Synthesis of phosphonodithioate, oxathiaphosphinin, oxathiaphosphole, and dithiaphosphole derivatives from the reaction of lawesson's reagent with phenolic mannich bases and oxime derivatives

Article abstract of DOI:10.1080/10426500802487607

The reaction of Lawesson's reagent 1a, with niclosamide 2 proceeded by thionation and formation of carbothioamide 3 and the zwitterionic oxathiaphosphinin 4a. LR reacted with 8-hydroxyquinoline (5), 2-methylquinoline-4-ol (7), and -naphthol (9) to give th

Full text of DOI:10.1080/10426500802487607

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Synthesis of
Phosphonodithioate,
Oxathiaphosphinin,
Oxathiaphosphole, and
Dithiaphosphole Derivatives
from the Reaction of
Lawesson's Reagent with
Phenolic Mannich Bases and
Oxime Derivatives
Soher S. Maigali a , Fouad M. Soliman a , Rashad
Shabana a & Marwa El-Hussieny a
a Department of Organometallic and
Organometalloid Chemistry, National Research
Center, Dokki, Cairo, Egypt
Version of record first published: 04 Sep 2009.
To cite this article: Soher S. Maigali, Fouad M. Soliman, Rashad Shabana &
Marwa El-Hussieny (2009): Synthesis of Phosphonodithioate, Oxathiaphosphinin,
Oxathiaphosphole, and Dithiaphosphole Derivatives from the Reaction of Lawesson's
Reagent with Phenolic Mannich Bases and Oxime Derivatives, Phosphorus, Sulfur, and
Silicon and the Related Elements, 184:9, 2408-2426
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Phosphorus, Sulfur, and Silicon, 184:2408–2426, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802487607
Synthesis of Phosphonodithioate, Oxathiaphosphinin,
Oxathiaphosphole, and Dithiaphosphole Derivatives from
the Reaction of Lawesson’s Reagent with Phenolic
Mannich Bases and Oxime Derivatives
Soher S. Maigali, Rashad Shabana, Marwa El-Hussieny,
and Fouad M. Soliman
Department of Organometallic and Organometalloid Chemistry,
National Research Center, Dokki, Cairo, Egypt
The reaction of Lawesson’s reagent 1a, with niclosamide 2 proceeded by thionation
and formation of carbothioamide 3 and the zwitterionic oxathiaphosphinin 4a. LR
reacted with 8-hydroxyquinoline (5), 2-methylquinoline-4-ol (7), and β-naphthol
(9) to give the phosphonodithioates 6, 8, or 10. The reaction of LR with the Man-
nich bases 11 and 14 afforded the oxathiaphosphinins 13 and 15, whereas the
phosphonodithioates 17 and 19 were isolated in the case of Mannich bases 16 and
18. LR reacted with phthalimide Mannich base 20 to give the dithione 21 and
N-methylphthalimide (22). Reaction of ketone monoxime 23 with LR resulted in
the formation of the oxathiaphosphole 24 and the dithiaphosphole 25, whereas the
monoxime 26 afforded the thioxoethanone thioxime 27. Ketone dioximes 28 and 34
afforded the phosphonodithioates 29 and 36, respectively, when they were allowed
to react with LR, whereas the dioxime 30 gave compounds 32 and 33. Moreover, the
molluscicidal potency of the newly synthesized compounds against Biomphalaria
glabrata snails was studied, too.
Keywords Dithiaphosphole; Lawesson’s reagent; oxaphosphole; oxathiaphosphinins;
phosphonodithioates
INTRODUCTION
Lawesson’s
reagent
2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiaphos-
phetane-2,4-disulfide (1a) has been shown to be a good starting mate-
rial for the construction of cyclic systems containing phosphorus and
sulfur.1–3 This reagent is used also in thionation of carbonyl-containing
compounds.4–6 Lawesson’s reagent 1a exists in equilibrium with the
Received 9 January 2008; accepted 18 September 2008.
Address correspondence to Fouad M. Soliman, Department of Organometallic and
Organometalloid Chemistry, National Research Center, El Tahrir St. (El-Bohooth St.),
Dokki, Cairo, 12622, Egypt. E-mail: solimanfma@hotmail.com
2408

