Efficient synthesis routes for various phthalimido phosphor esters as antimicrobial agents in terms of structure-activity relationship

Article abstract of DOI:10.1007/s00706-009-0244-1

A series of phthalimido phosphor derivatives α-amino-phosphonates, amidophosphonates, phosphonic acid diamides, and oxadiazaphospholes-were prepared by applying different types of phosphorus(III) reagents to 2-methoxy-1H-isoindole-1,3(2H)-dione and 2-anilino-1H-isoindole-1,3(2H)-dione. On the basis of bioassay results, some of the new phosphoryl imides could be considered as lead molecules to be modified in order to improve their antibiotic activity. Springer-Verlag 2010.

Full text of DOI:10.1007/s00706-009-0244-1

Monatsh Chem (2010) 141:219–228
DOI 10.1007/s00706-009-0244-1
ORIGINAL PAPER
Efficient synthesis routes for various phthalimido phosphor esters
as antimicrobial agents in terms of structure–activity relationship
•
Wafaa Mahmoud Abdou Rizk E. Khidre
Received: 21 October 2009 / Accepted: 23 December 2009 / Published online: 13 February 2010
Ó Springer-Verlag 2010
Abstract A series of phthalimido phosphor derivatives—
a-amino-phosphonates, amidophosphonates, phosphonic
acid diamides, and oxadiazaphospholes—were prepared by
applying different types of phosphorus(III) reagents to
2-methoxy-1H-isoindole-1,3(2H)-dione and 2-anilino-1H-
isoindole-1,3(2H)-dione. On the basis of bioassay results,
some of the new phosphoryl imides could be considered as
lead molecules to be modified in order to improve their
antibiotic activity.
2a–2c, dialkyl hydrogenphosphonates 11a–11c, and tris-
(dialkylamino)phosphines 9a and 9b to 2-methoxy-1H-
isoindole-1,3(2H)-dione (1, N-methoxyphthalimide) and
2-anilino-1H-isoindole-1,3(2H)-dione (15).
Consecutively, a series of phosphorylated isoindole
derivatives were synthesized and screened for their phar-
macological activities. Even though many phosphorylated
phthalimides are well known as pesticides [2], several
derivatives have recently been reported to exhibit anes-
thetic activity superior to that of procaine [10, 11], and in
addition they represent the core unit found in a number of
alkaloid families [12, 13].
Keywords Phosphorylation ꢀ 1H-Isoindole-1,3(2H)-
dione-2-derivatives ꢀ Structure–activity relationship ꢀ
Amidophosphates ꢀ Antibiotics
Results and discussion
Introduction
In the presence of excess trialkyl phosphites 2a–2c, the
reaction with N-methoxyphthalimide (1) led to the forma-
tion of the corresponding a-aminophosphonates 6a–6c in
*77% yield (Scheme 1). The identities of 6a and 6b were
established by comparing their melting points and infrared
(IR) spectra with the appropriate authentic samples [14–
18]. Diisopropyl [(1,3-dihydro-1,3-dioxo-2H-isoindol-2-
yl)methyl]phosphonate (6c), prepared in this work for the
first time, gave comparable analytical and spectroscopic
data.
Trivalent phosphorous acid derivatives are mainly used for
preparation of organophosphorus compounds suitable as
flame retardants, corrosion inhibitors, detergents, and
lubricants [1], and additives to these, as well as agricultural
chemicals and pharmaceuticals [2]. Some work has been
done on the reactions of tri- and pentavalent phosphorus
reagents with N-phthalimides in order to synthesize the
relevant phosphorylated derivatives for applications [3–9].
On the whole, the reactions followed the predicted routes,
although surprising outcomes were observed in a few cases
[9]. In our present work, a new and efficient procedure for
phosphorylating two phthalimide derivatives is described.
The strategy depends on applying trialkyl phosphites
Remarkably, the mass spectra of a-aminophosphonates
6 did not display the corresponding ion peak; nevertheless,
they showed a base ion peak at m/z = 160 that was
assigned to the N-methylphthalimide ion, and another
prominent peak for the corresponding phosphonic acid
anion ½ðROÞ2POꢁꢂ. The major pathways of the fragmen-
tation of 6 (e.g., 6c) to positive ions are outlined in
Scheme 2. In favor of this result, upon heating 6c as a
representable example above its melting point (120 °C)
W. M. Abdou (&) ꢀ R. E. Khidre
Chemical Industries Division, National Research Centre,
Dokki, 12622 Giza, Egypt
e-mail: wabdou@link.net; wabdou@intouch.com
123

220
W. M. Abdou, R. E. Khidre
Scheme 1
O
N
O
O
OMe
/ 100 oC
neat
:P(OR)3
(excess)
OMe
N:
P
R
+
R
R
O
2a-2c
3
1
O
N
O
N
O
N
O
P
OH
P
- ROH
OR
OR
P(OMe)(OR)3
R
R
R
O
6a-6c
O
O
5
4
O
/ 150 oC
OR
HOP
NMe
+
6c
OR
O
7
2a-6a, R = OMe
2b-6b, R = OEt
2c-6c, R = OPr-i
AcOH
1
+
2c
7
Scheme 2
.
O
O
O
.
+ H
N
CH3
P
OR
OR
N
- P(O)(OR)2
O
O
+
A
)
6c
(m/z = 160, 100%
(M not observed)
.
+ H
- C9H7NO2
- CH3
.
O
O
N
O
H
P
OR
OR
H
B (m/z = 145, 33%)
R = i-C3H7, (m/z = 166, 58%)
- CONH
.
