Zirconium Oxide-Catalyzed Direct Amidation of Unactivated Esters under Continuous-Flow Conditions

Article abstract of DOI:10.1002/adsc.202001496

A sustainable and environmentally benign direct amidation reaction of unactivated esters with amines has been developed in a continuous-flow system. A commercially available amorphous zirconium oxide was found to be an efficient catalyst for this reaction. While the typical amidation of esters with amines requires a stoichiometric amount of a promoter or metal activator, the present continuous-flow method enabled the direct amidation reaction under additive-free conditions with an extensive diversity towards various functional groups. High yields of the products were obtained with a nearly equimolar proportion of starting materials to reduce byproduct formation, which renders this process applicable for use in a sequential-flow system. (Figure presented.).

Full text of DOI:10.1002/adsc.202001496

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DOI: 10.1002/adsc.202001496
Very Important Publication
Zirconium Oxide-Catalyzed Direct Amidation of Unactivated
Esters under Continuous-Flow Conditions
Md. Nurnobi Rashed,a Koichiro Masuda,a Tomohiro Ichitsuka,a, b
Nagatoshi Koumura,a,* Kazuhiko Sato,a,* and Shū Kobayashia, c,*
a
Interdisciplinary Research Center for Catalytic Chemistry
National Institute of Advanced Industrial Science and Technology
Central 5, Higashi 1-1-1, Tsukuba, Ibaraki, 305-8565 (Japan)
E-mail: n-koumura@aist.go.jp; k.sato@aist.go.jp
b
Research Institute of Chemical Process Technology
National Institute of Advanced Industrial Science and Technology
Nigatake 4-2-1, Sendai, Miyagi, 983-8551 (Japan)
Department of Chemistry, School of Science
c
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033, (Japan)
E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
Manuscript received: December 1, 2020; Revised manuscript received: December 24, 2020;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202001496
amidation of esters with amines to give amides has
Abstract: A sustainable and environmentally be-
nign direct amidation reaction of unactivated esters
received growing attention, since it generates an
alcohol as the only co-product.[2] Moreover, the
with amines has been developed in a continuous-
formation of amide bonds has been investigated
flow system. A commercially available amorphous
intensively due to the importance of this functional
zirconium oxide was found to be an efficient
group in peptides and proteins, in addition to its
catalyst for this reaction. While the typical amida-
presence in various fine chemicals, polymers, and
tion of esters with amines requires a stoichiometric
pharmaceuticals.[3]
amount of a promoter or metal activator, the present
continuous-flow method enabled the direct amida-
Although several methods have been reported for
the amidation of esters, the development of atom-
tion reaction under additive-free conditions with an
economical green synthetic routes that do not generate
extensive diversity towards various functional
waste or require the use of hazardous reagents remains
groups. High yields of the products were obtained
a challenge.[4] Usually, the direct amidation reaction of
with a nearly equimolar proportion of starting
esters with amines requires a stoichiometric amount of
materials to reduce byproduct formation, which
promoter or metal activator.[5] Unlike reactive carbox-
renders this process applicable for use in a
ylic acid phenyl esters, the alkyl esters of carboxylic
sequential-flow system.
acids are inert substrates, and harsh reaction conditions
are generally required to promote the amidation
reaction.[6] Notable examples of some homogeneous
Keywords: amidation reaction; unactivated esters;
catalytic systems have been developed for use in the
amorphous zirconium oxide; additive-free conditions;
ester-to-amide transformation, which involve combina-
continuous-flow method
tions of metal alkoxides with additives, or the
azeotropic removal of the alcohol co-product
(Scheme 1(1), A and B).[7] However, these homoge-
Esters are one of the most important and ubiquitous neous catalytic systems do not tend to favor catalyst
functional groups in natural and synthetic organic reuse, since catalyst-product separation can be chal-
compounds.[1] Therefore, the transformation of ester lenging. To the best of our knowledge, the first
groups into other functional groups under mild and heterogeneous Nb2O5 catalytic system for this type of
neutral conditions is particularly desirable in the reaction was developed by Shimizu and co-
context of organic synthesis. In particular, the direct workers,[3a,b] where the required reaction time for the
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Table 1. Catalyst screening for the amidation reaction of
methylbenzoate (1a) with hexylamine (2a) via the batch
method.
