A green one-pot synthesis of N-alkyl-2-(2-oxoazepan-1-yl)-2-arylacetamide derivatives via an Ugi four-center, three-component reaction in water

Article abstract of DOI:10.1016/j.tetlet.2012.10.075

This work describes a green and efficient one-pot synthesis of N-alkyl-2-(2-oxoazepan-1-yl)-2-arylacetamide derivatives via an Ugi four-center, three-component reaction of 6-aminohexanoic acid, aromatic aldehydes, and isocyanide derivatives in water under

Full text of DOI:10.1016/j.tetlet.2012.10.075

Tetrahedron Letters 53 (2012) 7088–7092
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A green one-pot synthesis of N-alkyl-2-(2-oxoazepan-1-yl)-2-arylacetamide
derivatives via an Ugi four-center, three-component reaction in water
Mohammad Ali Rasouli a, Mohammad Mahdavi b, Parviz Rashidi Ranjbar a, Mina Saeedi b, Abbas Shafiee b,
Alireza Foroumadi b,c,
⇑
a School of Chemistry, University College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran
b Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medicinal Sciences, Tehran, Iran
c Drug Design & Development Research Center, Tehran University of Medicinal Sciences, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2012
Revised 29 September 2012
Accepted 18 October 2012
Available online 24 October 2012
This work describes a green and efficient one-pot synthesis of N-alkyl-2-(2-oxoazepan-1-yl)-2-arylaceta-
mide derivatives via an Ugi four-center, three-component reaction of 6-aminohexanoic acid, aromatic
aldehydes, and isocyanide derivatives in water under reflux conditions in the absence of a catalyst.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
N-Alkyl-2-(2-oxoazepan-1-yl)-2-
arylacetamides
Multicomponent reactions (MCRs)
Heterocycles
Azepan-2-ones
Practical application of multicomponent reactions (MCRs) in
modern organic synthesis has been proved repeatedly. They have
become efficient and important tools in the synthesis of cyclic
and acyclic compounds due to their atom economy, simple proce-
dures, straightforward reaction design, facile execution, and con-
vergence.1 The Ugi four-component coupling2 is one of the most
common examples of MCRs. A literature survey revealed that a
wide range of heterocycles3 has been prepared, and many success-
ful drug discoveries have been accomplished4 through Ugi reac-
tions. Several modifications of the classic Ugi reaction have been
described, which usually involve variation of one of the compo-
nents, or the introduction of a linkage between two of them. A use-
ful variation of the Ugi reaction involves the use of amino acids as
reactants incorporating both the carboxylic acid and amine func-
tionality (Schemes 1 and 2).5
We focused our attention on N-alkyl-2-(2-oxoazepan-1-yl)-2-
arylacetamides as these compounds possess an azepan-2-one (cap-
rolactam) scaffold, which represents a bioactive moiety in many
drugs.8 A detailed study by Fox et al. described the synthesis of
3-(acylamino)azepan-2-one derivatives as stable broad-spectrum
chemokine inhibitors resistant to metabolism in vivo (Fig. 1).9 Also,
Warshawsky et al. reported that the azepan-2-ones are valuable as
inhibitors of matrix metalloproteinase.10
O
COOH
NH2
MeOH
O
+
ArCHO + R N C
N
R
N
H
Various reports on the synthesis of cyclic amides (lactams)5,6
using the Ugi reaction encouraged us, in connection with our ongo-
ing research interest in the development of new and efficient
methods for the preparation of novel heterocycles, especially bio-
active molecules,7 to investigate a practical protocol for the prepa-
ration of novel N-alkyl-2-(2-oxoazepan-1-yl)-2-arylacetamide
derivatives 9 (Scheme 3).
Ar
1
2
3
4
Scheme 1. Synthesis of alicyclic b-lactams 4 via the reaction of b-amino acids 1,
aromatic aldehydes 2, and isocyanides 3.5a
O
H
N
H
H
N
n
O
⇑
Corresponding author. Tel.: +98 21 66954708; fax: +98 21 66461178.
E-mail address: aforoumadi@yahoo.com (A. Foroumadi).
Figure 1. 3-(Acylamino)azepan-2-one derivatives as chemokine inhibitors.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.075

