Synthesis of a new urea derivative: A dual-functional organocatalyst for Knoevenagel condensation in water

Article abstract of DOI:10.1016/j.tetlet.2013.07.116

A phenylalanine-urea compound-catalyzed Knoevenagel condensation in water is reported. Various aldehydes and active methylene compounds undergo condensation at room temperature to give the desired products in high yields. The mechanism of the condensation of aldehydes with Meldrum's acid catalyzed by the novel urea derivative is also disclosed.

Full text of DOI:10.1016/j.tetlet.2013.07.116

Tetrahedron Letters 54 (2013) 5370–5373
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of a new urea derivative: a dual-functional organocatalyst
for Knoevenagel condensation in water
⇑
⇑
Wen-Jun Le, Hong-Fei Lu , Jun-Tao Zhou, He-Long Cheng, Yu-Hua Gao
School of Biology and Chemical Engineering, Jiangsu University of Science and Technology, Zhenjiang 212003, Jiangsu, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A phenylalanine–urea compound-catalyzed Knoevenagel condensation in water is reported. Various
aldehydes and active methylene compounds undergo condensation at room temperature to give the
desired products in high yields. The mechanism of the condensation of aldehydes with Meldrum’s acid
catalyzed by the novel urea derivative is also disclosed.
Received 2 April 2013
Revised 13 July 2013
Accepted 22 July 2013
Available online 27 July 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Phenylalanine
Urea compound
Knoevenagel condensation
Aqueous
The Knoevenagel condensation1 is a common and powerful
method for carbon–carbon bond formation in organic synthesis.
Various catalysts, such as Lewis acids,2 zeolites,3 ionic liquids,4
surfactants,5 and organocatalyst,6 have been employed to catalyze
this kind of reaction in recent decades. The List group reported the
first example of enantioselective Knoevenagel condensation using
proline-derived catalysts.7 This reaction has been studied exten-
sively, and a wide range of conditions have been reported to carry
out this seemingly simple transformation. The condensation was
also previously reported to be performed by urea8 under solvent-
free conditions at 100 °C.
OMe
O
O
OH
O
SOCl2, MeOH
1
2
NH3+Cl-
NH2
triphosgene
triethylamine
toluene
H
N
O
O
N
HN
OMe
NCO
O
2-aminopyridine
DCM
a
3
In the 1980s, Breslow showed that the use of water as an envi-
ronmentally benign solvent can significantly enhance the rate of
some organic reactions due to the hydrophobic effects.9 The
Knoevenagel condensation has been carried out in water at 75 °C
in the absence of catalyst.10 However, reversible dehydration con-
densation in water is a difficult transformation in principle, be-
cause the large excess of water pushes the equilibrium in favor
of the hydrated compounds.11 To date, catalytic Knoevenagel con-
densation in water under neutral conditions has been only re-
ported by Fujita and co-workers12 as their work called the use of
palladium, a precious metal. Therefore, much effort still needs to
be made to develop efficient catalyst with cheap or commercially
available reagents, which will definitely extend the application
scope of Knoevenagel–Doebner reaction in organic synthesis.13
Scheme 1. Synthesis of compound 3a.
Urea/thiourea derivatives as organocatalysts have proven to be
effective for the nucleophilic addition reactions of imines, alde-
hydes, and electron-deficient olefins.14 They have been success-
fully applied to asymmetric organocatalysis, such as asymmetric
Strecker reactions,15 Michael reactions,16 Mannich reactions,17
and Henry reactions.18 However, urea derivatives based on phenyl-
alanine scaffold as organocatalysts for the condensation have not
been reported. At the very onset, we have prepared an ester-
protection of amino acid (1) and the isocyanate group (2)
(Scheme 1) via successively modifying the two functional groups
of L-phenylalanine, to synthesize a urea derivative based on amino
acid scaffolds. Finally we obtained a new compound: (R)-methyl
3-phenyl-2-(3-(pyridin-2-yl)ureido)propanoate (3a) (Scheme 1),
which was recrystallized from ethanol to afford white crystals suit-
able for X-ray crystallography analysis. The crystal structure is
shown in Figure 1.
