An efficient synthesis and antibacterial screening of novel oxazepine α-aminophosphonates by ultrasound approach

Article abstract of DOI:10.1080/10426500802713259

An efficient synthesis of novel -aminophosphonates by the reaction of quino[2,3-b][1,5]benzoxazepines with triethyl phosphite in the presence of the easily available, inexpensive, and nontoxic catalyst p-toluene sulphonic acid (p-TSA). This method affords the -aminophosphonates under the influence of ultrasound irradiation in solvent-free conditions, in short reaction times (4-6 min), high yields (80-90%), with improved purity. The synthesized -aminophosphonates show antibacterial activity against Gram-positive and Gram-negative bacteria. Supplemental materials are available for this article. Go to the publisher′s online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

Full text of DOI:10.1080/10426500802713259

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An Efficient Synthesis and Antibacterial
Screening of Novel Oxazepine α-
Aminophosphonates by Ultrasound
Approach
Swapnil S. Sonar a , Sandip A. Sadaphal a , Vilas B. Labade a
Bapurao B. Shingate a & Murlidhar S. Shingare a
,
a Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada
University, Aurangabad, India
Version of record first published: 28 Dec 2009.
To cite this article: Swapnil S. Sonar , Sandip A. Sadaphal , Vilas B. Labade , Bapurao B. Shingate &
Murlidhar S. Shingare (2009): An Efficient Synthesis and Antibacterial Screening of Novel Oxazepine
α-Aminophosphonates by Ultrasound Approach, Phosphorus, Sulfur, and Silicon and the Related
Elements, 185:1, 65-73
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Phosphorus, Sulfur, and Silicon, 185:65–73, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802713259
AN EFFICIENT SYNTHESIS AND ANTIBACTERIAL
SCREENING OF NOVEL OXAZEPINE
α-AMINOPHOSPHONATES BY ULTRASOUND APPROACH
Swapnil S. Sonar, Sandip A. Sadaphal, Vilas B. Labade,
Bapurao B. Shingate, and Murlidhar S. Shingare
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University,
Aurangabad, India
An efficient synthesis of novel α-aminophosphonates by the reaction of quino[2,3-b]
[1,5]benzoxazepines with triethyl phosphite in the presence of the easily available, inex-
pensive, and nontoxic catalyst p-toluene sulphonic acid (p-TSA). This method affords the
α-aminophosphonates under the influence of ultrasound irradiation in solvent-free condi-
tions, in short reaction times (4–6 min), high yields (80–90%), with improved purity. The
synthesized α-aminophosphonates show antibacterial activity against Gram-positive and
Gram-negative bacteria.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental
file.
Keywords α-Aminophosphonates; p-TSA; quino[2,3-b][1,5]benzoxazepine; solvent-free; tri-
ethyl phosphite; ultrasound irradiation
INTRODUCTION
Phosphorus chemistry ranges over a wide field of science including biochemistry
and technology. In the new century, many phosphorus compounds will play a vital role
in new high-tech areas such as life science, medical drugs, and nanometer technology.1
Phosphonates functionalized with amino groups have attracted considerable attention since
they are considered as structural analogues of the corresponding α-amino acids, and their
utilities as enzyme inhibitors, antibiotics, pharmacological agents, peptidomimetics, hapten
design in antibody generation, and many other applications are well documented.2 In
addition, phosphonates show antibacterial activity with the quinoline nucleus.3
Quinoline ring systems represent a major class of heterocycles, as they occur in var-
ious natural products, especially in alkaloids.4 They possess diverse biological and phys-
iological activities such as antimalarial,5a anti-inflammatory,5b antitumor,5c DNA binding
Received 12 September 2008; accepted 14 December 2008.
The authors are thankful to the Head, Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada
University, Aurangabad, India for providing laboratory facilities.
