Reductive amination/cyclization of levulinic acid to pyrrolidones: Versus pyrrolidines by switching the catalyst from AlCl3 to RuCl3 under mild conditions

Article abstract of DOI:10.1039/c7gc00999b

Herein the reductive amination/cyclization of levulinic acid using phenylsilane was presented to selectively produce pyrrolidones versus pyrrolidines under mild conditions by switching the catalyst from AlCl₃ to RuCl₃. Using AlCl₃ as the catalyst, pyrrolidones were solely obtained at room temperature, while RuCl₃ as the catalyst selectively afforded pyrrolidines in high yields at 45 °C.

Full text of DOI:10.1039/c7gc00999b

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Reductive Amination/Cyclization of Levulinic Acid to Pyrrolidones
versus Pyrrolidines by Switching the Catalyst from AlCl3 to RuCl3
under Mild Conditions
Received 00th January 20xx,
Accepted 00th January 20xx
Cailing Wua,b, Xiaoying Luoa,b, Hongye Zhanga, Xinwei Liua,b, Guipeng Jia,b, Zhenghui Liua,b and
DOI: 10.1039/x0xx00000x
Zhimin Liua,b
*
www.rsc.org/
Herein the reductive amination/cyclization of levulinic acid using
phenylsilane was presented to selectively produce pyrrolidones
versus pyrrolidines under mild conditions by switching the
catalyst from AlCl3 to RuCl3. Using AlCl3 as the catalyst,
pyrrolidones were solely obtained at room temperature, while
RuCl3 as the catalyst selectively afforded pyrrolidines in high
yieldsat 45°C.
pyrrolidines from LA, especially under mild conditions, is still
highly desirable.
Aluminum chloride (AlCl3) is a cheap and readily available
Lewis acid, which has been widely applied in catalysis,
including the reductive amination of carbonyl compounds.25
Herein we report the reductive amination/cyclization of LA
using PhSiH3 to pyrrolidones versus pyrrolidines by switching
the catalyst from AlCl3 to RuCl3 under mild conditions, as
illustrated in Scheme 1. It was demonstrated that AlCl3 could
afford pyrrolidones in high yields at room temperature, while
RuCl3 resulted in the selective production of pyrrolidines in
The production of chemicals from biomass or biomass
platform compounds has attracted much attention due to the
requirements of green and sustainable chemistry in the past
2
decades.1, Levulinic acid (LA) has been considered as an
high yields at 45°C.
important platform compound from lignocellulose3-6, which
has been applied in the synthesis of various value-added
chemicals such as g-valerolactone, 1,4-pentanediol, 2-
methyltetrahydrofuran, N-alkyl-5-methyl-2-pyrrolidones, and
so on.7 Pyrrolidones and pyrrolidines are very important
O
O
AlCl3.6H2O (5 mol%)
PhSiH3
RuCl3.3H2O (1 mol%)
PhSiH3
OH
Ar
N
Ar-NH2
+
N
Ar
45 oC
30 oC
O
Scheme 1 Selective production of pyrrolidones versus pyrrolidines.
structural motifs with wide applications in pharmaceutical,
agrochemical and material industries,8,
9
and they are
generally synthesized via the petroleum-based routes.10-16
In our initial experiments, the acylation of LA with aniline
and phenylsilane was performed as a model reaction to screen
the reaction conditions, and the results are listed in Table 1.As
expected, the reaction did not occur without any catalysts. To
our delight, AlCl3 was very effective for this reaction at room
temperature, solely affording 5-methyl-1-phenylpyrrolidin-2-
one (1b) in a yield of 77% within 3h (Table 1, entry 2).
Prolonging reaction time to 6 h and 12h, the yields of 1b
Recently, pyrrolidones have been reported to be produced
from the reaction of LA and primary amines by reductive
17, 18
amination using various reducing reagents including H2
or
HCOOH19-23. However, N-substituted pyrrolidines have not
been synthesised in these systems. More recently, Sakai’s
group reported that pyrrolidones versus pyrrolidines could be
selectively produced from LA and primary amines via
reductive amination/cyalization using a hydrosilane catalyzed
increased to 84% and 93%, respectively (Table 1, entries 3, 4).
