Chitosan functionalized by citric acid: an efficient catalyst for one-pot synthesis of 2,4-diamino-5H-[1]benzopyrano[2,3-b]pyridine-3-carbonitriles 5-(arylthio) or 5-[(arylmethyl)thio] substituted

Article abstract of DOI:10.1080/17415993.2016.1275633

Chitosan (CS) functionalized by citric acid has been used as an efficient catalyst for the preparation of 2,4-diamino-5H-[1]benzopyrano[2,3-b]pyridine-3-carbonitriles 5-(arylthio) or 5-[(arylmethyl)thio] substituted by a multicomponent reaction of salicyl

Full text of DOI:10.1080/17415993.2016.1275633

Journal of Sulfur Chemistry
ISSN: 1741-5993 (Print) 1741-6000 (Online) Journal homepage: http://www.tandfonline.com/loi/gsrp20
Chitosan functionalized by citric acid: an efficient
catalyst for one-pot synthesis of 2,4-diamino-5H-
[1]benzopyrano[2,3-b]pyridine-3-carbonitriles 5-
(arylthio) or 5-[(arylmethyl)thio] substituted
Javad Safaei-Ghomi, Maryam Tavazo, Mohammad Reza Vakili & Hossein
Shahbazi-Alavi
To cite this article: Javad Safaei-Ghomi, Maryam Tavazo, Mohammad Reza Vakili
& Hossein Shahbazi-Alavi (2017): Chitosan functionalized by citric acid: an efficient
catalyst for one-pot synthesis of 2,4-diamino-5H-[1]benzopyrano[2,3-b]pyridine-3-
carbonitriles 5-(arylthio) or 5-[(arylmethyl)thio] substituted, Journal of Sulfur Chemistry, DOI:
10.1080/17415993.2016.1275633
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Date: 01 February 2017, At: 12:19

JOURNAL OF SULFUR CHEMISTRY, 2017
http://dx.doi.org/10.1080/17415993.2016.1275633
Chitosan functionalized by citric acid: an efficient catalyst for
one-pot synthesis of 2,4-diamino-5H-[1]benzopyrano[2,3-
b]pyridine-3-carbonitriles 5-(arylthio) or 5-[(arylmethyl)thio]
substituted
Javad Safaei-Ghomi a, Maryam Tavazoa, Mohammad Reza Vakilib and
Hossein Shahbazi-Alavia,c
aDepartment of Organic Chemistry, Faculty of Chemistry, University of Kashan, Kashan, Iran; bDepartment of
Chemistry, Firoozabad Branch, Islamic Azad University, Fars, Iran; cYoung Researchers and Elite Club, Kashan
Branch, Islamic Azad University, Kashan, Iran
ABSTRACT
ARTICLE HISTORY
Received 13 September 2016
Accepted 19 December 2016
Chitosan (CS) functionalized by citric acid has been used as an
efficient catalyst for the preparation of 2,4-diamino-5H-[1]benzopy-
rano[2,3-b]pyridine-3-carbonitriles5-(arylthio)or5-[(arylmethyl)thio]
substituted by a multicomponent reaction of salicylaldehydes, thiols
and 2 equiv. of malononitrile under reflux condition in ethanol. Use
of simple and readily available starting materials, excellent yields in
short times, reusability of the catalyst and little catalyst loading are
some of the important features of this protocol. The structure of CS
functionalized by citric acid was confirmed by infrared spectroscopy
(FT-IR), X-ray diffraction, thermogravimetric analysis and differential
scanning calorimetry.
KEYWORDS
Benzopyranopyridines;
functionalized chitosan; citric
acid; multicomponent
reaction; one-pot synthesis
1. Introduction
Benzopyranopyridines exhibit important biological properties, such as antipsychotic [1],
anti-inflammatory and analgesic [2], anti-allergic [3], antiasthma [4], antibacterial [5]
activities, and can also serve as synthetic intermediates for many kinds of pharmaceu-
ticals or drug precursors [6–8]. Therefore, the development of novel, simple and clean
methods for the synthesis of benzopyranopyridines is of great interest. The synthesis of
benzopyranopyridine derivatives has been reported in the presence of diverse catalysts,
such as K2CO3 [9], Et3N [10,11], NaOH [12] and ZrP2O7 nanoparticles [13]. The combi-
nation of multicomponent reactions (MCRs) with a suitable catalyst could improve their
CONTACT Javad Safaei-Ghomi
safaei@kashanu.ac.ir
Department of Organic Chemistry, Faculty of Chemistry,
University of Kashan, PO Box 87317-51167, Kashan, Iran
© 2017 Informa UK Limited, trading as Taylor & Francis Group