M. A. Rasouli et al. / Tetrahedron Letters 53 (2012) 7088–7092
7089
COOH
NH2
MeOOC
H
CONHR
MeOOC
H
CONHR
MeOH
TiCl4
+
ArCHO +
+
R
N
C
H
Ar
H
COOMe
Ar
H
COOMe
N
H
N
H
COOMe
5
2
3
6
7
Scheme 2. Titanium catalysis in the Ugi reaction of glutamate (an
a
-amino acid) (5), aromatic aldehydes 2, and isocyanides 3.5b
R
HN
Ar
H2O, reflux
18-24 h
O
ArCHO
+
+
R
HO2C
NH2
N
C
O
N
8
2
3
9
Scheme 3. Ugi three-component reaction of 6-aminohexanoic acid (8), aromatic aldehydes 2, and isocyanides 3.
Table 1
Synthesis of N-alkyl-2-(2-oxoazepan-1-yl)-2-arylacetamide derivatives 914
Entry
Aldehyde 2
Isocyanide 3
Product 9
Time (h)
Yielda (%)
CHO
N
C
C
C
C
C
HN
1
9a
9b
9c
9d
9e
20
80
77
87
92
O
O
N
CHO
N
N
N
N
MeO
HN
2
3
4
5
19
19
18
19
O
OMe
CHO
O
N
F
HN
O
F
O
N
CHO
O2N
HN
O
NO2
O
N
CHO
Cl
HN
75
O
Cl
O
N
(continued on next page)

7090
M. A. Rasouli et al. / Tetrahedron Letters 53 (2012) 7088–7092
Table 1 (continued)
Entry
Aldehyde 2
Isocyanide 3
Product 9
Time (h)
Yielda (%)
CHO
N
C
C
C
C
Me
HN
6
7
8
9f
21
77
O
Me
O
N
CHO
Cl
N
N
N
Cl
HN
9g
22
74
O
O
O
N
CHO
NO2
HN
NO2
9h
22
82
O
N
CHO
CHO
Me
HN
Me
9
9i
9j
48
22
10b
O
O
N
Me
N
N
C
C
HN
10
62
O
Me
O
N
CHO
OMe
O
HN
11
12
13
9k
22
24
20
69
73
82
MeO
OMe
MeO
O
N
CHO
F
N
N
C
C
HN
O
F
9l
O
N
CHO
NO2
O2N
HN
9m
O
O
N
a
Isolated yields.
Yield refers to chromatographic analysis.
b
Herein, we describe the reaction of 6-aminohexanoic acid (8),
aromatic aldehydes 2, and isocyanides 3 (Scheme 3), as a suitable
procedure for replacing traditional synthetic methods toward aze-
pan-2-ones.11
To optimize the conditions for the preparation of N-alkyl-2-(2-
oxoazepan-1-yl)-2-arylacetamide derivatives 9, we began our
studies by investigating the reaction of 6-aminohexanoic acid (8),
p-methoxybenzaldehyde, and cyclohexyl isocyanide (Table 1, entry

