Polyfunctional derivatives of isocytosine. Effect of hydration on prototropic tautomerism of 2-(2-hydroxyethyl)amino-6-methylpyrimidin-4(3H)-one

Article abstract of DOI:10.1007/s11176-005-0287-x

Hydration of 2-(2-hydroxyethyl)amino-6-methylpyrimidin-4(3H)-one forms an equilibrium mixture of 4-oxo-3,4-dihydro and 4-hydroxy tautomers. The intermediate in mutual transitions of these tautomers has a zwitter ionic structure. The equilibrium shifts to the 4-oxo-3,4-dihydro form as the polarity of the medium decreases. 2005 Pleiades Publishing, Inc.

Full text of DOI:10.1007/s11176-005-0287-x

Russian Journal of General Chemistry, Vol. 75, No. 4, 2005, pp. 639 644. Translated from Zhurnal Obshchei Khimii, Vol. 75, No. 4, 2005,
pp. 677 682.
Original Russian Text Copyright
2005 by Erkin, Krutikov.
Polyfunctional Derivatives of Isocytosine. Effect of Hydration
on Prototropic Tautomerism
of 2-(2-Hydroxyethyl)amino-6-methylpyrimidin-4(3H)-one
A. V. Erkin and V. I. Krutikov
St. Petersburg State Institute of Technology, St. Petersburg, Russia
Received September 9, 2004
Abstract Hydration of 2-(2-hydroxyethyl)amino-6-methylpyrimidin-4(3H)-one forms an equilibrium mix-
ture of 4-oxo-3,4-dihydro and 4-hydroxy tautomers. The intermediate in mutual transitions of these tautomers
has a zwitter ionic structure. The equilibrium shifts to the 4-oxo-3,4-dihydro form as the polarity of the
medium decreases.
The prototropic tautomerism of 2-amino-4-oxo-
pyrimidines and its dependence on specific solvation
has repeatedly been studied on isocytosine as an
example. In a neutral aqueous solution, isocytosine
exists as a mixture of 4-oxo-1,4-dihydro and 4-oxo-
3,4-dihydro tautomers [1, 2], the latter prevailing in
less polar media [1, 3, 4]. Existence of the 4-hydroxy
tautomer of isocytosine and its zwitter ionic analog is
not ruled out completely, but is considered unlikely
by formal reasons [2]. At the same time, the 4-oxo-
3,4-dihydro and 4-hydroxy tautomers form a pair
involved in intermolecular proton transfer on iso-
cytosine hydration [5].
Similar reactions of 3,6-dimethyl-2-(methylsul-
fanyl)pyrimidin-4(3H)-one (IV) and 1,6-dimethyl-2-
(methylsulfanyl)pyrimidin-4(1H)-one
(V)
with
2-aminoethanol gave the model compounds 2-(2-
hydroxyethyl)amino-3,6-dimethylpyrimidin-4(3H)-
one (VI) and 2-(2-hydroxyethyl)amino-1,6-dimethyl-
pyrimidin-4(1H)-one (VII), respectively, and required
methyl sulfides IV and V, by exhaustive S,N-dime-
thylation of thioxoketone III with excess dimethyl
sulfate by our modified procedure [9].
The other model compound 2-(4-methoxy-6-me-
thylpyrimidin-2-yl)aminoethyl acetate (X) was syn-
thesized by consecutive acetylation of substituted iso-
cytosine I with excess acetic anhydride in absolute
pyridine, exchange chlorination of 2-(6-methyl-4-oxo-
3,4-dihydropyrimidin-2-yl)aminoethyl acetate (VIII)
with phosphoryl chloride, and methoxylation of 2-(4-
chloro-6-methylpyrimidin-2-yl)aminoethyl acetate
(IX) with sodium methylate in absolute methanol.
Contrary to expectations, the latter reaction is not
accompanied by elimination of the acetyl protective
group even with a 3-fold excess of sodium methylate,
and deacetylation of ester X in aqueous alkali gives
rise to 2-(4-methoxy-6-methylpyrimidin-2-yl)amino-
ethyl acetate (X) that is impossible to crystallize from
various solvents because of its extreme hygroscopicity.
