Solvent-free synthesis of arylamides and arylimides, analogues of acetylcholine

Article abstract of DOI:10.1081/SCC-200066665

Several arylamides and arylimides, novel inhibitors of acetylcholinesterase, were obtained under solventless conditions; the target molecules were produced with a good overall yield and short reaction times. 2017-2023 Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/SCC-200066665

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Solvent‐Free Synthesis of
Arylamides and Arylimides,
Analogues of Acetylcholine
J. Trujillo‐Ferrara a , José Correa‐Basurto a , Judith
Espinosa a , Jazmín García a , Francisco Martínez b &
René Miranda c
a Escuela Superior de Medicina, Instituto Politécnico
Nacional, Sección de Estudios del Posgrado e
investigación y Departamento de Bioquímica, Plan
de San Luis y Díaz Mirón , México
b Unidad Profesional Interdisciplinaria de
Biotecnología, Instituto Politécnico Nacional,
Departamento de Química , Barrio Ticomán, México
c Facultad de Estudios Superiores Cuautitlán,
Departamento de Química , Universidad Nacional
Autónoma de México , Col. Santa Maria de las
Torres, Cuautitlán Izcalli, México
Published online: 16 Aug 2006.
To cite this article: J. Trujillo‐Ferrara , José Correa‐Basurto , Judith Espinosa ,
Jazmín García , Francisco Martínez & René Miranda (2005) Solvent‐Free Synthesis of
Arylamides and Arylimides, Analogues of Acetylcholine, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 35:15,
2017-2023, DOI: 10.1081/SCC-200066665
To link to this article: http://dx.doi.org/10.1081/SCC-200066665

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Synthetic Communicationsw, 35: 2017–2023, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200066665
Solvent-Free Synthesis of Arylamides and
Arylimides, Analogues of Acetylcholine
´
J. Trujillo-Ferrara, Jose Correa-Basurto, Judith Espinosa,
´
´ ´
Escuela Superior de Medicina, Instituto Politecnico Nacional, Seccion de
´
and Jazmın Garcıa
´ ´
Estudios del Posgrado e investigacion y Departamento de Bioquımica,
´ ´ ´
Plan de San Luis y Dıaz Miron, Mexico
´
Francisco Martınez
Unidad Profesional Interdisciplinaria de Biotecnologıa,
´ ´
Instituto Politecnico Nacional, Departamento de Quımica,
´
´ ´
Barrio Ticoman, Mexico
´
Rene Miranda
´ ´
Facultad de Estudios Superiores Cuautitlan, Departamento de Quımica,
´ ´
Universidad Nacional Autonoma de Mexico, Col. Santa Maria de las
´ ´
Torres, Cuautitlan Izcalli, Mexico
Abstract: Several arylamides and arylimides, novel inhibitors of acetylcholinesterase,
were obtained under solventless conditions; the target molecules were produced with a
good overall yield and short reaction times.
Keywords: Solvent-free, anilines, imides, acetylcholinesterase, Alzheimer’s disease
INTRODUCTION
Several clinical trials have shown that acetylcholinesterase inhibitors
(ACHEIs) are promising drugs in the treatment of Alzheimer’s disease
Received in the USA September 11, 2004
Address correspondence to J. Trujillo-Ferrara, Escuela Superior de Medicina,
´ ´
Instituto Politecnico Nacional, Seccion de Estudios del Posgrado e investigacion y
´
´
´ ´ ´
Departamento de Bioquımica, Plan de San Luis y Dıaz Miron, Mexico, D.F. 11340,
´
Mexico. Tel/Fax: þ52 55 57296000 Ext. 62744; E-mail: jtrujillo@ipn.mx
2017

