Novel bis-(3-cyano-2-pyridones) derivatives: synthesis and fluorescent properties

Article abstract of DOI:10.1007/s11164-020-04373-8

Abstract: Novel substituted bis-(3-cyano-2-pyridone) derivatives were prepared via a powerful method using enaminonitriles push–pull dienes as key building blocks. The synthesis was performed in three steps from easily accessible starting materials in goo

Full text of DOI:10.1007/s11164-020-04373-8

Research on Chemical Intermediates (2021) 47:1331–1348
https://doi.org/10.1007/s11164-020-04373-8
Novel bis‑(3‑cyano‑2‑pyridones) derivatives: synthesis
and fuorescent properties
Nawel Mehiaoui1 · Zahira Kibou1,2 · Thibault Gallavardin3 · Stéphane Leleu3 ·
Xavier Franck3 · Ricardo F. Mendes4 · Filipe A. Almeida Paz4 · Artur M. S. Silva5 ·
Noureddine Choukchou‑Braham1
Received: 21 September 2020 / Accepted: 11 December 2020 / Published online: 11 January 2021
© The Author(s), under exclusive licence to Springer Nature B.V. part of Springer Nature 2021
Abstract
Novel substituted bis-(3-cyano-2-pyridone) derivatives were prepared via a power-
ful method using enaminonitriles push–pull dienes as key building blocks. The syn-
thesis was performed in three steps from easily accessible starting materials in good
yields. All target products were structurally elucidated by spectroscopic data. The
reaction mechanism for formation of bis (3-cyano-2-pyridone) derivatives was pro-
posed. The structures of enaminonitriles 3a and bis-pyridones 4c were confrmed by
single-crystal X-ray difraction. The forescent study of some bis (3-cyano-2-pyri-
dones) derivatives was reported.
Graphical abstract
Keywords Bis (2-pyridones) · Diamines · Enaminonitriles · Green synthesis ·
Molecular fuorescence
*
Zahira Kibou
zahira_kibou@yahoo.fr
Extended author information available on the last page of the article
Vol.:(0123456789)
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Introduction
The development of new and efcient protocols to prepare nitrogen-heterocyclic
compounds has received great interest in organic chemistry [1, 2]. Numerous syn-
thetic methods to prepare N-heterocyclic compounds have been reported over the
years [3, 4] since these structures are present in many natural compounds, as for
example 2-pyridones (Fig. 1).
2-Pyridone derivatives constitute an important class of heterocycles due to their
diverse biological properties, such as antibacterial and antifungal activities. [5, 6].
They are also described as inhibitors of DNA gyrase [7], partial agonist of nicotinic
cholinergic receptors (nAChRs), [8]. Phosphodiesterase 3 (PDE 3) inhibitors (mil-
rinone, amrinone) [9–11], tissue factor VIIa inhibitor [12], and selective AMPA
receptor antagonist [13–15]. 2-pyridones scafolds fnding versatile applications in
pharmaceuticals [16], agrochemicals [17], and organic functional materials [7].
Moreover, 2-pyridone ring is one of the most classes of fuorophores, with several
photo functional applications [18], this skeleton exhibits a strong emission in difer-
ent regions of spectrum. Recently, they are a much interest in the development of
convenient methodologies of the synthesis of 2-pyridones from simple and available
starting materials to their fuorescent properties [19–21].
According to the literature, 2-pyridone derivatives are one of the most popu-
lar scafolds used in the synthesis of heterocycles such quinolines, β-lactams, qui-
nolizidines, pyridines, piperidines, and indolizidines and many alkaloids systems
and peptides [22, 23]. In recent studies, some of these compounds proved to have
a remarkable efect in vitro as powerful cell growth inhibitors for many types of
human tumour [24]. However, there are only a few methods reported in the litera-
ture for their preparation. These include multicomponent reactions (MCRs) using
Meldrum’s acid with substituted benzaldehyde and the active methylene compounds
[25]. Another method was reported by Cocco et al. from a sequence of reactions
using 3-amino-3-dialkylaminopropenoates with bis-(2,4,6-trichlorophenyl)malonate
[26, 27]. Demuner et al. have also reported the synthesis of bis-2-pyridones from
commercial dehydroacetic acid (DHA). DHA was converted into 4-hydroxy-6-meth-
ylpyridin-2(1H)-ones, which was then condensed with several aliphatic aldehydes
to produce bis-2-pyridones [28]. Recently, Sanad et al. have employed bis-(2-cy-
anoacetamide) and benzylidenemalononitrile in the presence of a variety of base
catalysts, including DBU, piperidine, DABCO, and triethylamine to prepare bis-
(6-amino-2-oxo-4-phenyl-1,2-dihydropyridine-3,5-dicarbonitrile) derivatives [29].
Fig. 1 Some natural products bearing a pyridone moiety
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Novel bis‑(3‑cyano‑2‑pyridones) derivatives: synthesis…
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Following to our interest on the synthesis of heterocyclic compounds [30–35],
we describe here a synthesis of a new class of bis-2-pyridone compounds (Fig. 2)
with fuorescent properties, there is no publication about fuorescent properties of
bis-pyridones.
Experimental
General information
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 Perkin Elmer Spectrum with ATR accessory.
