Efficient multicomponent synthesis of 2-aminopyridines catalysed by basic mesoporous materials

Article abstract of DOI:10.1007/s11164-020-04144-5

Abstract: An efficient and green procedure for the synthesis of 2-aminopyridines derivatives via four-component reaction of acetophenone, malononitrile, triethoxymethane and different primary amines has been developed using different surfactant-containing

Full text of DOI:10.1007/s11164-020-04144-5

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-020-04144-5
Efcient multicomponent synthesis of 2‑aminopyridines
catalysed by basic mesoporous materials
Fatiha Nouali1 · Zahira Kibou1,2 · Bouhadjar Boukoussa3,4
·
Noureddine Choukchou‑Braham1 · Abdelkader Bengueddach3 ·
Didier Villemin5 · Rachida Hamacha3
Received: 20 November 2019 / Accepted: 30 March 2020
© Springer Nature B.V. 2020
Abstract
An efcient and green procedure for the synthesis of 2-aminopyridines derivatives
via four-component reaction of acetophenone, malononitrile, triethoxymethane and
diferent primary amines has been developed using diferent surfactant-containing
mesoporous catalysts. The advantages of this approach are easy operational method,
high product yields and reusable catalysts without losing their catalytic activity.
Graphic abstract
Keywords Multicomponent reactions of 2-aminopyridines synthesis · Solvent-free ·
Mesoporous materials · MCM-41 · Catalyst reuse
*
Zahira Kibou
zahira_kibou@yahoo.fr
Extended author information available on the last page of the article
Vol.:(0123456789)
1 3

F. Nouali et al.
Introduction
Multicomponent reactions (MCRs) have received considerable attention and are
known as some of the most important reactions in organic and medicinal chem-
istry [1–11]. One-pot multicomponent reactions are the useful path for the fac-
ile synthesis of heterocycles with a biological value [12–15]. In recent years, the
challenge in organic synthesis has been the development of new MCRs using
catalytic systems as well as MCM-41, clean, environmentally benign, efcient
basic recyclable catalysts for the synthesis of heterocyclic compounds [16–18].
The structures of 2-aminopyridines and its derivatives are a class of nitrogen
heterocyclic compounds that have drawn much attention, due to their biological
and pharmaceutical activities [19–24]. The development of clean synthetic routes
towards nitrogen-containing heterocycles is of great importance to both synthetic
and medicinal chemists [25–27]. So, it is important to fnd simple and conveni-
ent procedures for the synthesis of 2-aminopyridines with diferent substitutes in
their moiety, with the aim of obtaining some novel heterocyclic compounds with
potentially enhanced properties.
In the continuation of our research program on the development of green
methodologies in the synthesis of biological important compounds using readily
available, inexpensive and environmentally friendly catalysts [28–34], we wish
to report in this work a new multicomponent reaction of 2-aminopyridines using
mesoporous catalysts.
In the last decades, a particular interest was set on the use of the mesoporous
silica in catalysis and adsorption [35–46], due to their higher specifc surface
areas and pore size compared to the zeolites. These catalysts may be easily recov-
ered at the end of a reaction and can be reused in several cycles. Among these
materials, the mesoporous silica MCM-41 has known very wide applications due
to its bi-dimensional structure and its ordered pores [47, 48]. The mesoporous
silica MCM-41 has been applied in several catalytic reactions as acid/base and/
or redox catalysts. However, due to the surface of the mesoporous silica MCM-
41 containing only the silanol groups, several eforts have been made in order to
activate its surface and make it useful in basic catalysis.
Among the most used methods for modifying the surface of the mesoporous sil-
ica, there is the dispersion of the metal oxides, the dispersion of the polymers having
a basic character and the functionalization by amine groups. However, some of these
methods can afect the structural and textural properties of the modifed material. A
particular interest has been devoted to the use of mesoporous silica containing its
own surfactant without any modifcation, the non-calcined mesoporous silica with a
strong basicity from the siloxy group bonded with CTA+ [47]. These attractive cata-
lysts have also been tested in diferent reactions which require basic catalysts such as
Knoevenagel and Claisen–Schmidt condensations [48], Michael additions–cycload-
dition reactions of CO2 with epoxides [48], cycloaddition of 4-nitrophenyl azide
[34] and condensation of acetophenone with ethyl cyanoacetate [48].
Herein, we report a facile and rapid one-pot four-component route to the
synthesis of 3-cyano-2-aminopyridines in the presence or absence of Al, Ga or
1 3

