Reaction of 2-imino-2H-chromene-3-carboxamide with some phosphorus esters: Synthesis of some novel chromenes containing phosphorus heterocycles and phosphonate groups and their antioxidant and cytotoxicity properties

Article abstract of DOI:10.1080/00397911.2019.1652323

Novel chromenyl α-aminophosphonic acid 4 and dialkyl chromenyl phosphonate 6 have been obtained. In addition, some novel types of chromene fused with phosphorus heterocycles such as chromeno[4,3-c][1,2]azaphospholes 5 and 7, chromeno[2,3-d][1,3,2]diazaphosphinine 8 and 1,2-oxaphosphinino[3,4-c]pyridine 10 have been synthesized. The methodology depended on treatment of 2-imino-2H-chromene-3-carboxamide (1) with some phosphorus esters. The synthesized compounds were evaluated for antioxidant and cytotoxic activities. Among the synthesized compounds, compound 5 exhibited the most antioxidant activity with IC₅₀ = 2.8 μg/mL in comparison with ascorbic acid as standard antioxidant. Also, compound 5 had significant cytotoxic effects against four cancer cell lines. Its IC₅₀ values ranged between 4.96 and 7.44 μg/mL in comparison to doxorubicin (IC₅₀ = 0.426–0.493 μg/mL).

Full text of DOI:10.1080/00397911.2019.1652323

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Reaction of 2-imino-2H-chromene-3-carboxamide
with some phosphorus esters: Synthesis of
some novel chromenes containing phosphorus
heterocycles and phosphonate groups and their
antioxidant and cytotoxicity properties
Tarik E. Ali, Mohammed A. Assiri, Hafez M. El-Shaaer, Mohamed M. Hassan,
Ahmed M. Fouda & Noha M. Hassanin
To cite this article: Tarik E. Ali, Mohammed A. Assiri, Hafez M. El-Shaaer, Mohamed M. Hassan,
Ahmed M. Fouda & Noha M. Hassanin (2019): Reaction of 2-imino-2H-chromene-3-carboxamide
with some phosphorus esters: Synthesis of some novel chromenes containing phosphorus
heterocycles and phosphonate groups and their antioxidant and cytotoxicity properties, Synthetic
Communications, DOI: 10.1080/00397911.2019.1652323
To link to this article: https://doi.org/10.1080/00397911.2019.1652323
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https://doi.org/10.1080/00397911.2019.1652323
Reaction of 2-imino-2H-chromene-3-carboxamide with
some phosphorus esters: Synthesis of some novel
chromenes containing phosphorus heterocycles and
phosphonate groups and their antioxidant and
cytotoxicity properties
a,b
a,c
b
Tarik E. Ali
, Mohammed A. Assiri , Hafez M. El-Shaaer , Mohamed M.
b
a
b
Hassan , Ahmed M. Fouda , and Noha M. Hassanin
a
b
Department of Chemistry, Faculty of Science, King Khalid University, Abha, Saudi Arabia; Department
c
of Chemistry, Faculty of Education, Ain Shams University, Cairo, Egypt; Research Center for Advanced
Materials Science, King Khalid University, Abha, Saudi Arabia
ABSTRACT
ARTICLE HISTORY
Novel chromenyl a-aminophosphonic acid 4 and dialkyl chromenyl
phosphonate 6 have been obtained. In addition, some novel types
of chromene fused with phosphorus heterocycles such as chro-
meno[4,3-c][1,2]azaphospholes 5 and 7, chromeno[2,3-d][1,3,2]diaza-
phosphinine 8 and 1,2-oxaphosphinino[3,4-c]pyridine 10 have been
synthesized. The methodology depended on treatment of 2-imino-
Received 11 June 2019
KEYWORDS
Antioxidant; 1,2-
azaphosphole; chromene;
cytotoxicity; 1,3,2-
diazaphosphinine; 1,2-
oxaphosphinino; phospho-
nate; phosphorus esters
2H-chromene-3-carboxamide (1) with some phosphorus esters. The
synthesized compounds were evaluated for antioxidant and cyto-
toxic activities. Among the synthesized compounds, compound 5
exhibited the most antioxidant activity with IC50 ¼ 2.8 lg/mL in
comparison with ascorbic acid as standard antioxidant. Also, com-
pound 5 had significant cytotoxic effects against four cancer cell
lines. Its IC50 values ranged between 4.96 and 7.44 lg/mL in com-
parison to doxorubicin (IC50 ¼ 0.426–0.493 lg/mL).