2
J. SAFAEI-GHOMI ET AL.
Scheme 1. Synthesis of benzopyranopyridines 4a–i (see Table 3) using CS@ CA.
effectiveness from operating cost and environmental points of view. Chitosan (CS) is a
biopolymer that can be used as green catalyst in many reactions [14–16]. The presence of
both hydroxyl and amino groups in CS makes it useful as an efficient catalyst [17]. The
capability of CS-based materials to form open-network, macroporous, high-surface-area
hydrogels with available basic surface sites has provided their use not only as macrochelat-
ing ligands for active metal catalysts and as a support to disperse nanosized particles, but
also as a direct organocatalyst [18]. The CS can be utilized as a support for the preparation
of heterogeneous catalysts in the form of colloids, flakes, gel beads, fibers or immobilized
on inorganic supports (silica, titania, alumina or other metal oxides) [19,20]. Meanwhile,
the sulfonic acid groups were introduced onto CS through cross-linking with sulfosuccinic
acid. The catalytic activity increased as the amount of sulfonic acid groups present in CS
increased [21].
Citric acid (CA) is a very inexpensive, commercially available and the relatively non-
toxic, water-soluble organoacid, which has been widely used in organic reactions [22–24].
This study describes the functionalization of biopolymer CS, using the CA as an excellent
catalyst. In this work, CS functionalized by CA has been used as an efficient catalyst for
the preparation of benzopyranopyridines by an MCR of salicylaldehydes 1, thiols 3, and 2
equiv. of malononitrile (2) under reflux condition in ethanol (Scheme 1).
2. Results and discussion
CS reacts with CA in two steps (Scheme 2). In this study, five resins (R) with various ratios
of CS and CA were synthesized (Table 1). The prepared resins are insoluble in protic sol-
vents, such as methanol, ethanol, water and aprotic solvents, such as dimethylformamide
(DMF), dimethylacetamide, and N-methyl-2-pyrrolidone. The results of the fabrication
were bright yellow resin beads with a hard texture because of the cross-linkages of CA.
Microscopic pictures of this type of resin are shown in Figure 1. The average diameter of
the particles was about 200 μm.
The acid capacity of the resins R1–R5 is given in Table 1. R5 was characterized by the
highest value of acidic capacity (8.8 mmol/g). Therefore, the catalyst was synthesized from
CA and CS with a molar ratio of 6:1 for CA to the amine groups of CS.
The FT-IR spectra of the resins and CS (Figure 2) revealed that some new peaks were
formed due to new functional groups, which were introduced in the products. These resins
showed new sharp peaks at 1700–1710 cm−1 which could point to the existence of acidic
groups, and shoulders of broad absorption peaks at about 1610–1635 cm−1 due to stretch-
ing of the carbonyl of amide groups which are formed from the reaction of COOH of

JOURNAL OF SULFUR CHEMISTRY
3
Scheme 2. Preparation of CS functionalized by CA.
CA with NH2 of CS. CA could produce amidation with the amino groups of CS and
esterification with the hydroxyl groups of CS [25].
The X-ray diffraction (XRD) pattern of CS (Figure 3(a)) showed two sharp peaks at
11.4 and 20.2 (2Theta). The XRD pattern of catalyst (resin R5) (Figure 3(b)) indicated just
a sharp peak at 18 (2Theta) due to decrease in the degree of crystallinity of the resin.
The thermal properties of CS and R5 were evaluated by means of thermogravi-
metric analysis/differential gravimetry (TGA/DTG) (Figure 4) and differential scanning
calorimetry (DSC) (Figure 5) under nitrogen atmosphere at a heating rate of 10°C/min.
The weight loss at 40–150°C for CS is due to the moisture vaporization. The other weight
loss at 200–350°C is due to the degradation of CS. The temperature of 10% weight loss
for R5 was 212.5°C and the residual weight percent for resin (R5) was 36.25% at 600°C.

