Rapid Synthesis of N-Alkyl-2-imino-2H-chromene-3-carboxamides Catalyzed by a Keplerate-type Giant Nanoporous Isopolyoxomolybdate

Full text of DOI:10.1080/00304948.2018.1537732

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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Rapid Synthesis of N-Alkyl-2-imino-2H-chromene-3-
carboxamides Catalyzed by a Keplerate-type Giant
Nanoporous Isopolyoxomolybdate
Arsalan Jooya, Abolghasem Davoodnia, Mehri Fattahi & Niloofar Tavakoli-
Hoseini
To cite this article: Arsalan Jooya, Abolghasem Davoodnia, Mehri Fattahi & Niloofar Tavakoli-
Hoseini (2018) Rapid Synthesis of N-Alkyl-2-imino-2H-chromene-3-carboxamides Catalyzed by
a Keplerate-type Giant Nanoporous Isopolyoxomolybdate, Organic Preparations and Procedures
International, 50:6, 565-574, DOI: 10.1080/00304948.2018.1537732
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Organic Preparations and Procedures International, 50:565–574, 2018
# 2018 Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2018.1537732
Rapid Synthesis of N-Alkyl-2-imino-2H-chromene-
3-carboxamides Catalyzed by a Keplerate-type
Giant Nanoporous Isopolyoxomolybdate
Arsalan Jooya,1 Abolghasem Davoodnia,1
Niloofar Tavakoli-Hoseini2
Mehri Fattahi,1 and
1Department of Chemistry, Mashhad Branch, Islamic Azad University,
Mashhad 91756-87119, Iran
2Young Researchers and Elite Club, Mashhad Branch, Islamic Azad
University, Mashhad, Iran
Among the six-membered oxygen-containing heterocycles, chromene derivatives have
received considerable attention due to their biological and pharmacological properties,
such as anticancer,1,2 antibacterial,3 antihypertensive,4 antiviral,5 antimalarial,6 anti-
leishmanial,7 anti-HIV,8 anticonvulsant,9 and antifungal10 activities. Certain derivatives
of chromenes induce apoptosis in cancer cell lines.11,12 They have also been widely
employed as cosmetics,13 pigments,13 and potent biodegradable agrochemicals,14 and
are found in natural alkaloids, tocopherols, flavonoids, and anthocyanins.15 A number
of compounds with the chromene moiety are known as potential inhibitors of notum
pectinacetylesterase,16 hMAO,17 aldose reductase,18 dihydrofolate reductase,19 TNF-
a,20 and acetylcholinesterase.21
Functionalized 2-iminochromenes have been a subject of increasing interest. A
number of these compounds are used as protein tyrosine kinase (PTK) inhibitors,22,23 as
well as anti-Alzheimer,24 antimicrobial,25 anticancer,26 and cytotoxic27 agents. These
compounds are important intermediates in chemical synthesis.28–31 In spite of these
properties, a closer look at the literature disclosed that there are few reports on the syn-
thesis of 2-iminochromenes. The classic method for the synthesis of these compounds
is the reaction of salicylaldehydes with active methylene compounds prompted by cata-
lysts such as potassium phthalimide,32 NaHCO3 or Na2CO3,30 polyethylene polyamine
functionalized polyacrylonitrile fiber,33 and piperidine in the presence34 or absence35 of
microwave irradiation. Although each of these individual methods has its own merits,
some suffer from limitations such as unsatisfactory yields, long reaction times, and the
use of relatively expensive catalysts. These findings make further improvements for the
synthesis of these compounds essential.
Received March 16, 2018; in final form June 6, 2018.
Address correspondence to Abolghasem Davoodnia, Department of Chemistry, Mashhad
Branch, Islamic Azad University, Mashhad 91756-87119, Iran. E-mail: adavoodnia@mshdiau.ac.ir
Color versions of one or more of the figures in the article can be found online at www.tandfon-
line.com/uopp.
565

566
Davoodnia et al.
Scheme 1. {Mo132} catalyzed synthesis of N-alkyl-2-imino-2H-chromene-3-carboxamides.
