Synthesis of novel 3-phenyl-2-oxido/sulfido-1,3,4,2-benzoxadiazaphosphepines

Article abstract of DOI:10.1080/00397911.2018.1468466

An efficient and facile synthetic approach towards a series of novel 3-phenyl-2-oxido/sulfido-2,3-dihydro-1,3,4,2-benzoxadiazaphosphepines 2–7 was described. The method depended on the cyclocondensation of equimolar ratios of salicylaldehyde phenylhydrazone (1) with different examples of phosphorus halides and phosphorus sulfides in toluene containing triethylamine as a catalyst. In the same manner, the fusion of salicylaldehyde phenylhydrazone (1) with triethyl phosphate in the presence of DBU afforded the 2-ethoxy-1,3,4,2-benzoxa-diazaphosphepine 8, while a fusion of compound 1 with diethyl phosphite and tris(2-chloroethyl)phosphite led to the formation of new examples of 1,2-benzoxaphospholes 9 and 10, respectively. Interestingly, the reaction of compound 1 with diethyl ethoxycarbonyl phosphonate in ethanol containing DBU as a catalyst furnished the chromeno[3,4-d][1,2,3]diazaphosphole derivative 12 as a regioselective product.

Full text of DOI:10.1080/00397911.2018.1468466

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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Synthesis of novel 3-phenyl-2-oxido/sulfido-1,3,4,2-
benzoxadiazaphosphepines
Tarik E. Ali, Mohammed A. Assiri & I. S. Yahia
To cite this article: Tarik E. Ali, Mohammed A. Assiri & I. S. Yahia (2018): Synthesis of novel
3-phenyl-2-oxido/sulfido-1,3,4,2-benzoxadiazaphosphepines, Synthetic Communications, DOI:
10.1080/00397911.2018.1468466
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https://doi.org/10.1080/00397911.2018.1468466
Synthesis of novel 3-phenyl-2-oxido/sulfido-1,3,4,2-
benzoxadiazaphosphepines
Tarik E. Alia, Mohammed A. Assirib,c, and I. S. Yahiad,e
b
aDepartment of Chemistry, Faculty of Education, Ain Shams University, Roxy, Cairo, Egypt; Advanced
Materials and Green Chemistry, Chemistry Department, Faculty of Science, King Khalid University, Abha,
c
Saudi Arabia; Research Center for Advanced Materials Science, King Khalid University, Abha, Saudi
d
Arabia; Advanced Functional Materials & Optoelectronic Laboratory, Department of Physics, Faculty of
e
Science, King Khalid University, Abha, Saudi Arabia; Nanoscience Laboratory for Environmental and
Bio-medical Applications, Semiconductor Lab., Department of Physics, Faculty of Education, Ain Shams
University, Roxy, Cairo, Egypt
ABSTRACT
ARTICLE HISTORY
Received 3 March 2018
An efficient and facile synthetic approach towards a series of novel
3-phenyl-2-oxido/sulfido-2,3-dihydro-1,3,4,2-benzoxadiazaphosphepines
2–7 was described. The method depended on the cyclocondensation
of equimolar ratios of salicylaldehyde phenylhydrazone (1) with differ-
ent examples of phosphorus halides and phosphorus sulfides in tolu-
ene containing triethylamine as a catalyst. In the same manner, the
fusion of salicylaldehyde phenylhydrazone (1) with triethyl phosphate
in the presence of DBU afforded the 2-ethoxy-1,3,4,2-benzoxa-diaza-
phosphepine 8, while a fusion of compound 1 with diethyl phosphite
and tris(2-chloroethyl)phosphite led to the formation of new examples
of 1,2-benzoxaphospholes 9 and 10, respectively. Interestingly, the
reaction of compound 1 with diethyl ethoxycarbonyl phosphonate in
ethanol containing DBU as a catalyst furnished the chromeno[3,4-
d][1,2,3]diazaphosphole derivative 12 as a regioselective product.
KEYWORDS
1,3,4,2-
Benzoxadiazaphosphepine;
1,2-benzoxaphosphole;
1,2,3-diazaphosphole; salicy-
laldehyde phenylhydrazone
GRAPHICAL ABSTRACT
Ph
Ph
HN
N
HN
O
N
P
OEt
O
NH
H
N
P
P
N
Ph
O
O
P
O
O
O
O
OEt
O
Y
X
Introduction
During the last years, phosphorus heterocycles attracted the interest of both industrial and
pharmaceutical researchers.[1–7] Different applications for phosphorus heterocycles were
developed,[8,9] for example, they served as pesticide,[10] anticancer,[11] and antineoplastic
agents.[12] In the course of developing our previous studies, we have synthesized some
CONTACT Tarik E. Ali
tarik_elsayed1975@yahoo.com; tarekelsaied@edu.asuedu.eg
Department of Chemistry,
Faculty of Education, Ain Shams University, Roxy, 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 2018 Taylor & Francis

