Continuous Synthesis of Aryl Amines from Phenols Utilizing Integrated Packed-Bed Flow Systems

Article abstract of DOI:10.1002/anie.202005109

Aryl amines are important pharmaceutical intermediates among other numerous applications. Herein, an environmentally benign route and novel approach to aryl amine synthesis using dehydrative amination of phenols with amines and styrene under continuous-flow conditions was developed. Inexpensive and readily available phenols were efficiently converted into the corresponding aryl amines, with small amounts of easily removable co-products (i.e., H₂O and alkanes), in multistep continuous-flow reactors in the presence of heterogeneous Pd catalysts. The high product selectivity and functional-group tolerance of this method allowed aryl amines with diverse functional groups to be selectively obtained in high yields over a continuous operation time of one week.

Full text of DOI:10.1002/anie.202005109

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How to cite:
International Edition: doi.org/10.1002/anie.202005109
German Edition: doi.org/10.1002/ange.202005109
Amination
Hot Paper
Continuous Synthesis of Aryl Amines from Phenols Utilizing
Integrated Packed-Bed Flow Systems
Tomohiro Ichitsuka,* Ikko Takahashi, Nagatoshi Koumura,* Kazuhiko Sato, and
Shu Kobayashi*
¯
Abstract: Aryl amines are important pharmaceutical inter-
mediates among other numerous applications. Herein, an
environmentally benign route and novel approach to aryl
amine synthesis using dehydrative amination of phenols with
amines and styrene under continuous-flow conditions was
developed. Inexpensive and readily available phenols were
efficiently converted into the corresponding aryl amines, with
small amounts of easily removable co-products (i.e., H2O and
alkanes), in multistep continuous-flow reactors in the presence
of heterogeneous Pd catalysts. The high product selectivity and
functional-group tolerance of this method allowed aryl amines
with diverse functional groups to be selectively obtained in high
yields over a continuous operation time of one week.
Despite these advantages, the amination must be carried
out at high temperatures and under high pressures in batch
reactors, such as autoclaves.[9] Additionally, the highly prac-
tical reactions affording structurally more complex aryl
amines have not yet been established. This is due to the
incompatibility of this approach to thermally labile and easily
reducible functional groups and the competitive generation of
cyclohexylamines through the hydrogenation of imine inter-
mediates, which greatly reduces product selectivity (Fig-
ure 1c).[9,13] In 2015, Li and co-workers reported an improved
method using Pd/C and trifluoroacetic acid as catalysts and
R
ecently, considerable research effort has been directed at
the development of synthetic routes to aryl amines, because
these are important building blocks for pharmaceuticals,
agrochemicals, organic dyes, functional polymers, etc.[1]
À
Transition metal catalyzed C N coupling reactions (e.g.,
Buchwald–Hartwig amination) are powerful methods for
synthesizing diversely functionalized aryl amines (Figure 1a),
but pose the problem of high environmental loading, stoi-
chiometric/excess amounts of strong bases, and require the
use of expensive aryl (pseudo)halides, thus generating large
amounts of by-products and featuring limited functional-
group tolerance.[2–8] In contrast, Pd-catalyzed dehydrative
amination of phenols has attracted attention as a new
environmentally benign route to aryl amines (Figure 1b).[9–12]
In this reaction, cyclohexanones are formed by hydrogenation
of phenols over a Pd catalyst and react with amines to give
imines (Figure 1c), which undergo dehydrogenative re-aro-
matization to afford aryl amines. The advantages of this route
are i) generation of water as the only co-product, ii) easy
removal of heterogeneous catalysts and H2 or H2 donors as
additives after the reaction, and iii) low cost and availability of
the phenols, which are produced from coal and lignocellulosic
biomass and are a more attractive sources of aromatic rings.
[*] T. Ichitsuka, I. Takahashi, N. Koumura, K. Sato, S. Kobayashi
Interdisciplinary Research Center for Catalytic Chemistry (IRC3)
National Institute of Advanced Industrial Science and Technology
(AIST)
Central 5, Higashi 1-1-1, Tsukuba, Ibaraki 305-8565 (Japan)
E-mail: ichitsuka-t@aist.go.jp
Figure 1. Summary of previous works and the present study.
n-koumura@aist.go.jp
shu_kobayashi@chem.s.u-tokyo.ac.jp
À
a) Modern transition metal catalyzed C N cross-couplings of aryl
(pseudo)halides with amines in the presence of a base. b) Pd-catalyzed
dehydrative amination of phenols. c) Proposed mechanism of Pd-
catalyzed dehydrative amination. d) Design of an integrated continu-
ous-flow reactor for the dehydrative amination of phenols.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202005109.
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sodium formate as a hydrogen source to improve the product
selectivity and conditions of the amination reaction at the
expense of increased chemical waste generation.[10] Further-
more, the developed method remains inapplicable to some
functional groups. For example, it is difficult to apply to amino
acids or amines bearing olefin, nitrile, and halide groups,
which are sensitive to reducing and high-temperature con-
ditions.