Efcient multicomponent synthesis of 2‑aminopyridines…
Si-MCM-41 as-synthesized catalysts under free solvent conditions. The compara-
tive studies have been performed between homogeneous and heterogeneous catal-
ysis for the synthesis of 2-aminopyridines derivatives.
Experimental
Materials and physical measurements
All products were prepared in our laboratory and analysed by spectroscopic meth-
ods. The melting points were measured using a Bank Kofer Heizbank apparatus
standard WME 50–260 °C without particular correction. IR spectra were performed
on solid samples using a Fourier transform PerkinElmer Spectrum with ATR acces-
1
sory. Only signifcant absorptions are listed. The H and 13C NMR spectra were
recorded on a Bruker AC 400 spectrometers at 400 and 100 MHz, respectively.
Samples were recorded in CDCl3 solutions using TMS as an internal standard. The
chemical shifts are expressed in δ units (ppm) and quoted downfeld from TMS. The
multiplicities are reported as: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet
(Scheme 1).
Synthesis
General synthesis of 2‑aminopyridines without catalyst
A mixture of acetophenone (10 mmol), 10 mmol of malononitrile, 10 mmol of tri-
ethoxymethane and primary amine (10 mmol) was heated for 3 h at 100 °C. After
the completion of the reaction, the residue was purifed by column chromatography
over silica gel using a mixture of nhexane–EtOAc (8:1) as the eluent to give desired
compounds.
General synthesis of 2‑aminopyridines with catalyst
A mixture of equi-molar amount of the four compounds: acetophenone; malononi-
trile, triethoxyethane and benzylamine with 0.001 mol of (X-MCM-41), was stirred
at room temperature without solvent. After the completion of the reaction, the cata-
lyst was separated by fltration.
R2
HN
O
NC
R1
CN
CN
N
Formation of
Heterocycle
+
+
CH(OEt)3
+
R2NH2
R1
CH3
Scheme 1 Four-component synthesis of 2-aminopyridines
1 3

F. Nouali et al.
X‑MCM‑41: Si‑MCM‑41, Al‑MCM‑41, Ga‑MCM‑41
2‑(Benzylamino)‑4‑phenylnicotinonitrile 4a White solid, mp 95 °C; IR νmax (neat/
1
cm−1): 1575 (C=C); 1531 (C=C); 2215 (CN); 3361 (NH); NMR H (CDCl3) δH
ppm : 4.6 (2H, d, JH–H =5.2 Hz, NH–CH2); 5.60 (1H, t, JH–H =4.6 Hz, NH–CH2);
6.69 (1H, d, JH–H =4.6 Hz, CH=CH); 7.28–7.30 (5H, m, Harom); 7.46–7.58 (5H,
m, Harom); 8.30 (1H, d, JH–H =4.6 Hz, CH=CH); RMN 13C (CDCl3) δC: 45.6;
90.1; 113.1;116.9; 128.7–129.8; 136.7; 152; 154.50; 159.2; EIMS m/z (% relative
abundance): 286 (M+H, 100), 208 (23), 91 (93); HRMS (ESI-QTOF): Calcd for:
C19H16N3 M+H 286,1339; Found: 286,1345.
2‑(Cyclohexylamino)‑4‑phenylnicotinonitrile 4b Yellow solid, mp 189 °C; IR νmax
1
(neat/cm−1):1572 (C=C); 1533 (C=C); 2217 (CN); 3362 (NH); RMN H (CDCl3)
1.49–1.75 (m, 2H, –(CH2)4–); 1.75 (1H, q, CH–NH); 5.22(1H, s, NH); 6.33 (1H, d,
JH–H=5.8 Hz, CH=CH–N); 7.325–7.56 (5H, m, Harom); 8.26 (1H, d, JH-H=5.7 Hz,
CH=CH–N); RMN 13C (CDCl3) δC: 11.1; 23.6; 46.5; 88.3; 105.1; 117.0; 127.3–
129.3;152.3; 155.3; 156.2; EIMS m/z (% relative abundance): 277 (M+H, 100), (19),
HRMS (ESI-QTOF): Calcd for: C18H20N3 M+H 277,1324; Found: 277,1122.
2‑(Hexylamino)‑4‑phenylnicotinonitrile 4c Yellow solid, mp 120 °C; IR νmax (neat/
1
cm−1): 1571 (C=C); 1532 (C=C); 2215 (CN); 3360 (NH); RMN H (CDCl3) δH:
0.98 (3H, t, JH–H =7.2 Hz, –(CH2)5–CH3); 1.29 (2H, m, –N–CH2–CH2–CH2–CH3);
1.30 (2H, m, N–CH2–CH2–CH2 CH2–CH2–CH3); 1.33 (2H, t, JH-H=4.20 Hz N–
CH2–CH2 CH2–CH2–CH2–CH3), 1.52 (2H, t, JH–H=4.20 Hz N–CH2–CH2 CH2–
CH2–CH2–CH3), 3.53 (2H, t, JH–H=4.20 Hz,m, N–CH2–CH2 CH2–CH2–CH2 –CH3);
5.36 (1H, t, JH–H=4.20 Hz, NH); 6.63 (1H, d, JH–H=5.8 Hz, CH=CH–N); 7.35–7.56
(5H, m, Harom); 8.31 (1H, d, JH–H=5.7 Hz, CH=CH–N); RMN 13C (CDCl3)δC:
14.1; 22.6; 26.5; 32.6; 44.5; 88.3; 105.1;113.4;117; 126.2–127.5;136.4;152.3 155.3;
155.3; EIMS m/z (% relative abundance): 280 (M+H, 100), 200 (19), HRMS (ESI-
QTOF): Calcd for: C18H22N3 M+H 279,1422; Found: 279,1345.
2‑(Propylamino)‑4‑phenylnicotinonitrile 4d Yellow solid, mp 111 °C; IR νmax (neat/
cm−1): 1583 (C=C), 1554 (C=C); 2219 (CN); 3383 (NH);RMN 1H (CDCl3): δH 1.01
(3H, t, JH–H =7.4 Hz, –(CH2)2–CH3); 1.56 (2H, m, –N–CH2–CH2–CH3); 3.11 (2H,
m, –N–CH2–CH2–CH3); 5.22(1H, t, JH–H=4.20 Hz, NH); 6.64 (1H, d, JH-H=5.8 Hz,
CH=CH–N); 7.325–7.56 (5H, m, Harom); 8.26 (1H, d, JH–H=5.7 Hz, CH=CH–N);
RMN 13C (CDCl3) δC: 11.1; 23.6; 46.5; 88.3; 105.1; 117; 127.3–129.3;152.3; 155.3;
156.2; EIMS m/z (% relative abundance): 237 (M+H, 100), (20), HRMS (ESI-
QTOF): Calcd for: C15H16N3 M+H 237,1422; Found: 237,1235.
2‑(Butylamino)‑4‑phenylnicotinonitrile 4e White solid, mp 159 °C; IR νmax cm−1:
1583 (C=C), 1554 (C=C); 2219 (CN); 3383 (NH); RMN 1H (CDCl3)δH: 0.91 (3H,
t, JH–H=7.2 Hz, –(CH2)3–CH3); 1.32 (2H, m, –N–CH2–CH2–CH2–CH3); 1.33 (2H,
m, N–CH2–CH2–CH2–CH3); 2.64 (2H, t, JH–H=4.20 Hz N–CH2–CH2–CH2–CH3);
5.36 (1H, t, JH–H=4.20 Hz, NH); 6.63 (1H, d, JH–H=5.8 Hz, CH=CH–N); 7.35–7.56
1 3

