A convenient route to novel fluorinated 1, 2, 4, 3-triazaphospholo[1, 5-a]pyridines and pyrido[1, 2-b][1, 2, 4, 5]triazaphosphinines

Article abstract of DOI:10.24820/ark.5550190.p010.478

A simple synthetic approach to the construction of novel fluorinated 5-oxo(thioxo)-2-oxido(sulfido)-1, 2, 4, 3-triazaphospholo[1, 5-a]pyridines 2-14 and pyrido[1, 2-b][1, 2, 4, 5]triazaphosphinines 16, 19 and 22, was achieved. The method depends on the treatment of 1, 6-diamino-4-(4-fluorophenyl)-2-oxo-1, 2-dihydropyridine-3, 5-dicarbonitrile (1) with some different types of phosphorus reagents such as phosphorus acid, and their esters, phosphorus halides as well as phosphorus sulfides. Structures of all the synthesized products were established by elemental analysis and spectral tools.

Full text of DOI:10.24820/ark.5550190.p010.478

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A convenient route to novel fluorinated 1,2,4,3-triazaphospholo[1,5-a]pyridines and
pyrido[1,2-b][1,2,4,5]triazaphosphinines
a,b
c
c*
d,e
Mohammed A. Assiri , Somaia M. Abdel-Kariem , Tarik E. Ali , and I. S. Yahia
aAdvanced Materials and Green Chemistry, Chemistry Department, Faculty of Science, King Khalid University,
Abha, Saudi Arabia
b
Research Center for Advanced Materials Science (RCAMS), King Khalid University, Abha, Saudi Arabia.
c
Department of Chemistry, Faculty of Education, Ain Shams University, Roxy, Cairo, Egypt
d
Advanced Functional Materials & Optoelectronic Laboratory (AFMOL), Department of Physics, Faculty of
Science, King Khalid University, Abha, Saudi Arabia
Nanoscience Laboratory for Environmental and Bio-medical Applications (NLEBA), Semiconductor Lab.,
e
Department of Physics, Faculty of Education, Ain Shams University, Roxy, Cairo, Egypt
E-mail: tarik_elsayed1975@yahoo.com; tarekelsaied@edu.asuedu.eg
Received 01-09-2018
Accepted 04-23-2018
Published on line 07-01-2018
Abstract
A simple synthetic approach to the construction of novel fluorinated 5-oxo(thioxo)-2-oxido(sulfido)-1,2,4,3-
triazaphospholo[1,5-a]pyridines 2–14 and pyrido[1,2-b][1,2,4,5]triazaphosphinines 16, 19 and 22, was
achieved. The method depends on the treatment of 1,6-diamino-4-(4-fluorophenyl)-2-oxo-1,2-
dihydropyridine-3,5-dicarbonitrile (1) with some different types of phosphorus reagents such as phosphorus
acid, and their esters, phosphorus halides as well as phosphorus sulfides. Structures of all the synthesized
products were established by elemental analysis and spectral tools.
Keywords: 1,6-Diaminopyridine, cyclization, 1,2,4,3-triazaphospholes, 1,2,4,5-triazaphosphinines
DOI: https://doi.org/10.24820/ark.5550190.p010.478
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Introduction
Phosphorus-nitrogen compounds have gained considerable attention due to their biological and
1
2
3
pharmacological effects, such as antimicrobial, insecticidal, and herbicidal properties. Especially, different
4
isomers of triazaphospholes possess multiple biological properties including antibacterial and antineoplastic
activities. Also, several triazaphosphinine derivatives are present in the pharmaceutical field where they are
used as antitumor agents. On the other hand, the pyridine ring is of considerable interest since it is the key
component in a range of bioactive naturally occurring and synthetic compounds. The pyridine-3,5-
dicarbonitrile was chosen as an important structural scaffold for the design of a reaction-based library. A
number of the researches reported the biological activities of pyridine dicarbonitrile as being analgesic, anti-
HIV, anti-Alzheimer, anticancer, anti-inflammatory and antibacterial agents.
5
6
-8
9
1
0
1
1
1
2
13
14
15
Because of the
characteristic properties of the fluorine atom, such as its small size, strong electronegativity and the low
1
6
polarizability of the C–F bond, it have considerable effect on the biological properties of a molecule. The
presence of fluorine into a drug causes simultaneous modulation of its electronic, lipophilic, and steric
parameters, which lead to a strong influence in the pharmacokinetic and pharmacodynamics properties of
1
7
drugs. In the light of these facts, and as a continuation of our reported work on construction of bioactive
1
8-20
phosphorus heterocycles,
the present work studies the chemical reactivity of 1,6-diamino-4-(4-
fluorophenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (1) towards some different phosphorus reagents,
which lead to the formation of novel fluorine compounds containing functionalized 1,2,4,3-
triazaphospholo[1,5-a]pyridines and pyrido[1,2-b][1,2,4,5]triazaphosphinines.
Results and Discussion
The starting material, 1,6-diamino-4-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (1) was
synthesized in one step by the reaction of 4-fluorobenzaldehyde, malononitrile and cyanoacetohydrazide in
2
1
absolute ethanol containing a few drops of piperidine as a catalyst (Scheme 1). The chemical structure of
compound 1 was in accordance with its spectral data. The IR spectrum exhibited vibrational bands for NH
2
,
-1
1
CN, and C=O at 3392–3111, 2219 and 1667 cm , respectively. The H-NMR spectrum showed signals due to
two NH groups at δ 5.68 and 7.97, 8.48 ppm and AB system of phenyl group at δ 7.41 and 7.59 (J=9.2 Hz)
ppm. Also, the C-NMR spectrum displayed the aromatic carbon atoms and the nitrile groups at the expected
chemical shifts.
2
1
3
CHO
O
NC
NH2
H
EtOH
N
N
+
NC
CN
+
H N
CN
2
piperidine
NH2
O
F
CN
F
1
(85%)
Scheme 1. Synthesis of 1,6-diamino-4-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (1).
