One-pot synthesis of pyrrolidones from levulinic acid and amines/nitroarenes/nitriles over the Ir-PVP catalyst

Article abstract of DOI:10.1039/d0gc01725f

The synthesis of pyrrolidones via reductive amination of levulinic acid with aniline was examined over polypyrrolidone-stabilized metal nanoparticle catalysts. Among them, Ir metal was the most effective and applicable for the reductive amination of levulinic acid with nitroarenes/nitriles. Importantly, this catalyst was used for the one-pot synthesis of the anti-inflammatory drug indoprofen from 2-formylbenzoic acid and 2-(4-nitrophenyl)propanoic acid.

Full text of DOI:10.1039/d0gc01725f

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One-pot synthesis of pyrrolidones from levulinic
acid and amines/nitroarenes/nitriles over the
Ir-PVP catalyst†
Cite this: DOI: 10.1039/d0gc01725f
Received 21st May 2020,
a,c
Chandan Chaudhari,*a Masaya Shiraishi,b Yoshihide Nishida,a Katsutoshi Sato
Accepted 10th August 2020
a
DOI: 10.1039/d0gc01725f
and Katsutoshi Nagaoka
*
rsc.li/greenchem
The synthesis of pyrrolidones via reductive amination of levulinic an amine, using formic acid and an expensive phosphine
acid with aniline was examined over polypyrrolidone-stabilized ligand.4 Later, an Ir complex was reported for reductive amin-
metal nanoparticle catalysts. Among them, Ir metal was the most ation using a mixture of formic acid/sodium formate under
effective and applicable for the reductive amination of levulinic acidic reaction conditions.5 Garcia et al. examined ligand-free
acid with nitroarenes/nitriles. Importantly, this catalyst was used reductive amination of LA in the presence of the [Ru3(CO)12]
for the one-pot synthesis of the anti-inflammatory drug indo- catalyst under neutral conditions.6 Heterogeneous NHC-based
profen from 2-formylbenzoic acid and 2-(4-nitrophenyl)propanoic Ru, Au/ZrO2, and RANEY® nickel catalysts have also been
acid.
reported using formic acid as the hydrogen source but these
catalysts require high temperature (120–180 °C).7 In addition,
Fe complexes, InI3, and AlCl3 have been investigated as cata-
lysts for the reductive amination of LA with hydrosilane as the
hydrogen source. However, the high cost of hydrosilane and
waste issues make it unfavorable for reductive amination.8
Some non-catalytic methods showed excellent activity but
some of them require high temperature (100–200 °C) and criti-
cal purification processes.9 Compared with hydrosilane and
formic acid, H2 gas is an atom-economical hydrogen source
for the direct reductive amination of LA. In 1947, Frank
reported the RANEY® nickel catalyzed synthesis of pyrrolidone
via reductive amination of LA with methyl amine under harsh
conditions (140 °C, 70–140 bar H2).10 Homogeneous Ir cata-
lysts were reported for the reductive amination of LA and
amines using hydrogen gas, but these catalysts have drawbacks
such as the need for catalyst–product separation and special
handling of catalysts.11 Several heterogeneous Pt, Pd, Ru, Ni,
and FeNi catalysts have been reported.12 However, these cata-
lytic systems suffer from drawbacks, namely, the need for the
use of additives, high temperature (>100 °C), and high
pressure (>10 bar H2). Furthermore, the reported catalysts were
designed for the reductive amination of LA with amines only
(Table S2†).
Due to the limited stock of fossil fuels, the catalytic transform-
ation of renewable biomass into useful chemicals has gained
much attention from both academia and industry.1 For
example, biomass-derived levulinic acid (LA), which can be
produced by acid hydrolysis of carbohydrates, is used for the
synthesis of
a
wide range of chemicals, including
N-substituted-5-methyl-pyrrolidones, γ-valerolactone, 2-methyl
tetrahydrofuran, 1,4-pentanediol, β-acetylacrylic acid, and
δ-amino levulinic acid.2 In particular, N-substituted-5-methyl-
pyrrolidones, which are produced by reductive amination of
LA, are used as surfactants, solvents, and pharmaceutical
intermediates.3 The reductive amination of LA involves three
steps: (i) formation of an imine, (ii) hydrogenation of the
imine, and (iii) cyclization of the resulting amine (Scheme 1).
