The Ugi reaction in a polyethylene glycol medium: A mild, protocol for

Article abstract of DOI:10.3184/174751911X13128244394427

A mild, efficient, and eco-friendly method for the Ugi reaction between a carboxylic acid, an amine, a carbonyl compound and an isocyanide to give a bisamide is described using PEG-H₂O as a solvent. Reactants of poor watersolubility could be us

Full text of DOI:10.3184/174751911X13128244394427

444 RESEARCH PAPER
AUGUST, 444–447
JOURNAL OF CHEMICAL RESEARCH 2011
The Ugi reaction in a polyethylene glycol medium: a mild, protocol for
the production of compound libraries
Teng-fei Niu, Guo-ping Lu and Chun Cai*
School of Chemical Engineering, Nanjing University of Science &Technology, Nanjing 210094, P. R. China
A mild, efficient, and eco-friendly method for the Ugi reaction between a carboxylic acid, an amine, a carbonyl
compound and an isocyanide to give a bisamide is described using PEG–H2O as a solvent. Reactants of poor water-
solubility could be used in an aqueous medium without significant decrease in the yield. No side products were
observed. The advantages of this protocol are short reaction time and easy isolation of the precipitated product when
compared to reactions carried out in methanol.
Keywords: green chemistry, multicomponent reaction, Ugi reaction, PEG–H2O medium, isocyanides, poor water-solubility
reactants
In modern organic chemistry, environmental friendly chemical
synthesis is gaining considerable interest in both academic and
industrial research. Multicomponent reactions1,2 (MCRs) are
used in “green chemistry”. Since their atom economy, facile
execution and high efficiency allow a wide range of compo-
nents to be subjected to one pot reactions making it possible to
prepare numerous products within a few steps. One of the most
commonly used MCRs is the Ugi four-component reaction, in
which a carboxylic acid, an amine, a carbonyl compound, and
an isocyanide are reacted to form amide derivatives.3,4 Recently,
the Ugi reaction has been developed to generate natural prod-
ucts and drugs in high yields and high diastereoselectivities.5–9
Recent examples include pyrazinones,10 β-turn mimics,11
carfentanil,12 remifentanil,12 and the anti-schistosomal drug
praziquantel (PZQ).13
“Green chemistry” involves a reduction in pollutants such as
organic solvents whose recovery is regulated by evermore
strict laws. In order to fulfill this, it is better to use water as
solvent, which can be advantageous as a medium for reaction
and workup relative to flammable, volatile, or toxic organic
solvents.14 Moreover, the recognition of biomolecules by
receptors usually takes place in water at room temperature
Fig. 1 Some natural products and drugs synthesised through
the Ugi reaction.
under close to neutral pH. Water as a solvent has been wildly
accepted for organic transformation.15–18 However, most Ugi
reactions have been performed in organic solvents such as
MeOH, CH2Cl2.
Since the discovery by Pirrung and coworkers19 that multi-
component reactions can be accelerated in aqueous medium
compared to organic solvents, some Ugi reactions have been
performed in water. For example, Kanizsai et al.,20,22 Pirrung
et al.21 and Szakonyi et al.23 have reported that β-lactam deriv-
atives were synthesised successfully in aqueous medium with
high yields and high diastereoselectivities as compared with
that in MeOH. Abbas et al. reported that an acetal was used in
an Ugi-MCR to furnish selenocysteine peptides in one step as
model compounds for selenocysteine peptides and proteins.24
An Ugi-Smiles type reaction has also been performed in water
instead of methanol or toluene by Kaïm and coworkers.25 How-
ever, water has not enjoyed extensive use in the Ugi reaction,
due to the poor solubility of the reactants which reduce the
yield. For example, β-amino acid needed to be completely dis-
solved in water,20,22 but in some examples a concentration of
only 0.1M could be achieved.19,26 Raising the reaction tempera-
ture can be effective. Recently, Kaïm et al. reported an Ugi-
Smiles coupling reaction in water at 90°C, while methanol
required 40°C.25 Thus it was urgent to develop a mild method-
ology which could increase the solubility of the reactants
in water efficiently. Herein, we describe an efficient, mild
and high concentration method for the Ugi reaction using
PEG–H2O as solvent.