The 1,6-diamino groups are ready-made nucleophilic centers for the synthesis of fused phosphorus
2
2
heterocyclic rings via their reaction with phosphorus reagents having labile halogen atoms. Thus, treatment
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of compound 1 with phenylphosphonic dichloride in dry dioxane containing two equivalent amounts of
triethylamine led to the formation of 7-(4-fluorophenyl)-2-oxido-5-oxo-2-phenyl-1,2,3,5-tetrahydro[1,2,4,3]
triazaphospholo[1,5-a]pyridine-6,8-dicarbonitrile (2) in moderate yield (Scheme 2). Similarly, compound 1
reacted with phosphorus oxychloride under the same reaction conditions to give the 2-hydroxy-1,2,4,3-
triazaphospholo[1,5-a]pyridine derivative 4 (Scheme 2). The proposed mechanism for this reaction can be
explained by cyclization of 1,6-diaminopyridine 1 with phosphorus oxychloride to give the nonisolable
intermediate 3 which underwent hydrolysis by the effect of air-moisture (Scheme 2). In a similar manner,
treatment of compound 1 with phosphorus tribromide in dry dioxane containing triethylamine, did not give
the expected 7-(4-fluorophenyl)-5-oxo-1,5-dihydro[1,2,4,3]triazaphospholo[1,5-a]pyridine-6,8-dicarbonitrile
(5). This reaction gave the 1,2,4,3-triazaphospholo[1,5-a]pyridine-8-carboxamide derivative 6 in moderate
yield. However, the product 5 was isolated from the reaction of hexaethylphosphorus triamide with
compound 1 in dry dioxane (Scheme 3). We assumed that compound 5 underwent partial hydrolysis in situ for
one nitrile group because of by-product HBr and air-moisture (Scheme 3). The IR spectra of compounds 2, 4, 5
-1
1
and 6 showed absorption bands at regions 3371–3198 (NH
2
, NH) and 1229–1227 (P=O) cm . Also, the H-NMR
spectra of these compounds revealed the NH protons at region δ 8.26–9.15 ppm, while the protons of OH and
1
3
CONH
these compounds displayed the expected signals of all carbon atoms. The presence of the carbon atom of
CONH in compound 6 at δ 170.6 ppm supported the partial hydrolysis process. Moreover, the molecular ion
peaks of these compounds were recorded at m/z 391, 331, 297 and 315, respectively, in thier mass spectra.
2
in compounds 4 and 6 were observed at δ 3.38 and 8.47 ppm, respectively. The C-NMR spectra of
2
3
1
The P-NMR spectrum of compound 2 recorded a singlet at δ 32.1 ppm.
O
O
H
H
N
NC
N
O
NC
O
N
N
P
Air-mositure
P
Cl
OH
N
H
N
H
CN
CN
F
F
3
4
(88%)
dioxane
POCl3
Et N
3
O
O
H
NC
NH2
NC
N
O
N
PhP(O)Cl2
dioxane
N
P
Ph
N
H
NH2
Et N
3
CN
CN
(62%)
F
F
1
2
Scheme 2. Reaction of compound 1 with phenylphosphonic dichloride and phosphorus oxychloride.
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O
O
NC
N
NC
NH2
N
P(NEt2)
3
N
P
N
H
dioxane
NH2
CN
CN
F
F
5
(43%)
1
dioxane
PBr3
Et N
3
O
O
N
NC
NC
N
N
N
Partial
hydrolysis
P
P
N
H
N
H
CN
F
O
NH2
F
5
6
(45%)
Scheme 3. Reaction of compound 1 with hexaethylphosphorus triamide and phosphorus tribromide.
We also studied the reaction of compound 1 with two examples of phosphorus sulfides. Thus, 1,6-
diamino-4-(4-fluorophenyl)-2-thioxo-1,2-dihydropyridine-3,5-dicarbonitrile (7) was isolated as a result of
sulfuration process when compound 1 reacted with equivalent amount of phosphorus pentasulfide in dry
dioxane (Scheme 4). The spectroscopic data of compound 7 confirmed the disappearance of C=O group. In
1
3
-1
addition, its IR and C-NMR spectra revealed new C=S group in them at 1164 cm and δ 179.0 ppm,
respectively. When this reaction was carried out by using two folds of phosphorus pentasulfide, the 2-sulfanyl-
2-sulfido-5-thioxo-1,2,3,5-tetrahydro[1,2,4,3]triazaphospholo[1,5-a]pyridine 8 was formed (Scheme 4). The
product 8 was also isolated via treatment of the 1,6-diaminopyridine 7 with phosphorus pentasulfide under
the same reaction conditions (Scheme 4). On the other hand, compound 1 was treated with Lawesson`s
reagent (LR) in dry dioxane to give a moderate yield of 7-(4-fluorophenyl)-2-(4-methoxyphenyl)-2-sulfido-5-
thioxo-1,2,3,5-tetrahydro-1,2,4,3-triazaphospholo[1,5-a]pyridine-6,8-dicarbonitrile (9) (Scheme 4). In addition,
compound 9 was also obtained from treatment of compound 7 with LR in dry dioxane (Scheme 4). Similarly,
treatment of compound 1 with O,O-diethyldithiophosphoric acid (formed in situ) in absolute ethanol yielded
the 2-ethoxy-2-sulfido-1,2,3,5-tetrahydro-1,2,4,3-triazaphospholo[1,5-a]pyridine derivative 10 (Scheme 4). In
+
the mass spectra of compounds 8, 9 and 10, they revealed their expected molecular ion peaks (M ). The most
1
characteristic signals in their H-NMR spectra are those of the sulfanyl, methoxy, and ethoxy protons. They
appeared at δ 4.63 (SH), 3.81 (OCH
3
), and 1.08, 3.46 (CH
3
CH
2
O) ppm. Also, the specific carbon atoms of C=S
1
3
groups of compounds 8 and 9 were observed at δ 179.2 and 178.3 ppm, respectively, in their C-NMR spectra.
3
1
Moreover, the P-NMR spectrum of compound 9 displayed a singlet at δ 54.5 ppm which supported the
2
3
proposed structure.
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O
H
N
NC
S
N
P
OEt
N
H
CN
F
S
1
0 (38%)
H
N
NC
S
N
P
1
:2.2
SH
EtOH (EtO) P(S)SH
2
N
H
3
8%
CN
F
O
8
NC
NH2
NH2
P S
P S
2 5
N
2
5
4
2%
dioxane
dioxane
S
CN
NC
NH2
F
N
1
1:1
NH2
LR
dioxane
CN
F
S
N
7 (56%)
LR
dioxane
3%
H
4
5%
NC
S
N
P
4
N
H
CN
OMe
OMe
F
9
S
MeO
P
S
S
P
S
LR =
Scheme 4. Reaction of compound 1 with some phosphorus sulfides.
Next, the present study was extended to investigate the interaction of the 1,6-diaminopyridine 1 with
o
three examples of phosphorus esters. Thus, when compound 1 was fused with triethyl phosphate at 80–90 C,
the 2-ethoxy-7-(4-fluorophenyl)-2-oxido-2-oxo-1,2,3,5-tetrahydro[1,2,4,3]triazaphospholo[1,5-a]pyridine-6,8-
dicarbonitrile (11) was isolated (Scheme 5). In the same manner, the 1,2,4,3-triazaphospholo[1,5-a]pyridine
derivatives 12 and 13 were produced by fusion of compound 1 with diethyl phosphite and tris(2-chloroethyl)
phosphite, respectively (Scheme 5). The IR spectra of compounds 11–13 recorded the absorption bands of NH
-1
and P=O groups at regions 3295–3429 and 1228–1230 cm , respectively. The characteristic protons of these
1
compounds were observed in their H-NMR spectra. For example, the P–H proton was recorded as a doublet
at δ 6.47 (JPH=711 Hz) in compound 12, while the ethoxy protons of compound 11 were resonated as triplet
and quartet at δ 1.21 (CH
3
) and 3.06 (CH ) ppm, respectively. Also, the chloroethoxy moiety in compound 13
2
was displayed as two triplets at δ 3.54 and 3.83 ppm. Furthermore, the carbon atoms of the ethoxy fragments
in compounds 11 and 13 were displayed at δ 18.5, 60.0 and 45.0, 62.5 ppm, respectively. Compounds 11-13
recorded the expected molecular ion peaks in their mass spectra.