Address correspondence to Murlidhar S. Shingare, Department of Chemistry, Dr. Babasaheb Ambedkar
Marathwada University, Aurangabad-431 004 MS, India. E-mail: prof msshingare@rediffmail.com
65

66
S. S. SONAR ET AL.
capacity,5d and antibacterial properties.5e Recently, quinoline has been employed in the
study of bio-organic and bio-organometallic processes.5f Seven-membered heterocycles
with two heteroatoms in the 1,4-position are known to possess diverse biological activ-
ities. In particular, derivatives of benzoxazepine exhibit a broad spectrum of biological
properties such as neurotropic and psychotropic,6a anti-inflammatory,6b anticonvulsive,6c
antagonistic properties against prostaglandin,6d high ceiling diuretics,6e and antidepres-
sant activities.6f The metal complexes of quino[2,3-b][1,5]benzoxazepines show effective
antibacterial and antifungal activities.7 There are very few reports on the synthesis of
quino[2,3-b][1,5]benzoxazepines.8
Generally, α-aminophosphonates are prepared by the nucleophilic addition of
phosphite to imine in the presence of a Brønsted acid9a or Lewis acids such as ZnCl2,9b
BF3.Et2O,9c CdI2/benzene,9d and CdI2/microwave.9e α-Aminophosphonates also have
been synthesized by the one-pot reaction of phosphite with imines generated in situ
from aldehydes and amines in organic solvents using InCl3,10a ZrCl4,10b GaI3,10c
BiCl3,10d and SbCl3/Al2O3. In addition, the solvent-free transformation of phosphite
10e
to α-aminophosphonates could be accomplished in the presence of TFA,11a LiClO4,11b
metal triflates,11c and Na2CaP2O7.11d There is only one report for the synthesis of
α-aminophosphonates by ultrasound irradiation.12
In recent years, solvent-free organic syntheses have offered more advantages as
compared to their homogeneous counterparts due to the growing concern for the influence
of organic solvent on the environment as well as on the human body, and also concern for
economical demands and simplicity in the processes.13
Ultrasound irradiation has been established as an important technique in synthetic
organic chemistry. It has been used as an efficient heating source for organic reactions.
Shorter reaction time is the main advantage of ultrasound-assisted reactions. Simple ex-
perimental procedure, very high yields, increased selectivities, and clean reaction of many
ultrasound-induced organic transformations offer additional convenience in the field of
synthetic organic chemistry.14
It is noted that p-toluene sulfonic acid (p-TSA) has been exploited as a catalyst in
organic synthesis.15 We have investigated the synthesis of α-aminophosphonates in the
presence of p-TSA as a catalyst. It was found that p-TSA is an effective promoter in the
synthesis of α-hydroxyphosphonates by the reaction of quino[2,3-b][1,5]benzoxazepine
with triethyl phosphite.
In continuation of our research devoted to the phosphorus chemistry3,16 and our inter-
est in the development of novel synthetic methodologies,17 in this article we report a simple,
efficient, and rapid method for the synthesis of novel oxazepine α-aminophosphonates un-
der ultrasonic irradiation.
RESULTS AND DISCUSSION
Imines 3(a–j) were prepared from substituted 2-chloroquinoline-3-carbaldehyde
1(a–j) and 2-hydroxy aniline 2 in absolute ethanol in the presence of a catalytic amount of
acetic acid. The product formed at room temperature in excellent yields (95–98%).
Quino[2,3-b][1,5]benzoxazepines 4(a–j) were synthesized by the cyclization of
imines 3(a–j) under basic conditions (DMF, K2CO3) at 60◦C in 98–100% yields and
were confirmed by IR, 1H NMR, and mass spectroscopic data and elemental analysis.
The one-pot syntheses of quino[2,3-b][1,5]benzoxazepines 4(a–j) were also carried
out by in situ generation of imine from the condensation of 2-chloroquinolin-3-carbaldehyde

NOVEL OXAZEPINE α-AMINOPHOSPHONATES
67
Table I Effect of catalysts on the synthesis of α-aminophosphonates 5a
Entry
Catalyst
Time (min)
Yield (%)b
1
2
3
4
5
6
7
—
90
60
60
60
30
20
5
10
20
35
40
55
60
90
FeCl3
CaCl2
NiCl2
CdCl2
HgCl2
p-TSA
a4a (2.5 mmol) was treated with triethyl phosphite (5 mmol) under solvent-free condition.
bIsolated yields based upon starting aldehyde.
and 2-hydroxy aniline followed by the cyclization under basic conditions. But the
cyclization of pure imine 3(a–j) afforded quino[2,3-b][1,5]benzoxazepine in higher yields
(overall yield 97–99%) than that arising from the one-pot procedure (86–90%).