At 50 °C, 91% yield of 1b was obtained within 3h, and
by expensive indium catalysts (i.e., In(OAc)3 to InI3) at 120°
C.24
Though such progress has been made, developing new
prolonging the reaction time to 12h, the high yield still
remained (Table 1, entries 6, 7). The above results indicated
that higher temperature was favorable to the production of 1b
and that 1b could not be further reduced under the
efficient catalysts for selective production of pyrrolidones or
,
experimental conditions. Both ZnCl2 and CuCl2 were also
effective for this reaction to produce 1b, however, displaying
much lower activity compared to AlCl3 (Table 1, entries 8 and
9). In the case of RuCl3 as the catalyst 1b was obtained only in
a yield of 3% under the same other conditions, while 2-
methyl-1-phenylpyrrolidine (1c) and 2-methyl-1-phenylpyrrole
aBeijing National Laboratory for Mole cular Sciences, Key Laboratory of
Colloid,Interface and Thermodynamics, CAS Research/Education Center for
Excellence in Molecular Sciences,Institute of Chemistry, Chinese Academy
ofSciences,Beijing 100190, China;
bUniversity of Chinese Academy of Sciences, Beijing 100049, China.
E-mail: liuzm@iccas.ac.cn
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
(
1d) were obtained in yields of 84% and 8%, respectively
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Table 2AlCl3-catalyzed reductive amination of keto acids with different aminesa
(Table 1, entry 10).For comparison, In(OAc)3 and InI3 were also
tested under the standard conditions (Table 1, entries 11, 12).
It was found that In(OAc)3 as the catalyst resulted in the
production of 1b in a yield of 83% accompanied with 1c (9%)
as a by-product, displaying worse performance than AlCl3. InI3
afforded 1c in a yield of 95%, showing similar activity to
RuCl3.3H2O. Among the tested catalysts, AlCl3 displayed the
best performance for the production of 1b, which was
selected as the catalyst for the further investigation.
Entry
1
Substrate
n
1
Product
Yield b/%
93/90
1
1
1
1
1
1
1
1
1
As the amount of PhSiH3 decreased to 2 equiv., the 1b yield
declined to 78%, suggesting that the amount of PhSiH3 had
considerable influence on the production of 1b. It was
indicated that 3 equiv. of PhSiH3 was required for getting high
yield of 1b.Other hydrosilanes including Et2SiH2, Ph2SiH2,
EtO3SiH, Ph3SiH and (CH3O)2CH3SiH were also examined for
this reaction (Table 1, entries 13-17), and it was demonstrated
that PhSiH3 displayed the best performance.
2
3
96/93
91/87
56/50
91/90
91/88
92/89
88/87
44c/40
90/83
87/83
4
6
Table 1The acylation of LA with aniline and hydrosilanesa
7
8
Entry
1
Catalyst
-
Silane/nbmmol
PhSiH3/3
PhSiH3/3
PhSiH3/3
PhSiH3/3
PhSiH3/2
PhSiH3/3
PhSiH3/3
Temp./oC Time/h Yieldc/%
30
30
30
30
30
50
50
50
50
50
30
30
30
30
30
45
12
3
-
9
2
AlCl3.6H2O
AlCl3.6H2O
AlCl3.6H2O
AlCl3.6H2O
AlCl3.6H2O
AlCl3.6H2O
77
84
93/90e
78
91
95
40
45
3d
3
6
10
11
4
12
12
3
5
6
7
12
12
12
12
12
12
12
12
12
12
12
8
ZnCl2.6H2O PhSiH3/4
CuCl2.2H2O PhSiH3/4
RuCl3.3H2O PhSiH3/4
1
1
2
9
12
13
14
10
11
12
13
14
15
16
17
In(OAc)3
InI3
PhSiH3/4
83
0f
PhSiH3/4
88/81
89/87
AlCl3.6H2O
AlCl3.6H2O
Et2SiH2/4.5
Ph2SiH2/4.5
0
45
57
0
AlCl3.6H2O (EtO)3SiH/9
AlCl3.6H2O Ph3SiH/9
AlCl3.6H2O (CH3O)2CH3SiH/9 30
62
2
2
2
15
16
17
91/88
92/87
90/85
aReaction conditions: aniline (1mmol), levulinic acid (1mmol), catalyst (5mol%).
bn refers tommol of hydrosilane.cYielddetermined by GC analysis using dodecane
as the internal standard.dYield of 1c: 84%, yield of1d: 8%.e Isolated yield.f1c was
obtained in a yield of 95%.
