Lactate-Based Ionic Liquid Catalyzed Reductive Amination/Cyclization of Keto Acids under Mild Conditions: A Metal-Free Route to Synthesize Lactams

Article abstract of DOI:10.1021/acscatal.7b02231

Task-specific ionic liquids (ILs) have shown promising applications in catalysis. Herein we present lactate-based IL (e.g., 1-butyl-3-methylimidazolium lactate, [BMIm][Lac]) catalyzed reductive amination/cyclization of keto acids using triethoxysilane as a reducing agent, which provides a metal-free route to synthesis of lactams under mild conditions, even at room temperature. [BMIm][Lac] combined with (EtO)₃SiH afforded a series of five- and six-membered lactams in good to excellent yields at 80 °C within 1 h, showing comparable performance to the best metal-based catalyst reported to date. The mechanism investigation indicated that the ILs (e.g., [BMIm][Lac]) served as a multifunctional catalyst, which could activate hydrosilanes and simultaneously catalyzed the cyclization of LA with amines.

Full text of DOI:10.1021/acscatal.7b02231

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Letter
Lactate-Based Ionic Liquid Catalyzed Reductive Amination/Cyclization of
Keto Acids under Mild Conditions: A Metal-Free Route to Synthesize Lactams
Cailing Wu, Hongye Zhang, Bo Yu, Yu Chen, Zhengang Ke, Shien Guo, and Zhimin Liu
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b02231 • Publication Date (Web): 13 Oct 2017
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Lactate-Based Ionic Liquid Catalyzed Reductive Amination/
Cyclization of Keto Acids under Mild Conditions: A Metal-Free
Route to Synthesize Lactams
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Cailing Wu,a, b Hongye Zhang,a Bo Yu,a Yu Chen,a, b Zhengang Ke,a, b Shien Guo,a, b Zhimin Liu*a,b
aBeijing National Laboratory for Molecular Sciences, Key Laboratory of Colloid, Interface and Thermodynamics, CAS Re-
search/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing
100190, China
bUniversity of Chinese Academy of Sciences, Beijing 100049, China.
ABSTRACT: Task-specific ionic liquids (ILs) have shown promising applications in catalysis. Herein we present lactate-based IL
(e.g., 1-butyl-3-methylimidazolium lactate, [BMIm][Lac]) catalyzed reductive amination/cyclization of keto acids using triethox-
ysilane as a reducing agent, which provides a metal-free route to synthesis of lactams under mild conditions, even at room tempera-
ture. [BMIm][Lac] combining with (EtO)3SiH afforded a series of five and six-membered lactams in good to excellent yields at
80°C within 1 h, showing comparable performance to the best metal-based catalyst reported to date. The mechanism investigation
indicated that the ILs (e.g., [BMIm][Lac]) served as a multifunctional catalyst, which could activate hydrosilanes and simultaneous-
ly catalyzed the cyclization of LA with amines.
KEYWORDS: biomass, levulinic acid, reductive amination, ionic liquid, lactams, conversion
Biomass-based routes to synthesis of chemicals or fuels
have been paid much attention with the demands of green and
sustainable development.1-3 Due to the complicated chemical
structures of the naturally raw materials such as cellulose,
lignin, etc., biomass platform compounds are instead used as
feedstocks for the synthesis of chemicals. Levulinic acid (LA),
as one of the most promising platform compounds,4 can be
produced from cellulose, starch, or C6 sugars via acid-
catalyzed hydrolysis,5-8 which has been applied in the
production of many value-added chemicals including γ–
Scheme l. Chemical structures of the lactate anion and cations of the
lactate-based ILs.
valerolactone, 1,4-pentanediol, 2-methyltetrahydrofuran, N-
alkyl-5-methyl-2-pyrrolidones.9-11Reductive
amination/cyclization of LA is a promising route to synthesize
N-alkyl-5-methyl-2-pyrrolidones that are important structural
motifs with wide applications in pharmaceutical, agrochemical
and material industries.12,13 Various metal-based catalysts have
been explored for the LA reductive amination to produce
lactams or pyrrolidines using different reducing agent. 14-21 For
Ionic liquids (ILs), composed entirely of ions, exhibit
unique features such as high thermal and chemical stability,
negligible vapor pressure, excellent solvent power, and
tunable properties, ect..22-24 In particular, ILs can be designed
with specific task via choice or functionalization of cations or
anions, and thus have been widely applied in many areas, such
as chemical reactions,22 material synthesis,25,26 separation and
fractionation.27 Specially, ILs has been extensively used in
biomass processing and chemical transformation,28-31 for
instance, degradation of cellulose, conversion of sugars to 5-
hydroxymethylfurfural (HMF), as well as enzymatic
hydrolysis of IL-pretreated cellulose. Lactic acid is an
environmentally friendly bio-based chemical derived from
carbohydrates or glycerol via chemical and fermentation
routes.32-35 Lactate-based ILs are considered to be non-toxic
example, indium acetate(In(OAc) ) was shown to be very
3
effective for LA reductive amination to lactams using PhSiH3
as a reducing agent at 120°C. However, no metal-free catalyst
has been reported for LA reductive amination/cyclization to
lactams in a literature survey to date.
