Chemistry of phosphorus ylides. Part 22 [1]. Effect of newly synthesized niclosamide Mannich bases, phosphopyranones, phosphoranylidenes, and oxaphosphinin on some metabolic aspects of Biomphalaria alexandrina

Article abstract of DOI:10.1007/s00706-004-0226-2

Niclosamide reacts with secondary amines and formaldehyde under the condition of Mannich reaction, to give new Mannich bases. The reaction of these niclosamide Mannich bases with active phosphacumulene ylides affords the corresponding phenyliminopyranone,

Full text of DOI:10.1007/s00706-004-0226-2

Monatshefte f€ur Chemie 136, 241–251 (2005)
DOI 10.1007/s00706-004-0226-2
Chemistry of Phosphorus Ylides.
Part 22 [1]. Effect of Newly Synthesized
Niclosamide Mannich Bases,
Phosphopyranones, Phosphoranylidenes,
and Oxaphosphinin on Some Metabolic
ꢀ
Aspects of Biomphalaria Alexandrina
Fouad M. Solimany, Medhat M. Said, and Soher S. Maigali
Department of Pesticide Chemistry, National Research Centre, Dokki, Cairo, Egypt
Received November 20, 2003; accepted (revised) June 16, 2004
Published online January 24, 2005 # Springer-Verlag 2005
Summary. Niclosamide reacts with secondary amines and formaldehyde under the condition of
Mannich reaction, to give new Mannich bases. The reaction of these niclosamide Mannich bases with
active phosphacumulene ylides affords the corresponding phenyliminopyranone, pyranone, and py-
ranthione, respectively. When Wittig reaction was carried out on the pyranone, using p-nitrobenzalde-
hyde, a new arylidene and triphenylphosphine oxide were obtained. On the other hand, stabilized
phosphonium ylides affect the transylidation of niclosamide Mannich bases to the correspond-
ing phosphoranylidenes. When diphenylmethylenetriphenylphosphorane reacts with a niclosamide
Mannich base, an oxaphosphinin was obtained. The molluscicidal potency of the newly synthesized
derivatives against Biomphalaria alexandrina was studied, too.
Keywords. Niclosamide; Phosphonium ylides; Pyranone derivatives; Transylidation; Phosphorany-
lidenes; Oxaphosphinin; Molluscicidal potency.
Introduction
Niclosamide [5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide] (1) is the
active ingredient of bayluscide, which has been used as molluscicide of great
significance in the last decade [2]. It is widely used in control programmes, and
is still the molluscicide of choice [2], since it is effective against most aquatic
snails and its activity persists for several months [3]. Due to its high activity at
Dedicated to Professor Dr. Hans Jurgen Bestmann on the occasion of his 79th birthday
ꢀ
y
Corresponding author. E-mail: solimanfma@hotmail.com

242
F. M. Soliman et al.
all stages of the snail life cycle [4], it has proved to be effective as molluscicidal
[5], ovicidal [6], and anthelmintic agent [7]. Besides, niclosamide is introduced as
an official drug in many pharmacopoeas [8]. Although certain algae, aquatic plants,
are damaged, it does not adversely affect any economically important crop plants
and shows no cumulative toxicity on animals [9].
Therefore, the present investigation has been aimed to synthesize new niclos-
amide Mannich base derivatives 2a–2d and to react them with active nucleophilic
phosphacumulene reagents, namely (N-phenyliminovinylidene)- (3a), (2-oxovinyl-
idene)- (3b), and=or (2-thioxovinylidene)triphenylphosphorane (3c). These active
phosphacumulene ylides are some of the most important phosphorus reagents, used
for the synthesis of heterocyclic phosphorus compounds [10]. A comparative study
on the behavior of the Mannich bases 2a–2d towards the stabilized phosphonium
ylides 8a–8f or 12 and the iminophosphorane 14 has been performed, too.
Results and Discussion
The Mannich reaction was carried out in neutral media using the bifunctional
compound niclosamide (1) as substrate, formaldehyde and a base as the reagents.
The bases employed were dimethyl-, diethylamine, piperidine, and morpholine.
The Mannich bases produced 2a–2d were isolated as yellow crystalline solid free
bases. Only one product was isolated when either one or two mol-equivalents of
the reagents were employed, which proves the presence of only one reactive centre.
Absence of the OH absorption band in the IR of 5-chloro-N-(2-chloro-4-nitrophe-
nyl)-2-hydroxy-3-(dimethylaminomethyl)-benzamide (2a) is due to the presence of
the intramolecular hydrogen bonding of the hydroxyl hydrogen with the basic
nitrogen being a weak band which has been superimposed upon the NH absorption
band near ꢀꢀ¼ 3420 cmꢁ1. The IR also shows the carbonyl amide at 1671 cmꢁ1.
1
The H NMR spectrum of compound 2a shows bands at ꢁ ¼ 2.8 (2CH3, s), 4.2
(CH2, s), 4.5 (NH, s) ppm exchangeable with D2O. The aromatic protons appear at
ꢁ ¼ 8.2–8.9 (5H, aromatic, m) ppm. Moreover, the OH appears at ꢁ ¼ 15 ppm
Scheme 1

