REACTION OF THIOUREIDOMETHYLENEBISPHOSPHONIC ACIDS...: I.
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dissolved in a mixture of 16 ml of MeOH, 4 ml of
water, and 8 ml of triethylamine. Isothiocyanate,
12 mmol, was then added, and the mixture was heated
for 10 h at 60°C (with AdNCS or t-BuNCS, the
mixture was kept for two weeks at 40°C) and then
evaporated at 40°С in a water-jet-pump vacuum to
obtain a viscous oily residue. The residue was
dissolved in 30 ml of water, and the solution was
treated with activated charcoal, filtered, and by-
products were extracted with ether (3×15 ml). The
ethereal solution was evaporated at 40°С to obtain a
(2-R-Imino-4-methylthiazol-2,3-dihydro-1,3-thi-
azol-3-yl)methylenebisphosphonic acids VIa–VIc.
Concentrated HBr, 4 ml (~40 mmol), and 11 mmol of
bromoacetone were added to a solution of 10 mmol of
N3-R-thioureidomethylenebisphosphonic acid, prepared
as described above. The mixture was refluxed for
10 min, cooled, and the product was filtered off.
[2-Cyclohexylimino-4-(4-methylphenyl)-2,3-dihyd-
ro-1,3-thiazol-3-yl]methylenebisphosphonic acid
(VId). Acetic acid, 5 ml, and 11 mmol of 4-me-
thylphenyl bromomethyl ketone were asses to a
solution of 10 mmol of (N3-cyclohexyl)thioureidome-
thylenebisphosphonic acid, prepared as described
above. The mixture was refluxed for 40 h. During this
period, the product precipitated. It was filtered off,
washed with МеOH and acetone, and dried in air.
1
viscous oily residue. According to H NMR data, the
residue contained thioureidomethylenebisphosphonic
acid and 2.1–2.5 equiv of triethylamine. It was
dissolved in 20 ml of МеОН, and the solution was
used in the synthesis of thiazsoles and thiazolines.
(2-R-Imino-4-Ar-4-hydroxythiazolin-3-yl)me-
thylenebisphosphonic acids IVa–IVe. A solution of
10 mmol of N3-(Ad or t-Bu)thioureidomethylene-
bisphosphonic acid, prepared as described above, was
acidified with 50 mmol of АsОН, after which 1.1 equiv
of haloketone was added, and the mixture was stirred
for 6 h at room temperature (according to the 31Р NMR
spectrum, the mixture consisted almost exclusively of
thiazoline). Water, 5 ml, was then added, and the mix-
ture was acidified with 2 ml (~20 mmol) of con-
centrated HBr. Crystals formed and were filtered off,
washed with methanol and acetone, and dried in air.
According to the 31Р NMR spectrum of the reaction
mixture, two isomeric thiazoles, VI (56 %) and V (44%),
formed during reaction, but the product that crystal-
lized was a pure compound VId.
(4-Methyl-2-phenylimino-2,3-dihydro-1,3-thia-
zol-3-yl]methylenebisphosphonic acid (VIe). Phenyl
isothiocyanate, 11 mmol, was added to 10 mmol of
aminomethylenebisphosphonic acid in a mixture of
16 ml of МеОН, 4 ml of water, and 6.2 ml (45 mmol)
of triethylamine. The mixture was heated for 3 h at 60°С,
cooled, and acidified with 0.3 ml (5.3 mmol) of acetic
acid. Bromoacetone, 11 mmol, was added, the mixture
was stirred and left for 24 h at room temperature, after
which it was acidified with 4 ml of conc. HCl. The
product crystallized after rubbing with a glass rod. It
was filtered off, washed with МеОН and acetone, and
dried in air.
Product IVb precipitated as a solvate with one
molecule of МеОН, and Ad-substituted compounds
IVc–IVe, as complexes with 1/2 NEt3.
(3-R-4-R'-5-R''-2,3-dihydro-1,3-thiazol-2-yl-
imino)methylenebisphosphonic acids Va–Vu. Water,
3 ml, was added to the thoureid solution, and it was
acidified with HCl to рН 1–2. Haloketone, 1 equiv,
was then added, and the mixture was refluxed for
30 min. After cooling, the product was filtered off,
washed with methanol and acetone, and dried in air.
[2-(4-Nitrophenyl)imino-4-R-2,3-dihydro-1,3-
thiazol-3-yl]methylenebisphosphonic acids VIf and
VIg were prepared like VId, refluxed for 3 h, and the
products precipitated after cooling and acidifying with
4 ml of conc. HBr. The product was filtered off,
washed with МеOH and acetone, and dried in air.
(3-Phenyl-4-methyl-2,3-dihydro-1,3-thiazol-2-
ylimino)methylenebisphosphonic acid (Vc). Phenyl-
thioureidomethylenebisphosphonic acid trisodium salt
trihydrate, 4.96 g, was dissolved in a mixture of 30 ml
of water, 10 ml of МеОН, and 22 mmol of HCl, after
which 1.05 ml (13 mmol) of bromoacetone was added.
The mixture was stirred until homogeneous and left at
room temperature. After 8 h the product began to
precipitate. After 5 days the precipitate was filtered
off, washed in succession with aqueous methanol,
methanol, and acetone, and dried in air.
[2-(4-Chlorophenyl)imino-4-(4-methylphenyl)-2,3-
dihydro-1,3-thiazol-3-yl]methylenebisphosphonic
acid (VIh) was prepared like VId and refluxed for 6 h.
After cooling, the product gradually precipitated. It
was filtered off, washed with МеOH and acetone, and
dried in air.
By 31Р NMR data, the reaction mixture contained
two isomeric thiazoles, VI and V, in a ca. 1:1 ratio, but
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 1 2009
Chuiko
