COMMUNICATIONS
DOI: 10.1002/adsc.201300741
Suzuki–Miyaura Cross-Coupling under Solvent-Free Conditions
a
a,b
a
Andrey F. Asachenko, Kristina R. Sorochkina, Pavel B. Dzhevakov,
a
a,b,
Maxim A. Topchiy, and Mikhail S. Nechaev *
A. V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences, 119991 Moscow, Russian Federation
M. V. Lomonosov Moscow State University, 119991 Moscow, Russian Federation
a
b
Received: August 15, 2013; Published online: November 27, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300741.
Abstract: A solvent-free reaction protocol for
Suzuki–Miyaura cross-couplings was developed.
tool to avoid the use of microwave and ultrasonic ir-
radiation or ball mill equipment.
(
Hetero)aryl bromides and chlorides are coupled
One of the key problems of organic reactions under
solvent-free conditions is the homogeneity of the re-
action medium. Conventional reactants in the Suzuki–
Miyaura reaction are arylboronic acids. However,
these compounds are solids with high melting points,
they are also non-soluble in aryl halides, and exhibit
low stability under basic aerobic conditions. To avoid
these problems we utilized pinacol arylboronates.
These compounds have high thermal and hydrolytic
stability. Pinacol arylboronates are liquids or solids
with low melting points and are miscible with aryl
halides.
with pinacol arylboronates in high yields. The reac-
tion is catalyzed by conventional bis(triphenylphos-
phine)palladium(II) chloride [(PPh ) PdCl ] and/or
palladium(II) acetate/SPhos [Pd ACHTUNGTERNN(UNG OAc) /SPhos]
under air.
3
2
2
2
Keywords: carbenes; palladium; phosphanes; sol-
vent-free reactions; Suzuki–Miyaura cross-coupling
Various palladium catalysts were tested: well-de-
[
7]
A challenge facing organic chemists is the develop- fined NHC complexes 1–5; expanded ring NHC
[
8]
9]
ment of new processes that are not only efficient, se- complexes recently developed in our group 6 and 7;
[
lective, and high yielding but also environmentally the well-defined catalytic system Pd(OAc) /SPhos;
AHCTUNGTRENNUNG
2
friendly. The measure of “greenness” of a process is as well as the conventional commercially available
[
1]
the E factor, introduced by Sheldon. It is defined as palladium sources PdCl , Pd
A
H
U
G
E
N
N
(dba) , Pd
A
T
N
T
E
N
N
(OAc) , and
2
2
3
2
the ratio of weight of waste to weight of product. The (Ph P) PdCl .
3
2
2
E factor for many pharmaceuticals has been estimat-
As shown in Table 1, the study begins with an opti-
[
2]
ed to exceed 100. The largest contributors to the mization of the operating conditions on a model reac-
magnitude of E factor are organic solvents, many of tion involving phenyl bromide and pinacol p-tolylbor-
which are ecologically harmful and require expensive onate. When triethylamine or sodium carbonate was
regeneration. Thus, elimination of solvents from or- used as a base, no coupling products were observed.
ganic synthesis is of high importance.
Stronger bases such as potassium carbonate, lithium,
In the last two decades several approaches to elimi- and sodium hydroxides gave moderate yields. When
nate solvents from organic synthesis were developed. potassium hydroxide was used, a virtually quantitative
Of special interest is the Suzuki–Miyaura reaction yield was obtained.
that is a highly important synthetic tool in medicinal
chemistry. Couplings of aryl halides with boronic catalytic system (Table 2). Tests were performed on
The next step of our work was optimization of the
[3]
acids have been performed under microwave irradia- a model reaction, the coupling of pinacol p-tolyl-
[
4]
[5]
tion,[ ultrasonic irradiation, and ball mill activa-
A
H
U
G
E
N
N
ACHTUNGTRENNGNUa te and deactivated sterically hindered 2-bro-
6]
tion.
In this work we have performed a systematic study no or low activity (entries 1–3). All NHC complexes
of the Suzuki–Miyaura reaction under solvent-free exhibited good catalytic activity giving 62–81% yields
conditions using cheap bases, commercially available (entries 4–12). The Pd CAHTUNGTERNNGN(U OAc) /SPhos catalytic system
2
catalysts, and without use of an inert atmosphere and gave a virtually quantitative yield. Surprisingly, simple
highly pure reagents. We also focused on the utiliza- (Ph P) PdCl has shown an excellent performance.
3
2
2
tion of conventional and simple heating as activation Notably, reactions were performed under aerobic con-
Adv. Synth. Catal. 2013, 355, 3553 – 3557
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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