Easy solventless synthesis of new mono and bis amino-5H-chromeno [3,4-c] pyridin-5-one derivatives

Article abstract of DOI:10.1016/j.tet.2016.01.063

A new series of mono and bis amino-5H-chromeno [3,4-c] pyridin-5-one derivatives were prepared via the reaction of primary amines with 4-(2-(dimethylamino)vinyl)-2-oxo-2H-chromene-3-carbonitrile 3. The X-rays structures of 4-(hexylamino)-5H-chromeno[3.4-c

Full text of DOI:10.1016/j.tet.2016.01.063

Accepted Manuscript
Easy Solventless Synthesis of new mono and bis amino-5H-chromeno [3,4-c]
pyridin-5-one derivatives
Zahira Kibou, Didier Villemin, Jean-François Lohier, Nawel Cheikh, Nathalie Bar,
Noureddine Choukchou-Braham
PII:
S0040-4020(16)30063-1
10.1016/j.tet.2016.01.063
TET 27470
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 2 December 2015
Revised Date: 27 January 2016
Accepted Date: 31 January 2016
Please cite this article as: Kibou Z, Villemin D, Lohier J-F, Cheikh N, Bar N, Choukchou-Braham N,
Easy Solventless Synthesis of new mono and bis amino-5H-chromeno [3,4-c] pyridin-5-one derivatives,
Tetrahedron (2016), doi: 10.1016/j.tet.2016.01.063.
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ACCEPTED MANUSCRIPT
Easy Solventless Synthesis of new mono and bis amino-5H-chromeno [3,4-c]
pyridin-5-one derivatives. Zahira Kibou, Didier Villemin*, Jean-François Lohier, Nawel
Cheikh, Nathalie Bar, Noureddine Choukchou-Braham.
O
R
N
O
O
HN
CN
CN
O
O
O
R-NH2
(CH3O)2CHN(CH3)2
RT, 2h
CH3
90° C, 3 h
N
89%
75-90%

ACCEPTED MANUSCRIPT
Easy Solventless Synthesis of new mono and bis amino-5H-
chromeno [3,4-c] pyridin-5-one derivatives.
Zahira Kibou,a.b,c Didier Villemin,a,* Jean-François Lohier,a Nawel
Cheikh,b.d Nathalie Bar,a Noureddine Choukchou-Brahamb
a
Normandie Univ. France, ENSICAEN, LCMT, UMR CNRS 6507, INC3M,
FR 3038, Labex EMC3, Labex SynOrg, 14050 Caen, France.
b
Laboratoire de Catalyse et Synthèse en Chimie Organique, Faculté des
Sciences, Université de Tlemcen, BP 119, 13000 Tlemcen, Algeria
c
Centre Universitaire Ain Témouchent, Institut des Sciences et de la
Technologie, BP 284, 46000 Ain Témouchent, Algeria
d
Université de Béchar, Faculté des Sciences et Technologie, BP 417, 08000
Béchar, Algeria
*Corresponding author: Tel : +231452840 ; fax :+231452877 ; e-mail address :
didier.villemin@ensicaen.fr
Abstract:
A new series of mono and bis amino-5H-chromeno [3,4-c] pyridin-5-one
derivatives were prepared via the reaction of primary amines with 4-(2-
(dimethylamino)vinyl)-2-oxo-2H-chromene-3-carbonitrile 3. The X-rays
structures of 4-(hexylamino)-5H-chromeno[3.4-c]pyridin-5-one 4a are reported
and discussed. The proposed synthesis method provides several advantages
including a simple chemistry handling, mild reaction conditions and an
environmentally friendly synthesis pathway.
Keywords: 2-oxo -2-chromene-3-carbonitrile, amino-5H-chromeno [3,4-c]
pyridin-5-one derivatives, N,N-dimethylformamide dimethyl acetal, solvent-free
reactions.
1

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1 Introduction
Substituted chromenopyridines are an important class of heterocyclic
compounds. They are biologically active and constitute important components in
many natural compounds.1-5 For example, coumarins condensed to pyridine ring
constitute the core of naturally occurring alkaloids as santiagonamine.6
Figure 1. Structure of the Santiagonamine
Some of these chromenopyridines are particularly useful in the pharmaceutical
research as they exhibit several biological activities including antibacterial7,
antitumor,8 antiasthmatic9 and hypotensive features.10 To our knowledge, few
syntheses of chromenopyridines are reported in the literature,11-14 and they are
usually carried out in organic solvents.15
Furthermore, the reactivity of enamines is well-known for a long time and
generally, the enamines carrying electrowithdrawing groups react with primary
amines by addition and elimination reactions leading to new enamines which
can conduct to ring formation.16
Scheme 1. Reaction of primary amines with enamines carrying
toelectrowithdrawing group Z.
In a previous work, we have already described the reaction of enaminonitriles
with primary amines into aminopyridines (Scheme 2). 17
2

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X = H, Me OMe.
R = alkyl or aryl group.
Scheme 2. Reactions of primary amines with enaminonitriles affording
aminopyridines, in solvent free conditions.
For this purpose, the reaction of 4-(2-(dimethylamino)vinyl)-2-oxo-2H-
chromene-3-carbonitriles with primary amines has been investigated (Scheme
3).
N
N
sovent -free
reflux, 3h
CN
O
NHR
R-NH2 +
O
O
O
4a-h
3
Scheme 3: Transformation of 3 into aminopyridines with various conditions.
literature18
the
However,
reported
the
same
reaction
with
cyanoenaminocoumarin 3 and primary amines leading to the formation of
pyridin-2(1H)-imine derivatives (Scheme 4) and not to the expected 2-
aminopyridine compounds.
N
R
N
CN
O
AcOH
NH
R-NH2 +
reflux, 3h
O
O
O
3
Scheme 4: Transformation of 3 into pyridin-2(1H)-imine derivatives according
to H.M. El-Shaaer.18
3