By the same reason, pyrimidine XI hydrochloride
could not be isolated crystalline by treatment with
saturated HCl solutions in absolute diethyl ether or
ethanol.
The aim of the present work was to study the effect
of hydration on the prototropic tautomerism of a poly-
functional isocytosine derivative, 2-(2-hydroxyethyl)-
amino-6-methylpyrimidin-4(3H)-one (I), by UV
spectroscopy.
The prototropic tautomerism of substituted iso-
cytosine I in ethanol have been by Agai et al. who
provided unambiguous evidence to show that this
compound exists exclusively as the 4-oxo-3,4-dihydro
tautomer.
Compound I was synthesized by amination of 6-
methyl-2-(methylsulfanyl)pyrimidin-4(3H)-one (II)
with excess 2-aminoethanol in rigid conditions, and
thio ether II, by S-methylation of 6-methyl-2-thio-
uracil (III) with equimolar amount of dimethyl sulfate
in aqueous alkali. Unlike the other known syntheses
of compound I via cyclocondensation of 2-(hydroxy-
ethyl)guanidine with ethyl acetoacetate [7] and amina-
tion of thio ether II with a mixture of 2-aminoethanol
and its hydrochloride [8], our procedure is more facile
to realize.
The UV spectra of compound I in neutral aqueous
4
solutions [c (0.5 1.5) 10 M] contain a broad
asymmetric band with a maximum at 272 nm (log
3.71) and a shoulder at 285 nm (Fig. 1a). At the same
time, the optical density of solutions of compound I
1070-3632/05/7504-0639 2005 Pleiades Publishing, Inc.

640
ERKIN, KRUTIKOV
O
N
O
N
O
N
O
HO
NH2
Me2SO4
Ac2O
HN
S
HN
HN
HN
N
HO
AcO
N
MeS
Me
Me
Me
Me
N
H
H
H
III
II
Me
MeS
I
VIII
O
Cl
O
N
POCl3
Me2SO4
N
N
N
+
AcO
N
H
Me
MeS
N
Me
Me
N
Me
IV
V
IX
HO
HO
NH2
NH2
MeONa
OMe
N
O
O
Me
N
N
N
AcO
HO
HO
N
N
H
N
Me
Me
N
Me
N
H
H
Me
VI
VII
X
linearly varies with concentration only in the range
(0.5 1.25) 10 M, whereas at higher concentrations,
negative deviations from the Bouguer law are ob-
served. The possible reason for this phenomenon is
hydration of isocytosine I followed by prototropic
rearrangement.
effect [log 3.98 (ethanol) and 4.00 (DMF)], as the
polarity of the solvent decreases (the normalized Di-
mroth Reichrdt polarity parameters ENT for water,
ethanol, and DMF are 1.000, 0.654, and 0.404, respec-
tively [10]) (Fig. 1b). Such a negative solvatochro-
mism of isocytosine I is a qualitative criterion of its
hydration.
4
To obtain evidence for hydration, we compared the
spectra of compound I in water, ethanol, and DMF
and found out that the absorption band gets narrower
and suffers a bathochroic shift to 289 (ethanol) and
290 nm (DMF), accompanied by a hyperchromic
The presence in molecule I of two potential hydra-
tion centers, amide and guanidine, necessitates as-
sessment of the degree of involvement of each of
them in hydrogen bonding. Comparing the UV spectra
(a)
(b)
12000
20000
1
2
3
10000
15000
4
2
8000
3
10000
6000
4000
2000
5
1
5000
0
0
200 220
240 260 280 300 320
220
240
260
280
300
320
, nm
4
Fig. 1. UV spectra of 2-(2-hydroxyethyl)amino-6-methylpyrimidin-4(3H)-one (I) in (a) water [concentration (1) 0.5 10
(2) 0.75 10 , (3) 10 , (4) 1.25 10 , and (5) 1.5 10 M], (b) (1) water, (2) ethanol, and (3) DMF.