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O
P
O
P
O
O
O
H
N
H
NC
NC
NH2 EtO
OEt
NC
O
EtO
OEt
N
O
N
N
N
OEt
H
P
P
H
OEt
N
H
N
H
fusion
0-90 C
NH2
fusion
80-90 C
o
o
8
CN
CN
CN
F
F
F
1
1
2 (40%)
11 (57%)
fusion
0-90 C
P(OCH CH Cl)
2
2
3
o
8
O
H
NC
N
N
Cl
P
O
N
H
CN
F
13 (43%)
Scheme 5. Reaction of compound 1 with some phosphorus esters.
Compound 13 was ready to cyclize into the annulated triheterocyclic system 14 by heating in absolute
2
4
ethanol containing a few drops of triethylamine (Scheme 6). The oxazaphospholotriazaphospholopyridine
structure 14 was deduced from analytical and spectroscopic data. In the IR spectrum, the only NH group was
-1
1
observed at 3417 cm . In the H-NMR spectrum, the protons of two methylene groups were observed at δ
1
3
2
.91 and 3.60 ppm, while their resonances in C-NMR spectrum were at δ 42.5 and 60.0 ppm. The presence of
the molecular ion peak for compound 14 at m/z 341 was the strongest evidence for the cyclization process.
O
O
H
N
NC
NC
N
Cl
N
N
O
P
P
O
EtOH
N
H
N
H
Et N
3
CN
CN
F
F
1
4 (88%)
1
3
Scheme 6. Cyclization of compound 13 into 14.
The 1,6-diamino groups as active nucleophilic centers can be used to react with aldehyde and dialkyl
phosphite under the Kabachnik-Fields reaction condition to form new 1,2,4,5-triazaphosphinine (cyclic α-
2
5,26
aminophosphonate).
Thus, compound 1 condensed with acetaldehyde in the presence of diethyl
phosphite or phenyl dichlorophosphine at room temperature, followed by heating under reflux to yield two
isomeric forms of pyrido[1,2-b][1,2,4,5]triazaphosphinines 16 and 19, respectively (Scheme 7). The formation
of product 16 took place easily via condensation of the more chemically active N-amino group with
acetaldehyde, followed by phospha-Michael addition of phosphorus atom to form the nonisolable
α-aminophosphonate 15. The latter intermediate underwent cyclization by removal of ethanol molecule
2
7
(
Scheme 7). Also, the formation of compound 19 occurred easily via condensation of the two amino groups
with acetaldehyde and phenyl dichlorophosphine affording the nonisolable intermediate 17 which underwent
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hydrolysis of labile chlorine atom by the eliminated water to form the intermediate 18. This intermediate
2
8
could easily transform into the isolated product 19 via phospha-Michael addition reaction (Scheme 7). The IR
-1
spectra of compounds 16 and 19 recorded the absorption bands of P=O groups at 1236 and 1237 cm ,
1
respectively. In their H-NMR spectra, the P–CH protons appeared at δ 4.50 (q, JPCH=18.6 Hz) and 4.14–4.20
1
3
(
m) ppm, respectively, while the carbon atoms of the P–CH moieties in their C-NMR spectra, were resonated
at δ 53.5 (d, JPC=150 Hz) and 45.5 (d, JPC=138 Hz) ppm for 16 and 19, respectively. The phosphorus chemical
3
1
shift of compound 16 showed a singlet at δ 22.2 ppm in its P-NMR spectrum which confirmed the proposed
structure. The mass spectra of 16 and 19 recorded the expected molecular ion peaks at m/z 387 and 419,
respectively.
O
O
H
OEt
O
H
CH CHO
HP(O)(OEt)2
NC
NH2
NH2
3
NC
N
P
N
N
OEt
H C
3
Fusion
NH2
o
8
0-90 C
CN
CN
F
BF .Et O
F
3
2
1
15
CH CHO Fusion
3
o
PhPCl2 80-90 C
- EtOH
CH3
O
O
H
N
CH3
NC
N
NC
H
N
N
Cl
O
P
N
H
P
N
H
OEt
Ph
CN
CN
F
F
17
16 (35%)
H O
2
CH3
O
O
H
N
N
CH3
NC
N
NC
H
N
Phospha-
O
P
O
P
H
N
H
N
H
Michael addition
Ph
Ph
CN
CN
F
F
19 (45%)
18
Scheme 7. Reaction of compound 1 with acetaldehyde in the presence of diethylphosphite and phenyl
dichlorophosphine.
An addition of phosphorous acid to an acidic solution of compound 1 in the presence of formaldehyde led
to the formation of the interesting novel pyrido[1,2-b][1,2,4,5]triazaphosphininyl methyl phosphonic acid 22
(Scheme 8). The reaction took place smoothly via condensation of N-amino group with formaldehyde,
followed by phospha-Michael addition of phosphorous acid to form the nonisolable aminophosphonic acid 20.
The latter acid underwent cyclization by removal of water molecule to give the nonisolable pyrido[1,2-a]
[1,2,4,5] triazaphosphinine 21, that underwent additional methylphosphorylation process at N–1 to isolate the
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2
9
novel pyrido[1,2-a][1,2,4,5]triazaphosphininylmethyl phosphonic acid 22 (Scheme 8). The IR spectrum of
-1
compound 22 showed absorption bands at 3418 (br, OH, NH), 2964 (CHaliphatic) and 1230 (P=O) cm . In its
1
H-NMR spectrum, the protons of P–CH fragments were displayed as a multiplet at δ 4.54–5.15 ppm, while
2
1
3
the carbon atoms of these fragments were recorded as two doublets at δ 45.0 and 50.5 ppm in the C-NMR
spectrum. The P-NMR spectrum of compound 22 was the strongest evidence for the proposed structure, due
to the presence of two signals at δ 11.7 and 19.2 ppm. Finally, its molecular ion peak (M ) was observed at
m/z 408, in the mass spectrum.
3
1
3
0
+
O
O
H
H
OH
O
H
NC
NH2
NH2
NC
N
P
N
N
OH
HCHO, HP(O)(OH)2
diluted HCl (10%)
NH2
CN
CN
F
F
1
20
-
H O
2
HO
O
P
O
O
OH
H
N
H
HCHO
HP(O)(OH)2
O
NC
NC
N
H
N
N
O
P
P
N
H
N
H
OH
OH
CN
CN
F
F
2
1
2
2 (55%)
Scheme 8. Reaction of compound 1 with formaldehyde in the presence of phosphorous acid.