Lawesson’s Reagent with Phenolic Mannich Bases
2409
monomeric form 1b, which can be incorporated with the substrate.7
The development in the application of this powerful reagent provide
an overview about novel reactions and uses of Lawesson’s reagent in
the synthesis of new organophosphorus and sulfur compounds that
are of potential interest in industrial8 and pharmacological purposes.9
As an ongoing program devoted to produce new bioactive hetero-
cyclic phosphorus substances,3,10 it was of interest to investigate the
reaction of niclosamide 2, 8-hydroxyquinoline (5), 2-methylquinoline-
4-ol (7), and β-naphthol (9) with Lawesson’s reagent 1b and compare
the reactivity of these phenolic compounds with the phenolic Mannich
bases 11, 14, 16, 18, and 20 toward LR 1b. The reaction of ketone
oxime derivatives 23, 26, 28, 30, and 34 with the same reagent 1b has
been studied. Moreover, the biological evaluation of the synthesized
compounds as molluscicidal against Biomphalaria glabrata snails has
been performed.
RESULTS AND DISCUSSION
Niclosamide [5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide]
(2) is the active ingredient of bayluscide, which has been used as a
molluscicide of great significance in the last decade.11 It was also intro-
duced as an official drug in many pharmacopoeas.12 Moreover, the syn-
thesis of carbothioamides is of great interest due to their applications
in syntheses, medicine, and agar chemistry.13 Therefore, the aim of the
present investigation has been extended to synthesize carbothioamide
3, from the reaction of niclosamide 2 and Lawesson’s reagent 1b. When
the bifunctional niclosamide 2 was reacted with one mol equivalent of
LR 1b in boiling dry acetonitrile for one day, [5-chloro-N-(2-chloro-4-
nitrophenyl)-2-hydroxybenzene carbothioamide] (3) was only isolated
in fairly good yield. The structure of the carbothioamide 3 was elu-
cidated from elemental microanalysis and spectroscopic data. The IR
spectrum of 3 showed absorption bands at v 3447 (OH), 3098 (NH),
1613 (C C, aromatics) and disclosed the absence of (C O, amide) and
1
presence of C=S absorption band at 1168 cm−1. In the H NMR spec-
trum of 3, signals were observed at δ 10.87 (s, 1H, OH), 9.04 (s, 1H, NH)
(exchangeable with D2O), and 6.7–8.3 (m, 6H, aromatics). Its 13C NMR
spectrum showed signals at δ 194.62 (C S), 157.83 (C-N) ppm, and in
the MS of 3 m/e = 341 (M−), when the reaction was repeated using one
mol equivalent of niclosamide 2 and two mol equivalents of LR 1b, the
carbothioamide 3 was isolated together with 2-chloro-N-(6-chloro-2-(4-
methoxyphenyl)-2-sulfanylene-4H-benzo [e][1,3,2]oxathiaphosphinin-
4-ylidene)-4-nitrobenzene amine (4). The elemental microanalysis, IR,

2410
S. S. Maigali et al.
1H, 31P NMR, and MS data agreed with structure 4. The IR spectrum
showed absorption bands at 2921 (OCH3) and 1594 (C N), 1525 (C C,
aromatics), 1348–1284 (C-O-C), and 628 cm−1 (P S). It revealed the
1
absence of (C O, amide), NH, and OH groups. In the H NMR spec-
trum of 4, signals were observed at δ 3.8 (s, 3H, OCH3) and 6.8–8.6 (m,
10H, aromatics). A signal at δ 14.02 ppm was observed in the 31P NMR,
which fits with the zwitterionic oxathiaphosphinin 4a rather than 4b,14
and in the mass spectrum, the M+ was found at m/e = 511. It is be-
lieved that LR reacted firstly with niclosamide 2 as thionating agent to
form the thioxo derivative 3. The last compound 3 reacted with another
molecule of LR by addition to give the intermediate phosphonodithioic
acid A, which cyclized with expulsion of hydrogen sulfide to give the
dipolar oxathiaphosphinin 4a (Scheme 1).
It has been found that 8-hydroxyquinoline (5) was used in controlling
photodegradation of the neem-based pesticide azardirachtin-A.15 Its
derivatives are used in several pharmacological purposes as antimalar-
ial drugs,16 and their copper complexes are useful as chemotherapeu-
tic agents.17,18 Moreover, their antiretroviral activity in HIV-infected
cells was tested.19 Therefore, when 8-hydroxyquinoline (5) was allowed
to react with LR 1b under the reflux temperature in acetonitrile for
10 h, the corresponding (4-methoxyphenyl)phosphonodithioic acid-O-
quinolin-8-yl ester (6) was obtained. The IR spectrum of 6 confirms the
proposed structure. It revealed the absence of OH group and presence
of SH band at v 2373, 2954 (OCH3),20 1595 (C C, aromatics), 1385–
1
1289 (C-O-C),20 and 692 cm−1 (P S).21 Its H NMR spectrum showed
signals at δ 3.7 (s, 3H, OCH3), 6.2 (s, 1H, SH, exchangeable with D2O),
and 6.9–8.9 (m, 10H, aromatics). The 31P NMR shift recorded for 6 was
at δ 14.1 ppm and the mass spectrum of 6 showed an ion peak at m/e
348 (M+) (Scheme 2).
In addition, the reactions of 2-methylquinoline-4-ol (7), and/or β-
naphthol (9) with LR 1b were studied. These reactions were per-
formed under the same experimental conditions to give the (4-methoxy-
phenyl)phosphonodithioic acid O-(2-methylquinolin-4-yl) ester (8) and
O-naphthalen-6-yl S-hydrogen 4-methoxyphenylphosphonodithioate
(10), respectively. Compounds 6 and 8 were equally obtained, irrespec-
tive of whether one or two mol equivalents of Lawesson’s reagent 1b
was used. It could be demonstrated that the formation of phospho-
nodithioates 6, 8, and 10 from the reaction of Lawesson’s reagent 1b
and the phenolic compounds 5, 7, and 9 occurred by the nucleophilic
attack of the oxygen center of the phenolic compounds 5, 7, and 9 to the
electron-deficient center in the monomeric species of LR 1b, followed
by migration of the proton to the electron-rich center of the molecules
(Scheme 2).