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This work questioned our own results and has forced us to reconsider all the
analysis of our products. Fortunately, we were able to obtain a crystallized
product by the reaction of the cyanoenaminocoumarin 3 with N-hexylamine.
The structure of this product was characterized by NMR spectroscopy and
mainly by X-rays diffraction. This later methodology demonstrated
unambiguously the formation of the moiety 2-aminopyridine.
In this paper, we generalize the reaction of 4-[2-(dimethylamino) vinyl]-2-oxo-
2H-1-chromeno-3-carbonitrile 3 with primary amines and diamines to prepare
mono 4-amino-5H-chromeno[3,4-c]pyridin-5-ones 4a-h and bis 4-amino-5H-
chromeno[3,4-c]pyridin-5-ones 5a-h structures ( Figure 2).
R
O
HN
O
HN
NH
O
O
N
N
O
O
N
4a-h
5a-h
Figure 2. Structures of chromenopyridines 4a-h and bis-chromenopyridines 5a-
h
2. Results
a) Synthesis of the 4-(2-(dimethylamino)vinyl)-2-oxo-2H-chromene-3-carbo
nitrile 3:
This starting reactant 3 is prepared in two steps. The first one consists in the
preparation of the 4-methyl-2-oxo-2H-chromene-3-carbonitrile 2. We found
that, 2-hydroxy-acetophenone 1 reacts successfully with ethyl 2-cyanoacetate in
the presence of either ammonium acetate or ammonium carbonate in solventless
conditions. The results revealed, when the reaction proceeds under microwave
irradiations, the desired product 2 was obtained upon a very short reaction time
4

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(6 min). Using classical heating reaction conditions at 80 °C, the reaction time
increases to 180 minutes and the results are summarized in Table 1.
Table 1: Synthesis of 4-methyl-2-oxo-2H-chromene-3-carbonitrile 2
CH3
OH
O
CN
O
CN
Base
+
O
∆/ΜW
CO2Et
2
1
Yield a, b (%)
Product
Time (min)
Base
83a
180
NH4OAc
90a
68b
73b
(NH4)2CO3
180
6
2
NH4OAc
(NH4)2CO3
6
a Isolated yield of the reaction carried out under solvent-free conditions with conventional heating
b Isolated yield of the reaction carried out under solvent-free conditions under microwave activation
Furthermore Meerwein et al19 described the synthesis of enamine by the reaction
of N,N-dimethylformamide dimethyl acetal (DMFDMA) with acidic carbon
compounds. This reaction was used for the synthesis of numerous heterocyclic
compounds.20
The reaction of 4-methyl-2-oxo-2H-chromene-3-carbonitrile 2 with one
equivalent of N,N-dimethylformamide dimethyl acetal (DMFDMA) was
performed under mild conditions without solvent, at room temperature and
during two hours. A reaction yield of 89 % was reached after a simple
purification by diethyl ether. The structure of 4-methyl-2-oxo-2H-chromene-3-
1
carbonitrile 3 was elucidated based on spectroscopic analysis. The H NMR
spectrum showed two singlet signals at δH = 3.01 and 3.30 ppm corresponding to
the two methyl groups of NMe2 moiety. The formation of the C=C band
exhibited two characteristic doublets for CH=CH-N proton at δH = 5.53 ppm and
5

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at 8.53 for CH=CH-N with a characteristic coupling constant of 12 Hz.
Moreover, the mass spectrum gave a molecular ion peak at m/z 241
corresponding to (M+H+). The compound 3 has been already described but its
preparation involves always toxic organic solvents as xylene.
N
CH3
CN
CN
89%
O
MeO
MeO
without solvent
RT, 2h
N
+
O
O
O
2
3
Scheme 5. Synthesis of 3 from cyanocoumarin 2.
b) Synthesis of Chromenopyridine with N-hexylamine
The reaction of N-hexylamine with cyanoenaminocoumarin 3 was performed
by mixing the reagents without solvent and heating at 90° C for two hours,
affording the product 4a obtained after crystallisation in a mixture of
acetonitrile-isopropanol.
The structure of compound 4a was firstly characterized by IR, mass
1
13
spectroscopy, H and C NMR. We should admit that none of these techniques
allows concluding clearly either the 2-aminopyridine or the iminopiperidine
structure was obtained. However, X-rays crystallography of compound 4a
confirmed undoubtedly the structure of the chromenopyridine (Figure 3). 22
6

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Figure 3. Crystal structure of compound 4a.
Intramolecular H-bond between N2-H1… O2 is present within the molecule 4a
to form a 6-membered ring.
Crystal packing is governed by two intermolecular weak interactions of CH…O
and CH…N type leading to infinite sheets of molecules along
axis. As
well, Pi…Pi stacking occurs between aromatic rings, distance between two
planes is about 3.40 Å.
Figure 4. Crystal packing of compound 4a.
A mechanism of the reaction can be proposed (Scheme 7). It is noteworthy that
the structure of aminopyridine involves that primary amine acts as nucleophile
7

ACCEPTED MANUSCRIPT
on the carbon of nitrile and not as what could seem obvious, on the carbon of the
enamine as in classical results.
Scheme 6. Supposed mechanism for the formation of iminopiperidine.
R
R
N
NHR'2
O
N
R
N
O
O HN
O HN
N
NH2R
NR'2
H
O
O
O
NH
O
NR'2
4 a-h
Scheme 7. Plausible mechanism for the formation of 2-aminopyridine moiety
.
c) Generalization synthesis
We extended the synthesis of chromenopyridines with various amines and
diamines.
Monoamines
We prepared new chromenopyridine structures (amino-5H-chromeno [3,4-c]
pyridin-5-ones) 4a-h by nucleophilic addition of primary amines on 3-cyano-4-
enaminocoumarin 3 (Table 2).
The reaction was performed following a simple procedure by mixing the
reagents in dry conditions and heating at 90° C. After 3 hours of the reaction, the
products 4a-h were obtained in very good yields. The structures of the
compounds 4a-h were established on the basis of the spectroscopic data.
Table 2: Synthesis of mono (amino-5H-chromeno[3,4-c]pyridin-5-ones) 4a-h
R
O
HN
O
CN
O
O
R-NH2
N
90° C, 3 h
75-90%
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_______________________________________________________________________
Entry
Yield (%)
R-NH2
Product
________________________________________________________________________
O HN
O
N
1
90
80
Hexylamine
Allylamine
4a
O HN
O
N
2
4b
O HN
3
Benzylamine
O
N
88
4c
O HN
O
N
Propylamine
Butylamine
4
5
83
89
4d
O HN
O
N
4e
O HN
O
N
Methylamine
75
85
6
4f
O HN
7
Cyclohexylamine
O
N
4g
O HN
81
8
2-phenylethylamine
O
N
4h
______________________________________________________________________
9

