Three component synthesis of new (1,3,4-Thiadiazolamino)methylphosphonates, their glycoside and oxygenated alkylthio analogs

Article abstract of DOI:10.1080/10426507.2013.797417

A number of (1,3,4-thiadiazol-2-ylamino)methylphosphonate derivatives were synthesized in a three component reaction. The thioglycoside derivatives and oxygenated alkylthio analogs were also prepared by reaction with halo sugars or different acyclic oxygenated alkyl halides.

Full text of DOI:10.1080/10426507.2013.797417

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Phosphorus, Sulfur, and Silicon and the
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Three Component
Synthesis of New (1,3,4-
Thiadiazolamino)Methylphosphonates,
Their Glycoside and Oxygenated
Alkylthio Analogs
Wael A. El-Sayed a b & Omar M. Ali c d
a Department of Photochemistry , National Research Centre , El-
Dokki , Cairo , Egypt
Click for updates
b Department of Chemistry, Faculty of Science , NBU University ,
Arar KSA
c Department of Chemistry, Faculty of Science , Menoufia
University , Shebin El-Koam , Egypt
d Faculty of Medical and Applied Science , Taif University , Taif Saudi
Arabia
Accepted author version posted online: 26 Jul 2013.Published
online: 03 Dec 2013.
To cite this article: Wael A. El-Sayed & Omar M. Ali (2014) Three Component Synthesis of New (1,3,4-
Thiadiazolamino)Methylphosphonates, Their Glycoside and Oxygenated Alkylthio Analogs, Phosphorus,
Sulfur, and Silicon and the Related Elements, 189:1, 88-97, DOI: 10.1080/10426507.2013.797417
To link to this article: http://dx.doi.org/10.1080/10426507.2013.797417
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Phosphorus, Sulfur, and Silicon, 189:88–97, 2014
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2013.797417
THREE COMPONENT SYNTHESIS OF NEW
(1,3,4-THIADIAZOLAMINO)METHYLPHOSPHONATES,
THEIR GLYCOSIDE AND OXYGENATED ALKYLTHIO
ANALOGS
Wael A. El-Sayed1,2 and Omar M. Ali3,4
1Department of Photochemistry, National Research Centre, El-Dokki, Cairo, Egypt
2Department of Chemistry, Faculty of Science, NBU University, Arar KSA
3Department of Chemistry, Faculty of Science, Menoufia University, Shebin
El-Koam, Egypt
4Faculty of Medical and Applied Science, Taif University, Taif Saudi Arabia
GRAPHICAL ABSTRACT
Abstract A number of (1,3,4-thiadiazol-2-ylamino)methylphosphonate derivatives were syn-
thesized in a three component reaction. The thioglycoside derivatives and oxygenated alkylthio
analogs were also prepared by reaction with halo sugars or different acyclic oxygenated alkyl
halides.
Keywords Phosphonates; 1,3,4-thiadiazoles; thioglycosides
INTRODUCTION
1,3,4-Thiadiazoles exhibit a broad spectrum of biological activities, possibly due
to the presence of the toxophoric NeCe S moiety.1 They find applications as antibacte-
rial, antitumor, anti-inflammatory, pesticides, herbicides, dyes, and lubricants agents.2–6
Organophosphorus compounds play important roles in various areas of functional materi-
als science,7 biochemistry,8 and in catalysis chemistry as ligands.9 Phosphonate containing
heterocycles are an important class of active compounds10 and recent studies have indicated
that heterocyclic analogues containing phosphorus showed interesting bioactivities.11 Vari-
ous potent antibiotics,12 enzyme inhibitors,13 pharmacological agents,14,15 and herbicides,16
are 1-aminophosphonic acids, 1-aminoalkyl phosphonates, or their peptide analogs. Their
outstanding properties mainly stem from the structural relationship to their carboxylic
Received 22 January 2013; accepted 16 April 2013.
Address correspondence to Omar M. Ali, Department of Photochemistry, National Research Centre,
El-Dokki, Cairo, Egypt; and Department of Chemistry, Faculty of Science, NBU University, KSA. E-mail:
omali 66@hotmail.com
88

(THIADIAZOLAMINO)METHYLPHOSPHONATES AND THEIR THIOGLYCOSIDES
89
counterparts, the α-amino acids. Thus, the phosphonate moiety mimics the tetrahedral in-
termediate formed during the enzymatic peptide hydrolysis and consequently many reviews
have reported their chemistry and biological interest.17,18 1-Aminoalkyl phosphonates are
also the key substrates in the synthesis of various phosphonopeptides.19–21 It has been
also shown that the presence of a phosphonyl group can influence the biological func-
tions of heterocyclic systems.22 Owing to such a wide range of applications, the synthesis
of phosphonate compounds via C P bond formation in three component reactions using
proper phosphite reagent is enjoying growing interest and is an ever green and widely used
method23,24 in phosphonate synthesis. On the other hand, the glycosylthio heterocycles
including modifications of both the glycon and aglycon parts have stimulated extensive
research as biological inhibitors.25–28 Owing to the above facts and our interest in the at-
tachment of sugar moieties to new substituted heterocycles,29–32 it will be of synthetic and
biological interest to synthesize new aminophosphonates linked to glycosylthio derivatives
of the 1,3,4-thiadiazole ring system.