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and pharmaceutically acceptable, and have been used as green
Table 1. The reaction did not proceed without any catalyst
solvents for organic synthesis.36-38
(Table 1, entry 1). To our delight, all the tested lactate-based
ILs with different cations were very effective for this reaction,
affording 5-methyl-1-phenylpyrrolidin-2-one (1b) in excellent
yields using triethoxysilane ((EtO)3SiH) as a reducing agent at
80°C within 1 h (Table 1, entries 2-6). To explore other
reaction conditions, [BMIm][Lac] was selected as the catalyst.
For comparasion, other imidazole-based ILs including
[BMIm]Cl, [BMIm]Br, [BMIm]I, [BMIm]BF4, [BSO3MIm]Cl,
[BMIm](CF3SO3), [Bmim][OAc] were examined, and they
were found to exhibit inferior activity compared to the lactate-
based ILs (Table 1, entries 7-13). These findings indicated that
the lactate-based ILs were effecient catalysts of this reaction,
and the lactate anion played the key role in catalyzing the re-
action. The influence of temperature was investigated. As
listed in Table 1 (entries 2, 14, 15), the reaction could proceed
even at room temperature, producing 1b in a yield of 44%
within 1h. Prolonging the reaction time to 3 h and 6 h, the 1b
yield increased to 75% and 91%, respectively. Notably, 5-
methyl-1-phenyl-1,5-dihydro-pyrrol-2-one (B) and/or 5-
methyl-1-phenyl-1,3-dihydro-pyrrol-2-one (B') were detected
in the reaction solutions performed at 30 °C and 50 °C within
1 h, while it was not detectable in the reaction solution of 80
°C. This suggested that B and/or B' were intermediates of the
final product, and they could convert to 1b rapidly at high
temperature (e.g., 80 °C) under the experimental conditions.
4
5
6
7
8
9
Herein, we reported a series of lactate-based ILs with
different cations as illustrated in Scheme 1. They were found
to be capable of efficiently catalyzing the reductive amination
of LA using hydrosilane without any metal catalysts or
addictives under mild conditions, even at room temperature.
All the lactate-based ILs showed very high performances for
the
LA
reductive
amination.
Using
1-butyl-3-
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methylimidazolium lactate ([BMIm][Lac]) as the catalyst,
combined with (EtO)3SiH, a series of lactams were obtained in
excellent yields in most cases. The combination of the IL with
(EtO)3SiH showed better performance than the best metal-
based catalyst reported to date.21,39 The mechanism
investigation indicated that the ILs (e.g., [BMIm][Lac]) served
as a multifunctional catalyst, which could activate hydrosilane
and simultaneously catalysed the cyclization of LA and amine.
Table 1. IL-catalyzed reductive amination of levulinic acid
with hydrosilanes.a
Entry
1
2
3
4
5
6
7
8
Catalyst
--
Silane/equiv.