2
T. E. ALI ET AL.
bioactive fused phosphorus seven-membered rings such as 1,2,4-triazino[4,3-f][1,5,6,2]thia-
diazaphosphepine (A), 1,2,4-triazino[4,3-f][1,2,5,6,3]tetrazaphosphepine (B),[13] and
chromono[2,3-e][1,2,4,3]triazaphosphepines (C)[14] (Fig. 1). Also, a series of 1,3,4,2-
oxadiazaphosphepino[6,7-c]quinolinones (D) as first examples of 1,3,4,2-oxadiazaphosphe-
pine rings was constructed in our last article[15] (Fig. 1). In continuation of an ongoing
program on the synthesis of novel phosphorus heterocycles,[16–18] we planned to synthesize
a novel class of 1,3,4,2-benzoxadiazaphosphepine heterocycles via the treatment of salicylal-
dehyde phenylhydrazone with different examples of phosphorus halides, phosphorus
sulfides, and phosphorus esters.
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 13C
NMR spectra were measured on Gemini-300BB spectrometer (400 and 100 MHz), using
DMSO-d6 as a solvent and TMS as an internal standard. 31P NMR spectra were
measured on a Bruker (162 MHz) spectrophotometer using DMSO-d6 as a solvent, TMS
as an internal standard and 85% H3PO4 as an external reference. Mass spectra were
recorded on a Gas Chromatographic GCMSqp 1000 ex Shimadzu instrument at 70 eV.
Elemental microanalysis was performed Perkin-Elmer 2400II 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 2,3-diphenyl-2-oxido-2,3-dihydro-1,3,4,2-benzoxadiazaphosphepine (2)
A solution of phenylphosphonic dichloride (0.35 ml, 2.5 mmol) in toluene (5 ml) was
added dropwise to a solution of compound 1 (0.53 g, 2.5 mmol) in toluene (30 ml) in
the presence of a catalytic amount of triethylamine (0.35 ml, 5 mmol) at 5–10 ꢀC for
30 min. The mixture was heated under reflux for 10 h. The formed solid was filtered off,
washed with water several times and crystallized from diluted dioxane to give pale green
solid in 78% yield; mp 236–238 ꢀC. IR (KBr), (ꢀmax, cmꢁ1): 3098 (C–Harom), 1609
(C¼N), 1530 (C¼C), 1199 (P¼O), 1089 (O–C). 1H NMR (400 MHz, DMSO-d6):
7.52–7.59 (m, 4H, Ph–H), 7.74 (d, 3H, J ¼ 5.2 Hz, Ph–H), 7.85–7.90 (m, 3H, Ph–H),
8.12–8.21 (m, 4H, Ph–H), 8.91 (s, 1H, CH¼N). 13C NMR (100 MHz, DMSO-d6): 116.7
(A)
(B)
(C)
(D)
X
P
Ph
N
H3C
N
N
Y
O
N
N
H3C
N
N
N
O
O
NH
NH
P(Ph)3
S
O
O
N
N
P
Y
CH3
P(Ph)3
N
Ph
N
N
O
N
H
X
Ph
H3C
CH3
Figure 1. Structures of some bioactive fused phosphorus seven-membered rings.

