Green Chemistry

View Article Online

PAPER View Journal | View Issue

An efficient approach for the synthesis of

Cite this: Green Chem., 2017, 19,
5-hydroxy-chromeno[2,3-b]pyridines under
catalyst and solvent free conditions†
Published on 28 July 2017. Downloaded by University of Delhi on 04/10/2017 09:51:49.

4153

Shruti Gupta and Jitender M. Khurana *

Received 17th May 2017,
Accepted 25th July 2017
DOI: 10.1039/c7gc01463e
rsc.li/greenchem
An efficient and sustainable method has been developed for the synthesis of novel 5-hydroxy-chromeno
[2,3-b]pyridines by the reaction of 3-formylchromone, aromatic amines and malononitrile under catalyst
and solvent-free conditions by simply stirring the components magnetically or by grinding at room temp-
erature. Excellent yields, environmentally benign reaction conditions and easy workup are the advantages
of this protocol. The structures have been established unambiguously.

Introduction Grinding technique, a useful mechanochemistry approach,

Nitrogen-containing heterocycles are vital because of their
abundance in nature as well as in synthetic compounds.
Chromenopyridines, which bear two main cores of chromene
and pyridine rings fused together in a single molecule, have
been reported to exhibit several biological activities such as
glucocorticoid receptor (GR) agonistic,1 hypotensive,2 anti-
arthritic,3 antirheumatic,4 antibacterial5 and antiasthmatic
activities.6 Some of these also display anti-proliferative and
metastasis inhibitory activities by targeting topoisomerases.7
Several methods have been reported for the synthesis of
chromenopyridines owing to their importance. The earlier
reports include the synthesis of a variety of tricyclic and tetra-
cyclic condensed chromenopyridines using an aza-Wittig reac-
tion of N-vinylic phosphazenes with functionalized aldehydes,8
a multicomponent reaction between salicylaldehyde, malono-
nitrile and thiophenol, an intramolecular Diels–Alder reaction
of pyrimidines, followed by a retro Diels–Alder reaction,9 the
AuCl3-catalyzed [3 + 2 + 1] cycloaddition of an aldehyde with
an aldimine of a glycine ester bearing a terminal triple bond,10
and the Suzuki–Miyaura cross-coupling of bromo arylcarboxy-
lates with o-hydroxyarylboronic acids.11 The reported methods
for the synthesis of chromenopyridines suffer from limitations
such as harsh reaction conditions, expensive catalysts and
toxic organic solvents. Consequently, the development of new,
efficient and environmentally benign procedures for the
synthesis of heterocycles containing chromeno[2,3-b]pyridines
is deemed worthy of investigation.
Department of Chemistry, University of Delhi, New Delhi-110 007, India.
E-mail: jmkhurana1@yahoo.co.in, jmkhurana@chemistry.du.ac.in
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c7gc01463e
involves grinding of two macroscopic particles together
leading to the formation of a liquid phase prior to reaction,
i.e., the formation of a eutectic melt of uniform distribution
where the reacting components being in close proximity are
poised to react in a controlled way.12 Therefore, in continu-
ation of our research13 on the synthesis of biologically active
heterocyclic compounds with diverse applications through
hybridization, we decided to investigate the synthesis of novel
5-hydroxy-chromeno[2,3-b]pyridines.
Results and discussion
We report in this paper efficient and sustainable methods for
the syntheses of novel 5-hydroxy-chromeno[2,3-b]pyridines in
excellent yields by simply stirring the components magneti-
cally at room temperature or by simply grinding 3-formyl-
chromone, aromatic amines and malononitrile at room tem-
perature under catalyst and solvent free conditions. Initially,
the reactions of 3-formylchromone (Ia) (1.0 mmol), malono-
nitrile (II) (1.0 mmol) and 4-fluoroaniline (IIIa) (1.0 mmol)
were attempted in different solvents. The reaction was first
attempted in water as a solvent but there was no reaction even
after 5 h (Table 1, entry 1). The reaction was then carried out
in EtOH at room temperature which afforded the desired
product, 1-(4-fluorophenyl)-5-hydroxy-2-imino-2,10a-dihydro-
1H-chromeno[2,3-b]pyridine-3-carbonitrile (IVa), in 82% yield
in 10 min (Scheme 1) (Table 1, entry 2). The reaction when
carried out in acetonitrile was observed to be complete in
5 min but gave only a 72% yield of the desired product IVa
after separation (Table 1, entry 3). The above reactions per-
formed in glycerol and ethylene glycol were complete in
10 min though with inferior yields of 66% and 71% of the

