L-Proline and thiourea co-catalyzed condensation of acetone

Article abstract of DOI:10.1016/j.tet.2016.05.039

Amino acid and primary amine/amide co-catalyzed acetone condensation was investigated. It was found that L-proline had overwhelming catalytic activity over other amino acids as well as the analogues with similar structures. Surprisingly, thiourea, a very cheap and stable chemical, was found to be the favorable co-catalyst. Co-catalyzed by the recyclable L-proline and thiourea, condensation of acetone led to the useful products mesityl oxide (MO), diacetone alcohol (DAA) and isophorone (IP) in the excellent 96.3% total selectivity.

Full text of DOI:10.1016/j.tet.2016.05.039

Accepted Manuscript
l-Proline and thiourea co-catalyzed condensation of acetone
Lin Xu, Fang Wang, Jiejun Huang, Chenggen Yang, Lei Yu, Yining Fan
PII:
S0040-4020(16)30424-0
10.1016/j.tet.2016.05.039
TET 27766
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 29 April 2016
Revised Date: 11 May 2016
Accepted Date: 13 May 2016
Please cite this article as: Xu L, Wang F, Huang J, Yang C, Yu L, Fan Y, l-Proline and thiourea co-
catalyzed condensation of acetone, Tetrahedron (2016), doi: 10.1016/j.tet.2016.05.039.
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L-proline and thiourea co-catalyzed
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condensation of acetone
Lin Xu, Fang Wang, Jiejun Huang, Chenggen Yang Lei Yu* and Yining Fan*

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Tetrahedron
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L-proline and thiourea co-catalyzed condensation of acetone
a,b,c
d
b,c
c
a,b,c
a,
Lin Xu
, Fang Wang , Jiejun Huang , Chenggen Yang, Lei Yu
∗ and Yining Fan ∗
a
Key Laboratory of Mesoscopic Chemistry of MOE, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093
Jiangsu Yangnong Chemical Group Co. Ltd., Yangzhou 225009, China
Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, School of Chemistry and Chemical
b
c
Engineering, Yangzhou University, Yangzhou 225002, People’s Republic of China
d
Yangzhou Polytechnology Institute, Yangzhou 225127, People’s Republic of China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Amino acid and primary amine/amide co-catalyzed acetone condensation was investigated. It
was found that L-proline had overwhelming catalytic activity over other amino acids as well as
the analogues with similar structures. Surprisingly, thiourea, a very cheap and stable chemical,
was found to be the favorable co-catalyst. Co-catalyzed by the recyclable L-proline and thiourea,
condensation of acetone led to the useful products mesityl oxide (MO), diacetone alcohol
Available online
(DAA) and isophorone (IP) in the excellent 96.3% total selectivity.
Keywords:
2
009 Elsevier Ltd. All rights reserved
.
Organocatalysis
Acetone condensation
L-Proline
Thiourea
Green synthesis
1
.
Introduction
Acetone is a bulk chemical that is generated as a by-product in
the process of cumene oxidative cracking to produce phenol.
Currently, 0.62 t of acetone is generated when producing 1 t of
Yet, organocatalysis is an interesting research subject with
both academic value and industrial application potential.