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Diamines
This successful achievement has motivated the synthesis of a new series of
hexacyclic (or more) molecules: the bis-chromenopyridines. For this purpose,
one equivalent of diamine reacted with two equivalents of 3-cyano-4-
enaminocoumarin 3. However, the choice of an appropriate reaction medium is
of crucial importance for a successful synthesis. Unfortunately addition of a
solvent was necessary to enhance the reaction kinetics probably because the
addition is double on both sides of the diamine (Scheme 8). The reaction was
refluxed in DMF for 3 hours. After evaporation of the solvent and successive
washings with diethyl ether, new hexacyclic «bis-Chromenopyridines» 5a-h
products were obtained. To our knowledge, they are not described in the
literature. The results of this new series of molecules are presented in Table 3.
The structures of compounds 5a-h were deduced from mass spectroscopy data,
13
1H and C NMR, and IR. The mass spectroscopy of 5b displayed a molecular
ion peak at m/z 479, which is in agreement with the proposed structure. The IR
spectrum of this compound showed strong absorption band at 3260 cm-1 due to
the NH group. The H1 NMR spectrum of 5b revealed a large singlet for the NH
groups (δ= 6.61 ppm), and the aromatic moieties showed multiplets in the
aromatic region of the spectrum (δ= 7.31-7.48 ppm). As shown in Table 3, this
synthesis process was successfully applied to other types of diamines. The
spectroscopic data of the obtained products confirmed the formation of proposed
structures listed in the Table 3.
O
HN
O
NH
O
CN
O
N
O
N
O
Diamine
N
DMF/∆
5a-h
3
Scheme 8: Synthesis of bis (amino-5H-chromeno [3,4-c] pyridin-5-ones) 5a-h
10

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Table 3: Synthesis of bis (amino-5H-chromeno [3,4-c] pyridin-5-ones) 5a-h
Entry
Yield (%)
Diamine
Product
O
HN
NH O
O
N N
O
Ethane1,2diamine
12
9
5a
O
HN
N
NH
O
O
N
O
O
Propane-1,3diamine
15
22
10
11
12
13
5b
( )2
O
O
HN
HN
NH O
O
O
N
N
N
Butane-1,4diamine
Hexane-1,6-diamine
5c
( )4
NH O
N
O
O
O
28
31
5d
( )6
O
O
HN
HN
NH
NH
O
O
O
O
N
N
N
Octane-1,8-diamine
5e
( )10
N
35
41
14
15
Dodecane-1,12-diamine
m-Xylenediamine
5f
O
HN
NH O
O
N
N
O
5g
O
HN
NH
O
O
N
N
O
38
16 trans-Cyclohexane-1,2-diamine
5h
11

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Scheme 8: Synthesis of bis (amino-5H-chromeno [3,4-c] pyridin-5-ones) 5a-h
3. Conclusion
The reaction of the cyanoenaminocoumarin 3 with primary amines leads to the
chromenopyridines and not to the iminopiperidines previously described3. We
successfully demonstrated an efficient and practical procedure for the
preparation of a wide range of novel mono and bis (amino-5H-chromeno [3,4-
c] pyridin-5-ones) starting from a cyanoenaminocoumarin 3 as a key
precursor and several primary amines or diamines. The mild reaction
conditions, the simple synthesis pathway, the environmentally friendly
procedure and the good yields obtained are the most significant advantages of
this synthesis strategy proposed for the preparation of the chromenopyridines.
Acknowledgement
The authors wish to thank Karine Jarsalé for the mass spectroscopy spectra. The authors also
wish to thank “Ministère de l’Enseignement Supérieur et de la Recherche Scientifique
Algérien” (MESRS) for the financial support in the framework of PNR programme 2011. We
gratefully acknowledge financial support from the ‘Ministère de la Recherche et des
Nouvelles Technologies’, CNRS (Centre National de la Recherche Scientifique), the ‘Région
Basse-Normandie’ and the European Union (FEDER funding). The authors acknowledge the
financial support of the french Agence Nationale de la Recherche (ANR), through the
program “Investissements d’Avenir”(ANR-10-LABX-09-01), LabEx EMC3.
1. Experimental
4.1. General information
The melting points were measured using a Bank Kofler 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 significant absorptions
1
are listed. The H NMR and 13C NMR spectra were recorded on a Brüker AC 400
spectrometers at 400 MHz. Samples were recorded in CDCl3 solutions using TMS as an
internal standard. The chemical shifts are expressed in δ units (ppm) and quoted downfield
from TMS. The multiplicities are reported as: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet. Mass spectra were recorded on a QTOF Micro (Waters), ionization electrospray
12