4
J. SAFAEI-GHOMI ET AL.
Table 1. Properties of CS@CA R1–R5.
Resin type
Weight of CAa (g)
CA/CSb
Acid capacityc
R1
R2
R3
R4
R5
1.825
2.738
3.652
4.563
5.475
2
3
4
5
6
6.5
6.8
7.0
8.4
8.8
a1.000 g of CS ≡ 4.7538 mmol of amino groups.
bCA/CS amino groups molar ratio.
cmmol/g.
Figure 1. Optical microscopic images of the resin R5.
Figure 2. FT-IR spectra of (a) CS, (b) R1, (c) R2, (d) R3, (e) R4 and (f) R5.
The DTG of CS showed a peak at 313.3°C, while the DTG of R5 indicated two peaks at
261.7°C and 356.9°C. The DSC thermogram of CS exhibited two peaks, an endothermic
broad peak at about 100°C due to dehydration of CS and another exothermic at about

JOURNAL OF SULFUR CHEMISTRY
5
Figure 3. XRD patterns of CS (a) and resin R5 (b).
Figure 4. TGA/DTG patterns of CS (a) and resin R5 (b).
Figure 5. DSC patterns of CS (a) and resin R5 (b).
308°C peak because of exothermic decomposition of CS. The DSC of R5 represented a
broad endothermic peak at about 200°C, a couple of sharp endothermic peaks at about
330°C and an exothermic peak at 375°C. These results showed that heat stability of R5 is
satisfactory.

6
J. SAFAEI-GHOMI ET AL.
Initially, we focused on systematic evaluation of different catalysts for the model reaction
of salicylaldehyde 1 (R1 =H) (1.5 mmol), malononitrile (2) (3.0 mmol) and benzenethiol
3 (R1 =C6H5) (1.5 mmol) in different solvents. Meanwhile, the model reaction was car-
ried out in the presence of various catalysts, such as morpholine, p-toluenesulfonic acid
(p-TSA), Nafion-H, CA, CS and CS@CA. When the reaction was carried out using p-TSA,
Nafion-H and CA as the catalyst, the product was obtained in moderate to good yields
of 45%, 53% and 62%, respectively. We employed various conditions and found that the
reaction gave satisfying result in the presence of CS functionalized by CA under reflux con-
dition in ethanol. The chemical nature and the existing form of the catalyst play a vital role
in the reaction [26–28]. The reaction was carried out with different amounts of CS func-
tionalized by CA as a catalyst. Consequently, 0.008 g of CS@CA was suitable for 1.5 mmol
of thiol 3, and an excessive amount of CS@CA did not change the yield significantly.
In Table 2, we compared these results with the ones obtained in the presence of other
catalysts. We calculated turn over number (TON) of different catalysts. The result showed
that the CS@CA is more effective than the other catalysts.
Table 2. Optimization of reaction conditions for the synthesis of 4a using different catalysts.a
Entry
Solvent (reflux)
Catalyst
TON
Time (min)
Yield%b
1
2
3
4
5
6
7
8
EtOH
EtOH
EtOH
CH3CN
EtOH
EtOH
EtOH
H2O
–
–
6.5
200
120
120
120
100
100
100
50
50
35
35
35
Trace
51
60
55
45
53
62
52
68
78
88
92
92
86
76
72
66
Morpholine (8 mol%)
CS (0.04 g)
CS0.04 g)
p-TSA (4 mol%)
Nafion-H (0.02 g)
CA (5 mol%)
CS@CA (R5) (0.008 g)
CS@CA (R5) (0.008 g)
CS@CA (R5) (0.008 g)
CS@CA (R5) (0.006 g)
CS@CA (R5) (0.008 g)
CS@CA (R5) (0.01 g)
CS@CA (R4) (0.01 g)
CS@CA (R3) (0.01 g)
CS@CA (R2) (0.01 g)
CS@CA (R1) (0.01 g)
2.3 × 103
2.1 × 103
12
2.5 × 102
13
9.8 × 103
1.2 × 104
1.5 × 104
2.1 × 104
1.7 × 104
1.3 × 104
–
9
DMF
10
11
12
13
14
15
16
17
CH3CN
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
35
35
35
40
–
–
–
40
aSalicylaldehyde 1 (R1 = H) (1.5 mmol), malononitrile (2) (3.0 mmol) and benzenethiol 3 (R2 = C6H5) (1.5 mmol).
bIsolated yields.
Table 3. Synthesis of benzopyranopyridines 4a–i using CS@CA (0.008 g for 1.5 mmol of thiol 3) under
reflux condition in ethanol.
Entry
R1 in aldehyde 1
R2 in thiol 3
C6H5–
4-MeC6H4–
C6H5CH2–
2-furanylmethyl–
C6H5–
4-MeC6H4–
C6H5CH2–
Product
Time (min)
Yield%a
m.p. found
m.p reported
1
2
3
4
5
6
7
8
9
H
H
H
H
Br
Br
Br
Br
Me
4a
4b
4c
4d
4e
4f
4g
4h
4i
35
40
40
40
35
35
35
35
40
92
87
88
85
94
90
89
86
84
220–222
223–225
175–177
200–201
214–216
212–214
205–207
223–225
280–282
215–217 [11]
223–225 [9]
173–175 [11]
194–197 [11]
215–217 [13]
213–215 [13]
206–208 [13]
225–227 [13]
–
2-furanylmethyl–
4-ClC6H4–
aIsolated yields.