Results and discussion
To improve the poor solubility of reactants in water and avoid
possible side reactions, we focused our research on finding a
“green” medium which can disperse organic molecules in
water efficiently. Some surfactants and phase transfer catalysts
have been tested by a prototype Ugi reaction of aniline,
benzaldehyde, phenylformic acid and ethyl isocyanoacetate
(Table 1). The starting materials were selected using one crite-
rion: poor solubility in water. We found that the reaction was
completed within 3h in pure water and a medium yield was
obtained (Table 1, entry 1). However, the starting materials
were found to adhere to the vessel. The reactants were not
dispersed in water efficiently if no additives were added. How-
ever, phase transfer catalysts, such as TEBA (benzyl trimethyl-
ammonium chloride) and TBAB (tetra-n-butylammonium
bromide), did not efficiently increase the water solubility of
reactants, and only a slight increase in the yield was observed
(Table 1, entries 2, 4). SDS (sodium dodecylsulfate) worked
better than TBAB and TEBA, but was still undesirable (Table
1, entry 6). Adding more PTC did not work, either (Table 1,
entries 3, 5, 7). Mironov et al. found surfactants such as cetyl-
pyridinium chloride and bovine serum albumin could increase
* Correspondent. E-mail: c.cai@mail.njust.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2011 445
Table 1 Selected Ugi reactions under various reaction
Table 3 Selected Ugi reaction in different organic solventsa
conditionsa
Entry
Solvent
Time/h
Yield/%
1
2
3
4
5
MeOH
EtOH
MeCN
CH2Cl2
THF
8
8
12
12
12
76
72
63
58
56
a Reaction condition: 1, 3mmol; 2, 3mmol; 3, 3mmol; 4,
3 mmol, solvent 3 mL, rt. Reactions were detected by TLC.
with that in PEG–H2O (1:3) medium, the selected Ugi reaction
was studied under various conditions summarised in Table 3.
This reaction gave the highest yield in methanol in a reason-
able reaction time (Table 3, entry 1). The result can be compared
with the 74% yield obtained by using PEG–H2O (1:3) for 3
hours (Table 2, entry 6). Other solvents such as MeCN, CH2Cl2
resulted in mild yield and long reaction time (Table 3, entries
2, 3, 4, and 5). Obviously the PEG–H2O (1:3) medium can
accelerate the reaction efficiently without significant decrease
of the yield. This might be attributed to the hydrophobic effect
and enhanced hydrogen bonding.20
Entry
Solvent
Time/h
Yield/%
1
2
Pure water
3
46
TBAB-H2O (0.1M)
TBAB-H2O (0.2M)
TEBA-H2O (0.1M)
TEBA-H2O (0.2M)
SDS-H2O (0.1M)
SDS-H2O (0.2M)
PEG–H2O (1:1)
TX10-H2O (1:9)
TX10-H2O (1:4)
4
48
3
4
48
4
4
51
5
4
50
6
4
57
7
4
59b
73b
68b
65b
8
4
9
4.5
6
10
a Reaction condition: 1, 3mmol; 2, 3mmol; 3, 3mmol; 4, 3mmol,
solvent 3mL, mechanical stirring, rt.
With the optimal conditions in hand, we examined a series
of reactions in PEG–H2O and MeOH (Table 4). We found that
the reactions were finished when the precipitates did not
increase and the solution became clear. With the exceptions of
products 5b, 5f, 5h, and 5k, the other compounds precipitated
from the PEG–H2O medium and were isolated by filtration.
The results revealed that the reaction proceeded successfully
in PEG–H2O and provided about a 3-fold acceleration over
MeOH. In PEG–H2O, most of the yields were similar to those
in MeOH. However, in some cases the results decreased
significantly, such as (Table 4, entries 8, 11). HPLC test showed
that the precipitated products contained some starting reactants.