To make the dehydrative amination of phenols compat-
ible with fine-chemical synthesis, we relied on the use of
a flow technique,[14] because it was thought that the problems
of low functional-group tolerance and product selectivity
were partially attributable to the conflict between hydro-
genation and dehydrogenation reactions proceeding in the
same reactor. Inspired by continuous-flow systems compris-
ing multiple column reactors,[15–17] we designed a setup in
which the first (hydrogenation)[18–20] and second (condensa-
tion- dehydrogenation)[21,22] steps were performed in separate
reactors and then serially integrated (Figure 1d). In the first
column reactor, packed with a hydrogenation catalyst,
phenols would be efficiently and continuously converted
into the corresponding cyclohexanones, which were then
mixed with amines and introduced into the next column
reactor. Thus, consecutive condensation and dehydrogenation
would proceed smoothly to afford the desired aryl amines
without any by-products because of the absence of hydrogen.
Furthermore, division of the flow reactors would enable the
use of a hydrogen scavenger in the second stage[21–23] to more
reliably control product selectivity. This segmentation and
integration strategy could significantly improve the amine
scope and product selectivity, while some features of flow
reactors loaded with heterogeneous catalysts could not only
increase reaction efficiency, but also allow reaction conditions
milder than those used in the corresponding batch reactions
to realize the continuous synthesis of various aryl amines.[24,25]
The dehydrative coupling of phenol (1a) with p-anisidine
(2a) was chosen as a model reaction, which, consisted of
hydrogenation (first stage) and consecutive condensation and
dehydrogenation (second stage). Initially, we optimized
a continuous-flow system for the hydrogenation of phenols
over heterogeneous catalysts to produce the desired cyclo-
hexanone derivatives (first stage, flow reactor I).[26] As shown
in Figure 2a, a toluene solution of 1a (0.24m, 0.10 mLminÀ1)
and hydrogen gas (5.0 mLminÀ1) were passed through the
column reactor (diameter= 5.0 mm, length = 10 cm) contain-
ing a heterogeneous Pd catalyst at 1408C. The reaction
mixture, collected from the outlet of the back-pressure
regulator that controlled the internal pressure (0.2 MPa) of
the flow reactor, was analyzed by gas chromatography.
Catalyst screening revealed that Pd/C could fully convert 1a
into cyclohexanone (3a) with excellent selectivity (cyclo-
hexanone/cyclohexanol = 99:1 molmolÀ1). The column reac-
Figure 2. Application of an integrated continuous-flow reactor to dehydrative amination. a) Setup of the integrated continuous-flow reactor for the
dehydrative amination of phenols. b) Optimization of reaction conditions for the second stage. c) Ten-gram-scale synthesis of aryl amine 4aa by
long-term operation of the integrated continuous-flow reactor.
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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).
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Table 2: Scope with respect to the amines.[a]
[a] Yield of the isolated product. [b] 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 for the second stage. [c] The second-stage reaction was performed at 1608C. [d] The second-stage reaction was performed at 1508C. [e] 1,4-
Dioxane was used as a solvent for the amines 2 instead of toluene. [f] 4’ah was obtained in 6% yield via the undesired hydrogenation of a nitro group
(see the Supporting Information). [g] 4aj was also produced in 11% yield by the unfavorable dehydrogenation from a cyclohexene moiety.
sterically hindered o-cresol (1d) was converted into the
corresponding product (4da) in 82% yield under modified
conditions. Notably, the ester-group-bearing 4 fa was obtained
in 97% yield without any undesirable reactions of the ester
moiety such as reduction and ester–amide exchange. More-
over, naturally abundant phenols and their derivatives were
successfully converted into the corresponding aryl amines,
that is, lignin pyrolysis-produced guaiacol (1g) was converted
into 4ga in 74% yield, while tyrosol methyl ether (1h)
afforded 4ha in moderate yield, and carvacrol (1i), a mono-
terpene derivative found in the essential oil of oregano, was
converted into the desired amine 4ia in 37% yield.
Next, we investigated the scope with respect to the amines
using 1a as a coupling partner (Table 2). The anilines 2b–
e were converted into the corresponding diaryl amines 4ab–
ae, and even sterically hindered 2,4,6-trimethylaniline (2d)
reacted to give 4ad in 62% yield. Additionally, the reaction of
2e, bearing a hydrogenation-sensitive chloro substituent,
proceeded to afford the corresponding diaryl amine 4ae in
42% yield without loss of the chloro group. Even 4af and 4ag,
bearing acetyl and cyano groups, respectively, which are also
sensitive to hydrogenation, were successfully synthesized in
the corresponding yields of 94% and 69% without the
undesirable reduction of these functional groups. Further-
more, the use of 4-nitroaniline (2h) gave the desired aryl
amine 4ah in 29% yield, while the undesired N,N’-diphenyl-
benzene-1,4-diamine (4’ah) was produced as a byproduct in
6% yield by the consecutive hydrogenation and phenylation
of a nitro moiety.