RESULTS AND DISCUSSION
Among three-component condensation reactions, the addition of nucleophiles to in
situ generated C N bonds has become an extremely useful process for the synthesis of
various nitrogen-containing molecules such as α-amino phosphonates.33 In this investi-
gation, 5-amino-1,3,4-thiadiazole-2-thiol (1)34 was allowed to react in a three component
reaction with p-chloro- or p-bromobenzaldehyde and triphenyl phosphite in the presence
of a catalytic amount of perchloric acid to afford the corresponding aminophosphonate
1
derivatives 2a,b, respectively with 70–71% yields. The H NMR spectra of 2a,b showed
the CH–N signal as singlet at δ 3.91 and 4.01 for 2a and 2b respectively, and the NH signals
at δ 6.22, 6.05, 11.97, and 12.18.
The key compounds 2a,b were used as starting materials for the synthesis of a num-
ber of substituted thiadiazolyl aminophosphonate thioglycosides and acyclic nucleoside
analogs. Thus, reaction of 2a,b with 2,3,4,6-tetra-O-acetyl-α-D-gluco- 3 and 2,3,4-tri-O-
acetyl-α-D-xylopyranosyl bromide 4 in acetone in the presence of potassium hydroxide
afforded the corresponding thioglycoside derivatives 5 and 6, respectively with 77–79%
yields. The IR spectra of the thioglycosides 5a,b and 6a,b showed characteristic absorption
bands in the carbonyl frequency region at 1737–1746 cm−1 in addition to the NH absorption
bands at 3323–3361 cm−1. The 1H NMR spectra showed the signals of the acetyl methyl
protons as singlets at δ 1.90–2.15 and the anomeric proton signal as doublet at δ 5.77–5.87
with a coupling constant of 9.8–10.2 Hz indicating the β-orientation of the thioglycosidic
bond. The anomeric proton of β-N-glucosides having an adjacent C S was reported35–38 to
appear at higher chemical shift (δ 6.9–7.2) due to the anisotropic deshielding effect of the
C S group.36,38 The 13C NMR spectra of 5a,b and 6a,b showed a signal at δ 82.11–83.29
corresponding to the anomeric C-1 which also confirmed the β-configuration. The absence
of a signal corresponding to a thiocarbonyl carbon atom in the 13C NMR spectra of 5a,b
and 6a,b confirmed that the attachment of the sugar moiety has been taken place at the
sulfur atom rather than to the nitrogen atom which has also been supported by the chemical
shift of the anomeric proton. This attachment also agreed with the mode of their prepara-
tion. When the glycosides 5a,b and 6a,b were treated with methanolic ammonia at 0◦C,
the deacetylated S-glucoside derivatives 7a,b and 8a,b, respectively were obtained with
79–81% yields (Scheme 1). Their IR spectra showed absorption bands at 3440–3467 cm−1

90
W. A. EL-SAYED AND O. M. ALI
Scheme 1 Synthesis of (1,3,4-Thiadiazol-2-yl-amino) methylphosphonates.

(THIADIAZOLAMINO)METHYLPHOSPHONATES AND THEIR THIOGLYCOSIDES
91
and the 1H NMR spectra are in agreement with the assigned structures (see experimental
part).
The thiadiazolylaminophosphonate derivatives 2a,b have been reacted with different
acyclic oxygenated alkyl halides to give a series of oxygenated open chain derivatives
of 1,3,4-thiadiazole. Reaction of the 2a,b with 2-(2-chloroethoxy)ethanol, 1-chloro-2-
methoxyethane, or 3-chloropropane-1,2-diol in DMF (dimethylformamide) at 70◦C af-
1
forded the S-substituted acyclic analogs 9–11, respectively with 74–77% yields. The H
NMR spectra of 10a,b showed signals corresponding to the OCH3 at δ 3.81 and 3.88 in
addition to the CH2 signals in the range 3.56–4.31. The IR spectra of 11a,b showed the
hydroxyl absorption bands at 3482–3485. Their 1H NMR spectra revealed the presence of
CH2 signals at δ 3.66–4.14 in addition to the signals of hydroxyl proton at δ 3.66–5.02.
EXPERIMENTAL
All solvents were dried by standard methods. Melting points were determined with a
Kofler block apparatus and are uncorrected. IR spectra (ν/cm−1, KBr pellets) were recorded
with a Perkin-Elmer Model 1720 FTIR spectrometer. The 1H and 13C NMR spectra were
measured in DMSO-d6 with a Bruker AC-300 FT spectrometer operating at 300 MHz (1H)
and 75 MHz (13C), respectively. The chemical shifts in ppm are expressed on the δ scale
using tetramethylsilane as internal standard. Coupling constants J are given in Hz. Mass
spectra were measured on a Kratos 50 TC spectrometer. TLC was performed on Merck
silica gel 60-F254 pre-coated plastic plates. Microanalyses were performed in the unit of
microanalysis at Cairo University, Cairo.
