Reaction of 2-Imino-2H-chromene-3-carboxamide with Phosphorus Isothiocyanates: First Synthesis of Novel Chromeno[2,3-d]pyrimidinyl and Bis(chromeno[2,3-d]pyrimidinyl)phosphines and Chromeno[2′,3′:4,5]pyrimido[2,1-d][1,3,5,2]triazaphosphinine

Article abstract of DOI:10.1002/jhet.3552

Novel chromeno[2,3-d]pyrimidinyl and bis(chromeno[2,3-d]pyrimidinyl)phosphines and chromeno[2′,3′:4,5]pyrimido[2,1-d][1,3,5,2]triazaphosphinine were obtained in a simple one-pot procedure via treatment of 2-imino-2H-chromene-3-carboxamide with phenyl phosphorus isothiocyanates. Possible reaction mechanisms were proposed. The structures of the obtained products were confirmed by elemental analyses and spectral tools.

Full text of DOI:10.1002/jhet.3552

Month 2019
Reaction of 2-Imino-2H-chromene-3-carboxamide with Phosphorus Iso-
thiocyanates: First Synthesis of Novel Chromeno[2,3-d]pyrimidinyl and
Bis(chromeno[2,3-d]pyrimidinyl)phosphines and Chromeno[20,30:4,5]
pyrimido[2,1-d][1,3,5,2]triazaphosphinine
Mohammed A. Assiri,a,b Tarik E. Ali,a,c
Noha M. Hassanin,c I. S. Yahia,b,d,e and Gamal B. Sakre
*
aDepartment of Chemistry, Faculty of Science, King Khalid University, Abha, Saudi Arabia
bResearch Center for Advanced Materials Science, King Khalid University, Abha, Saudi Arabia
cDepartment of Chemistry, Faculty of Education, Ain Shams University, Roxy, Cairo, Egypt
dAdvanced Functional Materials & Optoelectronic Laboratory, Department of Physics, Faculty of Science, King Khalid
University, Abha, Saudi Arabia
eNanoscience Laboratory for Environmental and Biomedical Applications, Semiconductor Lab., Department of Physics,
Faculty of Education, Ain Shams University, Roxy, Cairo, Egypt
*E-mail: tarik_elsayed1975@yahoo.com, tismail@kku.edu.sa
Received November 5, 2018
DOI 10.1002/jhet.3552
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
Novel
chromeno[2,3-d]pyrimidinyl
and
bis(chromeno[2,3-d]pyrimidinyl)phosphines
and
chromeno[20,30:4,5]pyrimido[2,1-d][1,3,5,2]triazaphosphinine were obtained in a simple one-pot procedure
via treatment of 2-imino-2H-chromene-3-carboxamide with phenyl phosphorus isothiocyanates. Possible re-
action mechanisms were proposed. The structures of the obtained products were confirmed by elemental
analyses and spectral tools.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
hand, phosphorus-containing compounds continue to
attract a great interest because of the diversity of
pharmacological activities, especially when they are
associated with different heterocycles [6]. For example,
they were used as antitumor [7], antineoplastic [8],
anti-inflammatory [9], and antimicrobial agents [10].
In our recent article [11], we studied the chemical
reactivity of 2-imino-2H-chromene-3-carboxamide (1)
toward some phosphorus sulfides, which led to the
Oxygen-containing heterocyclic compounds are
biologically attractive scaffolds and known as naturally
and synthetic bioactive molecules [1,2]. Among them,
some fused polycyclic chromene compounds have
received synthetic attention because of their important
biological properties such as antioxidant [3], anticancer
[4], and antimicrobial [5] properties. On the other
© 2019 Wiley Periodicals, Inc.

M. A. Assiri, T. E. Ali, N. M. Hassanin, I. S. Yahia, and G. B. Sakr
Vol 000
formation of 2-sulfido-2,3-dihydro-4H-chromeno[2,3-d]
[1,3,2]diazaphosphinines. Considering the aforementioned
facts and our program research on the development of
new heterocyclic organophosphorus compounds [12–15],
we herein reported the synthesis of phosphorus-containing
compounds possessing multi-heterocyclic rings via
treatment of 2-imino-2H-chromene-3-carboxamide (1)
with some phenyl phosphorus isothiocyanate reagents.
potassium thiocyanate were stirred and heated in dry
dioxane under reflux for 1 h, followed by addition of an
equimolar amount of compound 1, and then further
heated for 8 h. The separated product was identified
as N-[4-oxo-3,4-dihydro-2H-chromeno[2,3-d]pyrimidin-2-
ylidene]-P,P-diphenylphosphinous amide (2) (Scheme 2).