In a search for an efficient catalyst and the best experimental reaction conditions, the
reaction of quino[2,3-b][1,5]benzoxazepines 4a with triethyl phosphite under the influence
of ultrasonic irradiation has been considered as a standard model reaction. All the reactions
were carried out at room temperature under solvent-free conditions. When the reaction was
carried out in the absence of catalyst, the product formed in very low yield (10%) after
prolonged reaction time (Table I, entry 1). In the next step, we have screened different
catalysts for the model reaction, such as FeCl3, CaCl2, CdCl2, HgCl2, and p-TSA. By the
use of FeCl3, CaCl2, and NiCl2, as catalysts the product formed in poor yields 20–40%
(Table I, entries 2–4), whereas when using CdCl2 and HgCl2, the product was formed in
moderate yields 55–60% (Table I, entries 5 and 6). The best result was obtained using
25 mol% of p-TSA at room temperature under solvent-free conditions. The product was
obtained within 5 min in 90% yield (Table I, entry 7).
To determine the appropriate concentration of the catalyst p-TSA, we investigated
the model reaction at different concentrations of catalyst: 5, 10, 15, 20, and 25 mol%. The
product formed in 72, 77, 85, 90, and 90% yields respectively. This indicates that 20 mol%
of p-TSA is sufficient for the best result by considering the reaction time and yield of
product (Table II, entry 4).
Various substituted 2-chloro-quinoline-carbaldehydes having different substituents
such as CH3, OCH3, OC2H5, F, and Cl were used for the synthesis of oxazepine
α-aminophosphonates. The reaction was compatible with all the substituents, and no
competitive nucleophilic methyl/ethyl ether cleavage was observed for the substrate having
OCH3 or OC2H5 groups.
With these optimized reaction conditions, we have synthesized α-aminophosphonates
(5a–j) by reacting quino[2,3-b][1,5]benzoxazepines (4a–j) with triethyl phosphite in the
presence of p-TSA (Scheme 1). All the reactions were carried out under the influence of

68
S. S. SONAR ET AL.
Scheme 1
ultrasonic irradiation in solvent-free conditions at room temperature. The products formed
within 4–6 min in 80–90% yield (Table III). The identities of the products were confirmed
by IR, 1H NMR, mass spectroscopic data, and elemental analysis.
We have also carried out the identical reactions by conventional methods. In compar-
ison with ultrasonic method, the product was obtained in longer reaction time and lower
yields (Table III).
All novel synthesized α-aminophosphonates were screened for antibacterial activi-
ties against Gram-positive Bacillus subtilis and Staphylococci aureus and Gram-negative
Escherichia coli and Salmonella aboney bacteria. The compounds tested were compared
against the standard (streptomycin) by measuring the diameter of the zone of inhibi-
tion. Almost all the compounds tested exhibited moderate activity against Gram-positive
Table II Effect of concentrations of p-TSA for synthesis of α-aminophosphonatesa 5
Entry
p-TSA (mol%)
Time (min)
Yield (%)b
1
2
3
4
5
5
10
15
20
25
15
12
10
5
72
77
85
90
90
5
a4a (2.5 mmol) was treated with triethyl phosphite (5 mmol) under solvent-free condi-
tions.
bIsolated yields based upon starting aldehyde.