2411

2412
S. S. Maigali et al.
SCHEME 2
It was of interest to prepare phenolic Mannich bases of niclosamide
11 (Scheme 3), 2-methylquinoline-4-ol 14, 8-hydroxyquinoline 16,
β-naphthol 18, and phthalimide 20 (Scheme 4), and react them with
Lawesson’s reagent 1b to synthesize new organic compounds contain-
ing phosphorus and sulfur of biological19 and industrial interest.15
When the reaction of LR was preformed using the Mannich bases
of niclosamide 11 and 2-methylquinoline-4-ol 14, the corresponding
new heterocyclic oxa-thiaphosphinins 13 and 15 were obtained,
whereas in the case of the Mannich bases 8-hydroxyquinoline 16
and β-naphthol 18 only the (4-methoxyphenyl)phosphonodithioic
acid O-(7-morpholin-4-yl methylqui-nolin-8-yl) ester (17) and O-1-
(morpholinomethyl)naphthalene-2-yl-S-hydrogen-4-methoxyphenylp-
hosphonodithioate (19) were isolated.
On the other hand, the phthalimide Mannich base 20 afforded
the isoindolinedithione 21 along with N-methyl phthalimide (22).
The corresponding 6-chloro-2-(methoxyphenyl)-2-thioxo-4H-2λ5benzo-
[e][1,3,2] oxathi-aphosphinin-8-carboxylic acid (2-chloro-4-nitrophenyl)

Lawesson’s Reagent with Phenolic Mannich Bases
2413
SCHEME 3
amide (13) was presumably obtained by electrophilic attack of LR
1b on the phenolic OH group to form the intermediate 12 followed
by the expulsion of the amine moiety to give 13. This finding also
exclude the elimination of the amine group from the Mannich base
11 to form the quinone-methylene that could react with LR to form
the oxathiaphosphinine 13. The IR spectrum of 13 showed no OH
absorption band, which was exhibited by Mannich base 11 at 3422
cm−1. Absorption bands were shown in compound 13 at v 3296 (NH),
2941 (OCH3), 2675 (CH2), 1648 (C O amide), 1391–1261 (C-O-C), and
1
615 cm−1 (P S). Its H NMR spectrum showed signals at δ 3.1 (s, 1H,
NH, exchangeable with D2O), 3.8 (s, 3H, OCH3), 4.2 (d, 2H, CH2 due
to coupling with P atom), and 6.9–8.9 (m, 10H, aromat). Presence of
the C O amide, OCH3, CH2 groups in compound 13 were also attested
by signals at δ 168.4, 55.22, and 22.75 ppm in its 13C NMR spectrum.
The 31P NMR shift recorded for compound 13 was δ 14.3 ppm,14 which
supported the zwitterionic adduct 13a rather than the cyclic structure
13b. In the MS of 13 the M+ was found at m/e 541. Compound 13 was

2414

Lawesson’s Reagent with Phenolic Mannich Bases
2415
equally obtained irrespective of whether one or two mol equivalents
of LR 1 were allowed to react with the Mannich base 11. This means
that no reaction was observed between LR and the amide groups of 11
(Scheme 3). Moreover, 2-(4-methoxyphenyl)-5-methyl-2-sulfanylene-
4H-[1,3,2]-oxathiaphosphinino[5,b-c]quinoline (15) was obtained from
the reaction of the Mannich base 14 with LR 1b. On the other hand,
when Mannich bases of 8-hydroxyquinoline 16 and β-naphthol 18 were
treated with one mol equivalent of Lawesson’s reagent 1 under similar
conditions, the corresponding (4-methoxyphenyl)phosphonodithioic
acid O-(7-morpholin-4-yl methylquinolin-8-yl) ester (17) and O-1-
(morpholi-nomethyl)naphthalene-2-yl-S-hydrogen-4-methoxyphenylp-
hosphonodithioate (19) were isolated, respectively. The structure of
compound 17 was elucidated from elemental analysis, IR, 1H, 31P
NMR, and MS data, which agreed with structure 17. In this case,
the addition occurred through nucleophilic attack of the phenolic OH
group on the phosphorus atom of LR followed by migration of a proton
to the sulfur anion to give the stable compound 17. Its IR spectrum
showed no OH absorption band, which is exhibited in the starting
Mannich base 16 at 3428 cm−1, and the presence of absorption bands
at ν 2370 (SH), 2879 (OCH3), 2571 (CH2), 1546 (C C, aromatics),
1
1339–1257 (C-O-C), and 629 cm−1 (P S). In the H NMR spectrum of
17, signals were observed at δ 2.5 (t, 4H, 2CH2 morpholin), 3.0 (t, 4H,
2CH2 morpholin), 3.7 (s, 3H, OCH3), 4.2 (s, 2H, CH2), 5.3 (s, 1H, SH
exchangeable with D2O), and 6.9–8.8 (m, 9H, aromatics). A signal at δ
14.07 was observed in the 31P NMR of the phosphonodithioate 17 and
in its MS spectrum the M+ was found m/e 447. In the same manner,
when compound 18 was treated with LR the phosphonothioate 19 was
obtained (Scheme 4).
We have also found that when the Mannich base of phthalimide 20
reacted with Lawesson’s reagent 1 in molar ratio 1:1 in dry benzene for
15 h, the corresponding 2-(morpholinomethyl)isoindoline-1,3-dithione
(21) and 2-methylisoindoline-1,3-dione (22) were obtained. It could be
concluded that LR affects thionation of phthalimide Mannich base 20
to give the dithione derivative 21 and/or split the amine moiety of 20
with the formation of the N-methyl derivative 22. The IR spectrum of
21 revealed the presence of absorption bands at ν 2623 (CH2), 1119
(C=S) cm−1 and absence of the two C O groups that were exhibited
1
by the Mannich base 20 at 1626 cm−1. Its H NMR spectrum showed
signals at δ 2.4 (t, 4H, 2CH2 morpholin), 3.0 (t, 4H. 2CH2 morpholin),
3.6 (s, 2H, CH2), and 7.3–7.8 (m, 4H, aromatics) ppm. Furthermore,
signals at δ 198.91, 22.83 ppm were observed in the 13C NMR spectrum
of 21 that are attributed to the two C=S, and CH2 groups. In its MS the