Recently, (NH4)42[MoVI72MoV60O372(CH3COO)30(H2O)72], a Keplerate-type giant-
ball nanoporous isopolyoxomolybdate denoted as {Mo132}, firstly synthesized and char-
acterized by Muller and co-workers,36 was used in our group as a catalyst for a series
of organic transformations. This new reusable catalyst performed well and showed a
high level of catalytic activity in the synthesis of 1,2,4,5-tetrasubstituted imidazoles,37
1,8-dioxo-octahydroxanthenes,38 1,8-dioxodecahydroacridines,38 polyhydroquinolines,39
dihydropyrano[3,2-c]chromenes,40 and biscoumarins.41
Based on these precedents and in extension of our previous work on the develop-
ment of new environmentally friendly methods for the synthesis of organic compounds
using reusable catalysts,42–48 we report here the application of {Mo132} as catalyst in
the synthesis of N-alkyl-2-imino-2H-chromene-3-carboxamides 3a-3i. This is done by
reaction of salicylaldehydes 1a and 1b with N-alkyl-2-cyanoacetamides 2a-2f using
{Mo132} as a reusable catalyst under solvent-free conditions (Scheme 1).
Compounds 2a-2f were prepared according to earlier methods.34,49,50 A pilot reac-
tion was tested using salicylaldehyde 1a (1 mmol) with N-benzyl-2-cyanoacetamide 2a
(1 mmol) in the presence of {Mo132} in different sets of reaction conditions. A sum-
mary of the optimization experiments is provided in Table 1. The advantages of per-
forming organic reactions under solvent-free conditions prompted us to study the
efficiency of {Mo132} in the model reaction under solvent-free conditions with different
catalyst amounts and temperatures. We were pleased to see that the reaction was effi-
ciently catalyzed by {Mo132} under solvent-free conditions at elevated temperature
leading to a high yield of product 3a. It is evident that the best result was obtained by
the application of 0.05 g of {Mo132} at 110 ꢀC (Entry 13). Higher amounts of the cata-
lyst and higher temperatures slightly reduced the yield of the product (Entries 14,15).
To prove the necessity of the catalyst, a blank reaction was also tested at 110 ꢀC under
solvent-free conditions. Low yield of the product 3a was obtained after 120 min (Entry
1). Subsequently, the reaction was performed in the presence of 0.05 g of the catalyst in
different solvents including H2O, MeOH, EtOH, CHCl3, and CH3CN; all gave good
yields of the product but none as high as under solvent-free conditions. Therefore, all
subsequent reactions were carried out using 0.05 g of the catalyst at 110 ꢀC under solv-
ent-free conditions.
Our results are shown in Table 2. As can be seen, all reactions proceed very
cleanly to give the corresponding 3a-3i in high yields over short reaction times, and no
undesirable side-products were observed, showing the high catalytic activity
of {Mo132}.
The structure of the products 3a-3i was deduced from their spectral and microana-
1
lytical data. In the H NMR spectra of all compounds 3a-3i, a splitting between the

N-Alkyl-2-imino-2H-chromene-3-carboxamides
567
Table 1
Optimization of Reaction Parameters for the Synthesis of Compound 3a Catalyzed
ꢁ
by {Mo132
}
Entry
Catalyst (g)
Solvent
T (ꢀC)
Time (min)
Isolated Yield (%)
1
2
3
4
5
6
7
8
———
0.02
0.02
0.02
0.03
0.03
0.03
0.04
0.04
0.04
0.05
0.05
0.05
0.05
0.06
0.05
0.05
0.05
0.05
0.05
———
———
———
———
———
———
———
———
———
———
———
———
———
———
110
80
100
110
80
100
110
80
100
110
80
100
110
120
110
120
50
50
40
30
30
25
20
15
15
15
15
12
15
15
45
30
20
60
50
27
69
72
78
77
81
85
84
86
90
87
91
98
95
96
82
80
84
75
78
9
10
11
12
13
14
15
16
17
18
19
20
H2O
Reflux
Reflux
Reflux
Reflux
Reflux
MeOH
EtOH
CHCl3
CH3CN
ꢁ
Reaction conditions: salicylaldehyde 1a (1 mmol) and N-benzyl-2-cyanoacetamide 2a (1mmol).