.
- CO
O
C6H5
D (m/z = 77, 58%)
C (m/z = 104, 72%)
123

Efficient synthesis routes for various phthalimido phosphor esters
221
O
O
N
SR1
P
O
O
P
RO
RO
(RO)2POH
H
SR1
N
OCH3
+
+
(R22N)3P
N:
(R22N)3
O
11a-c; a, R = Me; b, R = Et; c, R = Pri
1
O
O
9a, R2 = Me
8, R1 = Me
3A
O
O
O
P
[PhCO]2O2
- CH3OH
OR
OR
O
N
O
O
P(OR)2
N
(R22N)3P=S
10
N
O
R1
+
O
12
13a-c; R as in 11
7, R1 = Me
Scheme 4
Scheme 3
amidophosphonates 13a–13c as the sole reaction products
in *66% yield. This has been rationalized as proceeding
via rearrangement of the intermediate 12, which in turn
can be envisaged as arising by the condensation of 1 and
11 accompanied with elimination of a methanol molecule
(Scheme 4).
under reduced pressure, N-methylphthalimide (7) was iso-
lated (Scheme 1). Furthermore, when the same reaction
(1 ? 2c) was carried out in the presence of a protonating
agent (AcOH), compound
(Scheme 1).
7
was again obtained
A possible mechanism of this reaction involves the
initial formation of the phosphonium salt 3, which is
present in equilibrium with the salt 4, leading to the
intermediate 5. Further extrusion of an alcohol molecule
from 5 generates a-aminophosphonates 6. The latter step is
thought to involve a deoxygenation process, as the meth-
oxyl species serves as a source of oxygen necessary for the
formation of the phosphorus–oxygen bond in 6.
The recorded infrared and mass spectra and the analyt-
ical data of the products 13a and 13b are consistent with
their assignments [20]. Diisopropyl (1,3-dihydro-1,3-
dioxo-2H-isoindol-2-yl)phosphonate (13c) displayed a 31P
nuclear magnetic resonance (NMR) chemical shift of
14.6 ppm, which is in agreement with the presence of a
P–N linkage in the molecule [21]. Its IR spectrum showed
absorption bands at 1,780 and 1,722 cm-1, assigned to the
coupled C=O vibration of cyclic imides. The phosphonate
moiety of 13c in the 1H NMR spectrum appeared at
dH = 1.12, 1.13 (2dd, JH–H = 6.6, JP–H = 5.7 Hz, 12H,
(Me)2COP), 3.94 (sept, JP–H = 12.3 Hz, 2H, HCOP) ppm
and at dC = 15.9 (d, JP–C = 8.4 Hz, CH3COP) and 71.4 (d,
JP–C = 17 Hz, CHOP) ppm in its 13C NMR spectrum.
Furthermore, we have established that tris(dialkyla-
mino)phosphines 9a and 9b react with 1 by a pathway
analogous to that previously discussed for trialkyl phos-
phites in Scheme 1. However, the phosphines 9a and 9b
were found to be more reactive towards the imide
derivative 1, leading to P-[(1,3-dihydro-1,3-dioxo-2H-
isoindol-2-yl)methyl]-N,N,N0,N0-tetramethylphosphonic dia-
mide (14a) or the known tetraethyl derivative 14b [22]
in dramatically shorter time and higher yields, according to
the mechanism outlined in Scheme 5 [8, 9]. Thus, the
formation of the products 6 or 14 (Schemes 1 and 5)
was attributed to the efficiency of the phosphorus moi-
ety for the abstraction of a proton from the methyl group
in 1.
Similar formation of the salts 3 and 4 has been found
previously [8, 9] to proceed in reactions between sulfena-
mides 8 and tris(dimethylamino)phosphine (9a), whereby
N-alkylphthalimide 7 and tris(dimethylamino)thiophosphi-
nate (10) were the reaction products (Scheme 3).
It is worth mentioning here that the methods previously
described for the preparation of isoindolylmethyl phospho-
nates 6a and 6b are lengthy and indirect. For example,
compound 6b was synthesized in fair yield by treating
diethyl bromomethylphosphonate with N-(tert-butyldimeth-
ylsilyl)-phthalimide in the presence of tetrabutylammonium
fluoride [16], or by applying diethyl 1-hydroxyalkyl phos-
phonates to phthalimide in the presence of a complex formed
from diethyl diazenedicarboxylate and triphenylphosphine
[17]. Furthermore, the preparation of N-alkyl-phthalimide in
the present study provides an alternative to Gabriel synthesis
[19] from the halogen precursor for some branched alkyl-
amines such as isopropyl, for which a direct synthesis of
N-isopropylphthalimide was unsuccessful [9, 19].
The reaction of dialkyl hydrogenphosphonates 11a–11c
with N-methoxyphthalimide (1) was studied next.
However, the reaction between 1 and 11a–11c proceeded
only when a catalytic amount of triethylamine or ben-
zoylperoxide was present in the medium (best yield was
obtained with the peroxide), to yield the respective
Turning now to the scope of the above three reactions of
1 with phosphorus reagents 2, 9, and 11, the reactivity
observed in all these reagents seems to be attributed to the
formation of a P–O bond between the phosphorus reagent
and the methoxy oxygen of N-methoxyphthalimide.