NOVEL OXAZEPINE α-AMINOPHOSPHONATES
69
Table III Synthesis of oxazepine α-aminophosphonatesa (5a–j)
Conventional Method
Yield (%)c
Ultrasonic Method
Yield (%)c
Entry
Rb
Time (min)
Time (min)
Mp (◦C)
5a
5b
5c
5d
5e
5f
5g
5h
5i
H
30
80
5
6
6
5
6
5
4
4
5
4
90
84
81
80
89
85
82
85
86
88
192–194
153–155
113–115
133–135
119–121
120–122
150–152
180–182
134–136
144–146
6-CH3
7-CH3
8-CH3
6-OCH3
7-OCH3
6-OC2H5
6-F
30
30
25
25
30
25
25
30
25
76
73
73
75
74
72
76
72
76
7-F
6-Cl
5j
a4a–j (2.5 mmol) treated with triethyl phosphite (5 mmol) and p-TSA (20 mol%) under solvent-free condition.
bThe numbering is considered upon starting quinoline aldehyde.
cIsolated yields based upon 4a–j.
bacteria, and a few compounds were found to be active against the Gram-negative bacteria
used in this study (see Table IV in the Supplemental Materials online).
ANTIBACTERIAL ACTIVITY
All the compounds were screened for antibacterial activities against Gram-positive
Bacillus subtilis and Staphylococci aureus (ATCC 6538) and Gram-negative Escherichia
coli (ATCC 8739) and Salmonella aboney (NCTC 6017) bacteria using streptomycin
(strept.) as a standard. Petri dishes and necessary glassware were sterilized in a hot air
oven (190◦C, 45 min). Details are provided in the Supplemental Materials (see Supplemen-
tal Materials online).
CONCLUSION
In conclusion, p-TSA is an efficient catalyst for the synthesis of novel oxazepine
α-aminophosphonates by the reaction of quino[2,3-b][1,5]benzoxazepines (4a–j) with tri-
ethyl phosphite using an ultrasonic approach. The synthesized α-aminophosphonates show
moderate antibacterial activity against Gram-positive and Gram-negative bacteria. The
remarkable advantages offered by this method are solvent-free reaction condition, short
reaction time, ease of product isolation, and high yields.
EXPERIMENTAL
All melting points were determined in open capillaries in a paraffin bath and are
uncorrected. A Bandelin Sonorex (35 kHz) ultrasonic bath was used for ultrasonic irradi-
ation. 1H NMR spectra were recorded on Mercury Plus Varian in DMSO or CDCl3 at 400
MHz using TMS as an internal standard. IR spectra were recorded on a Perkin-Elmer FTIR
using KBr discs. Mass spectra were recorded on Micromass Quattro II using electrospray
ionization technique, showing (m+1) peak as a base peak. The elemental analysis was

70
S. S. SONAR ET AL.
carried out on Flash EA-1112, 50/60 Hz, 1400-VA CHNS analyzer. The progress of the
reactions was monitored by TLC.
Typical Experimental Procedure: 2-((2-Chloroquinolin-3-yl)
methyleneamino) phenol (3a-j)
To the stirred solution of 2-chloroquinoline-3-carbaldehyde (2.5 mmol) in absolute
ethanol (10 mL), 2-hydroxy aniline (3 mmol) and 4 to 5 drops of acetic acid were added at
room temperature. The progress of the reaction was monitored using TLC in solvent system
hexane:ethyl acetate (8:2). After completion of the reaction, it was poured onto crushed ice
and separated out as a yellow colored solid product.
Quinolino[3,2-b]benzodiazepine (4a–j)
A mixture of 2-((2-chloroquinolin-3-yl) methyleneamino) phenol (2.5 mmol) and
K2CO3 (3 mmol) in DMF (10 mL) was stirred at 60◦C in an oil bath for 1 h. The progress of
the reaction was monitored using TLC in solvent system hexane:ethyl acetate (8:2). After
the completion of the reaction, it was poured onto crushed ice and separated out as a solid
product. The crude product was recrystallized from ethyl acetate.
One-Pot Syntheses of Quinolino[3,2-b]benzodiazepine (4a–j)
A solution of 2-chloroquinoline-3-carbaldehyde (2.5 mmol), 2-hydroxyaniline
(3 mmol) in absolute ethanol (10 mL), and 4 to 5 drops of acetic acid was stirred at room
temperature for 10 min. The solvent was distilled out on rota-evaporator under reduced
pressure. To the yellow homogeneous residue DMF (10 mL) and K2CO3 (5 mmol), the
content was added and stirred at 60◦C in an oil bath for 2 h. After completion of the
reaction, as monitored by TLC, the reaction mass was poured onto crushed ice and the
solid product was separated out. The crude product was recrystallized from ethyl acetate.