This journal is © The Royal Society of Chemistry 2017 Green Chem., 2017, 19, 4153–4156 | 4153

Paper
Table 1 Optimization of the reaction conditions for the synthesis of
1-(4-fluorophenyl)-5-hydroxy-2-imino-2,10a-dihydro-1H-chromeno
[2,3-b]pyridine-3-carbonitrile a
S. no. Solvent Time (min) Yield (%)
1 H2O 300 —b
2 EtOH 10 82
3 CH3CN 5 72
4 Glycerol 10 66
5 Ethylene glycol 10 71
6 PEG-400 480 —c
7 —d 15 92
8 —e 5 94
Published on 28 July 2017. Downloaded by University of Delhi on 04/10/2017 09:51:49.
a
Reactions carried out using 3-formylchromone (1.0 mmol), 4-fluoro-
aniline (1.0 mmol), and malononitrile (1.0 mmol). b No reaction.
c
Incomplete reaction. d Reaction carried out by stirring under solvent
free conditions. e Reaction carried out by grinding the reactants.
Scheme 1
product, respectively (Table 1, entries 4 and 5). The same reac-
tion when attempted in PEG-400 was incomplete even after 8 h
as monitored by TLC using ethyl acetate : petroleum ether
(30 : 70, v/v) as a mobile phase (Table 1, entry 6). To our
delight, the reaction when carried out under neat conditions
by stirring the components at room temperature was complete
in 15 min and gave a 92% yield of the desired product
(Table 1, entry 7). The reaction was then attempted by grinding
the components under neat conditions which afforded a 94%
yield of IVa within 5 min (Table 1, entry 8). The completion of
the reaction is indicated by a distinct color change from a
colorless to a yellow colored product.
Therefore, it is evident from Table 1 that reactions
attempted using the grinding technique and by simply stirring
the components under neat conditions at room temperature
gave the highest yields of the desired product IVa.
Subsequently, the reactions of 3-formylchromone (Ia)
(1.0 mmol) and malononitrile (II) (1.0 mmol) were carried out
with different aromatic amines bearing electron-withdrawing
and electron-donating groups by stirring the components as
well as by grinding the components at room temperature
(Scheme 2 and Table 2). All the reactions proceeded smoothly
and were complete in less than 15 min to give the corres-
ponding chromeno[2,3-b]pyridine derivatives in excellent
yields. The reaction was generally faster by grinding and a dis-
tinct change in color to yellow indicated the completion of the
reaction. All our attempts to hydrolyse the imino group were
not successful. The structures of compounds (IVa–p) were con-
firmed by 1H NMR, 13C NMR, HRMS and IR spectroscopy.
4154 | Green Chem., 2017, 19, 4153–4156
View Article Online
Green Chemistry
Scheme 2
The IR spectrum of IVb showed peaks at 3314 cm−1 (N–H
stretch), 2298 cm−1 (C–N stretch), and 1149 cm−1 (C–O
stretch). The 1H NMR spectrum showed one NH proton
appearing as a doublet at δ 5.49 with J = 4.4 Hz. The methine
proton also appeared as a doublet at δ 6.20 with J = 5.6 Hz.
After D2O exchange, the NH proton disappeared and the
methine doublet was reduced to a singlet, confirming coupling
between both the protons. 8 aromatic protons appeared in the
range of δ 7.06–7.86. The vinylic proton of the pyridine ring
was observed at δ 8.08. A singlet was observed for OH at δ 9.54
as confirmed by D2O exchange. The 13C NMR spectrum
showed the imine carbon at δ 156.21, while the carbon
attached to the hydroxyl group was observed at δ 149.30. The
vinylic carbon of the pyridine ring and of the nitrile group
appeared at δ 141.76 and δ 116.73, respectively. The methine
carbon appeared at δ 73.15. The positions of peaks for
methine and quaternary carbons were assigned by using the
DEPT spectra of compound IVb.
A plausible reaction mechanism for the formation of
chromeno[2,3-b]pyridines IV is outlined in Scheme 3. The first
step is the condensation of malononitrile and 3-formyl-
chromone to give a Knoevenagel condensate A which under-
goes Michael-type addition with aromatic amines to give an
intermediate B. B undergoes intramolecular cyclization to
afford the desired compound IV. In an independent experi-
ment, 3-formylchromone and malononitrile were stirred
together to give a proposed intermediate A in 5 min which was
then treated with 4-fluoroaniline under stirring. The product
IVa was obtained in an excellent yield in another 10 min, thus
confirming the proposed pathway.
Experimental
All the chemicals are commercial and were purchased from
Sigma Aldrich or Merck and used as received. Thin layer
chromatography (GF254) was used to monitor reaction pro-
gress. Melting points were measured on Buchi M-560 melting
point apparatus and are uncorrected. IR (DCM) spectra were
recorded on a PerkinElmer FTIR spectrophotometer and the
values are expressed as νmax cm−1. The 1H NMR and 13C NMR
spectra were recorded on a Jeol JNM ECX-400P spectrometer at
400 and 100 MHz, respectively, using TMS as an internal stan-
dard. The chemical shift values are recorded on the δ scale
and the coupling constants ( J) are in Hz. Mass spectral data
were recorded on an Agilent 6520 QT (ESI-HRMS) mass
This journal is © The Royal Society of Chemistry 2017
 View Article Online