JOURNAL OF SULFUR CHEMISTRY
7
The acid capacity of the tested catalysts was measured by titration with NaOH solu-
tion. The results summarized in Table 1 show that the resin R5 exhibits a considerably
high acid capacity of 8.8 mmol/g. We tested the catalytic activity of resins (R1–R5) for the
model reaction of salicylaldehyde (1.5 mmol), malononitrile (3 mmol) and benzenethiol
Scheme 3. Schematic mechanism for the catalytic activity of CS@CA in the synthesis of titled
compound P.

8
J. SAFAEI-GHOMI ET AL.
(1.5 mmol) under reflux condition in ethanol. From the results, it is obvious that the resin
5 (R5) is the best catalyst among those examined, as given in Table 2. As the acid capacity
increases, the yield increases (Table 2). Therefore, acid capacity of catalyst is an important
factor in determining the activity of resins R1–R5.
The recyclability of CS@CA was further investigated because the possibility of a
repeated use of a heterogeneous catalyst is one of the most important issues for practi-
cal applications. After the separation from reaction mixture by filtration, the catalyst was
washed with ethanol and dried in air. The catalyst had been reused in model reaction for
five reaction cycles. It was found that the product yields decreased to a small extent on each
reuse (run 1, 92%; run 2, 92%; run 3, 91%; run 4, 91%; and run 5, 90%).
The reaction works well for salicylaldehydes 1 and different thiols 3. All the reactions
reached completion within 35–40 min to afford good yields of products 4. The yields of
recrystallized benzopyranopyridines 4a–i are given in Table 3.
A possible mechanism for the formation of benzopyranopyridines 4 is shown in
Scheme 3. Initially, salicylaldehyde reacts with 1 equiv. of malononitrile to form inter-
mediate I1 and subsequent intramolecular addition of the hydroxyl group to the C≡N
gives the cyclic intermediate I2. This compound undergoes addition with thiophenol 3
(R2 =C6H5) to afford phenylsulfanylchromene I3. The intermediate I3 reacts with another
equiv. of malononitrile to form intermediate I4, followed by intramolecular cyclization to
form intermediate I5. Finally the chromenopyridine P was formed by the tautomerization
of the imino group to the amino group. In this mechanism CS@CA acts as a highly efficient
=
=
and green organocatalyst activating the C O, C NH and Cand green organocatalyst acti-
vating theN groups for better reaction with nucleophiles. This proposed mechanism was
supported by the literature [11–13] and [24–31]. So, we were encouraged to use CS@CA
in the following optimization of the reaction conditions.
One issue of great importance in using insoluble catalysts is their specific surface areas
and porous network, necessary for the accessibility of the reactants to the active sites and
for enhanced mass transport and diffusion [18]. CS is commonly used in the form of flakes,
powder or hydrogel beads. It is clear that these physical forms suffer two major disadvan-
tages: the specific surface area is low and the majority of active binding sites are internal,
which result in a relatively slow adsorption kinetics and low adsorption capacity [32–34].
Thus, a way is needed to increase the surface area of CS so that the accessibility of the
reactants to the active sites can be more effective [25]. This study describes the function-
alization of biopolymer CS, using CA as a heterogeneous catalyst to increase the surface
area of CS. The persistence of the catalytic activity suggests that the active sites are located
in the external surface and not buried within the entangled network.
3. Conclusions
In conclusion, we have developed a straightforward and efficient approach to the synthesis
of benzopyranopyridines 4a–i by an MCR of salicylaldehydes 1, thiols 3, and 2 equiv. of
malononitrile (2) in the presence of CS functionalized by CA under reflux condition in
ethanol. The method offers several advantages, including rapid assembly of medicinally
privileged heterocyclic molecules, use of easily available starting products, high yields,
short reaction times, reusability of the catalyst, and little catalyst loading.