We attributed the incomplete reaction to the high reaction rates
which produced short reaction times. Starting materials were
inevitably co-precipitated when the products precipitated from
the PEG–H2O medium in the short reaction times, which
reduced the yield. The precipitation depends greatly on the
solubility and concentration of the starting materials (Table 4,
entries 8, 11). In dilute solutions, the reactants did not pre-
cipitate, and the yields were similar to those in MeOH.20
In conclusion, we report an efficient, mild and eco-friendly
method for the Ugi reaction in PEG–H2O medium. In this pro-
tocol, reactants with a poor water solubility could be utilized in
an aqueous medium in high concentration and no side products
were found. The unique solvating properties of PEG–H2OH
medium has a stimulating effect on the Ugi reaction with
respect to the high yield and the short reaction time. The
precipitation process was efficient and most of the products
were easily isolated by simple filtration.
b Reaction condition: 1, 3mmol; 2, 3mmol; 3, 3mmol; 4, 3mmol,
solvent 3mL, magnetic stirring, rt.
the water solubility of reactants, but a long reaction time was
needed.27 The yield was significantly increased in PEG–H2O
(Table 1, entry 8). No side reactions have been found. It is
important to notice that PEG is also non-toxic, cheap and eco-
friendly, fulfilling the principles of “green chemistry”.28–32
We optimised the volume ratio of PEG and water; the results
are summarised in Table 2. Obviously, the amount of water
played a key role in the reaction. No product was obtained in
pure PEG (Table 2, entry 1). The reaction proceeded slowly to
afford a medium yield when 25% water was utilised after 24 h
(Table 2, entry 2). By increasing the H2O/PEG ratio, a higher
yield was obtained and the product precipitated from the
solvent when the reaction was complete (Table 2, entry 4).
However, long reaction times were needed when the ratio came
to 1:5 (Table 2, entry 8). This is easily explained by a decrease
in the dispersal of the reactants. In dilute PEG–H2O solution,
the organic molecules were not dispersed efficiently and reac-
tants associated together, causing a long reaction time. When
the volume ratio of PEG and water came to 1:9 (Table 2, entry
9), the starting materials soon associated and adhered to the
vessel, as in pure water (Table 1, entry 1). It is found that 25%
ratio of PEG and water (Table 2, entry 6) was the best choice.
The product was insoluble in PEG–H2O medium which
facilitated its isolation.
It is well known that the Ugi reactions are often performed
in organic solvents like MeOH, MeCN, THF et al. To compare
Experimental
Melting points were determined uncorrected. Analytical TLC was
performed on glass plates precoated with silica gel impregnated with
a fluorescent indicator (254 nm). The plates were visualised by expo-
sure to UV light. 1H NMR spectra were recorded on Bruker DRX500
(500 MHz) and 13C NMR spectra on Bruker DRX500 (125 MHz)
spectrometer. Mass spectra were taken on a Finnigan TSQ Quantum–
MS instrument in the electrospray ionisation (ESI) mode. Elemental
analyses were performed on a Vario EL III recorder. PEG 400 was
purchased from the petrochemical plant of Jiangsu Haian. All other
chemicals (AR grade) were commercially available and used without
further purification.
Table 2 Influence of volume ratio of PEG and watera
Entry
Solvent
Time/h
Yield/%
1
2
3
4
5
6
7
8
9
Pure PEG
24
24
24
4
0
37b
58b
73
74
74
72
73
51
PEG–H2O (3:1)
PEG–H2O (2:1)
PEG–H2O (1:1)
PEG–H2O (1:2)
PEG–H2O (1:3)
PEG–H2O (1:4)
PEG–H2O (1:5)
PEG–H2O (1:9)
4
3
5
12
3
General procedure
A suspension of the amine (3 mmol) and aldehyde (3 mmol) in 3 mL
PEG–H2O was stirred at room temperature for 30–45 minutes. Isoni-
trile (3 mmol) and acid (3 mmol) were then added to the reaction
a Reaction condition: 1, 3mmol; 2, 3mmol; 3, 3mmol; 4, 3mmol,
solvent 3mL, rt. b no precipitate was found.