α-Aminophosphonates (5a–j)
Conventional method. Amixtureof quino[2,3-b][1,5]benzoxazepine (2.5mmol),
triethyl phosphite (5 mmol), and p-TSA (20 mol%) was stirred at room temperature for
25–30 min (Table III). The progress of the reaction was monitored using TLC and using
hexane:ethyl acetate (7:3). After completion of the reaction, the reaction mass was poured
onto crushed ice. The yellow colored solid was separated out, and the crude material was
recrystallized from ethanol.
Ultrasonic irradiation. A mixture of quino[2,3-b][1,5]benzoxazepine (2.5 mmol),
triethyl phosphite (5 mmol), and p-TSA (20 mol%) was irradiated under ultrasonic waves
at room temperature for 4–6 min (Table III). After completion of the reaction, as monitored
by TLC, the reaction mass was poured onto crushed ice. The yellow colored solid was
separated out, and the crude material was recrystallized from ethanol.
Spectral Data of Principal Compounds
1
4a: IR (KBr, cm−1): 1615 (C C), 1207 (C O C). H NMR (CDCl3, 400 MHz,
δ ppm): 8.56 (s, 1H, Ar CH), 8.22 (s, 1H, Ar CH), 7.99 (d, 1H, J = 8.52 Hz, Ar CH),

NOVEL OXAZEPINE α-AMINOPHOSPHONATES
71
7.84 (d, 1H, J = 8.12 Hz, Ar CH), 7.75 (td, 1H, J = 7.04, 1.4 Hz, Ar CH), 7.53 (td, 1H,
J = 6.04, 1 Hz, Ar CH), 7.43 (dd, 2H, J = 6.32, 1.6 Hz, Ar CH), 7.28 (m, 2H, Ar CH).
ES-MS: m/z 247. Elemental analysis: C16H10N2O Calc.: C: 78.03%, H: 4.09%, N: 11.38%;
Found: C: 78.08%, H: 4.14%, N: 11.43%.
1
5: IR (KBr, cm−1): 3280 (N H), 1615 (C C), 1248 (P O), 1040 (P O C). H
NMR (CDCl3, 400 MHz, δ ppm): 8.20 (d, 1H, J = 1.92 Hz, Ar CH), 7.98 (d, 1H, J =
8.44 Hz, Ar CH), 7.77 (d, 1H, J = 8.08 Hz, Ar CH), 7.70 (t, 1H, J = 7.28 Hz, Ar CH)
7.48 (td, 1H, J = 7.08, 0.92 Hz, Ar CH), 7.39 (dd, 1H, J = 6.6, 1.4 Hz, Ar CH), 6.98
(td, 1H, J = 6.16, 1.4 Hz, Ar CH), 6.87 (m, 2H, Ar CH), 5.0 (dd, 1H, J = 13.56, 5.6
Hz, P CH), 4.5 (d, 1H, J = 5.6 Hz, NH), 4.0 (m, 3H, O CH2), 3.8 (m, 1H, O CH), 1.2
(t, 6H, J = 5.72 Hz, CH3). ES-MS: m/z 385. Elemental analysis: C20H21N2O4P Calc.: C:
62.50%, H: 5.51%, N: 7.29%; Found: C: 63.00%, H: 5.93%, N: 7.36%.
5d: IR (KBr, cm−1): 3270 (N H), 1609 (C C), 1251 (P O), 1020 (P O C). 1H
NMR (DMSO-d6, 400 MHz, δ ppm): 8.42 (s, 1H, Ar CH), 7.74 (d, 1H, J = 8 Hz, Ar CH),
7.58 (d, 1H, J = 7.2 Hz, Ar CH), 7.42 (t, 1H, J = 8.0, 7.2 Hz, Ar CH), 7.12 (d, 1H,
J = 8.4 Hz, Ar CH), 6.85 (m, 2H, Ar CH), 6.66 (m, 2H, Ar CH), 5.0 (dd, 1H, J = 13.6,
6.4 Hz, P CH), 3.90 (m, 3H, O CH2), 3.80 (m, 1H, O CH), 2.62 (s, 3H, Ar CH3), 1.07
(t, 6H, J = 7.2 Hz, CH3). ES-MS: m/z 399. Elemental analysis: C21H23N2O4P Calc.: C:
63.31%, H: 5.82%, N: 7.03%; Found: C: 63.77%, H: 5.89%, N: 7.06%.