Entry
Catalyst
3a (%)[a]
1[b]
2
Nb2O5
TiO2
6
9
3
SiO2
6
4
CeO2
11
5
ZrO2 amorphous zirconia (ZrOÀ A)
46 (93)[d]
6[c]
7
ZrO-A
27 (71)[d]
ZrO2 crystalline zirconia (ZrOÀ C)
Nb/ZrO-A
Nb/CeO2
Nb/TiO2
Nb/SiO2
45 (86)[d]
8[e]
9[e]
10[e]
11[e]
12
13
14[c]
15
16
17
18
42 (76)[d]
Scheme 1. State of art for the different approaches to the
amidation of esters.
34
5
12
Zr/CeO2
8
°
51 (84)[d]
batch synthetic process was ~30 h at 140 C
(Scheme 1(1), B).
Mont. K10
Mont. K10
Zr4+À Mont.
Na+À Mont.
Nb5+À Mont.
Amberlyst-15
5 (9)[d]
Currently, to green and sustainable manufacturing,
the pharmaceutical and fine chemical industries have
been focusing on continuous-flow systems rather than
conventional batch production methods. The continu-
ous-flow reaction has substantial advantages over the
batch reaction in terms of its efficiency, easy handling,
scale-up with automatic control, high selectivity,
reproducibility, direct use of intermediates without any
purification, and, more importantly, in many cases, its
superior safety and environmental compatibility.[8] The
replacement of batch reactions with a continuous-flow
manner is of particular interest.[9] We therefore envi-
sioned establishing a new reaction under flow con-
ditions, and herein report the general, fast, and high-
yielding continuous-flow amidation of unactivated
esters with amines using a heterogeneous ZrO2 catalyst
(Scheme 1(2)).
28
7
15
2
[a] GC yields were calculated using n-dodecane as an internal
standard.
[b] Nb2O5 was prepared by the calcination of Nb2O5·nH2O
°
(CBMM) at 500 C for 3 h under air.
[c] Reaction conducted without MS 3Å.
[d] The yields of 3a after a 16 h reaction time are shown in
parentheses.
[e] Supported Nb and Zr catalysts (10 wt%) were prepared via a
wet impregnation method from an aqueous solution of
ammonium niobate(V) oxalate hydrate (C4H4NNbO9·xH2O)
and zirconium oxychloride hydrate (ZrCl2O·8H2O), respec-
tively.
As a preliminary investigation, catalyst screening
for the amidation reaction of methyl benzoate (1a) highest yield of the desired product N-hexylbenzamide
with hexylamine (2a) was performed under batch (3a) within 5 h (51%, Table 1, entry 13). Other
conditions, as shown in Table 1. The reaction was competitive catalysts were ZrOÀ A, ZrOÀ C, and Nb/
carried out using several commercially available Lewis ZrOÀ A, which afforded 46, 45, and 42% yields,
and Brønsted acid catalysts, including Nb2O5, TiO2, respectively, within the same reaction time (Table 1,
SiO2 (CARiACT Q-10), amorphous zirconia (denoted entries 5, 7–8). A longer reaction time of 16 h resulted
as ZrOÀ A), crystalline zirconia (denoted as ZrOÀ C), in the amorphous zirconia catalyst (ZrOÀ A) giving the
CeO2, Mont. K10, and Amberlyst-15. In addition, highest yield of 3a (93%), while the other crystalline
some supported and ion-exchanged Nb and Zr catalysts zirconia (ZrOÀ C), Nb/ZrOÀ A, and Mont. K10 cata-
(Nb/ZrOÀ A, Nb/CeO2, Nb/TiO2,, Nb/SiO2, Zr/CeO2, lysts gave 86, 76, and 84% yields, respectively
Nb5+À Mont., and Zr4+À Mont.) were prepared and their (Table 1, entries 5, 7, 8, 13). Furthermore, control
catalytic activities were compared with those of experiments in the absence of molecular sieves (MS
commercially available catalysts (Table 1). Among the 3Å) indicated that Brønsted acidic Mont. K10 was less
examined catalysts, the Mont. K10 catalyst gave the effective towards the amidation reaction compared to
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the Lewis acidic ZrOÀ A catalyst (Table 1, entries 6, recovered after 8 h (Table 2, entry 2). In contrast, low
14). Therefore, to achieve the full conversion of 1a to yields were observed when the crystalline ZrOÀ C and
3a under batch conditions, it is suggested that calcined ZrOÀ A catalysts were employed (Table 2,
molecular sieves play an important role in removing entries 3–4), suggesting that crystallinity of zirconium
methanol (a co-product) from the reaction mixture. species and/or its surface area are key factors for its
(see details in the Supporting Information (SI), catalytic activity. The Brønsted acidic Mont. K10
Table S1). In addition, a catalytic activity drop by exhibited very low catalytic activity in the amidation
methanol has made a huge difference between reaction under continuous-flow conditions (Table 2,
Brønsted and Lewis acid catalysts.