(EtO)3SiH/2
(EtO)3SiH/2
(EtO)3SiH/2
(EtO)3SiH/2
(EtO)3SiH/2
(EtO)3SiH/2
(EtO)3SiH/2
(EtO)3SiH/2
(EtO)3SiH/2
(EtO)3SiH/2
(EtO)3SiH/2
(EtO)3SiH/2
(EtO)3SiH/2
(EtO)3SiH/2
(EtO)3SiH/2
(EtO)3SiH/1.5
(EtO)3SiH/1
Ph2SiH2/2
Tem./oC
80
80
80
80
80
80
80
80
80
80
80
80
80
50
30
80
80
80
80
80
80
80
80
80
Yieldb
0
95
96
93
93
91
11
7
3
3
8
4
15
The amount of (EtO)3SiH was found to have an influence
on the 1b yield remarkably (Table 1, entries 2, 16, 17), which
decreased to 51% as the amount decreased to 1 equiv.. These
resultes indicated that 2 equiv. of (EtO)3SiH was required to
get a high 1b yield. In addition, other hydrosilanes including
phenylsilane (PhSiH3), poly-(methylhydrosiloxane) (PMHS),
diphenylsilane (Ph2SiH2), diethylsilane (Et2SiH2) and
methyldimethoxysilane (Me(OMe)2SiH) were also examined
in the reductive amination of LA with 1a (Table 1, entries 18-
22). As shown in Table 1, PhSiH3, Ph2SiH2 and Me(OMe)
2SiH were also effective for this reaction, however, displaying
much lower activity compared to (EtO)3SiH. Thus, (EtO)3SiH
was selected as the reducing agent for the reductive
amination/cyclization of LA.
[BMIm][Lac]
[HDBU][Lac]
[tBu4P][Lac]
[TMG][Lac]
[Et4N][Lac]
[BMIm]Cl
[BMIm]Br
[BMIm]I
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10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
[BMIm]BF4
[BSO3MIm]Cl
[BMIm](CF3SO3)
[BMIm][OAc]
[BMIm][Lac]
[BMIm][Lac]
[BMIm][Lac]
[BMIm][Lac]
[BMIm][Lac]
[BMIm][Lac]
[BMIm][Lac]
[BMIm][Lac]
[BMIm][Lac]
79
44/75c/91d
It was reported that In(OAc)3 and AlCl3.6H2O were
efficient catalysts for the reductive amination of LA with
amines.21,39 In the case of In(OAc)3 as the catalyst, solvents
(e.g., toluene) were required, and in the case of AlCl3.6H2O,
extra PhSiH3 was required to get a comparable product yield.
In this work, using [BMIm][Lac] as the catalyst, since it is
soluble in the reactants and products, no solvent is required,
which make the reaction process simpler. In addition, PhSiH3
was the most appropriate hydrosilane as In(OAc)3 and
AlCl3.6H2O acted as the catalyst, while (EtO)3SiH was the
best one in the case of [BMIm][Lac] as the catalyst. As known,
PhSiH3 is much more expensive than (EtO)3SiH.40 Therefore,
the combination of [BMIm][Lac] and (EtO)3SiH had obvious
advantages for the amination of LA compared to that of
In(OAc)3 or AlCl3.6H2O with PhSiH3. In this work, the activi-
ties of [BMIm][Lac], In(OAc)3 and AlCl3.6H2O for the reduc-
tive amination of LA with 1a were compared under the listed
conditions (Table 1, entries 23, 24). Obviously, [BMIm][Lac]
(20 mol%) combined with (EtO)3SiH showed similar activity
73
51
50
0
68
58
5
Et2SiH2/2
Me(OMe)2SiH/2
PhSiH3/2
PMHS/2
PhSiH3/2
PhSiH3/2
e
In(OAc)3
95
51
AlCl3.6H2Of
a Reaction conditions: IL (0.2 mmol), aniline(1 mmol), LA (1 mmol);
b
Determined by GC analysis using dodecane as the internal standard;
cReaction time: 3 h;
Reaction time: 6h;
1 mol%; 5 mol%.
d
e
f
g[HDBU][Lac]: 1,8-diazabicyclo[5.4.0]undec-7-enelactate; [TMG][Lac]:
tetramethylguanidine lactate.
The lactate-based ILs as illustrated in Scheme 1 were
synthesized via the neutralization of lactic acid with
corresponding bases. The formation of these ILs were
confirmed by 1H and 13C NMR analysis (see Supporting
Information). In our initial experiments, the reductive
amination of LA with aniline (1a) was performed to explore
the optimal reaction conditions, and the results are listed in
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Table 2. Reductive amination of levulinic acid with various
amines using triethoxysilane.a
to In(OAc)3 (1mol%, with phenylsilane) under the same other
conditions.
In addition, the IL [BMIm][Lac] could be readily
separated from the reaction solution, and it can be reused for
five times without obvious decrease in the yield of 1b (Figure
S1a). This indicated that the IL was stable and recyclable for
this reaction.