Only signifcant absorptions are listed. The 1H 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 multiplici-
ties are reported as: s, singlet; d, doublet; t, triplet; q, quartet; and m, multiplet. A
series of COSY, NOESY, HSQC, and HMBC NMR experiments were carried out
1
to assign both H and 13C signals. UV–visible absorption spectra were measured
with an Agilent Cary 60. Fluorescence was measured with a corrected Horiba Job-
lin Yvon Fluorolog 3 with diluted samples (OD<0.1). Fluorescence quantum yields
were measured using quinine sulphate in H2SO4 as a standard (QY=0.53) with
excitation at 350 nm. Single crystals of 3a and 4c were manually harvested from the
crystallization vials and immersed in highly viscous FOMBLIN Y perfuoropoly-
ether vacuum oil (LVAC 140/13, Sigma-Aldrich) to avoid degradation caused by the
evaporation of the solvent [36]. Crystals were mounted Mi Te Gen Micro Loops
with the help of a Stemi 2000 stereomicroscope equipped with Carl Zeiss lenses.
Crystal data were collected at 150(2) K on a Bruker X8 Kappa APEX II
CCD area-detector difractometer (Mo Kα graphite-monochromated radiation,
λ=0.71073 Å) controlled by the APEX3 software package [37] and equipped with
an Oxford Cryosystems Series 700 cryostream monitored remotely using the soft-
ware interface Cryopad [38]. Difraction images were processed using the software
package SAINT+, [39] and data were corrected for absorption by the multiscan
semi-empirical method implemented in SADABS 2016/2 [40].
Fig. 2 Structures of 3-cyano-2-pyridones and substituted bis-2-pyridones
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N. Mehiaoui et al.
Structures were solved using the algorithm implemented in SHELXT-2014/5
[41], which allowed the immediate location of almost all of the heaviest atoms com-
posing the molecular unit. The remaining missing and misplaced non-hydrogen
atoms were located from diference Fourier maps calculated from successive full-
matrix least-squares refnement cycles on F2 using the latest SHELXL from the
2018/3 release [42]. All structural refnements were performed using the graphical
interface ShelXle [43].
Hydrogen atoms bound to carbon were placed at their idealized positions using
appropriate HFIX instructions in SHELXL: 43 (aromatic carbon atoms), 23 (for
the ‒CH2‒ groups), 127 (for the disordered ‒CH3 group), and 1 (for the disordered
‒CH2‒ groups). These hydrogen atoms were included in subsequent refnement
cycles with isotropic thermal displacements parameters (Uiso) fxed at 1.2×Ueq of
the parent carbon atoms. We note that the type of hydrogen treatment for the latter
disordered ‒CH2‒ moieties was indeed necessary due to the fact that the molecule
sits, alongside with the described disorder, over an inversion centre which limited
the usage of the riding motion approximation for these atoms.
The last diference Fourier map synthesis showed for 3a, the highest peak (0.302
eÅ−3) and the deepest hole (−0.243 eÅ−3) located at 0.25 and 0.17 Å from H10A
and H10E, respectively; and for 4c, the highest peak (0.166 eÅ−3) and the deep-
est hole (−0.179 eÅ−3) located at 0.90 and 0.86 Å from C7 and N1, respectively.
Structural drawings have been created using the software package Crystal Impact
Diamond [44].
Crystallographic data (including structure factors) for the crystal structures of
compound 4c have been deposited with the Cambridge Crystallographic Data Cen-
tre. Copies of the data can be obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB2 2EZ, U.K. FAX: (+44) 1223 336,033. E-mail: https://
www.deposit@ccdc.cam.ac.uk.
Synthesis
General procedure for the preparation of compounds 2a–d
A mixture of methyl ketones 1a–d (10 mmol), ethyl 2-cyanoacetate (10 mmol),
and ammonium acetate (10 mmol) was heated at 50 °C for 3 h in the presence of
acetic acid (0.06 mL). The progress of the reaction was monitored by TLC. After
completion of the reaction, the reaction mixture was diluted with water (5 mL) and
was extracted with dichloromethane (3×10 mL). The organic extracts were com-
bined and further washed with water and dried over MgSO4. Finally, the solvent was
removed under vacuum, and the resulting product was purifed by distillation to give
pure compounds 2a–d.
Ethyl 2‑cyano‑3‑phenylbut‑2‑enoate 2a
Using acetophenone (1.20 g, 10 mmol), ethyl cyanoacetate (1.13 g, 10 mmol), and
ammonium acetate (0.77 g, 10 mmol) it was obtained 2a. Yield: 1.01 mg (47%),
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Novel bis‑(3‑cyano‑2‑pyridones) derivatives: synthesis…
1335
as brown oil. IR (νmax/cm−1): 1592 (C=C), 1650 (C=O), 2223 (CN).1HNMR
(400 MHz, CDCl3):δH 1.38 (3H, t, J=7.2 Hz, CO2CH2CH3), 2.69 (3H, s,
C=C–CH3), 4.34 (2H, q, J=7.2 Hz, CH2), 7.15–7.40 (5H, m, Ar).13C NMR
(101 MHz, CDCl3): δC 14.2 (CH3), 23.2 (OCH2–CH3), 62.0 (OCH2–CH3), 105.0
[C=C(CN)], 115.8 (CN), 127.3 (Carom), 128.7 (Carom), 130.4 (Carom), 140.3 (Carom),
162.0 (C=O), 172.1 [C=C(CN)].
