Silyl-protected dioxaborinanes: Application in the Suzuki cross-coupling reaction

Article abstract of DOI:10.1039/c3ob42099j

The synthesis of a range of novel silyl-protected dioxaborinanes as a column- and bench-stable boron reagent were found to be advantageous to achieving good yields in palladium-catalysed cross-coupling reactions under standard conditions. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/c3ob42099j

Organic &
Biomolecular Chemistry
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Silyl-protected dioxaborinanes: application in the
Suzuki cross-coupling reaction†
Cite this: Org. Biomol. Chem., 2014,
12, 47
Sean Goggins, Eleanor Rosevere, Clément Bellini, Joseph C. Allen, Barrie J. Marsh,
Mary F. Mahon and Christopher G. Frost*
Received 21st October 2013,
Accepted 6th November 2013
DOI: 10.1039/c3ob42099j
www.rsc.org/obc
The synthesis of a range of novel silyl-protected dioxaborinanes as
a column- and bench-stable boron reagent were found to be
advantageous to achieving good yields in palladium-catalysed
cross-coupling reactions under standard conditions.
For Suzuki cross-coupling reactions, boronic acids are the
coupling partners of choice in the majority of applications.
However, boronic acids can be difficult to synthesise and there
can often be issues with purification and manipulation. Also,
an excess of the boronic acid has to be used due to the compet-
ing formation of trimeric cyclic anhydrides (boroxines) and
protodeboronation processes, leading to difficulties in being
able to accurately measure reaction stoichiometry.1 A number
of elegant solutions to these problems have been presented
involving the use of preformed borate and boronate reagents
that can be isolated and stored prior to use (Fig. 1). These
include tris(hydroxy)borates,2 lithium trimethoxyborate
species,3 trifluoroborate salts4 and N-methyliminodiacetic acid
(MIDA) boronates.5 An important addition to this range of
donors is the cyclic triolborates synthesised by Miyaura.6
These borate reagents are reported to be stable in air and
water and more soluble in organic solvents than potassium tri-
fluoroborates. Recently, we described the synthesis of silyl-
protected dioxaborinanes and exemplified their use as a
coupling partner in the enantioselective synthesis of 4-aryl-
chroman-2-ones.7 In this paper we describe an alternative pro-
cedure to the synthesis of silyl-protected dioxaborinanes and
demonstrate their use as a boron reagent within the Suzuki
cross-coupling reaction.
Fig. 1 Organoboron reagents.
Scheme 1 General procedure for the synthesis of silyl-protected
dioxaborinanes.
room temperature in dichloromethane leads to the formation
of the same intermediate without losing any boronic acid to
boroxine formation. Following work-up, treatment with chloro-
trimethylsilane in the presence of triethylamine gives the silyl-
protected dioxaborinane in improved yields (Scheme 1). Also,
the concentration of the reaction mixture for both reactions
was found to be important in order to gain optimum yields via
the telescoped procedure. Purification can be achieved
through standard column chromatography to afford the
desired protected boron species. Once synthesised and puri-
fied, silyl-protected dioxaborinanes are stable on a bench-top
for several months without any decomposition being observed.
The synthesis was then applied to a wide range of commer-
cially available boronic acids and the corresponding silyl-pro-
tected dioxaborinanes were obtained in all cases (Table 1).
Simple aryl boronic acids gave excellent yields over the two
steps but yields decreased somewhat for both electron-with-
drawing aryl boronic acids as well as sterically demanding
Previously, we reported that heating boronic acids with
1,1,1-tris(hydroxymethyl)ethane 1, under Dean-Stark con-
ditions gives the dioxaborinane intermediate prior to silyla-
tion.7 Alternatively, stirring the boronic acid with the triol at
Department of Chemistry, University of Bath, Bath, BA2 7AY, UK.