Efcient multicomponent synthesis of 2‑aminopyridines…
(5H, m, Harom); 8.31 (1H, d, JH–H=5.8 Hz, CH=CH–N); RMN 13C (CDCl3)δC:
13.71 (CH3); 21.3; 32; 41.5; 88.3; 113.42; 117.01; 126.25–129.86; 136.88; 152.08;
155.34; 160.12. EIMS m/z (% relative abundance): 251 (M+H, 100), (19), HRMS
(ESI-QTOF): Calcd for: C16H18N3 M+H 251,1348; Found: 251,1356.
2‑(Benzylamino)‑4‑p‑tolylnicotinonitrile 5a White solid, mp 189 °C; IR νmax (neat/
cm−1): 1578,1533 (C=C); 2217 (CN); 3363 (NH); RMN 1H (CDCl3) δH: 2.41 (3H,
s,Ph-CH3); 4.68 (2H, d, JH–H =4.6 Hz, NH–CH2); 5.66 (1H, t, JH–H =4.6 Hz, NH–
CH2); 6.70 (1H, d, JH–H =4.6 Hz, CH=CH); 7.25–7.30 (5H, m, Harom); 7.46–7.58
(4H, m, Harom); 8.35 (1H, d, JH–H =4.6 Hz, CH=CH); RMN 13C (CDCl3) δC: 24.5
(Ph-CH3), 45.6 (CH2); 91.1 (C=C–CN); 113.4 (CH=CH); 116.8 (CN); 127.3–127.9
(5xCarom); 128.1–129.5 (5xCarom); 136 (Carom); 139.2 (Carom); 153.1 (CH=CH);
154.6 (C=C–CN); 160.1 (N=C–NH); EIMS m/z (% relative abundance): 300 (M+H,
80), 150 (25), HRMS (ESI-QTOF): Calcd for: C20H19N3 M+H 300,1244; Found:
300,1345.
2‑(Cyclohexylamino)‑4‑p‑tolylnicotinonitrile 5b Yellow solid, mp 189 °C; IR νmax
(neat/cm−1): 1575,1533 (C=C); 2221 (CN); 3365 (NH); RMN 1H (CDCl3) δH: 1.48–
1.76 (m, 2H, –(CH2)4–); 1.75 (1H, q, CH–NH); 2.35 (3H, s, –CH3); 5.22 (1H, s,
NH); 6.32 (1H, d, JH–H=5.8 Hz, CH=CH–N); 7.325–7.56 (5H, m, Harom); 8.26 (1H,
d, JH–H=5.7 Hz, CH=CH–N); RMN 13C (CDCl3) δC: 11.1; 23.6;24.4; 46.5; 88.3;
105.1; 117; 127.3–129.3;152.4; 155.3; 156.2; EIMS m/z (% relative abundance):
291 (M+H, 100), (19), HRMS (ESI-QTOF): Calcd for: C19H22N3 M+H 291,1224;
Found: 291,1155.
2‑(Hexylamino)‑4‑p‑tolylnicotinonitrile 5c Yellow solid, mp 220 °C; IR νmax(neat/
cm−1):1572,1532 (C=C); 2219(CN); 3363 (NH); RMN 1H (CDCl3) δH: 0.99 (3H, t,
JH–H =7.2 Hz, –(CH2)5–CH3); 1.27 (2H, m, –N–CH2–CH2–CH2–CH3); 1.30 (2H, m,
N–CH2–CH2–CH2 CH2–CH2–CH3); 1.32 (2H, t, JH–H=4.20 Hz N–CH2–CH2CH2–
CH2–CH2–CH3), 1.52 (2H, t, JH–H=4.20 Hz N–CH2–CH2 CH2–CH2–CH2–CH3),
2.35 ((3H, s, –CH3); 3.42 (2H, t, JH–H=4.20 Hz, m, N–CH2–CH2 CH2–CH2–CH2–
CH3); 5.29 (1H, t, JH–H=4.20 Hz, NH); 6.63 (1H, d, JH–H=5.8 Hz, CH=CH–N);
7.33–7.52 (5H, m, Harom); 8.28 (1H, d, JH–H=5.7 Hz, CH=CH–N); RMN 13C
(CDCl3) δC: 14.1; 22.61; 24.3; 26.5; 32.6; 43.4; 88.2; 105.1;113.3;117; 127.5–
136.4;152.3; 155.3; 155.6; EIMS m/z (% relative abundance): 293 (M+H, 100), 200
(19), HRMS (ESI-QTOF): Calcd for: C19H24N3 M+H 293,1322; Found: 293,1115.
2‑(Propylamino)‑4‑p‑tolylnicotinonitrile 5d Yellow solid, mp 181 °C; IR νmax (neat/
cm−1): 1570,1531 (C=C); 2217 (CN); 3365 (NH); NMR 1H (CDCl3) δH ppm 1.49–
1.75 (m, 2H, –(CH2)4–); 1.75 (1H, q, CH–NH); 2.35 (3H, s, –CH3); 5.31(1H, s,
NH); 6.29 (1H, d, JH–H=5.8 Hz, CH=CH–N); 7.25–7.49 (5H, m, Harom); 8.23 (1H,
d, JH–H=5.7 Hz, CH=CH–N); RMN 13C (CDCl3) δC: 10.1; 23.3; 24.3; 45.4; 88.4;
105.1; 117; 127.3-129.3;151.3; 155.3; 156.5; EIMS m/z (% relative abundance):
251 (M+H, 100), (19), HRMS (ESI-QTOF): Calcd for: C16H18N3 M+H 251,1324;
Found: 251,1223.
1 3

