Aminoborylation/Suzuki-Miyaura tandem cross coupling of aryl iodides as efficient and selective synthesis of unsymmetrical biaryls

Article abstract of DOI:10.1039/c1cc14605j

Sequential borylation of a first aryl iodide using a dialkylaminoborane followed by a Suzuki-Miyaura cross coupling of second aryl iodide ended up with an efficient, selective and practical synthesis of unsymmetrical biaryls. This tandem coupling shows a wide range of applicability.

Full text of DOI:10.1039/c1cc14605j

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COMMUNICATION
Aminoborylation/Suzuki–Miyaura tandem cross coupling of aryl iodides
as efficient and selective synthesis of unsymmetrical biarylswz
Ludovic Marciasini,a Nicolas Richy,b Michel Vaultierab and Mathieu Pucheault*ab
Received 27th July 2011, Accepted 20th September 2011
DOI: 10.1039/c1cc14605j
Sequential borylation of a first aryl iodide using a dialkyl-
aminoborane followed by a Suzuki–Miyaura cross coupling of
second aryl iodide ended up with an efficient, selective and
practical synthesis of unsymmetrical biaryls. This tandem
coupling shows a wide range of applicability.
appealing in some cases, it dramatically decreases the reaction
scope to the synthesis of few biphenyl compounds.
The other desymmetrisation approach is associated to the
use of different halides, one reacting usually significantly
faster than the other. In that regard, some nice methods have
been proposed by Gosmini et al.,18–20 using nickel18,19 or
cobalt20 based catalysts, for the cross coupling of Ar–I with
Ar–Br16 or Ar–Cl,19 and Ar–Br with Ar–Cl19 using stoichio-
metric amounts of Mn20 or a sacrificial anode18,19 (Mg, Zn) as
reducing agent.
Facilitated by the generalization of transition metal catalysed
cross coupling of organometallics, access to unsymmetrical
biaryl compounds has witnessed a large increase in its applica-
tion domains, from advanced material preparation to the
synthesis of bioactive molecules.1 Indeed, the classical
preparation of the biaryl scaffold involves the reaction
between an organometallic reagent, typically centred on
B,2–4 Si,5,6 Zn,7 Mg,8,9 or Sn,10 with an aryl halide or pseudo
halide, in the presence of transition metal complexes based on
Pd, Ni, Pt, Au or Rh. Despite its selectivity and efficiency these
methods rely usually on separate organometallic preparation,
involving tedious purification steps and stability issues.
The main method for selective cross coupling of aryl halides
relies on generating organometallics from one of the halide,
followed by an in situ cross coupling with the second partner.
As such, many examples can be found in the literature related
to in situ Negishi or Kumada crosscoupling, using zinc or
magnesium22 species as intermediates.
In our program focused on boron chemistry,23–28 we
thought about using aminoarylboranes
3 as a reagent
for Suzuki Miyaura cross coupling. These compounds are
simply prepared through palladium catalysed borylation of
aryl halides and triflates with diisopropylaminoborane 1.
Although this reaction led in most cases to very little biaryl
product 4, we envisioned to perform a one pot cross coupling
with an excess of aryl iodide 2. Indeed when using 5
equivalents of 4-methoxyphenyl iodide 2a, the biphenyl
compound 4aa was isolated in 71% yield, showing that
these aminoarylboranes could efficiently be used as partners
in Suzuki–Miyaura cross coupling. However, despite
our effort to optimize the catalytic system, a decrease in aryl
halide quantity systematically led to a mixture of the corres-
ponding aminoborane 3a and biaryl 4aa as sole products
(Scheme 1).
Alternatively, reductive coupling of aryl halides could lead
to similar products. Since Ullmann’s discovery of copper
mediated homocoupling of aryl iodides,1 several advanced
methods have been developed for the preparation of unsym-
metrical biaryl compounds including catalytic version of the
parent reaction. Homocoupling is now well documented and
can be performed using Pd,11–17 Ni,18,19 or Co20 complexes as
catalysts. In many cases attempts to adapt these methods to
the selective synthesis of unsymmetrical biaryls raise selectivity
issues. Indeed, the random reaction of two different aryl
halides putatively leads to a 1/2/1 mixture of homo- and
hetero-coupled products. This statistical reaction outcome
can be circumvented on the basis of a large reactivity differ-
ence between the two partners,11,21 usually taking advantages
of electronic variations on the aromatic rings as nicely shown
by Jutand et al.11 Although this approach would eventually be
a
´
Institut des Sciences Moleculaires, UMR CNRS 5255,
Universite Bordeaux 1, 351 Cours de la Liberation, F-33405 Talence
´
´
Cedex, France. E-mail: m.pucheault@ism.u-bordeaux1.fr
b
´
´
Chimie et Photonique Moleculaires, UMR CNRS 6510, Universite
Rennes 1, Campus de Beaulieu, 263 Avenue du Ge´ne´ral Leclerc,
F-35042 Rennes Cedex, France