9
Taking the optimal conditions in hand, various
substituted primary anilines were explored to react with LA
catalyzed by [BMIm][Lac] in the presence of (EtO)3SiH, and
the results are summarized in Table 2. Obviously, most of
primary anilines with electron-donating or electron-
withdrawing groups including methyl, methoxy, fluoro, chloro,
bromo and iodine were tolerated, affording the corresponding
products in excellent yields (Table 2, entries 1-9). For the
isomers of methyl-substituted anilines, the substitution
position of methyl group in the benzene ring considerably
impacted the reactivity of the amines with LA, and their
reactivity follows the order: p-methyl aniline > m-methyl
aniline > o-methyl aniline (Entries 2-4). Prolonging reaction
time (i.e., 2h) led to the increase in the product yields (Table 2,
entries 3, 4). Notably, the para-substituted anilines with
electron-donating groups, such as methyl- and methoxy-
substituted anilines showed similar reactivity to aniline 1a,
affording the corresponding products in excellent yields
(Table 2, entries 1, 2, 5). For the anilines substituted by
electron-withdrawing groups, such as fluoro-, chloro-, bromo-
and iodine-, they showed declined reactivity compared to
aniline, whereas excellent product yields were obtained as the
reaction time was prolonged to 2h (Table 2, entries 6-9).
However, p-trifluoromethyl aniline suffered from relatively
low reactivity (Table 2, entry 10), probably due to the strong
electron-withdrawing effect of the substitute. In addition, ben-
zylic amines and aliphatic amines were also examined, which
showed very high reactivity under the experimental conditions
(Table 2, entries 11-14). The above results showed that the
[BMIm][Lac]/(EtO)3SiH system was very effective for the
reductive amination of LA to produce corresponding N-alkyl-
5-methyl-2-pyrrolidones.
Entry
1
Amine
Product
Yield [%]b
95c (93)
10
11
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13
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2
3
4
5
6
7
91 (90)
74/91d (87)
56/72d(65)
95 (93)
91d (89)
93d (90)
8
92d(90)
9
89d (83)
36e (30)
10
11
12
92 (85)
91 (83)
In order to demonstrate the potential of the
[BMIm][Lac]/(EtO)3SiH
system,
the
reductive
amination/cyclization of 4-acetylbutyric acid with aniline
derivatives were conducted, and the results are shown in
Scheme 2. It was clear that 4-acetylbutyric acid could react with
different substituted anilines, affording the corresponding N-
alkyl-6-methyl-2-piperidinones in excellent yields. Notably,
prolonged reaction time (e.g., 2 h) was required for 4-
acetylbutyric acid to react with anilines compared to that for
LA.
13
96(90)
14
94(88)
a Reaction conditions: [BMIm][Lac] (0.2 mmol), amine (1 mmol), LA (1
mmol), (EtO)3SiH (2 mmol), 1 h; Determined by 1H NMR using
b
To gain deep insight into the role of the IL in catalysing
the reaction, the interaction of [BMIm][Lac] with (EtO)3SiH
was examined by NMR analysis. From the 1H NMR spectra of
mesitylene as the internal standard, followed by isolated yield in
c
parenthesis; Yield determined by GC analysis using dodecane as the
internal standard; d Reaction time: 2h; e Reaction time: 3 h.
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Scheme 2. Reductive amination of 4-acetylbutyric acid with
reaction, no N-(pentan-2-yl) aniline was detected, suggesting
various amines using triethoxysilane.a
that the imine could not be hydrogenated by (EtO)3SiH in the
presence [BMIm][Lac], which was identical to our previous
results,42 while different from that reported before.15,17,21 Based
on this control experiment, it can be deduced that A may be
formed from aniline and LA, and further rapidly convert to B
under the experimental conditions.
O
N
[BMIm][Lac]
O
O
(EtO)3SiH
80 o
R
NH2
+
R
C
OH
(Reaction time, isolated yield)
9
O
O
N
O
O
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Scheme 3. Control experiments of reductive amination of LA
with aniline using (EtO) 3SiH.
N
N
N
O
Cl
O
O
O
O
(2 h, 89%)
(3 h, 91%)
(2 h, 92%)
(2 h, 91%)
NH2
[BMIm][Lac]
80 oC, 1 h
(EtO)3SiH
80 oC, 1 h
OH
+
N
N
(a)
O
O
aReaction conditions: IL (0.2 mmol), aniline (1 mmol), 4-
acetylbutyric acid (1 mmol), (EtO)3SiH (2 mmol).
