Efficient one pot synthesis of chromenonaphthyridine derivatives by CuI/InCl3 catalyzed aza diels-alder reaction

Article abstract of DOI:10.3987/COM-17-13810

A mild and efficient method for the synthesis of chromenonaphthyridine derivatives via domino reaction of aminopyridine and different O-propargylated salicylaldehydes using CuI/InCl3 as an efficient catalyst, refluxed in acetonitrile is reported. Mild rea

Full text of DOI:10.3987/COM-17-13810

HETEROCYCLES, Vol. 96, No. 1, 2018
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HETEROCYCLES, Vol. 96, No. 1, 2018, pp. 43 - 49. © 2018 The Japan Institute of Heterocyclic Chemistry
Received, 8th September, 2017, Accepted, 14th December, 2017, Published online, 21st December, 2017
DOI: 10.3987/COM-17-13810
EFFICIENT ONE POT SYNTHESIS OF CHROMENONAPHTHYRIDINE
DERIVATIVES BY CuI/InCl3 CATALYZED AZA DIELS-ALDER
REACTION
Pradip Kumar Maji* and Ayan Mahalanobish
Department of Chemistry, Bidhan Chandra College, Asansol, West Bengal, India.
E-mail: pradip_maji@yahoo.co.in
Abstract
–
A
mild and efficient method for the synthesis of
chromenonaphthyridine derivatives via domino reaction of aminopyridine and
different O-propargylated salicylaldehydes using CuI/InCl3 as an efficient catalyst,
refluxed in acetonitrile is reported. Mild reaction condition, operational simplicity,
good to excellent yield and easy isolation of product is the silent feature of this
reaction.
INTRODUCTION
Heterocycles are omnipresent in nature and possess important biological and pharmacological activities.
They represent many core structures of pharmaceutically important molecules. Naphthyridine derivatives
are one of the most important classes of such compounds. Recently synthesis of different heterocyclic
compounds including naphthyridine moiety has been reported, as they have potent pharmaceutical as well
as excellent biological activity.1 Several naphthyridines derivatives display antibacterial activity,2
medicinal use in cardiac insufficiencies and infarction,3 anticonvulsant activity,4 anti-human
cytomegalovirus (HCMV) inhibitors,5 and anticancer activity.6
The development of eco-friendly process in terms of sustainable chemistry has become a focal point in
chemical research in recent years. The hetero Diels-Alder reaction is one of the most efficient and
powerful synthetic tool for the synthesis of heterocycles.7 Recently various transition metal salts8 is used
as catalyst in hetero Diels-Alder reaction among which copper and indium trichloride have been
extensively used in organic synthesis. Both copper and indium chloride have gained a considerable
attention in organic synthesis due to their commercial availability, stable in air, inexpensive and non-toxic
nature. Moreover copper can easily activate the terminal alkyne9 bond and indium trichloride coordinate
with imine double bond and facilitate in cyclization through hetero Diels-Alder reaction. So many reports
are available in the literature of indium trichloride as a green and potentially Lewis acid catalyst to

