Ruthenium-catalyzed conversion of levulinic acid to pyrrolidines by reductive amination

Article abstract of DOI:10.1002/cssc.201100344

Combo deal: An aqueous solution of levulinic acid (LA) and formic acid (FA) derived from biomass-based carbohydrates can be converted efficiently to pyrrolidines via a ruthenium catalyst without need for an energy-intensive separation of LA or an external H₂ source. The ruthenium catalyst combines two processes: decomposition of FA to H₂ and reductive amination of LA with an amine. Copyright

Full text of DOI:10.1002/cssc.201100344

DOI: 10.1002/cssc.201100344
Ruthenium-Catalyzed Conversion of Levulinic Acid to Pyrrolidines by
Reductive Amination
Yao-Bing Huang, Jian-Jun Dai, Xiao-Jian Deng, Yan-Chao Qu, Qing-Xiang Guo, and Yao Fu*[a]
The current global mass consumption of non-renewable fossil
fuels is forcing academic and industrial scientists to find alter-
native sustainable resources.[1] The transformation of biomass
into fuels and value-added chemicals[2] could be crucial to this
endeavour and has been a strong research focus in recent
years. Carbohydrates, the main component of biomass, could
be converted into many chemicals such as ethanol, hydroxy-
methylfurfural (HMF),[3] levulinic acid (LA),[4] and furfural.[5]
Levulinic acid, an important platform chemical,[6] can also be
produced by large-scale hydrolysis of furfurylalcohol or bio-
based cellulosic feedstocks.[7] Moreover, LA is a promising start-
ing material for many different useful intermediates and fine
chemicals by oxidation,[8] reduction,[9] condensation,[10] and
esterification[11] (Scheme 1). For example, g-valerolactone may
be used as a liquid fuel, food additive and solvent;[12] 5-amino-
levulinic acid is a highly active, biodegradable, and nontoxic
herbicide and insecticide.[13]
lyst could be used to transform LA to 5-methyl-2-pyrrolidone
by gas-phase reductive amination. Recently, Manzer et al.[17,14a]
reported that LA and its ester can be transformed into N-alkyl-
5-methyprrolidones with a variety of metals. Furthermore, they
developed a one-step process for converting LA and nitro
compounds into aryl-, alkyl-, and cycloalkylpyrrolidones.[18]
Under the same reaction conditions, aryl and alkyl nitriles
could also react with LA in the presence of Ir/SiO2, Ru/Al2O3,
and Pd/C.[14b] However, these procedures usually require either
high pressure/temperature or have a low to moderate yield.
Thus, a more novel and efficient system is required.
According to the research of Beller,[19] Laurenczy,[20] and
others,[21] formic acid (FA) will decompose under mild condi-
tions to yield hydrogen. Furthermore, Horvꢀth et al. have de-
veloped a pioneering route using LA/FA mixtures obtained by
glucose dehydration for the synthesis of g-valerolactone.[12b]
Herein we report a new route to convert LA derived from bio-
mass-based carbohydrates to
pyrrolidines without need of an
external H2 supply.[22] The hydro-
genation step was accomplished
with formic acid produced from
acidic dehydration of biomass-
based carbohydrates. The advan-
tages of the new route are its
good atom economy and that it
avoids the energy-intense ex-
traction of LA from its aqueous
solution with formic acid.
(Scheme 2).
We began our research with
Scheme 1. Conversion of LA to useful compounds.