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positive (ESI), lockspray PEG, infusion introduction (5 mL/min), source temperature 80°C,
desolvatation temperature 120 °C.
4.2. Synthesis of 4-methyl-2-oxo-2H-chromene-3-carbonitrile 2 :
General procedure A: one pot synthesis of compound 2 using conventional heating
In a round-bottomed flask equipped with a condenser, a mixture of 2-hydroxyacetophenone 1
(0.01 mol; 1.13 g), ethyl cyanoacetate (0.01 mol; 0.96 g) and ammonium acetate (0.01 mol;
0.77 g) or ammonium carbonate (0.01 mol; 0.96 g) were stirred at 80 °C for 3h. The
precipitate was filtered, washed with ethanol, dried and crystallized from ethanol to give 2 in
the yield of 83 % with ammonium acetate and 90% with ammonium carbonate.
General procedure B: on -pot synthesis of compound 2 using microwave irradiations
A mixture of 2-hydroxyacetophenone 1 (0.01 mol; 1.13 g), ethyl cyanoacetate (0.01
mol; 0.96 g) and ammonium acetate (0.01 mol; 0.77 g) or ammonium carbonate (0.01 mol;
0.96 g) were irradiated under microwave conditions for 6 min. The reaction mixture was
cooled down to room temperature, diluted with 30 mL of CH2Cl2. The organic layer obtained
was washed with water (3 × 20 mL), saturated NaCl (10 mL), dried on MgSO4, filtered then
evaporated under vacuum. The compound 2 were obtained as a white solid in the yield of
68% with ammonium acetate and 73% with ammonium carbonate; mp 196°C, IR νmax
(neat/cm-1): 1525 (C=C), 1583 (C=C), 1683( C=O); 2219 (CN) ; 1H NMR (CDCl3) δH: 2.77
(3H, s, CH3); 7.25-7.44 ( 2H, m, Harom); 7.68-7.76 (2H, m, Harom). 13C NMR (CDCl3) δC : 24.3
(CH3); 87.7 (C=C(CN); 116.3 (CN); 121.6-128.4 (5XCarom); 150.3 (C=C-O); 156.3 (C=O);
172.1 (C=C-CH3).
4.3. Synthesis of 4-(2-(dimethylamino)vinyl)-2-oxo-2H-chromene-3-carbonitrile 3
A mixture of 4-methyl-2-oxo-2H-chromene-3-carbonitrile 2 (10 mmol ; 1.85 g) and N,N-
dimethylformamide dimethyl acetal (10 mmol, 1.19 g) were stirred at room temperature
without solvent during 2 hours. The solution take increasingly a dark burn color. The purple
solid obtained was washed several times with diethyl ether and crystallised in absolute ethanol
1
to provide product 3 as a green solid (89%). mp 202°C; H NMR (CDCl3) δH: 3.01 (3H, s,
CH3); 3.30 (3H, s, CH3); 5.53 (1H, d, JH-H = 12.0 Hz, CH=CH-N); 7.26-7.78 (4H, m, Harom );
8.53 (1H, d, JH-H = 12.0 Hz, CH=CH-N); 13C NMR (CDCl3) δC : 37.2 (CH3); 46.4 (CH3); 81.9
(C=C (CN)); 87.9 (C=C-N); 117.8 (CN); 119.4 (C=C); 124.3-124.5 (4x Carom); 133.2 (C=C-
N); 153.0 (C-O); 160.3 (C=O); 178.2 (C=C(CN)); IR (neat/cm-1): 1513 (C=C) ; 1598
13

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(C=C) ;1683 (C=O); 2219(CN);; HRMS (ES-QTOF) calcd for C14H13N2O2 M+H 241.1311.
Found 241.1302.
4.4. Synthesis of chromenopyridines and bis-chromenopyridines
4.4.1. General method 1: Synthesis of chromenopyridines 4a-h:
A mixture of 3 (10 mmol) and primary amine (10 mmol) was heated for 2 h. After the
completion of the reaction, the crude product obtained was washed several times with
diethylether and filtered to give chromenopyridines derivatives 4a-h.
4.4.1.1. 4-(hexylamino)-5H-chromeno[3.4-c]pyridin-5-one 4a:
The general procedure 1 using (0.48 g; 2 mmol) of 4-(2-(dimethylamino)vinyl)-2-oxo-2H-
chromene-3-carbonitrile 3 and (0.20 g; 2 mmol) of hexylamine produced 90% of 4a as a
1
white solid, mp : 68 °C. IR νmax (neat/ cm-1): 1586 (C=C); 1618 (C=O); 3352 (NH); H NMR
(CDCl3) δH: 0.84 (3H, t, JH-H = 12.2 Hz, -(CH2)5- CH3); 1.28 (2H, m, -CH2 –CH3); 1.33 (2H,
m, N-CH2-CH2-(CH2)3 –CH3); 1.34 (2H, m, N-CH2-CH2-CH2-(CH2)2 –CH3) ; 1.59 (2H, m,
N-CH2-CH2-(CH2)3 –CH3), 2.51 ( t, JH-H = 12.2 Hz, N-CH2-CH2-CH2-CH2-CH2 –CH3) ; 3.52
(1H, t, JH-H = 4.0 Hz, NH); 7.34-7.41 (4H, m, Harom); 8.22 (1H, d, JH-H = 5.8 Hz, CH=CH-N);
8.60 (1H, d, JH-H = 5.8 Hz, CH=CH-N) ; 13C NMR (CDCl3) δC : 14.3 (-(CH2)5- CH3); 22.3 (N-
CH2-CH2-CH2-CH2-CH2 –CH3); 26.7 (N-CH2- CH2-CH2 CH2- CH2 –CH3); 31.1 (N-CH2-
CH2-CH2-CH2-CH2 –CH3); 31.5 (N-CH2- CH2-CH2-CH2-CH2 –CH3); 40.2 (N-CH2-CH2-CH2
–CH3); 98.0 (C=C-CN ); 113.5 (CH=CH-N); 125.1-126.12 (4×Carom); 132.93(Carom); 144.1
(CH=CH-N); 152.2 (Carom); 155.34 (C=C-CN); 159.1 (N=C-NH) ; 161.7 (C=O). HRMS (ES-
QTOF) calcd for C18H21N2O2 M+H 297.1603. Found 297.1613.
4.4.1.2. 4-(allylamino)-5H-chromeno[3.4-c]pyridin-5-one 4b:
The general procedure 1 using (0.48 g; 2 mmol) of 4-(2-(dimethylamino)vinyl)-2-oxo-2H-
chromene-3-carbonitrile 3 and (0.15 g; 2 mmol) of allylamine gave 80% of 4b as white
1
solid, mp : 189 °C. IR νmax (neat/ cm-1): 1586 (C=C); 3355 (NH); H NMR (CDCl3) δH : 4.63-
4.65 (2H, m, NHCH2); 5.26-5.33 (2H, m, CH=CH2-N); 5.88 ( 1H, s large , NH); 5.99-6.09
(1H, m, CH=CH2-N); 6.27 (1H, d, JH-H = 9.2 Hz, CH=CH); 7.55-7.59 (4H, m, Harom); 8.89(
1H, d, JH-H = 9.2 Hz, CH=CH);13C NMR (CDCl3) δC : 46.2 (CH2); 90.3 (C=CN); 109.1
(C=C); 113.1 (CH=CHN); 116.6 (CH=CH2); 128.2-129.8 (4×Carom); 134.3 (CH=CH); 136.8
(Carom); 152.1 (CH=CH-N); 154.5 (C=C); 159.2 (N=C-NH); 160.1 (C=O); EIMS m/z (%
14