123

222
W. M. Abdou, R. E. Khidre
O
O
OMe
+ 2a-c
P(NR1
)
2 3
N:
N:
PH2
(NR1
1
+
15
P(OR)3-H
+
N
)
2 3
Ph
9a, 9b
a, R1 = Me; b, R1 = Et
O
O
3B
19
O
O
O
O
R
O
P
OH
NR1
NR1
- NHR1
2
RO
P
H
N
O
N
+
2
N
N
O
P
(NR1
Ph
2
OR
)
2 3
O
14a, 14b
a, R1 = Me; b, R1 = Et
5B
18
Scheme 7
Scheme 5
Scheme 8. The parallel N-alkyl derivatives 18a (10%) or
18b (11%) were also formed in the reactions of 15 with
11a and 11b. N-alkylation of 15 by trialkyl phosphites
and dialkyl hydrogenphosphonates contributes, however,
to their potentialities as alkylating agents for acids, phe-
nols, thiols, and amino groups [25, 26]. Activity of the
phosphorus compounds as alkylating agents increases
in the order: (RO)2P(O)R \ (RO)2P(O)H \ (RO)3P(O);
(R=CH3) [27].
Next, since potential biological activities are recorded
for several substrates incorporating a N–P linkage, trialkyl
phosphites 2a–2c, dialkyl hydrogenphosphonates 11a–11c,
and tris(dialkylamino)phosphines 9a and 9b were applied
in a systematic study to 2-anilino-1H-isoindole-1,3(2H)-
dione (15, 2-anilinophthalimide). On heating 15 at 100 °C
with 2a–2c for *20 h, dialkyl (3-alkoxy-1-hydroxy-2H-
isoindol-2-yl)phenylphosphoramidoates 17a–17c were
obtained in *74% yield. Furthermore, N-alkylated
hydrazines 18a [23] and 18b [24] were isolated in *13%
yield in the case of the reactions with 2a and 2b
(Scheme 6). Conceivably, the nucleophilic addition of the
phosphite phosphorus to the terminal nitrogen of the aza-
group takes place to yield the dipolar species 16. The
intermediate 16 then undergoes intramolecular group
translocation to yield 17a and 17b.
Conversely, when tris(dialkylamino)phosphines 9a and
9b were applied to the hydrazine 15, oxadiazaphospholes
22a and 22b were isolated in *72% yield (Scheme 9).
The structure elucidation of 22 was based on elemental
analysis, molecular weight determination (MS), and spec-
troscopic data [27, 28]. The IR spectra of 22a and 22b
O
O
The mechanism for the N-alkylation process is depicted
in Scheme 7. This is based on direct attack by the anionic
center in 19 on the alkoxy-alkyl group of the reagent 2 to
give N-alkylated products 18a and 18b.
+ HOP(OR)2
OR
OR
P
11
+
17a, 17b
15
N
O
N
[PhCO]2O2
Ph
Similarly, when a mixture of the hydrazine 15, dialkyl
hydrogen-phosphonates 11a–11c, and benzoylperoxide
was heated at 100 °C, phosphoramidoates 20a–20c were
formed through the loss of a molecule of H2O according to
20a-20c
a, R = Me, b, R = Et, c, R = i-Pr
Scheme 8
O
+ P(NR1
9a, 9b
)
2 3
P(NR1
Ph
)
2 2
O
O
P(OR)3
Ph
H
N
N
15
N
N
N
N
P(OR)3
+
- HNR1
2
Ph
OH
O
O
16
21
2a 2c
-
15
OH
O
O
P
OR
+ HOH
- HNR1
2
OR
OR
Ph
Ph
O
R
N
N
+
N
N
N
N
P
Ph
O
O
NR1
OH
17a-17c
22a, 22b
a, R1 = Me, b, R1 = Et
2
18a 18b
,
a
b
c
, R = Me, , R = Et, , R = i-Pr
Scheme 6
Scheme 9
123

Efficient synthesis routes for various phthalimido phosphor esters
223
showed the presence of an intense band at 1,258 cm-1 for
free P=O absorption, two bands due to absorption of the
PNR1 moiety (1,320, 838 cm-1), and a broad band at
3,430 cm-1 assigned to the OH group. The 31P NMR
spectrum of 22a recorded a positive shift at dP =
14.4 ppm, which is within the range expected for the
Furthermore, the prepared compounds were tested for
their antifungal activity against Saccharomyces cerevisiae,
Candida albicans, and Aspergillus niger (recultured) by the
agar diffusion method [33]. The data were compared with
fluconazole (F) as a standard drug. The diameter of the
zone of inhibition and minimum inhibitory concentration
values are given in Table 1.
1
assigned structure [29, 30]. H and 13C NMR spectra also
supported this conclusion. In the mass spectrum, a promi-
nent peak at m/z = 91 arises from OP ꢃNMe2, at 182 from
C6H5NPꢃ (O)NMe2, and the base peak m/z = 237 from
[Mꢃ–(O–PNMe2)]. Obviously, compounds 22 were formed
through an initial condensation of the aminophosphines 9–
15 to give the intermediate 21 accompanied by elimination
of a dialkyl amine molecule. Stabilization of 21 was
attained by reacting with fortuitous water leading to the
formation of oxadiazaphospholes 22a and 22b, accompa-
nied by extrusion of dialkyl amine.
Inspection of the data obtained in the antibacterial and
antifungal screening of different phosphorylated phthali-
mides revealed that all tested compounds have moderate to
good antimicrobial properties when compared with avail-
able drugs A and F. In general, these data indicate only
marginal differences in potency of the tested phosphorus
derivatives due to the phosphorus ester substituent, i.e., R
or R1 in phosphorus moiety P(O)(OR)2 or P(O)(NR21).