LA, formic acid, and primary
amines with various catalysts in
Additionally, pyrrolidines, such as 5-methyl-N-(methyl, aryl,
alkyl, cycloalkyl)-2-pyrrolidone, are used as industrial solvents,
surfactants, and complexing agents.[14] They are also employed
in pharmaceutical formulations, transdermal patch formulation,
grease removal formulation, agrochemical composition and
stripping formulation.[14]
the absence of solvent. On trying different ruthenium catalysts,
we found that combining dichloro(p-cymene)ruthenium(II)
dimer 1 with different phosphine ligands L1–L6 afforded good
results (Table 1, entries 1–6). When the ligand was changed to
To produce pyrrolidines from LA, Shilling[15] and Crook[16] re-
ported that silica gel-supported nickel or the Raney nickel cata-
[a] Y.-B. Huang, J.-J. Dai, X.-J. Deng, Y.-C. Qu, Prof. Q.-X. Guo, Prof. Y. Fu
Anhui Province Key Laboratory of Biomass Clean Energy
Department of Chemistry
University of Science and Technology of China
Hefei 230026 (PR China)
Fax. (+86)551-360-6689
E-mail: fuyao@ustc.edu.cn
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cssc.201100344.
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ChemSusChem 2011, 4, 1578 – 1581

stituent on the phenyl ring gave
higher yield of 94%
(Scheme 3,1b). n-Butylamine
a
and 2-methoxyethanamine, rep-
resentative of straight-chain
alkyl-amines, gave the corre-
sponding pyrrolidines in good to
excellent
yields
(Sche-
Scheme 2. Previous route vs. new transformation.
Table 1. Optimization of the model reaction.
me 3,1c,1d). However, the reac-
tion using a secondary amine
gave a moderate yield (69%),
most likely due to sterics (Scheme 3,1e). By using excess LA
and FA, cyclohexylmethanamine gave 1f in 79% yield
(Scheme 3, 1f). Several arylamines were also selected to syn-
thesize 5-methyl-N-arylpyrrolidines. An obvious electric effect
was determined: the activity of arylamines decreased when
the substituent became more electron-withdrawing (Scheme 3,
2a–2d) and showed the arylamine to react more easily with
FA. An ortho-substituent on the phenyl ring further decreased
the reactivity (Scheme 3, 2e).
These results demonstrate that pyrrolidines can be prepared
easily from LA, which is in turn obtained via acidic dehydration
of biomass-derived carbohydrates without an external H2
supply. We looked next into making the transformation practi-
cal for the acidic dehydration process in water. As illustrated in
our previous work,[12c] LA could be produced simply from sev-
eral types of biomass-based carbohydrates in yields between
35%–58% (Table 2). The yield of FA is higher than that of LA
and H2 sourced from FA decomposed would be enough for
further use in hydrogenations.
Entry
R
Catalyst[a]
Ligand[b]
T
[8C]
t
[h]
Yield[c]
[%]
1
2
3
4
5
6
7
8
9
10[d]
11[e]
12
13[d]
14[d]
15[d]
16
17[d]
18
19
20
21
22
23[f]
24[f]
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
RuCl3·H2O
Ru(PPh3)3Cl2
Ru/C
1
1
1
1
1
1
1
1
1
1
1
1
–
L1
–
–
120
120
120
120
120
120
120
120
120
120
120
100
80
12
12
12
12
12
12
12
12
12
12
12
12
12
12
6
12
12
12
12
12
12
12
12
12
3
5
34
7
L1
L2
L3
L4
L5
L6
L4
L4
L4
L4
L4
L4
–
L4
L4
L4
L5
L6
L1
L4
–
83
76
95
21
22
94
70
94
93
80
85
8
20
50
38
28
43
8
60
80
80
80
1
1
1
1
A 50 wt% aqueous solution of LA/formic acid (1:1) was pre-
pared to simulate an acidic dehydration system. Strikingly, we
found that the transformation of LA to pyrrolidines could be
achieved in the simulated system with only a slightly lower
yield (Scheme 4). Notably, a 25 wt% ammonia or methylamine
solution could be used instead of their gaseous forms as the
amine sources to produce the corresponding pyrrolidines
(Scheme 4,1g,1f). Compared to their amine gas equivalents,
these raw materials are much cheaper and they can be more
conveniently handled.