The product 2 was formed through a nucleophilic
addition of an amino group at the isothiocyanate A to
form the phosphinyl thiourea B, which underwent
cyclization via attack of an imino group at C═S, followed
by loss of H2S molecule (Scheme 2). The molecular ion
peak of compound 2 in its mass spectrum appeared at m/
z 397 (M+, 13%), which confirmed its structure. Also,
its IR spectrum showed the functional groups NH, C═O,
and C═N at 3340, 1705, and 1660 cmꢀ1, respectively.
Moreover, its 1H-NMR spectrum displayed the new
protons of diphenylphosphine moiety and only one D2O-
exchangeable signal at δ 8.47 ppm for the NH proton.
Similarly, the bis-isothiocyanate D was produced by
reaction of P,P-dichlorophenylphosphine with two folds
of potassium thiocyanate in dry dioxane. Addition of an
equimolar amount of compound 1 to the prepared bis-
isothiocyanate D in dry dioxane furnished the novel
chromeno[20,30:4,5]pyrimido[2,1-d][1,3,5,2]
triazaphosphinine derivative 3 as a sole product in one pot
(Scheme 3). The suggested mechanism for this reaction
proposed a nucleophilic addition of amino group of
compound 1 at one isothiocyanate moiety to give the
nonisolable intermediate E. The latter intermediate
underwent cyclization via attack of NH amidic at the
second isothiocyanate moiety to form the nonisolable
triazaphosphinine F. Removal of H2S molecule from the
intermediate F formed the final polyheterocyclic system 3
(Scheme 3). The mass spectrum was a good evidence for
the formation of compound 3, which recorded its M+ at
RESULTS AND DISCUSSION
The
starting
material
2-imino-2H-chromene-3-
carboxamide (1) was prepared according to the reported
method by cyclization of salicylaldehyde with
cyanoacetamide in absolute ethanol containing a few
drops of triethylamine (Scheme 1) [16]. 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 phosphorus
reagents.
Reaction of phenyl phosphorus halides with potassium
thiocyanate can form chemically active phosphorus
isothiocyanate in situ [17]. These reagents can react with
2-imino-2H-chromene-3-carboxamide (1), forming novel
interesting phosphorus-containing heterocycles. Thus,
equimolar amounts of P-chlorodiphenylphosphine and
Scheme 1. Preparation of 2-imino-2H-chromene-3-carboxamide (1).
Scheme 2. The reaction of (Ph)2PCl, KSCN, and compound 1 in ratio of 1:1:1.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
First Synthesis of Novel Chromeno[2,3-d]pyrimidinyl and Bis(chromeno[2,3-d]
pyrimidinyl)phosphines and Chromeno[20,30:4,5]pyrimido [2,1-d][1,3,5,2]
Triazaphosphinine
Scheme 3. The reaction of PhPCl2, KSCN, and compound 1 in ratio of 1:2:1.
Scheme 4. The reaction of PhPCl2, KSCN, and compound 1 in ratio of
1:2:2.
m/z 378. The specific functional NH, C═O, and C═S were
displayed in the IR spectrum of compound 3 at 3420, 1716,
and 1180 cmꢀ1, respectively. Its 1H-NMR spectrum
revealed the NH proton of thioamide group at δ
12.04 ppm, while its 13C-NMR spectrum displayed the
characteristic carbon atoms of C═S, C═O, C-12a, and C-
13a at δ 186.7, 164.4, 151.6, and 154.3 ppm, respectively.
In the same manner, when compound 1 was added to the
bis-isothiocyanate D in double amounts in dry dioxane, the
bis-{chromeno[2,3-d]pyrimidinyl}phosphorus diamide 4
was obtained in 28% yield (Scheme 4). The formation of
compound 4 was similar to the formation of compound 2
as shown in Scheme 4. The IR spectrum of compound 4
displayed absorption bands at 3420 (NH), 1716 (C═O),
and 1668 (C═N) cmꢀ1. Also, its 1H-NMR spectrum
revealed two D2O-exchangeable signals at δ 8.24 and
8.71 ppm due to NH protons, which suggested that the
two chromenopyrimidine moieties were neither
equivalent nor at the same plane [18]. This suggestion
was also proved by 13C-NMR spectrum that displayed
two signals for each carbon atom such as the carbonyl
group, which appeared at δ 163.4 and 165.1 ppm.