Nevertheless, it has been pointed out that an important role
could be played by the nature of the type of the phosphorus
moiety. Thus, according to our results, phosphoramidoates
14a, 14b, 20a–20c, 22a, and 22b, which include a P–N
bond, seem to be the most active antibiotic agents for both
tested bacteria and fungi strains. Finally, pharmacological
activity of different types of organophosphorus compounds
tested here increases in the order: N–P(O)(OR)2 \ CH2-
P(O)(NR12)2 \ N–P(O)(NR21)2.
Pharmacological evaluation
The prepared phthalimide derivatives bearing a phosphorus
moiety were screened for their antimicrobial activity
against Escherichia coli, Bacillus subtilis, and Klebsiella
pneumoniae (recultured) bacterial strains by the disc dif-
fusion method [31, 32]. The data were compared with
amoxicillin (A) as a standard drug. The diameter of the
zone of inhibition and minimum inhibitory concentration
values are given in Table 1.
These preliminary results lead us to conclude that this
type of compounds should be studied in detail for their
applications in diverse areas, although their toxicity should
also be tested. Further study is in progress.
Table 1 Antibiotic activity of
synthesized phthalimido
phosphor derivatives
Sample
Bacterial strains
Fungal strains
K. pneumoniae
E. coli
B. subtilis
S. cerevisiae
C. albicans
A. niger
6a
11a (8.32)b
13 (8.32)
18 (8.32)
20 (8.32)
28 (8.32)
25 (8.32)
18 (8.32)
18 (8.32)
15 (30.6)
11 (30.6)
9 (14.5)
19 (8.32)
20 (8.32)
28 (8.32)
27 (8.32)
25 (8.32)
28 (8.32)
27 (8.32)
25 (8.32)
12 (30.6)
13 (30.6)
16 (30.6)
21 (8.32)
22 (8.32)
28 (14.52)
19 (8.23)
20 (8.23)
25 (8.23)
–
14 (30.6)
12 (30.6)
15 (30.6)
20 (8.32)
22 (8.32)
24 (8.32)
20 (8.32)
28 (8.32)
10 (30.6)
14 (30.6)
11 (30.6)
23 (8.32)
14.6 (14.5)
55 (2.2)
15 (30.6)
13 (30.6)
10 (30.6)
23 (8.32)
18 (8.32)
25 (8.23)
23 (8.23)
26 (8.32)
22 (8.32)
21 (8.32)
25 (8.32)
28 (8.32)
30 (8.32)
27 (8.32)
18 (14.5)
25 (14.5)
–
9 (30.6)
11 (30.6)
30 (8.32)
32 (8.32)
34 (8.32)
25 (14.5)
21 (8.32)
24 (8.32)
17 (14.5)
18 (14.5)
29 (8.23)
18 (8.23)
25 (8.23)
32 (8.23)
19 (14.5)
18 (14.5)
–
25 (8.32)
22 (8.32)
21 (8.32)
23 (8.32)
24 (8.32)
16 (14.5)
22 (8.32)
20 (8.32)
25 (8.32)
22 (8.32)
20 (8.32)
27 (8.32
21 (8.32)
32 (8.32)
25 (14.5)
26 (8.32)
–
6b
6c
13a
13b
13c
14a
14b
17a
17b
17c
20a
20b
20c
22a
22b
A
a
Diameter (mm) of zone of
inhibition
16 (14.5)
22 (8.32)
28 (14.52)
21 (8.23)
28 (8.23)
24 (8.23)
–
b
Minimum inhibitory
concentration values (MIC/
lg cm-3
)
20 (8.32)
20 (8.32)
21 (8.23)
–
A: Amoxicillin is used as an
antibacterial standard
F: Fluconazole is used as an
antifungal standard
F
28 (8.23)
30 (8.23)
25 (8.23)
123

224
W. M. Abdou, R. E. Khidre
Diisopropyl [(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)
methyl]phosphonate (6c, C15H20NO5P)
Conclusion
Yield 77%; m.p.: 58–60 °C (pentane); IR (KBr):
v = 1,781, 1,724 (C(1,3)=O), 1268 (P=O), 1,048 (P–O–C)
We have been successful in utilizing 2-methoxy- and
2-anilinophthalimide for one-pot synthesis of novel and rather
inaccessible phosphonates and amidoates with potential
biological activity. Compounds 6c, 13c, 14a, 17a–17c,
20a–20c, 22a, and 22b are new phthalimido-phosphory-
lated derivatives and have been characterized by spectral
and analytical data. Finally, on the basis of bioassay results,
products 20a–20c could be considered as lead molecules to
be modified in order to improve their antibiotic activity.
1
cm-1; H NMR (500 MHz, CDCl3): d = 1.13, 1.24 (2dd,
JH–H = 6.6, JP–H = 5.7 Hz, 12H, iso-Me2COP), 3.28,
4
2
3.42 (2d, JP–H = 22.5 Hz, 2H, H2C), 4.31 (septet,
3JP–H = 13.2 Hz, 2H, HCOP), 7.76, 7.88 (2d,
JH–H = 4.4 Hz, 4H, H–Ar) ppm; 13C NMR (125 MHz,
3
CDCl3): d = 23.19 (d, JP–C = 7.6 Hz, Me2COP), 34.76
1
2
(d, JP–C = 136.4 Hz, N–C–P), 71.2 (d, JP–C = 17.4 Hz,
CHOP), 127.8, 132.5, 133.6 (C–Ar), 170.4, 170.6
(C(1,3)=O) ppm; 31P NMR (202 MHz, CDCl3):
d = 27.8 ppm; MS (EI, 70 eV): m/z (%) = 160 (100)
[M?–OP(OC3H7)2], 166 (58) [OP(OC3H7)2], 145 (33), 104
(72), 77 (8).