Ethyl 2‑cyano‑3‑p‑tolylbut‑2‑enoate 2b
Using 1-p-tolyl-ethanone (1.34 g, 10 mmol), ethyl cyanoacetate (1.13 g, 10 mmol),
and ammonium acetate (0.77 g, 10 mmol) it was obtained 2b. Yield: 1.03 mg (45%),
1
as brown oil. IR (νmax/cm−1): 1680 (C=C), 1727 (C=O), 2223 (CN). H NMR
(400 MHz, CDCl3):δH 1.38 (3H, t, J=7.1 Hz, CO2CH2CH3), 2.39 (3H, s, Ph-CH3),
2.67 (3H, s, C=C–CH3), 4.33 (2H, q, J=7.1 Hz, CH2), 7.38–7.06 (m, 4H, Ar). 13
C
NMR (101 MHz, CDCl3): δC 14.0 (CH3), 23.1 (Ph–CH3), 26.7 (OCH2–CH3), 61.8
(OCH2CH3), 104.4 [C=C(CN)], 116.4 (CN), 127.3 (Carom), 129.4 (Carom), 137.4
(Carom), 141.0 (Carom); 162.3 (C=O), 172.3 [C=C(CN)].
Ethyl 2‑cyano‑3‑(2,4‑dichlorophenyl)but‑2‑enoate 2c
Using 1-(2, 4-dichlorophenyl)ethanone, (1.89 g, 10 mmol) of ethyl cyanoacetate
(1.13 g, 10 mmol), and ammonium acetate (0.77 g, 10 mmol) it was obtained 2c.
Yield: 1.42 mg (50%), as brown oil.IR (KBr) (νmax/cm−1): 1614 (C=C), 1737 (C=O),
2230 (CN). 1H NMR (400 MHz, CDCl3): δH 1.18 (3H, t, J=7.1 Hz, CO2CH2CH3),
2.50 (3H, s, C=C–CH3), 4.12 (2H, q, J=7.1 Hz, CH2), 7.45 (s, 1H, Ar), 7.13 (d,
J=5.7 Hz, 1H, Ar), 6.98 (d, J=8.3 Hz, 1H). 13C NMR (101 MHz, CDCl3): δC 13.5
(CH3), 26.2 (OCH2–CH3), 62.1 (OCH2–CH3), 109.0 [C=C(CN)], 114.6(CN), 127.3
(Carom), 128.8 (Carom), 135.1 (Carom), 136.8 (Carom), 159.9 (C=O), 166.8 [C=C(CN)].
Ethyl 2‑cyano‑3‑(4‑nitrophenyl)but‑2‑enoate 2d
Using of 1-(4-nitrophenyl) ethanone (1.65 g, 10 mmol), ethyl cyanoacetate, and
ammonium acetate (1.13 g, 10 mmol) it was obtained 2d. Yield: (62%), as white
1
solid, mp 154 °C.IR (νmax/cm−1): 1614 (C=C), 1727 (C=O), 2223 (CN). HNMR
(400 MHz, CDCl3): δH1.57 (3H, t, J 7.1 Hz, CO2CH2CH3), 2.41 (3H, s, Ph–CH3),
3.57 (2H, q, J=7.1 Hz, CH2), 5.33 (3H, s, C=C–CH3), 7.15–7.95 (m, 4H, Ar), 13
C
NMR (101 MHz, CDCl3): δC 21.3 (CH3), 88.0 (OCH2–CH3), 111.0 (OCH2–CH3),
117.2 [C=C(CN)], 124.2 (Carom), 124.4 (Carom), 127.1 (Carom), 129.3 (Carom), 136.2
(CN), 159.8 (C=O), 160.2 [C=C(CN)].
General procedure for the preparation of compounds 3a–d
An equimolar mixture of compound 2a–d (10 mmol) and of DMFDMA (10 mmol)
was stirred at room temperature. When the reaction was completed (monitored by
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N. Mehiaoui et al.
TLC), the solid obtained was washed with absolute ethanol and diethyl ether (Et2O)
to provide pure products (3a–d).
Ethyl 2‑cyano‑5‑dimethylamino‑3‑phenylpenta‑2,4‑dienoate 3a
Using 2a (2.15 g, 10 mmol) and DMFDMA (1.19 g, 10 mmol) it was obtained
compound 3a (69%), as yellow solid, mp 130˚C. IR (νmax/cm−1): 1508 (C=C),
1
1613 (C=C), 1677 (C=O), 2192 (CN). H NMR (400 MHz, CDCl3): δH 1.22
(3H, t, J=7.1 Hz, CH2–CH3), 2.93 (3H, s, NCH3), 3.01 (3H, s, NCH3), 4.14 (2H,
q, J=7.1 Hz, CH2–CH3), 6.62 (1H, d, J=12.6 Hz, CH=CH–N), 7.12 (1H, d,
J=12.6 Hz, CH=CH–N), 7.21–7.45 (5H, m, Ar). 13C NMR (101 MHz, CDCl3):
δC14.9 (CH2–CH3), 38.0 (NCH3), 45.9 (NCH3), 59.9 (CH2–CH3), 82.9 [C=C(CN)],
99.6 (C=C–N), 120.3 (CN), 128.7–138.3 (6 Carom), 158.0 (C=C–N), 165.3 (C=O),
169.0 [C=C(CN)]. Calcd. for C16H18N2O2: 71.09 C, 6.71 H, 10.36 N. Found: 70.28
C, 6.67 H and 10.71 N.