7
Organocatalysts avoid the transition metal residual in product and
thus are especially welcome in pharmaceutical intermediate
production. Amino acids are a kind of cheap, abundant and
practical organocatalysts that have been comprehensively
1
phenol. Because of the extremely higher demand of phenol than
acetone, this material is largely excess in market. Thus,
developing technologies that consume acetone to produce high-
value products is desirable. Among reported applications,
acetone condensation is a simple but very useful organic reaction
that leads to a mixture of mesityl oxide (MO), diacetone alcohol
8
employed in many organic reactions. However, because amino
acids are abundant natural chiral compounds, they are always
employed as cheap chiral catalysts or ligands in asymmetric
synthesis while the applications to produce bulky chemicals are
(
DAA) and isophorone (IP). All of the above products can be
9
separated by rectification in large-scale production and are useful
chemicals: MO is an important intermediate in organic synthesis,
pharmaceutical chemistry, agricultural chemistry, polymer and
usually ignored. During our continuous investigations on green
1
0-11
techniques,
we pay much attention to amino acid-catalyzed
11
green transformations with industrial potential. In 2015, we
2
3
have reported the L-proline and piperazine co-catalyzed
materials science and even in natural product syntheses; DAA
is widely employed to prepare preservative, anti-freeze agent,
1
1a
condensation of acetone to produce MO, DAA and IP. The
solvent-free reactions led to MO, DAA and IP in 81.1% total
4
extractant et. al.; IP is a good high boiling point solvent for
5
12
lacquer and coating materials. Although acetone condensation is
selectivity, while 38.3% of acetone was converted. The catalyst
an atom-economic process that generates no waste by itself, the
present technologies require strong alkaline conditions, high
catalyst loading and harsh reaction conditions that generate
L-proline could by recycled in 71.1% yield, but the co-catalyst
piperazine, as a liquid dissolved in acetone, was not recoverable
Table 1, entry 1). Using polymer resin-supported catalyst
poly(N-isopropylacrylamide-co-L-proline-co-piperidine) (PNLD)
enhanced the catalyst recovery ratio to 85.3%, but led to
decreased acetone conversion ratio (24.1%) and total product
selectivity (78.7%, Teble 1, entry 2). Inorganic bases, such as
(
6
harmful and corrosive wastes. Thus, developing more eco-
friendly catalyst system for the reaction is of good application
value.
2 3 2
NaOAc, Na CO , NaOH or Ca(OH) , afforded elevated acetone
—
——
∗
∗
Corresponding author. Tel.: +86-514-87979061; fax: +86-514-87975244; e-mail: yulei@yzu.edu.cn
Corresponding author. Tel.: +86-25-8359462; Fax: +86-25-83317761; e-mail: ynfan@nju.edu.cn

ACCEPTED MANUSCRIPT
2
Tetrahedron
conversion, but were not recoverable and led to very poor total
4
L-histidine 2d
L-arginine 2e
7.59
3.8
<1
product selectivity, which was an even more important
consideration factor from industrial point view (Table 1, entry 3).
Recently, we tried to further improve the methodology by wide
screenings of amino acids and amines/amides as catalysts and co-
catalysts. It was found that L-proline had overwhelming catalytic
activity over other amino acids as well as the analogues with
similar structures. Surprisingly, thiourea, the very cheap and
stable chemical, was unexpectedly found to be the favorable co-
catalyst that obviously enhanced the total product selectivity to
5
10.76
a
5
g of acetone (86.21 mmol) and 4.35 mmol of amino acid were heated in a
o
sealed tube at 90 C for 4 h.
b
Acetone conversion detected by GC.
Relationships of catalyst structures with the reaction were then
investigated by using a series of amino acids with typical
chemical structures (Table 3). 5-Aminopentanoic acid 2f and 2-
aminopentanoic acid 2g, the reductive ring-open product of L-
proline 2c, resulted in the largely decreased acetone conversions
9
6.3%. In the reaction, both L-proline and thiourea could be
(
Table 3, entries 2-3 vs 1). Piperidine-2-carboxylic acid 2h, also
recycled in very high yields (Table 1, entry 4). Herein, we wish
to report our findings.
an otho-substituted cyclic amino acid but with its ring size larger
than L-proline 2c, had almost no catalytic effect for the reaction
Table 1
(
Table 3, entry 4). Although pyrrolidine-3-carboxylic acid 2i was
Comparison of the methodologies
also a cyclic amino acid with same ring size to 2c, different
substitution position of carboxyl acid obviously reduced its
catalytic activity for the reaction (Table 3, entry 5). Finally a
reaction using D-proline 2j as catalyst was tested and led to
26.8% acetone conversion, showing that chiral configuration of
the catalyst did not affect the reaction (Table 3, entry 6).
a
b
c
Entry
1
Catalyst (mol %)
C (%)
8.3
S (%)
81.1
R (%)
Ref
11a
Table 3
d
L-proline (5),
piperazine (2.3)
PNLD
71.1,
0
Acetone condensation catalyzed by molecules similar to L-
3
e
a
proline
2
3
24.1
56.8
78.7
85.3
11a
11a
L-proline (5),
Inorg. bases (2.3)
0
f
60.5
96.3
b
Entry
1
Catalyst 2
Chemical structure
C (%)
27.1
4
L-proline (5),
thiourea (2.3)
d
9
9
5.7,
6.3
3
6.6
This work
g
a
2c (L-proline)
Highest acetone conversion.
b
c
d
e
f
Highest total selectivity of MO, DAA and IP.