Experimental
Melting points were measured on an Electrothermal melt-
ing point apparatus. IR spectra were recorded on a Perkin
Elmer 317 grating IR spectrophotometer using KBr pellets.
1H and 13C NMR spectra were measured on a Jeol ECA
500 MHz instrument using SiMe4 as an internal reference.
31P NMR spectra were recorded by using the same
instrument, relative to external H3PO4 (85%). Mass spectra
were recorded on a Jeol JMS-A X 500 spectrometer. Ele-
mental analyses were carried out at the Microanalysis
Laboratory, Cairo University, Cairo, Egypt. The appropri-
ate precautions in handling moisture-sensitive compounds
were considered. Solvents were dried by standard tech-
niques. TLC: Merck 0.2 mm silica gel 60 F154 aluminum
plates. Column chromatography (CC): silica gel (Kieselgel
60 mesh, particle size 0.2–0.5 mm; E. Merck, Darmstadt).
All yields are based on the starting substrate 1 or 15.
(B) Reaction of 1 with 2c in the presence of glacial acetic
acid. Synthesis of compound 7
A mixture of 0.8 g 1 (0.5 mmol) and 4 cm3 triisopropyl
phosphite (2c, as a representative example) was heated at
100 °C in the presence of 0.5 cm3 AcOH for *15 h
(TLC). After evaporation of the volatile materials in vacuo,
the residue was triturated with 5 cm3 hexane to give
N-phenylphthalimide (7). Yield 90%; m.p.: 133–135 °C
(cyclohexane; Ref. [19] m.p.: 133–135 °C).
(C) Pyrolysis of 6c
In a cold finger sublimator 0.3 g 6c was heated at 120 °C
(bath temperature) under reduced pressure (5 torr) for
30 min. The material that sublimed was collected,
recrystallized from cyclohexane, and proved to be
N-methylphthalimide (7) by mixed melting points
(100 mg, 63%). Diethyl hydrogenphosphonate was also
detected in the receiver by the development of violet
color on addition of 3,5-dinitrobenzoic acid in the pres-
ence of alkali [32].
Reaction of N-methoxyphthalimide (1) with trialkyl
phosphites 2a–2c
(A) In absence of solvent. Synthesis of compounds 6a–6c
A mixture of 0.8 g 1 (0.5 mmol) and 4 cm3 trialkyl phos-
phite (trimethyl 2a, triethyl 2b, or triisopropyl phosphite
2c) was heated at 100 °C in absence of solvent for *20 h
(TLC). Excess of the phosphite was removed under vac-
uum. The residue was washed several times with light
petroleum and crystallized from the appropriate solvent to
give the corresponding phosphonate 6a–6c.
Reaction of 1 with dialkyl hydrogenphosphonates
11a–11c. Synthesis of compounds 13a–13c
A mixture of 0.8 g N-methoxyphthalimide (1, 0.5 mmol)
and 4 cm3 dialkyl hydrogenphosphonate (dimethyl 11a,
diethyl 11b, or diisopropyl phosphonate 11c) was heated at
100 °C in the presence of a catalytic amount of benzoyl-
peroxide for *15 h (TLC). Excess of the volatile materials
was removed under vacuum, and the residue was washed
several times with light petroleum and crystallized from the
appropriate solvent to give the corresponding phosphonate
13a–13c.
Dimethyl [(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)
methyl]phosphonate (6a)
Yield 77%; m.p.: 115–117 °C (pentane; Refs. [13, 15]
m.p.: 113–117 °C).
Diethyl [(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl]
phosphonate (6b)
Yield 78%; m.p.: 66–68 °C (pentane; Ref. [16–18] m.p.:
67 °C).
123

Efficient synthesis routes for various phthalimido phosphor esters
225
Dimethyl (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)
phosphonate (13a)
Reaction of 2-anilino-1H-isoindole-1,3(2H)-dione (15)
with 2a–2c. Synthesis of compounds 17a–17c
Yield 77%; m.p.: 112–113 °C (pentane; Ref. [20] m.p.:
112 °C).
A mixture of 0.5 g 15 (2.1 mmol) and 4 cm3 2a–2c was
heated at 100 °C in absence of solvent for *20 h (TLC).
Working up the product mixture in the usual manner
afforded 17a–17c. N-alkylated hydrazines 18a and 18b
were also isolated from the reactions of 2a and 2b by
fractional crystallization.
Diethyl (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)phospho-
nate (13b)
Yield 68%; m.p.: 74–76 °C (cyclohexane; Ref. [20] m.p.:
73 °C).