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relative abundance): 253 (M+H, 25), 133 (100), HRMS (ES-QTOF) calcd for C15H13N2O2
M+H 253.1215. Found 253.1209.
4.4.1.3. 4-(benzylamino)-5H-chromeno[3.4-c]pyridin-5-one 4c:
The general procedure 1 using (0.48 g; 2 mmol) of 4-(2-(dimethylamino)vinyl)-2-oxo-2H-
chromene-3-carbonitrile 3 and (0.21 g; 2 mmol) of benzylamine gave 88% of 4c as white
solid, mp : 212 °C. IR νmax (neat/ cm-1): 1584 (C=C); 1620 (C=O); 3356 (NH); 1H NMR
(CDCl3) δH : 4.46 (2H, d, JH-H = 5.1 Hz, NH-CH2); 5.25 (1H, t, JH-H = 5.1 Hz, NH; 6.69 (1H,
d, JH-H = 4.6 Hz, CH=CH); 7.28-7.30 (4H, m, Harom); 7.46-7.58 (5H, m, Harom ); 9.51 (1H, d,
JH-H = 4.6 Hz, CH=CH); 13C NMR (CDCl3) δC : 45.6 (CH2); 91.7 (C=C-CN); 113.1
(CH=CH); 116.9 (CN); 127.6-128.2 (5×Carom); 128.7-129.8 (4×Carom); 136.78 (Carom); 136.4
(Carom); 152.1 (CH=CH); 154.5 (C=C-CN); 159.3 (N=C-NH) ; 160.1 (C=O). EIMS m/z (%
relative abundance): 303 (M+H, 50), 245 (100) ; HRMS (ES-QTOF) calcd for C19H14N2O2
M+H 303.1119. Found 303.1112.
4.4.1.4. 4-(propylamino)-5H-chromeno[3.4-c]pyridin-5-one 4d :
The general procedure 1 using (0.48 g; 2 mmol) of 4-(2-(dimethylamino)vinyl)-2-oxo-2H-
chromene-3-carbonitrile 3 and (0.14 g; 2 mmol) of propylamine gave 83% of 4d as a white
solid, mp : 91 °C. IR νmax (neat/ cm-1): 1588 (C=C); 1618 (C=O); 3354 (NH); 1H NMR
(CDCl3) δH: 0.96 (3H, t, JH-H = 12.3 Hz, CH3); 1.66 (2H, m, -N-CH2- CH2 –CH3); 2.51 (2H,
m, N-CH2-CH2–CH3);–CH3) ; 3.50 (1H, t, JH-H = 4.0 Hz, NH); 7.34-7.65(4H, m, Harom); 8.24
(1H, d, JH-H = 5.8 Hz, CH=CH-N); 8.62 (1H, d, JH-H = 5.8 Hz, CH=CH-N) ; 13C NMR
(CDCl3) δC : 11.9 (-(CH2)2- CH3); 22.5 (N-CH2-CH2–CH3); 40.2 –(CH2-CH2–CH3); 98.0
(C=C-CN ); 103.9 (CH=CH-N); 125.1-126.3 (4×Carom); 133.0(Carom); 144.2 (CH=CH-N);
152.2 (Carom); 155.4 (C=C-CN); 159.2 (N=C-NH) ; 161.7 (C=O). HRMS (ES-QTOF) calcd
for C15H15N2O2 M+H 255.1133. Found 255.1112.
4.4.1.5. 4-(butylamino)-5H-chromeno[3.4-c]pyridin-5-one 4e:
The general procedure 1 using (0.48 g; 2 mmol) of 4-(2-(dimethylamino)vinyl)-2-oxo-2H-
chromene-3-carbonitrile 3 and (0.146 g; 2 mmol) of butylamine gave 89% of 4e as a white
1
solid, mp : 228 °C. IR νmax (neat/ cm-1): 1585 (C=C); 1619 (C=O); 3358 (NH); H
NMR(CDCl3) δH: 0.98 (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); 2.65 ( 2H, t, JH-H = 7.2 Hz, N-CH2-CH2-CH2 –
15

