P. T. Baraldi et al. / Tetrahedron Letters 55 (2014) 2090–2092
2091
harsh and unusual process conditions (e.g. high temperatures and
pressures) can be utilized. Such reaction conditions are called No-
vel Process Windows and allow the reaction rate to be increased by
idic parts to design an operationally simple continuous-flow setup,
which can be implemented in any chemistry laboratory (Fig. 2). A
single syringe, mounted on a syringe pump, was used to introduce
6
so-called chemical intensification. Thereby, high temperatures are
the reactants into a 200
consisted of aldehyde (1 equiv), ethyl acetoacetate or methyl
acetoacetate (3.4 equiv), and 28% NH OH (10 equiv) dissolved in
ethanol. The microreactor was fabricated from PFA capillary tubing
lL capillary microreactor. The solution
used to accelerate the reaction rate significantly.7 By-product for-
mation can be minimized by limiting the exposure time of the
reaction mixture in the hot zone to that required. Nowadays, the
use of continuous-flow reactors in medicinal chemistry and the
pharmaceutical industry has increased as a reliable tool to scale
synthetic routes from a few milligrams (required for lead discovery
4
0
0
(perfluoroalkoxyalkane) (200 lL, 0.02 inner diameter, 100 cm
length). A back pressure regulator (BPR) (100 psi) was used to
avoid gas formation upon heating the reaction mixture. In our
hands, no additional quench was required to avoid microreactor
and pharmacokinetic studies) to
a few grams (for further
8
14
exploratory toxicology studies). Moreover, microreactor technol-
ogy is commonly used in medicinal chemistry for hazardous
reactions, such as Curtius rearrangements,9 diazotizations,
clogging. Precipitation could be avoided by using ethanol as a
1
5
polar solvent and minimizing the reaction time to that required
kinetically. At the outlet, the pressure was released and the
product was collected in a round bottom flask.
10
1
1
12
nitrations, and fluorinations.
In this Letter, we report on the efficient and rapid preparation of
a variety of 1,4-dihydropyridines, relevant for medicinal chemistry,
Initial optimization experiments with 3-nitrobenzaldehyde and
methyl acetoacetate demonstrated that elevated reaction temper-
atures were crucial to boost the reaction yield. Optimal isolated
yields were obtained at 120 °C with a residence time of only six
minutes. It should be noted that the presence of a back pressure
regulator allowed use of ethanol as a green solvent under super-
heated conditions. Such superheated reaction mixtures are not
easy to process on a batch scale. Next, a series of different 1,
within
processing.
a
capillary microreactor using high temperature
1
3
We initiated our investigations by assembling the microreactor
setup. We made use of commercially available and cheap microflu-
4
-dihydropyridines was prepared in our microreactor system. As
can be seen from Table 1, all the reactions were completed within
–11 min representing a significant acceleration compared to the
O
H
R
6
R
16
1
COOR1
corresponding batch experiments (5–7 h). Our procedure was
compatible with a variety of different benzaldehydes, varying from
electron-neutral, over electron-poor and electron-rich. Also, an
aliphatic aldehyde was tolerated, however, a somewhat lower
yield was obtained. Interestingly, some heterocyclic aldehydes
could be used as reaction partners.
R OOC
O
O
R1
BPR
100 psi)
Me
N
H
Me
O
(
NH4OH, EtOH
immersed in an oil bath
Figure 2. Schematic representation for the Hantzsch reaction in continuous flow.
Table 1
Substrate scope for the Hantzsch dihydropyridine synthesis in continuous-flow
R
O
H
1
COOR1
Me
O
O
NH4OH
R OOC
+
R1
R
O
EtOH, 120 ºC, 6-11 min
Me
N
H
Me
NO2
EtOOC
Me
COOEt
Me
EtOOC
Me
COOEt
EtOOC
Me
COOEt
Me
N
H
N
H
Me
N
H
1
2
3
6
4%
45%
73%
1
1 min residence time
6 min residence time
6 min residence time
NO2
Cl
Cl
Cl
MeOOC
Me
COOMe
Me
EtOOC
Me
COOEt
EtOOC
Me
COOEt
N
H
N
H
Me
N
H
Me
4
5
6
8
0%
88%
75%
6
min residence time
10 min residence time
10 min residence time
Me
O
O
EtOOC
Me
COOEt
Me
EtOOC
Me
COOEt
Me
EtOOC
Me
COOEt
Me
N
H
N
H
N
H
7
8
9
5
6%
71%
67%
6
min residence time
6 min residence time
6 min residence time
Yields are those for isolated products on a 1 mmol scale.