Table 2
Synthesis of N-alkyl-2-imino-2H-chromene-3-carboxamides 3a-3i Catalysed
by {Mo132
}
Time Isolated
Product (min) Yield (%)
mp
lit. mp
(ꢀC)
Entry
X
H
R
(ꢀC)
1
2
3
4
5
6
7
8
9
CH2Ph
3a
3b
3c
12
5
10
8
98
83
90
90
92
90
85
89
91
133-135
133 [34]
Br n-Bu
n-Bu
152-154 New Compound
165-168 New Compound
155-157 New Compound
138-139 New Compound
201-203
170-172
H
Br CH2CH2Ph 3d
CH2CH2Ph 3e
Br Cyclohexyl 3f
H
7
10
10
10
15
207-209 [30]
172-174 [28]
H
H
H
Cyclohexyl 3g
Me
3h
3i
160-163 Not reported [31]
68-70 New Compound
Octyl
ꢁ
Reaction conditions: an salicylaldehyde 1a or 1b (1 mmol), N-alkyl-2-cyanoacetamide 2a-2f
(1 mmol), {Mo132} (0.05 g), 110 ꢀC, solvent-free.
amidic NH group with its vicinal proton(s) can be observed. Such splitting is expected
when the proton exchange in the NH group is slow. For example, as shown in the
1
expanded views of the H NMR spectrum of compound 3b in CDCl3 (Figure 1), an

568
Davoodnia et al.
Figure 1. Expanded views of the 1H NMR spectrum of compound 3b in CDCl3.
A2X splitting pattern for the -NH-CH2- group is seen in which the NH appears as a
broadened triplet at d ¼ 10.19 ppm. However, since the methylene group in -NH-CH2-
can be also split with another vicinal methylene group (-NH-CH2-CH2-), it appears as
quartet at d ¼ 3.44 ppm, as expected. The methine group in the pyran ring is also seen
as a doublet at d ¼ 8.38 ppm with the coupling constant J ¼ 1.2 Hz as the result of a
five-bond zig-zag coupling. Long-range couplings across five bonds are rare,51,52 but
can be observed under favorable circumstances in rigid conformations. These signals
along with other signals including a triplet, a sextet and a quintet at d ¼ 0.96, 1.42, and
1.61 ppm, respectively, for the CH3CH2CH2- group, a broadened singlet at d 7.66 ppm
for the ¼ NH group as well as the characteristic signals for aromatic protons indicated
the formation of compound 3b. The IR spectrum of compound 3b showed the NH and
C ¼ O absorption bands at 3319, 3193, and 1676 cmꢂ1, respectively. Moreover, the 13C
NMR spectrum and elemental analysis data are consistent with the assigned structure
3b with molecular formula C14H15BrN2O2 (See Experimental Section).
The recovery and catalytic activity of recycled {Mo132} was also investigated using
the same model reaction. Upon completion of the first run, the reaction mixture was
cooled to room temperature and hot ethanol was added. The catalyst was collected by

N-Alkyl-2-imino-2H-chromene-3-carboxamides
569
Scheme 2. Plausible mechanism for the formation of compounds 3a-3i.
filtration and washed with a small portion of hot ethanol and subsequently dried at
60 ꢀC under vacuum for 1 h before being reused in a similar reaction. The catalyst could
be used at least four times without significant reduction in its activity (98, 97, 95, and
95% yields for first to fourth use, respectively).
A mechanistic rationalization for this reaction is provided in Scheme 2. On the
basis of our previous reports,37,40,41 it is reasonable to assume that several accessible
€
Mo sites and NH4 groups in {Mo132} could act as Lewis acid and Bronsted acid cen-
ters, respectively, and therefore promote the necessary reactions. The catalyst would
play a significant role in increasing the electrophilic character of the electrophiles in the
reaction. As shown, the intermediate II is readily formed in situ by Knoevenagel con-
densation of activated salicylaldehydes 1a and 1b with corresponding N-alkyl-2-cyanoa-
cetamides 2a-2f, in enolic form, via the intermediate I. Finally, cyclization of the
intermediate II gave the products 3a-3i. Under these conditions, however, attempts to
isolate the proposed intermediates failed even after careful monitoring of the reactions.