Ethyl 2‑cyano‑5‑dimethylamino‑3‑p‑tolylpenta‑2,4‑dienoate 3b
From 2b (2.29 g, 10 mmol) and N, N-dimethylformamide dimethyl acetal (1.19 g,
10 mmol), it was obtained compound 3b (58%) as yellow solid, mp 156˚C. IR (νmax
/
1
cm−1): 1505 (C=C), 1608 (C=C), 1680 (C=O), 2197 (CN). H NMR (400 MHz,
DMSO-d6): δH 1.22 (3H, t, J=7.1 Hz, CH2–CH3), 2.36 (3H, s, Ph–CH3), 2.97
(3H, s, NCH3), 3.02 (3H, s, NCH3), 4.13 (2H, q, J=7.1 Hz, CH2–CH3), 6.66 (1H,
d, J=12.6 Hz, CH=CH–N), 7.25 (1H, d, J=12.6 Hz, CH=CH–N), 7.08–7.24 (m,
4Harom), 13C NMR (101 MHz, DMSO-d6): δC 14.9 (CH2CH3), 38.0 (NCH3), 21.4
(Ph–CH3), 45.8 (NCH3), 59.8 (CH2–CH3), 82.9 (C=C(CN), 99.7 (C=C–N), 120.4
(CN), 129.0–138.5 (6Carom), 158.0 (C=C–N), 165.3 (C=O), 169.17 [C=C(CN)].
Calcd. For C17H20N2O2: 71.81 C, 7.09 H, 9.85. Found: 71.89 C, 7.26 H, 10.77 N.
Ethyl 2‑cyano‑3‑(2,4‑dichlorophenyl)‑5‑dimethylaminopenta‑2,4‑dienoate 3c
From 2c(2.84 g, 10 mmol) and N,N-dimethylformamide dimethyl acetal (1.19 g,
10 mmol), it was obtained compound 3c(70%) as yellow solid, mp 168˚C. IR (νmax
/
cm−1): 1509 (C=C), 1607 (C=C), 1682 (C=O), 220.1 (CN). 1H NMR (DMSO-d6):
δH 1.22 (3H, t, J=7.10 Hz, CH2–CH3), 2.99 (3H, s, NCH3), 3.08 (3H, s, NCH3),
4.13 (2H, q, J=7.1 Hz, CH2–CH3). 5.75 (1H, d, J=12.8 Hz, CH=CH–N), 6.66
(1H, d,=12,8 Hz, CH=CH–N) 7,10–7,39 (3H, m, Harom), 13C NMR (101 MHz,
DMSO-d6): δC 14.5 (CH2CH3), 38.1 (NCH3), 45.7 (NCH3), 60.1 (CH2CH3), 82.8
(C=C(CN)), 98.8 (C=C–N), 119.7 (CN), 127.5–135.2 (6 Carom), 136.2 (C=C–N),
164.4 (C=O), 165.1 (C=C(CN)).Calcd. for C16H16Cl2N2O2: 56.65 C, 4.75 H,
8.26 N. Found: 57.07 C, 4.70 H, 8.16 N.
Ethyl 2‑cyano‑5‑dimethylamino‑3‑(4‑nitrophenyl)penta‑2,4 dienoate 3d
From (2.60 g, 10 mmol) of 2dand N,N-dimethylformamide dimethyl acetal (1.19 g,
10 mmol), it was obtained compound 3d(54%) as yellow solid, mp 185˚C. IR (νmax
/
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Novel bis‑(3‑cyano‑2‑pyridones) derivatives: synthesis…
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1
cm−1): 1509 (C=C), 1607 (C=C) 1682(C=O), 2201 (CN). H NMR (400 MHz,
DMSO-d6): δH 1.22 (3H, t, J=7.10 Hz, CH2–CH3), 3.00 (3H, s, NCH3), 3.05 (3H, s,
NCH3), 4.15 (2H, q, J=7.1 Hz, CH2–CH3), 6.67 (1H, d, J=12.8 Hz, CH=CH–N),
7.12 (1H, d, J=12.8 Hz, CH=CH–N), 7.51 (2H, d, H arom), 8.28 (2H, d, H arom). 13
C
NMR (101 MHz, DMSO-d6): δC 14.8 (CH2CH3), 38.1 (NCH3), 45.7 (NCH3), 60.1
(CH2CH3), 82.4 (C=C (CN)), 99.4 (C=C–N), 120.0 (CN), 124.0–146.3 (6 Carom),
148.1 (C=C–N), 164.9 (C=O), 166.4 [C=C(CN)].Calcd. for C16H17N3O4: 60.94 C,
5.43 H; 13.33 N. Found: 60.91 C, 5.30 H, 13.43 N.
A mixture of enaminonitriles 3a–d (20 mmol), primary diamines (10 mmol) was
dissolved in DMF (20 mL) and heated for a 24 h. The progress of the reaction was
monitored by TLC (n-hexane/ethyl acetate=2/8) to make sure about the completion
of the reaction. After cooling, the white solid product was isolated through fltration
and thorough washing with diethyl ether to give bis-2-pyridone derivatives 4a–j.