F. Nouali et al.
2‑(Butylamino)‑4‑p‑tolylnicotinonitrile 5e White solid, mp 147 °C; IR νmax cm−1:
1582 (C=C), 1553 (C=C); 2222 (CN); 3381 (NH); RMN 1H (CDCl3) δH: 0,91 (3H,
t, JH–H=7.2 Hz, –(CH2)3– CH3); 1.33 (2H, m, –N–CH2–CH2–CH2–CH3); 1.34 (2H,
m, N–CH2–CH2–CH2–CH3); 2.40 (3H, s,Ph-CH3); 2.66 (2H, t, JH–H=4.8 Hz, N–
CH2–CH2–CH2–CH3); 5.34 (1H, t, JH–H=4.8 Hz, NH); 6.61 (1H, d, JH–H=5.9 Hz,
CH=CH–N); 7.36–7.58 (5H, m, Harom); 8.27 (1H, d, JH–H=5.9 Hz, CH=CH–N);
RMN 13C (CDCl3) δC: 13.5; 21.33; 24.51;33.5; 42.4; 87.9; 113.6; 117.51; 126.3–
130.1; 137.9 (Carom); 153.1 (CH=CH–N); 155.3 (C=C–CN); 159.5; EIMS m/z
(% relative abundance): 251 (M+H, 100), (19), HRMS (ESI-QTOF): Calcd for:
C17H20N3 M+H 265,1667; Found: 251,1670.
Results and discussion
So we wish to report an efcient one-pot four-component method for the preparation
of 2-aminopyridines. Moreover, to the best of our knowledge, this paper is the frst
report on the synthesis of some 2-aminopyridines using as-synthesized mesoporous
catalyst.
Initially, we have synthesized Al, Ga or Al-MCM-41 mesoporous materials con-
taining CTA+ by a direct method of crystallization according to the literature [37].
The detailed experimental procedures for the preparation of diferent as-synthesized
mesoporous materials are well detailed and characterized in our previously pub-
lished work [39].
Among the various methods developed for that purpose, multicomponent reac-
tions involving domino processes answer perfectly to the green chemistry princi-
ples. In this context, and in connection with our recent investigation on the synthesis
of nitrogen heterocycles under solvent-free conditions, frstly, we describe one-pot
four-component approach to synthesis 2-aminopyridines efciently without catalyst.
This approach is a process in which four easily accessible components are combined
together in a single reaction l to produce a fnal product 4–5 (Table 1).
However, using acetophenone with benzylamine gives good yields. After 3 h of
heating at 100 °C all, the products 4–5 were purifed by column chromatography
and isolated in yields ranging from 66 to 76% (Table 1). From this result, and in
continuation of our interest in using solid catalysts in the synthesis of heterocy-
cles, we describe here a simple and green strategy based on the new MCRs using
MCM-41 as a powerful, recyclable and safe catalyst for the preparation of novel
and known 3-cyano-2-aminopyridines 4–5 derivatives. Initially, a model reaction
was conducted using acetophenone (0.1 mol), malononitrile (0.1 mol), triethoxym-
ethane (0.1 mol) and benzylamine (0.1 mol) at room temperature in the presence
of 0.001 mol (X-MCM-41) as catalyst under solvent-free conditions (Table 2); the
product 4a is confrmed by their NMR, IR and MS analysis.
The reaction proceeded best at ambient temperature without heating in the pres-
ence of Si-MCM-41 to provide good yield 89% in a short time (15 min), and the
results are summarized in Table 2, by against studying this reaction without hetero-
geneous catalyst leads to a product mixture.
1 3