Chemistry of Phosphorus Ylides
243
(exchangeable with D2O). Presence of carbonyl amide group in 2a is also attested
by a signal at ꢁ ¼ 169.72 (C¼O, NH) in its 13C NMR spectrum, and in the mass
spectrum m=e is found at 384 (Mþ) (Scheme 1).
When the active phosphacumulene ylides, namely, (N-phenyliminovinylidene)-
(3a), (2-oxovinylidene)- (3b), and=or (2-thioxovinylidene)triphenylphosphorane
(3c), reacted with niclosamide Mannich bases 2a–2d in dry boiling toluene for
4 h, in case of 3a, 6 h with 3b, and for 8 h with 3c by addition with cyclization, the
corresponding phenyliminopyranone 6a, pyranone 6b, and thioxopyranone 6c were
formed. The structure of 6-chloro-N-(2-chloro-4-nitrophenyl)-3,4-dihydro-2-(phe-
nylimino)-3-(triphenylphosphoranylidene)-2H-1-benzopyran-8-carboxamide (6a)
1
was elucidated from elemental analysis and spectroscopic data. The H NMR
spectrum of 6a shows signals at ꢁ ¼ 3.3 (CH2, d, due to P atom), 4.2 (NH, s)
exchangeable with D2O and 7.3–8.3 (27H, aromatic, m) ppm. Its IR spectrum
shows no OH absorption band which is exhibited by the Mannich bases 2. Absorp-
tion bands are shown by compound 6a at ꢀꢀ¼ 3419 (NH), 1674 (C¼O, NH), 1610
(P¼C) [11], and 1436 (P-aryl) cmꢁ1 [12]. The 31P NMR of 6a recordes a signal at
ꢁ ¼ 16.82 ppm, which supports the phosphoranylidene structure [13]. In the MS of
6a the m=e ¼ 716 (Mþ) (Scheme 2).
Compounds 6a–6c are equally obtained, irrespective whether one or two mol-
equivalents of the phosphacumulenes 3a–3c are used.
Scheme 2