Conclusions
We suggested a simple method for the synthesis of some novel functionalized 1,2,4,3-triazaphospholo[1,5-a]
pyridines 2–14 and pyrido[1,2-b][1,2,4,5]triazaphosphinine 16, 19 and 22 by the reaction of 1,6-diamino-4-(4-
fluorophenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (1) with some different phosphorus reagents under
mild reaction conditions.
Experimental Section
General. The melting points were determined in an open capillary tube on a digital Stuart SMP-3 apparatus.
1
Infrared spectra were measured on a Perkin-Elmer 293 spectrophotometer using KBr disks. H-NMR spectra
1
3
31
were recorded on a Bruker 400 and 600 MHz spectrometer. C- and P-NMR spectra were recorded on
a Bruker 600 MHz spectrometer operating at 150 and 242 MHz, respectively. Chemical shifts are reported in
1
13
ppm with respect to the references and are stated relative to tetramethylsilane (TMS) for H- and C-NMR
3
1
and to 85% phosphoric acid for the P-NMR. Mass spectra were recorded on a Gas Chromatographic GCMSqp
000 ex Shimadzu instrument at 70 ev. Elemental microanalysis was performed Perkin-Elmer 2400II at the
1
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Chemical War department, Ministry of Defense. The purity of the synthesized compounds was checked by thin
layer chromatography (TLC) and elemental microanalysis.
Synthesis of 1,6-diamino-4-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (1). A mixture of
4-fluorobenzaldehyde (0.27 ml, 2.5 mmol), malononitrile (0.165 g, 2.5 mmol) and cyanoacetohydrazide (0.25
g, 2.5 mmol) in absolute ethanol (30 ml) containing a few drops of piperidine, was heated under reflux for 5 h.
After cooling, the formed solid was filtered and recrystallized from DMF to afford beige crystals in 85% yield
o
-1
(
0.57 g); mp 315−317 C. IR (KBr), (max, cm ): 3392, 3292 (NH
2
), 3187, 3111 (NH ), 2219 (2 CN), 1667 (C=O),
2
1
1
9
3
4
2
613 (C=C). H-NMR (400 MHz, DMSO-d
.2 and 2.0 Hz, Ar–H), 7.97 (s, 1H, NH), 8.48 (s, 1H, NH). C-NMR (100 MHz, DMSO-d ): 74.5 (C–5), 86.6 (C–
), 115.5 (CN), 116.0 (CN), 130.6 (C–4), 130.9 (C–2`,6`), 156.6 (C–3`,5`), 158.6 (C–1`), 159.1 (C–6), 161.8 (C–
`), 164.3 (C=O). MS (EI, m/z): 269 (M , 100%). Anal. calcd. for C13
6.01%. Found: C, 57.63; H, 2.61; N, 25.62%.
6
): 5.68 (s, 2H, NH ), 7.41 (td, 2H, J 9.2 and 2.8 Hz, Ar–H), 7.59 (td, 2H, J
2
1
3
6
+
H
8
FN O (269.23): C, 57.99; H, 2.99; N,
5
Synthesis of 7-(4-fluorophenyl)-2-oxido-5-oxo-2-phenyl-1,2,3,5-tetrahydro[1,2,4,3]triazaphospholo[1,5-a]
pyridine-6,8-dicarbonitrile (2). A solution of phenylphosphonic dichloride (0.35 ml, 2.5 mmol) in dry dioxane
(
5 ml), was added dropwise to a solution of compound 1 (0.675 g, 2.5 mmol) in dry dioxane (30 ml) in
o
presence of a catalytic amount of triethylamine (0.35 ml, 5 mmol) at 5−10 C for 30 minutes. The mixture was
heated under reflux for 4 hours then filtered off to remove triethyl ammonium chloride. The filtrate was
concentrated into its third volume and left to cool. The formed solid was filtered off and crystallized from
EtOH to give pale yellow solid in 62% yield (0.61 g); mp 287−289 C. IR (KBr), (max, cm ): 3294, 3198 (2 NH),
2
o
-1
1
218 (2 CN), 1671 (C=O), 1629 (C=C), 1229 (P=O). H-NMR (400 MHz, DMSO-d
6
): 6.92 (dd, 1H, J 8.4 and 4.2
Hz, Ph–H), 7.18–7.26 (m, 4H, Ph–H and Ar–H), 7.40–7.41 (m, 3H, Ph–H and Ar–H), 7.50 (dd, 1H, J 7.8 and 2.4
1
3
Hz, Ar–H), 8.79 (s, 1H, NH), 9.15 (s, 1H, NH). C-NMR (100 MHz, DMSO-d
6
): 75.0 (C–5), 87.1 (C–3), 116.2
(
1
CN), 116.4 (CN), 120.2 (C–3``,5``), 127.6 (C–2``,6``), 130.3 (C–4), 132.1 (C–2`,6`), 135.4 (C–4``), 137.4 (C-1``),
3
1
56.2 (C–3`,5`), 157.8 (C–1`), 158.5 (C–6), 161.5 (C–4`), 165.0 (C=O). P-NMR (242 MHz, DMSO-d
6
): 32.1 ppm.
MS (EI, m/z): 393 (M+2, 20%). Anal. calcd. for C19
8.03; H, 2.55; N, 17.57%.
H11FN
5
O
2
P (391.30): C, 58.32; H, 2.83; N, 17.89%. Found: C,
5
Synthesis of 7-(4-fluorophenyl)-2-hydroxy-2-oxido-5-oxo-1,2,3,5-tetrahydro[1,2,4,3]triazaphospholo[1,5-a]
pyridine-6,8-dicarbonitrile (4). A solution of phosphorus oxychloride (0.25 ml, 2.5 mmol) in dry dioxane (5 ml),
was added dropwise to a solution of compound 1 (0.675 g, 2.5 mmol) in dry dioxane (30 ml) in presence of
o
a catalytic amount of triethylamine (0.35 ml, 5 mmol) at 5−10 C for 30 minutes. The mixture was heated
under reflux for 10 hours then filtered off to remove triethyl ammonium chloride. The filterate mixture was
concentrated into its third volume and left to cool. The formed solid was filtered off and crystallized from
o
-1
diluted ethanol to give white solid in 88% yield (0.73 g); mp 303−306 C. IR (KBr), (max, cm ): 3390 (br, OH),
1
3
294, 3198 (2 NH), 2218 (2 CN), 1671 (C=O), 1629 (C=C), 1229 (P=O). H-NMR (400 MHz, DMSO-d
6
): 3.38 (br,
1
H, OH), 7.38–7.43 (m, 2H, Ar–H), 7.50 (d, 1H, J 8.4 Hz, Ar–H), 7.58–7.62 (m, 1H, Ar–H), 8.26 (s, 1H, NH), 8.82
1
3
(
(
(
s, 1H, NH). C-NMR (100 MHz, DMSO-d ): 75.4 (C–5), 86.1 (C–3), 115.5 (CN), 115.8 (CN), 130.6 (C–4), 133.3
C–2`,6`), 155.4 (C–3`,5`), 157.0 (C–1`), 159.8 (C–6), 160.8 (C–4`), 164.8 (C=O). MS (EI, m/z): 333 (M+2, 8%), 332
M+1, 9%), 331 (M , 13%). Anal. calcd. for C13
6
+
H
7
FN
5
3
O P (331.20): C, 47.14; H, 2.13; N, 21.14%. Found: C, 46.83;
H, 1.85; N, 20.79%.
