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N
Br
Boc
O
(i) TMSOTf, NH
2
NHBoc
HN
N
toluene/ethanol (4:3)
50 °C, 8 min
0.3 mol% Pd(PPh
3
)
4
H
+
B( OH )
2
N
H
toluene/ethanol (4:3)
aq. K
3
PO
4
150 °C, 20 min
(ii) aqueous K
2
CO
3
(microextraction)
N
H
O
Boc
HN
Pd/C (H Cube Pro)
NH
toluene/ethanol (4:3)
40 °C
H
N
N
bi ar y l unit
74% overall yield
HO
N
NH
t
Bu
O
t
Bu
HN
O
HN
O
Bn
OMe
NH
O
Me
O
Atazanavir
Figure 13.11 Continuous flow synthesis of the biaryl unit of atazanavir via a multi-
step continuous flow synthesis and microfluidic extraction.
bromide as a phase-transfer catalyst and aqueous potassium phosphate. The
resulting biphasic mixture was delivered to a micro packed-bed reactor to
ensure good mixing between the two phases. Several biaryls (14 examples)
could be prepared in good to excellent overall yields (83-99%).
A similar strategy was used to prepare the biaryl unit of atazanavir, an HIV
protease inhibitor.
36
A three-step continuous flow protocol was developed,
including a Suzuki-Miyaura cross-coupling, hydrazine formation and hy-
drogenation step (Figure 13.11). Neutralization of the stream after hydrazine
formation was achieved by quenching the mixture with aqueous potassium
carbonate. The aqueous layer was separated from the product stream in an
inline liquid-liquid extraction device. The overall yield for the continuous
flow process was 74%.
13.4.2 Mizoroki-Heck Alkenylation in Flow
The Mizoroki-Heck alkenylation constitutes a powerful transformation to
establish the coupling between an aryl halide and an olefin. Together with
Suzuki-Miyaura coupling, this transformation has been very popular as a
test reaction for the development of novel continuous flow microreactor
techniques.
The combination of microreactors and spectroscopic detection techniques
results in a so-called integrated microreactor environment, which allows for
online reaction monitoring.
37
When such spectroscopic detection systems
are further combined with logic and feedback control software, reactions can
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