Highest catalyst recovery ratio.
Recovery ratio of L-proline.
2
3
2f
7.0
<1
Recovery ratio of piperazine.
NaOAc, Na
2
3 2
CO , NaOH or Ca(OH) was employed.
g
Recovery ratio of thiourea.
2g
2
.
Results and discussion
4
5
2h
2i
<1
5.3
Initially, we chose several typical amino acids with different
13
isoelectric points as catalyst. After heating acetone with 5
o
mol % of amino acids at 90 C for 4 h, the reaction mixtures were
sent to GC analysis and the results were listed in Table 2. It was
found that L-proline 2c was the only preferable catalyst for the
reaction, resulting in 27.1% acetone conversion (Table 2, entry 3).
Other amino acids, such as L-glusate 2a, L-cysteine 2b, L-
histidine 2d and L-arginine 2e, only led to traces of acetone
conversion (Table 2, entries 1-2, 4-5). It was notable that L-
cysteine 2b and L-histidine 2d that had lower or higher
isoelectric point than L-proline 2c both resulted in very poor
acetone conversions (Table 2, entries 2, 4). These results
suggested that the acid-base property of the amino acid was not a
key factor for the reaction.
6
2j (D-proline)
26.8
a
5
g of acetone (86.21 mmol) and 4.35 mmol of amino acid were heated in a
o
sealed tube at 90 C for 4 h.
b
Acetone conversion detected by GC.
As shown by the above results, it was suggested that chemical
structure of the catalyst was the key factor of the reaction. In
organocatalysis processes, the reactions of organocatalysts with
substrates first generated activated intermediates. In the catalysis
processes of acetone condensation, acetone 1 first condensed
with amine group of catalyst to generate the intermediate 6 (eqn.
Table 2
a
Amino acids-catalyzed acetone condensation
1
1a, 14a
1
),
which combined with another molecular of acetone to
14b-c
generate 7.
Compared with chain-amino acids 2f and 2g, the
structure of L-proline 2c facilitated the formation of
intramolecular C-H bond that stablized the intermediate 7 (Figure
b
Entry
Catalyst 2
L-glusate 2a
L-cysteine 2b
L-proline 2c
Isoelectric point C (%)
1). The cyclic piperidine-2-carboxylic acid 2h might also
1
2
3
3.22
5.05
6.30
<1
<1
condense with acetone, and generated the the intermediate 8. But
different from the five membered ring that was in envelope
configuration, the six-membered ring of 2h exsisted as boat
conformation and in intermediate 8, the distances of N to H (3.65
27.1

ACCEPTED MANUSCRIPT
3
Å) was much further than that in 7 (1.88 Å), as calculated by
computational calculation. Thus, failing to generate the
intermediate stabilized by H bond led to the low acetone
conversion of the reaction catalyzed by 2h (Table 3, entry 4).
Positions of carboxyl acid were also a key factor for the reaction.
As shown in Figure 1, in intermediate 9 generated from
pyrrolidine-3-carboxylic acid 2i, the distances of reaction sites as
well as the N to H were too far to take further reaction and thus
led to obviously reduced acetone conversion (Table 3, entry 5).