446 JOURNAL OF CHEMICAL RESEARCH 2011
Table 4 Ugi reaction in MeOH and PEG–H2Oa
Entry
R1
R2
R3
R4
Product
Method Aa
Yield/%c
Method Bb
Yield/%c
t/h
t/h
12
1
2
4-NO2
4-Br
H
H
H
H
CH2CO2Et
CH2CO2Et
5b
5c
48
3
37
87
41
84
1
3
4
5
6
4-Me
2-Me
H
H
H
H
H
H
CH2CO2Et
CH2CO2Et
CH2CO2Et
CH2CO2Et
5d
5e
5f
4
8
77
70
42
74
1.5
3
75
72
40
73
H
4-NO2
4-Cl
24
4
12
H
5g
1
7
8
H
H
4-MeO
H
H
CH2CO2Et
CH2CO2Et
5h
5i
24
50
75
6
51
4-NO2
1.5
0.5
64/73d/78e
9
H
H
H
H
4-Cl
CH2CO2Et
CH2CO2Et
5j
4
8
86
34
1
3
83
36
10
4-Me
5k
11
12
H
H
H
H
H
H
Cy
5l
1
2
91
85
0.5
1
77/85d/88e
PhCH2
5m
80
b
a Reaction condition: 1a, 3mmol; 2a, 3mmol; 3a, 3mmol; 4a, 3mmol; MeOH 3mL; rt. Reactions were detected by TLC. Reaction
condition: 1a, 3mmol; 2a, 3mmol; 3a, 3mmol; 4a, 3mmol; PEG–H2O 3mL, rt. c Isolated yield. d For another 3 hours reaction at 60°C. e
0.1M of reactants.
mixture and stirring was continued for 0.5–12 hours. For solids, the
products were isolated by filtration and purified by column chroma-
tography with n-hexane/EtOAc (v:v=2:1). For oily products, 2 mL of
dichloromethane was added to the reaction mixtures. The aqueous
layer was separated, and concentrated under reduced pressure to
give the crude products and purified by column chromatography with
n-hexane/EtOAc (v:v=2:1) to afford the desired product .
4.24–4.20 (q, J = 7.0 Hz, 2H, CH2), 4.14–4.11 (q, J = 5.0 Hz, 2H, CH2
of Et), 1.30–1.27 (t, J = 7.0 Hz, 3H, , CH3 of Et); 13C NMR (125 MHz,
CDCl3) δ 171.2 (C=O), 169.6 (C=O), 169.6 (C=O), 140.1, 135.6,
133.9, 132.0, 131.6, 130.4, 129.8, 128.9, 128.7, 128.5, 127.8 and
121.2 (C aromatic), 65.8 (CH), 61.5 (CH2 of Et), 41.7 (CH2), 14.1
(CH3 of Et); ESI-MS: m/z = 496 [M+1]+.Anal. Calcd for C25H23BrN2O4:
C, 60.62; H, 4.68; N, 5.66; O, 12.92 . Found: C, 60.59; H, 4.65;
N, 5.68; O, 12.91%.
[2-(Benzoyl-phenyl-amino)-2-phenyl-acetylamino]-acetic
acid
1
ethyl ester (5a): White solid, 74% yield, M.p. 146–148°C; H NMR
(500 MHz, CDCl3) δ 7.36–7.33 (m, 4H, aromatic), 7.29–7.28 (m, 3H,
aromatic), 7.20 (t, J = 7.5 Hz, 1H, aromatic), 7.15 (t, J = 7.5 Hz, 2H,
aromatic), 7.03 (t, J = 2.5 Hz,, 5H, aromatic), 6.56 (s, 1H, CH), 6.26
(m, 1H, NH), 4.25–4.20 (q, J = 7.0 Hz, 2H, CH2), 4.15 (d, J = 5.0 Hz,
2H, CH2 of Et), 1.35 (t, J = 7.0 Hz, 3H, CH3 of Et); 13C NMR (125
MHz, CDCl3) δ 171.3 (C=O), 169.7 (C=O), 169.6 (C=O), 141.3,
135.8, 134.3, 130.1, 129.6, 128.6, 128.5, 127.6 and 127.2 (C aro-
matic), 66.8 (CH), 61.5 (CH2 of Et), 41.7 (CH2), 14.1 (CH3 of Et);
ESI-MS: m/z = 417 [M+1]+. Anal. Calcd for C25H24N2O4: C, 72.10;
H, 5.81; N, 6.73; O, 15.37. Found: C, 72.12; H, 5.80; N, 6.77; O,
15.33%.