⇑
Corresponding authors.
E-mail addresses: zjluhf1979@hotmail.com (H.-F. Lu), gaoyuhua1964@163.com
(Y.-H. Gao).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.116

W.-J. Le et al. / Tetrahedron Letters 54 (2013) 5370–5373
5371
H
H
N
N
O
O
O
O
NH
HN
N
HN
N
O
O
O
O
HN
O
3b
3c
3d
Figure 2. The structures of compounds 3b–d.
Table 2
3a-Catalyzed Knoevenagel condensation of aldehydes 4 with Meldrum’s acid 5a
O
O
3a
(10 mol%)
H2O, rt
O
O
+
CHO
R
R
O
O
O
Figure 1. The crystal structure of compound 3a.
O
4
5a
6
Yieldb (%)
79
Table 1
Entry
1
Aldehydes (4)
Product
Time (h)
6
Comparison of catalysts for the synthesis of 6a in water at room temperaturea
CHO
O
6a
O
O
catalyst
H2O, rt
O
+
CHO
CHO
O
O
O
O
2
6b
6
81
NO2
4a
5a
6a
CHO
Entry
Catalyst
Product
Time (h)
Yieldd (%)
3
4
5
6
7
6c
6da
6e
6f
6
6
4
6
4
75
80
94
83
93
1
2
3
4
5
6
7
8
None
F
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
24
24
24
24
12
12
12
12
12
12
24
24
—
4
Cl
CHO
N
17
19
83
36
82
83
74
76
—
F and Nb
3a
OH
3b
3c
CHO
3d
H3CO
9
3ac
10
11
12
3dc
BiCl3
FeCl3
CHO
—
Cl
a
Reaction conditions: aldehyde 4a (0.50 mmol), Meldrum’s acid 5a (0.50 mmol),
and catalyst (10 mol %) in H2O (5.0 mL) at room temperature.
An equimolar mixture of the phenylalanine (F) and 2-aminopyridine (N) is
added to the reaction.
Reaction conditions: aldehyde 4a (0.50 mmol), Meldrum’s acid 5a (0.50 mmol),
and catalyst (10 mol %) in THF (5.0 mL) at room temperature.
CHO
CHO
H3CO
6g
b
H3CO
H3CO
c
d
Isolated yield of the pure compound.
8
6h
4
90
HO
OCH3
In the event we found that compound 3a effectively promotes
the Knoevenagel reaction of benzaldehyde (4a) with Meldrum’s
acid (5a) to furnish product 6a in good yield (Table 1), by carrying
out the reaction in water at room temperature. However, as re-
ported by Snyder early in 1961,19 the condensation was accompa-
nied with competing Michael addition of 5a to form bis-Meldrum’s
acid adducts. For example, when the reaction is run in water at
75 °C, a mixture of products in a 7:93 ratio was observed with
bis-Meldrum’s acid adducts as the major product (Scheme 2).20
9
CHO
6i
6j
6
4
87
88
O
10
CHO
CHO
11
6k
8
83
a
Aldehyde 4d with 5a under the above conditions results in concurrent dehy-
dration-cyclization providing coumarin-3-carboxylic acid as the final product.
b
Isolated yield of the pure compound.
To identify the best catalyst, the reaction of benzaldehyde (4a)
with Meldrum’s acid (5a) was chosen as the model reaction. We
designed and synthesized other three urea derivatives (Fig. 2)
according to the above process and investigate their catalytic prop-
erties in the Knoevenagel reaction. Meanwhile, we have obtained
crystals 3c (Fig. 2) which was suitable for X-ray crystallography
analysis (see the crystal structure of 3c in the Supplementary data).
We also investigated phenylalanine (F), 2-aminopyridine (N), and
O
O
O
O
O
O
O
O
O
O
no catalyst
H2O, 75 oC, 2 h
+
:
O
O
CHO
+
O
O
O
O
Ph
93
Ph
4a
5a
Yield (%):
7
Scheme 2. A competition between Knoevenagel condensation and Michael
addition.