2
3
4
5
6
7
8
PhNH
c-C
4-FC
3-FC
2-FC
2
10a
28.5
26.4
28.4
28.6
27.5
31.0
28.2
70.7
70.1
72.6
73.2
77.9
70.5
70.8
8.0
8.5
8.5
7.6
7.7
11.4
7.1
2.3
2.1
3.7
2.2
2.6
3.1
1.6
81.0
6
H
11NH
2
10b
10c
10d
10e
80.7
84.8
83.0
88.2
85.0
79.5
6
H
4
NH
2
2
6
H
4
NH
NH
NH
4-MeOC
,4,5-(MeO)
6
H
4
2
C
6
F
5
2
10f
6
H
4
NH
2
10g
NH
3
3
C
6
H
2
2
9
29.0
70.7
8.5
3.8
83.0
1
0h
PhNHNH
PhC(O)NH
PhC(S)NH
TsNH
C(O)NH
C(S)NH
1
0
1
2
3
4
5
2
10i
30.1
29.5
33.8
30.0
30.6
35.8
73.3
74.3
78.1
75.1
77.7
78.6
10.2
8.3
0.1
4.5
2.9
1.8
3.0
3.2
83.6
87.1
91.6
81.3
87.4
96.3
1
1
1
1
1
2
10j
2
10k
10.6
4.4
2
10l
NH
2
2
10m
10n
6.7
NH
2
2
14.5
a
5
g of acetone (86.21 mmol), 4.35 mmol of L-proline 2c (5 mol %) and 1.98
o
mmol of co-catalyst 10 (2.3 mol %) were heated in a sealed tube at 90 C for
4
h.
b
Acetone conversion detected by GC.
Based on the above experimental results as well as references,
Figure 1 Chemical structure of the intermediates 7, 8 and 9
calculated with density functional theory (DFT) at B3LYP/6-31G(d)
level.
a plausible mechanism was suggested. As shown in Table 4, the
thioamides were superior co-catalysts over amides (Table 4,
entries 12 vs 11, 15 vs 14), probably due to the fact that
thioamides were able to rearrange into the highly nucleophilic -
L-proline 2c was lowly soluble in acetone as well as other
solvents. Thus, the reaction could not be optimized by increasing
L-proline dosage. As primary amines might also react with
acetone to generate the acvivate intermediate, we then tried to
15
SH intermediates (eqn. 1). In catalysis circle, condensation of
acetone with L-proline 2c initially gave the intermediate 6 (eqn.
14
1
). Similarly, co-catalyst thiourea 10n reacted with another
optimize the reaction by adding them as co-catalysts. PhNH
2
10a
15
molecule of acetone to generate the intermediate 11 (eqn. 2).
and c-C 10b, as typical examples for both aromatic and
6 2
H11NH
Reaction of 6 with 11 afforded the hydrogen bond-stablized ionic
aliphatic amines, were first tested, but were found to be
ineffective since both of the acetone conversion and the total
selectivity were not obviously improved (Table 4, entries 2-3 vs
11a, 16
pair 12 (eqn. 3),
which released the co-catalyst 10n to give
the intermediate 13 (eqn. 3). Hydration of 13 led to the
intramolecular hydrogen bond-stablized intermediate 14, which
released the catalyst 2c and generated the product DAA 4 (eqn.
). Dehydration of 4 provided MO 3, which reacted with another
molecule of acetone to give IP 5 (eqn. 4).
1
). Introducing electron-withdrawing groups on aryl ring, 4-
FC NH 10c, 3-FC NH 10d, 2-FC NH 10e and
NH 10f slightly improved the total selectivities of the
6
H
5
4
2
6
H
4
2
6
H
4
2
4
C
6
F
2
reaction, but such optimizations were not worth the high cost of
fluoro compounds (Table 4, entries 4-7 vs 1). Electron-enriched
amines showed no obvious optimizations on both acetone
conversion and total selectivity of the products (Table 4, entries
8
2
-9 vs 1). PhNHNH 10i slightly improved both of the acetone
conversion and product selectivity (Table 4, entry 10, vs 1).
Amides and thioamides were also employed as co-catalyst for the
reaction. PhC(O)NH
reaction selectivity and its thio-analogue PhC(S)NH
resulted in a obvious increasing of the total product selectivity
Table 4, entries 11-12 vs 1). TsNH 10l did not show any total
selectivity improvement for the reaction (Table 4, entries 13 vs 1).
Urea 10m and thiourea 10n were also tested (Table 4, entries 14-
2
10j led to a mediate enhancement of the
2
10k
O
O
H
(
2
O
H N
HO
O
-10n
(3)
6
+ 11
NH2
N
N
S
OH
1
5) and it was notable that the cheap and abundant thiourea 10n
led to impressive improvements on both acetone conversion and
total product selectivity of the reaction (Table 4, entry 15 vs 1).