The production of LA by acid hydrolysis of carbohydrates is
accompanied by the generation of formic acid, which is there-
fore an attractive hydrogen source for the reductive amination
of LA. In 2011, Fu et al. developed the first homogeneous [Ru
(p-cymene)Cl2]2 catalyst for the reductive amination of LA with
aDepartment of Chemical Systems Engineering, Graduate School of Engineering,
Nagoya University Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan.
E-mail: nagaoka.katsutoshi@material.nagoya-u.ac.jp,
chaudhari.chandan.subhash@d.mbox.nagoya-u.ac.jp
bDepartment of Integrated Science and Technology, Faculty of Science and
Engineering, Oita University, 700 Dannoharu, Oita 870-1192, Japan
cElements Strategy Initiative for Catalysts and Batteries, Kyoto University,
1-30 Goryo-Ohara, Nishikyo-ku, Kyoto 615-8245, Japan
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0gc01725f
Scheme 1 Synthesis of N-substituted-5-methyl-pyrrolidones.
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Table 2 Reductive amination of LA with various aminesa
Amines are generally produced by hydrogenation of nitro-
arenes or nitriles, and the reductive amination of LA with
nitroarenes or nitriles is a direct and atom-economical way
synthesize pyrrolidones. In 2017, supported Pt catalysts were
examined for the reductive amination of ethyl levulinate with
nitro compounds at 120 °C.13 Next, Shimizu et al. developed a
Pt-MoOx/TiO2 catalyst for the reductive amination of LA by
amines or nitriles at 100–110 °C.14 Herein, we report the one-
pot synthesis of pyrrolines via reductive amination of LA with
amines, nitroarenes, and nitriles using the Ir-PVP catalyst
under mild conditions. To our knowledge, we have demon-
strated the first example of the one-pot synthesis of the anti-
inflammatory drug indoprofen via reductive amination of
2-formylbenzoic acid with 2-(4-nitrophenyl)propanoic acid.
Initially, we examined the reductive amination of LA (2)
with aniline (1) over various polyvinylpyrrolidone (PVP) stabil-
ized metal nanoparticles under mild reaction conditions (5
bar H2, 30 °C and neat conditions). As presented in Table 1,
the Ir-PVP catalyst demonstrated superiority, as evidenced by
the full conversion (99%) and high yield of pyrrolidone (95%).
Although Pt-PVP and Ru-PVP also showed high conversions,
only a moderate yield of pyrrolidone was obtained with the aro-
matic ring hydrogenated product (1-cyclohexyl-5-methyl-pyrro-
lidone). Diphenylamine (5) and N-cyclohexylaniline (6) were
obtained as byproducts in the presence of Pd-PVP. The Rh-PVP
catalyst was essentially inactive under the tested conditions.
To study the general applicability of the Ir-PVP catalyst, we
carried out the reactions of LA with various amines under the
aforementioned reaction conditions (Table 2). It should be noted
that 4-methoxyaniline, 4-methylaniline, and 4-chloroaniline are
solid amines, and we used methanol as the solvent to facilitate
better dispersion. Aniline with an electron-donating group or an
electron-withdrawing group gave high to moderate yields of the
corresponding pyrrolidone (entries 2–4). Benzylamine and
Entry
1
Substrate
Conv. (%)
99
Yieldb (%)
95
2c
99
98
3c
4c
99
99
62
50
5
6
99
99
80
93
7
85
74
8
99
99
96
90
87
65
9
10
a Reaction conditions: Amine (1 mmol), LA (2 mmol), catalyst
(1.4 mol%), H2 (5 bar), neat, 30 °C, 24 h. b GC yield. c Methanol was
used as the solvent in the case of solid amine (1 mL).