Taking the optimized reaction conditionsin hand, the
reactions of LA with various primary amines were conducted,
and the results are summarized in Table 2. It was
demonstrated that all the tested amines were acylated with
LA, producing the corresponding pyrrolidones inmoderate to
excellent yields at 30 °C within 12h. Most of the anilines, with
electron-donating or electron-withdrawing groups, including
methyl, methoxy, 4-bromo-, 4-chloro-, and 4-fluoro- groups
were well acylated, affording the corresponding products in
excellent yields. For 2-methyl aniline, it gave rise to a low
product yield (56%) (Table 2, entry 4), probably due to the
aReaction conditions: amine (1mmol), keto acid (1mmol), AlCl3.6H2O (5mol%), 12
h. bYield determined by 1H NMR analysis using mesitylene as the internal
standard, followed by isolated yield. cReaction time: 24h
steric effect. 4-Trifluoromethylaniline also afforded a low
product yield (44%)(Table 2, entry 10), probably ascribing to
the strong electron-withdrawing effect of the trifluoromethyl
group. Benzylic amines (Table 2, entries 12, 13) and
cyclohexylamine (Table 2, entry 11) were also able to convert
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Table 4Reductiveamination of keto acids catalyzed by RuCl3.6H2O a
into the corresponding N-benzyl and N-cyclohexyl
pyrrolidones in high yields. 4-Acetylbutyric acid instead of LA
was used to react with amines including aniline, para-methyl
aniline, para-methoxy aniline, para- chloro aniline, and the
corresponding N-alkyl-6-methyl-2-piperidinones in excellent
yields (Table 2, entries 14-17).The above results indicated that
the combination of AlCl3 and PhSiH3 was very effective for the
production of pyrrolidones from the reductive reaction of keto
acids with amines.
Entry
1
Substrate
n
Product
Yieldb/%
93/90
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
90/87
85/83
68/60
75/70
82/81
82/79
85/82
55/50
In the preliminary experiment, it was found that RuCl3 as
the catalyst could result in the production of 2-methyl-1-
phenylpyrrolidine (1c) as the main product accompanied with
considerable amount of 2-methyl-1-phenyl-pyrrole (1d) with
or without 1b. For example, when the temperature was 50
°C,
a
1c yield of 84% was achieved together with a 1d yield of
8%and small amount of 1b (3%) within 12h (Table 1, entry 10).
In order to get 1c as the main product and suppress the
formation of 1d, the reaction conditions were further
optimized. Hydrosilanes including EtSiH2, Ph2SiH2, EtO3SiH,
Ph3SiH, (CH3O)2CH3SiH, and (CH3)2PhSiH were examined (Table
S1, entries 1-6) for this reaction. It was found that PhSiH3 as
the reducing agent could afford1cin high yield.The reaction
was sensitive to the reaction temperature in the range from
30 to 50°C.It was indicated that high temperature was
favorable to the production of1c. At 45°C, a 1c yield of 93%
was achieved with small amounts of 1b (2%) and 1d (4%)
(Table 3, entry 4) within 24 h; however, further increasing
temperature to 100°C resulted in the reduction in the 1c yield,
and more 1d was produced (Table 3, entry 6).
10
11
1
2
90/85
88/83
Table3RuCl3.3H2O catalyzed the production of 2-methyl-1-phenylpyrrolidine (1c) from
LA and anilinea
aReaction conditions: amine (1 mmol), keto acid (1 mmol), RuCl3.6H2O (1 mol%).
bYield determined by 1H NMR analysis using mesitylene as the internal standard,
followed by isolated yield.
Entry
Temp./°C
Yieldb
1c
and the para-substitution resulted in the highest product yield
of 90%, while the orth-substitution afforded the lowest yield
of 68%. These results were similar to the production of
corresponding pyrrolidones (Table 2, entries 2-4). The Cl-, Br-
and F-substituted anilines showed the similar reactivity,
producing the corresponding pyrrolidines in high yields (82-
85%; Table 4, entries 6-8). However, the aniline with strong
electron-withdrawing group CF3 in the para-substitution
produced the target product in a low yield of 55%.The
reaction of4-acetylbutyric acid with aniline gave rise to 2-
methyl-1-phenylpiperidine in a high yield (Table 4, entry 11).