Green Chemistry Paper

Table 2 Synthesis of 1-aryl-5-hydroxy-2-imino-2,10a-dihydro-1H-chromeno[2,3-b]pyridine-3-carbonitrilea

Method A Method B

Entry R1 R2 Ar Product (IV) Time (min) Yield (%) Time (min) Yield (%)

1 H H 4-FC6H4 IVa 15 92 5 94
2 H H 4-ClC6H4 IVb 10 94 5 94
3 H H 4-BrC6H4 IVc 10 94 5 93
4 H H 3-ClC6H4 IVd 15 91 5 92
5 H H 4-(OCH3)C6H4 IVe 12 92 5 93
6 H H 4-(CH3)C6H4 IVf 10 94 5 94
7 H H 2-(CH3)C6H4 IVg 15 93 5 94
8 H H 3-C5H4N IVh 10 91 10 90
Published on 28 July 2017. Downloaded by University of Delhi on 04/10/2017 09:51:49.

9 H H 4-(COOCH3)C6H4 IVi 10 91 6 91
10 H H 4-IC6H4 IVj 10 93 10 92
11 H H 3-BrC6H4 IVk 15 90 10 91
12 H H 2,3-Cl2C6H3 IVl 15 94 10 94
13 H H 3-CN,4-FC6H3 IVm 12 93 5 93
14 H H 2,4-(OCH3)2C6H3 IVn 10 95 5 94
15 Br H 4-(OCH3)C6H4 IVo 15 90 10 92
16 Br H 4-IC6H4 IVp 10 90 10 90
17 Cl CH3 4-FC6H4 IVq 20 94 10 96
18 CH3 H 4-FC6H4 IVr 15 90 10 92
a
Reactions carried out using 3-formylchromone (1.0 mmol), aromatic amines (1.0 mmol), and malononitrile (1.0 mmol) by stirring (Method A)
and grinding (Method B).

General procedure for the synthesis of 1-aryl-5-hydroxy-2-

Scheme 3 Plausible mechanism for the synthesis of IV.
spectrometer. The 13C NMR spectra of IVd and IVp could not
be recorded due to their poor solubility.
imino-2,10a-dihydro-1H-chromeno[2,3-b]pyridine-3-
carbonitrile (IVa–p) [Method B]
A mixture of 3-formylchromone (1.0 mmol), aromatic amines
(1.0 mmol), and malononitrile (1.0 mmol) was taken in a
mortar, mixed thoroughly and ground well with a pestle at
room temperature under neat conditions. It was observed
that the mixture which was initially in a partial liquid state
solidified during the process of grinding to a light yellow
solid mass. Thin layer chromatography (TLC) using ethyl
acetate : petroleum ether (30 : 70, v/v) as a mobile phase, at this
moment, indicated the complete conversion into the desired
product. After the completion of the reaction, water (3 mL) was
added to the reaction mixture and the separated solid was
collected by filtration using a pump. The crude solid was
washed with hot ethanol (2–3 mL). The products were charac-
terized by IR, 1H NMR, 13C NMR and mass spectra.