Efcient multicomponent synthesis of 2‑aminopyridines…
Table 1 Four-component reaction of 2-aminopyridines derivatives without catalyst
R2
NH
O
NC
R1
CN
N
free-solvent
R2NH2
+
+
+
CH(OEt)3
R1
CH3
1 a-b
∆
CN
2 a-j
4-5
Entry
R1
C6H5–
R2
Product
Yield (%)
1
2
3
4
5
6
7
8
9
Benzyl-
Cyclohexyl-
Hexyl-
Propyl-
Butyl-
Benzyl-
Cyclohexyl-
Hexyl-
Propyl-
Butyl-
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
73
68
70
62
68
76
65
72
66
70
p-CH3C6H4-
10
Reaction conditions: acetohenone (1, 1 mmol), malononitrile (1 mmol), triethoxymethane (1 mmol), and
(2, 1 mmol) amine, 100 °C, 3 h
Table 2 Optimization of the reaction conditions in the synthesis of 4a
Ph
HN
NC
O
CN
CN
N
OEt
CH
X-MCM-41
r.t
+
PhCH2NH2
+
+
Ph
CH3
Ph
EtO
OEt
4a
Entry
Catalst
Time (min)
Yield (%)
1
2
3
Al-MCM-41
Ga-MCM-41
Si-MCM-41
30
20
15
67
75
89
1 3

F. Nouali et al.
To develop the scope of this reaction, and in order to evaluate the generality
of this model reaction, we encouraged to extend this reaction to a variety of 1a–b
with diferent primary amines 2a–j, so we have examined this reaction employing
the optimized conditions, and the results are summarized in Table 3.
It was clearly observed that the best results were obtained in the presence of
Si-MCM-41 as catalyst at room temperature. Then, the generality of the pro-
cedure was evaluated using various primary amines under optimized reaction
conditions. It was found that both using benzylamine as primary amine and Si-
MCM-41 reacted well in this process to aford the corresponding products in
Table 3 Synthesis of 2-aminopyridines catalysed by Al, Ga or Si-MCM-41 under solvent-free conditions
Entry
R1
R2
Catalyst
Product
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
C6H5–
Benzyl-
Cyclohexyl-
Hexyl-
Propyl-
Butyl-
Benzyl-
Cyclohexyl-
Hexyl-
Propyl-
Butyl-
Benzyl-
Cyclohexyl-
Hexyl-
Propyl-
Butyl-
Benzyl-
Cyclohexyl-
Hexyl-
Propyl-
Butyl-
Ga-MCM-41
4a
4b
4c
4d
4e
4a
4b
4c
4d
4e
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
5a
5b
5c
5d
5e
5a
5b
5c
5d
5e
30
35
40
50
55
28
30
38
45
49
15
20
25
30
45
28
22
20
28
35
22
20
17
25
35
13
18
20
25
35
67
70
73
70
78
75
79
80
73
80
89
80
82
75
81
70
83
85
79
88
78
80
82
75
88
92
88
85
80
88
C6H5–
Ga-MCM-41
Si-MCM-41
Al-MCM-41
GA-MCM-41
Si-MCM-41
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
C6H5–
p-Ch3C6H4–
p-Ch3C6H4–
p-Ch3C6H4–
Benzyl-
Cyclohexyl-
Hexyl-
Propyl-
Butyl-
Benzyl-
Cyclohexyl-
Hexyl-
Propyl-
Butyl-
1 3