2416
S. S. Maigali et al.
(M+) was found at m/e 279. Moreover, the IR spectrum of 22 revealed
the presence of absorption band of C O group at v 1665 cm−1. In its 1H
NMR spectrum the CH3 group appeared at δ 1.6 ppm as a singlet and
7.2–7.9 multiple 4H aromatics. The 13C NMR spectrum of 22 showed
signals at δ 169.14 (C O) and 39.87 (CH3) ppm. In the mass spectrum
M+ was found at m/e 162 (Scheme 4).
The work also focused on the reaction of LR 1b with ketone
monoximes 23 and 26 or dioximes 28, 30, and 34 derivatives. When
butane-2,3-dione oxime (23) was treated with equimolar amounts of
Lawesson’s reagent 1b in dry toluene under reflux for 15 min, 2-
(4-methoxyphenyl)-4,5-dimethyl-1,3,2-oxathiaphosphole-2-sulfide (24)
was obtained in a good yield, together with 2-(4-methoxyphenyl)-4,5-
dimethyl-1,3,2-dithiaphosphole-2-sulfide (25) in a moderate yield. Re-
action of the ketone monoxime 23 with LR 1b resulted in thionation of
the N-OH group22 and formation of the intermediate A, which reacted
with LR 1b to give the corresponding oxathiaphosphole 24. In addi-
tion, thionation of both the carbonyl and oxime groups of the ketone
monoxime 23 resulted in the formation of the intermediate B, which
reacted with LR to form the dithiaphosphole 25 (Scheme 5). The IR
spectrum of 24 revealed the absence of =N-OH and C O bands that
appeared in the starting material 23 at v 3384 and 1670 cm−1 and
showed bands at v 2837 (OCH3), 1594 (C C), 1300–1264 (C-O-C), 1128
1
(P-O-C), and 669 cm−1 (P S). The H NMR spectrum of 24 exhibited
signals at δ 1.5 (s, 6H, 2CH3), 3.8 (s, 3H, OCH3), and 7.0–8.3 (m, 4H,
aromatics) ppm whereas its 13C NMR spectrum revealed the absence of
C O and C N-OH groups and the presence of C-P, C-O, OCH3, and CH3
at δ 164.25, 128.23, 55.56, and 23.12 ppm, respectively. The 31P NMR
shifts for 24 were at δ 73.88 ppm. In the MS of 24 m/e = 273 (M+). The
structure of the dithiaphosphole 25 was elucidated from spectroscopic
data (Table I).
When 1,2-diphenylethane-1,2-dione oxime (26) was reacted with
Lawesson’s reagent 1b in dry boiling toluene for 5 h, the correspond-
ing 1,2-diphenyl-2-thioxoethanonethioxime (27) was only obtained in
1
a good yield. The elemental microanalysis, IR, H, 13C NMR, and MS
data agreed with structure 27. The IR spectrum showed no absorption
bands of =N-OH, and C O groups and revealed the presence of absorp-
tion bands at v 2370 (SH), 1624 (C N), and 1276 cm−1 (C=S). In the
1H NMR spectrum of 27, signals at δ 2.89 (s, 1H, SH exchangeable with
D2O) and 7.2–7.8 (m, 10H, aromatics) ppm were shown. The presence
of C=S and C N groups in 27 was also attested to by signals at δ 202.91
and 139.83 ppm in its 13C NMR spectrum and in the MS of 27 m/e =
258 (M+). Compound 27 was equally obtained irrespective of whether
one or two mol equivalents of LR 1b was used (Scheme 6).

2417

2418

Lawesson’s Reagent with Phenolic Mannich Bases
2419
TABLE I Spectroscopic Data (IR, NMR, and MS) for Compounds 8, 10,
15, 19, and 25
NMR: δ /ppm
Compound
no.
IR: ν /cm−1
1H NMR
31PNMR MS
8
2935 (OCH3, CH3), 2354 2.4 (s, 3H, CH3), 3.7 (s, 3H,
14.01
14.02
14.42
13.95
362
348
373
446
(SH), 1648 (C C, aro-
matics), 1362–1300 (C-
O-C), and 677 (P S)
OCH3), 5.7 (s, H, SH ex-
changeable with D2O), and
6.8–8.6 (m, 9H, aromatics)
10
15
19
2835 (CH3), 2373 (SH), 3.77 (s, 3H, OCH3), and 6.9–
1626 (C C, aromatics),
1304–1263 (C-O-C), and
665 (P S)
7.6 (m, 11H, aromatics, and
SH)
2940 (CH3), 2676 (CH2), 2.1 (s, 3H, CH3), 3.3 (s, 2H,
1393–1260(C-O-C),
1478 (P-C-aryl), and
612 (P S)
CH2), 3.7 (s, 3H, OCH3),
and 6.8–7.6 (m, 8H, aro-
matics)
2962 (OCH3), 2600 (CH2), 2.4 (t, 4H, 2CH2 morpholin),
2311 (SH), 1628 (C C,
aromatics), 1309–1289
(C-O-C), and 672 (P S)
3.1 (t, 4H, 2CH2 mor-
pholin), 3.5 (s, 1H, SH, ex-
changeable with D2O), 3.7
(s, 3H, OCH3) , 4.0 (s, 2H,
CH2), and 6.8–8.0 (m, 10H,
aromatics)
25
2833
(C C),
(C-O-C) and 687 (P S)
(OCH3),
1589 1.6 (s, 6H, 2CH3), 3.8 (s, 3H,
84.13
288
1313–1254
OCH3), and 7.9–8.1 (m, 4H,
aromatics)
In addition, the reaction of ethanediol dioxime (28) with Lawesson’s
reagent 1b was performed in boiling dimethylformamide and the cor-
responding compound 29 was isolated as a sole product. Structural
assignment for 29 was supported by the elemental microanalysis, MS,
IR, 1H, and 31P NMR spectroscopic data. The IR spectrum of compound
29 showed strong absorption bands at v 2833 OCH3, 2320 SH, 1624
1
C N, 1345–1225 (C-O-C), and 625 cm−1 (P S). The H NMR shifts of
29 were 2.49 (s, 2H, 2CH), 3.56 (s, 6H, 2OCH3), 5.07 (br, 2H, 2SH, ex-
changeable with D2O), and 6.88–7.59 (m, 8H, aromatics). The 31P NMR
spectrum showed signal at δ 13.24 ppm and in the mass spectrum m/e
493 (M+) (Scheme 6).
Moreover, when butane-2,3-dione dioxime (30) was allowed to re-
act with Lawesson’s reagent 1b in molar ratio in dry toluene at reflux
temperature for 15 min, compound 31 along with 33 was obtained.
Compound 31 was not isolated; however, upon in situ alkylated with
methyl iodide and/or ethyl iodide, compounds 32a, b were isolated.