The transformation was applied not only to anilines but
also to aliphatic amines; primary alkylamines including
sterically hindered cyclohexylamine (2k) were converted
into the desired N-alkylated anilines 4ai–ak in high yields. In
addition, morpholine (2l) and N-methylaniline (2m), which
are secondary amines, also reacted to give the tertiary anilines
4al and 4am, respectively, in the corresponding yields of 76%
and 36%. Notably, the developed method showed a high
functional-group tolerance, as the aryl amines 4an and 4ao
were successfully synthesized in good to excellent yields
without the undesirable hydrogenation of their nitrile and
alkene moieties. Furthermore, unprotected hydroxy and NH
indolyl groups were also tolerated, and the corresponding
products 4ap and 4aq were obtained in high yields. In
À
contrast to transition metal catalyzed C N couplings using
aryl halides, our flow process proceeded under neutral
conditions and was therefore compatible with base-sensitive
functional groups.[5] For instance, trifluoroacetamides, which
are viewed as representative protected amines, easily decom-
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pose under basic conditions. Herein, the reaction of 2r
Herein, we developed a method for the dehydrative
proceeded to afford the desired product 4ar in 91% yield with
complete retention of the trifluoroacetamide moiety.
amination of phenols using an integrated flow system and
heterogeneous Pd catalysts. The adopted protocol allowed
inexpensive and readily available phenols to be efficiently
reacted with amines in the presence of styrene to give the
corresponding aryl amines and only small amounts of easily
removable co-products (i.e., H2O and ethylbenzene). Fur-
thermore, the use of multistep continuous-flow methods with
heterogeneous catalysts and the use of a suitable hydrogen
scavenger significantly increased product selectivity and
functional-group tolerance. For instance, the developed flow
method was suitable for the synthesis of aryl amines having
various functional groups sensitive to hydrogenation and
bases. Moreover, the above method was superior to the
corresponding batch method in terms of side-reaction sup-
pression and selectivity control because of the high mixing
efficiency and short residence time of the former technique.
Thus, our method is a powerful and environmentally benign
Considering this aspect, we investigated the N-arylation of
amino acid derivatives, and this reaction is typically hindered
by racemization in the presence of bases.[27,28] The l-phenyl-
alanine methyl ester 2s was selected as a model substrate and
subjected to dehydrative amination in the continuous-flow
system to enantioselectively obtain the N-phenylated product
4as (98% ee), whereas the application of a batch method to
the same reaction afforded the desired product in lower yield
and with lower enantioselectivity (67%, 66% ee; see
Scheme S4 in the Supporting Information). The suppression
of racemization in the former case was ascribed to the neutral
reaction conditions and short residence time, in contrast to
batch method conditions. Considering the generation of an
imine intermediate, we envisioned a selective reaction of
diamines.[29] The diamine 2t bearing both aliphatic and aryl
amines afforded the diamine 4at arylated only at the aliphatic
amine in 79% yield and with quantitative selectivity, whereas
lower yield and selectivity were observed under batch
conditions (see Scheme S5). The high chemoselectivity
observed in the former case was attributed to the high
mixing efficiency of our flow method.
À
route to aryl amines as an alternative to the current C N
coupling reactions using aryl halides and realizes continuous
synthesis of aryl amines.
Conflict of interest
Finally, to demonstrate the utility of the integrated flow
system, we conducted a formal continuous synthesis of
The authors declare no conflict of interest.
phentolamine,
a
nonselective a-adrenergic antagonist[30]
À
(Figure 3) currently produced by the C N coupling of 3-
aminophenol (2u) with 4-bromotoluene in the presence of
bases to generate stoichiometric amounts of inorganic salts as
chemical waste.[31] Advantageously, our flow method allowed
4-bromotoluene to be replaced with p-cresol (1b) as a cou-
pling partner and thus avoid chemical waste generation. As
shown in Figure 3, 1b and 2u were continuously processed in
the integrated flow reactor to continuously produce the key
intermediate, 3-(p-tolylamino)phenol (4bu), at a rate of
4.6 gdayÀ1.
Keywords: amines · continuous-flow synthesis ·
heterogeneous catalysis · palladium · phenols
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Version of record online: && &&, &&&&
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Communications
Amination
T. Ichitsuka,* I. Takahashi, N. Koumura,*
K. Sato, S. Kobayashi*
&&&& — &&&&
Continuous Synthesis of Aryl Amines
from Phenols Utilizing Integrated Packed-
Bed Flow Systems
Flow with it: Dehydrative amination of
phenols under continuous-flow condi-
tions has been developed. In an inte-
grated packed-bed flow system contain-
ing heterogeneous Pd catalysts, phenols
reacted with amines to obtain aryl amines
and small amounts of easily removable
co-products. The method has high prod-
uct selectivity and excellent functional-
group tolerance, so that variously substi-
tuted aryl amines can be selectively
prepared in high yields.
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