244
F. M. Soliman et al.
When the Wittig reaction was carried out on pyranone derivative 6b using
p-nitrobenzaldehyde in dry boiling toluene for 8 h, the new exocyclic olefin,
6-chloro-N-(2-chloro-4-nitrophenyl)-3,4-dihydro-3-[(nitrophenyl)methylene]-2-oxo-
2H-1-benzopyran-8-carboxamide (7), and triphenylphosphine oxide were obtained.
The IR of 7 shows strong absorption bands at ꢀꢀ¼ 3419 (NH), 1739 (C¼O, pyran),
1674 (C¼O, NH) cmꢁ1, and lacks the presence of a peak arround 1440 (P–C) cmꢁ1.
Its 1H NMR spectrum exhibits signals at ꢁ ¼ 4.2 (CH2, s), 4.6 (NH, s) exchangeable
with D2O. In the MS of 7 the m=e ¼ 514 (Mþ) (Scheme 2).
We have also found that the niclosamide Mannich bases 2a–2d reacted with the
stabilized methylenetriphenylphosphoranes, namely, acetyl- (8a), methoxycarbo-
nyl- (8b), ethoxycarbonyl- (8c), formyl- (8d), or benzoyl-methylenetriphenyl-
phosphorane (8e), in dry boiling toluene for 10 h to give yellow crystalline
phosphoranylidenes 11a–11e. Compounds 11a–11e are equally obtained whether
one or two mol-equivalents of the Wittig reagents 8 were used with respect to one
mol-equivalent of 2. On the other hand, compound 2 reacted with phenylmethylene-
triphenylphosphorane (8f) in boiling ethanol for 5 h to give the phosphorane 11f.
The IR spectrum of 5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxy-3-[3-oxo-2-
(triphenylphosphoranylidene)butyl]benzamide (11a) taken as an example reveals
the presence of absorption bands at ꢀꢀ¼ 3544 (OH), 3468 (NH), 1672 (C¼O,
OCH3), 1662 (C¼O, NH), and 1448 (P-aryl) cmꢁ1. Its 1H NMR spectrum showed
signals at ꢁ ¼ 2.03 (CH3, s), 3.3 (CH2, d), 5.08 (NH, s), and 12.3 (OH) ppm
exchangeable with D2O and the aromatic protons appeared at ꢁ ¼ 7.2–8.4 (20H,
aromatic, m) ppm. Furthermore signals at ꢁ ¼ 169.45 and 166.56 ppm were
observed in the 13C NMR spectrum which were attributed to the carbonyl group.
Moreover, a signal at ꢁ ¼ þ23.34 was found in the 31P NMR of 11a (Scheme 2).
In the same sense, diphenylmethylenetriphenylphosphorane (12) reacted with
niclosamide Mannich bases 2 in ethanol to give the oxaphosphinin 13. The ele-
mental analysis, IR, 1H, 13C and 31P NMR data agree with structure 13. A signal at
ꢁ ¼ þ21.66 was observed in the 31P NMR spectrum of compound 13, which is in
accordance with the oxaphosphinin structure [14] (Scheme 2).
The reactions of phosphinimines are often analogous to those of phosphonium
ylides. But in their activity iminophosphoranes are inferior to phosphin alkylenes
[15]. We have found that niclosamide Mannich bases 2a–2d are inactive against
ethoxycarbonyltriphenylphosphinimine (14), even if the reactants were boiled in
toluene for a long time, they were recovered practically unchanged.
Biological Evaluation of the Tested Compounds
Materials
Snails: Field collected B. alexandrina snails (6–8 mm in diameter) were used to
test the molluscicidal potency of the tested chemicals, new Mannich bases and
organophosphorus niclosamide derivatives 2a–2d, 6a–6c, 11a–11f, and 13. Snails
were obtained from Abu-Rawash, Giza, Egypt and were maintained in the labora-
tory in glass aerated aquaria, filled with dechlorinated water and kept at 25ꢂC, fed
fresh lettuce leaves adlib and left for 45 days to ensure that they were free from
infection.

Chemistry of Phosphorus Ylides
245
Chemicals: The tested molluscicides, namely, niclosamide Mannich bases and
niclosamide organophosphorus derivatives, were prepared as mentioned in the text.
It is well known that organophosphorus compounds are the most important
group of pesticides due to their rapid metabolism, absence of accumulation in
the organism of animals, decomposition in the soil, and low chronic toxicity [16].
The use of molluscicides has always been considered to be a major supportive pro-
cedure in integrated schistosomiasis control [2]. Among synthetic compounds,
niclosamide (the active ingredient of bayluscide) is still the molluscicide of choice,
being highly active at all stages of the snail life cycle, effective on the schistosome
larvae, and not toxic to humans, domestic animals, and crops [17].
Therefore, the molluscicidal potency of the newly synthesized Mannich bases
2a–2d and organophosphorus niclosamide derivatives 6a–6c, 11a–11f, and 13
against Biomphalaria alexandrina snails, which is the specific intermediate host
to Schistosoma mansoni, was studied and compared with bayluscide. The results
showed that all the newly synthesized niclosamide derivatives 2a–2d, 6a–6c, 11a–
11f, and 13 have molluscicidal potency against B. alexandrina snails but most of
them recorded higher LC50 values, except compound 11f which showed a lower
value (LC50 of 0.0004 g=dm3) compared to bayluscide (LC50 of 0.0005 g=dm3) [9].
The presence of an OH group in the ortho position of niclosamide (1) is
responsible for its toxicity against B. alexandrina snails [18], due to the formation
of an intramolecular hydrogen bond with the oxygen of the carbonyl group [18].
This hydrogen bond reduced the polarity of the carbonyl group by decreasing the
partial negative charge on the oxygen atom of this group. This in turn increases the
chance of bonding with aminoacids of snail proteins most of which are enzymes.
The variable reported molluscicidal activity of the tested newly synthesized
compounds could be explained on the basis that all of them still have the reactive
Table 1. Molluscicidal potency of the tested compounds against B. alexandrina snails
Cmp. no.
LC5
g=dm3
LC10
g=dm3
LC50
g=dm3
LC90
g=dm3
1
–
–
0.0005
0.0301
0.0409
0.019
–
2a
0.103
0.0106
0.0106
0.0108
0.0101
0.0021
0.0044
0.0012
0.0036
0.0202
0.0109
0.0021
0.00012
0.003
0.06
2b
0.0101
0.009
0.10
2c
0.0293
0.08
2d
6a
0.005
0.030
0.00098
0.0022
0.00097
0.002
0.009
0.0303
0.021
0.007
0.0076
0.05
6b
0.0077
0.0041
0.0052
0.030
6c
11a
11b
11c
11e
11f
11d
13
0.0104
0.006
0.0208
0.0034
0.0004
0.007
0.0404
0.0056
0.0006
0.0098
0.004
0.0018
0.0009
0.0024
0.0009
0.0009
0.0019
LCX: The concentration at which X% of the populations died