[2-(Benzoyl-p-tolyl-amino)-2-phenyl-acetylamino]-acetic acid ethyl
1
ester (5d): White solid, 75% yield, M.p. 142-145°C; H NMR (500
MHz, CDCl3) δ 7.36–7.33 (m, 2H, aromatic), 7.29 (t, J = 2.5 Hz, 3H,
aromatic), 7.23–7.20 (m, 1H, aromatic), 7.16–7.13 (q, J = 7.5 Hz, 2H,
aromatic), 6.89–6.83 (q, J = 8.0 Hz, 4H, aromatic), 6.60 (t, J = 4.5 Hz,
1H, NH), 6.22 (s, 1H, CH), 4.24–4.20 (q, J = 7.0 Hz, 2H, CH2), 4.14–
4.13 (q, J = 2.5 Hz, CH2 of Et), 2.18 (s, 3H, CH3), 1.29 (t, J = 7.0 Hz,
3H, CH3 of Et); 13C NMR (125 MHz, CDCl3) δ 171.4 (C=O), 169.8
(C=O), 169.7 (C=O), 138.8, 137.0, 136.0, 134.4, 130.2, 129.7, 129.5,
129.2, 128.6, 128.5, 128.5 and 127.6 (C aromatic), 66.9 (CH), 61.5
(CH2 of Et), 41.7 (CH2), 20.9 (CH3), 14.1 (CH3 of Et); ESI-MS: m/z =
428 [M+1]+. Anal. Calcd for C26H26N2O4: C, 72.54; H, 6.09; N, 6.51;
O, 14.87. Found: C, 72.52; H, 6.08; N, 6.53; O, 14.88 %.
{2-[Benzoyl-(4-nitro-phenyl)-amino]-2-phenyl-acetylamino}-
acetic acid ethyl ester (5b):Yellow solid, yield 41%, M.p. 150–152°C;
1H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 8.5 Hz, 2H, aromatic),
7.33–7.28 (m, 2H, aromatic), 7.26–7.25 (m, 5H, aromatic), 7.20–7.20
(m, 1H, aromatic), 7.17–7.15 (m, 4H, aromatic), 6.49 (s, 1H, CH),
6.43 (t, J = 5.0 Hz, 1H, NH), 4.25–4.2 (q, J = 7.0 Hz, 2H, CH2),
4.17–4.10 (q, J = 5 Hz, 2H, CH2 of Et), 1.35 (t, J = 7.0 Hz, 3H, CH3 of
Et); 13C NMR (125 MHz, CDCl3) δ 171.0 (C=O), 169.5 (C=O), 147.0,
146.0, 135.1, 133.5, 131.1, 130.3, 130.3, 129.2, 128.9, 128.6, 128.1,
123.5 and 112.4 (C aromatic), 65.5 (CH), 61.6 (CH2 of Et), 41.7 (CH2),
14.1 (CH3 of Et); ESI-MS: m/z = 462 [M+1]+. Anal. Calcd for
C25H23N3O6: C, 65.07; H, 5.02; N, 9.11; O, 20.80. Found: C, 65.03;
H, 5.00; N, 9.09; O, 20.77%.
[2-(Benzoyl-o-tolyl-amino)-2-phenyl-acetylamino]-acetic acid ethyl
1
ester (5e): Yellow solid, 72% yield, M.p. 142–144°C; H NMR (500
MHz, CDCl3) δ 7.24–7.22 (m, 2H, aromatic), 7.20 (t, J = 7.5 Hz, 3H,
aromatic), 7.14 (t, J = 7.5 Hz, 2H, aromatic), 7.06–7.04 (m, 3H, aro-
matic), 7.00–6.99 (m, 2H, aromatic), 6.79 (d, J = 8.5 Hz, 2H, aroma-
tic), 6.51 (t, J = 5.0 Hz, 1H, NH), 6.25 (s, 1H, CH), 4.24–4.20 (q, J =
7.0 Hz, 2H, CH2), 4.14 (d, J = 5.5 Hz, 2H, CH2 of Et), 3.78 (s, 3H,
CH3), 1.29 (t, J = 7.5 Hz, 3H, CH3 of Et); 13C NMR (125 MHz, CDCl3)
δ 171.3 (C=O), 170.0 (C=O), 169.7 (C=O), 159.7, 141.2, 136.0, 131.7,
130.3, 129.5, 128.6, 128.5, 127.6, 127.2, 126.3 and 113.9 (C aroma-
tic), 65.8 (CH), 61.5 (CH2 of Et), 55.2 (CH3), 41.7 (CH2), 14.1 (CH3 of
Et); ESI-MS: m/z = 428 [M+1]+.Anal. Calcd for C26H26N2O4: C, 72.54;
H, 6.09; N, 6.51; O, 14.87. Found: C, 72.52; H, 6.08; N, 6.53; O,
14.88 %.