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3
(C–20,60), 118.2 (C–9), 119.4 (C–5a), 120.4 (C–40), 121.8 (C–7), 124.0 (C–300,500), 127.8
(C–200,600), 129.6 (C–30,50), 130.9 (C–6), 132.3 (C–400), 136.8 (C–8), 140.0 (d,
JPC ¼ 125 Hz, C–100), 142.3 (C–10), 147.0 (C–5), 159.6 (C–9a). 31P NMR (162 MHz,
DMSO-d6): 35.7 ppm. MS (EI, m/z): 334 (Mþ, 6%). Anal. calcd. for C19H15N2O2P
(334.32): C, 68.26%; H, 4.52%; N, 8.38%. Found: C, 67.91%; H, 4.25%; N, 8.02%.
Result and discussion
Salicylaldehyde phenylhydrazone (1) as the precursor material was prepared by the reac-
tion of salicylaldehyde with phenylhydrazine in ethanol according to the reported
method in the literature (Scheme 1).[19]
The hydroxyl and amino groups are ready-made nucleophilic centers for the synthesis
of fused phosphorus heterocyclic rings via their reaction with phosphorus halides with
eliminating of two molecules of hydrogen halides. Thus, treatment of compound 1 with
phenylphosphonic dichloride in toluene containing two equivalent amounts of triethyl-
amine led to the formation of 2,3-diphenyl-2-oxido-2,3-dihydro-1,3,4,2-benzoxadiaza-
phosphepine (2) in 78% yield (Scheme 2). Similarly, treatment of compound 1 with
phosphorus oxychloride and phosphorus tribromide in toluene containing triethylamine
furnished the intermediates A and B, respectively, which underwent hydrolysis to give
the isolated product 3 and 4, respectively (Scheme 2).
The structures of products 2, 3, and 4 were deduced from the analytical and spectro-
scopic data. The 1H NMR spectra of these compounds revealed the presence of
the aromatic protons in region d 6.92–8.24 ppm, while the P–H proton of compound 4
was observed as a doublet at d 7.74 with coupling constant 667 Hz. The 31P NMR spec-
trum of compound 2 showed a singlet at d 35.7 ppm while compound 4 exhibited a sig-
nal at d 7.8 ppm.[20] Moreover, the mass spectra of compounds 2, 3, and 4 recorded
their molecular ion peaks at m/z 334, 274, and 258, respectively. Although compound 4
may have two tautomeric forms because of phosphite–phosphonate tautomerism, but
1
the only phosphonate form was found in the IR, H, and 31P NMR spectra.
Also, we studied the reaction of compound 1 with three examples of phosphorus sul-
fides. Thus, 3-phenyl-2-sulfanyl-2-sulfido-2,3-dihydro-1,3,4,2-benzoxadiazaphosphepine
(5) was isolated as an orange solid when compound 1 reacted with equivalent amount
of phosphorus decasulfide in toluene (Scheme 3).[21] 2-Ethoxy-3-phenyl-2-sulfido-2,3-
dihydro-1,3,4,2-benzoxadiazaphosphepine (6) was also obtained from treatment of com-
pound 1 with O,O-diethyldithiophosphoric acid (formed in situ) in ethanol (Scheme 3).
Besides, compound 1 was treated with Lawesson’s reagent (LR) in toluene to give a good
yield of 2-(4-methoxy-phenyl)-3-phenyl-2-sulfido-2,3-dihydro-1,3,4,2-benzoxadiazaphos-
phepine (7) (Scheme 4). The formation of 2-sulfido-1,3,4,2-benzoxadiazaphosphepine
H
CHO
OH
N
H
N
N
Ph
EtOH
+
H2N
Ph
OH
1 (92%)
Scheme 1. Preparation of salicylaldehyde phenylhydrazone (1).

4
T. E. ALI ET AL.
rings can be explained on the basis of phosphorylation of the NH group by phosphorus
sulfide reagent to give the nonisolable intermediates C, D, and E, respectively. These
intermediates underwent fast intramolecular cyclization via attack of OH group through
addition or elimination reactions as shown in Schemes 3 and 4.
In the mass spectra of compounds 5–7, they showed their expected molecular ion
peaks (Mþ) which supported the proposed structures. The most characteristic signals in
1
their H NMR spectra were those of the sulfanyl, ethoxy, and methoxy protons. They
N
P
N
P
H2O
N
Ph
N
Ph
O
O
Cl
OH
O
O
A
3 (73%)
Toluene
Et3N
POCl3
Ph
6
N4
5a
NH
7
8
PhP(O)Cl2
3
N
`
N
Ph
2P
O
Toluene
Et3N
9a
``
O
Ph
OH
9
1
1
2 (78%)
Toluene
Et3N
PBr3
N
N
N
N
P
N
N
H2O
Ph
Ph
Ph
P
P
O
O
H
O
Br
OH
O
B
4 (60%)
Scheme 2. Reaction of compound 1 with some phosphorus halides.
Ph
Ph
N
S
P+
NH
N
P4S10
N
N
N
Ph
Toluene
S
P
O
OH
OH
S
1
SH
C
5 (63%)
S
P4S10
EtOH
EtO
P
SH
OEt
Ph
N
OEt
N
- EtOH
N
Ph
N
P
S
OEt
P
O
S
OH
OEt
6 (55%)
D
Scheme 3. Reaction of compound 1 with phosphorus decasulfide and O,O-diethyldithiophos-
phoric acid.

