Clean and fast cross-coupling of aryl halides in one-pot

Article abstract of DOI:10.3762/bjoc.10.87

Unsymmetrically coupled biaryls are synthesized in high yield starting from different aryl bromides and bis(pinacolato)diboron by carrying out the Miyaura borylation reaction followed by the Suzuki-Miyaura reaction in the same reaction pot over 1-2 mol % SiliaCat DPP-Pd. The SiliaCat DPP-Pd catalyst is air-stable and the method does not require the use of inert conditions. The use of non-toxic isopropanol or 2-butanol as reaction solvent further adds to the environmental benefits of this new green synthetic methodology.

Full text of DOI:10.3762/bjoc.10.87

Clean and fast cross-coupling of
aryl halides in one-pot
Valerica Pandarus1, Geneviève Gingras1, François Béland*1,
Rosaria Ciriminna2 and Mario Pagliaro*2
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 897–901.
1SiliCycle Inc., 2500, Parc-Technologique Blvd, Quebec City,
Quebec, Canada G1P 4S6 and 2Istituto per lo Studio dei Materiali
Nanostrutturati, CNR, via U. La Malfa 153, 90146 Palermo, Italy
doi:10.3762/bjoc.10.87
Received: 14 January 2014
Accepted: 03 April 2014
Published: 22 April 2014
Email:
François Béland* - FrancoisBeland@silicycle.com; Mario Pagliaro* -
mario.pagliaro@cnr.it
Associate Editor: C. Stephenson
* Corresponding author
© 2014 Pandarus et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
borylation; SiliaCat; Suzuki–Miyaura; cross-coupling; one-pot
Abstract
Unsymmetrically coupled biaryls are synthesized in high yield starting from different aryl bromides and bis(pinacolato)diboron by
carrying out the Miyaura borylation reaction followed by the Suzuki–Miyaura reaction in the same reaction pot over 1–2 mol %
SiliaCat DPP-Pd. The SiliaCat DPP-Pd catalyst is air-stable and the method does not require the use of inert conditions. The use of
non-toxic isopropanol or 2-butanol as reaction solvent further adds to the environmental benefits of this new green synthetic
methodology.
Findings
Affording valued biaryls and heterobiaryls, namely ubiquitous direct route to boronic esters [2], namely the cross-coupling of
chemical moieties in pharmaceuticals, natural products, bis(pinacolato)diboron (B2Pin2) with aryl or vinyl halides
photoactive species and many other functional molecules, the catalyzed by PdCl2(dppf) ([1,1′-bis(diphenylphos-
Suzuki–Miyaura cross-coupling reaction is widely employed by phino)ferrocene]palladium(II) dichloride) in the presence of
the fine chemicals and pharmaceutical industries [1]. The reac- excess KOAc at 80 °C in dioxane or in DMSO.
tion involves a boron-containing nucleophile (a variety of aryl
and heteroaryl boronic acids, esters, Ar-BBN, trifluoroborate In contrast to a number of Pd catalysts that are air sensitive,
and other boron species) and vinyl- or aryl halides as the elec- PdCl2(dppf) is air stable. This made the method more versatile
trophilic species. The use of the Suzuki–Miyaura reaction and provided a long awaited easy way to synthesize a broad
became routine both in industry and in research laboratories range of boronic esters that are conveniently used in place of
following Miyaura’s discovery from 1995. He demonstrated a boronic acids in the Suzuki–Miyaura reaction when reactive
897