1b, 95%
B and B', 8%
O
O
NH2
[BMIm][Lac]
80 oC, 1 h
(EtO)3SiH
80 oC, 1 h
OH
+
+
N
N
(b)
(c)
[BMIm][Lac], (EtO)3SiH and the mixture of [BMIm][Lac] and
1
(EtO)3SiH (Figure 1), it was observed that the H NMR signal
1b, 92%
B and B', 33%
N
belonging to H atom (1) from [BMIm]+ shifted upfield, and
the signals to H atom (4) from (Lac)- shifted downfield. And
the signals to H atoms (b, c) from (EtO)3SiH shifted downfield
from 3.86 and 1.25 ppm to 3.64 and 1.18 ppm, respectively.
All these shifts demonstrated that [BMIm][Lac] activated the
Si-H bond and make it possible involve in the reaction.
H
N
NH2
O
(EtO)3SiH
80 oC, 1 h
[BMIm][Lac]
80 oC, 1 h
0%
10%
Reaction conditions: aniline (1.0 mmol); [a] and [b] LA (1.0
mmol), (EtO)3SiH (2.0 mmol), [BMIm][Lac] (0.2 mmol); [c] 2-
pentanone (1.0 mmol), [BMIm][Lac] (0.2 mmol).
Notably, the control experiments Scheme 3a, b indicate
that both [BMIm][Lac] and (EtO)3SiH was able to individually
promote the formation of B, and (EtO)3SiH showed better
performance than [BMIm][Lac]. These results imply that in
the presence of the IL and (EtO)3SiH (i.e., in our reaction
systerm), the formation of B may undergo the generation of
silyl ether (A') by the reaction of aniline with LA and the IL-
activated (EtO)3SiH, followed by the release of siloxane.21
This may explained why 2 equiv. (EtO)3SiH was required to
get a high yield within 1h. As (EtO)3SiH was added into the
reaction solution of LA, aniline and [BMIm][Lac],
intermediate B disappeared and 1b was obtained in a high
yield of 95% at 80 °C after 1 h. Similarly, the addition of
[BMIm][Lac] into the reaction solution of LA, aniline and
(EtO)3SiH afforded a 1b yield of 92% without detectable B at
80 °C after 1 h. These findings suggested that (EtO)3SiH as a
reducing agent involved the formation of 1b via the reduction
of B, while the IL catalyzed the reaction. From the above
results, it can be concluded that the combination of (EtO)3SiH
and [BMIm][Lac] made the reaction proceed rapidly.
1
Figure 1. H NMR spectra of pure [BMIm][Lac], the mixture of
[BMIm][Lac] (0.1 mmol) and (EtO)3SiH (0.1 mmol) and pure
(EtO)3SiH; (CDCl3, 298 K).
In preliminary experiments, intermediate B was detected
in the reaction solutions performed at 30 °C and 50 °C, respec-
tively. In order to further reaveal the reaction pathway of the
reductive amination reaction of LA with aniline, control
experiments as illustrated in Scheme 3 were carried out. As
reported, amine could react with ketone to form imine.41
However, in this work no imine intermediate 4-(phenylimino)
pentanoic acid (A) was detected in the reaction solutions of
aniline and LA in the presence of [BMIm][Lac] or (EtO)3SiH.
Instead, cyclized intermediate B or B' was detected in yields
of 8% and 33%, respectively, under the experimental
conditions (Scheme 3a, b). To explored whether A can be
formed from aniline and LA or not, the reaction of aniline and
2-pentanone as a control reaction was performed in the pres-
ence of [BMIm][Lac] and (EtO)3SiH, and N-phenylpentan-2-
imine was obtained in a yield of 10% (Scheme 3c). In this
On the basis of the above results, a possible reaction
pathway
for
[BMIm][Lac]-catalyzed
reductive
amination/cyclization of LA using (EtO)3SiH as a reductant
was proposed as illustrated in Scheme 4. First, the
condensation between aniline and LA occurs to form a
ketimine A, which rapidly reacts with the IL-activiated
hydrosilane to form silyl ether.43-45 Subsequently, the
cyclization of the silyl ether occured, resulting in the
formation of B or B', which is finally reduced to pyrrolidone
by (EtO)3SiH catalyzed by the IL.
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Scheme 4. Possible reaction pathway of reductive amina-
tion/cyclization of LA
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o
yields at 80 C within 1-3 h. This approach to synthesize
lactams may find promising applications.
ASSOCIATED CONTENT
Supporting Information
General experimental procedures, yields determination and
characterization data. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: liuzm@iccas.ac.cn
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China
(Grant No 21373242 and 21125314) and the Chinese Academy of
Sciences.
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