GRAPHICAL ABSTRACT
CONTACT Tarik E. Ali
tarik_elsayed1975@yahoo.com, tismail@kku.edu.sa Department of Chemistry, Faculty of
Education, Ain Shams University, Roxy, 11711, Cairo, Egypt.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
T. E. ALI ET AL.
Introduction
Chromene nucleus present in many biologically active compounds because of their
[
1,2]
cumulative effect, especially in cancer drugs.
Our earlier work discovered a series of
chromene-based compounds, which preferentially kill several multi-drug resistant can-
[
3,4]
cer.
On the other hand, it is known that phosphorous acid and its mono- and die-
ster are stable and very important precursors for the synthesis of interesting
[
5]
organophosphorus compounds.
They can serve as isosteric analogs of phosphate
[
6]
esters and are used as target specific modulators of a variety of pesticides and thera-
[
7]
peutics.
Heterocyclic compounds having multiple phosphonate groups are also
important synthetic intermediates that find broad agricultural and industrial applica-
[
8–10]
tions.
The design and development of new antioxidant and anticancer drugs with
improved efficacy and minimal side effects is a major challenge in modern drug discov-
ery because of multidrug-resistance in tumor cells. The diverse biological activity of the
above compounds encouraged and prompted to synthesize the novel series of chro-
menes containing phosphorus atoms in form of phosphorous acid and its acyclic and
cyclic esters to explore new opportunities for structure optimization and diverse range
of mechanisms for a potent anticancer activity. The methodology depends on the reac-
tion of 2-imino-2H-chromene-3-carboxamide (1) with some phosphorus esters. All the
compounds screened for the antioxidant and anticancer activity.
Results and discussion
The starting material 2-imino-2H-chromene-3-carboxamide (1) was prepared according
to the reported method by a Knovenagel condensation and intramolecular cyclization of
salicylaldehyde with cyanoacetamide in absolute ethanol containing a few drops of trie-
[
11]
thylamine (Scheme 1).
The presence of two active nucleophilic and two electrophilic
centers in the molecule of 2-imino-2H-chromene-3-carboxamide (1) provides alternative
opportunities in the direction of the reaction with electrophilic and nucleophilic phos-
phorus esters.
Treatment of the carboxamide 1 with phosphorous (phosphonic) acid in dry dioxane,
in the presence of a catalytic amount of 4-toluenesulfonic acid, afforded the unexpected
[
12]
2-oxo-2H-chromene-3-carboxamide (2)
and did not give [3-(aminocarbonyl)-2-
amino-2H-chromen-4-yl]phosphonic acid (3) (Scheme 2). However, the one-pot reac-
tion of 2-imino-2H-chromene-3-carboxamide (1), formaldehyde and phosphorous acid
in diluted hydrochloric acid (50%) gave the chromenyl a-aminophosphonic acid 4 in
moderate yield (Scheme 2). This reaction proceeded through Kabachnik–Field reaction
Scheme 1. Preparation of 2-imino-2H-chromene-3-carboxamide (1).

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3
[
13]
conditions,
in which the carboxamide 1, was added to formaldehyde forming the N-
chromenoylaminomethanol intermediate A that underwent condensation with phos-
phorous acid to isolate the final product. The proposed structure of compound 4 was
confirmed by spectral data. Its IR spectrum presented absorption bands at 3388, 3320,
ꢀ
1
1
and 1719 cm due to OH, NH, and C¼O, respectively. Its H-NMR spectrum dis-
played the characteristic signal for P ꢀ CH protons at d 4.78 ppm (dd, J ¼ 23.2 and
2
6
.4 Hz), while the two NH protons were D O-exchanged signals at d 7.88 and 8.05 ppm.