Synthesis of 7-(4-fluorophenyl)- 5-oxo-1,5-dihydro[1,2,4,3]triazaphospholo[1,5-a]pyridine-6,8-dicarbonitrile
5). Hexaethylphosphorus triamide (0.68 ml, 2.5 mmol) was added to a solution of compound 1 (0.675 g, 2.5
(
mmol) in dry dioxane (30 ml). The mixture was heated under reflux for 10 hours. The solution was
concentrated to its half volume and left to cool. The oily product was treated with ethyl acetate to give solid
which was filtered off and crystallized from diluted ethanol to give pale yellow solid in yield 43% (0.32 g); mp
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o
-1
1
2
00−201 C. IR (KBr), (max, cm ): 3297 (NH), 3050 (C–Harom), 2214 (2 CN), 1665 (C=O). H-NMR (400 MHz,
1
3
DMSO-d ): 7.28 (d, 2H, J 9.0 Hz, Ar–H), 7.65 (d, 2H, J 7.2 Hz, Ar–H), 8.71 (s, 1H, NH). C-NMR (100 MHz, DMSO-
6
d
1
5
6
): 75.5 (C–5), 82.9 (C–3), 110.7 (CN), 112.6 (CN), 133.7 (C–4), 133.9 (C–2`,6`), 156.0 (C–3`,5`), 158.0 (C–1`),
+
60.1 (C–6), 161.8 (C–4`), 164.9 (C=O). MS (EI, m/z): 297 (M , 18%). Anal. calcd. for C13
H
15FN OP (297.18): C,
5
2.54; H, 1.70; N, 23.57. Found: C, 52.19; H, 1.53; N, 23.22%.
Synthesis
of
6-cyano-7-(4-fluorophenyl)-5-oxo-1,5-dihydro[1,2,4,3]triazaphospholo[1,5-a]pyridine-8-
carboxamide (6). A solution of phosphorus tribromide (0.25 ml, 2.5 mmol) in dry dioxane (5 ml), was added
dropwise to a solution of compound 1 (0.67 g, 5 mmol) in dry dioxane (60 ml) in presence of a catalytic
o
amount of triethylamine (0.7 ml, 10 mmol) at 5−10 C for 30 minutes. The mixture was heated under reflux for
10 hours. The reaction mixture was concentrated into its third volume and left to cool. The obtained oily
product was dissolved in distilled water (15 ml). The formed solid was filtered off and crystallized from diluted
o
-1
ethanol to give yellow solid in 45% yield (0.35 g); mp 294−297 C. IR (KBr), (max, cm ): 3371, 3283 (NH
2
), 3200
1
(
NH), 2215 (CN), 1682 (C=O), 1666 (C=O), 1607 (C=C). H-NMR (400 MHz, DMSO-d
.0 Hz, Ar–H), 7.58 (td, 2H, J 8.8 and 3.2 Hz, Ar–H), 8.47 (br, 2H, NH
6
): 7.41 (td, 2H, J 8.8 and
1
3
3
2
), 8.79 (br, 1H, NH). C-NMR (100 MHz,
DMSO-d ): 78.5 (C–5), 86.6 (C–3), 116.2 (CN), 130.6 (C–4), 130.9 (C–2`,6`), 156.6 (C–3`,5`), 158.6 (C–1`), 159.1
6
+
(
C–6), 161.8 (C–4`), 164.2 (C=O), 170.6 (C=O). MS (EI, m/z): 315 (M , 55%). Anal. calcd. for C13
H
7
FN
5
2
O P
(315.20): C, 49.53; H, 2.23; N, 22.21%. Found: C, 49.10; H, 1.94; N, 21.89%.
Synthesis of 1,6-diamino-4-(4-fluorophenyl)-2-thioxo-1,2-dihydropyridine-3,5-dicarbonitrile (7). A mixture of
phosphorus pentasulfide (0.55 g, 2.5 mmol) and compound 1 (0.675 g, 2.5 mmol) in dry dioxane (40 ml), was
heated under reflux for 5 hours. The reaction mixture was concentrated into its half volume and left to cool.
The formed solid was filtered off and crystallized from ethanol to give orange crystalline solid in 56% yield
o
-1
(
0.40 g); mp 285−286 C. IR (KBr), (max, cm ): 3374, 3283, 3204 (2 NH
2
), 2216 (2 CN), 1604 (C=C), 1164 (C=S).
), 7.41 (td, 2H, J 8.8 and 2.4 Hz, Ar–H), 7.59 (td, 2H, J=8.0 and
). C-NMR (100 MHz, DMSO-d ): 74.4 (C–5), 86.6 (C–3), 115.6 (CN), 116.2
CN), 130.6 (C–4), 131.0 (C–2`,6`), 156.6 (C–3`,5`), 158.6 (C–1`), 159.1 (C–6), 161.8 (C–4`), 179.0 (C=S). MS (EI,
1
H-NMR (400 MHz, DMSO-d
.8 Hz, Ar–H), 8.47 (s, 2H, NH
6
): 5.68 (s, 2H, NH
2
1
3
2
(
2
6
+,
m/z): 285 (M 100%). Anal. calcd. for C13
4.33; H, 2.54; N, 24.11; S, 10.85%.
Synthesis of 7-(4-fluorophenyl)-2-sulfanyl-2-sulfido-5-thioxo-1,2,3,5-tetrahydro[1,2,4,3]triazaphospholo
1,5-a]pyridine-6,8-dicarbonitrile (8). Method A. A mixture of phosphorus pentasulfide (0.55 g, 2.5 mmol) and
H
8
FN
5
S (285.30): C, 54.72; H, 2.82; N, 24.54; S, 11.23%. Found: C,
5
[
compound 7 (0.285 g, 1 mmol) in dry dioxane (20 ml), was heated under reflux for 8 hours. The reaction
mixture was concentrated into its half volume and left to cool. The formed solid was filtered off and
o
crystallized from ethanol to give orange solid in in 42% yield (0.16 g); mp 240−242 C.