Diisopropyl (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)phos-
phonate (13c, C14H18NO5P)
Dimethyl N-(1-hydroxy-3-methoxy-2H-isoindol-2-yl)-
N-phenylphosphoramidoate (17a, C17H19N2O5P)
Yield 66%; m.p.: 132–134 °C (CH2Cl2); IR (KBr):
v = 1,780, 1,722 (C(1,3)=O), 1262 (P=O), 1080 (P–O–C)
Yield 72%; m.p.: 126–128 °C (benzene); IR (KBr):
v = 3,340 (OH), 1,778, 1,726 (C(1,3)=O), 1,256 (P=O),
1
cm-1; H NMR (500 MHz, CDCl3): d = 1.12, 1.13 (2dd,
JH–H = 6.6, JP–H = 5.7 Hz, 12H, Me2COP), 3.94 (sept,
1,050 (P–O–C) cm-1
;
1H NMR (500 MHz, CDCl3):
4
3
d = 3.31 (s, 3H, MeO), 3.55 (d, JP–H = 11.8 Hz, 6H,
MeOP), 5.85 (br, 1H, HO, exchanges with D2O), 7.25–8.02
(m, 9H, H–Ar, H–Ph) ppm; 13C NMR (125 MHz, CDCl3):
3JP–H = 12.3 Hz, 2H, HCOP), 7.78, 7.88 (2d,
JH–H = 5.8 Hz, 4H, H–Ar) ppm; 13C NMR (125 MHz,
3
CDCl3): d = 15.9 (d, JP–C = 8.4 Hz, CH3COP), 71.4 (d,
3
d = 53.6 (d, JP–C = 7.7 Hz, MeOP), 58.3 (COMe), 98.3,
103.4, 103.5, 103.8, 119.7, 120.6, 121.3, 125.6, 133.2,
2JP–C = 17 Hz, CHOP), 126.7, 135.2, 133.8, 135.8 (C–Ar),
175.7, 169.4 (C(1,3)=O) ppm; 31P NMR (202 MHz,
CDCl3): d = 8.6 ppm; MS (EI, 70 eV): m/z (%) = 145
(100) [M?–OP(OC3H7)2], 166 (68) [OP(OC3H7)2], 104
(72).
3
138.7 (C–Ar, C–Ph), 140.7 (d, JP–C = 6.4 Hz, COMe),
3
152.6 (d, JP–C = 8.4 Hz, COH) ppm; 31P NMR
(202 MHz, CDCl3): d = 14.2 ppm; MS (EI, 70 eV): m/z
(%) = 361 (\5) [M?-1], 346 (9), 236 (100), 221 (52), 144
(62), 110 (52), 104 (28), 77 (54).
Reaction of 1 with tris(dialkylamino)phosphines 9a
and 9b. Synthesis of compounds 14a and 14b
Diethyl N-(3-ethoxy-1-hydroxy-2H-isoindol-2-yl)-
N-phenylphosphoramidoate (17b, C20H25N2O5P)
Yield 76%; m.p.: 116–118 °C (CH2Cl2); IR (KBr):
v = 3,345 (OH), 1,782, 1720 (C(1,3)=O), 1264 (P=O),
Phosphine 9a (R1 = Me) or 9b (R1 = Et) in 4 cm3 dry
THF was added dropwise to 0.8 g 1 (0.5 mmol) in 15 cm3
of the same solvent, and the reaction mixture was stirred at
room temperature for *10 h (TLC). Working up the
product mixture in the usual manner afforded 14a or 14b.
1082 (P–O–C) cm-1
;
1H NMR (500 MHz, CDCl3):
d = 1.21 (t, JH–H = 6.8 Hz, 3H, MeCO), 1.36 (dt,
JH–H = 6.4, JP–H = 4.8 Hz, 6H, MeCOP), 3.45 (q,
4
3
JH–H = 6.8 Hz, 2H, H2CO), 3.82 (dq, JP–H = 12.5 Hz,
P-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl]-
N,N,N0,N0-tetramethylphosphonic diamide
(14a, C13H18N3O3P)
4H, H2COP), 6.35 (s, 1H, OH, exchanges with D2O), 7.25–
8.02 (m, 9H, H–Ph, H–Ar) ppm; 13C NMR (125 MHz,
CDCl3): d = 14.3 (MeCO), 16.5 (MeCOP), 62.7 (d,
3JP–C = 6 Hz, CH2OP), 64.2 (CH2OC), 97.8, 102.3,
103.5, 103.8, 114.9, 120.6, 123.1, 125.4, 133.2, 140.3
Yield 80%; m.p.: 82–84 °C (pentane); IR (KBr):
v = 1,772, 1,720 (C(1,3)=O), 1256 (P=O), 860 [(N(Me2)]
1
3
cm-1; H NMR (500 MHz, CDCl3): d = 2.77, 2.84 (2d,
(C–Ar, C–Ph), 141.7 (d, JP–C = 6 Hz, COCH2), 140.8 (d,
3
3JP–H = 10.8 Hz, 12H, (Me2N–P), 3.28, 3.42 (2d,
2JP–H = 22.5 Hz, 2H, H2C), 7.77, 7.92 (2d, JHH = 5.8 Hz,
4H, H–Ar) ppm; 13C NMR (125 MHz, CDCl3): d = 35.5,
35.9 (2d, 2JP–C = 14.2 Hz, Me2N–P), 36.76 (d,
1JP–C = 141.2 Hz, N–C–P), 126.6, 132.5 (C- Ar), 175.8
(C(1,3)=O) ppm; 31P NMR (202 MHz, CDCl3):
d = 26.4 ppm; MS (EI, 70 eV): m/z (%) = 160 (100)
[M?–OP(NMe2)2], 135 (48) [OP(NMe2)2], 145 (38), 104
(66).
2JP–C = 8 Hz, C–N), 152.6 (d, JP–C = 5.5.4 Hz, COH)
ppm; 31P NMR (202 MHz, CDCl3): d = 14.8 ppm; MS
(EI, 70 eV): m/z (%) = 403 (11) [M?-1], 374 (17), 358
(28), 236 (100), 221 (35), 144 (62), 110 (52), 104 (28), 77
(54).