2018
J. Trujillo-Ferrara et al.
(AD).[1,2] Tacrine, galantamine, rivastigmine, and donepezil are some ACHEIs
currently used, but their clinical use is limited because of several undesirable
side effects, such as hepatotoxicity.[3–5] Therefore, the synthesis and study of
new compounds as ACHEIs is required[6] to improve their activity and reduce
adverse side effects.[7–9]
The chemistry of amides and imides has received great attention because
of the interesting pharmacological and industrial uses of this class of
molecules.[10,11] Among other methods,[12,13] these kinds of compounds can
be synthesized from the corresponding nitriles in various steps, using the
respective diamides by the action of SOCl2 in dioxane, or more generally from
the corresponding dicarboxilic acid.[14–16] However, many of these methods
require the employment of hazardous reagents and solvents.[17]
The classical method for obtaining amides is the pyrolysis of the salt of
the respective carboxylic acid in the presence of primary or secondary
amines, requiring around 1 h of heating at a high temperature; although it is
of preparative value, it is very tedious[18] as well as enviromentally toxic.
Therefore, in this study the maleic acid derivatives (1a–e, 2a–e) were
synthesized under simple eco-friendly (solventless) conditions. These
compounds were physically (mp) and spectroscopically identified by EIMS
1
and H and 13C NMR.
RESULTS AND DISCUSSION
Table 1 summarizes the results of the preparation of products 1a–e and 2a–e,
which were obtained in good yields, with low reaction times and an easy-to-
use method, and under environmentally friendly (solventless) conditions. The
products were readily isolated and purified by means of several washings with
water. Of particular interest was the production of 2b, directly obtained by the
action of sodium acetate 2a. In conclusion, an efficient and green chemical
Table 1. Amides and imides synthesized under solventless conditions
Mp (8C)
found (reported)
EIMSM þ ꢀ
m/z (% ra)
Products
R
Yield (%)
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
H
OH
210 (220–221)[19]
224 (220–223)[19]
224 (214–217)[20]
206 (163–165)[21]
198 (213–214)[19]
89 (88–89.5)[22]
185 (186)[23]
238 (235–237)[20]
153 (172–173)[21]
146 (145–148)[22]
99
97
97
98
96
85
80
82
75
78
191 (31)
207 (6)
235 (4)
206 (6)
221 (54)
173 (7)
233 (9)
217 (11)
188 (14)
203 (10)
CO2H
NH2
OCH3
H
OAc
CO2H
NH2
OCH3

Synthesis of Arylamides and Arylimides
2019
alternative was developed that could be used for synthesizing many other
related compounds.
For the structural attributions of the target compounds, first we verified by
the mass-spectrometric method that the molecular ions (Table 1) were in
agreement with the corresponding molecular weights, and that the common
þ
þ
þ
.
.
.
fragments [M-18] , [M-45] and [aniline] were present in all compounds
synthesized. The corresponding structures of the products became evident
from the respective nuclear-magnetic-resonance data (Tables 2 and 3) of the
compounds obtained, because the chemical shifts (1H, 13C) and the respective
coupling patterns on H are in agreement with previous reports.[7]
1
Finally, it is worth mentioning that these molecules continue to
be excellent acetylcholinesterase inhibitors; consequently, they could be
interesting drugs in the treatment of Alzheimer’s disease.
EXPERIMENTAL
The starting materials, maleic anhydride and the anilines, are commercially
available (Aldrich Chemical Co.) and were used without further purification.
The reactions were monotired by TLC using Watman precoated plates (silica
gel 60 F254, 0.25 mm). The product visualization was done using a 254-nm UV
1
lamp. The molecules obtained were identified by H and 13C NMR spectra
recorded on a Jeol GSX-270 spectrometer using DMSO-d6 as a solvent and
TMS as an internal reference. EIMS (70 ev) experiments were determined
on a Hewlett Packard 5989A mass spectrometer under the electron-impact
ionization mode and by direct insertion. Uncorrected melting points were
obtained in open-ended capillary tubes with an Electrothermal 9300 digital
apparatus.
General Procedures for the Preparation of 1a–e
1a–e. Equimolar quantities (10 mmol) of maleic anhydride and the corre-
sponding aniline were mixed at room temperature. The mixture was stirred
for 2 h and the reaction was monitored by TLC (acetone/ethanol 1:1; SiO2).
The products obtained (yellow solids) were suspended and washed with
H2O (3 ꢁ 30 mL) until reaching pH ffi 4. The resulting suspension was
filtered and then the corresponding amides were dried at 408C, yielding
96–99% of the desired products 1a–e.
General Procedures for the Preparation of 2a–e
2a–e. The starting materials 1a–e were transformed to the corresponding
N-arylimides (2a–e) by heating them for 4 h at 80–858C in the presence of