{2-[Benzoyl-(4-bromo-phenyl)-amino]-2-phenyl-acetylamino}-
acetic acid ethyl ester (5c): White solid, 84% yield, M.p. 166–168°C;
1H NMR (500 MHz, CDCl3) δ 7.33–7.28 (m, 7H, aromatic), 7.25 (t,
J = 7.5 Hz, 1H, aromatic), 7.19–7.14 (m, 4H, aromatic), 6.87 (d, J =
7.5 Hz, 2H, aromatic ), 6.43 (t, J = 5.0 Hz, 1H, NH), 6.34 (s, 1H, CH),
[2-(Benzoyl-phenyl-amino)-2-(4-nitro-phenyl)-acetylamino]-
acetic acid ethyl ester (5f):Yellow solid, 40% yield, M.p. 100–102°C;
1H NMR (500 MHz, CDCl3) δ 8.10 (d, J = 4.0 Hz, 2H, aromatic), 7.55

JOURNAL OF CHEMICAL RESEARCH 2011 447
(d, J = 8.5 Hz, 2H, aromatic), 7.35 (d, J = 7.5 Hz, 2H, aromatic),
7.28–7.23 (m, 1H, aromatic), 7.17 (t, J = 8 Hz, 2H, aromatic), 7.10–
7.09 (m, 4H, aromatic), 7.02 (s, 2H, aromatic, NH), 6.41 (s, 1H, CH),
4.26–4.22 (q, J = 7.0 Hz, 2H, CH2), 4,21–4.09 (m, 2H, CH2 of Et),
1.30 (t, J = 7 Hz, 3H, CH3 of Et); 13C NMR (125 MHz, CDCl3) δ 171.6
(C=O), 169.6 (C=O), 168.9 (C=O), 147.7, 141.5, 140.8, 135.1, 131.1,
129.7, 129.0, 128.6, 127.8 and 123.4 (C aromatic), 65.7 (CH), 61.7
(CH2 of Et), 41.6 (CH2), 14.2 (CH3 of Et); ESI-MS: m/z = 462 [M+1]+.
Anal. Calcd for C25H23N3O6: C, 65.07; H, 5.02; N, 9.11; O, 20.80.
Found: C, 65.00; H, 5.01; N, 9.08; O, 20.76%.
[2-(Benzoyl-phenyl-amino)-2-(4-chloro-phenyl)-acetylamino]-
acetic acid ethyl ester (5g):Yellow solid, 73% yield, M.p. 156–158°C;
1H NMR (500 MHz, CDCl3) δ 7.28 (d, J = 5 Hz, 2H, aromatic), 7.25–
7.20 (m, 5H, aromatic), 7.14 (t, J = 7.5 Hz, 2H, aromatic), 7.08 (t, J =
3.5 Hz, 3H, aromatic), 7.01 (t, J = 2.5 Hz, 2H, aromatic), 6.71 (t, J =
5.0 Hz, 1H, NH), 6.27 (s, 1H, CH), 4.25–4.21 (q, J = 7.0 Hz, 2H,
CH2), 4.15–4.13 (q, J = 3.0 Hz, 2H, CH2 of Et), 1.30 (t, J = 7.0 Hz, 3H,
CH3 of Et); 13C NMR (125 MHz, CDCl3) δ 171.4 (C=O), 169.7 (C=O),
169.5 (C=O), 141.0, 135.6, 134.6, 132.8, 131.7, 130.1, 129.7, 128.7,
128.7, 128.6, 127.7 and 127.5 (C aromatic), 65.6 (CH), 61.6 (CH2 of
Et), 41.6 (CH2), 14.2 (CH3 of Et); ESI-MS: m/z = 452 [M+1]+. Anal.
Calcd for C25H23ClN2O4: C, 66.59; H, 5.14; N, 6.21; O, 14.19. Found:
C, 66.56; H, 5.13; N, 6.20; O, 14.17 %.