,
4
4
4
4
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 4 2005

POLYFUNCTIONAL DERIVATIVES OF ISOCYTOSINE
641
4
4
10000
8000
0.6
5
3
2
0.5
3
5
6000
4000
2000
0
2
B
0.4
1
1
0.3
6
A
0.2
0.30
0.35
0.40
0.45
0.50
Dav
240
260
280
300
320
, nm
Fig. 2. UV spectra of the (1) neutral, (2) cationic, and
(3) anionic forms of 2-(2-hydroxyethyl)amino-6-methyl-
pyrimidin-4(3H)-one (I), (4) methylisocytosine VI,
(5) methylisocytosine VII, and (6) ester X.
Fig. 3. Optical density of solution i (D ) vs. average
i
optical density (D ) of other solutions at various
av
wavelengths (the numbers in the figure correspond to
the numbers of solutions in the table).
of compound I at various pHs with those of methyl-
isocytosine VII and ester X one can see that the spec-
tra of the neutral (pH 7) and anionic (pH 12) forms
of the former compound are similar to the spectrum of
ester X, implying preferential hydration of the amide
fragment (Fig. 2). Had the guanidine fragment been
hydrated, the spectra of the neutral and cationic (pH 2)
forms of compound I would have been similar to that
of methylisocytosine VII, which is not the case.
the spectra of compound I and its acetate VIII. In
addition to the aforesaid we should note that, as
judged from the presence in the spectra of the neutral
and anionic forms of isocytosine I and ester X of an
isosbestic point at 287 nm (Fig. 2b), interconversions
Optical densities (Dh) and their functions for solutions of
substituted isocytosine I
D
at
Solution (1) (5)
or optical
Even though the spectra of isocytosine I and ester
X are similar to each other, the band at 272 nm in the
spectrum of the former compound is asymmetric and
thus difficult to assign to individual absorption of the
4-hydroxy tautomer. On the other hand, the fact that
the spectra of compound I at varied concentration lack
the isobestic point allows no suggestions as to the
number of tautomers in the solution. In this connec-
tion we made use of the n-component test [11] and
found out the solutions of isocytosine I are not one-
component: The optical density of any of them Di
linearly varies with the average optical density Dav of
all the solutions at any wavelength, however, the
necessary condition for this dependence to pass
through the origin is not fulfilled. By contrast, the
ratio of the optical densities of two solutions at any
wavelength is constant within error (see table),
implying that the solutions of compound I contain
two tautomers. Of the possible tautomers, the most
probable are 4-oxo-3,4-dihydro (Ia) and 4-hydroxy
(Ib) tautomers. Evidence for this suggestion is
provided by the presence of an isosbestic point at
306 nm in the spectra of substituted isocytosine I,
methylisocytosine VI, and ester X (Fig. 2a). The use
of ester X rather than its H deacetylated analog XI as
a model compound is validated by the similarity of
density function 250 nm 260 nm 270 nm 280 nm 290 nm
1
2
3
4
0.204 0.265 0.300 0.294 0.262
0.264 0.344 0.405 0.389 0.353
0.333 0.438 0.511 0.492 0.452
0.395 0.533 0.616 0.597 0.554
0.345 0.460 0.524 0.511 0.476
0.308 0.408 0.471 0.456 0.419
0.104 0.143 0.171 0.162 0.157
0.044 0.064 0.066 0.067 0.066
0.025 0.030 0.040 0.036 0.033
0.087 0.125 0.145 0.141 0.135
0.037 0.052 0.053 0.055 0.057
5
Dav
D1
D2
D3
D4
D5
(D1
(D2
(D2
(D2
(D3
(D2
(D4
(D2
(D5
(D2
Dav
Dav
Dav
Dav
Dav
Dav)/
Dav)
Dav)/
Dav)
Dav)/
Dav)
Dav)/
Dav)
Dav)/
Dav)
2.36
2.23
2.59
2.42
2.37
1
1
1
1
1
0.56
1.98
0.84
0.46
1.95
0.81
0.60
2.19
0.80
0.54
2.10
0.82
0.50
2.05
0.86
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 4 2005

642
ERKIN, KRUTIKOV
H
H
H
H
.
H
H
.
.
.
.
.
O
O
N
O
O
H
O
H
O
+
N
H
.
.