In conclusion, we report here the synthesis of N-alkyl-2-imino-2H-chromene-3-car-
boxamides 3a-3i by reaction of salicylaldehydes 1a or 1b with N-alkyl-2-cyanoaceta-
mides 2a-2f using {Mo132} as a reusable catalyst. The reactions occur under solvent-
free conditions and furnish the expected products in high yields over short reaction
times. This property combined with ease of recovery and catalyst reusability makes this
method an economic, benign and waste-free chemical process for the synthesis of N-
alkyl-2-imino-2H-chromene-3-carboxamides.
Experimental Section
N-Alkyl-2-cyanoacetamides 2a-2f were prepared according to the literature proce-
dures.34,49,50 All reagents chemicals were available commercially from Merck and
Aldrich, and used without purification. Melting points were determined using a Stuart
SMP3 melting point apparatus and are uncorrected. The IR spectra were recorded as
1
KBr pellets on a Tensor 27 Bruker spectrophotometer. The H and 13C NMR spectra
were determined using Bruker 300 FT spectrometer at 300 and 75 MHz frequencies for
1H and 13C, respectively, in CDCl3 as the solvent with TMS as the internal reference.

570
Davoodnia et al.
Elemental analyses were performed on a Thermo Finnigan Flash EA microanalyzer.
The catalyst {Mo132} was prepared as previously reported.36–41
General Procedure for the Synthesis of N-Alkyl-2-imino-2H-chromene-3-
carboxamides (3a-3i) Catalyzed by {Mo132
}
A mixture of a salicylaldehyde (1a or 1b, 1 mmol), N-alkyl-2-cyanoacetamides (2a-2f,
1 mmol), and {Mo132} (0.05 g) was heated in an oil bath at 110 ꢀC for 5-15 min. After
completion of the reaction, monitored by TLC on silica gel (n-hexane-ethyl acetate,
3:2), the mixture was cooled to room temperature and hot ethanol (10 ml) was added.
The catalyst was collected by filtration and washed with a small portion of hot ethanol
(5 ml). The combined filtrate was concentrated by half and allowed to stand at room
temperature. The precipitated solid was collected by filtration, and recrystallized from
96% ethanol to give compounds 3a-3i in high yields (see Table 2).
Larger Scale Preparation of 3a
A mixture of salicylaldehyde (1a, 1.8 g, 15 mmol), N-benzyl-2-cyanoacetamide (2a,
2.6 g, 15 mmol), and {Mo132} (0.75 g) was heated in an oil bath at 110 ꢀC for 12 min.
After completion of the reaction, monitored by TLC on silica gel (n-hexane-ethyl acet-
ate, 3:2), the mixture was cooled to room temperature and hot ethanol (150 ml) was
added. The catalyst was collected by filtration and washed with a small portion of hot
ethanol (75 ml). The combined filtrate was concentrated by half and allowed to stand at
room temperature. The precipitated solid was collected by filtration, and recrystallized
from ethanol to give compound 3a in 98% yield (see Table 2).
N-Benzyl-2-imino-2H-chromene-3-carboxamide (3a)
1
FT-IR: t 3307 (NH), 3214 (NH), 1673 (C ¼ O) cmꢂ1. H NMR (300 MHz, CDCl3): d
4.68 (d, 2H, J ¼ 5.6 Hz, CH2), 7.14 (d, 1H, J ¼ 8.2 Hz, HAr), 7.22 (t, 1H, J ¼ 7.5 Hz,
HAr), 7.30-7.55 (m, 7H, HAr), 7.58 (s br., 1H, ¼NH), 8.53 (s, 1H, pyran CH), 10.74 (s
br., 1H, -CO-NH).
Anal. Calcd. for C17H14N2O2: C, 73.37; H, 5.07; N, 10.07. Found: C, 73.61; H,
5.19; N, 9.92.
6-Bromo-N-butyl-2-imino-2H-chromene-3-carboxamide (3b)
1
FT-IR: t 3319 (NH), 3193 (NH), 1676 (C ¼ O) cmꢂ1. H NMR (300 MHz, CDCl3): d
0.96 (t, 3H, J ¼ 7.2 Hz, CH3), 1.42 (sex, 2H, J ¼ 7.2 Hz, CH2), 1.61 (quin, 2H,
J ¼ 7.2 Hz, CH2), 3.44 (q, 2H, J ¼ 6.9 Hz, NCH2), 7.00 (d, 1H, J ¼ 8.7 Hz, HAr), 7.53
(dd, 1H, J ¼ 8.7, 2.3 Hz, HAr), 7.61 (d, 1H, J ¼ 2.3 Hz, HAr), 7.66 (s br., 1H, ¼NH),
8.38 (d, 1H, J ¼ 1.2 Hz, pyran CH with a long range coupling), 10.19 (s br., 1H, -CO-
NH). 13C NMR (75 MHz, CDCl3): d 13.8, 20.3, 31.4, 39.6, 116.4, 116.9, 120.6, 121.7,
131.5, 135.0, 139.9, 152.6, 156.9, 161.6.