[2-(Benzoyl-phenyl-amino)-2-(4-methoxy-phenyl)-acetylamino]-
acetic acid ethyl ester (5h):Yellow solid, 51% yield, M.p. 127–130°C;
1H NMR (500 MHz, CDCl3) δ 7.23 (d, J = 8.5 Hz, 2H, aromatic),
7.22–7.18 (m, 3H, aromatic), 7.14 (t, J = 7.5 Hz, 2H, aromatic), 7.05
(t, J = 3 Hz, 3H, aromatic), 6.99 (d, J = 2.5 Hz, 2H, aromatic), 6.79 (d,
J = 7.5 Hz, 2H, aromatic), 6.51 (t, J = 5.0 Hz, 1H, NH), 6.25 (s, 1H,
CH), 4.24–4.20 (q, J = 7.0 Hz, 2H, CH2), 4.14 (d, J = 5.5 Hz, 2H, CH2
of Et), 3.78 (s, 3H, OCH3), 1.29 (t, J = 7.0 Hz, 3H, CH3 of Et); 13C
NMR (125 MHz, CDCl3) δ 171.3 (C=O), 170.0 (C=O), 169.7 (C=O),
159.7, 141.2, 136.0, 131.7, 130.3, 129.5, 128.6, 128.5, 127.6, 127.2,
126.3 and 113.9 (C aromatic), 65.8 (CH), 61.5 (CH2 of Et), 55.2
(OCH3), 41.7 (CH2), 14.1 (CH3 of Et); ESI-MS: m/z = 444 [M+1]+.
Anal. Calcd for C26H26N2O5: C, 69.94; H, 5.87; N, 6.27; O, 17.92.
Found: C, 69.92; H, 5.85; N, 6.29; O, 17.91%.
128.6, 128.5, 128.3, 127.6 and 127.1 (C aromatic), 67.0 (CH), 61.5
(CH2 of Et), 41.7 (CH2), 21.3 (CH3), 14.1 (CH3 of Et); ESI-MS: m/z =
428 [M+1]+. Anal. Calcd for C26H26N2O4: C, 72.54; H, 6.09; N, 6.51;
O, 14.87. Found: C, 72.51; H, 6.07; N, 6.53; O, 14.85%.
N-(Cyclohexylcarbamoyl-phenyl-methyl)-N-phenyl-benzamide
1
(5l): White solid, 77% yield, M.p. 164–167°C; H NMR (500 MHz,
CDCl3) δ 7.32 (d, J = 9.5 Hz, 2H, aromatic), 7.29 (t, J = 3.5 Hz, 2H,
aromatic), 7.26 (d, J = 2.5 Hz, 3H, aromatic), 7.19 (d, J = 7.5 Hz, 1H,
aromatic), 7.13 (t, J = 7.5 Hz, 2H, aromatic), 7.02 (s, 5H, aromatic),
6.18 (s, 1H, CH), 5.85 (d, J = 7.5 Hz, 1H, NH), 3.91 (m, 1H, CH of
Cy), 1.99–1.90 (dd, J = 1.0 Hz, 2H, CH2 of Cy), 1.70–1.68 (m, 2H,
CH2 of Cy), 1.65–1.59 (m, 1H, CH2 of Cy), 1.40–1.35 (m, H, CH2 of
Cy), 1.23–1.11 (m, 3H, CH2 of Cy); 13C NMR (125 MHz, CDCl3) δ
171.37 (C=O), 168.6 (C=O), 141.4, 136.1, 134.9, 130.2, 130.1, 129.4,
128.5, 128.4, 127.6 and 127.1 (C aromatic), 66.9 (CH), 48.8 (CH of
Cy), 32.8, 25.5, 24.8, 24.7 (CH2 of Cy); ESI-MS: m/z = 413 [M+1]+.
Anal. Calcd for C27H28N2O2: C, 78.61; H, 6.84; N, 6.79; O, 7.76.
Found: C, 78.58; H, 6.82; N, 6.77; O, 7.78%.