Beilstein J. Org. Chem. 2014, 10, 897–901.
functional groups are present in the electrophilic aryl halides SiliaCat DPP-Pd is a commercially available catalyst [11] made
[3,4].
of an organosilica matrix functionalized with diphenylphos-
phine ligands bound to Pd2+ (Figure 1).
Several homogeneous palladium catalysts of enhanced versa-
tility for the cross-coupling of pinacolborane with aryl halides
have since been introduced, for example by Buchwald and
co-workers [5,6]. Of direct relevance to this research report,
Giroux and co-workers reported the homogeneously palladium-
catalyzed one-pot borylation/Suzuki coupling reactions already
in 1997 [7].
Figure 1: Chemical structure of SiliaCat DPP-Pd.
Yet, it remains desirable to efficiently heterogenize palladium
catalytic species used in cross-coupling reactions with the aim The catalyst, which is highly active in C–C coupling reactions
to prevent product contamination with palladium, reuse the [12], has typical 0.2–0.3 mmol/g palladium loading, a high
expensive catalyst and streamline the whole synthetic process surface area and large accessible mesoporosity (300–650 m2/g,
[8]. Furthermore, the replacement of DMSO or dioxane with a depending on the applied parameters of the sol–gel synthesis).
less toxic solvents is of obvious environmental and health rele-
vance.
The leach-proof and truly heterogeneous nature of SiliaCat
DPP-Pd in the synthesis of boronic acid pinacol esters has been
Sol–gel-entrapped catalysts are rapidly emerging as a promising recently shown elsewhere [10], wherein the issue of catalyst
tool for synthetic organic chemistry [9]. In this research context, recycling is also addressed in detail. Now we report a new
we have recently described the heterogeneously catalyzed syn- method that establishes a direct route, in one-pot, to unsym-
thesis of boronic acid pinacol esters using a wide range of aryl metrically coupled biaryls starting from two different aryl bro-
chlorides, bromides and iodides and bis(pinacolato)diboron as mides and bis(pinacolato)diboron without the need to isolate the
borylating agent over the sol–gel-entrapped SiliaCat DPP-Pd intermediate boronic acid pinacol ester. The overall process is
catalyst (Scheme 1) [10]:
described by Scheme 2.
Scheme 1: Heterogeneously catalyzed synthesis of boronic acid pinacol esters over SiliaCat DPP-Pd.
Scheme 2: Heterogeneously catalyzed cross-coupling of two aryl bromides by consecutive borylation and Suzuki–Miyaura reactions, both of which
are mediated by SiliaCat DPP-Pd.
898

Beilstein J. Org. Chem. 2014, 10, 897–901.
The SiliaCat DPP-Pd catalyst mediates the borylation and the sequence, the Suzuki–Miyaura reaction. Results in Table 1
subsequent Suzuki–Miyaura reaction in an elegant one-pot show that, following aqueous work-up, different unsym-
sequential synthesis. Hence, an aryl bromide is first converted metrically coupled compounds are obtained in good to
into the boronic acid pinacol ester (step 1 in Scheme 2). A excellent yields by coupling numerous different aryl bromides
different aryl bromide is then added along with aqueous base with different aryl halides, including heteroatom-containing
(step 2).
aryls.
The reaction is carried out in iPrOH or in 2-BuOH. No work-up In detail, entries 1 and 2 in Table 1 show that 3-bromophenol
is performed after the borylation in the first step, nor is any and 4-bromoanisole are entirely converted into the boronic acid
catalyst added prior to conducting the second step of the pinacol ester in 2–3 h over 2 mol % SiliaCat DPP-Pd. The same
Table 1: One-Pot SiliaCat DPP-Pd-catalysed borylationa and Suzuki–Miyaura couplingb reactions.
Conv/select
(Yield)d
(%)
Catalyst
(mol %)
Base
(equiv)
Solvent
(M)c
t
Entry
Substrate
Product
(h)
SiliaCat
DPP-Pd
2
KOAc
2.2
iPrOH
(0.75)
1
2
100/99
K2CO3
2.3
+ 8 mL
H2O
2
3
55
85
–
SiliaCat
DPP-Pd
2
KOAc
2.2
iPrOH
(0.75)
2
3
99/98
K2CO3
2.3
+ 8 mL
H2O
2
3
84.5
92/97 (88)
–
SiliaCat
DPP-Pd
2
KOAc
2.2
iPrOH
(0.75)
2
3
89
100/98
3
K2CO3
2.3
+ 8 mL
H2O
2
3
74
83
–
SiliaCat
DPP-Pd
2
KOAc
2.2
iPrOH
(0.75)
4
3
100/98
K2CO3
2.3
+ 8 mL
H2O
2
3
70
82
–
SiliaCat
DPP-Pd
2
KOAc
2.2
iPrOH
(0.75)
1
2
90
100/99
5
K2CO3
2.3
+ 8 mL
H2O
1
3
81
–
99/95 (89)
899