Anal. Calcd. for C14H15BrN2O2: C, 52.03; H, 4.68; N, 8.67. Found: C, 52.24; H,
4.53; N, 8.49.

N-Alkyl-2-imino-2H-chromene-3-carboxamides
N-Butyl-2-imino-2H-chromene-3-carboxamide (3c)
571
1
FT-IR: t 3317 (NH), 3192 (NH), 1677 (C ¼ O) cmꢂ1. H NMR (300 MHz, CDCl3): d
0.98 (t, 3H, J ¼ 7.2 Hz, CH3), 1.44 (sex, 2H, J ¼ 7.2 Hz, CH2), 1.63 (quin, 2H,
J ¼ 7.2 Hz, CH2), 3.46 (q, 2H, J ¼ 6.9 Hz, NCH2), 7.14 (d, 1H, J ¼ 8.2 Hz, HAr), 7.22 (t,
1H, J ¼ 7.5 Hz, HAr), 7.45-7.54 (m, 2H, HAr), 7.57 (s br., 1H, ¼NH), 8.49 (s, 1H, pyran
CH), 10.28 (s br., 1H, -CO-NH). 13C NMR (75 MHz, CDCl3): d 13.8, 20.3, 31.4, 39.5,
115.2, 116.5, 124.0, 125.2, 132.4, 133.9, 141.3, 153.8, 157.6, 161.4.
Anal. Calcd. for C14H16N2O2: C, 68.83; H, 6.60; N, 11.47. Found: C, 68.60; H,
6.77; N, 11.28.
6-Bromo-2-imino-N-(2-phenyl)ethyl-2H-chromene-3-carboxamide (3d)
1
FT-IR: t 3309 (NH), 3217 (NH), 1670 (C ¼ O) cmꢂ1. H NMR (300 MHz, CDCl3): d
2.95 (t, 2H, J ¼ 7.2 Hz, CH2), 3.71 (q, 2H, J ¼ 7.3 Hz, NCH2), 7.02 (d, 1H, J ¼ 8.7 Hz,
HAr), 7.22-7.37 (m, 5H, HAr), 7.55 (dd, 1H, J ¼ 8.7, 2.3 Hz, HAr), 7.61 (s br., 1H,
¼NH), 7.63 (d, 1H, J ¼ 2.3 Hz, HAr), 8.40 (s, 1H, pyran CH), 10.29 (s br., 1H, -CO-
NH). 13C NMR (75 MHz, CDCl3): d 35.7, 41.4, 116.4, 116.9, 120.6, 121.6, 126.4,
128.5, 128.9, 131.5, 135.1, 139.2, 140.0, 152.6, 156.7, 161.7.
Anal. Calcd. for C18H15BrN2O2: C, 58.24; H, 4.07; N, 7.55. Found: C, 58.48; H,
3.92; N, 7.67.
2-Imino-N-(2-phenyl)ethyl-2H-chromene-3-carboxamide (3e)
1
FT-IR: t 3283 (NH), 3190 (NH), 1673 (C ¼ O) cmꢂ1. H NMR (300 MHz, CDCl3): d
2.95 (t, 2H, J ¼ 7.2 Hz, CH2), 3.72 (q, 2H, J ¼ 7.4 Hz, NCH2), 7.13 (d, 1H, J ¼ 8.2 Hz,
HAr), 7.17-7.37 (m, 6H, HAr), 7.44-7.52 (m, 2H, HAr), 7.53 (s br., 1H, ¼NH), 8.48 (s,
1H, pyran CH), 10.40 (s br., 1H, -CO-NH). 13C NMR (75 MHz, CDCl3): d 35.7, 41.4,
115.2, 118.9, 120.5, 124.1, 126.4, 128.5, 128.9, 129.5, 132.5, 139.3, 141.5, 153.8,
157.5, 162.3.