4-methoxybenzylamine were efficiently transformed into the amination of LA with nitroarenes (Table 3). These reactions
corresponding pyrrolidone (entries 5 and 6). The reduction were performed in methanol because all the nitro compounds
amination of linear and branched amines proceeded to deliver except nitrobenzene were solids. The reaction of LA and nitro-
the desired products in high yields (entries 7–10).
benzene for 72 h afforded a 95% yield of the desired pyrroli-
Furthermore, the general applicability of Ir-PVP was done (entry 1). The catalyst was tolerant toward different func-
expanded for the one-pot synthesis of pyrrolidone via reductive tional groups of nitrobenzene and efficiently converted it to
the corresponding pyrrolidone (entries 2–5).
We also carried out one-pot syntheses of pyrrolidones from
LA and nitriles under the same conditions (10 bar H2 and
Table 1 Reductive amination of levulinic acid over various catalystsa
methanol). Benzonitrile with an electron-donating or electron-
withdrawing group on the phenyl ring afforded good yields of
pyrrolidones (Table 4, entries 2–5).
N-Substituted isoindolinones are important scaffolds in
medicinal chemistry owing to their wide range of biological
Yieldb (%) Yieldb (%) Yieldb (%) Yieldb (%)
activities. For instance, indoprofen is a nonsteroidal anti-
Entry Catalyst Conv. (%)
3
4
5
6
inflammatory drug with an isoindolinone skeleton.15 Several
catalysts have been reported for the synthesis of isoindoline
using high temperature and/or high pressure.8a,c,11,12e,g
1
Ir-PVP
99
95
75
61
68
5
3
0
0
0
0
0
15
0
14
0
0
0
14
0
0
2
3
Pt-PVP 99
Pd-PVP 94
Ru-PVP 99
Rh-PVP 80
Reductive amination of 2-formylbenzoic acid with various
amines was carried out using methanol under 10 bar H2
(Table 5). An electron-donating group containing aniline gave
a higher yield than an electron-withdrawing group containing
4
5c
a Reaction conditions: 1 (1 mmol), 2 (2 mmol), catalyst (1.4 mol%), H2
(5 bar), neat, 30 °C, 24 h. b GC yield. c Unknown byproducts were obtained.
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Table 3 One-pot synthesis of pyrrolidone from LA and nitroarenesa
Table 5 Reductive amination of 2-formylbenzoic acid with aminesa
Entry
1
Substrate
Conv. (%)
99
Yieldb (%)
95
Entry
1
Substrate
Conv. (%)
99
Yieldb (%)
95
2
99
88
2
99
73
3
4
99
99
84
64
3
4
5
6
99
99
99
99
85
50
57
83
5
99
74
a Reaction conditions: Nitroarene (1 mmol), LA (2 mmol), catalyst
(1.4 mol%), H2 (10 bar), methanol (1 mL), 30 °C, 72 h. b GC yield.
7
8
99
99
96
99
Table 4 One-pot synthesis of pyrrolidone from LA and nitrilesa
9
99
99
77
97
10
Entry
1
Substrate
Conv. (%)
99
Yieldb (%)
95
a Reaction conditions: Amine (1 mmol), 2-formylbenzoic acid
(2 mmol), catalyst (1.4 mol%), H2 (10 bar), methanol (1 mL), 30 °C,
24 h. b GC yield.
2
99
88
3
4
5
87
99
99
78
89
88
Scheme 2 One-pot synthesis of indoprofen from 2-formylbenzoic acid
and 2-(4-nitrophenyl)propionic acid.
a Reaction conditions: Nitrile (1 mmol), LA (2 mmol), catalyst
(1.4 mol%), H2 (10 bar), methanol (1 mL), 30 °C, 72 h. b GC yield.
