Cross-Coupling Chemistry in Continuous Flow - New Trends in Cross-Coupling: Theory and Applications - page 636

reactions, which normally take several hours or days in traditional batch re-
actors, could be accelerated significantly (16 min residence time).
13.5 Carbon-Heteroatom Bond Formation
in Continuous Flow
13.5.1 C-N Bond Formation in Flow
The palladium-catalyzed amination reaction, also known as the Buchwald-
Hartwig reaction, constitutes one of the most important tools to establish a
C-N bond. However, formation of inorganic precipitates leads to irreversible
blockage of the microreactor channels. A first strategy involved the devel-
opment of biphasic reaction conditions that allowed both organic and in-
organic particles to be dissolved. 58 A micro packed-bed reactor, filled with
stainless-steel spheres as an inert packing material, was employed to es-
tablish vigorous mixing between the two phases and a phase-transfer catalyst
[tetrabutylammonium bromide (TBAB)] was used in combination with
aqueous potassium hydroxide as a base. Excellent yields of biarylamines
could be obtained in less than 10 min.
A second strategy involves the use of acoustic irradiation to break up
particle agglomerates. 59 This proved to be a powerful method to deal with
solid precipitates in continuous flow microreactors and allowed the C-N
coupling reaction to be performed under optimal reaction conditions.
A BrettPhos precatalyst (0.1-1 mol%) was used to effect the coupling of aryl
chlorides, bromides and triflates with primary amines without microreactor
clogging with short residence times (20 s-5 min) (Figure 13.28).
A microfluidic chip was developed by the same group to integrate both
ultrasonication and heating on the same device. 60
This acoustic irradiation strategy was further used in multistep
continuous flow syntheses that involved an amination step. 61,62 The
synthesis of arylpyrazoles was achieved via a Pd-catalyzed amination
with hydrazines followed by a hydrolysis-cyclocondensation sequence with
b-diketones. 61 The first step was carried out in a capillary microreactor
which was immersed in an ultrasonic bath (Figure 13.29). Several arylpyr-
azoles could be prepared in good yield. Another example involves the
formation of 1-substituted benzotriazoles via an amination-hydrogenation-
diazotization-cyclization; sequence. 62 All reactions were performed consecu-
tively in an uninterrupted continuous flow setup and required ultrasonication
to avoid clogging in the amination step.
A third strategy involves the use of soluble organic bases and polar
solvents, which circumvents the formation of salt precipitation. 63-65 A
palladium-catalyzed amination strategy was used for the continuous flow
synthesis of imatinib base (Gleevec) (Figure 13.30). 66 The intermediate of
imatinib was synthesized in an automated fashion employing immobilized
reagents and a catch-and-release strategy. 67 The compound was sub-
sequently released with DBU and merged with a stream of amine, BrettPhos