N
N
HO
HO
HO
N
H
N
N
Me
Me
Me
N
N
H
H
Ia
A
Ib
1
of tautomers Ia and Ib occur via intermediate forma-
tion of zwitter ion A.
The H NMR spectra were measured on a Bruker AC-
200 instrument (200.13 MHz) in DMSO-d6, internal
reference residual DMSO proton signals. Elemental
analysis was performed on a Hewlett Packard B-185
analyzer.
The unexpected similarity of the UV spectra of
compound I in the protic ethanol and aprotic DMF
makes us to suggest that its tautomerization is as-
sociated not only with specific hydrogen bonding, but
also with the high polarity of the medium. Actually,
addition of the less polar ethanol to aqueous solutions
of isocytosine I produces a sharp bathochromic shift
of the absorption maximum of this compound, that
overtakes the absorption maximum of methylisocyto-
sine VI at ethanol concentrations above 20 vol%. In
other words, increase of the polarity of the ethanol
water mixture shifts the absorption maximum of com-
pound I hypsochromically (Fig. 4). These data
provide unambiguous evidence to show that the equi-
librium mixture of tautomers Ia and Ib can exist only
in aqueous solution whose polarity parameter ENT is no
lower than 0.95. In solutions with ENT 0.95 30.92, the
4-hydroxy tautomer Ib fast converts into the 4-oxo-
3,4-dihydro tautomer Ia, and it is the latter form in
which isocytosine I exists exclusively in solutions
with ENT < 0.92.
The purity of the synthesized compounds was
controlled by TLC on Silufol UV-254 plates in the
systems 1-butanol acetic acid water, 1:1:1 (A),
chloroform methanol, 9:1 (B), acetone hexane, 2:1
(C), and acetone hexane, 1:1 + 2 drops of pyridine
(D). Development was performed with UV light.
The normalized Dimroth Reichardt parameters ETN
for 5:95, 10:90, 15:85, 20:80, and 50:50 (vol%)
mixtures were obtained by interpolation [12].
6-Methyl-2-(methylsulfanyl)methylpyrimidin-
4(3H)-one (II) and 6-methyl-2-thiouracil (III) were
synthesized as described in [13].
2-(2-Hydroxyethyl)amino-6-methylpyrimidin-
4(3H)-one (I). A mixture of 6.24 g of thio ether II
and 4.88 g of 2-aminoethanol was heated at 140 C
until methanethiol no longer evolved. After cooling to
40 C, the reaction mixture was diluted with 15 ml of
water, the suspension that formed was neutralized
with acetic acid, and the precipitate that formed was
filtered off and recrystallized from water. After drying
at 80 C for 10 h, 5.2 g (77 %) of compound I was
obtained, mp 209 C (published data [6, 7]: mp 204
EXPERIMENTAL
The UV spectra were obtained on an SF-26 spec-
trophotometer in quartz cells 1 cm thick at solution
concentrations of 10 4 M, unless otherwise specified.
1
205 C), Rf 0.52 (A). H NMR spectrum, , ppm:
2.00 s (3H, Me), 3.31 m (4H, CH2), 4.84 br.s (1H,
OH), 5.39 s (1H, CH), 6.43 br.s (1H, NHe), 10.47 br.s
(1H, NH).
20
15
3,6-Dimethyl-2-(methylsulfanyl)pyrimidin-
4(3H)-one (IV) and 1,6-dimethyl-2-(methylsulfa-
nyl)pyrimidin-4(1H)-one (V). Thioxoketone III,
28.4 g, was added to a solution of 18 g of NaOH in
72 ml of water. When compound III had dissolved
completely, 50.4 g of dimethyl sulfate was added
dropwise with vigorous stirring. The reaction mixture
was heated at 70 C for 2 h and then cooled to 20 C
over the course of 12 h. The precipitate that formed
was filtered off and recrystallized from water. After
drying in a vacuum over P2O5, 14 g (41%) of methyl
sulfide IV was obtained, mp 92 C (published data [9]:
10
5
0
0.6
0.7
0.8
0.9
1.0
ENT
Fig. 4. Change of the absorption maximum ( ) of
2-(2-hydroxyethyl)amino-6-methylpyrimidin-4(3H)-one
vs. polarity of the medium (E ).