1‑[(3‑Cyano‑2‑oxo‑4‑phenylpyridin‑1(2H)‑yl)
methyl]‑2‑oxo‑4‑phenyl‑1,2‑dihydro‑pyridine‑3‑carbonitrile 4a
From (0.54 g, 20 mmol) of 3b and of 1, 2-ethylenediamine (0.06 g, 10 mmol) it was
obtained compound 3c (57%) as yellow solid, mp=249 °C. IR (νmax/cm−1): 1609
(C=C), 1653 (C=C), 1683 (C=O), 219 2 (CN).1H NMR (400 MHz, DMSO-d6): δH
4.37–4.39 (4H, s, 2 CH2), 6.49 (2H, d, J=7.0 Hz, 2 CH=CH–N), 7.51–7.65 (10H,
m, Harom), 7.97 (2H, d, J=7.0 Hz, 2 CH=CH–N), 13C NMR (101 MHz, DMSO-
d6): δC48.6 (CH2), 100.8 (C=C (CN)), 107.3 (C=C–N), 116.7 (CN), 128.7–136.0
(6× Carom), 144.3 (C=C–N), 160.1 (C=O), 160.6[C=C(CN)].Calcd for C26H18N4O2:
74.63 C, 4.34 H, 13.39 N. Found: 75.16 N, 4.30 H, 13.46 N.
1‑[3‑(3‑Cyano‑2‑oxo‑4‑phenylpyridin‑1(2H)‑yl)
propyl]‑2‑oxo‑4‑phenyl‑1,2‑dihydro‑pyridine‑3‑carbonitrile 4b
From 3b (0.54 g, 20 mmol) and butane-1,4-diamine (0.08 g, 10 mmol) it was
obtained compound 4b(60%), mp=220 ˚C as white solid. IR (νmax/cm−1): 1512
(C=C), 1600 (C=C), 1645 (C=O), 2221 (CN).1H NMR (400 MHz, DMSO-d6):
δH 1.71–1.80 (4H, s, 2 CH2), 4.00–4.08 (4H, s, 2 CH2), 6.51 (2H, d, J=7.0 Hz, 2
CH=CH–N), 7.51–7.65 (10H, m, Harom), 8.13 (2H, d, J=7.0 Hz, 2 CH=CH–N),
13C NMR (101 MHz, DMSO-d6): δC 25.9 (C–CH2–CH2), 49.5 (C–CH2–CH2), 100.8
(C=C(CN)), 107.2 (C=C–N), 116.8 (CN), 128.6–136.0 (6 Carom), 144.3 (C=C–N),
159.8 (C=O), 160.4 (C=C(CN)). Calcd. for C28H22N4O2: 75.3 C, 4.97 H, 12.55 N.
Found: 75.36 C, 4.89 H, 12.75 N.
1‑[3‑(3‑yano‑2‑oxo‑4‑phenylpyridin‑1(2H)‑yl)
propyl]‑2oxo‑4‑phenyl‑1,2‑dihydropyri‑dine ‑3‑carbonitrile 4c
From 3b (0.54 g, 20 mmol) and hexane-1,6-diamine (0.11 g, 10 mmol) it was
obtained compound 4c (54%), mp 251 ˚C as white solid. IR (νmax/cm1) 1509
1
(C=C), 1623 (C=C), 1690 (C=O), 2223 (CN). H NMR (400 MHz, DMSO-d6):
δH 1.29–1.42 (4H, s, 2 CH2), 1.64–1.77 (4H, s, 2 CH2), 3.92–4.08 (4H, s, 2 CH2),
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N. Mehiaoui et al.
6.53 (2H, d, J=7.0 Hz, 2 CH=CH–N), 7.53–7.68 (10H, m, Harom), 8.15 (2H, d,
J=7.0 Hz, 2 CH=CH–N). 13C NMR (101 MHz, DMSO-d6): δC 26.0 (C–CH2–CH2),
28.7 (C–CH2–CH2), 49.8 (C–CH2–CH2), 100.7 (C=C(CN)), 107.1 (C=C–N), 116.8
(CN), 128.5–136.0 (6 Carom), 144.2 (C=C–N), 159.7 (C=O), 160.3 (C=C(CN)).
Calcd. C30H26N4O2: 75.93 C, 5.52 H, 11.61 N. Found: 75.82 C, 5.52 H, 11.68 N.