2420
S. S. Maigali et al.
The products 32a, b and 33 were identified by elemental analyses and
1
spectroscopic data. The H NMR spectrum of 32a showed the singlet
at δ 2.1 due to the two CH3, the two SCH3 protons appeared as dou-
blet at 2.5 ppm (due to the presence of P atom), a singlet at 3.8 ppm
is due to the two OCH3 protons, and a multiple at δ 6.9–7.9 aromat-
ics protons. The IR spectrum of 32a confirmed the proposed struc-
ture, showing no absorption for the two =NOH groups. The OCH3,
C N, and P S groups appeared at v 2800, 1560, and 692 cm−1, re-
spectively, in its IR spectrum, whereas its 13C NMR spectrum revealed
the presence of the signals at δ 159.5 (C N-O), 55.4 (OCH3), 32 (CH3),
and 14.9 (SCH3). The 31P NMR shifts recorded for 32a at δ 105.15–
106.12 ppm is in conformity for similar structures,22 and its MS m/e
= 547 (M−). In case of alkylation with ethyl iodide, 32b was isolated
under the same experimental conditions. The structure of 32b was
based on its elemental microanalysis, IR, 1H, 31P NMR, as well as
its mass spectrum. The IR spectrum of 32b exhibited the presence of
2927 (CH3), 2867 (OCH3), 1591 (C N), and 600 cm−1 (P S), and the
absence of =N-OH groups. Its 1H NMR spectrum showed the pres-
ence of signals at δ 1.3 (t, 6H, 2S-CH2-CH3), 2.2 (s, 6H, 2CH3), 3.2 (q,
4H, 2S-CH2-CH3), 3.8 (s, 6H, 2OCH3), and 6.9–7.9 (m, 8H, aromat-
ics) ppm. The 31P NMR spectrum showed peaks at δ 104.91–104.96,
which is in accordance with earlier findings of such structures,22 and
the mass of 32b m/e = 577 (M+). In addition, the structure of the second
product, namely, 7,8-dihydro-7,8-bis-(methoxyphenyl)-3,4-dimethyl-
7,8-disulfanylene-1,6,2,5,7,8-dioxadiazadiphosphocine (33), was sup-
1
ported by the elemental analysis, IR, H, 31P NMR, and MS spectro-
scopic data. The IR spectrum is characterized by the absence of =NOH
groups and the presence of absorption bands at v 2925 (OCH3), 1653
(C N), 1297, 1364 (C-O-C), and 602 cm−1 (P S). The 1H NMR spectrum
of 33 revealed the presence of signals at δ 2.1 (s, 6H, 2CH3), 3.8 (s, 6H,
2OCH3), and 7.1–7.9 (m, 8H, aromatics). The 31P NMR shifts recorded
for 33 at δ 104.54 ppm. The MS supported the structure of compound
33 and showed the molecular ion peak at m/e = 454 (Scheme 6).
When 1,2-diphenylethane-1,2-dione dioxime (34) was reacted with
LR 1b in dry toluene under reflux for 15 min, compound 35 was ob-
tained. Compound 35 was not isolated, and subjected to alkylation in
situ with methyl iodide, compound 36 was isolated. The IR spectrum
of 36 showed no =N-OH groups and the presence of absorption bands
at 2926 (OCH3), 1592 (C N), 1267–1179 (C-O-C), and 697 cm−1 (P S).
1
In its H NMR spectrum signals were at δ 2.8 (d, 6H, 2SCH3 due to
presence of P atom), 3.7 (s, 6H, 2OCH3) and 6.8–8.1 (m, 18H, aromat-
ics) ppm. The 31P NMR shift recorded for 36 at δ 104.5 ppm, which is