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HETEROCYCLES, Vol. 96, No. 1, 2018
construct carbon-carbon bond or carbon-heteroatom bonds such as hetero Diels-Alder reaction.10 Some of
them suffer from several disadvantages such as long reaction time, low yield and harsh reaction condition.
Very recently Alonso et al. reported the experimental and theoretical study of cyclo-addition reaction of
3-pyridylaldimine and alkene or alkyne for the synthesis of 1,5-naphthyridine11 using BF3·OEt2 as Lewis
acid catalyst from 3-aminopyridine, aldehyde and alkyne or alkene. In view of the immense biological
and pharmaceutical utility of naphthyridine and its derivatives, and wide applicability of transition metal
in hetero Diels-Alder reaction motivate us to synthesize the chromenonaphthyridine derivatives via
domino reaction of aminopyridine and differents O-propargylated salicylaldehydes using CuI/InCl3 as a
catalyst in the refluxed condition. To the best of our knowledge there is no such report about the synthesis
of chromenonaphthyridine derivatives by aza Diels-Alder reaction. Herein, we report our present
investigation.
RESULTS AND DISCUSSION
In this aza Diels-Alder reaction 3-aminopyrdine (1) and O-propargylated salicylaldehyde(4a) were
allowed to react in the presence of 5 mol% of InCl3 and 10 mol% of CuI in acetonitrile at refluxing
condition, afforded the corresponding 1,5-chromenonaphthyridine derivative (5a) in good yield (Scheme
1). Initially, this reaction was performed with 3-aminopyridne and propargylated salicylaldehyde in the
presence of 5 mol% CuI in acetonitrile at refluxed condition. But the product obtained with very low
yield.
R1
N
OHC
O
NH2
R1
+
O
N
N
4
5
1
Scheme 1. Reagent and conditions: InCl3 (5 mol%), CuI (10 mol%), MeCN, reflux, 2-3 h
But when this similar reaction was carried out in the presence of 20, or 10 mol% of CuI at reflux in
acetonitrile, it took long time to complete the reaction. Increasing the % of catalyst loading had no
significant effect on the yield of product. Hence to find out the optimum reaction condition we used
indium trichloride as Lewis acids along with CuI under the same reaction condition as indium chloride
effectively activate the imine double bond by co-ordinating the imine nitrogen and facilitate the hetero
Diels-Alder reaction. It was also found that 5 mol% indium trichloride efficiently increased the yield of
the product and also reduced the reaction time. A test reaction was performed using O-propargylated
salicylaldehyde (1 mmol) and 3-aminopyridine (1 mmol) refluxed in acetonitrile in order to establish the

HETEROCYCLES, Vol. 96, No. 1, 2018
45
catalytic activity of indium trichloride (5 mol%) and CuI (10 mol%) and better result was obtained. To
explore the generality of this aza Diels-Alder reaction, we extended this reaction of 3-aminopyridine with
different O-propargylated salicylaldehyde under similar conditions afforded respective
chromenonaphthyridine derivatives in high yields. Differents O-propargylated salicylaldehyde containing
electron-withdrawing and electron-donating substituent at meta or para-position exhibited equal activity
towards the formation of product in good to excellent yields. The results are summarized in Table 1.
Table 1. Synthesis of chromenonaphthyridine derivatives
Entry
Amine
Aldehydes
Products
Yields
92%
NH2
CHO
O
N
1.
N
O
N
4a
1
5a
Cl
Cl
CHO
O
N
2.
3.
1
1
95%
89%
O
4b
N
5b
NO2
O2N
CHO
O
N
O
4c
N
5c
CHO
O
N
4.
5.
1
1
91%
85%
O
N
5d
4d
CHO
N
OMe
O
O
OMe
N
4e
5e
Br
O
Br
CHO
N
6.
1
92%
O
4f
N
5f