ACCEPTED MANUSCRIPT
CH3) ; 5.89 (1H, t, JH-H = 4,0 Hz, NH); 6.68 (1H, d, JH-H = 5.8 Hz, CH=CH-N); 7.32-7.58 (4H,
m, Harom); 8.98 (1H, d, JH-H = 5.8 Hz, CH=CH-N); 13C NMR (CDCl3) δC : 13.8 (-(CH2)3- CH3);
21.3 (N-CH2-CH2-CH2 –CH3); 33.5 (N-CH2-CH2-CH2 –CH3); 42.8 (N-CH2-CH2-CH2 –CH3);
88.2 (C=C-CN ); 113.5 (CH=CH-N); 126.1-130.0 (4×Carom); 136.8 (Carom); 152.1 (CH=CH-
N); 155.3 (C=C-CN); 162.2 (N=C-NH) ; 164.1 (C=O); EIMS m/z (% relative abundance):
269 (M+H, 25), 88 (100), HRMS (ES-QTOF) calcd for C16H17N2O2 M+H 269.1115. Found
269.1102.
4.4.1.6. 4-(methylamino)-5H-chromeno[3.4-c]pyridin-5-one 4f:
The general procedure 1 using (0.48 g; 2 mmol) of 4-(2-(dimethylamino)vinyl)-2-oxo-2H-
chromene-3-carbonitrile 3 and (0.15 g; 2 mmol) of methylamine gave 75% of 4f as a white
solid, mp : 208°C. IR νmax (neat/ cm-1): 1583 (C=C), 1558 (C=C); 1618 (C=O); 3383 (NH). 1H
NMR (CDCl3) δH: 2.98 (3H, d, JH-H = 4.00 Hz, CH3); 5.25 (1H, t, JH-H = 4.0 Hz, NH);
6.94(1H, d, JH-H = 5.8 Hz, CH=CH-N); 7.30-7.54 (4H, m, Harom); 9.33 (1H, d, JH-H = 5.8 Hz,
CH=CH-N); 13C NMR (CDCl3) δC : 29.7 (CH3); 89.1 (C=C- ); 111.3 (CH=CH-N); 116.0
(CN); 128.1-129.4 (4×Carom); 136.66 (Carom); 152.0 (CH=CH-N); 152.4(C=C-); 160.3 (N=C-
NH); 160.1 (C=O); EIMS m/z (% relative abundance): 227 (M+H, 28), 180(100), HRMS
(ES-QTOF) calcd for C13H11N2O2 M+H 227.1519. Found 227.1511.
4.4.1.7. 4-(cyclohexylamino)-5H-chromeno[3.4-c]pyridin-5-one 4g:
The general procedure 1 using (0.48 g; 2 mmol) of 4-(2-(dimethylamino)vinyl)-2-oxo-2H-
chromene-3-carbonitrile 3 and (0,19 g; 2 mmol) of cyclohexylamine gave 85% of 4g as a
1
white solid, mp : 206 °C. IR νmax (neat/ cm-1): 1584 (C=C); 1620 (C=O); 3353 (NH) ; H
NMR (CDCl3) δH : 1.12-1.82 (10H, m, 5 X-(CH2)-); 2.30 (1H, s, CH); 3.35 (1H, s, NH); 6.62
(1H, d, JH-H = 8.2 Hz, CH=CH); 7.38-7.98 (4H, m, Harom); 8.27 (1H, d, JH-H = 8.2 Hz,
CH=CH); 13C NMR (CDCl3) δC : 26.2 (2 X-(CH2)-); 28.1 ( -CH2-) 31.36 (2 X-(CH2)-); 54.2
(CH-N); 94.6 (C=C); 117.14 (CH=CH-); 125.3-126.2 (4×Carom); 133.0(Carom); 143.8
(CH=CH-N); 152.2 (C=C); 152.38 (Carom); 153.4 (C-O); 160.2 (N=C-NH) ; 178.6 (C=O).
HRMS (ES-QTOF) calcd for C18H19N2O2 M+H 295.1447. Found 295.1443.
4.4.1.8. 4-(phenethylamino)-5H-chromeno[3.4-c]pyridin-5-one 4h:
The general procedure 1 using (0.48 g; 2 mmol) of 4-(2-(dimethylamino)vinyl)-2-oxo-2H-
chromene-3-carbonitrile 3 and (0.24 g; 2 mmol) of phenylethylamine gave 81% of 4h as a
16

ACCEPTED MANUSCRIPT
white solid, mp : 202 °C. IR νmax (neat/ cm-1): 1581 (C=C); 1619 (C=O); 3352 (NH); 1H
NMR (CDCl3) δH : 2.90 (2H, t, NH-CH2-CH2); 3.04 (2H, t, NH-CH2-CH2); 3.82 (1H, q, JH-H
=
4.0 Hz, NH); 7.25-7.35 (5H, m, Harom); 7.43-7.67 (4H, m, Harom ); 8.27 (1H, d, JH-H = 4.4 Hz,
CH=CH); 8.48 (1H, d, JH-H = 4.4 Hz, CH=CH); 13C NMR (CDCl3) δC : 33.4 (CH2); 41.2
(CH2); 101.3 (C=C-CN); 110.2 (CH=CH); 127.58-127.3 (4×Carom); 128.7-129.3 (6×Carom);
135.7 (Carom); 136.4 (Carom); 150.1 (CH=CH); 155.5 (C=C-CN); 158.2 (N=C-NH) ; 161.2
(C=O). HRMS (ES-QTOF) calcd for C20H17N2O2 M+H 317.1290. Found 317.1274.
4.4.2. General method 2: Synthesis of Bis-chromenopyridines 5a-h:
To a solution of 4-(2-(dimethylamino)vinyl)-2-oxo-2H-chromene-3-carbonitrile 3 (0.48g; 2
mmol) in DMF was added (1 mmol ) of diamine, the mixture was refluxed for 4 to 6 h. The
solvent was evaporated and the residue was crystallised in absolute ethanol to give bis-
chromenopyridines derivatives 5a-h.
4.4.2.1.4-(2-(5-oxo-5H-chromeno[3.4-c]pyridin-4-ylamino)ethylamino)-5H-chromeno[3.4-
c]pyridin-5-one 5a :
The general procedure 2 using 4-(2-(dimethylamino)vinyl)-2-oxo-2H-chromene-3-carbonitrile
3 (0.48 g; 2 mmol) and (0.06 g; 1 mmol) of ethane-1.2-diamine gave 12% of 5a as a white
1
solid. mp : 260 °C. IR νmax (neat/ cm-1): 1593 (C=C); 1618 (C=O); 3254 (NH); H NMR
(CDCl3) δH : 4.02 (4H, m, 2×NH-CH2), 4.75 (2H, s large, 2×NH); 7.34 (2H, d, JH-H= 8.4 Hz,
2×CH=CH-N); 7.44-7.84 (8H, m, Harom); 8.64 (2H,d, JH-H= 8.3 Hz , 2× CH=CH-N); 13C NMR
(CDCl3) δC : 39.9 ( 2× C-NH) ; 109.2 (2× -C=C); 117.9 (2×C=CH); 128.1-136.3 (12×Carom);
143.4 (2 ×N=C); 158.3 (2× C=CH); 161.5 (2× CN-C=C) ; 168.2 (2 × C=O). HRMS (ES-
QTOF) calcd for C26H19N4O4 M+H 451.1406. Found 451.1386.
4.4.2.2.4-(3-(5-oxo-5H-chromeno[3.4-c]pyridin-4-ylamino)propylamino)-5H-chromeno[3.4-
c]pyridin-5-one 5b:
The general procedure 2 using 4-(2-(dimethylamino)vinyl)-2-oxo-2H-chromene-3-carbonitrile
3 (0.48 g; 2mmol) and (0.07 g ; 1 mmol ) of propane-1,3-diamine gave 15% of 5b as a
white solid, mp : 220 °C.IR νmax (neat/ cm-1): 1597 (C=C); 1610 (C=O); 3263 (NH); 1H NMR
(CDCl3) δH : 1.69 (2H, s, CH2); 4.64 (4H, m, 2×NHCH2); 6.88 (2H, s large, 2×NH); 6.68
(2H, d, JH-H= 8.3 Hz, 2 ×CH=CH-N); 7.18-7.45 (8H, m, Harom); 8.54 (2H,d, JH-H= 8.3 Hz , 2 ×
CH=CH-N); 13C NMR (CDCl3) δC : 30.5 (CH2); 44.8 (2×CH2); 107.8 (2× -C=C); 117.1
17