246
F. M. Soliman et al.
groups of the niclosamide nucleus with different chemically reactive phosphorus
moieties added, most of them are organophosphorus groups.
On the other hand, the biochemical investigation has been performed on snail
metabolism. The most potent organophosphorus molluscicides 11f, 11e, 13, and
6c, showing LC50 values between 0.0004–0.0041 g=dm3 were selected for this
study. We found that these four organophosphours niclosamide derivatives have
an inhibitory effect on the most important glycolytic enzymes in tissue homo-
genates of B. alexandrina snails, as hexokinase (HK), pyruvate kinase (PK), and
phosphoglucoisomerase (PGI). Although bayluscide showed a slightly higher inhib-
itory effect on hexokinase (HK) and glucose phosphate isomerase (PGI) compared
to the organophosphorus derivatives 11f and 13, the four niclosamide derivatives
6c, 11e, 11f, and 13 showed a remarkably higher inhibition rate of pyruvate kinase.
Pyruvate kinase is an enzyme of critical importance for schistosome parasites, as
homolactate fermenter within snail tissues [19].
Inhibition of hexokinase, pyruvate kinase, and glucose phosphate isomerase
with the four tested compounds 6c, 11e, 11f, and 13 and of hexokinase together
with glucose phosphate isomerase only with bayluscide could be effective in
decreasing the compatibility of B. alexandrina snails and hence S. mansoni
infection.
It was found that the sublethal and less pollutant concentrations, LC5 (1=10 of
LC50) were able to affect the compatibility of B. alexandrina to parasitic infection.
Table 2. Levels of hexokinase (HK), pyruvate kinase (PK), and glucose phosphate isomerase (PGI) in
field collected, control and molluscicide-treated snails
Snail group
Enzymes
HK
PK
PGI
Control
Mean ꢃ S.D.
Mean ꢃ S.D.
P<
9.8 ꢃ 2.7
3.9 ꢃ 0.58
0.01
1.8 ꢃ 0.62
1.51 ꢃ 0.52
n.s.
1.47 ꢃ 0.48
0.89 ꢃ 0.21
0.01
1-Bayluscide treated
% change
59.4
11.11
39.17
6c-Treated
11e-Treated
11f-Treated
13-Treated
Mean ꢃ S.D.
P<
% change
2.6 ꢃ 0.82
0.001
0.98 ꢃ 0.138
0.01
1.27 ꢃ 0.32
n.s.
72.9
44.4
13.6
Mean ꢃ S.D.
P<
% change
8.0 ꢃ 0.49
0.05
0.46 ꢃ 0.08
0.001
1.29 ꢃ 0.19
n.s.
16.6
72.2
12.24
Mean ꢃ S.D.
P<
% change
3.7 ꢃ 1.6
0.01
0.39 ꢃ 0.29
0.01
1.19 ꢃ 0.38
n.s.
61.4
77.8
19.0
Mean ꢃ S.D.
P<
% change
9.4 ꢃ 0.32
n.s.
0.304 ꢃ 0.1
0.001
1.17 ꢃ 0.42
n.s.
2.08
83.3
20.4
– Values are means ꢃ S.D. of four independent experiments
– P<0.05 ꢄ significant, P<0.01 ꢄ highly significant, n.s. ¼ no significance
– Enzymatic activities are expressed as mol=min=g tissue
– S.D. ¼ Standard deviation
– % change ¼ Percent change from control group