2
1
3
Also, its C-NMR spectrum revealed the presence of carbon atoms of P ꢀ CH , C¼O
2
and C¼N at d 58.6 (d, J ¼ 151.5 Hz), 162.9 and 160.7 ppm, respectively. Furthermore,
the molecular ion peak of compound 4 appeared at m/z 282 in its mass spectrum.
Likewise, treatment of compound 1 with diethyl phosphite in the presence of
ꢁ
BF .Et O as a catalyst at 80ꢀ90 C furnished the expected nonisolable chromenyl-4-
3
2
phosphonate B or C, which underwent cyclization through a nucleophilic attack of an
amino group at phosphorus atom with the elimination of ethanol molecule affording 4-
amino-1-ethoxy-1-oxido-1,9b-dihydro-chromeno[4,3-c][1,2]azaphosphole-3(2H)-one (5)
1
(
Scheme 3). The H-NMR spectrum of this product did not record the H ꢀ 4 of com-
pound 1 that confirmed occurrence the addition reaction at this position. Moreover, its
1
3
C-NMR spectrum revealed the specific carbon atoms CH , CH , and C ꢀ 9b at d 16.6,
3
2
6
0.9 and 33.3 (d, J ¼ 116.5 Hz) ppm, respectively. Furthermore, the cyclization pro-
PC
cess during the formation of this product was supported by the mass spectrum which
þ
recorded the molecular ion peak at m/z 280 (M , 26%).
In the same manner, the reaction of compound 1 with tris(2-chloroethyl)phosphite in
ꢁ
the presence of BF .Et O as a catalyst at 80ꢀ90 C underwent Michael addition of
3
2
Scheme 2. Reaction of compound 1 with phosphorous acid in 4-TsOH and with phosphorous acid in
presence of formaldehyde and hydrochloric acid.

4
T. E. ALI ET AL.
Scheme 3. Reaction of compound 1 with diethyl phosphite in the presence of BF . Et O as a catalyst
3
2
o
at 80ꢀ90 C.
phosphorus atom at position C–4 forming the intermediate D. The latter intermediate
eliminated 2-chloroethanol molecule by addition of drops of water to give the nonisol-
able chromenyl phosphonate E. This intermediate underwent rearrangement to furnish
the isolated dialkyl chromenyl phosphonate 6 and so the cyclization took place via a
nucleophilic attack of amino group at phosphorus atom with removal of 2-chloroetha-
nol molecule affording 4-amino- 1-(2-chloroethoxy)-1-oxido-1,9b-dihydrochromeno[4,3-
1
c][1,2]azaphosphole-3(2H)-one (7) (Scheme 4). The H-NMR spectrum of compound 6
displayed the presence of two groups of ClCH CH O and two NH groups as well as
2
2
2
1
the P–CH proton as a doublet at d 3.76 (JPCH ¼ 20.4 Hz) ppm. Also, the H-NMR spec-
trum of compound 7 recorded one group of ClCH CH O as two triplets at d 3.41 and
2
2
4
.31 (JHH ¼ 6.8 Hz) ppm, and one amidic NH proton as a broad signal at 10.7 ppm,
13
while the P–CH proton as a doublet at d 4.62 (J
spectrum of compound 6 showed the characteristic carbon atoms at d 34.9 (ClCH ),
¼ 19.2 Hz) ppm. The C-NMR
PCH
2
5
5.7 (OCH ), 43.6 (d, J ¼ 146.6 Hz, P–CH), and 161.1 (C¼O) ppm Moreover, the
2
PC
1
3
C-NMR spectrum of compound 7 revealed the specific carbon atoms ClCH , OCH ,
2
2
and C ꢀ 9b at d 34.8, 55.7, and 46.9 (d, J ¼130.8 Hz) ppm, respectively. Furthermore,
PC
the mass spectrum of compound 6 recorded its molecular ion peaks at m/z 398 (M þ 4,
þ
1
%) 396 (M þ 2, 6%), and 394 (M , 10%) in ratio 1:6:10 which supported the presence
[
14]
of two chlorine atoms.