Diphenyl (4-Halophenyl)-(5-mercapto-1,3,4-thiadiazol-2-ylamino)-meth
yl-phosphonate (2a,b)
General Procedure. HClO4 (0.201 g, 2 mmol) was added to a solution of the
aldehyde (2 mmol) and 5-amino-1,3,4-thiadiazole-2-thiol (1) (0.266 g, 2 mmol) in dry
acetonitrile. The mixture was stirred at reflux for 15 min and then triphenyl phosphite
(0.621 g, 2 mmol) was added. After completion of the reaction (6 h), the reaction mixture
was quenched with aq. saturated NaHCO3 followed by brine solution and then extracted
with CH2Cl2, dried over Na2SO4, and concentrated under vacuum. The crude mixture was
purified by column chromatography on silica gel (hexane:ethyl acetate, 4:1) to afford pure
products.
Diphenyl (4-Chlorophenyl)-(5-mercapto-1,3,4-thiadiazol-2-ylamino)-met
hyl-phosphonate (2a). Yellow powder; Yield: 0.686 g (70%). mp. 243–244◦C; IR: 800,
998, 1161, 1253, 1278, 1483, 1618, 2969, 3368 1H NMR: 3.91 (s, 1H, CHN), 6.22 (s, 1H,
NH), 7.30–7.42 (m, 3H, Ar-H), 7.47 (d, 2H, J = 8.2, Ar-H), 7.68–7.75 (m, 2H, Ar-H), 7.79
(d, 2H, J = 8.2, Ar-H), 7.84–7.92 (m, 2H, Ar-H), 8.01–8.14 (m, 3H, Ar-H), 12.18 (s, 1H,
NH). 13C NMR: 58.7 (CHN), 112.1–151.2 (Ar-18C), 160.8 (C N), 182.1 (C S). MS (EI):
m/z = 490 ([M + H]+). Anal. Calcd. for C21H17ClN3O3PS2: C, 51.48; H, 3.50; N, 8.58.
Found: C, 51.39; H, 3.42; N, 8.39.
Diphenyl (4-Bromophenyl)-(5-mercapto-1,3,4-thiadiazol-2-ylamino)-met
hylphosphonate (2b). Yellow powder; Yield: 0.759 g (71%). mp. 231–232◦C. IR: 765,
972, 1127, 1245, 1298, 1493, 1620, 2966, 3290. 1H NMR: 4.01 (s, 1H, CHN), 6.05 (s, 1H,
NH), 7.23–7.35 (m, 3H, Ar-H), 7.39 (d, 2H, J = 8.2, Ar-H), 7.62–7.72 (m, 2H, Ar-H),

92
W. A. EL-SAYED AND O. M. ALI
7.76 (d, 2H, J = 8.2, Ar-H), 7.85–7.92 (m, 2H, Ar-H), 8.12–8.23 (m, 3H, Ar-H), 11.97 (s,
1H, NH). 13C NMR: 58.7 (CHN), 114.1–151.6 (Ar-18C), 160.5 (C N), 181.8 (C S). MS
(EI): m/z = 534 ([M + H]+). Anal. Calcd. for C21H17BrN3O3PS2: C, 47.20; H, 3.21; N,
7.86. Found: C, 47.02; H, 3.11; N, 7.69.
Diphenyl (4-Chlorophenyl)-{5-[(O-acetyl-β-D-glycopyranosyl)thio]-1,3,4-
thiadiazol-2-ylamino}methylphosphonates (5a,b). General procedure: To a solu-
tion of 2a,b (2 mmol) in aqueous KOH (0.112 g, 2 mmol, in 1 mL distilled water) was added
a solution of 2,3,4,6-tetra-O-acetyl-α-D-gluco- or 2,3,4-tetra-O-acetyl-α-D-xylopyranosyl
bromide (2.2 mmol) in acetone (20 mL). The reaction mixture was stirred at room temper-
ature for 5–7 h. until the reaction was judged complete by TLC (CHCl3/MeOH 99.5:0.5.
The solvent was evaporated under reduced pressure at 40◦C and the residue was washed
with distilled water to remove the KBr formed. The product was dried, and crystallized
from ethanol.