Chemistry of Phosphorus Ylides
247
Snails treated with LC5 of the four tested compounds 6c, 11e, 11f, and 13 were
metabolically disturbed and render less suitable for the development of the parasite
(S. mansoni larvae) within snails tissue compared to bayluscide (1). This inspires
more hope for their application in the intervention of schistosomiasis, especially,
when used at their sublethal concentrations (LC5).
Conclusion
The reaction of the bifunctional Mannich base derivatives 2a–2d with phospha-
cumulene ylides 3a–3c represents a new approach to the construction of new
heterocycles. These phosphonium ylides react only with the phenolic OH group
rather than the NH group of the Mannich bases 2a–2d, to give first the phos-
phonium ylides 4, which are transformed into 5 by nucleophilic substitution of
the dialkylamine anion. Elimination of the amine anion from 5 results in the
formation of phenylimino-, oxo-, and thioxophosphoranylidene benzopyran car-
boxamide derivatives 6a–6c. On the other hand, transylidation of niclosamide
Mannich base derivatives 2a–2d, using the stabilized methylenetriphenyl-
phosphoranes 8a–8f or 12, results in the expulsion of the amine, with the for-
mation of the unstable quinone-methylene 9. The latter reacts with the
phosphoranes 8 by nucleophilic addition to the methylene group giving the di-
polar adduct 10. The R moiety in 10, which is electron withdrawing in nature,
would stabilize formation of the new alkylated phosphoranylidene benzamide
derivatives 11 via migration of the ꢂ-proton to the electron rich centre of the
molecule. Moreover, the quinone-methylene 9 affords directly the oxaphosphinin
13, in case, when diphenylmethylenetriphenylphosphorane (12) reacts with
niclosamide Mannich bases 2. No reaction was observed when the imino-
phosphorane 14 was allowed to react with niclosamide Mannich bases 2 under
different reaction conditions.
Experimental
All melting points are uncorrected. The solvents were dried and distilled. Reactions were carried out
under nitrogen atmosphere. Elemental analyses were carried out at the ‘‘Microanalysis Department’’,
National Research Centre; their results were in agreement with the calculated values. The IR spectra
1
were measured in KBr on a Perkin-Elmer infracord Spectrometer Model 157 (Grating). The H and
13C NMR spectra were recorded on a Varian Spectrometer at 90 (22.5) MHz, using TMS as an internal
reference. 31P NMR spectra were run, relative to external H3PO4 (85%), with a Varian FT-80 Spectro-
meter at 36.5 MHz, mass Spectra were obtained on a Varian MATCH-4B instrument.
Mannich Reaction on Niclosamide (5-Chloro-N-(2-chloro-4-nitrophenyl)-2-
hydroxybenzamide; 1)
General Procedure: An aqueous solution of formaldehyde (40%, 0.01 mol) was added dropwise with
stirring to niclosamide (1) [20] and the amine (0.011mol) in about 40 cm3 of ethanol while maintaining
the temperature below 10ꢂC. The reaction mixture was then boiled under reflux for 2 h and left
overnight at room temperature. After removing the volatile materials under reduced pressure, the
product was isolated and recrystallized from ethanol. When the above described procedure was