N
T
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 4 2005

POLYFUNCTIONAL DERIVATIVES OF ISOCYTOSINE
643
mp 94 C), Rf 0.79 (B). Found, %: C 48.58; H 4.60;
N 16.28. C7H10N2OS. Calculated, %: C 49.41; H 5.88;
N 16.47.
2-aminoethanol. Yield 0.14 g (17%), mp 226 C
(decomp.) (published data [17]: mp 255 C), Rf 0.29
1
(A). H NMR spectrum, , ppm: 2.17 s (3H, Me),
3.28, 3.35 m (5H, CH2 + NMe), 3.49, 3.52 d (2H,
CH2), 4.76 s (1H, OH), 5.40 s (1H, CH), 6.84 s (1H,
NHe). Found, %: C 51.51; 6.55; N 22.02. C8H13N3O2.
Calculated, %: C 52.46; H 7.10; N 22.95.
Hydrolysis of the reaction product with conc. HCl
(100 C, 1 h) gave 3,6-dimethyluracil, mp 274 C
(decomp.) (published data [14]: mp 274 C), Rf 0.55
(C). UV spectrum, max, nm (log ): 260 (3.93) (pH
7), 280 (4.04) (pH 12); the bathochromic shift of the
absorption maximum in the UV spectrum of 3,6-di-
methyluracil in going from neutral to alkaline solution
suggests [15] the 4-oxo-3,4-dihydro configuration of
sulfide IV.
2-(6-Methyl-4-oxo-3,4-dihydropyrimidin-2-yl)-
aminoethyl acetate (VIII). Acetic anhydride, 1.53 g,
was added with vigorous stirring to a hot (80 C) sus-
pension of 1.69 g of compound III in 3 ml of absolute
pyridine. The mixture was then heated at 100 C for
1 h and cooled to room temperature. The precipitate
that formed was filetered off and recrystallized from
water. After drying at 80 C for 10 h, 1.16 g (55%) of
The mother liquor after separation of compound
IV was treated with chloroform (4 50 ml), the first
extract was separated and three following were com-
bined {by contrast to the original procedure [9], this
procedure makes it possible to obtain methyl sulfide
V containing no admixture of isomer IV}. The chloro-
form was removed from the combined extract, and
the residue was recrystallized from water. After drying
in a vacuum over phosphorus pentoxide, 1.5 g (4.4%)
of methyl sulfide V was obtained, mp 229 C (pub-
lished data [9]: mp 207 C), Rf 0.46 (B). Found, %: C
48.46; H 4.98; N 16.14. C7H10N2OS. Calculated, %:
C 49.41; H 5.88; N 16.47.
1
acetate VIII was obtained, mp 173 C, Rf 0.27 (B). H
NMR spectrum, , ppm: 2.02 s (6H, Ac + Me), 3.49,
3.52 d (2H, CH2), 4.07, 4.10, 4.13 t (2H, CH2), 5.37 s
(1H, CH), 6.40 br.s (1H, NHe), 10.49 br.s (1H, NH).
UV spectrum, max, nm (log ): 270 (3.70), 285 sh.
Found, %: C 51.22; H 6.46; N 19.85. C9H13N3O3.
Calculated, %: C 51.18; H 6.16; N 19.91.
2-(4-Chloro-6-methylpyrimidin-2-yl)aminoethyl
acetate (IX). A mixture of 2.41 g of acetate VIII and
16.7 g of phosphoryl chloride was refluxed for 3 h
and excess phosphoryl chloride was removed in a
vacuum. Finely crushed ice was added to the residue,
the resulting suspension was neutralized with 9%
aqueous ammonia, and the precipitate was filtered off
and dried in a vacuum. After recrystallization from di-
ethyl ether and drying in a vacuum, 0.94 g (36%) of
chloropyrimidine IX was obtained, mp 124 C, Rf
Hydrolysis of the reaction product with conc. HCl
(100 C, 1 h) gave 1,6-dimethyluracil, mp 230 C
(published data [16]: mp 224 225 C), Rf 0.34 (C).