Diphenyl (4-Chlorophenyl)-{5-[(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos
yl)-thio]-1,3,4-thiadiazol-2-ylamino}methylphosphonate (5a). Pale yellow sol
id; Yield: 1.279 g (78%). mp. 146–147◦C. IR: 999, 1157, 1223, 1287, 1461, 1618, 1746,
1
3011, 3323. H NMR: 1.95, 2.02, 2.11, 2.13 (4s, 12H, 4 CH3CO), 4.02 (s, 1H, CHN),
ꢁ
4.07−4.11 (m, 1H, H-5), 4.15 (dd, 1H, J6,6 = 11.4, J5,6 = 2.8, H-6), 4.30−4.35 (m, 1H,
H-6ꢁ), 4.96 (t, 1H, J3,4 = 9.3, H-4), 5.27 (dd, 1H, J2,3 = 9.6, J3,4 = 9.3, H-3), 5.38 (t,
1H, J2,3 = 9.6, H-2), 5.77 (d, 1H, J1,2 = 10.2, H-1), 6.15 (s, 1H, NH), 7.29−7.37 (m, 3H,
Ar-H), 7.48 (d, 2H, J = 8.2, Ar-H), 7.69−7.68 (m, 2H, Ar-H), 7.75 (d, 2H, J = 8.2, Ar-H),
7.82−7.91 (m, 2H, Ar-H), 8.10−8.24 (m, 3H, Ar-H) ppm. 13C NMR: 19.3, 19.6, 20.7, 20.8
(4CH3CO), 62.7 (C-6), 64.2 (C-4), 68.7 (C-3), 69.5 (CHN), 71.3 (C-2), 71.9 (C-5), 82.1
(C-1), 126.1–150.2 (Ar-18C), 156.4, 157.1 (2C=N), 169.7, 170.3, 171.3, 171.5 (4C=O).
MS (EI) = 820 ([M+H]+). Anal. Calcd. for C35H35ClN3O12PS2: C, 51.25; H, 4.30; N,
5.12. Found, C, 51.12; H, 4.22; N, 5.02.
Diphenyl (4-Bromophenyl){5-[(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosy
l)-thio]-1,3,4-thiadiazol-2-ylamino}methylphosphonate (5b). Pale yellow solid;
Yield 1.366 g (79%). mp. 140–141◦C. IR: 1039, 1124, 1225, 1265, 1459, 1610, 1737, 2985,
3323. 1H NMR: 1.90, 2.04, 2.12, 2.15 (4s, 12H, 4 CH3CO), 3.96 (s, 1H, CHN), 4.07−4.11
(m, 1H, H-5), 4.15 (dd, 1H, J6,6 = 11.4, J5,6 = 2.8, H-6), 4.21−4.26 (m, 1H, H-6ꢁ), 4.61
ꢁ
(t, 1H, J3,4 = 9.3, H-4), 5.40 (dd, 1H, J2,3 = 9.6, J3,4 = 9.3 Hz, H-3), 5.66 (t, 1H, J2,3
=
9.6, H-2), 5.87 (d, 1H, J1,2 = 10.2, H-1), 6.02 (s, 1H, NH), 6.62−6.76 (m, 3H, Ar-H), 7.28
(d, 2H, J = 8.2, Ar-H), 7.70−7.77 (m, 2H, Ar-H), 7.81 (d, 2H, J = 8.2, Ar-H), 7.85−7.95
(m, 2H, Ar-H), 8.09–8.24 (m, 3H, Ar-H). 13C NMR: 19.3, 19.7, 20.7, 20.8 (4CH3CO), 62.6
(C-6), 64.6 (C-4), 68.4 (C-3), 69.6 (CHN), 71.3 (C-2), 71.9 (C-5), 82.1 (C-1), 119.1–150.6
(Ar-18C), 156.2, 157.1 (2C=N), 169.7, 170.4, 171.4, 171.6 (4C=O). MS (EI) = 863 (M+).
Anal. Calcd. for C35H35BrN3O12PS2: C, 48.62; H, 4.08; N, 4.86. Found: C, 48.49; H, 4.02;
N, 4.69.
Diphenyl (4-Chlorophenyl){5-[(2,3,4-tri-O-acetyl-β-D-xylopyranosyl)thio
]-1,3,4-thiadiazol-2-ylamino}methylphosphonate (6a). Pale yellow solid; Yield:
1.220 g (77%). mp. 143–144◦C. IR: 708, 1046, 1151, 1228, 1280, 1466, 1616, 1746, 2972,
ꢁ
3324. 1H NMR: 1.95, 2.08, 2.12 (3s, 9H, 3 CH3CO), 4.02 (s, 1H, CHN), 4.15 (dd, 1H, J5,5
=
11.4, J4,5 = 2.8, H-5), 4.30−4.34 (m, 1H, H-5ꢁ), 5.21 (t, 1H, J3,4 = 9.3, H-4), 5.26 (dd, 1H,
J2,3 = 9.6, J3,4 = 9.3, H-3), 5.33 (t, 1H, J2,3 = 9.6, H-2), 5.77 (d, 1H, J1,2 = 9.8, H-1), 6.15 (s,
1H, NH), 7.29−7.39 (m, 3H, Ar-H), 7.44 (d, 2H, J = 8.2, Ar-H), 7.70−7.76 (m, 2H, Ar-H),
7.79 (d, 2H, J = 8.2, Ar-H), 7.83−7.90 (m, 2H, Ar-H), 8.12−8.26 (m, 3H, Ar-H). 13C NMR:
19.4, 20.7, 20.9 (3CH3CO), 63.7 (C-5), 64.9 (C-4), 68.8 (C-3), 69.6 (CHN) 71.3 (C-2), 83.2

(THIADIAZOLAMINO)METHYLPHOSPHONATES AND THEIR THIOGLYCOSIDES
93
(C-1), 127.1–150.4 (Ar-18C), 156.4, 157.3 (2C N), 169.7, 170.4, 171.8 (3C O). MS
(EI) = 748 ([M + H]+). Anal. Calcd. for C32H31ClN3O10PS2. C, 51.37; H, 4.18; N, 5.62.