12
13
Table 4
Co-catalyst screenings
a
Selectivity (%)
C (%)
Entry
1
Co-catalyst 10
b
MO DAA
72.2 7.3
IP
Total
81.7
Moreover, catalyst recycle & reuse tests were performed using
a reaction magnified to 3 mol acetone scale. The experimental
results were given in Table 5. After each reaction, the catalyst L-
-
27.1
2.2

ACCEPTED MANUSCRIPT
4
Tetrahedron
proline 2c and co-catalyst thiourea 10n could be recycled in
4.3 Procedures for catalyst recycle & reuse test
more than 90% yield (Table 5, entries 1-4). After a supplement of
the lost catalyst and co-catalyst, the recycled 2c and 10n were
employed in next turn of reactions, giving acetone conversion in
1
74 g of acetone (3 mol), 17.26 g of L-proline 2c (0.15 mol, 5
mol %) and 5.33 g of thiourea 10n (0.07 mol, 2.3 mol %) were
heated in a sealed autoclave at 90 C for 4 h and then cooled to
room temperature by cold water. The precipitated catalyst & co-
catalyst 2c and 10n were isolated from the reaction liquid by
o
3
4.5-36.6% yield while the total selectivity of the products
mantained above 95%.
o
Table 5
Catalyst recycle & reuse test
filtration. Evaporation of the filtrate (0.3 kpa, 120 C) afforded
a
another part of recycled 2c and 10n as the residue and the liquid
product mixture as the fraction. The product mixture was sent to
GC analysis. The recycled 2c and 10n mixtures was combined
and sent to next turn of reaction after a supplement of the lost
weight (Contents of 2c and 10n were determined by
spectrophotography and chem-titrimetry analysis respectively, as
given in ESI).
Selectivity (%)
Recycle
NO.
R1
(%)
R2
(%)
C
(%)
Entry
b
b
b
MO DAA
IP
Total
95.4
96.3
96.1
96.1
c
1
2
3
0
95.0
95.7
93.9
94.7
95.2
91.9
96.3
93.9
36.6
34.7
36.2
34.5
77.9
79.9
79.2
80.1
13.1
12.7
13.6
12.9
4.1
3.7
3.3
3.1
Acknowledgements
1
2
3
This work was financially supported by NNSFC (21202141),
Priority Academic Program Development (PAPD) of Jiangsu
Higher Education Institutions, the Key Science & Technology
Specific Projects of Yangzhou (YZ20122029), the Innovation
Foundation of Yangzhou University (2015CXJ009), and the
High-Level Talent Foundation of Yangzhou University. We
thank the analysis centre of Yangzhou University for assistances.
4
a
1
74 g of acetone (3 mol), 17.26 g of L-proline 2c (0.15 mol, 5 mol %) and
5
.33 g of thiourea 10n (0.07 mol, 2.3 mol %) were heated in a sealed
o
autoclave at 90 C for 4 h.
b
R1 = recovery ratio of L-proline 2c; R2 = recovery ratio of thiourea 10n; C
=
Acetone conversion. Detailed analysis procedures of these parameters were
given in ESI.
First use.
Supplementary data
c
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016
3
.
Conclusions
In conclusion, we investigated amino acid and primary
amine/amide co-catalyzed condensation of acetone to
produce the industrially important products MO, DAA and IP.
It was found that L-proline had overwhelmingly superior
catalytic activity over other amino acids, regardless of their
isoelectric points and chemical structures. The phenomenon was
suggested to be ascribed to the unique chemical structure of L-
proline, which allowed the generation of the moderately stable
intermediate that facilitated the reaction. A series of primary
amines/amides were screened as co-catalysts and it was found
that the cheap and abundant material thiourea were good co-
catalyst, leading to the excellent 96.3% total product selectivity.
In the reaction, more than 90% of the catalyst and co-catalyst
could be recycled and reused in next turn of reaction without
deactivation. More investigations on organocatalysis are ongoing
in our laboratory.
References and notes
1. Bai, W.-B.; Yu, X.-H.; Ding, W.; Xing, R.-T.; Liu, Y. Chem. Ent.
Manag. 2013, 3, 84.
2
.