w This article is part of the ChemComm ‘Emerging Investigators 2012’
themed issue.
z Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, 1H, 13C, 11B, and 19F NMR spectra.
See DOI 10.1039/c1cc14605j
Scheme 1 Synthesis and reactivity of aminoarylboranes.
Chem. Commun., 2012, 48, 1553–1555 1553
c
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Table 1 Reaction condition optimization
Table 2 Palladium catalysed selective unsymmetrical biaryl synthesis
Entry
ROH
H2O
Base
Conv. (yielda)
1
2
3
4
5
—
—
K2CO3 2 eq.
Cs2CO3 2 eq.
Cs2CO3 2 eq.
Cs2CO3 2 eq.
Cs2CO3 2 eq.
80% (76%)
85% (74%)
100% (quant.)
75% (71%)
72% (68%)
MeOH
EtOH
Glycol
EtOH
10 eq.
10 eq.
10 eq.
30 eq.
a
Isolated yield after purification by flash chromatography.
Encouraged by these promising results, we decided to take
advantage of the borylation selectivity to perform an in situ
cross coupling with a second aryl iodide. This borylation
Suzuki–Miyaura tandem sequence has been exploited nicely
on aryl chlorides using tetrahydroxydiboron29 to generate a
boronic acid intermediate through the addition of an aqueous
solution of K2CO3. Other scarce examples can be found using
dialkoxyborane in the borylation step;30,31 evaporation between
the two steps was required to remove excess borane and for
toluene to DMF solvent swap.31 Interestingly, aminoaryl-
boranes are sufficiently stable to resist aqueous work up, even
following a short flash column chromatography. However, in
the presence of alcohols, they readily transform into the corres-
ponding boronates, the latter being more easily hydrolyzed.
Optimization of the reaction conditions for the second step of
the sequence led to the use of a 1/1 mixture of ethanol and water
as additive and Cs2CO3 as a base under refluxing conditions.
The presence of water was found not to be detrimental to the
reaction. Palladium source and KI additive were optimized for
the borylation step in previous studies,26,27 and therefore
remained unchanged. Keeping Et3N as sole base for the second
step led to decent yields but in average 5–10% below those
obtained with inorganic bases (Table 1).
Entry
1
Ar1I
Ar2I
Product
Yielda
64%
2b
2c
2
3
2b
2a
2d
2e
84%
91%
4
2a
2f
85%
5
6
2a
2b
2b
2a
Quant.
56%
7
8
2c
2d
2f
80%
87%
We then embarked into exploring the scope of this reaction
and were pleased to find that conversion was reaching in most
cases 100%, affording unsymmetrical biaryls in 80–90%
isolated yield (Table 2). The borylation step tolerates a
wide range of substituents from electron-donating (Table 2,
entries 3–11, 14, 15, 18, and 21–25) to electron-withdrawing
groups (Table 2, entries 12, 16, and 26). The substituent
position on the first aryl iodide has almost no incidence on
yields (Table 2, entries 1, 8 and 11). Very similarly for the
second step, electronic demand of the substituent has little
influence on yields (Table 2, electron rich: entries 1 and 2;
electron poor entries 12, 22). Indeed, Suzuki Miyaura cross
coupling is known to be favoured using electron rich boron
derivatives, prone to transmetallation and electron deficient
aryl halides, prone to faster oxidative addition. This general
trend can be found in most cases; best yields are obtained with
methoxy derived arylaminoborane intermediates, lower yield
being obtained when methoxyaryl iodides are employed in the
2e
9
2d
2f
2f
81%
39%
10
2d
11
12
2c
2g
2e
2h
80%
78%
13
2e
2i
73%
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1554 Chem. Commun., 2012, 48, 1553–1555

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Table 2 (continued )
yet to be applied to heteroaromatics. The reaction was even
slightly halide selective as 4,40-dibromobiphenyl could be synthe-
sized in 47% yield using 4-bromo-1-iodobenzene 2s as sole
reagent; less than 5% of iodine containing aromatics were isolated
from the reaction mixture other than the starting material.
Overall, we have developed an efficient and straightforward
access to unsymmetrical biphenyls directly from aryl iodides
by using a tandem borylation/Suzuki–Miyaura cross coupling.
It is noteworthy that the same reaction using bromoarenes in
lieu of aryl iodides led to the same products, showing the wide
applicability of that sequence for the practical preparation of
such unsymmetrical biaryl compounds.
Entry
Ar1I
Ar2I
Product
Yielda
83%
14
2c
2g
15
2a
2j
68%
16
17
2k
2l
64%
88%
Johnson, Matthey and Co., Ltd. is gratefully acknowledged
for a loan of palladium.
2m
2n
Notes and references
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89%
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2m
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second step. Overall, halides, nitro, trifluoromethyl, alkyl,
alkoxygroup, naphthyl substituent can equally be utilized.
So far the only found limitation is related to the competitive
reduction of carbonyl groups by the dialkylaminoborane 1 and is
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 1553–1555 1555