Similarly, compound 7 recorded its molecular ion peaks at
m/z 316 (M þ 2, 2.6%) and 314 (M , 7%) in ratio 1:3 that confirmed the presence of
þ
one chlorine atom.
Next, the chemical reactivity of compound 1 towards triethyl phosphate was studied.
Therefore, a fusion of compound 1 with excess amounts of triethyl phosphate at
ꢁ
8
0 ꢀ 90 C for 10 h yielded the chromenodiazaphosphinine derivative 8 (Scheme 5). The

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5
Scheme 4. Reaction of compound 1 with tris(2-chloroethyl)phosphite in the presence of BF .Et O as a
3
2
o
catalyst at 80ꢀ90 C.
spectral data of this product suggested its existence in two tautomeric forms 8A and
8
B. Its IR spectrum showed absorption bands at 3420 (br, OH and NH), 1709 (C¼O)
ꢀ1 1
and 1662 (C¼N) cm . Moreover, its H-NMR spectrum showed the ethoxy protons at
d 1.02 ꢀ 1.39 (CH ) and 3.88 ꢀ 3.97 (CH ), whereas the protons NH and OH appeared
3
2
13
as D O-exchanged signals at d 8.22 and 8.70 ppm, respectively. Also, the C-NMR spec-
2
trum recorded doublet signals at d 12.2, 14.9 (CH ), 63.7, 64.7 (OCH ), 146.0, 148.8
3
2
(
C ꢀ 5) and 163.4, 165.2 (C ꢀ 4) ppm. Its mass spectrum displayed the molecular ion
þ
peak M at m/z 278 which supported the proposed structure.
The interesting point in this work was the reaction of compound 1 with triethyl
phosphonoacetate. The reaction was carried out in ethanolic sodium ethoxide to give
the interesting benzoxaphosphorino[3,4-c]pyridine system 10A,B and not the chro-
[
15]
meno[3,4-c] azaphosphinine system 9 (Scheme 6).
Because the spectral data of
compounds 9 and 10A,B are similar and hence difficult to differentiate, the expected
products were investigated by means of quantum mechanical calculations combined
1
13
31
with infrared and NMR ( H, C, and P) spectral data. The obtained results of the
theoretical calculations will be published in the individual article. However, density
functional theory (DFT) using B3LYP method at 6-31G(d,p) and 6-311þþG(d,p)
[
16,17]
basis sets were used.
Two possible pathways for this reaction were explored
which resulted in the formation of two regioisomeric products 9 and 10 with differ-
ent ring skeletons. Initially, the tautomeric stability for both products was predicted
1
13
31
in favor of the hydroxy-keto tautomeric structure. The H-, C- and P-NMR

6
T. E. ALI ET AL.
o
Scheme 5. Reaction of compound 1 with of triethyl phosphate at 80ꢀ90 C.
chemical shifts were also computed for
9
and 10 using GIAO-B3LYP/6-
3
11þþG(d,p) calculations in DMSO solvent modeled by the PCM method.
The computational results revealed that the product 10 was favored with an energy
difference of 9.44 kcal/mol. Aided by the calculated frequencies and chemical shifts,
the observed infrared bands and NMR resonances were confidently assigned and a
better match for product 10 was achieved. In addition, the proposed mechanism for
both reaction pathways was theoretically studied based on the calculated electronic
structure for reaction intermediates and thermodynamic parameters for the involved
steps. The results preferred the pathway which led to the formation of compound
1
0 (in favor of regioisomer A) as a regioselective product.