1‑[(3‑Cyano‑2‑oxo‑4‑p‑tolylpyridin‑1(2H)‑yl)
methyl]‑2‑oxo‑4‑p‑tolyl‑1,2‑dihydro‑pyridine‑3‑carbonitrile 4d:
From 3b (0.58 g, 20 mmol) and 1,2-ethylenediamine (0.06 g, 10 mmol), it was
obtained compound 4d (46%), mp=235 °C as white solid. IR (νmax/cm1): 1509
1
(C=C), 1598 (C=C), 1652 (C=O), 2221 (CN). H NMR (400 MHz, DMSO-d6):
δH 2.39 (6H, s, 2 Ph-CH3), 4.34–4.36 (4H, m, 2 CH2), 6.49 (2H, d, J=7.0 Hz, 2
CH=CH–N), 7.34–7.58 (10H, m, Harom), 7.96 (2H, d, J=7.0 Hz, 2 CH=CH–N),13C
NMR (400 MHz, DMSO-d6): δC 21.4 (Ph-CH3), 45.4 (N–CH2–CH2), 100.6
(C=C(CN)), 106.9 (C=C–N), 116.5 (CN), 128.5–141.3 (6 Carom),144.2 (C=CN),
158.5 (C=O), 160.7 (C=C(CN)). Calcd. for C28H22N4O2: 75.32 C, 4.97 H, 12.55 N.
Found: 73.69 C, 4.95 H, 12.57 N.
1‑[3‑(3‑Cyano‑2‑oxo‑4‑p‑tolylpyridin‑1(2H)‑yl)
propyl]‑2oxo‑4‑p‑tolyl‑1,2‑dihydropyridine‑3‑carbonitrile 4e
From 3b (0.56 g, 20 mmol) and butane-1,4-diamine (0.08 g, 10 mmol) it was
obtained compound 4e (70%), mp=264 ˚C as white solid. IR (νmax/cm−1): 1506
1
(C=C), 1596 (C=C), 1652 (C=O), 2218 (CN). H NMR (400 MHz, DMSO-d6):
δH 1.70–1.76 (N–CH2–CH2), 2.39 (6H, s, 2 Ph-CH3), 3.99–4.06 (4H, m, 2 CH2),
6.52 (2H, d, J=7.0 Hz, 2 CH=CH–N), 7.34–7.58 (10H, m, Harom), 8.14 (2H, d,
J=7.0 Hz, 2 CH=CH–N). 13C NMR (400 MHz, DMSO-d6): δC 21.4 (Ph-CH3), 25.9
(N–CH2CH2), 49.4 (NCH2CH2), 100.4 [C=C(CN)], 107.1 (C=C–N), 116.9 (CN),
128.5–141.1 (6 Carom), 144.1 (C=C–N), 159.7 (C=O), 160.5 [C=C(CN)]. Calcd. for
C30H26N4O2: 75.93 C, 5.52 H, 11.81 N. Found: 76.15 C, 5.54 H, 11.71 N.
1‑[3‑(3‑Cyano‑4‑(4‑nitrophenyl)‑2‑oxopyridin‑1(2H)‑yl)
propyl]‑4‑(4‑nitrophenyl)‑2‑oxo‑1,2‑dihydropyridine‑3‑carbonitrile 4j
From 3d (0.70 g, 20 mmol) and butane-1,4-diamine (0.08 g, 10 mmol) it was
obtained compound 4j (62%), mp=257 ˚C as white solid. IR(νmax/cm−1): 1521
1
(C=C), 1600 (C=C), 1653 (C=O), 2224 (CN). H NMR (400 MHz, DMSO-d6):δH
1.73–1.79 (4H, m, 2 CH2), 4.03–4.09 (4H, m, 2 CH2), 6.60 (2H, d, J=7.0 Hz, 2
CH=CH–N), 7.90–7.94 (4H, m, Harom), 8.24 (2H, d, J=7.0 Hz, 2 CH=CH–N),
8.37–8.41 (4H, m, Harom), 13C NMR (101 MHz, DMSO-d6): δC 25.9 (N–CH2CH2),
49.7 (NCH2CH2), 101.5 (C=C(CN)), 107.0 (C=C–N), 116.3 (CN), 124.4–144.9
(Carom), 149.0 (C=C–N), 157.8 (C=O), 160.1 (C=C(CN)). Calcd. for C28H20N6O6:
62.68 C, 3.76 H, 15.66 N. Found: 62.48 C, 3.86 H, 15.66 N.
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Novel bis‑(3‑cyano‑2‑pyridones) derivatives: synthesis…
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1‑[3‑(3‑Cyano‑4‑(4‑nitrophenyl)‑2‑oxopyridin‑1(2H)‑yl)
propyl]‑4‑(4‑nitrophenyl)‑2‑oxo‑1,2‑dihydropyridine‑3‑carbonitrile 4 k
From 3d (0.70 g, 20 mmol) and hexane-1,6-diamine (0.11 g, 10 mmol) it was
obtained compound 4 k (49%), mp=259 °C as white solid. IR (νmax/cm−1): 1522
1
(C=C), 1603 (C=C), 1646 (C=O), 2222 (CN). H NMR (400 MHz, DMSO-
d6) δH 1.20–1.27 (4H, m, 2 CH2), 1.72–1.81 (4H, m, 2 CH2), 4.03–4.10 (4H, m,
2 CH2), 6.60 (2H, d, J=7.0 Hz, 2 CH=CH–N), 7.89–7.93 (4H, m, H arom), 8.24
(2H, d, J=7.0 Hz, 2 CH=CH–N), 8.36–8.43 (4H, m, Harom), 13C NMR (101 MHz,
DMSO-d6) δC 25.6 (N–CH2–CH2), 28.6 (N–CH2–CH2), 49.4 (NCH2CH2), 101.0
(C=C(CN)), 106.5 (C=CN), 116.3 (CN), 130.2 (6 Carom), 142.1 (C=CN), 145.0
(C=O), 159.7 (C=C(CN)).Calcd for C30H24N6O6: 63.82 C, 4.28 H, 14.89 N. Found:
62.64 C, 3.79 H, 15.35 N.
Crystallographic data
Crystal data for 3a: C16H18N2O2, M=270.32, monoclinic, space group I2/a,
Z=8, a=14.898(2) Å, b=13.702(2) Å, c=14.929(2) Å, β=109.276(3)º,
V=2876.8(7) Å3, μ(Mo-Kα)=0.083 mm−1, Dc =1.248 g cm−3, yellow block with
crystal size of 0.19×0.19×0.17 mm3. Of a total of 28,362 refections collected,
2647 were independent (Rint =0.070). Final R1=0.0432 [I>2σ(I)] and wR2=0.1105
(all data). Data completeness to theta=25.24°, 100%. CCDC1943247.
Crystal data for 4c: C15H13N2O, M=237.27, monoclinic, space group P21/c,
Z=4, a=10.5232(13) Å, b=7.4031(10) Å, c=15.729(2) Å, β=101.261(3)º,
V=1201.8(3) Å3, μ(Mo-Kα)=0.08 mm−1, Dc =1.311 g cm−3, colourless plate with
crystal size of 0.14×0.12×0.04 mm3. Of a total of 8279 refections collected, 2207
were independent (Rint =0.034). Final R1=0.0351 [I>2σ(I)] and wR2=0.0955 (all
data). Data completeness to theta=25.4°, 99.9%. CCDC1936900.
Results and discussion
The synthesis of bis-2-pyridone derivatives was based on three steps, the frst and
the second ones were previously published by our group [45]. First, we have pre-
pared easily α,β-unsaturated compounds 2a–c in moderate yield, via a Knoevenagel
condensation, of aromatic ketones with ethyl cyanoacetate, catalyzed by ammonium
acetate, under solvent-free conditions (Table 1).
The second step is the formation of enaminonitriles 3a–d as key intermediate
scafolds from olefns 2a–c. Enaminonitriles are known to be very reactive interme-
diates and serve as push–pull dienes. Here we have prepared enaminonitriles 3a–d
by reacting olefns 2a–d with one equivalent of N,N-dimethylformamide dimethyl
acetal (DMFDMA) under mild solvent-free conditions, at ambient temperature for
2 h (Table 2).
The structure of compound 3aas a key intermediate was frstly characterized by
spectroscopic analysis and by single-crystal X-ray difraction analysis (Fig. 3).
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N. Mehiaoui et al.
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Novel bis‑(3‑cyano‑2‑pyridones) derivatives: synthesis…
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N. Mehiaoui et al.
Fig. 3 Molecular unit present in compound 3a
Compound 3a crystallizes in the centrosymmetric monoclinic Ia/2 space group
with the asymmetric unit being composed of a sole enaminonitrile molecular unit
as depicted in Fig. 3. The molecule close packs mediated mainly by weak hydro-
gen bonding interactions; of the C‒H···O type, with the refned dC···O interatomic
distances being found in the 2.885(2)–3.369(3) Å range, having<(CHO) interac-
tion angles in the 126–155º interval; and of the C‒H···N type, with the refned dC···N
interatomic distances found in the 3.478(3)–3.572(3) Å range having<(CHO) inter-
action angles in the 168–171º interval. Despite the presence of an aromatic ring, no
structurally signifcant π–π interaction is present in the crystal structure.
The fnal step of this synthesis is the bis-2-pyridone ring formation, through
the reaction of 3a–d with various diamines in the presence of DMF, at refux, in
49–85% yield (Fig. 4).
Product 4c was identifed as a bis–2-pyridone by spectroscopic analysis, includ-
ing 2D NMR spectroscopy (Fig. 5). The COSY experiment of 4c confrmed a corre-
lation between the signal of the proton (CH2; HA) at 1.36 ppm with that at 1.72 ppm
(CH2; HB), which exhibits a cross peak with the signal at 1.36 ppm (CH2; HA) and
3.99 ppm (CH2; HC). The signal at 8.14 ppm (CH; HG) exhibits a correlation with
that at 6.52 ppm (CH2; HG).