120
140
120
120
120
120
120
1
RuCl3·H2O
1
–
72
5
Reaction conditions: LA/FA/amine=1:1:1, 1. [a] 1 mol%. [b] 3 mol%.
[c] GC-MS yield. [d] Catalyst 0.5 mol%. [e] Catalyst 0.2 mol%. [f] LA/FA/
amine=2:2:1.
Finally, we applied the catalytic system to the transformation
of glucose into pyrrolidines and enlarged the process to a lab-
oratory-scale (Scheme 5). Acidic dehydration with additional
treatment gave an aqueous mixture (50 mL, 42 wt% LA,
17 wt% formic acid) from glucose (400 mL, 15 wt% aqueous
solution),[12c] to which the catalyst and amines were added. Re-
ductive amination at 808C produced the 5-methyl-N-octyl-2-
pyrrolidone, an industrial surfactant, in 62% yield. The overall
yield of the pyrrolidone from glucose is 34%. Supported phos-
phine ligands containing ruthenium enable the recycling of
the expensive catalytic from the reaction mixture. Our future
work would focus on preparing the supported heterogeneous
catalyst.
PtBu3, the reaction reached full conversion and gave a 95%
yield according to GC. Other ligands, dppp and tppts showed
low activity (entries 8–9). On lowering the catalyst loading to
0.5 mol% and 0.2 mol%, the yields were 94% and 70% respec-
tively (entries 10–11). When the reaction temperature was low-
ered to 808C, the catalyst still showed high efficiency (en-
tries 12–15). The reaction gave poor results in the absence of
the catalyst (entry 16). When a phenylamine ligand was em-
ployed under the optimal conditions, the yield was only 20%
and some side product (N-phenylformamide) was detected
(entry 17). However, by changing the ratio of LA/FA/amine to
2:2:1, the yield of the target product increased and the side
product was suppressed (entries 17–24).[23]
In summary, we have developed a convenient and effective
procedure that converts LA derived from biomass-based carbo-
hydrates into pyrrolidines with [Ru(p-cymene)Cl2]2/t-Bu3PHBF4
catalysis without need for intermediate purification or an exter-
These experiments produced a small library of pyrrolidines.
The isolated yield of 5-methyl-N-benzyl-2-pyrrolidines from
benzyl-amine is 92% (Scheme 3,1a). An electron donating sub-
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Scheme 5. Transformation of glucose to pyrrolidines.
nal H2 supply.[24] This procedure can be utilized to
produce a family of building blocks that may find im-
portant application as intermediates or final chemi-
cals in industry. In a laboratory-scale experiment, glu-
cose was transformed into pyrrolidine in 34% yield
by an operationally simple sequence (acidic dehydra-
tion and Ru-catalyzed reductive amination). Further
research would focus on the effective catalytic con-
version of LA to different value-added chemicals and
biofuels.
Scheme 3. Transformation of LA/FA to pyrrolidines with different amines in neat condi-
tions. Conditions A: LA (1 mmol), FA (1 mmol), amine (1 mmol), 1 (0.5 mol%), t-Bu3PHBF4
(1.5 mol%), 808C, 12 h. Isolated yields. Conditions B: LA (2 mmol), FA (2 mmol), amine
(1 mmol), 1 (1 mol%) t-Bu3PHBF4 (3 mol%) 1208C, 12 h. Isolated yields. [a] LA/FA/
amine=2:2:1 (mmol).
Experimental Section
Table 2. LA and FA prepared from acid-catalyzed biomass carbohydrates
at 2208C, as detailed in our previous work.[12c]
Levulinic acid (LA, 99%), formic acid (FA, 98%), Ru catalyst and a-
cellulose were supplied by Aladdin Reagent Co. Ltd. The ligands
used in the literature were all purchased from Alfa Aesar. Glucose
and amines were purchased from Sinopharm Chemical Reagent
Co. Ltd. All reactions were carried out in an oven-dried flask under
an atmosphere of nitrogen. Flash column chromatography was
performed with silica gel (200–300 mesh). NMR spectra were re-
corded using a Bruker Avance 300 and 400 instruments. Gas chro-
matographic (GC) analyses were performed on a Shimadzu GC-
2014 Series GC System. GC-MS analysis was performed on Thermo
Scientific AS 3000 Series GC-MS System. MS analyses were per-
formed on Finnigan LCQ advantage Max Series MS System.