N-(Benzylcarbamoyl-phenyl-methyl)-N-phenyl-benzamide (5m):
White solid, 80% yield, M.p. 172–175°C; 1H NMR (500 MHz, CDCl3)
δ 7.32–7.30 (m, 7H, aromatic), 7.28–7.22 (m, 5H, aromatic), 7.20 (d,
J = 7 Hz, 1H, aromatic), 7.14 (t, J = 7.5 Hz, 2H, aromatic), 7.10–7.03
(m, 5H, aromatic), 6.34 (s, 1H, NH), 6.21 (s, 1H, CH), 4.61–4.56 (q,
J = 6.0 Hz, 2H, CH2), 13C NMR (125 MHz, CDCl3) δ 171.3 (C=O),
169.6 (C=O), 141.4, 138.1, 136.0, 134.6, 130.2, 129.5, 128.6, 128.6,
128.6, 128.4, 127.6, 127.4 and 127.2 (C aromatic), 67.0 (CH), 43.8
(CH2); ESI-MS: m/z = 421 [M+1]+. Anal. Calcd for: C28H24N2O2:
C, 79.98; H, 5.75; N, 6.66; O, 7.61. Found: C, 79.96; H, 5.74; N, 6.63;
O, 7.58%.
Received 31 May 2011; accepted 14 July 2011
Paper 1100719 doi: 10.3184/174751911X13128244394427
Published online: 29 August 2011
References
{2-[(4-Nitro-benzoyl)-phenyl-amino]-2-phenyl-acetylamino}-
acetic acid ethyl ester (5i): Bronze solid, 64% yield, M.p. 167–180°C;
1H NMR (500 MHz, CDCl3) δ 8.00 (d, J = 8.5 Hz, 2H, aromatic), 7.49
(d, J = 8.5 Hz, 2H, aromatic), 7.29–7.26 (m ,5H, aromatic), 7.05–6.99
(q, J = 6 Hz, 5H, aromatic), 6.33 (t, J = 5.0 Hz, 1H, NH), 6.32 (s, 1H,
CH), 4.23–4.19 (q, J = 7.0 Hz, 2H, CH2), 4.18–4.13 (m, 2H, CH2 of
Et), 1.29 (t, J = 7.5 Hz, 3H, CH3 of Et); 13C NMR (125 MHz, CDCl3)
δ 169.5 (C=O), 169.3 (C=O), 169.2 (C=O), 147.8, 142.3, 139.9, 133.5,
130.5, 130.4, 130.1, 129.3, 129.0, 128.8, 128.7, 128.6, 128.5, 128.0,
127.6 and 122.9 (C aromatic), 66.2 (CH), 61.6 (CH2 of Et), 41.7 (CH2),
14.1 (CH3 of Et); ESI-MS: m/z = 462 [M+1]+. Anal. Calcd for
C25H23N3O6: C, 65.07; H, 5.02; N, 9.11; O, 20.80. Found: C, 65.05; H,
5.03; N, 9.09; O, 20.76%.
{2-[(4-Chloro-benzoyl)-phenyl-amino]-2-phenyl-acetylamino}-
acetic acid ethyl ester (5j): White solid, 83% yield, M.p. 142–145°C;
1H NMR (500 MHz, CDCl3) δ 7.34–7.29 (m, 4H, aromatic), 7.28–7.26
(m, 3H, aromatic), 7.14–7.11 (m, 2H, aromatic), 7.08–7.04 (m, 3, aro-
matic), 7.00 (s, 2H, aromatic), 6.46 (t, J = 5.0 Hz, 1H, NH), 6.25 (s,
1H, CH), 4.24–4.2 (q, J = 7.5 Hz, 2H, CH2), 4.14 (d, J = 5.5 Hz, 2H,
CH2 of Et), 1.29 (t, J = 7.5 Hz, 3H, CH3 of Et); 13C NMR (125 MHz,
CDCl3) δ 170.2 (C=O), 169.6 (C=O), 141.0, 135.7, 134.3, 134.1,
130.3, 130.2, 130.1, 128.7, 128.7, 128.6, 128.5, 127.9 and 127.5 (C
aromatic), 66.7 (CH), 61.5 (CH2 of Et), 41.7 (CH2), 14.1 (CH3 of Et);
ESI-MS: m/z = 452 [M+1]+. Anal. Calcd for C25H23ClN2O4: C, 66.59;
H, 5.14; N, 6.21; O, 14.19. Found: C, 66.58; H, 5.11; N, 6.19;
O, 14.17 %.
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acetic acid ethyl ester (5k):Yellow solid, 36% yield, M.p. 128–130°C;
1H NMR (500 MHz, CDCl3) δ 7.35–7.33 (q, J = 4 Hz, 2H, aromatic),
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