General procedure for the synthesis of 1-aryl-5-hydroxy-2-

imino-2,10a-dihydro-1H-chromeno[2,3-b]pyridine-3-
carbonitrile (IVa–p) [Method A]
A mixture of 3-formylchromone (1.0 mmol), aromatic amines
(1.0 mmol) and malononitrile (1.0 mmol) was stirred magneti-
cally at room temperature on a magnetic stirrer under neat
conditions. The progress of the reaction was monitored by TLC
using ethyl acetate : petroleum ether (30 : 70, v/v) as a mobile
phase. There was a distinct color change from nearly colorless
to yellowish color. After the completion of the reaction
(Table 2), water (3 mL) was added to the reaction mixture and
the mixture was stirred, and the separated solid was collected
by filtration using a pump. The crude solid was washed with
hot ethanol (2–3 mL). After drying, the products were charac-
terized by IR, 1H NMR, 13C NMR and mass spectra.
Conclusion
In conclusion, a highly sustainable and efficient multi-
component synthesis of novel chromeno[2,3-b]pyridines under
solvent and catalyst free conditions at room temperature has
been reported. The notable features of this methodology are
eco-friendly reaction conditions, no side product, the avoid-
ance of toxic catalysts and solvents, and easy purification.
Acknowledgements
S. G. is thankful to UGC, New Delhi, India, for the award of
Junior and Senior Research Fellowship. The authors acknowl-

This journal is © The Royal Society of Chemistry 2017 Green Chem., 2017, 19, 4153–4156 | 4155

Paper
edge the University of Delhi for providing Research grant and
DU-DST purse grant.
References
1 D. S. Weinstein, H. Gong, A. M. Doweyko, et al., J. Med.
Chem., 2011, 54, 7318.
2 N. M. Evdokimov, A. S. Kireev, A. A. Yakovenko, et al.,
J. Org. Chem., 2007, 72, 3443.
Published on 28 July 2017. Downloaded by University of Delhi on 04/10/2017 09:51:49.
3 D. R. Anderson, S. Hegde, E. Reinhard, et al., Bioorg. Med.
Chem. Lett., 2005, 15, 1587.
4 J. A. Bristol, E. H. Gold, I. Gross, R. G. Lovey and J. Long,
J. Med. Chem., 1981, 24, 1010.
5 A. El-Saghier, M. Naili, B. Rammash, N. Saleh and
K. Kreddan, ARKIVOC, 2007, xvi, 83.
6 K. Ukawa, T. Ishiguro, H. Kuriki and A. Nohara, Chem.
Pharm. Bull., 1985, 33, 4432.
4156 | Green Chem., 2017, 19, 4153–4156
View Article Online
Green Chemistry
7 M. S. Al-Said, M. M. Ghorab and Y. M. Nissan, Chem. Cent.
J., 2012, 64, 1.
8 (a) F. Palacios, C. Alonso, P. Amezua and G. Rubiales,
J. Org. Chem., 2002, 67, 1941; (b) F. Palacios, C. Alonso and
G. Rubiales, J. Org. Chem., 1997, 62, 1146.
9 W. A. W. Stolle, A. E. Frissen, A. T. M. Marcelis and
H. C. van der Plas, J. Org. Chem., 1992, 57, 3000.
10 K. S. Gayen and D. K. Maiti, RSC Adv., 2014, 4, 10204.
11 K. Vishnumurthy and A. Makriyannis, J. Comb. Chem.,
2010, 12, 664.
12 G. Rothenberg, A. P. Downie, C. L. Raston and J. L. Scott,
J. Am. Chem. Soc., 2002, 123, 8701.
13 (a) S. Gupta, P. Saluja and J. M. Khurana, Tetrahedron, 2016,
72, 3986; (b) G. Khanna, K. Aggarwal and J. M. Khurana, RSC
Adv., 2015, 5, 46448; (c) M. Rajeswari, P. Saluja and
J. M. Khurana, RSC Adv., 2016, 6, 1307; (d) H. Singh,
J. Sindhu, J. M. Khurana, C. Sharma and K. R. Aneja,
Eur. J. Med. Chem., 2014, 77, 145; (e) G. Khanna, P. Saluja and
J. M. Khurana, Tetrahedron Lett., 2016, 57, 5852.
This journal is © The Royal Society of Chemistry 2017