(a) Wang, H.-J.; Pan, B.-W.; Zhang, W.-H.; Yang, C.; Liu, X.-L.; Zhao,
Z.; Feng, T.-T.; Zhou, Y.; Yuan, W.-C. Tetrahedron 2015, 71, 8131. (b)
Hall, J. F. B.; Bourne, R. A.; Han, X.; Earley, J. H.; Poliakoff, M.;
George, M. W. Green Chem. 2013, 15, 177. (c) Pulis, A. P.; Aggarwal,
V. K. J. Am. Chem. Soc. 2012, 134, 7570. (d) Russo, A. T.; Amezcua,
K. L.; Huynh, V. A.; Rousslang, Z. M.; Cordes, D. B. Tetrahedron Lett.
2
011, 52, 6823.
3
4
.
.
Sharma, M. K.; Banwell, M. G.; Willis, A. C.; Rae, A. D. Chem. Asian
J. 2012, 7, 676.
For selected recent patents, please see: (a) Liu, J.-M.; Feng, Y.-T.; Li,
Y.-L.; Liu, Y.-P. Chinese Pat. 104,946,116, 2015 [Chem. Abstr.
2015,163, 537640]. (b) Qin, S.; He, S. Chinese Pat. 104,987,615, 2015
[Chem. Abstr. 2015,163, 618428]. (c) Huang, J.-W. Chinese Pat.
1
04,963,222, 2015 [Chem. Abstr. 2015,163, 586684].
5
6
.
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Gan, X.-P.; Wang, Y.; Ge, X.-P.; Li, W.; Zhang, X.-Z.; Zhu, W.-J.;
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Abstr. 2016,164, 225520]; (b) Nan, J.; Yu, H.-B.; Zhang, J.-C.; Zhang,
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X.-M. Chinese Pat. 104,355,975, 2015 [Chem. Abstr. 2015, 162,
4
.
Experimental Section
4
.1 General Method
GC analysis of the reactions was performed by using a Shimadzu
GC-2014 instrument. The detailed conditions were given in ESI.
The acetone conversions and product selectivities were obtained
through internal standard curves. The L-proline contents were
determined by spectrophotography analysis. The thiourea
contents were determined by chem-titrimetry analysis. Details of
the above methods were given in ESI. Computational calculation
employed density functional theory (DFT) at B3LYP/6-31G(d)
3
52865]; (c) Nan, J.; Yu, H.-B.; Zhang, J.-C.; Zhang, Y.-T.; Geng, S.;
Qu, X.-L.; Zhu, J.-J.; Xiao, H.; Liu, Y.; Jiang, X.-D.; Zhang, X.-M.
Chinese Pat. 104,355,976, 2015 [Chem. Abstr. 2015,162, 352866]; (d)
Ji, Z.-Q.; Wu, W.-J.; Wei, S.-P.; Shi, B.-J. Chinese Pat. 101,768,175,
2
010 [Chem. Abstr. 2010,153, 248965]; (e) Patel, H. A.; Sharma, S. K.;
Jasra, R. V. J. Mol. Catal. A: Chem. 2008, 286, 31. (f) Salvapati, G. S.;
Ramanamurty, K. V.; Janardanarao, M. J. Mol. Catal. 1989, 54, 9.
For selected articles, please see: (a) Gatzenmeier, T.; van Gemmeren,
M.; Xie, Y.-W.; Höfler, D.; Leutzsch, M.; List, B. Science 2016, 351,
1
7
level using Gaussian 09 programme.
7
8
.
.
4
.2 General procedure for acetone condensation
9
1
1
49. (b) Jungbauer, S. H.; Huber, S. M. J. Am. Chem. Soc. 2015, 137,
2110. (c) James, T.; van Gemmeren, M.; List, B. Chem. Rev. 2015,
15, 9388.
To a 15 mL pressure tube, 5 g of acetone (86.21 mmol), 4.35
mmol of L-proline 2c (5 mol %) and 1.98 mmol of co-catalyst 10
(a) Karamthulla, S.; Pal, S.; Parvin, T.;Choudhury, L. H. RSC Adv.
(
2.3 mol %) were added. The tube was then sealed and heated at
2
014, 4, 15319. (b) Brahmachari, G.; Das, S. RSC Adv. 2014, 4, 7380.
o
9
0 C for 4 h. The mixture was cooled to room temperature and
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