JOURNAL OF SULFUR CHEMISTRY
9
4. Experimental design
4.1. Materials and apparatus
Reagent-grade chemicals were purchased from Sigma-Aldrich or Merck and were used
without further purification. CS with 70–85% degree of acetylation and average-molecular
weight of 100,000–300,000 was purchased from Sigma-Aldrich. 1H NMR and 13C NMR
spectra were recorded on Bruker Avance-400 MHz spectrometer using DMSO-d6 as sol-
vent. FT-IR spectra were recorded on a Tensor 27 instrument, using KBr pellets. TGAs were
recorded on a Mettler TA4000 instrument with a heating rate of 10°C/min under nitro-
gen atmosphere. DSC analyses were performed on a Shimadzu DSC-50 instrument with
a heating rate of 10°C/min under nitrogen atmosphere. Wide-angle XRD measurements
were performed at room temperature on a Bruker – D8 X-ray diffractometer (operating
at 40 kV and 30 mA) with graphite monochromatized Cu Kα radiation (λ = 1.54118 Å).
The scanning rate was 2°/min.
4.2. Synthesis of CS functionalized by CA
To prepare the resins, 0.5 g of CS powder (2.38 mmol NH2) was mixed with aqueous solu-
tions of various amounts of CA with CA/NH2(CS) molar ratios: 2, 3, 4, 5 and 6. The mixture
was stirred overnight using a magnetic stirrer to make a final solution at a CS concentration
of 4 wt%. The solution was placed in polystyrene Petri dishes and maintained at 70–80°C
for 5 h. Unreacted CA was removed from the product using a Soxhlet apparatus by washing
with distilled water for 48 h.
4.3. Back titration
The degree of substitution indicates the average number of acid groups present in the poly-
mer. To determine the degree of substitution of carboxylic acid groups, a certain amount of
the CS@CA was soaked in 5 mL of 0.1N NaOH solution at the ambient temperature. Then,
the excess of NaOH solution was titrated with 0.1N HCl in the presence of phenolphthalein
as the indicator.
4.4. General procedure for the preparation of benzopyranopyridines 4a–i
A mixture of a selected salicylaldehyde 1 (1.5 mmol), malononitrile 2 (3 mmol), a desired
thiol 3 (1.5 mmol) and 0.008 g of CS@CA as catalyst (CA and CS with a molar ratio of 6:1)
was stirred in 15 mL of anhydrous ethanol under reflux condition. The reaction was moni-
tored by TLC. The formed precipitate was isolated by filtration. The product was dissolved
in DMF (5 mL) and the catalyst was filtered. Then, water (10 mL) was added to the filtrate
which resulted in the crystallization of the product 4. The resulting crystalline structure
was filtered and dried with a vacuum pump.
4.5. Representative spectral data
2,4-Diamino-5-(phenylthio)-5H-[1]benzopyrano[2,3-b]pyridine-3-carbonitrile4a: yield 92%,
yellow solid, m.p. 220–222°C. IR (KBr): ν = 3429, 3355 (NH2), 2203 (C≡N), 1623