5372
W.-J. Le et al. / Tetrahedron Letters 54 (2013) 5370–5373
Table 3
3a-catalyzed Doebner–Knoevenagel condensation of aldehydes 4 with Malonic acid 5ba
3a
(10 mol%)
CHO
COOH
COOH
O
O
organic base
+
+
COOH
HO
OH
H2O, rt
R
R
R
5b
8
4
7
Entry
R (4)
Product
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
H
4-Cl
2-Cl
4-CH3
4-OCH3
7a
7b
7c
7d
7e
7f
12
6
12
6
6
6
91
89
84
92
94
95
91
3,4-(OCH3)2
3,5-(OCH3)2, 4-OH
7g
6
a
Reaction conditions: aldehyde 4 (0.50 mmol), Malonic acid 5b (0.60 mmol), pyridine (1 mmol) and 3a (10 mol %) in H2O (5.0 mL) at room temperature.
Isolated yield of the pure compound.
b
H
Table 4
O
The effects of catalysts on the reaction of 2-phenyl propanal and diethyl malonatea
H
N
Ar
O
catalyst
TEA 2 eqv.
O
CHO
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
+
+
N
N
Ph
Ph
Ph
H20 : EtOH (1:1)
r.t
H
O
Ar
CHO
Ph
A
Entry
catalyst
Time (h)
Yieldb (%)
erc
O
O
(i)
4
1
2
3a
3c
72
72
82
81
21.26:78.74
37.43:62.57
O
O
(ii)
N
H
N
O
a
5a
Reaction conditions: 2-phenyl propanal (0.1 mmol), diethyl malonate
(0.15 mmol), catalyst (20 mol %), TEA (0.2 mmol), water (1.0 mL), EtOH (1.0 mL).
O
O
HN
O
b
N
Yield of isolated product.
Determined by HPLC analysis on a chiral stationary phase.
O
Ph
c
O
Ph
3a
N
H
N
yields under the same conditions in prolonged reaction time (entry
11). Aromatic aldehydes bearing electron-donating substituents
gave the desired products in high yields, while those aromatic ald-
edydes carrying electron-withdrawing group gave the products
with moderate yields in prolonged time. It should be pointed out
that electron-rich aromatic aldehydes are more reactive than the
electron-deficient aldehydes at room temperature (entries 5, 7
and 8) as noted by Dumas et al.20
(iii)
H
O
O
O
Ar
H
Ar
O
O
H
O
B
O
6
O
O
Scheme 3. Proposed mechanism for the catalytic Knoevenagel condensation by 3a.
In addition, aromatic aldehydes with malonic acid also con-
densed smoothly under the same conditions. Notably, in contrast
to the previous work,21 we mainly obtained 2-benzylidene-malon-
ic acids (8), but not decarboxylation products (7) under the above
conditions (Table 3). However, at elevated temperature22 or in the
presence of an organic base23 interestingly, the product distribu-
tion between decarboxylation products 7 and 2-benzylidene-
malonic acids 8 was obviously changed. As shown in Table 3, the
reaction gave decarboxylation product 7 with significant yield
when 2 equiv of pyridine was added into the reaction system.
The results showed that ortho substituent substrates needed longer
reaction time to achieve high yield compared to para substituent
substrates (entries 2 and 3). The aromatic aldehyde carrying elec-
tron-donating substituents similarly gave excellent yields under
the same conditions in Doebner–Knoevenagel condensation.
Therefore, it indicated that electron-donating substituents in the
aromatic ring can accelerate the reaction.
The mechanism of these reactions is not clear at present. How-
ever, a proposed mechanism for the catalytic Knoevenagel conden-
sation of aldehyde 4 with 5a catalyzed by compound 3a is shown
in Scheme 3. The urea component of this catalyst would operate
via activation of the aldehyde through direct hydrogen bonding24
or through a water based network, while the pyridine unit serves
as an internal organic base which would deprotonate Meldrum’s
acid nucleophile. This would place the deprotonated acid in close
an equimolar mixture of F and N as catalysts in the model reaction.