The structure of compound 10A was also established through IR, NMR and mass
spectral data. Its IR spectrum showed characteristic absorption bands at 3365 (br,
ꢀ
1
1
OH), 3164 (NH), 2202 (CꢂN) and 1678 (C¼O
) cm . Also, its H-NMR spec-
amide
trum showed the presence of CH , OCH , NH and OH at d 1.03, 3.43, 10.34, and
3
2
1
1.53 ppm, respectively. Other evidence for the structure of compound 10A was pro-
1
3
vided by C-NMR spectrum. It displayed the characteristic carbon atoms of CꢂN,
C ꢀ 2, and C¼O at d 116.2, 160.7, and 164.3 ppm, respectively. Also, there was a char-
acteristic doublet at d 119.9 ppm with coupling constant of about 113 Hz corresponded
3
1
to P ꢀ C atom. The P-NMR spectrum of compound 10A showed a signal at d 14.0
4
a
(
d, J ¼ 12.96 Hz) ppm. Its mass spectrum showed the molecular ion peak at m/z 318.
Thus, we can explain the formation of the product 10A as shown in Scheme 6. The
reaction proceeded through Michael-addition of phosphonoacetate at position C ꢀ 4 of
compound 1 with the help of a basic catalyst. The formed intermediate G underwent
ring-opening and rotation to give the intermediate H. The latter intermediate under-
went easily double cyclizations by removal of two ethanol molecules through double
nucleophilic attacks of NH at COOEt and OH at P(O)(OEt) to form the nonisolable
2
2
tetrahydrobenzoxa-phosphorino[3,4-c]pyridine L. Auto-oxidation of the latter inter-
mediate L led to the formation of M that rearranged into the more stable isomer 10A
(Scheme 6).

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7
Scheme 6. Reaction of compound 1 with triethyl phosphonoacetate in ethanolic sodium ethoxide.
Antioxidant activity
The antioxidant activities of the synthesized compounds were evaluated by in vitro
DPPH method in order to compare the results and to establish some structure-antioxi-
dant activity relationships. The evaluation study was carried out at various concentra-
tions at 50, 75, and 100 lg/mL. DPPH (2,2-diphenyl-1-picrylhydrazyl)radical scavenging

8
T. E. ALI ET AL.
Table 1. DPPH radical scavenging ability of the synthesized compounds 1, 4–8, and 10 relative to
the standard antioxidant ascorbic acid.
The percentage (%) antioxidant activity ± SD
Compd. No.
50 (lg/mL)
75 (lg/mL)
100 (lg/mL)
IC50 (lg/mL)
1
4
5
6
7
8
24.32 ± 0.21
54.26 ± 0.36
72.11 ± 0.19
63.44 ± 0.13
63.16 ± 0.41
59.42 ± 0.32
64.34 ± 0.53
67.35 ± 0.19
32.23 ± 0.22
59.92 ± 0.39
83.08 ± 0.17
75.10 ± 0.14
71.53 ± 0.43
71.97 ± 0.29
74.26 ± 0.54
73.01 ± 0.18
40.63 ± 0.20
66.86 ± 0.40
95.31 ± 0.18
84.56 ± 0.15
79.72 ± 0.42
83.75 ± 0.31
85.72 ± 0.52
84.16 ± 0.21
128.97
33.94
2.80
17.31
10.17
30.37
17.06
1.11
1
0
Ascorbic acid
activity evaluation is a standard assay in antioxidant activity studies and offers a rapid
technique for screening the radical scavenging activity of specific compounds or
[
18,19]
extracts.