10
J. SAFAEI-GHOMI ET AL.
1
(C N), 1575, 1404 (C C), 697 (C–S–C) cm−1. H NMR (400 MHz, DMSO-d6): δ
(ppm) = 5.73 (s, 1H, H-5), 6.50–6.70 (2H, m, H-7 and H-9), 6.74–6.78 (3H, m, H-6, H-8
and H-4ꢀ), 6.94 (s, 2H, NH2), 7.05–7.11 (4H, m, NH2 and two ArH), 7.15–7.30 (m, 2H, H-
2ꢀ and H-6ꢀ). 13C NMR (100 MHz, DMSO-d6): δ (ppm) = 43.12 (C-5), 70.8 (C-3), 86.90
(C-4a), 116.01 (C≡N), 116.5 (C-9), 121.5 (C-7), 123.9 (C-4ꢀ), 128.60 (C-2ꢀ,6ꢀ), 128.64 (C-
8), 129.50 (C-6), 129.70 (C-3ꢀ,5ꢀ), 134.2 (C-5a), 137.7 (C-1ꢀ), 150.90 (C-9a), 156.40 (C-2),
159.7 (C-4), 160.90 (C-10a). Analysis for C19H14N4OS: calcd. C 65.88, H 4.07, N 16.17,
found C 65.81, H 4.13, N 16.04.
=
=
2,4-Diamino-5-[(4-methylphenyl)thio]-5H-[1]benzopyrano[2,3-b]pyridine-3-carbonitrile
4b: yield 87%, yellow solid, m.p. 223–225°C. IR (KBr): ν = 3457, 3349 (NH2), 2198
1
(C≡N), 1623 (C N), 1563 and 1400 (C C), 730 (C–S–C) cm−1. H NMR (400 MHz,
DMSO-d6): δ (ppm) = 2.19 (s, 3H, CH3), 5.66 (s, 1H, H-5), 6.46 (br s, 2H, NH2), 6.61
(d, J = 7.9 Hz, H-9 and H-7), 6.79 (d, J = 7.9 Hz, 1H, H-6), 6.90 (m, 4H, NH2 and two
ArH), 7.11 (d, J = 6.8 Hz, 1H, H-8), 7.19 (d, J = 7.3 Hz, 2H, H-2ꢀ,6ꢀ). 13C NMR (100 MHz,
DMSO-d6): δ (ppm) = 21.2 (CH3), 43.11 (C-5), 70.8 (C-3), 86.3 (C-4a), 115.7 (C≡N),
116.4 (C-9), 121.8 (C-7), 123.6 (C-2ꢀ,6ꢀ), 127.0 (C-8), 128.2 (C-6), 128.6 (C-3ꢀ,5ꢀ), 129.8
(C-4a), 136.9 (C-1ꢀ) , 138.3 (C-4ꢀ), 151.33 (C-9a), 156.3 (C-2), 160.08 (C-4), 160.25 (C-
10). Analysis for C20H16N4OS: calcd. C 66.65, H 4.47, N 15.54; found C 66.55, H 4.54, N
15.45.
=
=
2,4-Diamino-5-[(phenylmethyl)thio]-5H-[1]benzopyrano[2,3-b]pyridine-3-carbonitrile 4c:
yield 88%, yellow solid, m.p. 175–177°C. IR (KBr): ν = 3377, 3439 (NH2), 2200 (C≡N),
1
1627 (C N), 1545 and 1485 (C C), 701 (C–S–C) cm−1. H NMR (400 MHz, DMSO-
d6): δ (ppm) = 3.49 (ABq, 2H, J = 12 Hz, CH2), 5.48 (s, 1H, H5), 6.55 (bs, 2H, NH2),
6.83 (bs, 2H, NH2), 7.03–7.21 (m, 7H, ArH), 7.33 (m, 2H, ArH). 13C NMR (100 MHz,
DMSO-d6): δ (ppm) = 35.02 (CH2), 44.01 (C-5), 70.90 (C-3), 87.01 (C-4a), 117.6 (C≡N),
118.3 (C-9), 119.3 (C-7), 122.8 (C-4ꢀ), 124.2 (C-8), 124.3 (C-3ꢀ,5ꢀ), 129.6 (C-2ꢀ,6ꢀ), 133.2
(C-6), 133.3 (C-5a), 136.6 (C-1ꢀ), 143.7 (C-9a), 152.9 (C-2), 159.9 (C-4), 160.2 (C-10a).
Analysis for C20H16N4OS: calcd. C 66.65, H 4.47, N 15.54; found C 66.46, H 4.55, N
15.38.
=
=
2,4-Diamino-5-[(2-furanylmethyl)thio]-5H-[1]benzopyrano[2,3-b]pyridine-3-carbonitrile
4d: yield 85%, yellow solid, m.p. 200–201°C. IR (KBr): ν = 3440, 3386 (stretching,
NH2), 2203 (C≡N), 1612 (C N), 1588 and 1487 (C C), 750 (C–S–C) cm−1. 1H NMR
(400 MHz, DMSO-d6): δ (ppm) = 3.51 (ABq, 2H, J = 12 Hz, CH2), 5.46 (s, 1H, H-5), 5.99
(d, J = 3.4 Hz, 1H, C-5ꢀ), 6.23 (m, 1H, C-4ꢀ), 6.55 (bs, 2H, NH2), 6.79 (bs, 2H, NH2), 7.10
(d, 1H, J = 8 Hz, C-9), 7.17 (t, 1H, J = 8 Hz, C-7), 7.24 (d, J = 2 Hz, 1H, C-3ꢀ), 7.31 (t, 2H,
J = 8 Hz, H-6,8). 13C NMR (100 MHz, DMSO-d6): δ (ppm) = 25.9 (CH2), 36.03 (C-5),
71.0 (C-3), 87.9 (C-4a), 107.8 (C-5ꢀ), 111.0 (C-4ꢀ), 116.5 (C-9), 116.9 (C≡N), 129.0 (C-7),
129.7 (C-6,8), 133.8 (C-5a), 142.7 (C-3ꢀ), 149.4 (C-9a), 151.2 (C-1ꢀ), 157.1 (C-2), 160.03
(C-4), 160.10 (C-10a). Analysis for C18H14N4O2S: calcd. C 61.70, H 4.03, N 15.99; found
C 61.61, H 4.12, N 15.90.
=
=
2,4-Diamino-7-bromo-5-(phenylthio)-5H-[1]benzopyrano[2,3-b]pyridine-3-carbonitrile4e:
yield 94%, yellow solid, m.p. 214–216°C. IR (KBr): ν = 3458, 3332, 3276 (NH2), 3072
1
(C–H), 2200 (C≡N), 1653 (C N), 1602 and 1415 (C C), 750 (C–S–C) cm−1. H
=
=
NMR (400 MHz, DMSO-d6): δ (ppm) = 5.31 (s, 1H, H-5), 6.80 (d, J = 8.7 Hz, 1H, H-9),