ACCEPTED MANUSCRIPT
(2×C=CH); 124.1-134.8 (12×Carom); 154.1 (2 ×N=C); 156.9 (2× C=CH); 160.5 (2× CN-C=C)
166.3 (2 × C=O). HRMS (ES-QTOF) calcd for C27H21N4O4 M+H 465.1563 Found 465.1537.
4.4.2.3.4-(4-(5-oxo-5H-chromeno[3.4-c]pyridin-4-ylamino)butylamino)-5H-chromeno[3.4-
c]pyridin-5-one 5c:
The general procedure 2 using 4-(2-(dimethylamino)vinyl)-2-oxo-2H-chromene-3-carbonitrile
3 (0.48 g; 2 mmol) and (0.10 g ; 1 mmol ) of butane-1,4diamine gave 22% of 5c as a
1
yellow solid, mp : 201 °C. IR νmax (neat/ cm-1): 1596 (C=C); 1682 (C=O); 3260 (NH). H
NMR (CDCl3) δH :1.15- 1.67 (4H, m, 2 × CH2); 1.69-2.30 (4H, m, 2 × CH2-NH); 6.61 (2H, s
large, 2 × NH); 6.69 (2H, d, JH-H= 8.3 Hz; 2×CH=CH-N); 7.31-7.48 (8H, m, Harom); 8.69
13
(2H,d, JH-H= 8.3 Hz ; CH=CH-N); C NMR (CDCl3) δC : 28.5 (CH2); 45.6 (2×CH2); 104.8
(2× CN-C=C); 117.3 (2×C=CH); 124.3-135.7 (12×Carom); 157.0 (2×C=CH); 159.4
(2× C=CH); 162.3 (2×CN-C=C); 166.3 (2×C=O). EIMS m/z (% relative abundance): 479
(M+H, 20), 240 (100), 158 (14); HRMS (ES-QTOF) calcd for C28H23N4O4 M+H 479.1719
Found 479.1709.
4.4.2.4.4-(6-(5-oxo-5H-chromeno[3.4-c]pyridin-4-ylamino)hexylamino)-5H-chromeno[3.4-
c]pyridin-5-one 5d:
The general procedure 2 using 4-(2-(dimethylamino)vinyl)-2-oxo-2H-chromene-3-carbonitrile
3 (0.48 g; 2 mmol) and (0.12 g ; 1 mmol ) of hexane-1,6-diamine gave 28% of 5d as a
1
yellow solid, mp : 235°C. IR νmax (neat/ cm-1): 1581 (C=C); 1690 (C=O); 3406 (NH). H
NMR(CDCl3) δH : 1.30- 1.35 (4H, m, 2×CH2); 1.37-1.54 (4H, m, 2×CH2); 3.35 (4H, m,
2×CH2-NH); 6.45 (2H, s large, 2 × NH); 6.77 (2H, d, JH-H= 8.9 Hz, 2 × CH=CH-N); 7.31-7.56
(8H, m, Harom); 8.69 (2H, d, JH-H =8.9 Hz, CH=CH-N); 13C NMR (CDCl3) δC : 28.4 (2×CH2);
42.4 (2× CH2); 109.1 (2× CN-C=C); 117.1 (2×C=CH); 127.3-139.9 (12×Carom); 151.4
(2×C=CH); 158.5 (2× C=CH); 164.7 (2×CN-C=C); 166.3 (2 ×C=O). HRMS (ES-QTOF)
calcd for C30H27N4O4 M+H 507.2032. Found 507.2028.
4.4.2.5.4-(8-(5-oxo-5H-chromeno[3.4-c]pyridin-4-ylamino)octylamino)-5H-chromeno[3.4-
c]pyridin-5-one 5e:
The general procedure 2 using 4-(2-(dimethylamino)vinyl)-2-oxo-2H-chromene-3-carbonitrile
3 (0.48 g; 2 mmol) and (0.15 g ; 1 mmol ) of octane-1,8-diamine gave 31% of 5d as a
yellow solid, mp: 221°C. IR νmax (neat/ cm-1): 1598 (C=C); 1688 (C=O); 3409 (NH). 1H NMR
(CDCl3) δH :1.24- 1.37 (12H, m, 6×CH2); 2.54-3.29 (4H, m, 2×CH2-NH); 6,58 (2H, s large,
18