A freshly prepared DPPH solution exhibits a deep purple color with an
absorption maximum at 517 nm. This purple color generally disappears when an anti-
oxidant is present in the medium. Thus, the antioxidant molecule can quench DPPH
free radical (i.e. by providing hydrogen atoms or by electron donating, conceivable) and
convert them to a colorless product (i.e. 2,2-diphenyl-1-picrylhydrazine), resulting in a
decrease in absorbance. Hence, more rapidly the absorbance decrease, the more potent
the antioxidant activity of the compound. Percentage activity of DMF solutions of the
synthesized compounds was examined and compared (Table 1). We can conclude from
the obtained results that the synthesized compounds showed promising radical scaveng-
ing abilities by the used method and compared with ascorbic acid as a standard antioxi-
dant. The results displayed that most of the synthesized compounds exhibited good
radical scavenging abilities at lower concentrations. However, the gradual increase in
the activity in all cases was observed with increase in the concentrations of the tested
compounds. It was perceived that compounds 4 and 8 displayed moderate antioxidant
properties. Also, compounds 6, 7, and 10 showed good antioxidative activities, while
compound 5 recorded as the most potent antioxidant agent in comparison with ascorbic
acid as standard antioxidant. It seemed that the presence of 1,3,2-diazaphosphinine and
1,2-azaphosphole rings that have NH groups and conjugated systems created a notice-
able increase of antioxidative properties of compounds 4ꢀ8 and 10 in comparison with
the starting material 1. On the other hand, compounds 6, 7, and 10 containing ethyl
phosphonate moieties showed good scavenging activities because these groups made sta-
bilization after H–abstraction from position 2 and 5, beside the carbonyl groups that
helped to stabilization of nitrogen atom of amino groups. The higher antioxidant activ-
ities of compound 5 can be explained by the existence of functionalized 1,2-azaphosp-
hole rings that have free-radical at position 3a and 9a beside the original active amino
groups. The conjugation between free radicals at positions 3a and 9a with carbonyl
groups and p electrons of the aromatic rings represented the main factor for increasing
the stability of the radical structures.
Cytotoxicity evaluations
The in vitro cytotoxicity of the synthesized compounds 1, 4–8, and 10 was evaluated
against human colon carcinoma HCT-116, hepatocellular carcinoma Hep-G2, lung

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9
Table 2. Cytotoxicity (IC , lg/mL) of the synthesized compounds 1, 4–8, and 10
50
against human cancer cell lines in comparison with Doxorubicin.
IC50 (mg/mL)
Compound
HCT-116
Hep-G2
A-549
MCF-7
1
4
5
6
7
8
>500
89.3
7.44
34.5
17.9
209
>500
62.3
4.96
23.9
12.2
120.5
84.7
0.467
>500
51.8
6.85
28.6
15.4
241
>500
92.9
7.42
51.7
22.6
216.7
121.2
0.469
1
0
119
0.493
113
0.426
Doxorubicin
carcinoma A-549 and breast adenocarcinoma MCF-7, using the crystal violet viability
[
20–23]
assay.
The IC50 values of the novel synthesized compounds (IC50 ¼ 4.96–241 lg/mL)
were comparable to that of doxorubicin and summarized in Table 2. Compounds 1, 8,
and 10 were found to be less active while compounds 4, 5, 6, and 7 showed good cyto-
toxicity against all investigated cancer cell lines. Compound 4 had the acceptable IC50
values of 62.3 and 51.8 lg/mL against Hep-G2 and A-549 cancer cells, respectively,
while compound 6 exhibited its best cytotoxicity against the Hep-G2 and A-549cell line,
with IC50 value of 23.9 and 28.6 lg/mL, respectively, which employed in relation to
doxorubicin. Compound 7 exhibited high cytotoxic activity against all four cell lines in
range (IC50 ¼ 22.6–12.2 lg/mL). In addition compound 5 demonstrated very effective
cytotoxicity against all four cell lines that employed in relation to doxorubicin. Based
on the results in Table 2, it can be concluded that the type of phosphorus heterocycle
attached to the chromene moiety is a major determinant of the pharmacological proper-
ties of the synthesized products. Therefore, the presence of acyclic or cyclic phosphonic
acid and their esters moieties attached to the chromene moiety in compounds 4–7
could be considered to be the factor responsible for the high cytotoxicity against cancer
cells in comparison with the compounds 1, 8, and 10. These results provide evidence
that the characteristic chemical features of phosphonate group is a key factor for their
cytotoxicity and play a useful role in elucidating the mechanisms of action in relation to
the synthesized compounds in future research programs. Additionally, the presence of
1,2-azaphosphole as cyclic ethyl phosphonate ester in the chromeno[4,3-c][1,2]aza-
phospholes 5 and 7 displayed the best activities as a system with potentially strong cyto-
toxicity against all four cell lines.