248
F. M. Soliman et al.: Chemistry of Phosphorus Ylides
Table 3. Physical and analytical data for niclosamide Mannich bases 2a–2d, phenyliminopyranone 6a, pyranone
6b, thioxopyranone 6c, exocyclic olefin 7, phosphoranylidenes 11a–11f, and oxaphosphinin 13
Cpd. no.
Mol. Wt=g molꢁ1
Formula
Mp=ꢂC
Yield=%
Solvent for crystallization
2a
2b
384
412
424
426
716
641
657
514
657
673
657
643
719
703
780
C16H15N3O4Cl2
C18H19N3O4Cl2
C19H19N3O4Cl2
C18H17N3O5Cl2
C40H28N3O4PCl2
C34H23N2O5PCl2
C34H23N2O4SPCl2
C23H13N3O7Cl2
C35H27N2O5PCl2
C35H27N2O6PCl2
C36H29N2O6PCl2
C34H25N2O5PCl2
C40H29N2O5PCl2
C40H29N2O4PCl2
C46H34N2O4PCl2
228
340
232
300
244
264
252
214
220
228
188
245
186
215
205
92%
90%
87%
95%
87%
85%
83%
38%
79%
80%
79%
78%
82%
76%
74%
Ethanol
Ethanol
2c
Ethanol
2d
Ethanol
6a
Chloroform=Pet.ether
Ethyl acetate=Pet.ether
Chloroform=Pet.ether
Chloroform=Light pet.
Ethyl acetate=n-Hexane
Acetone=n-hexane
Benzene=Pet.ether
Methylene chloride=n-Hexane
Chloroform=n-Hexane
Ethyl acetate=n-Hexane
Methylene chloride=n-Hexane
6b
6c
7
11a
11b
11c
11d
11e
11f
13
performed using two mol-equivalents of both the base and aqueous formaldehyde no change in the
nature of the products was observed and the corresponding niclosamide Mannich bases 2a–2d were
obtained, respectively.
The Reaction of Niclosamide Mannich Base 2c with Phosphacumulenes 3a–3c
Preparation of Phenyliminopyranone 4a, Pyranone 4b, and Thioxopyranone 4c
General Procedure: To a solution of niclosamide Mannich base 2c (0.01 mol) in 20 cm3 of dry toluene,
was added a solution of (N-phenyliminovinylidene)- (3a) [21], (2-oxovinylidene)- (3b) [22], and (2-
thioxovinylidene)triphenylphosphorane (3c) [22] (0.011 mol) in 30 cm3 of dry toluene. The reaction
mixture was refluxed for 4 h when 3a was used, 6 h in case of 3b, and for 8 h with 3c. After the solvent
had been distilled off under reduced pressure, the residue was crystallized from the appropriate solvent.
Yields, analytical and spectroscopic data are presented in Tables 3 and 4.
When the reaction was performed using one mol-equivalent of niclosamide Mannich base deriva-
tive 2d and the phosphacumulenes 3a–3c, the same phenyliminopyranone 6a, pyranone 6b, and
thioxopyranone 6c were obtained irrespective of the amine used.
When the reaction was repeated using one mol-equivalent of niclosamide Mannich base 2c and two
mol-equivalents of the phosphacumulenes 3a–3c, the same products 6a–6c were isolated, too.
The Reaction of Pyranone 6b with p-Nitrobenzaldehyde
A mixture of the pyranone derivative 6b (0.64 g, 0.001 mol) and p-nitrobenzaldehyde (0.17 g,
0.0011 mol) in dry toluene (20 cm3) was refluxed for 8 h. Toluene was distilled off and the residue
was crystallized from benzene to give the exocyclic olefin 7, 6-chloro-N-(2-chloro-4-nitrophenyl)-
3,4-dihydro-3-[(nitrophenyl)methylene]-2-oxo-2H-1-benzopyran-8-carboxamide (7) as pale green-
ish crystals.
The benzene filtrate yielded upon concentration and addition of n-hexane colourless crystals of
triphenylphosphine oxide, mp and mixed mp 151ꢂC [23] (62%).

