Angewandte
Communications
Chemie
tor packed with a mixture of Pd/C and Celite (1:10 w/w,
hypothesized that this problem could be mitigated through
ꢀ 1.1 g) allowed us to continuously produce 3a with excellent
yield at least for 24 hours. The Pd turnover frequency reached
32 hÀ1, while the space-time yield was as high as
1.70 kgdayÀ1 LÀ1. The high productivity and selectivity were
attributed to the higher mixing efficiency and shorter
residence times compared to those of batch methods, which
motivated us to design a sequential process with an integrated
flow reactor. Hence, column reactor I was connected with
column reactor II to perform the condensation of 2a with 3a,
followed by dehydrogenation, which was the second stage of
the desired dehydrative amination (Figure 2a). At the second
stage, a toluene solution of 3a (0.24m, 0.10 mLminÀ1) from
the first-stage column reactor was separated from unreacted
H2 and mixed with a toluene solution of 2a (0.20m,
0.10 mLminÀ1) with a T-shaped mixer. The mixture was
preheated to 1408C in a coil reactor (diameter= 1.0 mm,
length = 100 cm), and continuously introduced into the
second-stage column reactor filled with a heterogeneous Pd
catalyst and Celite. Catalyst screening (Figure 2b, entries 1–
5) showed that although the highest conversion was observed
for Pd(OH)2/C, both the desired diaryl amine (4aa) and the
undesired cyclohexylamine (5aa) were obtained in a molar
ratio of about 1:2. This result indicated that the side product
5aa was generated through hydrogen transfer, that is, the
the use of oxidants or hydrogen scavengers,[21–23] and the
corresponding screening (Figure 2b, entries 6–8) revealed
that styrene (2 equiv) acted as a good hydrogen scavenger
to achieve excellent product selectivity. Under optimal
reaction conditions [column reactor diameter= 10 mm,
length = 10 cm; catalyst = mixture of Pd(OH)2/C and Celiteꢀ
(1:10 w/w, ꢀ 4.9 g)], the desired diaryl amine 4aa could be
continuously produced as the sole product in excellent yield
for at least 24 hours (Figure 2b, entry 8).
The robustness of the integrated flow reactor was tested
by the long-term synthesis of 4aa (Figure 2c), over the course
of one week a 96% yield (38.6 g) of 4aa was produced. The
developed system showed
a high space-time yield of
0.31 kgLÀ1 dayÀ1 and a high catalyst turnover number in
each column reactor (5372 for hydrogenation and 267 for
consecutive condensation and dehydrogenation). Inductivity
coupled plasma atomic emission spectroscopy analysis
revealed that after a one-week operation, only 53 mg of Pd
(0.06% of loaded Pd) was present in 4aa before purification,
therefore the extent of Pd leaching was negligible.
The developed flow reactor was then used to prepare
various aryl amines (Table 1). When the scope with respect to
the phenol was examined using 2a as a coupling partner under
optimized reaction conditions, alkyl-group-bearing phenols
(1b—e) reacted smoothly to afford the desired diaryl amines
4ba–ea in good to excellent yields. Among these phenols,
À
imine intermediate was reduced by the Pd H species formed
through the dehydrogenation of another imine.[10,13] It was
Table 1: Scope with respect to the phenols.[a]
[a] Yields of isolated products. [b] Column reactor I (inner diameter=10 mm, length=50 mm) packed with Pd/C-Celiteꢀ (1:10 w/w, ꢀ2.2 g) was used
at 1508C for the first stage. [c] Column reactor II (inner diameter=10 mm, length=200 mm) packed with Pd(OH)2/C-Celiteꢀ (1:10 w/w, ꢀ9.8 g) was
used at 1408C for the second stage. [d] Column reactor II (inner diameter=10 mm, length=200 mm) packed with Pd(OH)2/C-Celiteꢀ (1:10 w/w,
ꢀ9.8 g) was used at 1508C for the second stage. [e] Column reactor II (inner diameter=10 mm, length=200 mm) packed with Pd(OH)2/C-Celiteꢀ
(1:10 w/w, ꢀ9.8 g) was used at 1608C for the second stage. [f] Co-products generated by excess dehydrogenation of the methylene chain of 4 were
obtained (see the Supporting Information).
Angew. Chem. Int. Ed. 2020, 59, 1 – 7
ꢀ 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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