Method B. A mixture of phosphorus pentasulfide (1.22 g, 5.5 mmol) and compound 1 (0.675 g, 2.5 mmol) in
dry dioxane (40 ml), was heated under reflux for 8 hours. The reaction mixture was concentrated into its half
volume and left to cool. The formed solid was filtered off and crystallized from ethanol to give orange
o
-1
crystalline solid in yield 38% (0.36 g); mp 242−243 C. IR (KBr), (max, cm ): 3303, 3199 (2 NH), 2700 (br, SH),
1
2
7
7
1
216 (2 CN), 1608 (C=C), 1163 (C=S), 764 (P=S). H-NMR (400 MHz, DMSO-d
.2 Hz, Ar–H), 7.48 (t, 2H, J 8.0 Hz, Ar–H), 8.99 (s, 1H, NH), 9.55 (brs, 1H, NH). C-NMR (100 MHz, DMSO-d ):
5.7 (C–5), 85.8 (C–3), 111.2 (CN), 112.4 (CN), 131.9 (C–4), 132.9 (C–2`,6`), 156.0 (C–3`,5`), 158.3 (C–1`),
59.6 (C–6), 161.2 (C–4`), 179.2 (C=S). MS (EI, m/z): 381 (M+2, 2%), 380 (M+1, 7%), 379 (M , 35%). Anal. calcd.
6
): 4.63 (brs, 1H, SH), 7.12 (t, 2H, J
1
3
6
+
for C13
H
7
FN
5
PS (379.39): C, 41.15; H, 1.86; N, 18.46; S, 25.35%. Found: C, 40.79; H, 1.59; N, 18.08; S, 25.02%.
3
Synthesis of 7-(4-fluorophenyl)-2-(4-methoxyphenyl)-5-oxo-2-sulfido-5-thioxo-1,2,3,5-tetrahydro[1,2,4,3]
triazaphospholo[1,5-a]pyridine-6,8-dicarbonitrile (9). Lawesson's reagent (0.5 g, 1.25 mmol) was added to
a solution of compound 1 (0.330 g, 1.25 mmol) or compound 7 (0.356, 1.25 mmol) in dry dioxane (30 ml). The
mixtures were heated under reflux for 8 hours. The solutions were concentrated to their half volumes and left
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Assiri, M. A. et al.
to cool. The oily products were treated with diethyl ether to give solids which were filtered off and crystallized
o
from diluted ethanol to give orange solids in 45% yield (0.25 g) and 43% (0.24 g), respectively; mp 278−280 C.
-1
IR (KBr), (max, cm ): 3310, 3199 (2 NH), 3073 (C–Harom), 2965 (C–Haliph), 2217 (2 CN), 1637, 1617 (C=C), 1079
1
(
7
1
(
O–C), 844 (P=S). H-NMR (400 MHz, DMSO-d
6
): 3.81 (s, 3H, OCH
3
), 6.53 (s, 1H, NH), 7.39–7.45 (m, 4H, Ar–H),
): 55.0 (OCH ), 74.5 (C–5), 86.6 (C–3),
15.8 (CN), 116.2 (CN), 121.5 (C-3``,5``), 130.5 (C-2``,6``), 130.7 (C–4), 130.8 (C–2`,6`), 132.0 (C-1``), 153.6
1
3
.57–7.63 (m, 4H, Ar–H), 8.76 (s, 1H, NH). C-NMR (100 MHz, DMSO-d
6
3
3
1
C-4``), 156.6 (C–3`,5`), 158.6 (C–1`), 159.1 (C–6), 161.9 (C–4`), 178.3 (C=S). P-NMR (242 MHz, DMSO-d
ppm. MS (EI, m/z): 453 (M , 20%). Anal. calcd. for C20
6
): 54.5
+
H
13FN OPS (453.46): C, 52.97; H, 2.89; N, 15.44; S,
5
14.14%. Found: C, 52.59; H, 2.61; N, 15.09; S, 13.79%.
Synthesis of 2-ethoxy-7-(4-fluorophenyl)-5-oxo-2-sulfido-1,2,3,5-tetrahydro[1,2,4,3]triazaphospholo[1,5-a]
pyridine-6,8-dicarbonitrile (10). A solution of phosphorus pentasulfide (1.11 g, 5 mmol) in absolute ethanol
(30 ml) was heated under reflux for 1 hour to give O,O-diethyldithiophosphoric acid (formed in situ).
Compound 1 (0.675 g, 5 mmol) was added to the previous ethanolic solution. The mixture was heated under
reflux for 8 hours. The reaction mixture was concentrated into its half volume and left to cool. After adding
some water, the formed solid was filtered off and crystallized from diluted ethanol to give yellow crystals in
o
-1
3
(
8% yield (0.35 g); mp 298−300 C. IR (KBr), (max, cm ): 3392, 3291 (2 NH), 2214 (2 CN), 1667 (C=O), 1630
1
C=C), 1111 (P–O–C), 704 (P=S). H-NMR (400 MHz, DMSO-d
6
): 1.08 (t, 3H, J 7.2 Hz, CH ), 3.46 (q, 2H, J 7.2 Hz,
3
CH ), 7.41 (td, 2H, J 8.8 and 2.0 Hz, Ar–H), 7.59 (td, 2H, J 6.4 and 2.4 Hz, Ar–H), 8.47 (s, 1H, NH), 9.26 (s, 1H,
2
1
3
NH). C-NMR (100 MHz, DMSO-d
6
): 18.5 (CH
3
), 56.0 (CH
2
), 74.5 (C–5), 86.6 (C–3), 115.5 (CN), 116.2 (CN),
1
3
30.6 (C–4), 130.9 (C–2`,6`), 156.6 (C–3`,5`), 158.6 (C–1`), 159.1 (C–6), 161.8 (C–4`), 164.2 (C=O). MS (EI, m/z):
+,
75 (M 35%). Anal. calcd. for C15
H11FN
5
2
O PS (375.32): C, 48.00; H, 2.95; N, 18.65; S, 8.52%. Found: C, 47.63;
H, 2.61; N, 18.28; S, 8.09%.
Synthesis of 2-ethoxy-7-(4-fluorophenyl)-2-oxido-5-oxo-1,2,3,5-tetrahydro[1,2,4,3]triazaphospholo[1,5-a]
pyridine-6,8-dicarbonitrile (11). A mixture of triethyl phosphate (0.85 ml, 5 mmol) and compound 1 (0.67 g,
2
.5 mmol) was fused on water bath for 10 hours. The oily product was dissolved in hot diluted ethanol and left
o
to cool. The formed solid was filtered off and dried to give red solid in 57% yield (0.52 g); mp 262−265 C. IR
-1
(KBr), (max, cm ): 3429 (br, 2 NH), 2976, 2935 (C–Haliph), 2213 (2 CN), 1660 (C=O), 1600 (C=C), 1228 (P=O),
1
1093 (P–O–C). H-NMR (400 MHz, DMSO-d
6
): 1.21 (t, 3H, J 7.2 Hz, CH
3
), 3.06 (q, 2H, J 7.2 Hz, CH ), 5.69 (brs,
2
1
3
1
H, NH), 7.41 (td, 2H, J 9.2 and 2.4 Hz, Ar–H), 7.58 (td, 2H, J 8.4 and 2.8 Hz, Ar–H), 8.49 (brs, 1H, NH).