entry 5). We assume that this is due to the co-existence
After optimization of the batch conditions, we of methanol in a catalyst column which could not be
subsequently focused on the development of the flow removed by molecular sieves under continuous-flow
amidation reaction using model substrates 1a and 2a. conditions at elevated temperature.
More specifically, a mixture of 1a (0.25 M) and 2a
Subsequently, optimization of the reaction condi-
(0.38 M) was pumped at a flow rate of 0.1 mL·minÀ 1 tions was carried out in the continuous-flow system
through a SUS column (Ø 10 mm I.D×100 mmL). using the ZrOÀ A catalyst (Table 3). Since the removal
The column was filled with a mixture of a catalyst and of methanol with molecular sieves was required during
molecular sieves in a 2:1 ratio. Initially, solvent the batch reaction, optimization under flow conditions
screening was performed using the optimal ZrOÀ A began with a high loading of molecular sieves (i.e.,
°
catalyst at 140 C in a continuous flow system, where ~4 g ZrOÀ A and ~8 g MS 3 Å, Table 3, entry 1).
diethylene glycol dimethyl ether (diglyme) was found Furthermore, the amidation reaction was also per-
to be the best solvent for this reaction (80% yield of formed in the absence of molecular sieves (i.e., ~6 g
3a; see details in SI, Table S2). Using other compatible ZrOÀ A, Table 3, entry 2). In contrast to the case of the
catalysts from the batch reaction, the flow amidation
reaction was performed, and the results are listed in
Table 2. It was observed that the amidation reaction
did not proceed in the absence of the catalyst (Table 2,
Table 3. Optimization of the amidation reaction of 1a with 2a
in a continuous-flow system.
entry 1), while the amorphous ZrOÀ A catalyst in the
conversion of 1a, with a 80% yield of product being
Table 2. Catalyst screening for the amidation reaction of 1a
with 2a in a continuous-flow system.
Entry
Temp. ( C)
Conv. (%)
3a (%)[a]
°
Table 2, entry 2
140
140
140
150
160
160
160
86
85
85
93
99
99
99
80
81
80
91
98
98
98
1[b]
2[c]
3[c]
4[c]
Entry
Catalyst[a]
Conv. (%)
3a (%)[b]
5[c,d]
6[c,d,e]
1
2
MS 3 Å
ZrOÀ A
<1%
86
51
47
16
0
80
45
38
12
[a] Yields were determined by GC using n-dodecane as an
internal standard.
3
ZrOÀ C
4[c]
5
ZrOÀ A
[b] A 10 mm × 200 mm column was used with a ZrOÀ A:MS 3Å
ratio of 4:8 (w/w).
Mont. K10
[a] A catalyst:MS 3Å ratio of 4:2 (w/w) was used.
[c] Approximately 6 g of ZrOÀ A catalyst (without MS 3Å) was
used in a Ø 10 mm×100 mm column.
[d] [1a]=0.4 M.
[b] Yields were determined by GC analysis using n-dodecane as
an internal standard.
[c]
°
The catalyst was calcined at 200 C for 3 h in air prior to use.
[e] [2a]=1.2 equiv. of [1a].
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batch method, it was observed that the conversion and surface. Following washing of the catalyst with
°
selectivity did not change significantly in the absence diglyme at 160 C for 5 h, its catalytic performance
°
or presence of molecular sieves at 140 C, even when was regenerated, returning the product yield to 98%
an increased amount of catalyst was used. These once again (see details in SI, Figure S3). These results
results suggest that the molecular sieves have little indicate that our catalytic system should be highly
influence on the continuous-flow system. To under- suitable for application in a continuous-flow amidation
stand this in better detail, a control continuous-flow reaction. In addition, a space-time yield (STY) of
reaction between product 3a (0.25 M) and methanol 7.03 ghÀ 1 dLÀ 1 was achieved with a turnover frequency
(1.5 equiv.) was performed at 140 C (see details in SI, (TOF) of 3.3 hÀ 1.