Diisopropyl N-(1-hydroxy-3-isopropoxy-2H-isoindol-2-yl)-
N-phenylphosphoramidoate (17c, C23H31N2O5P)
Yield 74%; m.p.: 121–122 °C (cyclohexane); IR (KBr):
v = 3,355 (OH), 1,774, 1,724 (C(1,3)=O), 1,262 (P=O),
;
1088 (P–O–C) cm-1 1H NMR (500 MHz, CDCl3):
P-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-
N,N,N0,N0-tetraethylphosphonic diamide (14b)
Yield 82%; m.p.: 102–104 °C (cyclohexane; Ref. [22]
m.p.: 101–102 °C).
d = 1.12–1.36 (m, 18H, iso-Me2CO), 3.41 (sept,
JH–H = 6.4 Hz, 1H, HCO), 3.82 (dsept, 2H, HCOP), 6.35
(br, 1H, OH, exchanges with D2O), 7.25–8.02 (m, 9H,
123

226
W. M. Abdou, R. E. Khidre
3
H–Ph, H–Ar) ppm; 13C NMR (125 MHz, CDCl3): d = 14.3
(MeCOP), 22.7 (MeCO), 72.7 (d, JP–C = 22.6 Hz,
CHOP), 74.2 (OCHC), 92.8, 97.5, 102.5, 103.5, 114.6,
169.2, 170.3 (2d, JP–C = 9.4 Hz, C=O) ppm; 31P NMR
(202 MHz, CDCl3): d = 10.4 ppm; MS (EI, 70 eV): m/z
(%) = 373 (9) [M?-1], 358 (28), 236 (100), 221 (13), 144
(52), 110 (44), 104 (18), 77 (54).
2
120.6, 121.3, 125.6, 133.2, 140.8 (C–Ar, C–Ph), 137.6 (d,
3
3JP–C = 8.6 Hz, COCH2), 152.4 (d, JP–C = 5.5.4 Hz,
Diisopropyl N-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-
N-phenylphosphoramidoate (20c, C20H23N2O5P)
COH) ppm; 31P NMR (202 MHz, CDCl3): d = 15.3 ppm;
MS (EI, 70 eV): m/z (%) = 445 (11) [M?-1], 402 (17),
386 (29), 237 (100), 221 (35), 144 (62), 110 (52), 104 (28),
77 (54).
Yield 74%; m.p.: 96–98 °C (pentane); IR (KBr):
v = 1,776, 1,726 (C(1,3)=O), 1,260 (P=O), 1,100 (P–O-
C) cm-1
;
1H NMR (500 MHz, CDCl3): d = 1.12, 1.36
4
2-(N-methyl-N-phenylamino)-1H-isoindole-1,3(2H)-dione
(18a)
(2dd, JH–H = 6.6, JP–H = 4.7 Hz, 12H, Me2COP), 3.72–
3.82 (sept, JP–H = 10.4 Hz, 2H, HCOP), 6.82–8.22 (m, 9H,
H–Ph, H–Ar) ppm; 13C NMR (125 MHz, CDCl3):
Yellow prisms; yield 14%; m.p.: 124–125 °C (hexane; Ref.
[23] m.p.: 124 °C).
2
d = 13.9 (Me2COP), 72.2 (d, JP–C = 6 Hz, CHOP),
119.2, 125.9, 126.3, 127.3, 127.6, 131.6, 132.1, 141.6
2-(N-ethyl-N-phenylamino)-1H-isoindole-1,3(2H)-dione
(18b)
3
(C–Ar, C–Ph), 167.8, 169.8 (2d, JP–C = 6.4 Hz, C=O)
ppm; 31P NMR (202 MHz, CDCl3): d = 10.8 ppm; MS
(EI, 70 eV): m/z (%) = 401 (12) [M?-1], 236 (100), 144
(72), 110 (60), 104 (28), 77 (58).
Yellow prisms; yield 16%; m.p.: 134–136 °C (hexane; Ref.
[24] m.p.: 134 °C).
Reaction of 14 with 11a–11c. Synthesis of compounds
20a–20c
Reaction of 15 with 9a and 9b. Synthesis of compounds
22a and 22b
A mixture of 0.5 g 15 (2.1 mmol) and 4 cm3 11a–11c was
heated at 100 °C in the presence of a catalytic amount
of benzoylperoxide for *20 h (TLC). Working up the
product mixture in the usual manner afforded the phos-
phoramidoates 20a–20c. N-alkylated hydrazides 18a (10%
yield) and 18b (11% yield) were also isolated from the
reactions of 11a and 11b by fractional crystallization.
Phosphine 9a (R1 = Me) or 9b (R1 = Et) in 4 cm3 dry
THF was added dropwise to 0.5 g 15 (2.1 mmol) in 15 cm3
of the same solvent, and the reaction mixture was stirred at
room temperature for *6 h (TLC). Working up the prod-
uct mixture in the usual manner afforded 22a and 22b.