Lawesson’s Reagent with Phenolic Mannich Bases
2421
in accordance with similar structures,22 and its mass spectrum showed
m/e 672. Formation of the phosphonodithioic acid derivatives 29, 32a,
b, and 36 occurred via addition of the dioximes 28, 30, and 34 to LR.
In the case of the reaction of the dioxime 30 and LR, part of compound
31 lost H2S and S to give the dioxadiazadiphosphocine 33.
CONCLUSION
The reaction of LR 1b with different functional compounds such as
phenolics, Mannich bases, ketone monoximes, and/or ketone dioximes
represents an interesting approach to the construction of new bioac-
tive compounds containing phosphorus and sulfur. The heterocyclic
oxathiaphosphinines 4, 13, 15, and 24 were obtained from the reaction
of niclosamide 2, niclosamide Mannich base 11, 2-methylquinoline4-ol
(14), and the ketone monoxime 23, respectively. Moreover, the phos-
phonothiaoates 6, 8, 10, 17, 19, 21, 32, and 36 were isolated from the
reaction of LR 1b with the phenolic compounds 5, 7, 9, Mannich bases
16, 18, and the ketone dioximes 28, 30, 34, respectively. We noticed also
that the behavior of LR toward the ketone monoximes is different from
that of the ketone dioximes. In the case of the monoximes, thionation
reactions occured, whereas the ketone dioxime afforded the formation
of the phosphonothioates. This process can be considered as a simple
route for the formation of the above-mentioned new compounds, which
are difficult to obtain by other conventional methods.
BIOLOGICAL EVALUATION OF THE TESTED COMPOUNDS
Schistosomiasis is estimated to affect 200 million people around the
world, causing high levels of morbidity and mortality in 74 countries
in tropical and subtropical areas. Egypt was one of the most highly
endemic areas in the world, with infection rates exceeding 80% in some
localities in the Nile Valley.23 As intermediate hosts, molluscs play a
major role in the transmission of schistosomes, because they are the
sites of an intense multiplication of the parasites. The use of mollusci-
cides has always been considered to be a major supportive procedure
in integrated schistosomiasis control.11 Among synthetic compounds,
niclosamide (the active ingredient of bayluscide) is still the mollusci-
cide of choice, being highly active at different stages of the snail life
cycle and also effective on the schistosome larvae. Niclosamide is not
toxic to humans, domestic animals, and crops.24 Therefore, the present
work aims to examine the efficacy of the newly prepared compounds
containing sulfur or containing phosphorus and sulfur derivatives as

2422
S. S. Maigali et al.
molluscicides for controlling such snails in the laboratory, hoping to
find a suitable one for eradicating the disease through its intermediate
host.
Materials
r
Snails: Biomphalaria glabrata snails used in this study were ob-
tained from colonies of the Schistosome Biological Supply Program
(SBSP), Theodor Bilharz Research Institute, Giza, Egypt. The orig-
inal stock of snail species were obtained from London University
and maintained for many years in the laboratory (SBSP). A group
of laboratory-produced snails of the same size (4–6 mm in diame-
ter) were used for testing the molluscicidal potency of the tested
compounds and were maintained in the laboratory in glass aerated
aquaria, containing dechlorinated tap water, nostoc algae, and let-
tuce leaves. The temperature was kept at 25◦C +1.
r
Chemicals: The tested molluscicides, namely, carbothioamide 3,
oxathiaphosphinines 4, 13, and 15, phosphonodithioates 6, 8, 10, 17,
19, 29, 32, and 36, isoindolinedithione 21, N-methylphthalimide 22,
oxathiaphosphole 24, dithiaphosphole 25, thioxoethanonthioxime
27, and dioxadiazadiphosphocine 33, were prepared as mentioned
in the text.
The molluscicidal potency of the newly synthesized compounds
against Biomphalaria glabrata snails, which the intermediate host
of Schistosoma mansoni was studied, and compared them with
niclosamide. The results showed that all newly tested compounds have
low or no molluscicidal potency against B. glabrata snails; however, two
compounds (3 and 33) showed highly molluscicidal activity against the
snails. Moreover, thionated niclosamide 3 determined 100% mortality
of B. glabrata at 0.1 ppm immediately, whereas compound 33 showed
100% mortality of the snails at 1.2 ppm compared to niclosamide, which
killed 100% of B. glabrata snails at 1.5 ppm after 2 h exposure.11
Therefore, further studies on the effect of these two newly
niclosamide derivatives 3 and oxime derivative 33 as promising mol-
luscicides are needed to ensure their safety on aquatic biota on larger
scale and their selective activity on target snails.
EXPERIMENTAL
All melting points were measured on a Gallenkamp electrothermal
melting point apparatus and were uncorrected. The infrared spectra