°
Table S3), whereby a slow amide-to-ester transforma-
Following optimized conditions (Table 3, entry 6),
tion resulted in a 2.6% yield of ester 1a. This implies substrate scopes were examined. Importantly, our
that ester 1a and amide 3a are in equilibrium at this catalytic system was found to be highly tolerant
temperature. Due to the continuous feeding of the towards a wide range of sterically diverse ester and
reaction mixture, the molecular sieves were saturated amine functionalities. The reaction scope with respect
with methanol, and at high temperatures, the activity to the reaction of various esters (1a–1o) with 2a was
of the molecular sieves was reduced, and so they were examined (Scheme 2), where electron-donating (1b–
not required in the continuous-flow system. Thus, to 1e) and withdrawing (1f–1g) substituents bearing
accomplish the full conversion of 1a to the desired benzoic acid esters were reacted efficiently to give
product, the reaction was conducted at higher temper- their corresponding amides in isolated yields of 35–
ature. Fortunately, a higher conversion was observed at 95%. Some heteroatom-containing aromatic and ali-
higher temperatures, and a 98% yield of the product phatic esters (1h–1k) were also successfully trans-
°
was obtained at 160 C (Table 3, entry 4). Furthermore, ferred to their analogous amides in 79–90% isolated
the optimum concentration of 1a was found to be yields. Similarly, aliphatic esters such as a decanoate
0.4 M, and 2a was successfully reduced to 1.2 equiv. ester (1l), a cinnamate ester (1m), and a sterically
to the substrate (Table 3, entries 5–6; see details in SI, hindered pivalate ester (1n) were also well tolerated in
Table S4). In this case, the material balance for 1a was this reaction to give their corresponding amides in high
determined to be 99%, where the molar ratio of 1a to isolated yields (73–81%). Furthermore, the enantiopure
2a was 1:1.2 (see details in SI, Table S5).
L-methyllactate (1o) was successfully converted to the
The durability and feasibility of the integrated corresponding enantiopure amide (3o, 99%) with
catalyst column in the flow system were then tested almost no racemization of the stereocenter (>97% ee,
over the long-time amidation of 1a under the see details in SI, Figure S31). It should be noted that
optimized reaction conditions. The developed system this is the first successful example of a catalytic
produced amide 3a in yields of 94–98% over the method for the preparation of enantiopure amides from
course of a 140 h period (Figure 1). However, towards challenging unactivated esters under continuous-flow
the end of the reaction, a gradual decrease in the yield conditions.
was observed. This was attributed to the accumulation
Subsequently, we surveyed the scope of amine
of a small amount of reactant or product on the catalyst component (Scheme 3). More specifically, benzylic
(2b, 2c) and aliphatic primary amines (2d), in addition
to heteroatom-containing primary amines, such as
furfuryl amine (2e), thiophenmethylamine (2f), and
propanolamine (2g), worked well under the standard
reaction conditions to give the desired products in 50–
88% isolated yield. On the other hand, non-nucleo-
philic aniline derivatives (2h–2j) and secondary
aliphatic amines (2k–2m) were found to be less
reactive towards the present catalytic system. Sim-
ilarly, no racemization was observed during the syn-
thesis of the optically active N-((R)-1-phenylethyl)-
benzamide (4c), as outlined in SI Figure S32.
Moreover, we successfully developed a continuous-
flow method for the direct synthesis of the anti-
depressant drug molecule Moclobemide[10] (Scheme 4),
which elucidates an alternative, facile, and environ-
mentally benign route for future applications.
In conclusion, we demonstrated an efficient route to
convert esters into amides under continuous-flow
conditions. The present flow system established an
Figure 1. Investigation of the durability of the ZrOÀ A catalyst
over a long-time amidation reaction. Reaction conditions:
catalyst (6 g), methyl benzoate (1a, 0.4 M), hexylamine (2a,
°
0.48 M), n-dodecane (0.05 M), reactor temperature 160 C, and
flow rate 0.10 mLminÀ 1.
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Scheme 2. The amidation of various esters with hexylamine. GC yields were determined using n-dodecane as an internal standard.