Found: C, 51.18; H, 4.12; N, 5.71.
Diphenyl (4-Bromophenyl){5-[(2,3,4-tri-O-acetyl-β-D-xylopyranosyl)thio
]-1,3,4-thiadiazol-2-ylamino}methylphosphonate (6b). Pale yellow solid; Yield:
1.236 g (78%). mp. 142–143◦C. IR: 701, 1041, 1142, 1231, 1277, 1453, 1614, 1746, 2963,
3361. 1H NMR: 1.97, 2.11, 2.14 (3s, 9H, 3 CH3CO), 3.99 (s, 1H, CHN), 4.25 (dd, 1H, J5,5
ꢁ
= 11.4, J4,5 = 2.8, H-5), 4.27−4.31 (m, 1H, H-5ꢁ), 5.28 (t, 1H, J3,4 = 9.3, H-4), 5.40 (dd,
1H, J2,3 = 9.6, J3,4 = 9.3, H-3), 5.45 (t, 1H, J2,3 = 9.6, H-2), 5.81 (d, 1H, J1,2 = 9.8, H-1),
6.11 (bs, 1H, NH), 7.18−7.24 (m, 3H, Ar-H), 7.28 (d, 2H, J = 8.2, Ar-H), 7.65−7.73 (m,
2H, Ar-H), 7.77 (d, 2H, J = 8.2, Ar-H), 7.82−7.91 (m, 2H, Ar-H), 8.12−8.27 (m, 3H, Ar-
H). 13C NMR: 19.4, 20.6, 20.9 (3CH3CO), 61.8 (C-5), 67.3 (C-4), 68.8 (C-3), 63.3 (CHN),
70.5 (C-2), 83.3 (C-1), 128.2–150.5 (Ar-18C), 157.4, 160.0 (2C N), 169.8, 170.7, 171.9
(3C O). MS (EI) = 791 (M+). Anal. Calcd. for C32H31BrN3O10PS2: C, 48.49; H, 3.94; N,
5.30. Found: C, 48.31; H, 4.05; N, 5.19.
Diphenyl (4-Halophenyl)-{5-[(β-D-glycopyranosyl)thio]-1,3,4-thiadiazol-
2-ylamino}methylphosphonates (7 a,b and 8a, b). General Procedure. A so-
lution of 5a,b and 6a,b (2 mmol) in methanolic ammonia solution (2M in methanol) was
stirred at 0◦C for 1 h then at room temperature for 8–11 h (TLC). The solvent was evap-
orated under reduced pressure and the residue was dissolved in absolute ethanol (12 mL)
and left over night to slow evaporation of the solvent to initiate the crystallization of the
compounds 7a,b and 8a,b.
Diphenyl (4-Chlorophenyl)-{5-[(β-D-glucopyranosyl)thio]-1,3,4-thiadiaz
ol-2-ylamino}methylphosphonate (7a). Brownish powder; Yield: 1.056 g (81%).
mp. 199–200◦C; IR: 804, 1048, 1108, 1205, 1285, 1482, 1618, 3051, 3365, 3467−3440.
1H NMR: 3.41–3.50 (m, 2H, H-6,6ꢁ), 3.55–3.59 (m, 1H, H-5), 3.75–3.82 (m, 2H, H-3,4),
3.97 (s, 1H, CHN), 4.21 (t, 1H, J2,3 = 9.2, H-2), 4.29 (t, 1H, J = 6.4, OH), 4.37–4.41
(m, 1H, OH), 4.92–4.96 (m, 1H, OH), 5.14 (t, 1H, J = 6.2, OH), 5.80 (d, 1H, J1,2
=
9.8, H-1), 6.08 (s, 1H, NH), 6.92–7.02 (m, 3H, Ar-H), 7.33–7.40 (d, 2H, J = 8.2, Ar-H),
7.66–7.78 (m, 4H, Ar-H), 7.84–7.92 (m, 2H, Ar-H), 8.02–8.15 (m, 3H, Ar-H). 13C NMR:
63.2 (C-6), 68.3 (C-4), 69.4 (CHN), 72.8 (C-3), 73.5 (C-2), 78.3 (C-5), 91.3 (C-1),
118.2–150.1 (Ar-18C), 157.0, 158.8 (2C N). MS (EI) = 652 ([M + H]+). Anal. Calcd.
For C27H27ClN3O8PS2: C, 49.73; H, 4.17; N, 6.44. Found: C, 49.52; H, 4.10; N, 6.25.