E-mail: c.g.frost@bath.ac.uk; Fax: +44 (0)1225 386231; Tel: +44 (0)1225 386142
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, characterisation data, copies of NMR spectra for compounds syn-
thesised. CCDC 944020. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c3ob42099j
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Table 1 Results of boronic acid protectiona
Entry
1
R
Yieldb (%)
96
Entry
10
R
Yieldb (%)
63
2a
2b
2j
2
3
95
49
11
12
2k
94
37
2c
2l
4
5
6
2d
2e
2f
56
70
98
13
14
15
2m
2n
2o
17
57
38
7
8
2g
2h
97
15
16
17
2p
2q
59
28
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Table 1 (Contd.)
Entry
9
R
Yieldb (%)
37
Entry
18
R
Yieldb (%)
27
2i
2r
a Reaction conditions: boronic acid (8 mmol) suspended in anhydrous CH2Cl2 (4 mL mmol−1) under N2. Tris(hydroxymethyl)ethane (1 eq.,
8 mmol) was then added and stirred until homogeneous (∼0.5 h), then MgSO4 added and stirred for an additional (0.25 h). Filtration and
concentration gives crude intermediate. Redissolved in anhydrous THF (2 mL mmol−1) under N2 and TEA (2 eq. 16 mmol) was added. At 0 °C,
TMSCl (1.5 eq., 12 mmol) added and left to stir overnight. Purification via silica gel column chromatography (hexane 8–2 EtOAc). b Isolated yields
over two steps.
containing a pyridine moiety.9 With this in mind, we decided
to choose 2-bromopyridine as the substrate for Suzuki cross-
coupling reactions with our silyl-protected dioxaborinanes to
identify any potential benefit the protecting group has over
standard boronic acids. Typically, a combination of solvents,
bases and ligands are required to obtain high yields in Suzuki
cross-coupling reactions, especially with difficult substrates.10
Therefore, a common set of conditions were chosen to identify
the optimum conditions for the cross-coupling reaction with
our dioxaborinanes (Table 2).
Surprisingly, when using conditions pioneered by Fu et al.,
that can deliver excellent yields using aryl chlorides as sub-
strates at room temperature, the Suzuki cross-coupling failed
to give any of the desired product (Table 2, entry 1).11 Con-
ditions typified by Buchwald et al., afforded 2-phenylpyridine
4a only in a modest yield (Table 2, entry 2).12 However, when
using standard Suzuki cross-coupling conditions of 1 mol%
Pd(PPh3)4 in ethanol, a near quantitative yield was obtained
Fig. 2 ORTEP drawing of 2k. Hydrogen atoms omitted for clarity.
substrates. Pleasingly, heteroaromatics were also tolerated
under the reaction conditions. The structure of silyl-protected
dioxaborinane 2k was confirmed by X-ray crystallography
(Fig. 2).
Previously, we have shown that silyl-protected dioxabori-
nanes provide superior yields as a boron reagent than boronic
acids, trifluoroborates and triol borates within rhodium-
catalysed conjugate addition reactions to arylidene Meldrum’s
acids.7 We therefore attempted to extend the application of the
silyl-protected dioxaborinanes by utilising them in Suzuki
cross-coupling reactions.
The Suzuki cross-coupling reaction between boronic acids
and aryl halides has developed into one of the most important
cross-coupling reactions and is a powerful and general method
for the formation of carbon–carbon bonds.8 In particular, the
construction of carbon–carbon bonds between hetero-
aromatics is of great interest as a variety of pharmaceutical
compounds are structured around heteroaryl motifs, often
(Table 2, entry 4). Lowering the catalytic loading and dropping
the equivalents of dioxaborinane only lead to a drop-off in
yield. Comparatively, when using the same conditions but
using phenylboronic acid as the coupling partner, a lower
yield was obtained (Table 2, entry 5). This interesting result
prompted a further study to compare the advantage silyl-
protected dioxaborinanes may have over boronic acids and
other boronic acid ester derivatives using a more challenging
substrate.