[a]
[b]
Isolated yields are shown in parentheses. 0.4 M Methylbenzoate and 0.5 M hexylamine were used. No external solvent was
[c]
[d]
[e]
passed through the T-mixer.
Ethyl ester was used instead of methyl ester.
>97% ee.
[1o]=0.6 M, >99% ee, catalyst:
°
Celite=2:1 at reactor temperature of 150 C.
remove the methanol formed as a co-product (see SI, Fig-
ure S2). The tube was equipped with a reflux condenser and
was placed on an EYELA PPV-3000 ChemiStation. The
alternative synthetic method for amides without any
requirement for additives. More specifically, the
reaction of unactivated esters with amines in the
presence of an amorphous ZrO2 catalyst was successful
in producing various amides. The described method-
ology is broad in scope and proceeds using only 1.2
equivalents of the amine nucleophile. Thus, our
method is preferably suited for the use in multi-step
organic synthesis in the context of the material
balance. Moreover, selective amide-bond formation
was achieved in the presence of various functional
groups, and without the racemization of the stereo-
centers of enantiopure substrates. Further study of this
continuous-flow rection is currently ongoing in our
laboratory, aiming an expansion of the scope as well as
the process intensification toward practical synthesis of
fine chemicals.
°
reaction mixture was heated to 160 C and stirred at 300 rpm for
5 h under aerobic conditions. After the designated reaction time,
the reaction mixture was cooled to room temperature, ethyl
acetate (3 mL) was added, and an aliquot was analyzed by GC
(SHIMADZU GC-2014 instrument) with flame ionization
detection using a DB-01 capillary column (30 m, 0.25 mm,
0.25 μm). A crude mixture was purified by column chromatog-
raphy on silica gel 60 (spherical, 50–100 μm, Kanto Chemical
Co., Ltd.) with hexane/ethyl acetate (70/30) as an eluent. An
1
isolated product was analyzed by GC, GC-MS, H, and 13C
NMR spectroscopy.
Typical procedure for the continuous flow amidation reaction:
A Ø 10 mm I.D×100 mm L SUS column was filled with the
ZrOÀ A catalyst (6 g, 0.86 mmol acid sites) and placed in an
EYELA MCR-1000 flow reactor (SI, figure S1). Initially,
diglyme was flowed through the column at a rate of 0.2 mL/min
flow rate to purge out the internal gases at room temperature,
°
and then with gradual heating to 160 C for ~1 h. Subsequently,
Experimental Section
the flow rate was set to 0.1 mL/min with a 0.5 MPa back
pressure. The reaction was initiated by changing the solvent
flow to the reaction feed (stock solution of 1a (0.40 M), 2a
(0.48 M), and n-dodecane (0.05 M) in diglyme) at a flow rate of
0.1 mL/min. The crude reaction mixture was collected from the
outlet using a fraction collector (EYELA DC-1000), and the
yield of product in each fraction was determined by GC
Typical procedure for catalytic amidation reaction in batch
conditions: A Pyrex test-tube (30.0 mL) was charged with 1a
(5.0 mmol), 2a (7.5 mmol), catalyst (250 mg), p-xylene
(5.0 mL), and n-dodecane (0.2 mmol, an internal standard). A
PTFE basket containing the molecular sieves (MS 3Å pellets,
0.5 g) was placed at the upper side of the reaction tube to
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Scheme 3. Amidation of various amines with methylbenzoate. GC yields were determined using n-dodecane as an internal standard.
Isolated yields are shown in parentheses. [a] 2c (99% ee) was used to give 4c in >99% ee. [b] [1a]=0.4 M and [2e]=0.48 M.
Acknowledgements
This work was supported in part by a Grant-in-Aid for Scientific
Research from the New Energy and Industrial Technology
Development Organization (NEDO) project, Japan. We thank
Dr. Liu Chao (Towa Pharmaceutical Co., Ltd) and Dr. Sandip
Agalave (Department of Chemistry, School of Science, The
University of Tokyo, Japan) for their special help and guidance
during optimization of the reaction.
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COMMUNICATIONS
Zirconium Oxide-Catalyzed Direct Amidation of Unactivated
Esters under Continuous-Flow Conditions
Adv. Synth. Catal. 2021, 363, 1–8
M. N. Rashed, K. Masuda, T. Ichitsuka, N. Koumura*, K.
Sato*, S. Kobayashi*