Table 4. Spectroscopic data (IR & NMR) for compounds 2b–2d, 6b–6c, 11b–11f, and 13
Cpd. no IR: ꢀꢀ=cmꢁ1
NMR: ꢁ=ppm
1H NMR
31P NMR 13C NMR
2b
3421 (NH), 1670
1.3 (t, 3H, CH2CH3)
3.1 (s, 2H, CH2)
–
168.54
(C¼O, amide)
(C¼O, amide)
4.3 (q, 2H, CH2CH3)
4.5 (s, 1H, NH)
7.5–8.3 (m, 5H, Ar)
15 (s, 1H, OH)
2c
3422 (NH), 1655
3.8 (s, 2H, CH2)
4.1 (s, 1H, NH)
–
–
–
–
(C¼O, amide)
7.1–8.7 (m, 15H, Ar)
8.3 (s, 1H, OH)
2d
3423 (NH), 1671
3.5 (s, 2H, CH2)
4.4 (s, 1H, NH)
(C¼O, amide)
7.2–8.2 (m, 13H, Ar)
8.6 (s, 1H, OH)
6b
6c
3429 (NH), 1731 (C¼O,
pyran), 1645 (C¼O,
amide), 1439 (P-aryl)
3.3 (d, 2H, CH2)
5.3 (s, 1H, NH)
21.26
25.82
21.55
165 (C¼O, amide)
185 (C¼O, pyran)
7.3–8.4 (m, 20H, Ar)
3427 (NH), 1635 (C¼O,
amide), 1439 (P-aryl),
1240 (C¼S)
3.21 (d, 2H, CH2)
3.9 (s, 1H, NH)
–
7.2–8.4 (m, 20H, Ar)
11b
3456 (OH), 3118 (NH),
1674 (C¼O, ester), 1662
(C¼O, amide),
2.7 (s, 3H, OCH3)
3.8 (d, 2H, CH2)
4.5 (s, 1H, NH)
165.72
163.52 (C¼O)
1447 (P-aryl)
7.0–8.4 (m, 20H, Ar)
12.1 (s, 1H, OH)
11c
3446 (OH), 2942 (NH),
1671 (C¼O, ester), 1663
(C¼O, amide), 1448
(P-aryl)
2.4 (d, 2H, CH2)
20.66
–
–
2.8 (t, 3H, CH2CH3)
3.82 (q, 2H, CH2CH3)
7.1–8.3 (m, 20H, Ar)
11.28 (s, 1H, OH)
11d
11e
11f
13
3484 (OH), 3120 (NH),
2.5 (d, 2H, CH2)
22.55
22.23
22.03
21.66
1733 (CHO), 1661 (C¼O, 4.3 (s, 1H, NH)
amide), 1447 (P-aryl)
7.3–8.4 (m, 20H, Ar)
12 (s, 1H, OH)
3566 (OH), 3488 (NH),
2.33 (s, 1H, NH)
3.81 (d, 2H, CH2)
183.25
1673 (C¼O, ester), 1660
168.62 (C¼O)
(C¼O, NH), 1434 (P-aryl) 7.3–8.2 (m, 25H, Ar)
11.9 (s, 1H, OH)
3421 (OH), 2364 (NH),
1664 (C¼O), 1436
(P-aryl)
2.8 (d, 2H, CH2)
4.7 (s, 1H, NH)
169.74 (C¼O)
169.73 (C¼O)
8.0 (s, 1H, OH)
7.2–8.1 (m, 25H, Ar)
3558 (NH), 1663 (C¼O),
2.4 (d, 2H, CH2)
4.1 (s, 1H, NH)
1447 (P-aryl)
7.0–8.0 (m, 30H, Ar)

250
F. M. Soliman et al.
The Reaction of Niclosamide Mannich Base 2c with the Stabilized Phosphonium
Ylides 8a–8e. Preparation of the Phosphoranylidenes 11a–11e
General Procedure: To a solution of niclosamide Mannich base 2c (0.01 mol) in 20 cm3 of dry toluene,
was added a solution of the methylenetriphenylphosphoranes 8a–8e [24–26] (0.01 mol) in 30cm3 of
dry toluene and the reaction mixture was refluxed for 10h. After the solvent was distilled off, the
residue was crystallized from the appropriate solvents. Yields, analytical and spectroscopic data are
presented in Tables 3 and 4.
The Reaction of Niclosamide Mannich Base 2c with Phenylmethylenetriphenylphosphorane
(8f) and Diphenylmethylenetriphenylphosphorane (12). Synthesis
of the Phosphoranylidene 11f and Oxaphosphinin 13
A solution of the Wittig reagents 8f [27] or 12 [28] (0.01 mol) in 20cm3 of absolute ethanol was treated
with 20 cm3 of a 0.01 M solution of sodium ethoxide in ethanol with continuous stirring, where the
orange colour of the phosphorane appeared immediately. The phosphorane solution was then added to
a solution of the Mannich base 2c in 30 cm3 of absolute ethanol and the reaction mixture was stirred
and boiled for 2 h at 25ꢂC. Ethanol was distilled off under reduced pressure and the remaining
precipitate was extracted with dry benzene. After the benzene extract had been concentrated, the
phosphoranylidene 11f and the oxaphosphinin 13 were precipitated. Yields, analytical and spectro-
scopic data are presented in Tables 3 and 4.
Attempted Reaction of Niclosamide Mannich Base 2c
with Ethoxycarbonyltriphenylphosphinimine (14)
No reaction was observed between the niclosamide Mannich base 2 and the phosphinimine 14 [29],
even if the reactants were boiled in THF or toluene for a long time, they were recovered unchanged.
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