The results are summarized in Table 1.
As shown in Table 1, in the absence of catalyst, the reaction did
not give any product even after 24 h (entry 1), and the yields de-
clined dramatically when the dual-functional catalyst 3a was re-
placed by other catalysts (entries 2–4). Furthermore, we applied
the corresponding phenyl version of 3a and applied it (3b, Fig. 2)
to the Knoevenagel reaction. But in this case the yield was de-
creased to 36% (entry 6). The strategy was also applicable to ala-
nine (entry 7). Another set of experiments was designed by using
the substituted pyridyl group in 3a as a catalyst (3d, Fig. 2) to study
the electronic effect. The catalysis with 3d afforded the desired
product in good yield (83%, entry 8). Reaction conducted in THF
gave the products in slightly decreased yields (entries 9 and 10).
Some Lewis acids such as BiCl3 and FeCl3 were also tested under
these conditions, but no condensation products were observed by
TLC (entries 11 and 12).
To demonstrate the utility and functional group compatibility of
catalyst 3a, different aldehydes with Meldrum’s acid were exam-
ined under the same conditions (Table 2). As shown in Table 2,
both aromatic aldehydes and aliphatic aldehydes were suitable
for the reactions with an easy isolation of the desired products in
satisfactory yields. Nevertheless, aliphatic aldehydes gave good

W.-J. Le et al. / Tetrahedron Letters 54 (2013) 5370–5373
5373
10. Bigi, F.; Carloni, S.; Ferrari, L.; Maggi, R.; Mazzacani, A.; Sartori, G. Tetrahedron
Lett. 2001, 42, 5203.
11. Li, C. J.; Chen, L. Chem. Soc. Rev. 2006, 35, 68.
12. Murase, T.; Nishijima, Y.; Fujita, M. J. Am. Chem. Soc. 2012, 134, 162.
13. (a) Han, J. J.; Xu, Y. F.; Su, Y. P.; She, X. G.; Pan, X. F. Catal. Commun. 2008, 9,
2077; (b) Jaggi, L.; Sushil, K. G.; Dau, D. A. Catal. Commun. 2012, 27, 38.
14. (a) Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2000, 39,
1279; (b) Wang, C. J.; Dong, X. Q.; Zhang, Z. H.; Xue, Z. Y.; Teng, H. L. J. Am.
Chem. Soc. 2008, 130, 8606.
15. (a) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901; (b) Vachal,
P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012.
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Hoashi, Y.; Yabuta, T.; Takemoto, Y. Tetrahedron Lett. 2004, 45, 9185.
17. (a) Tillman, A. L.; Ye, J. X.; Dixon, D. J. Chem. Commun. 2006, 1191; (b) Song, J.;
Shih, H. W.; Deng, L. Org. Lett. 2007, 9, 603.
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1643; (b) Jiang, X. X.; Zhang, Y. F.; Wu, L. P.; Zhang, G.; Liu, X.; Zhang, H. L.; Fu,
D.; Wang, R. Adv. Synth. Catal. 2009, 351, 2096.
19. Hedge, J. A.; Kruse, C. W.; Snyder, H. R. J. Org. Chem. 1961, 26, 3166.
20. Dumas, A. M.; Seed, A.; Zorzitto, A. K.; Fillion, E. Tetrahedron Lett. 2007, 48,
7072.
proximity to the aldehyde which would explain why no large ex-
cess of 1,3-dicarbonyl compounds is required for this reaction to
proceed in good yield. Additionally, the pyridine unit of this cata-
lyst is not capable of the decarboxylation due to steric effect.
And Meldrum’s acid 5a, which is water-soluble, exists in equilib-
rium with its enolate form because of its low pKa value (4.83).12
The enolate of 5a may also attack directly the activated aldehyde.
Recently, the reaction has been further explored using 2-phenyl
propanal and diethyl malonate as model substrates in the catalytic
asymmetric Knoevenagel condensation.7b The dual-functional cat-
alysts 3a and 3c were selected as representatives and the results
are summarized in Table 4. By comparing the enantio ratio of the
products (entries 1 and 2), we suppose that the phenyl group in
the catalyst is helpful to improve the enantioselectivity through
the interaction with reaction substrates, and 3a has proved to be
the more promising catalyst, which was therefore chosen for our
further studies.