Diphenyl (4-Bromophenyl)-{5-[(β-D-glucopyranosyl)thio]-1,3,4-thiadiaz
ol-2-ylamino}methylphosphonate (7b). Brownish powder; Yield: 1.114 g (80%).
mp. 203–204◦C. IR: 755, 1054, 1122, 1214, 1276, 1482, 1612, 3093, 3348, 3460–3449.
1H NMR: 3.42–3.50 (m, 2H, H-6,6ꢁ), 3.56–3.61 (m, 1H, H-5), 3.78–3.88 (m, 2H, H-3,4),
3.91 (s, 1H, CHN), 4.20 (t, 1H, J2,3 = 9.2, H-2), 4.36 (t, 1H, J = 6.4, OH), 4.46–4.50 (m,
1H, OH), 4.97–5.02 (m, 1H, OH), 5.12 (t, 1H, J = 6.2, OH), 5.79 (d, 1H, J1,2 = 9.8, H-1),
6.07 (s, 1H, NH), 6.73–6.87 (m, 3H, Ar-H), 7.44 (d, 2H, J = 8.2, Ar-H), 7.50–7.60 (m, 2H,
Ar-H), 7.76–7.92 5 m, 4H, Ar-H), 8.11–8.25 (m, 3H, Ar-H). 13C NMR: 63.7 (C-6), 68.8
(C-4), 69.8 (CHN), 71.1 (C-3), 73.7 (C-2), 78.3 (C-5), 91.3 (C-1), 117.4–150.1 (Ar-18C),
156.8, 158.2 (2C N). MS (EI) = 696 ([M + H]+). Anal. Cacld. for C27H27BrN3O8PS2:
C, 46.56; H, 3.91; N, 6.03. Found,%: C, 46.42; H, 3.82; N, 5.95.
Diphenyl (4-Chlorophenyl)-{5-[(β-D-xylopyranosyl)thio]-1,3,4-thiadiazol
-2-ylamino}methylphosphonate (8a). Pale yellow solid; Yield: 0.982 g (79%). mp.
1
198–199◦C; IR: 755, 1042, 1123, 1207, 1235, 1472, 1612, 2972, 3357, 3430−3449. H
NMR: 3.41−3.50 (m, 2H, H-5,5ꢁ), 3.80−3.94 (m, 3H, H-3,4 and CHN), 4.23 (t, 1H,

94
W. A. EL-SAYED AND O. M. ALI
J2,3 = 9.2, H-2), 4.42 (t, 1H, J = 6.4, OH), 4.50−4.54 (m, 1H, OH), 5.07 (t, 1H, J = 6.2,
OH), 5.78 (d, 1H, J1,2 = 9.8, H-1), 6.08 (s, 1H, NH), 7.10−7.14 (m, 3H, Ar-H), 7.37 (d,
2H, J = 8.2, Ar-H), 7.61−7.68 (m, 2H, Ar-H), 7.73 (d, 2H, J = 8.2, Ar-H), 7.82−7.91
(m, 2H, Ar-H), 8.08−8.20 (m, 3H, Ar-H). 13C NMR: 63.7 (C-5), 68.7 (C-4), 69.5 (CHN),
71.1 (C-3), 73.5 (C-2), 92.1 (C-1), 122.4–150.2 (Ar-18C), 156.7, 157.4 (2C N). MS (EI)
= 622 ([M + H]+). Anal. Calcd. for C26H25ClN3O7PS2: C, 50.20; H, 4.05; N, 6.76. Found:
C, 49.97; H, 4.00; N, 6.61.
Diphenyl (4-Bromophenyl)-{5-[(β-D-xylopyranosyl)thio]-1,3,4-thiadiazol
-2-ylamino}methylphosphonate (8b). Yellow solid; Yield: 1.066 g (80%). mp.
1
192–193◦C. IR: 758, 1040, 1124, 1211, 1239, 1475, 1617, 1617, 3359, 3460−3442. H
NMR: 3.42−3.51 (m, 2H, H-5,5ꢁ), 3.75−3.85 (m, 2H, H-3,4), 3.90 (s, 1H, CHN), 4.28 (t,
1H, J2,3 = 9.2, H-2), 4.41 (t, 1H, J = 6.4, OH), 4.45–4.49 (m, 1H, OH), 5.18 (t, 1H, J =
6.2, OH), 5.80 (d, 1H, J1,2 = 9.8, H-1), 6.02 (s, 1H, NH), 6.95−7.11 (m, 3H, Ar-H), 7.38
(d, 2H, J = 8.2, Ar-H), 7.64−7.71 (m, 2H, Ar-H), 7.74 (d, 2H, J = 8.2, Ar-H), 7.88–7.97
(m, 2H, Ar-H), 8.05−8.18 (m, 3H, Ar-H). 13C NMR: 63.6 (C-5), 68.5 (C-4), 69.7 (CHN),
71.5 (C-3), 73.7 (C-2), 92.4 (C-1), 120.4–151.0 (Ar-18C), 156.9, 157.5 (2C N). MS (EI)
= 666 ([M+H]+). Anal. Calcd. for C26H25BrN3O7PS2: C, 46.85; H, 3.78; N 6.30. Found:
C, 46.67; H, 3.64; N, 6.50.