The above results indicated that AlCl3 was an effective
catalyst for the production of pyrrolidones from the reductive
amination/cyclization of keto acids with amines using PhSiH3
as the reducing reagent, while RuCl3 resulted in the selective
production of pyrrolidines in high yields. That is, switching the
catalyst from AlCl3 to RuCl3 could lead to the selective
production of pyrrolidones versus pyrrolidines from the same
starting materials. To explore the reaction pathway, control
1b
40
18
2
1d
3
1
2
30
40
55
74
4
3
4 c
45
93
4
45
17
0
76
4
5
50
88
8
6
100
0
75
24
aReaction conditions: amine (1 mmol), levulinic acid (1 mmol), RuCl3.3H2O (1
mol%), PhSiH3 (4 mmol), 24 h. bYield determined by GC analysis using dodecane
as the internal standard. cReaction time: 12 h
Taking RuCl3 as the catalyst, the reactions of LA with
amines were performed in the presence of PhSiH3 at 45°C, and
the results are summarized in Table 4. Interestingly, a series of
pyrrolidines were obtained as the main products in good to
excellent yields. For example, aniline reacted with LA, giving
pyrrolidine in a yield of 93% (Table 4, entry 1). The methyl
aniline isomers showed different reactivity for the production
of corresponding pyrrolidines (Table 4, entries 2-4),
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experiments were performed. In the absence of PhSiH3, LA
was mixed with aniline and AlCl3, and the solution was
examined by GC-MS. A new signal assigning to 5-methyl-1-
Notes and references
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phenyl-1, 5-dihydro-pyrrol-2-one (
spectrum, suggesting that LA could react with aniline
catalyzed by AlCl3 to form intermediate. To the reaction
B) appeared in the GC-MS
B
solution of LA and aniline catalyzed by AlCl3 was PhSiH3 added,
4. R. S. A. Gretchen M. G. Maldonado, J. Dumesic and L. A. Curtiss,
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and 1b was obtained in a high yield. The reaction of 1b with
PhSiH3 was carried out in the presence of RuCl3 at 50 °C for
24h, and 1c was obtained in a yield of 80% (Scheme S1). This
suggests that in the reaction process of amine with LA the
resultant 1b could be further converted into 1c catalysed by
RuCl3 under the experimental conditions.
Based on the above experimental results and those
reportedpreviously,19,26 possible reaction pathway to form 1b
and 1c was proposed as illustrated in Scheme 2. First, LA
reacts with amine to form imine via dehydration,26 which
further dehydrates and cyclizes catalyzed by AlCl3 or RuCl3 to
form intermediate B or B’.19 Then
B was reduced to 1b by
PhSiH3 in the presence of AlCl3 or RuCl3, and 1b was further
converted into 1c catalyzed by RuCl3 (path 1). Besides path 1,
11. H. Lu and C. Li, Tetrahedron Lett., 2005, 46, 5983-5985.
12. Z. Li, L. Song and C. Li, J. Am. Chem. Soc., 2013, 135, 4640-4643.
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16. R. A. T. M. Abbenhuis, J. Boersma and G. van Koten, J. Org.
Chem., 1998, 63, 4282-4290.
in the presence of RuCl3, intermediate
hydrogenated by PhSiH3 to form intermediate
B
could also be
, which further
C
dehydrates to form the by-product 1d
.
17. J. D. Vidal, M. J. Climent, P. Concepcion, A. Corma, S. Iborra and
M. J. Sabater, ACS Catal., 2015, 5, 5812-5821.
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Tetrahedron Lett., 2016, 57, 766-771.
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ChemSusChem, 2011, 4, 1578-1581.
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Angew. Chem. Int. Ed., 2011, 50, 7815-7819.
Scheme 2 Possiblereaction pathway.
24. Y. Ogiwara, T. Uchiyama and N. Sakai, Angew. Chem. Int. Ed.,
2016, 55, 1864-1867.
Conclusions
25. V. Kumar, S. Sharma, U. Sharma, B. Singh and N. Kumar, Green
Chem., 2012, 14, 3410.
26. N. Azizi and M. Edrisi, Monatshefte für Chemie - Chemical
Monthly, 2015, 146, 1695-1698.
In summary, AlCl3 was an efficient catalyst for the
production of pyrrolidones from the reductive amination of
keto acids using PhSiH3 as a reducing reagent at room
temperature, while RuCl3 was effective for the selective
production of pyrrolidines at 45°C under the same other
conditions. These two cheap and readily available catalysts
may have promising applications in the production of
pyrrolidones and pyrrolidines.
Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (Grants Nos.21373242,
21125314) and Chinese Academy of Sciences.
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Reductive amination/cyclization of levulinic acid was presented to selectively produce
pyrrolidones versus pyrrolidines by switching the catalyst from AlCl3 to RuCl3 under mild
conditions.