ACCEPTED MANUSCRIPT
2×NH); 6.88 (2H, d, JH-H= 8.8 Hz, 2×CH=CH-N); 7.33-7.58 (8H, m, Harom); 8.69 (2H, d, JH-
13
H= 8.8 Hz, CH=CH-N); C NMR (CDCl3) δC : 26.4 (2×CH2); 45.1 (6× CH2); 107.2 (2×CN-
C=C); 117.4 (2×C=CH); 126.3-133.7 (12×Carom); 153.4 (2×C=CH); 153.3 (2×C=CH); 163.4
(2×CN-C=C); 168.4 (2×C=O); EIMS m/z (% relative abundance): 535 (M+H, 36), 221 (100),
HRMS (ES-QTOF) calcd for C32H31N4O4 M+H 535.1611. Found 535.1603.
4.4.2.6.4-(12-(5-oxo-5H-chromeno[3.4-c]pyridin-4-ylamino)dodecylamino)-5chromeno[3.4-
c]pyridin-5-one 5f:
The general procedure 2 using 4-(2-(dimethylamino)vinyl)-2-oxo-2H-chromene-3-carbonitrile
3 (0.48 g; 2 mmol) and (0.15 g ; 1 mmol ) of dodecane-1,12-diamine gave 35% of 5f as a
1
yellow solid, mp: 178°C. IR νmax (neat/ cm-1): 1567 (C=C); 1678 (C=O); 3401 (NH). H
NMR(CDCl3) δH : 1.26- 1.87 (20H, m, 10×CH2); 2.22-3.34 (4H, m, 2×CH2 NH); 6.69 (2H,s
large, 2 × NH); 7.17 (2H, d, JH-H = 8.2 Hz, 2×CH=CH-N); 7.29-7.48 (8H, m, Harom); 8.65 (2H,
d, JH-H = 8.2 Hz, CH=CH-N); 13C NMR (CDCl3) δC : 29.4 (2×CH2); 45.5 (8×CH2); 109.1
(2×CN-C=C); 117.2 (2×C=CH); 127.2-139.7 (12×Carom); 152.2 (2×C=CH); 163.4 (2×CN-
C=C); 168.4 (2×C=O); EIMS m/z (% relative abundance): 527 (M+H, 45), 264 (100), 158
(23), HRMS (ES-QTOF) calcd for C36H39N4O4 M+H 591.1213. Found 591.1208.
4.4.2.7.4-((3-((5-oxo-5H-chromeno[3.4-c]pyridin-4 ylamino)methyl)phenyl)methyl
amino)-5H-chromeno[3.4-c]pyridin-5-one 5g:
The general procedure 2 using 4-(2-(dimethylamino)vinyl)-2-oxo-2H-chromene-3-carbonitrile
3 (0.48 g; 2 mmol) and (0.17 g; 1 mmol ) of m-xylenediamine gave 41% of 5g as a yellow
1
solid, mp: 166°C. IR νmax (neat/ cm-1): 1554 (C =C); 1663(C=O); 3338 (NH). H NMR
(CDCl3) δH : 4.44 (4H, d, J H-H = 6.2 Hz; 2 × CH2-NH); 6.59 (2H, s large, 2 ×NH); 7.15 (2H,
d, J H-H = 5.2 Hz , 2×CH=CH-N); 7.16-7.28 (4H, m, Harom); 7.29-7.52 (8H, m, Harom); 8.69
13
(2H, d, J H- H=5.2 Hz, CH=CH-N); C NMR (CDCl3) δC : 21.3 (2×CH3); 45.5 (2×CH2);
117.3 (2×C=CH); 125.3-139.7 ; 138.0 (18×Carom); 142.2 (2 ×N=C); 153.5 (2×C=CH); 156.5
(2×C=CH); 164.3 (2× CN-C=C). EIMS m/z (% relative abundance): 527 (M+H, 45), 264
(100), 158 (23), HRMS (ES-QTOF) calcd for C32H23N4O4 M+H 527.1719. Found 527.1722.
4.4.2.8.4-(2-(5-oxo-5H-chromeno[3.4-c]pyridin-4-ylamino)cyclohexylamino)-5H-
chromeno[3.4-c]pyridin-5-one 5h
19

ACCEPTED MANUSCRIPT
The general procedure 2 using 4-(2-(dimethylamino)vinyl)-2-oxo-2H-chromene-3-carbonitrile
3 (0.48 g; 2 mmol) and (0.22 g ; 1 mmol ) of racemic trans-cyclohexane-1,2-diamine gave
38% of 5h as a yellow solid, mp: 182°C. IR νmax (neat/ cm-1): 1557 (C =C); 1661 (C=O); 3335
1
(NH); H NMR (CDCl3) δH : 1.12-1.80 (8H, m, 4 × CH2); 2.21 (1H, S, CH); 2.25 (1H, S,
CH); 4.49 (2H, s large, 2 ×NH); 6.37 (2H, d, JH-H= 8.3 Hz, 2 ×CH=CH-N); 7.34-7.73 (8H, m,
13
Harom); 8.35 (2H,d, JH-H= 8.3 Hz , 2×CH=CH-N); C NMR (CDCl3) δC : 21.2 (2 ×-(CH2)-);
22.2 (2 ×-(CH2)-); 56.2 (2×CH-N); 107.8 (2×-C=C); 117.8 (2×C=CH); 124.0-132.0
(12×Carom); 142.8 (2 ×N=C); 153.2 (2× C=CH); 155.5 (2×CN-C=C); 174.85 (2×C=O). HRMS
(ES-QTOF) calcd for C30H25N4O4 M+H 505.1876. Found 505.1873.
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22. Crystallographic data (excluding structure factors) for 4a have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication number CCDC-1038869. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, by emailing data_request@ccdc.
cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: 441223 336033.
21