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7.01–7.06 (m, 2H, H-4ꢀ and H-6), 7.10 (br s, 2H, NH2), 7.22–7.38 (m, 7H, NH2 and five
ArH). 13C NMR (100 MHz, DMSO-d6): δ (ppm) = 37.6 (C-5), 63.6 (C-3), 87.5 (C-4a),
117.9 (C≡N), 119.9 (C-7), 123.9 (C-9), 127.7 (C-4ꢀ), 128.5 (C-2ꢀ,6ꢀ), 128.9 (C-3ꢀ,5ꢀ), 129.1
(C-8), 129.6 (C-6), 129.9 (C-5a), 130.8 (C-1ꢀ), 135.8 (C-9a), 136.6 (C-2), 148.3 (C-4), 162.5
(C-10a). Analysis for C19H13BrN4OS: calcd. C, 53.66; H, 3.08; N, 13.17; found C 53.72, H
3.15, N 13.10.
2,4-Diamino-7-bromo-5-[(4-methylphenyl)thio]-5H-[1]benzopyrano[2,3-b]pyridine-3-
carbonitrile 4f: yield 90%, yellow solid, m.p. 212–214°C. IR (KBr): ν = 3455, 3333, 3275
(NH2), 3071 (C–H), 2203 (C≡N), 1650 (C N), 1604 and 1474 (C C), cm−1. 1H NMR
(400 MHz, DMSO-d6): δ (ppm) = 2.16 (s, 3H, CH3), 5.10 (s, 1H, H-5), 6.75 (d, J = 8.7 Hz,
1H, H-9), 7.10–7.15 (m, 2H, H-3ꢀ,5ꢀ), 7.15 (br s, 2H, NH2), 7.26–7.46 (m, 6H, NH2 and
four ArH). 13C NMR (100 MHz, DMSO-d6): δ (ppm) = 21.2 (CH3), 37.6 (C-5), 63.6 (C-
3), 86.3 (C-4a), 117.8 (C≡N), 119.6 (C-7), 123.8 (H-9), 127.6 (C-2ꢀ,6ꢀ), 128.2 (C-3ꢀ,5ꢀ),
128.3 (C-8), 128.8 (C-6), 129.2 (C-1ꢀ), 129.4 (C-4ꢀ), 129.7 (C-5a), 130.5 (C-9a), 136.5 (C-
2), 148.2 (C-4), 162.6 (C-10a). Analysis for C20H15BrN4OS: calcd. C 54.68, H 3.44, N 12.75;
found C 54.61, H 3.40, N 12.71.
=
=
2,4-Diamino-7-bromo-5-[(phenylmethyl)thio]-5H-[1]benzopyrano[2,3-b]pyridine-3-
carbonitrile 4g: yield 89%, yellow solid, m.p. 205–207°C. IR (KBr): ν = 3315, 3441 (NH2),
1
2189 (C≡N), 1663 (C N), 1600 and 1403 (C C) cm−1. H NMR (400 MHz, DMSO-
d6): δ (ppm) = 4.06–4.45 (ABq, 2H, J = 12 Hz, CH2), 4.67 (s, 1H, H-5), 6.48 (s, 1H, H-9),
6.88–6.90 (m, 5H, NH2 and three ArH), 7.37 (m, 6H, NH2 and four ArH). 13C NMR
(100 MHz, DMSO-d6): δ (ppm) = 33.34 (CH2), 38.89 (C-5), 71.13 (C-3), 87.29 (C-4a),
116.46 (C≡N), 116.93 (C-7), 123.03 (C-9), 124.68 (C-4ꢀ), 127.08 (C-3ꢀ,5ꢀ), 128.67 (C-
2ꢀ,6ꢀ), 129.00 (C-8), 129.07 (C-5a), 129.52 (C-6), 137.82 (C-1ꢀ), 151.36 (C-9a), 157.04 (C-2),