21. Berrué, F.; Antoniotti, S.; Thomas, O. P.; Amade, P. Eur. J. Org. Chem. 2007, 1743.
22. Raytchev, P. D.; Roussi, L.; Dutasta, J. P.; Martinez, A.; Dufaud, V. Catal. Commun.
2012, 28, 1.
23. Kemme, S. T.; Šmejkal, T.; Breit, B. Adv. Synth. Catal. 2008, 350, 989.
24. Gioia, C.; Hauville, A.; Bernardi, L.; Fini, F.; Ricci, A. Angew. Chem., Int. Ed. 2008,
47, 9236.
In summary, a simple method for the synthesis of novel urea
compounds based on amino acid scaffolds has been developed.26
We have successfully demonstrated a urea compound 3a-catalyzed
dehydration condensation in aqueous medium.27 Compound 3a is
an efficient organocatalyst for the C–C bond formation in water be-
tween aldehydes and active methylene at room temperature.
25. Yang, P. Y.; Wang, M.; He, C. Y.; Yao, S. Q. Chem. Commun. 2012, 835.
26. A typical procedure for synthesis of 3a: Drop-wise SOCl2 (1.6 mL, 22 mmol) was
added to a cooled (0 °C) suspension of L-phenylalanine (3.3 g, 20 mmol) in dry
MeOH (30 mL) about 30 min. The clear solution was stirred in an ice-bath for
30 min. Then the mixture was still stirred for 12 h at room temperature and
subsequently heated to 50 °C and reacted for 2 h, and the solvent was
evaporated under reduced pressure. The residue was dried in vacuum to give 1
as a white solid.25 This material was pure enough to be used in the next step
without further purification. To a cooled suspension of 1 (2.157 g, 10 mmol)
and triethylamine (1.5 mL, 11 mmol) in dry toluene (20 mL) at 0 °C was added
drop-wise a solution of triphosgene (1.48 g, 5 mmol) in 10 mL of dry toluene
over 30 min. The reaction mixture was stirred at 0 °C for 15 min and then
refluxed for 3 h. Upon cooling to room temperature, vacuum filtered, the
solvent was evaporated under reduced pressure to give the product 2 as
colorless oil. This material was also used in the next step without further
purification, assuming a quantitative yield. To a solution of 2-aminopyridine
(0.94 g, 10 mmol) in dry CH2Cl2 (10 mL) at room temperature was added drop-
wise a solution of 2 in 10 mL of dry CH2Cl2. The mixture was stirred for 12 h at
room temperature and the solvent was evaporated under reduced pressure to
give brown oil, which was subsequently diluted with 1% acetic acid solution
(20 mL) and extracted with ethyl acetate (3 Â 15 mL). The organic fractions
were washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4,
filtered and concentrated under reduced pressure. The crude product was
washed thoroughly with hexane, dried in vacuum and recrystallized from
ethanol which afforded a white crystalline product of 3a.
Acknowledgements
We would like to express our sincere appreciation to the anon-
ymous reviewers for their insightful comments, which have greatly
aided us in improving the quality of the paper. We are also grateful
to the support from Radiant Pharma & Tech Co., Ltd.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
07.116.
References and notes
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27. General procedure for the Knoevenagel condensation catalyzed by 3a: The catalyst
3a (10 mol %) and the aldehyde 4 (0.5 mmol) were suspended in water (5 mL),
and the solution was stirred at room temperature for 15 min. Then the active
methylene group 5 (5a, 0.5 mmol; 5b, 0.6 mmol) was added at the same
temperature. The reaction was monitored by TLC. After the completion of the
reaction, the reaction mixture was subsequently diluted with 1% HCl solution
(5 mL) and filtered. The residue was washed with water, dried in vacuum, and
the crude products obtained were purified by column chromatography or
recrystallized from ethanol to afford the pure product.
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