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HETEROCYCLES, Vol. 96, No. 1, 2018
The requisite starting materials (4a-f) required for this present study were synthesized12 by the reaction of
various substituted salicyaldehyde (2a-f) with propargyl bromide (3) in dry DMF, stirring at room
temperature in the presence of potassium carbonate (Scheme 2) and utilized without further purification.
4a. R1 = H
CHO
CHO
O
4b. R1 = 5-Cl
Br
OH
+
DMF (dry)
K2CO3
4c. R1 = 5-NO2
4d. R1 = 3,4-benzo
4e. R1 = 3-OMe
4f. R1 = 5-Br
R1
R1
4a-f
2
3
Scheme 2. Preparation of O-propargylated aldehyde
Plausible mechanistic rationalization for the formation of chromenonaphthyridine derivatives is depicted
in Scheme 3. Initially, imine (A) is formed which contained the aza-heterodiene moiety. This
aza-heterodiene undergoes intramolecular aza Diels-Alder reaction with the propargyl triple bond which
is activated by indium chloride followed by aromatization to give the desire products.
R
R
R
R
NH2
+
N
N
N
OHC
O
O
O
O
N
N
N
N
A
H
5
Scheme 3. Plausible mechanism
All the synthesized compounds are characterized by the elemental analysis and spectroscopic data.
In summary, we have described a novel, mild and efficient strategy for the synthesis of potentially
biologically active 1,5-naphthyridine derivatives by domino aza Diels-Alder reaction of aminopyridine
and O-propargylated salicylaldehydes. The methodology is simple, rapid, and inexpensive affording good
to high yields. In addition to its operational simplicity this procedure has the advantage of easy
availability and flexibility of starting materials, and short reaction times.
EXPERIMENTAL
Melting points were determined in an open capillary and are uncorrected. IR spectra were recorded on a
Perkin-Elmer spectrum II spectrometer on KBr disks. 1H and 13C NMR spectra were recorded at 300, 500
and 125 MHz respectively in CDCl3 (chemical shift in δ) with TMS as internal standard. Mass spectra
were recorded on a TOF MASS ES+ instrument respectively. Silica gel [(60-120 mesh), Spectrochem,

HETEROCYCLES, Vol. 96, No. 1, 2018
47
India] was used for chromatographic separation. Silica gel G [E-Merck (India)] was used for TLC.
Petroleum ether refers to the fraction boiling between 60-80 oC.
General Procedure:
A mixture of 3-aminopyridine (1a, 1.0 mmol), O-propargylated salicylaldehyde (4a, 1.0 mmol) were
taken in a round-bottom flask equipped with a stirring magnetic bar and allowed to stir in MeCN (15 mL)
at room temperature for 5 min. To this reaction mixture InCl3 (5 mol%) and CuI (10 mol%) were added
and the reaction mixture was refluxed for 2 h. After completion of the reaction, as indicated by TLC,
MeCN was evaporated, cooled to room temperature and ice cold water (10 mL) was added to the crude
reaction mass. Then aqueous layer was extracted with EtOAc (3 × 20 mL), and the combined organic
layers were washed with brine and dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The product was purified by column chromatography on silica gel (60-120 mesh) using
petroleum ether-EtOAc mixture (4:1) as eluent to afford the compounds 5a in good yield.
6H-Chromeno[4,3-b][1,5]naphthyridine (5a). Yield: 92%, mp 120 oC, IR (KBr): 1617, 1512, 1482 cm-1,
1H NMR (500 MHz, DMSO-d6): δH = 4.97 (s, 2H); 7.14 (m, 3H); 7.46 (m, 1H); 7.69 (m, 1H); 8.37 (s,
2H); 8.47 (s, 1H); 13C NMR (125 MHz, DMSO-d6): δC = 67.49, 108.24, 109.61, 111.61, 113.82, 116.98,
119.17, 122.80, 126.60, 130.93, 132.27, 133.71, 135.80, 164.51. MS m/z: 235 (M+ + H), Anal. Calcd for
C15H10N2O: C, 76.91; H, 4.30; N, 11.96; Found: C, 76.94; H, 4.37; N, 11.99.
2-Chloro-6H-chromeno[4,3-b][1,5]naphthyridine (5b). Yield: 95%, mp 181 oC, IR (KBr): 1615, 1566,
1467 cm-1, 1H NMR (300 MHz, DMSO-d6): δH = 5.07 (s, 2H); 7.32 (d, J = 9 Hz, 1H); 7.64 (d, J = 9 Hz,
2H); 7.70 (s, 2H); 7.99 (s, 1H); 8.80 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δC = 67.66, 107.46, 116.63,
123.98, 124.46, 124.70, 124.96, 125.89, 126.71, 127.78, 128.17, 128.29, 130.95, 135.37, 152.30. MS m/z:
269 (M+ + H), Anal. Calcd for C15H9ClN2O: C, 67.05; H, 3.38; N, 10.43; Found: C, 67.16; H, 3.42; N,
10.37.
o
2-Nitro-6H-chromeno[4,3-b][1,5]naphthyridine (5c). Yield: 89%, mp 200 C, IR (KBr): 1617, 1512,
1480 cm-1, 1H NMR (300 MHz, DMSO-d6): δH = 5.27 (s, 2H); 7.32 (m, 1H); 7.47 (s, 1H); 8.29 (m, 2H);
8.43 (s, 2H); 9.1 (s, 1H); MS m/z: 280 (M+ + H), Anal. Calcd for C15H9N3O3: C, 64.52; H, 3.25; N, 15.05;
Found: C, 64.65; H, 3.32; N, 14.97.
6H-Benzo[7,8]chromeno[4,3-b][1,5]naphthyridine (5d). Yield: 91%, mp 230 oC, IR (KBr): 1617, 1512,
1437 cm-1, 1H NMR (300 MHz, DMSO-d6): δH = 5.49 (s, 2H); 7.34 (d, J = 9 Hz, 2H); 7.51 (t, J = 6 Hz,
2H); 7.69 (t, J = 6 Hz, 2H); 7.96 (d, J = 6 Hz, 1H), 8.07 (d, J = 9 Hz, 1H); 8.54 (d, J = 9 Hz, 1H) 9.90 (d,
J = 9 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δC = 67.75, 114.71, 118.34, 124.51, 126.61, 127.95,
128.52, 130.07, 130.27, 130.58, 132.42, 133.79, 136.55, 142.39, 150.82, 157.88. MS m/z: 285 (M+ + H),
Anal. Calcd for C19H12N2O: C, 80.27; H, 4.25; N, 9.85; Found: C, 80.31; H, 4.19; N, 9.79.
4-Methoxy-6H-chromeno[4,3-b][1,5]naphthyridine (5e). Yield: 85%, mp 205 oC, IR(KBr): 1617, 1583,