Anal. Calcd. for C18H16N2O2: C, 73.95; H, 5.52; N, 9.58. Found: C, 73.71; H,
5.70; N, 9.72.
6-Bromo-N-cyclohexyl-2-imino-2H-chromene-3-carboxamide (3f)
1
FT-IR: t 3316 (NH), 3185 (NH), 1676 (C ¼ O) cmꢂ1. H NMR (300 MHz, CDCl3): d
1.25-2.02 (m, 10H, 5CH2 in cyclohexyl), 3.92-4.05 (m, 1H, CH in cyclohexyl), 7.02 (d,
1H, J ¼ 8.7 Hz, HAr), 7.54 (dd, 1H, J ¼ 8.7, 2.3 Hz, HAr), 7.62 (d, 1H, J ¼ 2.3 Hz, HAr),
7.66 (s br., 1H, ¼NH), 8.39 (s, 1H, pyran CH), 10.21 (d, 1H, J ¼ 7.2 Hz, -CO-NH).
Anal. Calcd. for C16H17BrN2O2: C, 55.03; H, 4.91; N, 8.02. Found: C, 54.85; H,
4.79; N, 8.28.
N-Cyclohexyl-2-imino-2H-chromene-3-carboxamide (3g)
1
FT-IR: t 3293 (NH), 3209 (NH), 1698 (C ¼ O) cmꢂ1. H NMR (300 MHz, CDCl3): d
1.17-1.94 (m, 10H, 5CH2 in cyclohexyl), 3.84-3.97 (m, 1H, CH in cyclohexyl), 7.04 (d,
1H, J ¼ 8.2 Hz, HAr), 7.11 (td, 1H, J ¼ 7.5, 0.9 Hz, HAr), 7.34-7.44 (m, 2H, HAr), 7.48

572
Davoodnia et al.
(s br., 1H, ¼NH), 8.39 (d, 1H, J ¼ 1.05 Hz, pyran CH with a long range coupling),
10.20 (d, 1H, J ¼ 6.4 Hz, -CO-NH).
Anal. Calcd. for C16H18N2O2: C, 71.09; H, 6.71; N, 10.36. Found: C, 71.28; H,
6.55; N, 10.19.
2-Imino-N-methyl-2H-chromene-3-carboxamide (3h)
1
FT-IR: t 3309 (NH), 3191 (NH), 1673 (C ¼ O) cmꢂ1. H NMR (300 MHz, CDCl3): d
3.05 (d, 3H, J ¼ 5.6 Hz, NCH3), 7.38-7.76 (m, 5H, HAr and ¼ NH), 8.80 (br., 1H, -CO-
NH), 8.95 (s, 1H, pyran CH).
Anal. Calcd. for C11H10N2O2: C, 65.34; H, 4.98; N, 13.85. Found: C, 65.60; H,
5.11; N, 13.63.
2-Imino-N-octyl-2H-chromene-3-carboxamide (3i)
1
FT-IR: t 3249 (NH), 3187 (NH), 1669 (C ¼ O) cmꢂ1. H NMR (300 MHz, CDCl3): d
0.80-1.70 (m, 15H, (CH2)6CH3), 3.35-3.55 (m, 2H, CH2), 7.13 (d, 1H, J ¼ 7.5 Hz, HAr),
7.20 (t, 1H, J ¼ 7.1 Hz, HAr), 7.42-7.54 (m, 2H, HAr), 7.58 (s br., 1H, ¼NH), 8.48 (s,
1H, pyran CH), 10.27 (s br., 1H, -CO-NH). 13C NMR (75 MHz, CDCl3): d 14.1, 22.7,
27.1, 29.2, 29.3 (two carbons at 29.28 and 29.34), 31.8, 39.9, 115.2, 119.0, 120.6,
124.1, 129.5, 132.5, 141.4, 153.8, 157.8, 162.1.
Anal. Calcd. for C18H24N2O2: C, 71.97; H, 8.05; N, 9.33. Found: C, 71.69; H,
7.94; N, 9.49.
Acknowledgments
This work was supported by Islamic Azad University, Mashhad Branch, Iran.
ORCID
Abolghasem Davoodnia
http://orcid.org/0000-0002-1425-8577
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