Furthermore, the molecular ion peak M+ for compound 4
was observed at m/z 532 (M+, 9%) in its mass spectrum.
We failed to obtain suitable crystals to conduct X-ray
crystallography to confirm these suggestions.
1
using KBr disks. H-NMR and 13C-NMR spectra were
measured on Gemini-300BB spectrometer (400 and
100 MHz), using DMSO-d6 as a solvent and TMS (δ) as
an internal standard. Mass spectra were recorded on a gas
chromatograph GCMSqp 1000 ex Shimadzu instrument
(Shimadzu Corp., Kyoto, Japan) at 70 eV and direct probe
controller inlet part to single quadropole mass analyzer in
Thermo Fisher Scientific gas chromatography/mass spec-
trometry (MS). Elemental microanalysis was performed
EXPERIMENTAL
The melting points were determined in an open capillary
tube on a digital Stuart SMP-3 apparatus. IR spectra were
measured on FTIR (Nicolet IS10) spectrophotometer
using KBr disks and PerkinElmer 293 spectrophotometer
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. A. Assiri, T. E. Ali, N. M. Hassanin, I. S. Yahia, and G. B. Sakr
Vol 000
on PerkinElmer 2400II at the Chemical War Department,
Ministry of Defense. The purity of the synthesized com-
pounds was checked by thin-layer chromatography and el-
emental microanalysis.
(378.34): C, 57.14%; H, 2.93%; N, 14.81%; S, 8.48%.
Found: C, 56.78%; H, 2.69%; N, 14.52%; S, 8.03%.
Synthesis of N,N0-bis{4-oxo-3,4-dihydro-2H-chromeno[2,3-
d]pyrimidin-2-ylidene}-P-phenylphosphonous diamide (4).
A mixture of P,P-dichlorophenylphosphine (0.7 mL,
5 mmol) and potassium thiocyanate (1 g, 10 mmol) in
dry dioxane (20 mL) was stirred at room temperature for
30 min and then heated under reflux for 1 h. The formed
inorganic salt was removed. A solution of compound 1
(1.88 g, 10 mmol) in dry dioxane (40 mL) was added to
the mixture and further heated under reflux for 12 h.
After being cooled, the solution was poured onto cold
water. The formed solid was filtered off and crystallized
from DMF/EtOH to give greenish solid in 28% yield; mp
212–214°C. IR (KBr), (v max, cmꢀ1): 3420 (br, NH),
Synthesis of N-[4-oxo-3,4-dihydro-2H-chromeno[2,3-d]
pyrimidin-2-ylidene]-P,P-diphenylphosphinous amide (2).
A
mixture of P-chlorodiphenylphosphine (0.6 mL,
5 mmol) and potassium thiocyanate (0.5 g, 5 mmol) in
dry dioxane (20 mL) was stirred at room temperature for
30 min and then heated under reflux for 1 h. The formed
inorganic salt was removed. A solution of compound 1
(0.94 g, 5 mmol) in dry dioxane (20 mL) was added to
the mixture and further heated under reflux for 8 h.
After being cooled, the solution was poured onto cold
water. The formed solid was filtered off and crystallized
from diluted dimethylformamide (DMF) to give yellow
solid in 42% yield; mp 177–179°C. IR (KBr), (v max,
cmꢀ1): 3420 (br, NH), 3010 (C–Harom), 1705 (C═O),
1
1716 (C═O), 1668 (C═N), 1609, 1550 (C═C). H-NMR
(400 MHz, DMSO-d6): 7.00 (d, 1H, J = 8.0 Hz, H-9),
7.09 (t, 1H, J = 8.0 Hz, H-7), 7.20–7.31 (m, 1H, H-70),
7.39–7.48 (m, 3H, p- and m-PhH), 7.56 (d, 1H,
J = 7.2 Hz, H-90), 7.68–7.74 (m, 2H, o-PhH), 7.77 (t,
1H, J = 7.6 Hz, H-8), 7.92 (d, 1H, J = 7.6 Hz, H-6),
8.04 (t, 1H, J = 8.0 Hz, H-80), 8.24 (s, 1H, NH,
exchangeable with D2O), 8.45 (d, 1H, J = 5.6 Hz, H-60),
8.71 (s, 1H, NH, exchangeable with D2O), 8.77 (s, 1H,
H-5), 9.02 (s, 1H, H-50). 13C-NMR (100 MHz,
DMSO-d6): 116.5, 116.7 (C-9), 117.0, 117.3 (C-4a),
1180.3, 118.8 (C-5a), 119.0, 121.5 (C-7), 125.2 (C-
30,5 phenyl), 125.7, 125.9 (C-6), 129.0 (C-10phenyl), 130.1
(C-20,60phenyl), 131.0 (C-40phenyl), 133.8, 134.4 (C-8),
146.0, 147.2 (C-5), 151.7, 153.6 (C-9a), 154.3, 157.6 (C-
10a), 159.4, 161.1 (C-2), 163.4, 165.1 (C-4). MS (m/z, I
%): 532 (M+, 9%). Anal. Calcd for C28H17N6O4P
(532.44): C, 63.16%; H, 3.22%; N, 15.78%. Found: C,
62.86%; H, 3.01%; N, 15.49%.