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HETEROCYCLES, Vol. 96, No. 1, 2018
1481 cm-1, 1H NMR (300 MHz, DMSO-d6): δH = 3.83 (s, 3H); 5.48 (s, 2H); 6.91 (t, J = 9 Hz, 2H); 7.18 (q,
13
J = 9 Hz, 2H); 7.80 (s, 1H); 7.93 (d, J = 6 Hz, 1H); 8.47 (d, J = 6 Hz, 1H); C NMR (100 MHz,
DMSO-d6): δC = 55.50, 67.36, 114.88, 116.60, 120.01, 122.02, 122.62, 124.37, 128.97, 132.84, 137.07,
143.50, 146.88, 148.67, 149.19, 152.41. MS m/z: 265 (M+ + H), Anal. Calcd for C16H12N2O2: C, 72.72; H,
4.58; N, 10.60; Found: C, 72.79; H, 4.65; N, 10.64.
o
2-Bromo-6H-chromeno[4,3-b][1,5]naphthyridine (5f). Yield: 92%, mp 190 C, IR (KBr): 1615, 1524,
1
1477 cm-1, H NMR (300 MHz, DMSO-d6): δH = 4.97 (s, 2H); 7.08 (m, 5H); 8.08 (s, 1H); 8.42 (s, 1H);
MS m/z: 312 (M+ + H), Anal. Calcd for C15H9BrN2O: C, 57.53; H, 2.90; N, 8.95; Found: C, 57.59; H,
2.98; N, 8.97.
ACKNOWLEDGEMENTS
Author is grateful to the Department of Science and Technology (DST, New Delhi) for financial support
under DST fast track project (No: SB/FT/CS-184/2012 dt-16-06-2014). Author is also sincerely
acknowledged IICB Kolkata and SAIF Nehu, Assam for spectral data.
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