Next, the reusability of Ir-PVP was studied for the reductive
amination of LA with aniline under optimized reaction con-
ditions. After the 1st cycle, the catalyst was separated by cen-
aniline (entries 2–4). The catalyst was able to transform trifugation from the reaction mixture, washed with acetone,
various amines such as linear and branched and amino alco- and dried at 40 °C for 12 h under vacuum. The dried catalyst
hols to the corresponding isoindolinones (entries 6–10). was used for the next cycle. The Ir-PVP catalyst was reused
Furthermore, the Ir-PVP catalyst was highly active for the syn- three times without any loss in activity (Fig. S4†). Additionally,
thesis of indoprofen (Scheme 2). Previously, indoprofen was we analysed the recovered catalyst by scanning transmission
synthesized in a two-step method via reductive amination of electron microscopy (STEM) and XRD to detect the aggregation
2-formylbenzoic acid using InCl3 and hydrosilane.16 Notably, of Ir nanoparticles. No aggregation was observed in the recov-
this is the first example of the one-step synthesis of indoprofen ered catalyst (Fig. S5 and S6†). Furthermore, XRD analysis
using a reductive amination approach.
showed that the crystallite size (1.22 nm) did not change in the
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reused catalyst (Fig. S7†). The time–yield profile for the reduc- Finally, cyclization of the secondary amine gives the pyrroli-
tive amination of LA by aniline was examined (Fig. S7†). It done product.
showed a consecutive reaction mechanism via the uncyclized
intermediate (4-anilinopentanoic acid). The yield of the uncy-
clized intermediate increased initially, and the intermediate
then underwent cyclization and transformed to the final
Conclusions
desired product.
In summary, the Ir-PVP catalyst was effective for the reductive
amination of levulinic acid under mild conditions (5 bar H2,
30 °C). This is the first direct method for the reductive amin-
ation of levulinic acid with amines/nitroarenes/nitriles.
Moreover, the catalyst was reused and showed excellent activity
for the reductive amination of 2-formylbenzoic acid as well.
Using this approach, the anti-inflammatory drug indoprofen
was synthesized for the first time. Reductive amination by the
Ir-PVP catalyst could offer an atom-economical route for the
synthesis of other isoindoline-based drugs and this possibility
will be explored in future work.
ð1Þ
ð2Þ
ð3Þ
Conflicts of interest
There are no conflicts to declare.
To study the reaction mechanism, we performed reactions
(1)–(3). Nitrobenzene was effectively hydrogenated to aniline
by using the Ir catalyst. The hydrogenation of nitrile proceeded
to give a primary amine with a secondary imine as the bypro-
duct. Probably, the primary amine was produced selectively in
the presence of the carbonyl group of LA due to quick trapping
of the generated primary amine as an imine simultaneously.
Next, the role of PVP in the catalytic cycle was also investigated.
A lower yield of pyrrolidone was obtained over the PVP-free Ir
catalyst due to the aggregation of Ir nanoparticles. On the
other hand, PVP-stabilized Ir nanoparticles with a small size
contain more number of surface sites which may be respon-
sible for the carbonyl functionality of LA which led to the high
yield of pyrrolidones.17 The low selectivity of Pt, Pd, Ru or Rh
catalysts can be explained by the Sabatier principle. Too weak
or too strong interaction between the catalyst surface and the
adsorbed species may lead to poor selectivity.18 However, the
effect of the large particle size of catalysts (Pd, Ru or Rh) on
selectivity cannot be ruled out. Additional work is necessary to
fully elucidate the reason for the high reactivity of Ir nano-
particles. From these results, we proposed a plausible mecha-
nism in which the reaction began with Ir-PVP catalyzed hydro-
genation of nitroarenes/nitriles to the corresponding primary
amine (Scheme 3). The condensation reaction between the
primary amine and LA generates an imine, which is hydrogen-
ated to a secondary amine in the presence of Ir nanoparticles.
Acknowledgements
This research was supported by the ACCEL program,
Japan Science and Technology Agency (JST), JPMJAC1501.
The authors thank T. Yamamoto, T. Toriyama, and Prof.
S. Matsumura for STEM analysis.
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