Beilstein J. Org. Chem. 2014, 10, 897–901.
Table 1: One-Pot SiliaCat DPP-Pd-catalysed borylationa and Suzuki–Miyaura couplingb reactions. (continued)
SiliaCat
DPP-Pd
1
KOAc
2.2
2-BuOH
(1.00)
1
2
98
100/99
6e
7e
8e
K2CO3
2.3
+ 8 mL
H2O
1
3
85
–
100/98 (94)
SiliaCat
DPP-Pd
1
KOAc
2.2
2-BuOH
(1.00)
1
2
98
100/99
K2CO3
2.3
+ 8 mL
H2O
3
17
35
86
–
SiliaCat
DPP-Pd
1
KOAc
2.2
2-BuOH
(1.00)
1
2
98
100/99
SiliaCat
DPP-Pd
1
K2CO3
2.3
+ 8 mL
H2O
1
3
63
95
Experimental conditions. aStep 1: Substrate 1 (10 mmol, 1 equiv), B2Pin2 (11 mmol, 1.1 equiv), KOAc (22 mmol, 2.2 equiv), 28 mL anhydrous iPrOH
(0.75 M molar concentration with respect to reagents), 2 mol % SiliaCat DPP-Pd (0.25 mmol/g palladium loading), at 82 °C. bStep 2: Substrate 2
(12 mmol, 1.2 equiv relative to substrate 1), K2CO3 (23 mmol, 2.3 equiv relative to substrate 1), 8 mL distillated H2O (iPrOH/H2O, 3.5:1, v/v). cMolar
concentration with respect to the substrate and to B2Pin2. dConversion/selectivity in cross-coupling product evaluated by GC–MS. Yield of the isolated
product is given in parentheses. eThe borylation reaction is carried out at 98 °C in 21 mL anhydrous 2-BuOH (1.0 M molar concentration with respect
to the reagents.
aryl halides are coupled with 4-bromotoluene or 2-bromo- Results displayed in Table 1, entry 7 show that when
toluene to form the Suzuki–Miyaura coupling product in, res- 4-bromopyridine hydrochloride is replaced by 4-chloropyridine
pectively, 85% and 92% yield in 3 h.
hydrochloride, only a 35% yield of the Suzuki coupling prod-
uct is obtained in 3 h over 1 mol % Pd catalyst. The yield grows
Table 1, entry 3 shows that 3-bromopyridine is entirely to 86% by prolonging the reaction time to 17 h. However, it is
converted in the boronic acid pinacol ester in 3 h over 2 mol % enough to add another 1 mol % Pd catalyst amount to the reac-
SiliaCat DPP-Pd. The resulting boronic ester is then smoothly tion mixture, after the borylation is complete, to observe 95%
coupled with 4-bromotoluene in 83% in 3 h, or with 2-bromo- conversion into the Suzuki coupling product in 3 h (Table 1,
toluene in 82% in 3 h (Table 1, entry 4), over the same amount entry 8).
of catalyst in the same reaction pot.
In conclusion, unsymmetrically coupled biaryls can be synthe-
Table 1, entry 5 shows the excellent applicability of SiliaCat sized in high yield starting from different aryl bromides and
DPP-Pd to the borylation of sterically ortho-substituted bis(pinacolato)diboron by carrying out the Miyaura borylation
2-bromotoluene, which is quantitatively converted into the reaction followed by the Suzuki–Miyaura reaction over
corresponding arylboronate in 2 h over 2 mol % catalyst. The 1–2 mol % catalytic amount of the sol–gel entrapped catalyst
latter arylboronate is then quantitatively coupled with SiliaCat DPP-Pd in the same reaction pot. There is no need to
4-bromopyridine hydrochloride in 3 h in the same reaction mix- isolate the intermediate boronic acid pinacol ester, while the air
ture. Table 1, entry 6 shows that the same quantitative conver- stable sol–gel entrapped palladium catalyst does not require the
sions are obtained for the same substrates by replacing use of inert conditions.
isopropanol with 2-BuOH. Only 1 mol % SiliaCat DPP-Pd is
enough to promote full conversion of the original halides into Finally, the use of isopropanol or 2-butanol as reaction solvents
the unsymmetrically coupled product.
further points out the environmental benefits of the method. As
900

Beilstein J. Org. Chem. 2014, 10, 897–901.
the fine chemicals and pharmaceutical industries are eventually
adopting green chemistry synthetic methodologies [13], this
method provides both industries with a clean route to valued
compounds that are widely used in many industrial sectors.
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
Acknowledgements
This article is gratefully dedicated to the memory of Mr.
Gaetano Irrera (1969-2013) for all he did to establish in
Palermo the new chemistry Institute of Italy’s CNR. We
acknowledge the valued assistance of Simon Bédard and Pierre-
Gilles Vaillancourt from the Quality Control Department of
SiliCycle Inc.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
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