General Procedure for the Synthesis of S-substituted (1,3,4-Thiadiazol-
2-ylamino)methylphosphonate Derivatives 9-11
To a solution of 2a, b (2 mmol) in dry DMF (15 mL) was added K2CO3
(0.276 g, 2 mmol) and the mixture was stirred at room temperature for 1 h. 2-(2-
Chloroethoxyethanol), 1-chloro-2-methoxyethane or 3-chloropropane-1,2-diol (2 mmol)
was added and stirring was continued for 8–10 h (TLC) at 70◦C. The solvent was
removed under reduced pressure and the residue was triturated with a mixture of
diethyl ether:petroleum ether (40−60) [50:50]. The resulting solid was filtered off and
recrystallized from ethanol to give the desired products.
Diphenyl (4-Chlorophenyl)-{5-[2-(2-hydroxyethoxy)ethylthio]-1,3,4-thia
diazol-2-ylamino}methylphosphonate (9a). Pale yellow solid; Yield: 0.867 g
(75%). mp. 148–149◦C; IR: 714, 822, 1047, 1122, 1207, 1225, 1468, 1612, 3020, 3314,
3457. 1H NMR: 3.33 (t, 2H, J = 5.2, CH2), 3.86 (t, 2H, J = 5.6, CH2), 3.97−4.26 (m, 3H,
CH2 and CHN), 4.61 (t, 2H, J = 5.2, CH2), 4.74−4.78 (m, 1H, OH), 6.24 (bs, 1H, NH),
7.14−7.21 (m, 3H, Ar-H), 7.25 (d, 2H, J = 8.2, Ar-H), 7.68–7.75 (m, 2H, Ar-H), 7.79 (d,
2H, J = 8.2, Ar-H), 7.83−7.91 (m, 2H, Ar-H), 8.10−8.24 (m, 3H, Ar-H). 13C NMR: 47.1,
62.9, 67.5, 70.6 (4CH2), 73.9 (CHN), 111.1−150.2 (Ar-18C), 163.2, 164.4 (2C N). MS
(EI) = 578 ([M + H]+). Anal. Calcd. for C25H25ClN3O5PS2: C, 51.95; H, 4.36; N, 7.27.
Found: C, 51.32; H, 4.24; N, 7.11.
Diphenyl (4-Bromophenyl)-{5-[2-(2-hydroxyethoxy)ethylthio]-1,3,4-thia
diazol-2-ylamino}methylphosphonate (9b). Pale yellow solid; Yield: 0.959 g
(77%). mp. 142–143◦C. IR: 820, 1041, 1126, 1212, 1245, 1470, 1615, 2972, 3367, 3479.
1HNMR: 3.42 (t, 2H, J = 5.2, CH2), 3.92−4.01 (m, 2H, CH2), 4.15−4.29 (m, 3H,
CH2, and CHN), 4.78 (t, 2H, J = 5.2, CH2), 4.77−4.81 (m, 1H, OH), 6.26 (s, 1H, NH),
7.14−7.23 (m, 3H, Ar-H), 7.28 (d, 2H, J = 8.2, Ar-H), 7.60−7.67 (m, 2H, Ar-H), 7.71 (d,
2H, J = 8.2, Ar-H), 7.85−7.93 (m, 2H, Ar-H), 8.10−8.23 (m, 3H, Ar-H). 13C NMR: 47.5,
62.2, 67.5, 71.1 (4 CH2), 75.2 (CHN), 115.2–150.1 (Ar-18C), 163.9, 164.2 (2C N). MS

(THIADIAZOLAMINO)METHYLPHOSPHONATES AND THEIR THIOGLYCOSIDES
95
(EI) = 622 ([M + H]+). Anal. Calcd. for C25H25BrN3O5PS2: C, 48.24; H, 4.05; N, 6.75.
Found: C, 48.36; H, 3.94; N, 6.88.
Diphenyl (4-Chlorophenyl)-[5-(2-methoxyethylthio)-1,3,4-thiadiazol-2-y
lamino]methylphosphonate (10a). Yellow solid; Yield: 0.833 g (76%). mp.
1
134–135◦C. IR: 712, 833, 1029, 1186, 1245, 1289, 1488, 1610, 3056, 3352. H NMR:
3.56 (t, 2H, J = 5.4, CH2), 3.81 (s, 3H, OCH3), 3.98−4.18 (m, 3H, CH2, and CHN), 6.05
(s, 1H, NH), 7.24−7.31 (m, 3H, Ar-H), 7.35 (d, 2H, J = 8.2, Ar-H), 7.65−7.71 (m, 2H,
Ar-H), 7.75 (d, 2H, J = 8.2, Ar-H), 7.87−7.96 (m, 2H, Ar-H), 8.08−8.21 (m, 3H, Ar-H).
13C NMR: 55.7 (OCH3), 61.0, 62.6 (2 CH2), 72.9 (CHN), 118.1−150.2 (Ar-18C), 162.9,
163.7 (2C N). MS (EI) = 548 ([M + H]+). Anal. Calcd. for C24H23ClN3O4PS2: C, 52.60;
H, 4.23; N, 7.67. Found,%: C, 52.48; H, 4.19; N, 7.50.
Diphenyl (4-Bromophenyl)-[5-(2-methoxyethylthio)-1,3,4-thiadiazol-2-yl
amino]methylphosphonate (10b). Yellow solid; Yield: 0.912 g (77%). mp.
137–138◦C. IR: 830, 1031, 1180, 1242, 1285, 1477, 1615, 3077, 3371. 1H NMR: 3.57 (t,
2H, J = 5.4, CH2), 3.88 (s, 3H, OCH3), 4.12–4.31 (m, 3H, CH2, and CHN), 6.21 (s, 1H,
NH), 7.03–7.16 (m, 3H, Ar-H), 7.36 (d, 2H, J = 8.2, Ar-H), 7.65–7.73 (m, 2H, Ar-H),
7.77 (d, 2H, J = 8.2, Ar-H), 7.90–7.98 (m, 2H, Ar-H), 8.14–8.25 (m, 3H, Ar-H). 13C
NMR: 58.2 (OCH3), 62.9, 67.5 (2 CH2), 73.9 (CHN), 111.1–149.2 (Ar-18C), 160.5, 161.3
(2C N). MS (EI) = 591 (M+). Anal. Cacld. for C24H23BrN3O4PS2: C, 48.65; H, 3.91; N,
7.09. Found,%: C, 48.51; H, 3.74; N, 7.20.
Diphenyl (4-Chlorophenyl)-[5-(2,3-dihydroxypropylthio)-1,3,4-thiadiazol
-2-ylamino]methylphosphonate (11a). Pale yellow solid; Yield: 0.835 g (74%). mp.
1
182–183◦C. IR: 755, 840, 1042, 1120, 1214, 1261, 1458, 1612, 2966, 3482. H NMR:
3.66−3.72 (m, 3H, CH2, and OH), 3.91−4.01 (m, 2H, CH2), 4.22−4.31 (m, 2H, CHN,
and CHOH), 4.58−4.62 (m, 1H, OH), 6.14 (bs, 1H, NH), 7.22−7.31 (m, 3H, Ar-H), 7.36
(d, 2H, J = 8.2, Ar-H), 7.61−7.69 (m, 2H, Ar-H), 7.73 (d, 2H, J = 8.2, Ar-H), 7.88−7.96
(m, 2H, Ar-H), 8.10−8.22 (m, 3H, Ar-H). 13C NMR: 43.2, 66.2 (2 CH2), 72.1 (CHN),
73.1 (CHOH), 119.1−150.9 (Ar-18C), 161.1, 163.2 (2C N). MS (EI) = 564 ([M + H]+).
Anal. Cacld. for C24H23ClN3O5PS2: C, 51.11; H, 4.11; N, 7.45. Found: C, 50.95; H, 4.02;
N, 7.36.
Diphenyl (4-Bromophenyl)-[5-(2,3-dihydroxypropylthio)-1,3,4-thiadiazol
-2-ylamino]methylphosphonate (11b). Pale yellow solid; Yield: 0.913 g (75%). mp.
179–180◦C. IR: 827, 1040, 1118, 1211, 1258, 1468, 1615, 2972, 3485. 1H NMR: 3.79−3.85
(m, 3H, CH2, and OH), 4.05−4.14 (m, 2H, CH2), 4.28−4.38 (m, 2H, CHN, and CHOH),
4.98−5.02 (m, 1H, OH), 6.15−6.19 (bs, 1H, NH), 7.25−7.37 (m, 3H, Ar-H), 7.41 (d,
2H, J = 8.2, Ar-H), 7.59−7.67 (m, 2H, Ar-H), 7.72 (d, 2H, J = 8.2, Ar-H), 7.88−7.98
(m, 2H, Ar-H), 8.12−8.24 (m, 3H, Ar-H). 13C NMR: 44.2, 66.6 (2 CH2), 72.8 (CHN),
73.2 (CHOH), 118.3−151.3 (Ar-18C), 161.5, 163.4 (2C=N). MS (EI) = 607 (M+). Anal.
Cacld. for C24H23BrN3O5PS2: C, 47.37; H, 3.81; N, 6.91. Found: C, 47.14; H, 3.68; N,
7.11.
CONCLUSION
New (1,3,4-thiadiazol-2-ylamino) methylphosphonate derivatives were synthesized
by a three component reaction of aromatic aldehyde, thiadiazolylamine, and triphenyl
phosphite. Glycosylation and alkylation, of the phosphonates linked to thiadiazole thioles,
with acyclic oxygenated halides lead to the formation of the S-substituted derivatives.

96
W. A. EL-SAYED AND O. M. ALI
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