): 18.5 (CH ), 60.0 (CH ), 74.5 (C–5), 86.6 (C–3), 115.6 (CN), 116.2 (CN), 130.6
C–4), 131.0 (C–2`,6`), 156.5 (C–3`,5`), 158.6 (C–1`), 159.1 (C–6), 161.8 (C–4`), 164.2 (C=O). MS (EI, m/z): 361
M+2, 5%), 360 (M+1, 18%). Anal. calcd. for C15 P (359.25): C, 50.15; H, 3.08; N, 19.49. Found: C,
9.78; H, 2.81; N, 19.12%.
Synthesis of 7-(4-fluorophenyl)-2-oxido-5-oxo-1,2,3,5-tetrahydro[1,2,4,3]triazaphospholo[1,5-a]pyridine-
,8-dicarbonitrile (12). A mixture of diethyl phosphite (0.7 ml, 5 mmol) and compound 1 (0.67 g, 2.5 mmol)
C-
NMR (100 MHz, DMSO-d
(
(
6
3
2
H11FN
5
O
3
4
6
was fused on water bath for 6 hours. The oily product was dissolved in hot diluted ethanol and left to cool. The
o
formed solid was filtered off and dried to give orange solid in 40% yield (0.31 g); mp 204−206 C. IR (KBr),
-1
1
(max, cm ): 3430, 3300 (br, 2 NH), 2216 (2 CN), 1667 (C=O), 1604 (C=C), 1230 (P=O). H-NMR (400 MHz,
DMSO-d
6
): 6.47 (1H, d, J 711 Hz, P–H), 6.22 (t, 1H, J 6 Hz, NH), 7.39 (dd, 2H, J 9.2 and 1.2 Hz, Ar–H),
7.53–
1
3
7.57 (m, 2H, Ar–H), 8.38 (brs, 1H, NH). C-NMR (100 MHz, DMSO-d
6
): 76.0 (C–5), 82.0 (C–3), 115.6 (CN),
1
15.9 (CN), 130.4 (C–4), 130.6 (C–2`,6`), 156.0 (C–3`,5`), 158.0 (C–1`), 159.0 (C–6), 161.0 (C–4`), 164.0 (C=O).
+
MS (EI, m/z): 315 (M , 18%). Anal. calcd. for C13
H
7
FN
5
2
O P (315.20): C, 49.53; H, 2.23; N, 22.21%. Found: C,
49.16; H, 1.90; N, 21.86%.
Synthesis of 2-(2-chloroethoxy)-7-(4-fluorophenyl)-5-oxo-1,2,3,5-tetrahydro[1,2,4,3]triazaphospholo[1,5-a]
pyridine-6,8-dicarbonitrile (13). A mixture of tris(2-chloroethyl)phosphite (0.9 ml, 5 mmol) and compound 1
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Assiri, M. A. et al.
(0.67 g, 2.5 mmol) was fused on water bath for 8 hours. The oily product was dissolved in hot diluted ethanol
and left to cool. The formed solid was filtered off and dried to give red solid in 43% yield (0.41 g); mp 205−208
o
-1
C. IR (KBr), (max, cm ): 3295, 3396 (2 NH), 2904 (C–Haliph), 2217 (2 CN), 1666 (C=O), 1631 (C=C), 1050
1
(P–O–C). H-NMR (400 MHz, DMSO-d
6
): 3.54 (t, 2H, J 5.6 Hz, CH
2
Cl), 3.83 (t, 2H, J 4.8 Hz, CH
2
O), 5.67 (brs, 1H,
):
O), 74.5 (C–5), 86.6 (C–3), 115.6 (CN), 116.2 (CN), 130.6 (C–4), 130.9 (C–2`,6`), 156.6
1
3
NH), 7.41 (t, 2H, J=8.8 Hz, Ar–H), 7.58 (t, 2H, J=8.4 Hz, Ar–H), 8.47 (br, 1H, NH). C-NMR (100 MHz, DMSO-d
5.0 (CH Cl), 62.5 (CH
C–3`,5`), 158.6 (C–1`), 159.1 (C–6), 161.0 (C–4`), 164.0 (C=O). MS (EI, m/z): 379 (M+2, 5%), 377 (M , 12%).
Anal. calcd. for C15 P (377.7): C, 47.70; H, 2.66; N, 18.54%. Found: C, 47.35; H, 2.29; N, 18.19%.
6
4
(
2
2
+
H
10ClFN
5
O
2
Synthesis of 8-(4-fluorophenyl)-6-oxo-2,3,6,10-tetrahydro[1,3,2]oxazaphospholo[3`,2`:2,3][1,2,4,3]triaza-
phospholo[1,5-a]pyridine-7,9-dicarbonitrile (14). A solution of compound 13 (0.38 g, 1 mmol) was heated in
absolute ethanol containing a few drops of triethylamine for 12 hours. After cooling, the solution was poured
into ice. The formed solid was filtered off and crystallized from diluted ethanol to give brick red solid in 88%
o
-1
yield (0.3 g); mp 123−125 C. IR (KBr), (max, cm ): 3417 (br, NH), 2964 (C–Haliph), 2219 (2 CN), 1660 (C=O),
1
1
603 (C=C), 1039 (P–O–C). H-NMR (400 MHz, DMSO-d
6
): 2.91 (s, 2H, CH
2
N), 3.60 (brs, 2H, CH
2
O), 7.41 (td, 2H,
):
O), 74.5 (C–5), 86.6 (C–3), 115.4 (CN), 116.2 (CN), 130.6 (C–4), 130.9 (C–2`,6`), 156.6
1
3
J 8.8 and 2.0 Hz, Ar–H), 7.59 (td, 2H, J 8.0 and 2.4 Hz, Ar–H), 7.97 (s, 1H, NH). C-NMR (150 MHz, DMSO-d
2.5 (CH N), 60.0 (CH
6
4
2
2
(
(
C–3`,5`), 158.6 (C–1`), 159.1 (C–6), 162.0 (C–4`), 164.3 (C=O). MS (EI, m/z): 343 (M+2, 1%), 342 (M+1, 6%), 341
+
M , 35%). Anal. calcd. for C15
H
9
FN
5
2
O P (341.24): C, 52.79; H, 2.65; N, 20.52%. Found: C, 52.43; H, 2.36; N,
2
0.19%.