Experimental
The melting points were determined in an open capillary tube on a digital Stuart SMP-
3
apparatus. Infrared spectra were measured on FT-IR (Nicolet IS10) spectrophotometer
1
using KBr disks and Perkin-Elmer 293 spectrophotometer using KBr disks. H- and
1
3
C-NMR spectra were measured on Gemini-300BB spectrometer (400 and 100 MHz),
31
using DMSO-d as a solvent and TMS (d) as an internal standard. P-NMR spectra
6
were measured on a Bruker (162 MHz) spectrophotometer using DMSO-d as a solvent,
6
TMS as an internal standard and 85% H PO as an external reference. Mass spectra
3
4
were recorded on a Gas Chromatographic GCMSQP 1000 EX Shimadzu instrument

1
0
T. E. ALI ET AL.
(Shimadzu, Kyoto, Japan) at 70 ev and direct probe controller inlet part to single quad-
ropole mass analyzer (Thermo Scientific GCMS). Elemental microanalysis was per-
formed on Perkin-Elmer 2400II (Perkin-Elmer, Waltham, MA) at the Chemical War
department, Ministry of Defense. The purity of the synthesized compounds was checked
by thin-layer chromatography (TLC) and elemental microanalysis.
Synthesis of (f[(2-imino-2H-chromen-3-yl)carbonyl]aminogmethyl)phosphonic
acid (4)
Phosphorous acid (0.41 g, 5 mmol) was added to a solution of compound 1 (0.94 g,
5
mmol) in 15% HCl (30 mL). Formaldehyde (1.7 mL, 5 mmol) was added dropwise to
the solution. The mixture was heated under reflux for 4 h. The solid formed on heating
was filtered off, washed with water and crystallized from diluted ethanol to give white
ꢁ
ꢀ1
solid in 43% yield (0.60 g); mp < 300 C. IR (KBr), (v max, cm ): 3388 (OH), 3320
NH), 3151 (NH), 3049 (CꢀH ), 2965 (CꢀH ), 1719 (C¼O), 1659 (C¼N), 1611,
(
1
arom
aliph
1
565 (C¼C), 1206 (P¼O). H-NMR (400 MHz, DMSO-d ): 3.47 (brs, 2H, P ꢀ OH,
6
exchangeable with D O), 4.78 (dd, 2H, J ¼ 23.2 and 6.4 Hz, CH ꢀP), 7.42 (t, 1H,
2
2
J ¼ 6.8 Hz, H ꢀ 6), 7.47 (d, 1H, J ¼ 8.0 Hz, H ꢀ 8), 7.73 (t, 1H, J ¼ 7.2 Hz, H ꢀ 7), 7.88 (s,
H, NH exchangeable with D O), 7.95 (d, 1H, J ¼ 7.6 Hz, H ꢀ 5), 8.05 (s, 1H, NH
1
2
13
exchangeable with D O), 8.85 (s, 1H, H ꢀ 4). C-NMR (100 MHz, DMSO-d ): 58.6 (d,
2
6
J ¼ 151.5 Hz, CH ꢀP), 116.6 (C ꢀ 8), 118.9 (C ꢀ 3), 119.8 (C ꢀ 4a), 125.5 (C ꢀ 6), 130.7
2
(
(
C ꢀ 5), 134.5 (C ꢀ 7), 148.2 (C ꢀ 4), 154.4 (C ꢀ 8a), 160.7 (C ꢀ 2), 162.9 (C¼O). MS
þ
m/z, I%): 284 (M þ 2, 2%), 283 (M þ 1, 9%), 282 (M , 41%). Anal. Calcd. for
C H N O P (282.19): C, 46.82%; H, 3.96%; N, 9.93%. Found: C, 46.49%; H, 3.63%;
1
1
11 2 5
N, 9.69%.
Full experimental details and spectral data of the synthesized compounds can be
accessed on the publisher’s website.
Funding
The authors extend their appreciation to the deanship of scientific research at King Khalid
University for funding this work through general research project under grant number [R.G.P1./
9
9/40].
ORCID
Tarik E. Ali
http://orcid.org/0000-0002-7992-3478
Noha M. Hassanin
http://orcid.org/0000-0001-8380-8432
References
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