM Explorer), 150 °C, 10 min.
Power max is a special cooling feature which enables microwave irradiation with concomitant cooling.
a
Isolated yields.
Yield over 3 steps.
b

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C. B. Baltus et al. / Tetrahedron Letters 54 (2013) 1211–1217
Table 5
SM couplings of 3a
Pd(DIPHOS)2
OH
OH
K2CO3
B
Br Ar
Ar
THF/H2O
µw
100 °C, 30 min, 100 W
3a
9
11
Entry
9
Product (11)
Yield (%)a
Conditions: ArBr (1 equiv), Pd(DIPHOS)2 (1 mol %), K2CO3 (2.4 equiv), THF/H2O 1:1 [5 mL for 1 mmol of ArB(OH)2], CEM Explorer microwave irradiation (100 W), 100 °C,
30 min.
a
Isolated yields.
Table 6
CM reactions on compounds 11b, c
6
(3 mol%)
R1
Ar
Ar
R1
CH2Cl2
45 °C
N2
11
5
12
E/Z ratioa
Entry
11
5 (equiv)
6
Time (h)
Product (12)
Yieldb (%)
a
Calculated by 1H NMR spectroscopy.
Isolated yields.
b
O
Cl
14a
H2
PS-NMM
Pd/C
NO2
NH2
NH
O
CH2Cl2
rt, 2 h
N
N
N
EtOH
rt,16 h
10b
13a
15a
72%
47%
H2
Pd/C
NO2
NH2
N
EtOH
rt, 16 h
N
O
O
12b
13b
75%
Scheme 2. Hydrogenation of compounds 10b and 12b (PS-NMM = polymer supported N-methylmorpholine base).

C. B. Baltus et al. / Tetrahedron Letters 54 (2013) 1211–1217
1217
thesized from their vinylaryl halide precursors in a single step.23
The solid state structures presented in the Supplementary data
(Fig. S1) have been deposited at the Cambridge Crystallographic
Centre.
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Acknowledgments
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Novartis is thanked for funding this work (PhD award to C.B.B.).
The EPSRC Mass Spectrometry Unit (Swansea) is thanked for HRMS
measurements. The EPSRC is also thanked for funding the National
Crystallography Service.24 Johnson Matthey PLC is thanked for a
loan of Pd salts. We are also indebted for the many useful referee
comments.
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Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
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