160.24 (C-4), 160.34 (C-10a). Analysis for C20H15BrN4OS: calcd. C 54.68, H 3.44, N 12.75;
found C 54.52, H 3.50, N 12.60.
=
=
2,4-Diamino-7-bromo-5-[(2-furanylmethyl)thio]-5H-[1]benzopyrano[2,3-b]pyridine-3-
carbonitrile 4h: yield 86%, yellow solid, m.p. 223–225°C. IR (KBr): ν = 3311, 3442 (NH2),
1
2194 (C≡N), 1656 (C N), 1404 (C C) cm−1. H NMR (400 MHz, DMSO-d6): δ
(ppm) = 4.14–4.56 (ABq, 2H, J = 12 Hz, CH2), 4.89 (s, 1H, H-5), 6.34 (s, 1H, J = 3.2 Hz,
H-5ꢀ), 6.46 (m, 1H, H-4ꢀ), 6.78-6.95 (m, 4H, 2 NH2 and two ArH), 7.39 (m, 1H, CH of
aromatic), 7.62 (m, 1H, H-3ꢀ). 13C NMR (100 MHz, DMSO-d6): δ (ppm) = 28.64 (CH2),
36.31 (C-5), 64.27 (C-3), 84.86 (C-4a), 108.77 (C-5ꢀ), 111.49 (C-4ꢀ), 116.50 (C≡N), 118.87
(C-7), 119.41(C-9), 124.14 (C-8), 125.50 (C-5a), 131.12 (C-6), 131.89 (C-3ꢀ), 143.26 (C-9a),
148.21 (C-1ꢀ), 150.72 (C-2), 155.24 (C-4), 160.5 (C-10a). Analysis for C18H13N4O2SBr:
calcd. C 50.36, H 3.05, N 13.05; found C 50.32, H 2.94, N 13.02.
=
=
2,4-Diamino-5-[(4-chlorophenyl)thio]-7-methyl-5H-[1]benzopyrano[2,3-b]pyridine-3-
carbonitrile 4i: yield 84%, yellow solid, m.p. 280–282°C. IR (KBr): ν = 3484, 3408 and
1
3372 (NH2), 3141 (CH), 2202 (C≡N), 1653 (C N), 1612 and 1474 (C C) cm−1. H
NMR (400 MHz, DMSO-d6): δ (ppm) = 2.19 (s, 3H, CH3), 5.67 (s, 1H, H-5), 6.46 (bs,
2H, NH2), 6.72 (d, J = 8.0 Hz, 1H, H-8), 6.75–7.82 (m, 8H, NH2 and six ArH). 13C NMR
(100 MHz, DMSO-d6): δ (ppm) = 21.2 (CH3), 43.1 (C-5), 70.8 (C-3), 86.7 (C-4a), 116.2
(C≡N), 117.0 (C-9), 122.3 (C-3ꢀ,5ꢀ), 124.1 and 128.7 (C-6,8), 127.5 (C-2ꢀ,6ꢀ), 129.1 and
129.4 (C-4ꢀ,5a), 136.4 (C-7), 138.8 (C-1ꢀ), 151.3 (C-9a), 156.7 and 160.0 (C-2,4), 160.2
=
=

12
J. SAFAEI-GHOMI ET AL.
(C-10a). Analysis for C20H15ClN4OS: calcd. C 60.83, H 3.83, N 14.19; found C 60.76, H
3.72, N 14.08%.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
The authors are grateful to the University of Kashan for supporting this work [grant number
159196/XXI].
ORCID
Javad Safaei-Ghomi http://orcid.org/0000-0002-9837-4478
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