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50 1C to produce the corresponding terminal alkyne. The product stream was
subsequently brought into contact with an aryl bromide to perform the Heck-
Cassar coupling at 120 1C. Although this procedure was used for the
production of a variety of diarylalkynes, the total residence time was 8 h.
13.4.10 Palladium-Catalyzed a-Arylation/Alkylation in Flow
Palladium-catalyzed a-arylation represents a versatile reaction which allows
the construction of carbon-carbon bonds between the a-position of a car-
bonyl and an aryl or vinyl moiety. A series of two micro packed-bed reactors
was used for the preparation of 3,3-disubstituted oxindoles in continuous
flow (Figure 13.25).
55
An XPhos second-generation precatalyst was used as a
catalyst and allowed for rapid activation. Biphasic reaction conditions, with
KOH as the base, were selected to avoid precipitate formation.
13.4.11 Direct Arylation in Flow
Inspired by selective biosynthetic pathways, C-H activation has emerged as a
promising new area for the construction of carbon-carbon bonds. An
intramolecular direct arylation to prepare biaryls has been transferred to
continuous flow (Figure 13.26).
56
A binary solvent system, N,N-dimethyla-
cetamide (DMA)-water (10 : 1), provided the highest conversion and select-
ivity and allowed optimal solubility of both organic and inorganic starting
materials. Nevertheless, solubility issues were encountered during the
course of the reaction and resulted in clogging of the microreactor. The use
of ultrasonication could eciently solve this problem, and several hetero-
cyclic biaryls could be prepared in continuous flow. However, long reaction
times (3-6 h) were still required to obtain high conversions.
R
2
X
ArX
R
2
Ar
O
O
N
R
1
N
R
1
100 °C
100 °C
ar yl ati on
al kyl ati on
α −
α −
Me
HO
O
N
NBoc
O
N
Bn
Bn
O
O
O
O
N
MOM
N
Me
N
Me
N
Me
84%
94%
79%
62%
Figure 13.25 Continuous flow synthesis of 3,3 disubstituted oxindoles via a
Pd-catalyzed a-arylation-alkylation.
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