Efcient multicomponent synthesis of 2‑aminopyridines…
Ga-MCM-41
Al-MCM-41
Si-MCM-41
4000 3500 3000 2500 2000 1500 1000 500
Wavenumber (cm-1)
Fig. 1 FTIR spectra of as-synthesized Si-MCM-41 and its modifed counterparts
Fig. 2 SEM images of as-synthesized Si-MCM-41 and its modifed counterparts
good to excellent yields 92% (Table 3). So we can note that these MCRs are a
selective synthesis of 2-aminopyridines using mesoporous catalyst.
The evolution of the yields is carried out in the following sequence: Si-
MCM-41>Al-MCM-41>Ga-MCM-41, and the as-synthesized Si-MCM-41 pre-
sents the best catalytic performance.
As shown in Fig. 1, all the catalysts have the same vibration bands of the as-
synthesized MCM-41, the bands appeared between 2800 and 2900 cm−1 corre-
sponding to the groups -CH2 and -CH3, and these bands also confrm the presence of
surfactant (CTA+) linked with siloxy anions (≡ SiO−) inside the pores of MCM-41
which are considered as basic sites [36, 39, 48]. The choice of incorporating Al and
Ga into the framework of Si-MCM-4 was to generate a bi-functional acid/base cata-
lyst. But according to the catalytic reaction, the MCRs were well governed by the
Si-MCM-41. This also shows that the reaction takes place with the basic catalyst Si-
MCM-41 due to the presence of higher density of the siloxy groups [49–56].
It is also necessary to take into account the factor of the morphology which can
afect the properties of catalyst. As shown in Fig. 2, it is clearly indicated that the
catalysts Si- and Al-MCM-41 have a spherical morphology, while the catalyst Ga-
MCM-41 has morphology in the form of aggregates probably due to the incorpo-
ration of the gallium leading subsequently to a slight destructuration of obtained
catalyst.
1 3

F. Nouali et al.
In order to examine the infuence of amount for heterogeneous catalysts on
MCRs, we have mixed 1a, 1 Eq of acetophenone, 1 Eq of malononitrile, 1 Eq of tri-
ethoxymethane and 1 Eq of propylamine using diferent amounts of as-synthesized
Si-MCM-41 (Fig. 3). The use of 10 mol% of as-synthesized Si-MCM-41 led to 80%
yield for 25-min reaction time. We note in Fig. 1 that increasing the amount of cata-
lyst has an impact on the reaction yield. Indeed, a 25-min reaction time led to a 89%
yield using 20 mol% (and 90% yield using 40 mol%) of as-synthesized Si-MCM-41.
The yield obtained after 10 min of reaction in the presence of 50% of catalyst is
about 98%. Thus, the reaction time can be minimized due to an increase in catalytic
amount of synthesized Si-MCM-41 catalyst and best results were obtained by per-
forming the reaction in the presence of 50 mol% of catalyst.
Furthermore, the reusability of Si-MCM-41 was also examined with the opti-
mized experiment conditions of the model reaction for the synthesis of product
5a: acetophenone (1 mmol), malononitrile (1 mmol), triethoxymethane (1 mmol)
and 0.1 mol of benzylamine or cyclohexylamine in the presence of Si-MCM-41
(10 mol %) at room temperature and reaction time for as-synthesized Si-MCM-41
being 15 min. After completion of the reaction, the catalyst was isolated by simple
fltration than the catalysts were fltered, washed with DMF and dried before use in
the following cycles, and the results are represented in Fig. 4. This study demon-
strated that Si-MCM-41 could be efectively used as a recyclable catalyst for this
new four-component reaction. The decrease in the activity of this catalyst during its
reuse is strongly linked to the leaching of surfactant following its exposure on vari-
ous occasions to treatment with solvents during cleaning. These results are in agree-
ment with our work published previously [56, 57].
Conclusion
In conclusion, we have described a novel and efcient protocol for one-pot syn-
thesis of 3-cyano-2-aminopyridines via a reaction between acetophenone deriva-
tive, malononitrile and triethoxymethane, using mesoporous materials as catalysts.
The reaction time and product yields have been improved in the following order:
Fig. 3 Efect of the catalyst
100
80
60
40
20
0
amount (as-synthesized Si-
MCM-41) on the yield of 5a
10
20
30
40
50
mol % mol % mol % mol % mol %
amount of catalysts
1 3

Efcient multicomponent synthesis of 2‑aminopyridines…
Benzylamine
100
90
80
70
60
50
40
30
20
10
0
Cyclohexylamine
1
2
3
4
5
Cycle Cycle Cycle Cycle Cycle
Run of cycle
Fig. 4 Catalyst reusability
Si-MCM-41>Al-MCM-41>Ga-MCM-41; as-synthesized Si-MCM-41 is particu-
larly efcient for this reaction at room temperature due to its higher number of ionic
pairs SiO−–CTA+. Mild conditions, good to excellent yields, reusable catalysts and
short reaction time are the advantages of the present method.
Acknowledgements We thank DGRSDT and the University of Tlemcen for funding this work.
References
1. A. Dömling, Chem. Rev. 106, 17 (2006)
2. J. Zhu, H. Bienaymé, Multicomponent Reactions (Wiley-VCH, Weinheim, 2005)
3. K. Kumaravel, G. Vasuki, Curr. Org. Chem. 13, 1820 (2009)
4. L.F. Tietze, Domino Reactions: Concepts for Efcient Organic Synthesis (Wiley-VCH, Wein-
heim, 2014)
5. R.V.A. Orru, M. de Greef, Synthesis 10, 1471 (2003)
6. M. Umkeherer, C. Kalinski, J. Kolb, C. Burdack, Tetrahedron Lett. 47, 2391 (2006)
7. L.F. Tietze, G. Brasche, K. Gericke, Domino Reactions in Organic Synthesis (Wiley-VCH, Wein-
heim, 2006)
8. A. Alizadeh, F. Mobahedi, A. Esmaili, Tetrahedron Lett. 47, 4469 (2006)
9. D. Pires, H. deOliveira, M.R.B. Pontel, J.S. Kazmierczak, R. Cargnelutti, D. Alve, R.J. Jacob,
Beilstein J. Org. Chem. 14, 2789 (2018)
10. R. Vroemans, Y. Verhaegen, M.-T.D. Thi, W. Dehaen, Beilstein J. Org. Chem. 14, 2689 (2018)
11. S. Kamalifar, H. Kiyani, Res Chem Int. Med. 45, 5975 (2019)
12. N. Elders, R.F. Schmitz, F.J.J. Kanter, E. Ruijter, M.B. Groen, R.V.A. Orru, J. Org. Chem. 72,
6135 (2007)
13. T.J.J. Müller, Chem. Heterocycl. Comp. 53, 381 (2017)
14. B. Groenendaal, E. Ruijter, R.V.A. Orru, Chem. Commun. 43, 5474 (2008)
15. B. Willy, T.J.J. Müller, Org. Lett. 13, 2082 (2011)
16. T.S. Jin, J.S. Zhang, A.Q. Wang, Y.S. Li, Ultrason. Sono Chem. 13, 220 (2006)
17. S. Rostamizadeh, A. AliMohammad, G.H. Mahdavinia, H. Sepehrian, S. Ebrahimia, Synthesis 8,
1356 (2010)
18. M. Gholinejad, F. Hamed, C. Nájera, Synlett 27, 1193 (2016)
19. F. Yates, R.T. Courts, A.F. Casy, in Pyridine and Its Derivatives Supplement IV, vol. 445, ed. by
R.A. Abramovitch (Wiley, New York, 1975)
1 3