Lawesson’s Reagent with Phenolic Mannich Bases
2423
were recorded in KBr pellets on a Pye unicam SP 3300 and FTIR
8101PC Shimadzu Infrared Spectrometers. NMR spectra were obtained
in deuterated CDCl3 or DMSO on a Varian MERCURY (1H: 300 MHz,
13C: 75 MHz) spectrometer using TMS as an internal reference. 31P
NMR spectra were run on the same spectrometer using H3PO4 (85%) as
external reference. Mass spectra were recorded on a Shimadzu GC-MS
QP 1000 Ex Spectrometer at (E I, 70 ev). Elemental analyses were car-
ried out at the Microanalytical Center of the National Research Center,
El-Tahrir Street, Dokki, Cairo. Their results were in agreement with
the calculated values.
The reported yields are of pure isolated materials obtained by column
chromatography using silica gel 60 (Merck).
Physical and spectroscopic data are shown in Tables I and II.
TABLE II Physical Data of Compounds 3, 4a, 6, 8, 10, 13, 15, 17, 19, 21,
22, 24, 25, 27, 29, 32a, 32b, 33, and 36
Compound
no.
Solvent of
crystallization
Yield
(%)
Mol. wt./g
mol−1
mp (◦C)
132
Formula
3
Pet. ether/ethyl
acetate
Pet. ether/ethyl
acetate
80
25
C13H8Cl2N2O3S
342
510
4a
208
C20H13Cl2N2O4PS2
6
8
199
210
200
185
115
212
149
Pet. ether/acetone
Benzene
Benzene/pet. ether
Ethanol
Benzene
Ethanol
75
75
35
85
40
85
55
C
C
C
C
C
C
C
16H14NO2PS2
17H16NO2PS2
17H15O2PS2
21H15Cl2N2O5PS2
18H16NO2PS2
21H23N2O3PS2
22H24NO3PS2
347
361
346
540
373
446
445
10
13
15
17
19
Chloroform/pet.
ether
21
22
175
231
n-Hexane/ethyl
acetate
n-Hexane/ethyl
acetate
75
85
C13H14N2OS2
C9H7NO2
278
161
24
25
27
29
32a
32b
33
160
51
Benzene
Benzene
80
35
65
85
75
75
25
40
C11H13O2PS2
272
288
257
492
548
576
454
672
C
C
C
C
C
C
C
11H13OPS3
14H11NS2
112–114 Cyclohexane
295
123
100
Ethanol
n-Hexane/acetone
n-Hexane/acetone
16H18N2O4P2S4
20H26N2O4P2S4
22H30N2O4P2S4
18H20N2O4P2S2
30H30N2O4P2S4
152–154 n-Hexane/acetone
Oily
36
n-Hexane/ethyl
acetate

2424
S. S. Maigali et al.
Reaction of Lawesson’s Reagent (1) with Phenolic
Compounds 2, 5, 7, and 9: Synthesis of Carbothioamide 3,
Oxathiaphosphinin 4, and Phosphonodithioic Acids 6, 8,
and 10
A solution of Lawesson’s reagent 125 (0.001 mol) in 20 mL of dry anhy-
drous acetonitrile was added under reflux and stirring to the solution of
phenolic compounds 2, 5, 7, and 9 (0.001 mol) in 30 mL of acetonitrile,
respectively. The reaction mixture was refluxed for one day in case of
2 and for 5–10 h in case of 5, 7, and 9, until no more of the starting
materials could be detected (TLC). Acetonitrile was distilled off under
reduced pressure and the remaining residue was crystallized from the
specified solvents to give the carbothioamide 3 and phosphonodithioic
acids 6, 8, and 10, respectively. When the reaction of niclosamide 2
was repeated using one mol equivalent of 2 and two mol equivalents of
LR, the same product of carbothioamide 3 was isolated together with
oxathiaphosphinin 4.
Reaction of Lawesson’s Reagent 1b with Phenolic Mannich
Bases 11, 14, 16, and 18: Synthesis of Oxathiaphosphinins 13
and 15 or Phosphonodithioic Acids 17 and 19
A mixture of Lawesson’s reagent 1 (0.001 mol) and phenolic Mannich
bases 11, 14, 16, and 18 (0.001 mol) was refluxed with stirring in an-
hydrous acetonitrile 50 mL for 72 h in case of 11 and for 5–8 h when
compounds 14, 16, and 18 were used, until no more of the starting
materials could be detected (TLC). The solvent was distilled off un-
der reduced pressure and the remaining residue was crystallized from
the specified solvent to give oxathiaphosphinins 13 and 15 or phospho-
nodithioic acids 17 and 19, respectively. When the reaction of LR 1 and
niclosamide Mannich base 11 was repeated by using 2 mol of LR and
1 mol of compound 11 the same product of oxathiaphosphinin 13 was
isolated, too.
Reaction of Lawesson’s Reagent 1 with Phthalimide Mannich
Base 20: Synthesis of 2-(Morpholinomethyl)isoindoline-1,3-
dithione (21) and 2-Methylisoindoline-1,3-dione (22)
A solution of LR 1 (0.001 mol) in 30 mL dry benzene was refluxed
with the solution of phthalimide Mannich base 20 (0.001 mol) until no
more of the starting materials could be detected (TLC). Benzene was
distilled off under reduced pressure and the remaining residue was

Lawesson’s Reagent with Phenolic Mannich Bases
2425
chromatographed on silica gel using n-hexane/ethyl acetate as eluent
(90:10, v/v) to give compounds 21 and 22.
Reaction of Lawesson’s Reagent 1 with Ketone Monoxime
Compounds 23 and 26: Synthesis of Oxathiaphosphole 24 and
Dithiaphosphole 25 or Thioxoethanonethioxime 27
To a solution of Lawesson’s reagent 1 (0.001 mol) in 20 mL of dry toluene
was added a solution of ketone monoxime 23 or 2626 (0.001 mol) in 30
mL toluene. The reaction mixture was refluxed for 15 min in case of
23 and for 5 h in case of 26. After the solvent have been distilled off,
the residue was chromatographed on silica gel using n-hexane/ethyl
acetate as eluent to give the oxathiaphosphole 24 and dithiaphosphole
25 or thioxoethanonethio oxime 27, respectively.
Reaction of Lawesson’s Reagent (1) with Ethanediol Dioxime
(28)
To a solution of Lawesson’s reagent 1 (0.001 mol) in 15 mL of dimethyl-
formamide was added a solution of the dioxime compound 28 (0.001
mol) in 15 mL dimethylformamide, and the reaction mixture was re-
fluxed for 2 h. The solvent was distilled off under reduced pressure, and
the residue was purified on silica gel by column with pet. ether/ethyl
acetate (30:70, v/v) as eluent and recrystallized from ethyl alcohol.
Compound 29 was synthesized as white crystals.
Reaction of Lawesson’s Reagent 1 with Butane-2,3-dione
Dioxime (30)
A mixture of Lawesson’s reagent 1 (0.001 mol) and the dioxime 30
(0.001 mol) was boiled under reflux in dry toluene for 15 min until no
more of the starting materials could be detected (TLC). The solution
was cooled in an ice bath and methyl iodide or ethyl iodide (0.001 mol)
and triethyl amine (0.0012 mol) was added drop-wise. Toluene was
distilled off under reduced pressure and the remaining residue was
chromatographed on silica gel using n-hexane/acetone as eluent, and
compounds 32a and 32b along with 33 were separated.
Reaction of Lawesson’s Reagent 1 with 1,2-Diphenylethane-
1,2-dione Dioxime (34)
A mixture of Lawesson’s reagent 1 (0.001 mol) and the dioxime 34
(0.001 mol) was boiled under reflux in dry toluene for 15 min until no
more of the starting materials could be detected (TLC). The solution