5e: IR (KBr, cm−1): 3273 (N H), 1610 (C C), 1249 (P O), 1020 (P O C). 1H
NMR (DMSO-d6, 400 MHz, δ ppm): 8.33 (s, 1H, Ar CH), 7.76 (d, 1H, J = 8.8 Hz,
Ar CH), 7.38 (d, 1H, J = 8.4 Hz, Ar CH), 7.30 (s, 1H, Ar CH), 7.07 (d, 1H, J = 6.4
Hz, Ar CH), 6.80 (m, 2H, Ar CH), 6.63 (m, 2H, Ar CH), 4.9 (dd, 1H, J = 12.4, 5.2
Hz, P CH), 3.94 (m, 3H, O CH2), 3.90 (m, 1H, O CH), 3.80 (s, 3H, Ar OCH3), 1.10
(t, 6H, J = 7.2 Hz, CH3). ES-MS: m/z 415. Elemental analysis: C21H23N2O5P Calc.: C:
60.87%, H: 5.59%, N: 6.76%; Found: C: 60.95%, H: 5.64%, N: 6.81%.
(5g) IR (KBr, cm−1): 3275 (N H), 1606 (C C), 1273 (P O), 1041 (P O C).
1H NMR (DMSO-d6, 400 MHz, δ ppm): 8.31 (d, 1H, J = 1.2 Hz, Ar CH), 7.75 (d, 1H,
J = 9.2 Hz, Ar CH), 7.35 (dd, 1H, J = 6.8, 2.4 Hz, Ar CH), 7.29 (d, 1H, J = 2.4 Hz,
Ar CH), 7.07 (d, 1H, J = 8.0 Hz, Ar CH), 6.86 (t, 1H, J = 8.0, 7.2 Hz, Ar CH), 6.79 (d,
1H, J = 6.8 Hz, Ar CH), 6.62 (m, 2H, Ar CH), 4.94 (dd, 1H, J = 12.4, 6.4 Hz, P CH),
4.13 (qua, 2H, J = 6.8 Hz, O CH2), 3.94 (m, 3H, O CH2), 3.84 (m, 1H, O CH), 1.37 (t,
3H, J = 6.8 Hz, CH3), 1.09 (t, 6H, J = 7.2 Hz, CH3). ES-MS: m/z 429. Elemental analysis:
C22H25N2O5P Calc.: C: 61.68%, H: 5.88%, N: 6.54%; Found: C: 61.72%, H: 5.94%, N:
6.60%.
1
5j: IR (KBr, cm−1): 3278 (N H), 1607 (C C), 1273 (P O), 1045 (P O C). H
NMR (DMSO-d6, 400 MHz, δ ppm): 8.43 (s, 1H, Ar CH), 8.06 (d, 1H, J = 1.2 Hz,
Ar CH), 7.87 (d, 1H, J = 8.8 Hz, Ar CH), 7.73 (dd, 1H, J = 7.2, 1.6 Hz, Ar CH), 7.09
(d, 1H, J = 8.0 Hz, Ar CH), 6.86 (m, 2H, Ar CH), 6.66 (m, 2H, Ar CH), 5.0 (dd, 1H,
J = 13.6, 6.4 Hz, 5P CH), 3.94 (m, 3H, O CH2), 3.82 (m, 1H, O CH), 1.10 (t, 6H, J =
7.2 Hz, CH3). ES-MS: m/z 419. Elemental analysis: C20H20N2O4ClP Calc.: C: 57.36%, H:
4.81%, N: 6.69%; Found: C: 57.39%, H: 4.87%, N: 6.74%.
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