M. A. Rasouli et al. / Tetrahedron Letters 53 (2012) 7088–7092
7091
O
+ H+
Ar
Ar
-H2O
Ar
H +
H2N
CO2H
C N R
N
CO2H
N
CO2
R
H
2
8
3
10
HN
Ar
HN
Ar
RN
Ar
N R
O
NR
O
Mumm
O
O
O
O
O
N
Ar
O
N
HN
9
12
11
Scheme 4. A possible mechanism for the synthesis of N-alkyl-2-(2-oxoazepan-1-yl)-2-arylacetamides 9.
2) in different organic solvents and water. It should be noted that
when the model reaction was run in polar protic solvents such as
methanol, ethanol, and water, similar results were obtained with
respect to the yield and reaction time. As regards the use of aque-
ous media in multicomponent reactions,12 we selected water as a
green medium for the above mentioned reaction to produce N-
cyclohexyl-2-(4-methoxyphenyl)-2-(2-oxoazepan-1-yl) acetamide
(9b). Water as the solvent has been used in isocyanide-based mul-
ticomponent reactions and is recommended not only due to envi-
ronmentally issues, but it also has other advantages including
simple product isolation and safety.5c,13
We found that when the reaction was carried out at ambient
temperature, no product was obtained and heating at reflux was
required. Also our investigations revealed that using stoichiometric
amounts of starting materials gave a moderate yield of 9b (50%);
increasing the amount of cyclohexyl isocyanide led to 1.2 mmol
to the formation of product 9b in a much better yield of 77%.
In order to show the generality and scope of this novel protocol,
we used various aromatic aldehydes and isocyanides in the reac-
tion in Scheme 3 under the optimized conditions. The results are
summarized in Table 1.
A mechanistic rationalization for this reaction is provided in
Scheme 4. On the basis of the well-established chemistry of isocy-
anides,2 the first step involves condensation of 6-aminohexanoic
acid (8) with the aromatic aldehyde 2 leading to the formation of
imine intermediate 10. This is followed by nucleophilic attack of
the isocyanide 3 on the imine, which is facilitated by protonation
of imine by the carboxylic acid to form the nitrilium carboxylate
intermediate 11. Next the nitrilium carbon might be attacked by
the carboxylate to form cyclic intermediate 12, which is converted
into product 9 via a Mumm rearrangement.
In conclusion, we have demonstrated that the Ugi four-center,
three-component reaction of 6-aminohexanoic acid, aromatic alde-
hydes, and isocyanides in water represents a direct access to N-al-
kyl-2-(2-oxoazepan-1-yl)-2-arylacetamide
derivatives.
The
present strategy may find value in synthesis, because it is opera-
tionally simple and green, the yields of the products are good,
and the starting materials are readily available. Also the protocol
does not need complex or expensive catalysis.
Acknowledgement
All the reactions reached completion within 18–24 h to afford
good yields of products which were characterized by mass spec-
trometry fragmentation pattern analysis, and 1H and 13C NMR
spectroscopy.14 For example, the peak at m/z: 358 for compound
9b represents the molecular ion (calculated mass for
This research was supported by grants from the research coun-
cil of Tehran University of Medical Sciences and the Iran National
Science Foundation (INSF).
Supplementary data
C
21H30N2O3). The 1H NMR spectrum of 9b consisted of multiplet
signals for the cyclohexyl and 2-azepanone rings (18H, 2.29–
1.14 ppm), an N-CH resonance (1H, 3.52 ppm) and an N-CH2 signal
(2H, 3.52 ppm). The proton associated with the methine group
(CH), gave a singlet at 5.92 ppm. The signals due to the four aro-
matic protons were observed around 7.11–6.90 ppm which were
observed as two doublets; 7.11 (d, J = 7.0 Hz, 2 H) and 6.90 (d,
J = 7.0 Hz, 2 H). Finally, the signal at 7.86 ppm was due to C6H11
NH group. The 13C NMR spectrum of 9b showed 19 distinct reso-
nances in agreement with the proposed structure. Characteristic
carbonyl carbon resonances were observed at 172.8 and
168.6 ppm. As expected, four signals were apparent in the aromatic
region due to symmetry, and the remaining 13 signals were ob-
served in the aliphatic region.
As can be seen in Table 1, electronic effects of substituents at-
tached to the aromatic aldehyde did not influence the reaction out-
come. In contrast, steric effects were more significant in the case of
an ortho-substituted benzaldehyde and the rate of reaction de-
creased dramatically. When the reaction of 6-aminohexanoic acid,
2-methylbenzaldehyde, and cyclohexyl isocyanide was conducted
under the optimized conditions, the corresponding product was
obtained in poor yield (10%) after 2 days. As expected, in the case
of 2,6-dimethylbenzaldehyde, no product was observed.
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/j.tet-
let.2012.10.075. These data include MOL files and InChiKeys of
the most important compounds described in this article.
References and notes
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aromatic aldehyde 2 (1 mmol), and isocyanide 3 (1.1 mmol) in H2O or
methanol (10 mL) was heated at reflux for 18–24 h. After completion of the
reaction, according to Table 1, the mixture was cooled to room temperature
and left to stand overnight. The precipitated product was filtered off and dried.
All the products were analytically pure without the need for recrystallization.
N-Cyclohexyl-2-(4-methoxyphenyl)-2-(2-oxoazepan-1-yl) acetamide (9b):
Yield: 77%, white solid. Mp 287 °C; IR (KBr): 3267, 3086, 2925, 2849, 1651,
1638, 1563, 1514, 1443 cmÀ1 1H NMR (DMSO-d6, 500 MHz): dH = 7.86 (s, 1H,
;
NH), 7.11 (d, J = 7.0 Hz, 2H, ArH), 6.90 (d, J = 7.0 Hz, 2H, ArH), 5.92 (s, 1H, CH),
3.74 (s, 3H, OMe), 3.52 (m, 1H, NCH, cyclohexyl), 3.19 (m, 2H, NCH2, 2-
azepanone), 2.29–1.14 (m, 18H, cyclohexyl and 2-azepanone); 13C NMR
(DMSO-d6, 125 MHz,): dC = 172.8, 168.6, 158.8, 130.1, 128.7, 113.8, 59.2, 55.1,
47.7, 44.4, 32.4, 32.2, 32.0, 26.5, 25.2, 24.7, 24.6, 24.5, 23.1; MS m/z (%) = 358
(M+, 5), 278 (5), 239 (10), 165 (10), 57 (60); Anal. Calcd for C21H30N2O3: C,
70.36; H, 8.44; N, 7.81; Found: C, 70.15; H, 8.66; N, 7.95.