Table 2. 1H NMR chemical shifts (ppm) and coupling constants (Hz) of 1a–e and 2a–e
Compounds
H-2
6.50
H-3
6.32
H-20
7.65
H-30
7.32
H-40
H-50
7.32
H-60
7.65
NH
CH3
1a
1b
7.08
—
10.45
10.52 s
—
—
6.48 d,
J ¼ 12.4
6.51 d,
J ¼ 11.9
6.48
6.29 d,
J ¼ 12.4
6.33 d,
J ¼ 11.9
6.31
7.43 d,
J ¼ 8.9
7.75 d,
J ¼ 8.9
7.41
6.75 d,
J ¼ 8.9
7.93 d,
J ¼ 8.6
6.59
6.75 d,
J ¼ 8.9
7.93 d,
J ¼ 8.6
6.59
7.43 d,
J ¼ 8.9
7.75 d,
J ¼ 8.9
7.41
1c
—
10.61 s
—
1d
1e
—
—
10.42
10.41 s
—
3.72 s
6.47 d,
J ¼ 12.1
7.17 s
6.31 d,
J ¼ 12.1
—
7.55 d,
J ¼ 9.0
7.34 d
7.35 d,
J ¼ 8.8
7.68 d,
J ¼ 8.6
7.10
6.91 d,
J ¼ 9.0
7.49 t
6.91 d,
J ¼ 9.0
7.49 t
7.55 d,
J ¼ 9.0
7.34 d
7.35 d,
J ¼ 8.8
7.68 d,
J ¼ 8.6
7.10
2a
2b
7.39 t
—
—
—
—
2.29
6.80 s
—
7.19 d,
J ¼ 8.8
8.01 d,
J ¼ 8.6
6.74
7.19 d,
J ¼ 8.8
8.01 d,
J ¼ 8.6
6.74
2c
7.22 s
—
—
—
—
2d
2e
7.02
6.82 s
6.6
—
—
—
10.42
—
—
3.82 s
7.23 d,
J ¼ 8.9
6.98 d,
J ¼ 8.9
6.98 d,
J ¼ 8.9
7.23 d,
J ¼ 8.9

Table 3. 13C NMR chemical shifts (ppm) of 1a–e and 2a–e
Compounds
C-10
C-20
C-30
C-40
C-50
C-60
C-1
C-2
C-3
C-4
CH3
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
139.4
130.2
143.2
144.5
131.9
131.5
129.0
131.6
148.4
123.8
119.5
122.2
119.3
120.2
121.8
126.8
126.8
126.9
127.3
127.6
128.5
115.8
131.0
114.5
114.5
128.9
122.2
128.9
114.6
114.5
123.8
154.8
126.2
144.4
156.4
127.7
149.7
127.8
148.4
159.2
128.5
115.8
131.0
114.5
114.5
128.9
122.2
129.0
114.6
114.5
119.5
122.2
119.3
120.2
121.8
126.8
126.7
126.9
127.3
127.6
165.2
163.4
164.2
—
131.7
132.4
132.3
—
130.4
131.9
130.7
—
166.7
167.1
167.5
—
—
—
—
—
163.4
169.9
169.2
170.0
—
132.3
134.6
234.1
134.9
—
131.5
—
—
167.1
—
—
55.7
—
21.0
—
—
—
—
—
—
55.5
169.8
134.2
—
—

2022
J. Trujillo-Ferrara et al.
sodium acetate. The reactions were monitored by TLC (acetone/ethanol 1:1,
SiO2). The resulting mixtures were cooled, and the imides washed with H2O
(3 ꢁ 30 mL) until reaching pH ffi 3. The solids were dried at 408C, yielding
70–80% of the corresponding products.
ACKNOWLEDGMENTS
The authors thank CONACYT, COFAA, and CGPI/IPN for financial support.
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