2-(Dimethylamino)-2,3-dihydro-3-phenyl[1–4]oxadiaza-
phospholo[5,4-a]isoindol-5-ol 2-oxide
(22a, C16H16N3O3P)
Dimethyl N-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-
N-phenylphosphoramidoate (20a, C16H15N2O5P)
Yield 69%; m.p.: 102–104 °C (MeCN); IR (KBr):
Yield 68%; m.p.: 84–86 °C (pentane); IR (KBr):
v = 1,780, 1,723 (C(1,3)=O), 1,266 (P=O), 1,058 (P–O-
;
C) cm-1 1H NMR (500 MHz, CDCl3): d = 3.57 (d,
v = 3,425 (OH), 1,258 (P=O), 1,320, 838 (PNMe) cm-1
;
1H NMR (500 MHz, CDCl3): d = 2.47, 2.49 (2d,
3JP–H = 10.8 Hz, 6H, Me2N–P), 6.91–8.12 (m, 9H, H–
Ph, H–Ar), 9.49 (s, 1H, OH, exchanges with D2O) ppm;
13C NMR (125 MHz, CDCl3): d = 35.5 (d, 3JP–C = 6 Hz,
Me2NP), 96.7, 100.9, 103.9, 122.5, 123.4, 126.3, 131.6,
132.3, 133.6, 141.4 (C–Ar, C–Ph), 147.7 (d,
JP–H = 14.3 Hz, 6H, 2OMe), 7.19–7.98 (m, 9H, H–Ph, H–
Ar) ppm; 13C NMR (125 MHz, CDCl3): d = 53.8 (d,
2JP–C = 11.7 Hz, MeOP), 118.6, 126.2, 127.3, 127.6,
127.8, 131.2, 132.7, 140.5 (C–Ar, C–Ph), 167.8, 172.3
3
(2d, JP–C = 6.4 Hz, C=O) ppm; 31P NMR (202 MHz,
3
2JP–C = 21 Hz, CO–P), 150.7 (d, JP–C = 4.8 Hz, COH)
CDCl3): d = 11.3 ppm; MS (EI, 70 eV): m/z (%) = 345
(15) [M?-1], 236 (100), 144 (72), 110 (60), 104 (28), 77
(58).
ppm; 31P NMR (202 MHz, CDCl3): d = 14.6 ppm; MS
(EI, 70 eV): m/z (%) = 329 (14) [M?-1], 237 (100), 221
(71), 146 (53), 104 (29), 77 (11).
Diethyl N-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-
N-phenylphosphoramidoate (20b, C18H19N2O5P)
2-(Diethylamino)-2,3-dihydro-3-phenyl[1–4]oxadiaza-
phospholo[5,4-a]isoindol-5-ol 2-oxide
(22b, C18H20N3O3P)
Yield 70%; m.p.: 90–92 °C (pentane); IR (KBr):
v = 1,780, 1,724 (C(1,3)=O), 1,260 (P=O), 1,048 (P–O–
C) cm-1
;
1H NMR (500 MHz, CDCl3): d = 1.14, 1.25
Yield 75%; m.p.: 114–116 °C (MeCN); IR (KBr):
v = 3,430 (OH), 1,260 (P=O), 1,320, 838 (NMe2) cm-1
;
4
(2dt, JH–H = 6.6, JP–H = 4.8 Hz, 6H, Me2COP), 3.72–
3.82 (2dq, 4H, H2COP), 6.85–8.13 (m, 9H, H–Ph, H–Ar)
ppm; 13C NMR (125 MHz, CDCl3): d = 16.4 (MeCOP),
1H NMR (500 MHz, CDCl3): d = 2.77, 2.84 (2d,
3JP–H = 10.8 Hz, 12H, (H3C)2N–P), 3.28, 3.42 (2d,
2JP–H = 22.5 Hz, 2H, H2C), 7.77, 7.92 (2d, JH–H = 5.8 Hz,
4H, H–Ar) ppm; 13C NMR (125 MHz, CDCl3): d = 35.5,
2
62.7 (d, JP–C = 12.6 Hz, CH2OP), 119.3, 120.3, 126.8,
127.4, 127.6, 131.6, 132.5, 133.2, 138.9 (C–Ar, C–Ph),
123

Efficient synthesis routes for various phthalimido phosphor esters
227
2
35.9 (2d, JP–C = 14.2 Hz, CH3N–P), 36.76 (d, JP–C
1
control, were inoculated with approximately 1.6 9 104 to
6 9 104 c.f.u. cm3. The cultures were incubated for 48 h at
35 °C, and growth was monitored visually. The lowest
concentration (highest dilution) required to arrest the
growth of fungus was regarded as MIC. Fluconazole (F)
was used as a standard drug; all data are presented in
Table 1.
=
141.2 Hz, N–C–P), 126.6, 132.5 (C–Ar), 175.8 (C(1,3)=O)
ppm; 31P NMR (202 MHz, CDCl3): d = 13.6 ppm; MS (EI,
70 eV): m/z (%) = 356 (13) [M?-1], 237 (100), 221 (44), 146
(71), 104 (25), 77 (36).
Antibacterial assay
Acknowledgments We are grateful to the National Central Lab of
Toxicology, Cairo, Egypt.
The prepared compounds were screened for antibacterial
activity against three bacterial strains by the disc diffusion
method. A standard inoculum (1–2 9 107 c.f.u. cm3 0.5
McFarland standards) was introduced on to the surface of
sterile agar plates, and a sterile glass spreader was used for
even distribution of the inoculum. The discs measuring
8.32 cm in diameter were prepared from Whatman no. 1
filter paper and sterilized by dry heat at 140 °C for 1 h. The
sterile discs previously soaked in a known concentration of
the test compounds were placed in nutrient agar medium.
Solvent and growth controls were kept. The plates were
inverted and incubated for 24 h at 37 °C. The inhibition
zones were measured and compared with the controls.
Minimum inhibitory concentration (MIC) was determined
by broth dilution technique. The nutrient broth, which
contained logarithmic serially twofold-diluted amounts of
test compound and controls, were incubated with approx-
imately 5 9 105 c.f.u. cm3 of actively dividing bacteria
cells. The cultures were incubated for 24 h at 37 °C and
growth was monitored visually and spectrophotometrically.
The lowest concentration (highest dilution) required to
arrest the growth of bacteria was regarded as MIC.
Amoxicillin (A) was used as a standard drug; all data are
presented in Table 1.
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123