F. Nouali et al.
20. R. Vardanyan, V. Hruby, Synthesis of Essentials Drugs, vol. 51 (Elsevier, Amsterdam, 2006)
21. F. Manna, F. Chimenti, A. Bolasco, B. Bizzarri, W. Filippelli, A. Filippelli, L.G. Gagliardi, Eur.
J. Med. Chem. 34, 245 (1999)
22. A. Altundas, S. Ayvaz, E. Logoglu, Med. Chem. Res. 20, 1 (2011)
23. Q. Luo, R. Huang, Q. Xiao, Y. Yao, J. Lin, S.-J. Yan, J. Org. Chem. 84, 1999 (2019)
24. X.X. Du, Q.X. Zi, Y.M. Wu, Y. Jin, J. Lin, S.J. Yan, Green Chem. 21, 150 (2019)
25. H. Suga, Y. Furihata, A. Sakamoto, K. Itoh, Y. Okumura, T. Tsuchida, A. Kakehi, T.J. Baba,
Org. Chem. 76, 7377 (2011)
26. J.M. DeLosSantos, Y. López, D. Aparicio, F. Palacios, J. Org. Chem. 73, 550 (2008)
27. W. Yu, Z.W. Zhai, D.E. Wedge, S.O. Duke, H.K. Wu, J.Q. Weng, C.X. Tan, Y.G. Zhang, X.H.
Liu, Res ChemIntermed 45, 5989 (2019)
28. Z. Kibou, N. Cheikh, N. Choukchou-Braham, B. Mostefa-Kara, M. Benabdellah, D. Villemin, J.
Mater. Environ. Sci. 3, 293 (2011)
29. N. Cheikh, D. Villemin, N. Bar, J.-F. Lohier, N. Choukchou-Braham, B. Mostefa- Kara, J. Sop-
kova, Tetrahedron 69, 1234 (2013)
30. D. Villemin, N. Cheikh, L. Liao, N. Bar, J.F. Lohier, J. Sopkova, N. Choukchou-Braham, B.
Mostefa-Kara, Tetrahedron 68, 4906 (2012)
31. Z. Kibou, N. Cheikh, D. Villemin, N. Choukchou-Braham, B. Mostefa-Kara, M. Benabdallah,
Int. J. Org. Chem 1, 242 (2011)
32. A. Berrichi, R. Bachir, S. Bedrane, N. Choukchou-Braham, K. Belkacemi, Res. Chem. Intermed.
45, 3481 (2019)
33. D. Villemin, Z. Belhadj, N. Cheikh, N. Choukchou-Braham, N. Bar, J.F. Lohier, Tetrahedron
Lett. 54, 1664 (2013)
34. A. Berrichi, R. Bachir, M. Benabdallah, N. Choukchou-Braham, Tetrahedron Lett. 56, 1302
(2015)
35. M.E. Davis, Nature 417, 813 (2002)
36. S. Izquierdo-Barba, M. Sánchez-Salcedo, M.J. Colilla, M.T. Portolés, M. Vallet-Regí, Acta Bio-
mater. 57, 2977 (2011)
37. B. Boukoussa, N. Aouad, R. Hamacha, A. Bengueddach, J. Phys. Chem. Solids 78, 78 (2015)
38. B. Boukoussa, F. Sebih, R. Hamacha, S. Bellahouel, A. Derdour, A. Bengueddach, Res Chem-
Intermed. 41, 2221 (2015)
39. K. Chikh, B. Boukoussa, L. Bouhadjar, M. Bencheikh, R. Hamacha, R. Meghabar, M. Belbachir,
A. Bengueddach, Res ChemIntermed 41, 6485 (2015)
40. A. Hakiki, R.M. Kerbadou, B. Boukoussa, H. HabibZahmani, F. Launay, A. Pailleret, F. Pil-
lier, S. Hacini, A. Bengueddach, R. Hamacha, J. Inorgan. Organometall. Polym. Mater. 29, 1773
(2019)
41. B. Boukoussa, A. Hakiki, N. Bouazizi, A.P. Beltrao-Nunes, F. Launay, A. Pailleret, F. Pillier, A.
Bengueddach, R. Hamacha, A. Azzouz, J. Mol. Struct. 1191, 175 (2019)
42. A. Hakiki, B. Boukoussa, H. HabibZahmani, R. Hamacha, N.E.H. HadjAbdelkader, F. Bekkar, F.
Bettahar, A.P. Nunes-Beltrao, S. Hacini, A. Bengueddach, A. Azzouz, Mater. Chem. Phys. 212,
415 (2018)
43. B. Boukoussa, R. Hamacha, A. Morsli, A. Bengueddach, Arab. J. Chem. 10, S2160 (2017)
44. B. Boukoussa, A. Hakiki, S. Moulai, K. Chikh, D.E. Kherroub, L. Bouhadjar, D. Guedal, K.
Messaoudi, F. Mokhtar, R. Hamacha, J. Mater. Sci. 53, 7372 (2018)
45. I. Terrab, R. Ouargli, B. Boukoussa, K. Ghomari, R. Hamacha, R. Roy, A. Azzouz, A. Bengued-
dach, Res. Chem. Intermed. 43, 3775 (2017)
46. Z. Abid, A. Hakiki, B. Boukoussa, F. Launay, H. Hamaizi, A. Bengueddach, R. Hamacha, J.
Mater. Sci. 54, 7679 (2019)
47. X. Liu, H. Sun, Y. Yang, J. Colloid Interface Sci. 319, 377 (2008)
48. P.R. Selvakannan, K. Mantri, J. Tardio, S.K. Bhargava, J. Colloid Interface Sci. 394, 475 (2013)
49. K.R. Kloetstra, M. VanLaren, H. VanBekkum, J. Chem. Soc., Faraday Trans. 93, 1211 (1997)
50. I. Sobczak, M. Ziolek, E. Pérez-Mayoral, D. Blasco-Jiménez, A. López-Peinado, J. Martín-
Aranda, Catal. Today 179, 159 (2012)
51. S. Roy, T. Chatterjee, M. Pramanik, A.S. Ro, A. Bhaumik, S.K. Manirul Islam, J. Mol. Catal. A:
Chem. 386, 78 (2014)
52. Y. Kubota, Y. Nishizaki, H. Ikeya, M. Saeki, M. Hida, S. Kawazu, Y. Yoshida, M.H. Fujii, Y.
Sugi, Microporous Mesoporous Mater. 70, 135 (2004)
53. Y. Kubota, H. Ikeya, Y. Sugi, T. Yamada, T. Tatsumi, J. Mol. Catal. A: Chem. 249, 181 (2006)
1 3