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5
Ph
Ph
N
S
NH
LR
N
N
P
Toluene
SH
OMe
OH
OH
E
1
- H2S
5
6
N4
N
5a
9a
`
6``
7
8
3
Ph
2P
1``
5``
4``
O
9
1
S
OMe
2``
3``
7 (75%)
S
S
P
S
MeO
P
S
S
P
S
+
LR
OMe
2
OMe
=
Scheme 4. Reaction of compound 1 with Lawesson’s reagent.
were displayed at d 3.33 (SH), 1.03, 4.01 (CH3CH2O), and 3.74 (OCH3) ppm. In the 13C
NMR spectra, the specific carbon atoms of CH3CH2O and OCH3 groups of compounds
6 and 7 were observed at d 14.3, 59.6, and 55.6 ppm, respectively. Moreover, the 31P
NMR spectrum of compound 7 showed a singlet at d 57.2 ppm.[22]
Next, the present work was extended to investigate the chemical behavior of the
hydrazone 1 towards four examples of phosphorus esters. Thus, when compound 1
was fused with triethyl phosphate at 80–90 ꢀC in the presence of 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU) as a catalyst, the 2-ethoxy-3-phenyl-2-oxido-2,3-dihydro-
1,3,4,2-benzoxadiazaphosphepine (8) was separated via the removal of two ethanol mol-
ecules (Scheme 5).
On contrary, the fusion of compound 1 with diethyl phosphite or tris(2-chloroethyl)
phosphite under the same reaction conditions, did not give the expected 1,3,4,2-benzox-
adiazaphosphepines 3 (Scheme 6). These reactions occurred via Michael addition of
phosphorus atom at the azomethine bond to form the nonisolable dialkyl a-hydrazino-
phosphonates G. The latter intermediate (R¼Et) was spontaneously cyclized by losing of
ethanol molecule to give the isolated compound 9 (Scheme 6).[23] On the other hand,
the intermediate G (R¼OCH2CH2Cl) underwent double cyclizations by elimination of
2-chloroethanol and hydrogen chloride molecules giving the nonisolable intermediate
I, that removed aniline molecule to yield the novel 2,3-dihydro[1,2]benzoxaphos-
pholo[2,3-b][1,4,2]oxazaphosphinine 5-oxide (10) (Scheme 6).
The IR spectrum of compound 9 showed the absorption bands of NH and P¼O
groups at 3415–3162 and 1230 cmꢁ1, respectively. The presence of the molecular ion
peak for this compound at m/z 304 in its mass spectrum confirmed the cyclization pro-
cess. However, the characteristic hydrogen and carbon atoms of compound 9 were
1
observed in their H and 13C NMR spectra. For example, the P–CH proton was shown
as a doublet at d 5.32 ppm (J ¼ 15.2 Hz) and the CH3CH2O protons were resonated as
triplet and quartet at d 0.77 (CH3) and 3.95 (CH2) ppm, while the two D2O-exchangeable

6
T. E. ALI ET AL.
Ph
Ph
N
NH
OEt
O
N
(EtO)3PO
N
P
80-90 oC
DBU
OEt
OH
OH
1
F
- EtOH
N
N
P
Ph
O
OEt
O
8 (53%)
Scheme 5. Reaction of compound 1 with triethyl phosphate.
Ph
NH
N
OH
1
HP(O)(OEt)2
80-90 oC
or
DBU
P(OCH2CH2Cl)3
Cl
O
PhNH
H
N
OR
RO
NH
P
P
N
Ph
H
- ROH
N
P
O
R
N
H
Ph
O
R=CH2CH2Cl
H
O
O
O
3
OH
H
R=H, OCH2CH2Cl
G
-HCl
R=Et
- ROH
PhNH
H
N
P
`
Ph
HN
O
NH
4
O
O
3
H
3a
5
6
I
O
2
P
- PhNH2
O
OEt
7a
1
7
1
2
N
9 (69%)
10
7
10b
3
10a
9
8
5
O4
P
O
6a
O
6
10 (48%)
Scheme 6. Reaction of compound 1 with diethyl phosphite and tris(2-chloroethyl) phosphite.