The construction of carbon–carbon bonds between two
heteroaryl reagents can be problematic for palladium-catalysed
coupling reactions due to hetero-atom lone pairs being able to
coordinate to the metal centre and subsequently poison the
catalyst.13 Benzo[b]thiophen-2-ylboronic acid, its neopentyl
glycol and pinacol derivatives, along with silyl-protected
dioxaborinane derivative 2n, were therefore chosen as boron
reagents in the Suzuki cross-coupling with 2-phenylpyridine
under our optimised conditions (Table 3).
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Table 2 Optimisation of the Suzuki cross-coupling reactiona
Entry
Catalyst
Pd2dba3
Base
Boron reagent
Solvent
Yieldj (%)
b
c
1
2
3
4
5
6
7
K3PO4 e
K3PO4
K2CO3 g
K2CO3 g
K2CO3 g
K2CO3 g
K2CO3
2a (1 eq.)
Dioxane 2–1 H2O
DMF 9–1 H2O
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
0
77
70
98
74
73
70
d
Pd(OAc)2
2a (0.8 eq.)
2a (1.5 eq.)
2a (1.5 eq.)
f
g
Pd(PPh3)4 h
Pd(PPh3)4 h
Pd(PPh3)4 h
Pd(PPh3)4 h
Pd(PPh3)4
i
Ph-B(OH)2
2a (1.3 eq.)
2a (1.1 eq.)
a Reaction conditions: catalyst, ligand and base dissolved in solvent under argon. Boron reagent in solvent then added followed by
2-bromopyridine (1 mmol). Reaction mixture then stirred for 18 hours at 100 °C. Purification via silica gel column chromatography (EtOAc
5–95 hexane). b 2.5 mol% Pd2dba3, 5 mol% PCy3. c 1.7 eq. d 2.5 mol% Pd(OAc)2, 5 mol% SPhos. e 3 eq. f 0.5 mol% Pd(PPh3)4. g 2 eq. h 1 mol%
Pd(PPh3)4. i 1.5 eq. j Isolated yields.
could be operating in a similar fashion and slowly releasing
Table 3 Comparative study of silyl-protected dioxaborinanes with
other boron reagentsa
the boronic acid under mild conditions for Suzuki cross-
coupling reactions without the need for additional water to be
added. However, it is also plausible that under basic con-
ditions, the trimethylsilyl group is removed leading to the for-
mation of a triol borate, which is a known active species
formed prior to oxidative insertion. Further investigations are
underway to determine the precise mechanism of the silyl-pro-
tected dioxaborinanes with coupling reactions. The pinacol-
protected benzothiophene derivative also furnished a high
yield of 4n showing that the silyl-protected dioxaborinane
competes favourably with existing protecting groups, and
offers an alternative option for the preparation of a stable
boron protecting group that has high reactivity in carbon–
carbon bond forming reactions.
Entry
1
Boron reagent
Yieldb (%)
50
2
3
67
91
Having found the optimum conditions for the Suzuki cross-
coupling using the silyl-protected dioxaborinane, the scope of
the reaction was then explored (Table 4). Pleasingly, the
desired product was obtained with all the dioxaborinanes that
were screened against 2-bromopyridine. Electron-donating
substituents on the aryl ring of the dioxaborinane gave near
quantitative yields of the bis-aryl compound (Table 4, entries
2, 11, 12). This is as expected as increased nucleophilicity of
the aryl ring accelerates transfer to the palladium catalyst
during the transmetallation step of the catalytic cycle.15 The
alkenyl dioxaborinane 2o also gave a near quantitative yield of
2-styrylpyridine, a result which is in accordance with Suzuki
and Miyaura’s findings in their seminal publication.16 Gene-
rally, aryl halides were tolerated giving good yields in some
cases (Table 4, entries 6, 7), but electron-withdrawing substitu-
ents on the aryl ring caused a decrease in yields (Table 4,
entries 4, 5, 8, 9). Heteroaromatics were also tolerated giving
good yields (Table 4, entries 13, 14) but bulkier groups and
larger aromatics gave decreased yields due to sterics. The use
of silyl-protected dioxaborinanes with 2-bromopyridine in
Suzuki cross-coupling reactions allows for the efficient for-
mation of 2-substituted pyridines; products which can be
4
2n
92
a Reaction conditions: Pd(PPh3)4 (0.01 mmol,
1
mol%), K2CO3
(2 mmol, 2 eq.) dissolved in ethanol (2 mL) under argon. Boron
reagent (1.5 mmol, 1.5 eq.) in ethanol (2 mL) was added followed by
2-bromopyridine (1 mmol, 1 eq.). Reaction mixture stirred for 18 hours
at 100 °C. Purification via silica gel column chromatography (hexane
95–5 EtOAc). b Isolated yields.