2426
S. S. Maigali et al.
was cooled in an ice bath and methyl iodide (0.001 mol) was added drop-
wise followed by triethyl amine (0.0012 mol). Toluene was distilled off
under reduced pressure and the residue was chromatographed on silica
gel using pet. ether/ethyl acetate (20:80, v/v) as eluent and compound
36 was separated as an oily compound.
REFERENCES
[1] N. M. Yousif, R. Shabana, and S.-O. Lawesson, Bull. Soc. Chim. Fr., 2, 283 (1986).
[2] R. Shabana, J. B. Rasmussen, and S.-O. Lawesson, Bull. Soc. Chim. Belg., 90, 103
(1981).
[3] R. Shabana, S. S. Maigali, S. A. Essawy, M. El-Hussieny, and F. M. Soliman, Egypt.
J. Chem., Special Issue (M. Sidky), 59 (2007).
[4] B. S. Pedersen, S. Scheibye, N. H. Nilsson, and S.-O. Lawesson, Bull. Soc. Chim.
Belg., 87, 223 (1978).
[5] H. Fritz, P. Hug, S.-O. Lawesson, E. Logemann, B. S. Pedersen, H. Sauter, S.
Scheibye, and T. Winkler, Bull. Soc. Chim. Belg., 87, 525 (1978).
[6] K. Clausen, B. S. Pedersen, S. Scheibye, S.-O. Lawesson, and J. H. Bowie, Org. Mass
Spectrom., 14, 101 (1979).
[7] M. Yoshifuji, K. Toyota, K. Ando, and N. Inamoto, Chem. Lett., 317 (1984).
[8] A. Lopusinski, Pol. Pl., 150, 517 (1990); Chem. Abstr., 115, 232509u (1991).
[9] P. Venkateswarlu and S. Ch. Venkata, Tetrahedron Lett., 45, 3207–3209 (2004).
[10] R. Shabana and S. S. Atrees, Phosphorus, Sulfur, and Silicon, 102, 9–13 (1995).
[11] S. Perrett and P. J. Whitfield, Parasitol. Today, 12, 156 (1996).
[12] F. M. Soliman, M. M. Said, and S. S. Maigali, Monatsh. Chem., 136, 241–251 (2005).
[13] B. S. Pedersen and S.-O. Lawesson, Bull. Soc. Chim. Belg., 86, 693 (1977).
[14] G. Erker, N. C. Aust, J. Am. Chem. Soc., 120, 4863–4864 (1998).
[15] S. Johnson, P. Dureja, and S. Dhingra, J. Environ. Sci. Health B, 38, 451–462 (2003).
[16] T. J. Egan, W. W. Mavuso, D. C. Ross, and H. M. Marques, J. Inorg. Biochem., 86,
137–145 (1997).
[17] K. G. Daniel, P. Gupta, R. H. Harach, W. C. Guida, and Q. P. Dou, Biochem. Phar-
macol., 67, 1139–1151 (2004).
[18] L. He, H. Chang, T. Chou, N. Savaraj, and C. C. Cheng, Eur. J. Med. Chem., 38,
101–107 (2003).
[19] M. A. Fakhfakh, A. Fournet, E. Prima, J.-F. Mouscadet, X. Franck, R. Hocquemiller,
and B. Figadere, Bioorg. Med. Chem., 11, 5013–5023 (2003).
[20] H.-L. Liu, H.-Y. Mao, X. Chen, H.-Y. Zhang, H.-W. Hou, Q-an. Wu, Y. Zhu, B.-X. Ye,
and L.-J. Yuan, Polyhedron, 23, 1799–1804 (2004).
[21] L. J. Bellamy, The Infrared Spectra of Complex Molecules, 3rd ed. (Wiley, New York,
1975), p. 348.
[22] S. Scheibye, R. Shabana, S.-O. Lawesson, and C. Romming, Tetrahedron, 38, 993
(1982).
[23] T. El-Khoby, N. Galal, and A. Fenwick, Parasitol. Today, 14, 92–96 (1998).
[24] R. F. Sturrock, R. K. Klumpp, J. H. Ouma, A. E. Butterworth, A. J. Fulford, H. C.
Kariuki, F. W. Thiongo, and D. Koech, Parasitology, 109, 443 (1994).
[25] I. Thomsen, K. Clausen, S. Scheibye, and S.-O. Lawesson, Org. Synth., 62, 157
(1984).
[26] K. Auwers and V. Meyer, Ber. Dtsch. Chem. Ges., 22, 540 (1889).