1
1660 (C═N), 1611, 1550 (C═C). H-NMR (400 MHz,
DMSO-d6): 6.58–6.87 (m, 2H, H-7 and H-9), 6.97–7.21
(m, 2H, p-PhH), 7.29–7.63 (m, 4H, m-PhH), 7.72–7.88
(m, 5H, H-8 and o-PhH), 8.05 (d, 1H, J = 6.4 Hz, H-
6), 8.47 (brs, 1H, NH, exchangeable with D2O), 9.05
(s, 1H, H-5). MS (m/z, I %): 397 (M+, 13%). Anal.
Calcd for C23H16N3O2P (397.36): C, 69.52%; H,
4.06%; N, 10.57%. Found: C, 69.15%; H, 3.88%; N,
10.19%.
Synthesis
chromeno[20,30:4,5]pyrimido[2,1-d] [1,3,5,2]triazaphosphinin-
6-one (3).
of
2-phenyl-4-thioxo-3,4-dihydro-2H,6H-
A mixture of P,P-dichlorophenylphosphine
(0.7 mL, 5 mmol) and potassium thiocyanate (1 g,
10 mmol) in dry dioxane (20 mL) was stirred at room
temperature for 30 min and then heated under reflux for
1 h. The formed inorganic salt was removed. A solution
of compound 1 (0.94 g, 5 mmol) in dry dioxane (20 mL)
was added to the aforementioned mixture and further
heated for 12 h. The mixture was cooled and poured onto
cold water. The formed solid was filtered off and
crystallized from DMF/EtOH to give pale brown solid in
38% yield; mp 206–208°C. IR (KBr), (v max, cmꢀ1):
3420 (br, NH), 3050 (C–Harom), 1716 (C═O), 1653, 1635
(C═N), 1608, 1557 (C═C), 1180 (C═S). 1H-NMR
(400 MHz, DMSO-d6): 7.00 (d, 1H, J = 8.0 Hz, H-11),
7.07 (t, 1H, J = 7.8 Hz, H-9), 7.18–7.30 (m, 2H, m-PhH),
7.46 (t, 1H, J = 8.0 Hz, H-10), 7.53 (t, 1H, J = 8.0 Hz,
p-PhH), 7.72–7.80 (m, 2H, o-PhH), 8.04 (d, 1H,
J = 8.0 Hz, H-8), 9.03 (s, 1H, H-7), 12.04 (br, 1H, NH
exchangeable with D2O). 13C-NMR (100 MHz,
DMSO-d6): 116.6 (C-11), 117.1 (C-6a), 118.8 (C-7a),
120.8 (C-30,50phenyl), 125.2 (C-9), 125.7 (C-10phenyl),
128.5, 128.7 (C-20,60phenyl), 130.2 (C-8), 130.9 (C-
40phenyl), 135.1 (C-10), 146.9 (C-7), 150.1 (C-11a), 151.6
(C-12a), 154.3 (C-13a), 164.4 (C-6), 186.7 (C-4). MS (m/
z, I %): 378 (M+, 3%). Anal. Calcd for C18H11N4O2PS
Acknowledgment. The authors express their appreciation to “The
Research Center for Advanced Materials Science (RCAMS)” at
King Khalid University for funding this work under grant
number RCAMS/KKU/003-18.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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First Synthesis of Novel Chromeno[2,3-d]pyrimidinyl and Bis(chromeno[2,3-d]
pyrimidinyl)phosphines and Chromeno[20,30:4,5]pyrimido [2,1-d][1,3,5,2]
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet