Hydroxymethylation of rhodanine

Article abstract of DOI:10.1134/S1070363210030230

Rhodanine in alcohol solution reacts with formaldehyde aqueous solution to form 3-hydroxymethylrhodanine. In the presence of triethylamine occurred also bis-hydroxymethylation at 5 position of the thiazolidine ring, but we failed to isolate the 3,5,5-trishydroxymethyl derivative in an individual form. The treatment of crude rhodanine 3,5,5-trishydroxymethyl derivative with benzaldehyde in boron trifluoride etherate leads to thioxo-8-phenyl-7,9-dioxa-1- thia-3-azaspiro[4.5]decan-4-one. The dissolution of the latter in aqueous alkali followed by neutralization with acid gives 5-sulfanyl-2-phenyl-1,3-dioxane-5- carboxylic acid.

Full text of DOI:10.1134/S1070363210030230

ISSN 1070-3632, Russian Journal of General Chemistry, 2010, Vol. 80, No. 3, pp. 507–510. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © Sun Min’yan’, S.M. Ramsh, S.Yu. Solov’eva, V.I. Zakharov, 2010, published in Zhurnal Obshchei Khimii, 2010, Vol. 80, No. 3,
pp. 485–488.
Hydroxymethylation of Rhodanine
Sun Min’yan’, S. M. Ramsh, S. Yu. Solov’eva, and V. I. Zakharov
St. Petersburg State Institute of Technology, Moskovskii pr. 26, St. Petersburg, 190013 Russia
e-mail: gsramsh@mail.wplus.net
Received October 13, 2009
Abstract―Rhodanine in alcohol solution reacts with formaldehyde aqueous solution to form 3-
hydroxymethylrhodanine. In the presence of triethylamine occurred also bis-hydroxymethylation at 5 position
of the thiazolidine ring, but we failed to isolate the 3,5,5-trishydroxymethyl derivative in an individual form.
The treatment of crude rhodanine 3,5,5-trishydroxymethyl derivative with benzaldehyde in boron trifluoride
etherate leads to thioxo-8-phenyl-7,9-dioxa-1-thia-3-azaspiro[4.5]decan-4-one. The dissolution of the latter in
aqueous alkali followed by neutralization with acid gives 5-sulfanyl-2-phenyl-1,3-dioxane-5-carboxylic acid.
DOI: 10.1134/S1070363210030230
In [1] has been argued that hydroxymethylation of
rhodanine (I) and its 5-R-methylidene derivatives by
the traditional way with formaldehyde in an organic
solvent in the presence of an organic base leads to 3-
hydroxymethylrhodanine (II) or 3-hydroxymethyl-5-
R-methylidenrhodanines, respectively. This method of
synthesis of these compounds was protected by the
USSR Inventor Certificates [2, 3]. Later on, the
hydroxymethylation of 5-R-5-methylidenerhodanines
was carried out also by the interaction in solid phase of
their triethylammonium salts with gaseous formal-
dehyde [4]. However, in [1], and in the invention
descriptions [2, 3] we did not find any information on
the preparation and properties of 3-hydroxy-
methylrhodanine (II), besides the mentioned state-
ment. The search for this compound in the databases
Beilstein (MDL CrossFire Commander) and CAS
(SciFinder) led to the same source materials [1–3].
Apparently, actually it has not been obtained.
It was found that in water–alcohol medium at room
temperature in the presence of ~3-fold excess of
formaldehyde, rhodanine I forms with formaldehyde a
monoadduct which, judging from the presence in the
IR spectrum of absorption bands of the thioamide
fragment [1], is 3-hydroxymethylrhodanine II. This
adduct is unstable and at the attempted recrystal-
lization from water or ethanol partially (85 and 70%,
respectively) splits formaldehyde off, converting into
the initial rhodanine I. Moreover, the dissociation of
the dissolved adduct II takes place at room tem-
perature: on the walls of the tube containing its solu-
tion in alcohol crystallizes rhodanine I.
In the 1H NMR spectrum of the product of
hydroxymethylation isolated from the reaction mixture
along with the signal of methylene protons of N-
hydroxymethyl group of the adduct II at 5.19 ppm
another signal at 5.28 ppm is often detected with an
intensity up to ~2–8% of the intensity of the first
signal. The latter signal probably is related to the
resonance of methylene protons of S-hydroxymethyl
group of the isomeric adduct, which we have failed to
isolate in the individual form.
Previously we showed that pseudothiohydantoin,
which is similar in the structure to rhodanine (I) and
creatinine, forms 5,5-bishydroxymethyl derivative
under the action of formaldehyde in weakly basic
medium [5, 6], while in the absence of a base in an
alcohol–water medium it adds one molecule of
formaldehyde to the exocyclic nitrogen atom with the
formation of 2'-monohydroxymethyl derivative [7].
The above results prompted us to study the reaction of
hydroxymethylation of rhodanine I with formaldehyde
in the presence and in the absence of the basic reagent.
At conducting hydroxymethylation with 4–5-fold
excess of formaldehyde in the presence of a catalytic
amount of triethylamine, despite the distinct indication
of the interaction, i.e., rapid dissolution of rhodanine I,
we failed to isolate an individual product of
hydroxymethylation: the oil remaining after removal of
1
the solvent consisted, according to H NMR spec-
507

508
SUN MIN’YAN’ et al.
HO
O
O
O
CH2O
N
N
HN
+
S
S
S
S
S
HO
S
II
I
O
HO
O
HN
N
CH2O
NEt3
OH
OH
S
S
S
S
trihydroxymethylrhodanine
I
O
O
HN
HN
RCHO
O
O
H+
H2O
OH
OH
BF3·Et2O
S
S
S
S
III
dihydroxymethylrhodanine
(1) NaOH,
(2) HCl
O
O
N
O
O
O
H2N
N
H2N
N
CH3
HS
H2N
S
IV
pseudothiohydantoin
creatinine
troscopy data, of rhodanine 3,5,5-trishydroxymethyl
different samples of the “recrystallized” spirane III the
content of the presumed dihydroxymethyl derivative
ranged from 34 to 66%, but complete conversion of
spirane III into the dihydroxymethyl derivative
through a “recrystallization” could not be reached. The
dihydroxymethyl derivative impurities could be easily
washed out from spirane III, but we failed to isolate it
in individual form from washing water or in special
experiments of splitting spirane III in toluene in the
presence of boron trifluoride etherate and its
hydrolysis in acidic aqueous–alcohol media: After
removal of the solvent a viscous oil was obtained,
which, according to NMR and TLC data, consisted of
a mixture of spirane III, the rhodanine 5,5-bis-
dihydroxymethyl derivative, and unidentified im-
purities.
1
derivative and unidentified impurities (in the H NMR
spectrum of this oil in DMSO-d6 there are the signals
of the protons of three methylene groups), but our
manipulations did not lead to its crystallization.
We treated this crude oil with benzaldehyde in
boron trifluoride etherate and obtained, by analogy
with [8], the corresponding spiro compound III. This
compound by its chemical nature is a cyclic acetal and
can be hydrolyzed in acidic medium with the
formation of the rhodanine 5,5-dihydroxymethyl
derivative. Apparently, it is the hydrolytic splitting of
the crude (with acidic impurities) spirane III owing to
the presence of residual moisture in the solvent that
can explain the appearance in the 1H NMR spectrum of
the substance “recrystallized” from commercial
toluene of an additional quadruplet (doublet of
doublets) at 3.76 and 3.65 ppm (J = 11.2 Hz)
characteristic of the spin system CHAHB, that lies close
to the corresponding quadruplets in the spectra of
similar 5,5-dihydroxymethyl derivatives of pseudo-
thiohydantoin (3.65 and 3.59 ppm, J = 10.8 Hz ) and
creatinine (3.44 and 3.39 ppm, J = 10.8 Hz) [5, 6]. In
When compound III was dissolved in aqueous
alkali and the resulting solution was neutralized,
derivative of thioglycolic acid IV precipitated. Its
structure was determined from the spectral charac-
teristics. The presence of characteristic vibration bands
of the carboxy and thiol groups in the IR spectrum,
1
signals of the protons in the H NMR spectrum, and
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509
HYDROXYMETHYLATION OF RHODANINE
the molecular ion [MH]– in the ESI mass spectrum, m/z
239.0386, is consistent with the structure IV. The easy
cleavage of thiazolidine ring in an alkaline medium
apparently owes to steric strain in the dioxane-spiro-
thiazolidine structure III.
reaction mixture of dark claret color was transferred to
a round-bottom flask, 50 ml of water was added and
then water was distilled off at a reduced pressure on a
rotary evaporator (temperature of the heating water
bath was 100°C) until an oily residue in the flask did
not yet solidify, but the distilled off water slowly
dropped into the receiver (approximately after 40–
50 min). Then to the remaining oil was added 25–30 ml
of alcohol, the resulting solution was boiled for
10 min, and alcohol was distilled off on a rotary
evaporator at a reduced pressure when the temperature
of heating bath was maintained at 80–100°C till oil
remained liquid, but the alcohol already slowly
distilled into the receiver (approximately after 1–2 h).
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker
AM-400 (400 MHz), solvent DMSO-d6. The IR
spectra were taken on a spectrophotometer Shimadzu
FTIR-8400S from KBr tablets. Elemental analysis was
performed on the analyzer LECO CHNS(O) 942. TLC
was performed on Silufol UV-254 plates, eluent
acetone–hexane, 1:1 (compound II) and 2:3 (com-
pounds III, IV). The mass spectrum of compound IV
was registered on a Bruker micrOTOF 10223 by ESI
(ElectroSpray Ionization) method in solution in
acetonitrile.
The residue was dark claret oil immiscible with
1
water (crude trihydroxymethylrhodanine). H NMR
spectrum, 400 MHz (DMSO-d6), δ, ppm, J, Hz: 5.17 s
(2H, NCH2OH); 3.80 d [2H, Jgem(AB) = 10.8, C4HA,
C6HA], 3.64 d [2H, Jgem(AB) = 10.8, C4HB, C6HB], 3.75 d
[2H, Jgem(AB) = 10.8, C4HA, C6HA], 3.71 d [2H, Jgem(AB) =
10.8, C4H, C6HB] (two quadruplet, overlapping).
3-(Hydroxymethyl)-2-thioxothiazolidin-4-one (II).
To a solution of 6.65 g (0.050 mol) of rhodanine I
in 50 ml of alcohol at 40°C was added 13.8 ml
(0.172 mol) of 37% formaldehyde. The reaction
mixture was stirred with a magnetic stirrer for 20 min
(complete dissolution does not occur), then the
reaction mixture was poured into a Petri dish and left
overnight (or the solvent was partially evaporated by a
flow of warm air over 2–3 h). Then to the reaction
mixture (yellow oil or oily solution) was added 50 ml
of water (oil and water do not mix) and allowed to
stand in a Petri dish overnight (or the solvent was
partially evaporated by a flow of warm air over 2–3 h).
The oil gradually solidified in water. The solid was
crushed, the resulting precipitate was filtered off and
dried in air for 10 h. Yield 6.59 g (81%), mp 45–47°C.
1H NMR (400 MHz, DMSO-d6), δ, ppm: 4.23 s (2H,
C5H2), 5.20 s (2H, NCH2OH). IR spectrum, ν, cm–1:
3434 [ν(O–H)], 1719 [ν(C=O)], 1229 (thioamide II),
1049 (thioamide I). Found, %: C 28.79; H 2.99; N
8.96; S 38.96. C4H5NO2S2. Calculated, %: C 29.44; H
3.09; N 8.58; S 39.29.
To 7.54 g (0.0338 mol) of crude trihydroxy-
methylrhodanine with stirring by a magnetic stirrer
was added 5.3 ml (5.539 g, 0.5219 mol) of benz-
aldehyde. The oil was not dissolved and the liquid
phase became red. To the resulting mixture was added
10 ml of boron trifluoride etherate, therewith the oil
thickened and yellow emulsion formed over it. The
thickened and split into lumps oil was rubbed with a
metallic spatula for 30 min, therewith it gradually
“diverged,” transforming into thick emulsion, while
occurred a slight warming and darkening of the
reaction mixture. After 3.5 h of stirring, the mixture
was left overnight. On the next day, the emulsion was
stirred by a magnetic stirrer for an hour, then 20 ml of
ether was added, and the stirring was continued for
another 1.5 h. There was a slight self-heating, the
reaction mass became less colored and gradualy
transformed from the emulsion to a suspension of a
yellow precipitate. The latter was filtered off on a
vacuum filter and dried in a vacuum desiccator for 4 h.
Yield of crude product 5.40 g (49% of rhodanine I,
2-Thioxo-8-phenyl-7,9-dioxa-1-thia-3-azaspiro-
[4.5]decan-4-one (III). To a flat-bottom flask with a
magnetic stirrer was loaded 5.18 g (0.0389 mol) of
rhodanine I and 14.2 ml (0.177 mol) of 37% form-
aldehyde, and at stirring was added 0.2 ml of tri-
ethylamine. The solution was warmed to 40–50°C, and
rhodanine dissolved completely. The stirring was
continued for 1 h at room temperature, then the solu-
tion was neutralized with 0.7 ml of 10% HCl. The
1
57% of trihydroxymethylrhodanine). H NMR spec-
trum, 400 MHz (DMSO-d6), δ, ppm, J, Hz: 7.37 m
(5H, C6H5), 5.71 s (1H, C2H), 4.48 d [2H, Jgem(AB) =
11.8, C4HA, C6HA], 4.44 d [2H, Jgem(AB) = 11.8, C4HB,
C6HB]. The spectrum also contains signals of
dihydroxymethylrhodanine (about 6%) 3.75 d [2H,
J
gem(AB) = 10.8, CHA], 3.64 d [2H, Jgem(AB) = 10.8,
CHA].
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SUN MIN’YAN’ et al.
To 5.00 g (0.0178 mol) of crude product was added
dissolved at stirring with a magnetic stirrer in 3.5 ml
(0.350 g, 8.75 mmol) of 10% aqueous NaOH. To the
resulting solution was added 12–15 drops of
concentrated HCl to pH = 4. After 2 h a white pre-
cipitate formed was filtered off, washed with 2×5 ml
of water, and dried first in air and then for 4 h in a
vacuum desiccator. Yield 0.120 g (70 %), mp 128–
130°C (from 6 ml of ethanol, the yield at the stage of
40 ml of water, the precipitate was carefully ground,
filtered off on a vacuum filter, washed with water,
3×15 ml (to pH 4–5 of washings) and dried for 4 h in a
vacuum desiccator. Yield 3.00 g (27% on rhodanine I,
60% at the stage of washing). The product was
recrystallized from toluene (4–5 ml of toluene per 0.1 g
of the substance) and dried in a vacuum desiccator for
5 h. Yield at the stage of recrystallization 40–50%, mp
198–200°C. 1H NMR spectrum, 400 MHz (DMSO-d6),
δ, ppm, J, Hz: 7.38 m (5H, C6H5), 5.74 s (1H, C2H),
4.50 d [2H, Jgem(AB) = 10.8, C4HA, C6HA], 4.45 d [2H,
1
recrystallization 50%). H NMR spectrum, 400 MHz
(DMSO-d6), δ, ppm, J, Hz: 13.38 br (1H, COOH), 7.41
m (5H, C6H5), 5.49 s (1H, C2H), 4.52 d [2H, Jgem(AB) =
10.8, C4HA, C6HA], 4.26 d [2H, Jgem(AB) = 10.8, C4H,
C6HA], 3.17 br (SH). IR spectrum, ν, cm–1: 3450
[ν(O–H)], 2577 [ν(S–H)], 1699 [ν(C=O)], 1380 [δ(O–H)],
1299, 1281 [ν(C–O)]. Found, %: C 53.47; H 5.28; S
13.14. [MH]–, m/z 239.0386. C11H12O4S. Calculated,
%: C 54.99; H 5.03; S 13.35. [MH]– 239.0384.
J
gem(AB) = 10.8, C4HB, C6HB]. IR spectrum, ν, cm–1:
3165 [ν(N–H)], 3075 [ν(N–H)], 1709 [ν(C=O)], 1220
(thioamide II), 1081 (thioamide I). Found, %: C 51.17;
H 3.98; N 4.83. C12H11NO3S2. Calculated, %: C 51.23;
H 3.94; N 4.98.
Attempt to prepare 5,5-di(hydroxymethyl)-2-
thioxothiazolidin-4-one. Combined filtrates obtained
after washing with water of crude spirane III (previous
experiment) was evaporated on a rotary evaporator in a
vacuum at a temperature of water bath 60–70°C for
1.5 h. The residue (about 2 ml of yellow syrup) was
poured from the flask to a beaker, and the precipitate
remained on the walls of the flask was washed out with
about 5 ml of water to a Petri dish. After 5 days, the
Petri dish with the remaining yellow oily liquid and a
small amount of yellow solid residue (about 1 ml) was
put to a flow of warm air for 3 h, therewith a visible
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5-Sulfanyl-2-phenyl-1,3-dioxane-5-carboxylic
acid (IV). 0.200 g (0.711 mmol) of compound III was
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 3 2010