Experimental Procedures for reaction without solvent or
in water: A disposable tube with a plastic screwcap top,
Teflon septum, and stir bar was charged with the desired
amount of catalyst (0.2~1 mol%) and ligand (3 eq to
metal). If the amine was a solid, it was added simultane-
ously. The tube was evacuated and refilled with nitrogen
three times. LA (1~2 mmol), FA (1~2 mmol), and amine
were added by syringe under a flow of nitrogen. (If the
reaction was in water, solutions of LA and FA were
added). The reaction was allowed to run for 6~12 h,
whereupon it was cooled to room temperature, then di-
luted with aqueous Na2CO3 solution. The resulting mix-
ture was extracted with diethyl ether. The separated or-
ganic layer was dried over anhydrous MgSO4, filtered
and concentrated under reduced pressure. The crude
product was purified by column chromatography on
silica gel.
Entry
Carbohydrate
LA yield
[mol%]
FA yield
[mol%]
1[a]
2[a]
3[a]
4[b]
microcrystalline cellulose
a-cellulose
starch
35.4
45.2
53.7
57.7
45
49
58
76
glucose
[a] Conditions: 20 g of carbohydrate in 400 mL of aqueous HCl (0.8m).
[b] Conditions: 15 wt% glucose in 400 mL of aqueous HCl (0.8m).
Experimental Procedures for converting glucose to pyr-
rolidines: 400 mL, 15 wt% glucose and 0.8m HCl solution
was loaded to a 500 mL stainless steel autoclave, which
was then heated to 2208C under vigorous stirring for
1 h. The mixture was transferred to a 200 mL flask and
then, after partial neutralization (pH 2) and filtration, to a
pressure-equalizing dropping funnel. The filtrate was dis-
tilled under vacuum and concentrated to 50 mL using a
Scheme 4. Transformation of LA/FA solution to pyrrolidines with different amines. Condi-
tions A: LA (1 mmol), FA (1 mmol), H2O (150 mg), amine (1 mmol), 1 (0.5 mol%) t-
Bu3PHBF4 (1.5 mol%), 808C, 12 h. Isolated yield (based on amine), 808C, 12 h. Isolated
yields. Conditions B: LA (2 mmol), FA (2 mmol), H2O (250 mg), amine (1 mmol), 1 (1
mol%) t-Bu3PHBF4 (3 mol%) 1208C, 12 h. Isolated yields (determined by amine). [a] LA/
FA/amine=1:1:3. Isolated yields (based on LA).
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ChemSusChem 2011, 4, 1578 – 1581

Patent 2002074760, 2002; e) L. E. Manzer, US Patent 20030055270,
2003.
cullet-packed column. Finally, the concentrated mixture of FA and
LA was added to the catalyst and amine. The autoclave was flush-
ed with nitrogen and stirred at 1000 rpm. The autoclave tempera-
ture was elevated to the target temperature in 30 min and cooled
in water to room temperature after the reaction. The reaction mix-
ture was sampled, diluted 100 times in acetone and analyzed by
GC-MS.
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The authors are grateful to the National Basic Research Program
of China (2012CB215305), the National Natural Science Founda-
tion of China (21172209), Chinese Academy of Science and the
Fundamental Research Funds for the Central Universities for the
financial support.
Keywords: amination · amines · homogeneous catalysis ·
renewable resources · ruthenium
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Received: July 6, 2011
Published online on September 16, 2011
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