We have obtained a single crystal of compound 4c which confrmed its bicyclic
structure. Compound 4c crystallizes in the centrosymmetric monoclinic P21/c space
group, with the asymmetric unit being composed of a half of the molecular unit:
1 3

Novel bis‑(3‑cyano‑2‑pyridones) derivatives: synthesis…
1343
DMF ,
reflux,
24h
H2N
O
O
NC
R
CO2Et
NC
R
CN
R
N
N
+
N
H2N
4a-k
3a-c
O
O
O
O
N
O
O
NC
NC
CN
CN
NC
CN
NC
O
CN
N
N
N
2
N
2
N
4
4c, 54 %
4a, 57%
4b, 60 %
O
NC
CN
O
N
O
O
O
N
2N
NC
CN
N
N
N
4
2
4d, 64 %
4e, 70 %
4f, 62 %
O
O
O
O
O
O
NC
NC
CN
CN
NC
CN
N
N
N
N
N
2N
2
4
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
O2N
NO2
4i, 58 %
4g, 77%
4h, 85 %
O
O
O
O
NC
CN
NC
CN
N
N
2
N
N
4
O2N
NO2
O2N
NO2
4j, 62 %
4k, 49 %
Fig. 4 Structures and yields of the cyclization to bis-2-pyridones 4a–k
the remaining portion of the molecule is formed by symmetry through an inver-
sion centre. The close packing in the solid state of individual units is very similar
as for the other crystalline compounds, mostly promoted by weak hydrogen bond-
ing interactions of the C‒H···N and C‒H···O types: dC···N distances found in the
3.4395(18)–3.4975(19) Å range with<(CHN) interaction angles ranging from 151
to155º; dC···O distances were found instead in the 3.2922(17)–3.3809(17) Å range
with the corresponding<(CHO) interaction angles in the range 131–138º. Weak π–π
contacts are present in this case, further promoting a close packing in the solid state
with inter-centroid distances in range of 3.7007(9)–3.8056(9) Å. The sole presence
of weak supramolecular interactions, allied with the high fexibility of the chain
between the cyano-2-pyridones backbones, leads to the existence of structural disor-
der for the four central ‒CH2‒ groups of the alkyl chain (Fig. 6).
We have study the fuorescence of these compounds in dichloromethane (Fig. 7).
The absorption and fuorescence emission spectral shapes depend only on the nature
of the pyridone and not on the alkyl chain length. All compounds absorb around
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N. Mehiaoui et al.
Fig. 5 COSY experiment and relative signs of coupling constants of 4c
350 nm; they emit at 415 nm, while nitro-containing compounds 4i, 4j and 4 k emit
at 460 nm; however, they are only slightly forescent since their fuorescence quan-
tum yield was measured to be below 0.01.
The mechanism of the described cyclization into bis-2-pyridones is proposed in
Scheme 1: starting by a condensation reaction of two equivalents of enaminonitriles
I with primary diamines to form intermediate II. The structures of bis-2-pyridones
IV were obtained by intramolecular cyclization followed by elimination of two mol-
ecules of ethanol.
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Novel bis‑(3‑cyano‑2‑pyridones) derivatives: synthesis…
1345
Fig. 6 Crystal structure of compound 4c (The disorder was refned with an occupancy rate of 50% in
each position)
Conclusion
Fig. 7 Absorption and fuorescence emission of pyridone dimers in dichloromethane
In conclusion, we have developed an efcient procedure to prepare a new series of
bis-2-pyridones and its various analogues using enaminonitriles as key intermedi-
ates and diamines in good yields. The fuorescence study demonstrates that the fuo-
rescence depends only on the nature of the pyridone and not on the alkyl chain.
The proposed syntheses are simple, with good yields and the scope of this approach
could be extended to the preparation of other families of molecules.
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N. Mehiaoui et al.
O
O
NH2
EtO
H2N
CN
NC
O
EtO
OEt
NC
N
OEt
N
R
N
N
H
R
O
H
R
II
I
CN
R
I
H
O
H
O
O
O
OEt
EtO
N
NC
CN
NC
CN
N
N
N
R
R
R
R
III
IV
Scheme 1 Proposed mechanism for the synthesis of compounds 4a–k
Acknowledgements The authors wish to thank Directorate General for Scientifc Research and Techno-
logical Development (DGRSDT) and the University of Tlemcen for the fnancial support. A part of this
work was developed within the scope of the projects CICECO-Aveiro Institute of Materials (FCT UID/
CTM/50011/2019) and QOPNA (FCT UID/QUI/00062/2013) through national funds and, where appli-
cable, co-fnanced by FEDER, within the PT2020 Partnership Agreement. RFM also gratefully acknowl-
edges FCT for a Junior Research Position (CEECIND/00553/2017)
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maps and institutional afliations.
Afliations
Nawel Mehiaoui1 · Zahira Kibou1,2 · Thibault Gallavardin3 · Stéphane Leleu3 ·
Xavier Franck3 · Ricardo F. Mendes4 · Filipe A. Almeida Paz4 · Artur M. S. Silva5 ·
Noureddine Choukchou‑Braham1
1
Laboratoire de Catalyse Et Synthèse en Chimie Organique, Faculté des Sciences, Université de
Tlemcen, BP 119, 13000 Tlemcen, Algeria
2
Centre Universitaire Ain Témouchent, Institut Des Sciences, BP 284, 46000 Ain Témouchent,
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N. Mehiaoui et al.
Algeria
3
4
5
COBRA (UMR6014 and FR 3038), Normandie Univ, CNRS, INSA Rouen, UNIROUEN,
76000 Rouen, France
Department of Chemistry, CICECO–Aveiro Institute of Materials, University of Aveiro,
3810-193 Aveiro, Portugal
Department of Chemistry, QOPNA & LAQV-REQUIMTE, University of Aveiro,
3810-193 Aveiro, Portugal
1 3