Synthesis
1,2,4,5]triazaphosphinine-7,9-dicarbonitrile (16). A mixture of compound 1 (0.675 g, 2.5 mmol) and
of
2-ethoxy-8-(4-fluorophenyl)-3-methyl-2-oxido-6-oxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-b]
[
o
acetaldehyde (0.132 g, 3 mmol) was warmed for 2 hour at 35−40 C, then added diethyl phosphite (0.4 ml,
.85 mmol) and two drops of trifluoroboron etherate. The reaction mixture was heated under reflux on water
2
bath for 10 hours. The reaction mixture was treated with ethyl acetate, giving crude solid which was
o
crystallized from diluted ethanol to give pale yellow solid in 35% yield (0.34 g); mp 252−254 C. IR (KBr), (max
,
-1
cm ): 3299, 3200 (2 NH), 3050 (C–Harom), 2925, 2858 (C–Haliph), 2216 (2 CN), 1667 (C=O), 1236 (P=O), 1000
1
(
P–O–C). H-NMR (400 MHz, DMSO-d
6
): 1.24 (t, 3H, J 7.2 Hz, CH
3
), 1.85 (d, 3H, J 2.5 Hz, CH ), 3.97 (q, 2H, J 7.2
3
Hz, CH
NH), 10.06 (s, 1H, NH). C-NMR (100 MHz, DMSO-d
CH ), 75.8 (C–5), 85.1 (C–3), 110.9 (CN), 112.0 (CN), 133.5 (C–4), 134.0, 134.7 (C–2`,6`), 155.6 (C–3`,5`),
2
), 4.50 (q, 1H, J 18.6 Hz, P–CH), 7.45 (d, 2H, J 9.8 Hz, Ar–H), 7.70 (d, 2H, J 11.2 Hz, Ar–H), 7.80 (s, 1H,
1
3
6
): 15.9 (CH
3
), 35.0 (CH ), 53.5 (d, J=150 Hz, P–CH), 63.0
3
(
2
3
1
1
3
1
58.1 (C–1`), 159.3 (C–6), 162.2 (C–4`), 167.3 (C=O). P-NMR (242 MHz, DMSO-d
87 (M , 8%). Anal. calcd. for C17
7.84%.
6
): 22.2 ppm. MS (EI, m/z):
+
H15FN
5
O
3
P (387.30): C, 52.72; H, 3.90; N, 18.08. Found: C, 52.39; H, 3.63; N,
Synthesis
of
8-(4-fluorophenyl)-3-methyl-2-oxido-6-oxo-2-phenyl-1,3,4,6-tetrahydro-2H-pyrido[1,2-b]
[
1,2,4,5]triazaphosphinine-7,9-dicarbonitrile (19). A mixture of compound 1 (0.675 g, 2.5 mmol) and
o
acetaldehyde (0.132 g, 3 mmol) was warmed for 2 hour at 35−40 C, then added P,P-dichlorophenylphosphine
0.34 ml, 2.5 mmol) and heated under reflux on water bath for 10 hours. The reaction mixture was treated
with cold water, giving crude solid which was crystallized from diluted ethanol to give pale yellow solid in 45%
(
o
-1
yield (0.47 g); mp 232−234 C. IR (KBr), (max, cm ): 3370, 3304 (2 NH), 2217 (2 CN), 1666 (C=O), 1611 (C=C),
1
1
8
7
1
1
237 (P=O). H-NMR (400 MHz, DMSO-d
6
): 2.08 (d, 3H, J 2.4 Hz, CH ), 4.14–4.20 (m, 1H, P–CH), 6.92 (dd, 1H, J
3
.4 and 4.2 Hz, Ph–H), 7.18–7.26 (m, 4H, Ar–H and Ph–H), 7.40–7.41 (m, 3H, Ar–H and Ph–H), 7.50 (dd, 1H, J
1
3
.8 and 2.4 Hz, Ph–H), 8.79 (s, 1H, NH), 9.15 (s, 1H, NH). C-NMR (100 MHz, DMSO-d
6
): 34.4 (CH ), 45.5 (d, J
3
38 Hz, P–CH), 75.0 (C–5), 82.0 (C–3), 116.2 (CN), 116.4 (CN), 120.3 (C–3``,5``), 127.6, 127.8 (C–2``,6``),
30.2 (C–4), 132.0 (C–2`,6`), 135.4 (C–4``), 137.4 (C–1``), 156.2 (C–3`,5`), 157.8 (C–1`), 159.1 (C–6), 161.6
Page 12
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Arkivoc 2018, v, 0-0
Assiri, M. A. et al.
+
(
C–4`), 167.5 (C=O). MS (EI, m/z): 419 (M , 8%). Anal. calcd. for C21
H15FN
5
O
2
P (419.34): C, 60.15; H, 3.61; N,
16.70%. Found: C, 59.82; H, 3.29; N, 16.34%.
Synthesis of {[7,9-dicyano-8-(4-fluorophenyl)-2-hydroxy-2-oxido-6-oxo-1,2,3,6-tetrahydro-4H-pyrido[1,2-b]
1,2,4,5]triazaphosphinine-4-yl]methyl}phosphonic acid (22). A solution of phosphorous acid (0.41 g, 5 mmol)
[
in distilled water (5 ml) was added dropwise to an acidic solution of compound 1 (0.67 g, 5 mmol) in diluted
hydrochloric acid (30 ml, 5%) in presence of formaldehyde (1 ml). The mixture was heated under reflux for 10
hours. The solvent was evaporated. After adding some cold water, the formed solid was filtered off and
o
-1
crystallized from diluted DMF to give yellow solid in 55% yield (0.56 g); mp 259−260 C. IR (KBr), (max, cm ):
3
418 (br OH and NH), 3077 (C–Harom), 2964, 2898 (C–Haliph), 2218 (2 CN), 1667 (C=O), 1603 (C=C), 1230 (P=O).
1
H-NMR (400 MHz, DMSO-d
Ar–H), 7.58 (td, 2H, J 9.2 and 4.0 Hz, Ar–H), 10.34 (s, 1H, NH). C-NMR (100 MHz, DMSO-d
6
): 4.54–5.15 (m, 4H, 2 P–CH ), 3.68 (br, 3H, P–OH), 7.43 (td, 2H, J 8.8 and 2.4 Hz,
2
1
3
6
): 45.0 (P–CH
2
),
5
0.5 (P–CH
2
), 76.3 (C–5), 90.4 (C–3), 114.8 (CN), 115.8 (CN), 130.5 (C–4), 130.6 (C–2`,6`), 154.4 (C–3`,5`),
3
1
154.8 (C–1`), 159.7 (C–6), 161.9 (C–4`), 164.4 (C=O). P-NMR (242 MHz, DMSO-d
6
): 11.7 and 19.2 ppm. MS (EI,
+
m/z): 409 (M+1, 6%), 408 (M , 32%). Anal. calcd. for C15
H12FN
5
6
O P (408.26): C, 44.13; H, 2.96; N, 17.15%.
Found: C, 43.61; H, 2.61; N, 16.83%.
Acknowledgements
The authors extend their appreciation to the Deanship of Scientific Research at King Khalid University for
funding this work through research groups program under grant number R.G.P.1/22/38.
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