The unprotected boronic acid delivered only a moderate
yield of product 4n, whilst the neopentyl glycol protected
species provided just a slight improvement. Surprisingly, the
structurally similar protecting group of the silyl-protected di-
oxaborinane provided a far superior yield in comparison. This
leads us to believe that the –OTMS group is playing a role
within the reaction mechanism. Recent investigations into the
rate of hydrolysis of boronic acid protecting groups have
revealed that a ‘slow-release’ mechanism from the protected
species to the free boronic acid suppresses the formation of
competing side-products.14 The silyl-protected dioxaborinanes
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Table 4 Scope of Suzuki cross-couplings with silyl-protected borinanesa
Entry
1
R
Yieldb (%)
98
Entry
10
R
Yieldb (%)
88
4a
4b
4j
2
3
96
80
11
12
4k
97
98
4c
4l
4
5
6
4d
4e
4f
48
67
87
13
14
15
4m
4n
4o
79
92
99
7
8
4g
4h
98
42
16
17
4p
4q
77
47
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Table 4 (Contd.)
Entry
R
Yieldb (%)
9
Entry
18
R
Yieldb (%)
20
9
4i
4r
a Reaction conditions: Pd(PPh3)4 (0.01 mmol, 1 mol%), K2CO3 (2 mmol, 2 eq.) dissolved in ethanol (2 mL) under argon. Silyl-protected
dioxaborinane (1.5 mmol, 1.5 eq.) in ethanol (2 mL) was added followed by 2-bromopyridine (1 mmol, 1 eq.). Reaction mixture stirred for
18 hours at 100 °C. Purification via silica gel column chromatography (hexane 95–5 EtOAc). b Isolated yields.
further functionalised via C–H activation methodology due to
the directing group nature of the pyridine moiety.
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Conclusions
In conclusion, we have shown that a wide range of silyl-
protected dioxaborinanes can be prepared on a gram-scale in a
mild and simple manner from their parent boronic acid. They
are both column- and bench-stable and we have also shown
that these dioxaborinanes perform exceptionally well in palla-
dium-catalysed cross-coupling reactions. In the scenario pre-
sented here, this allowed for the efficient construction of
highly functional bis(hetero)aryl compounds in very good
yields from basic starting materials. Mechanistic studies are
underway to understand the unique properties of silyl-
protected dioxaborinanes within coupling reactions and their
application to other reactions are also in progress.
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12 J. P. Wolfe, R. A. Singer, B. H. Yang and S. L. Buchwald,
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Acknowledgements
We are grateful to the University of Bath for funding. We
acknowledge the valuable assistance of Dr Anneke Lubben 13 I. Kondolff, H. Doucet and M. Santelli, J. Mol. Catal. A:
(Mass Spectrometry) and Dr John Lowe (NMR Spectroscopy).
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Notes and references
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Weinheim, Germany, 2005, pp. 1–99.
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52 | Org. Biomol. Chem., 2014, 12, 47–52
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