Efcient multicomponent synthesis of 2‑aminopyridines…
54. L. Martins, W. Hölderich, P. Hammer, D. Cardoso, J. Catal. 271, 220 (2010)
55. R. Srivastava, D. Srinivas, P. Ratnasamy, Tetrahedron Lett. 47, 4213 (2006)
56. B. Bouhadjar, S. Zeghada, B. BentabedAbabsa, R. Hamacha, A. Derdour, A. Bengueddach, F.
Mongin, Appl. Catal. A Gen. 489, 131 (2015)
57. B. Boukoussa, Z. Kibou, Z. Abid, R. Ouargli, N. Choukchou-Braham, D. Villemin, A. Bengued-
dach, R. Hamacha, Chem. Pap. 72, 289 (2018)
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maps and institutional afliations.
Afliations
Fatiha Nouali1 · Zahira Kibou1,2 · Bouhadjar Boukoussa3,4
·
Noureddine Choukchou‑Braham1 · Abdelkader Bengueddach3 ·
Didier Villemin5 · Rachida Hamacha3
1
Laboratoire de Catalyse Et Synthèse en Chimie Organique, Faculté des Sciences, Université de
Tlemcen, BP 119, 13000 Tlemcen, Algeria
2
Centre Universitaire Belhadj Bouchaib Ain Témouchent, Institut des Sciences, BP 284,
46000 Ain Témouchent, Algeria
3
Laboratoire de Chimie des Materiaux L.C.M, Université Oran1 Ahmed Ben Bella, BP 1524,
31000 El-Mnaouer, Oran, Algeria
4
Département de Génie des Matériaux, Faculté de Chimie, Université des Sciences et de la
Technologie Mohamed Boudiaf, BP 1505, 31000 El-Mnaouer, Oran, Algeria
5
Laboratoire de Chimie Moléculaire et Thioorganique, UMR CNRS 6507, INC3M, FR 3038,
ENSICAEN et Université de Caen Basse-Normandie, 14050 Caen, France
1 3