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SYNTHETIC COMMUNICATIONSV
7
NH were observed at d 4.68 and 9.08 ppm. Furthermore, the carbon atoms of CH3CH2O
moiety were resonated at d 17.2 and 59.6 ppm, whereas the P–CH carbon atom was
observed as a doublet at d 48.5 ppm (JPC ¼ 148 Hz). The 31P NMR spectrum of com-
1
pound 9 recorded a singlet at d 19.7 ppm. Similarly, the H and 13C NMR spectra of
1
product 10 gave strong evidence for the proposed structure. Its H NMR spectrum dis-
played four aromatic protons in region d 6.81–7.68 ppm, whereas its 13C NMR spectrum
confirmed the suggested structure by recording only nine carbon atoms (see
Experimental section). Furthermore, its mass spectrum displayed the molecular ion peak
at m/z 209 that proved for the cyclized structure.
The more interesting point in this work was the reaction of hydrazone 1 with diethyl
ethoxycarbonyl phosphonate in ethanol containing DBU as a catalyst. The annulated tri-
heterocyclic system 12 was obtained as a regioselective product without any traces of the
other product 11 (Scheme 7). A possible explanation for the course of the formation of
compound 12 is shown in Scheme 7. The reaction proceeded via Michael-addition of
phosphonoacetate at azomethine bond of compound 1 with help of a basic catalyst form-
ing the intermediate J. The latter intermediate underwent easily double cyclizations with
removal of two ethanol molecules via double nucleophilic attacks of NH at P(O)(OEt)2
Ph
NH
OEt
P
O
Ph
OEt
O
HN
O
NH
H
P
EtO
OEt
N
OEt
H
OH
O
EtOH
DBU
OH
OEt
1
J
Double
Nucleophilic
Cyclizations
- 2 EtOH
route b
route a
Ph
N
Ph
HN
N
HN
OEt
H
H
P
O
O
H
O
H
P
O
O
O
OEt
L
K
Standing on air
Standing on air
`
Ph
2
Ph
N
1
HN
HN
N 3
P
3a
OEt
9
6
9b
O
9a
5a
8
7
O
4
P
O
O
O
O
5
OEt
12 (72%)
11
Scheme 7. Reaction of compound 1 with diethyl ethoxycarbonyl phosphonate.

8
T. E. ALI ET AL.
and OH at COOEt (route a) to form the nonisolable chromeno[3,4-c][1,2]azaphosphinine
L. The oxidation of the intermediate L by air led to the formation the product 12.
The chromenodiazaphosphole structure 12 was established by the analytical and
spectroscopic tools. In its IR spectrum, the NH and C¼O groups were observed at 3270
and 1733 cmꢁ1, respectively, which supported its existence in lactonic form and not ami-
1
dic form in structure 11.[24] Also, in the H NMR spectrum of compound 12, the pro-
tons of CH3CH2O group were observed at d 1.29 and 4.34 ppm. In addition, its 13C
NMR spectrum displayed the carbon atoms of CH3CH2O and C¼O groups at d 15.8,
60.0, and 175.1 ppm, respectively. Finally, its 31P NMR spectrum exhibited a singlet at
d 25.3 ppm, whereas the mass spectrum recorded the molecular ion peak at m/z 342.
Conclusion
In summary, we have successfully synthesized a novel class of 1,3,4,2-benzoxadiaza-
phosphepines in one step by the treatment of salicylaldehyde phenylhydrazone with
different examples of phosphorus halides and phosphorus sulfides under mild reaction
conditions. In addition, two new examples of 1,2-benzoxaphospholes were obtained via the
fusion of hydrazone with some alkyl phosphites. The annulated chromeno[3,4-d][1,2,3]dia-
zaphosphole structure was also isolated as a regioselective product from the treatment of
hydrazone with diethyl ethoxycarbonyl phosphonate in basic medium. The obtained results
enrich the library of organophosphorus heterocycles and provide an efficient approach to
the preparation of phosphorus heterocycles incorporating N–P–O, O–P–O, and
C–P–O scaffolds.
Funding
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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