UV spectrum, max, nm (log ): 266 (4.00) (pH 7),
265 (3.88) (pH 12); the absence of bathocromic shift
of the absorption maximum in the UV spectrum of
1,6-dimethyluracil in going from the neutral to al-
kaline solution suggests [15] the 4-oxo-1,4-dihydro
configuration of methyl sulfide V.
1
0.66 (D). H NMR spectrum, , ppm: 1.99 s (3H, Ac),
2.26 s (3H, Me), 3.50, 3.53, 3.55 t (2H, CH2), 4.07,
4.10, 4.13 t (2H, CH2), 6.46 s (1H, CH), 7.45 s (1H,
NHe). Found, %: C 46.87; H 5.33; N 17.96. C9H12
ClN3O2. Calculated, %: C 47.05; H 5.22; N 18.30.
The mother liquor was reduced by 3/4, the precipitate
that formed was recrystallized from absolute ethanol
gave an additional 0.04 g (1.5%) of chloropyrimidine
IX. Its mixed sample with the main portion of the re-
action product showed no melting point depression.
2-(2-Hydroxyethyl)amino-3,6-dimethylpyrimi-
din-4(3H)-one (VI). A mixture of 1.02 g of methyl
sulfide IV and 0.73 g of 2-aminoethanol was heated
at 150 C until methanethiol no longer evolved. After
cooling to room temperature, the reaction mixture was
diluted with 3 ml of water, and the precipitate was
filtered off and recrystallized from water. After drying
in a vacuum over phosphorus pentoxide, 0.44 g (40%)
of methylisocytosine VI was obtained, mp 194 C
2-(4-Methoxy-6-methylpyrimidin-2-yl)amino-
ethyl acetate (X). Sodium, 0.14 g, dissolved in 5 ml
of absolute methanol was added dropwise with vi-
gorous stirring to a hot (50 C) solution of 0.94 g of
chloropyrimidine IX in 20 ml of absolute methanol.
The mixture was refluxed for 3 h, the precipitate was
filtered off, and the filtrate was evaporated in a
vacuum to dryness. The residue was refluxed with
10 ml of absolute diethyl ether, the undissolved re-
sidue was filtered off, and the filtrate was cooled to
25 C. A precipitate formed and was filtered off,
1
(published data [8]: mp 186 187 C), Rf 0.36 (A). H
NMR spectrum, , ppm: 2.03 s (3H, Me), 3.24 s (3H,
NMe), 3.39, 3.42, 3.44 t (2H, CH2), 3.53, 3.56 d (2H,
CH2), 4.60 br.s (1H, OH), 5.45 s (1H, CH), 6.83 br.s
(1H, NHe). Found, %: C 52.89; H 7.73; N 22.94.
C8H13N3O2. Calculated, %: C 52.46; H 7.10; N 22.95.
2-(2-Hydroxyethylamino)amino-1,6-dimethyl-
pyrimidin-4(1H)-one (VII) was prepared in a similar
way from 0.76 g of methyl sulfide V and 0.55 g of
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 4 2005

644
ERKIN, KRUTIKOV
washed with hexane, and dried in a vacuum to obtain
0.29 g (32%) of ester X, mp 58 C, Rf 0.35 (D). H
Sohar, P., Period. Polytech. Chem. Eng., 1971,
vol. 15, nos. 1 2, p. 43.
1
NMR spectrum, , ppm: 1.88 s (3H, Ac), 2.16 s (3H,
Me), 3.33, 3.35, 3.38 t (2H, CH2), 3.48, 3.51, 3.54 t
(2H, CH2), 3.80 s (3H, OMe), 5.77 s (1H, CH), 6.49 s
(1H, NHe). We failed to perform elemental analysis of
the product because of its decomposition.
7. Kawai, S., Sci. Papers Inst. Phys. Chem. Research,
1931, vol. 16, nos. 306 309, p. 24; Chem. Abstr.,
1931, vol. 25, 5665.
8. Hornyak, G. and Lempert, K., Acta Chim. Acad. Sci.
Hung., 1971, vol. 68, no. 3, p. 277.
9. Senda, S. and Suzui, A., Chem. Pharm. Bull., 1958,
vol. 6, p. 479, Chem. Abstr., 1959, vol. 53, 10237i.
ACKNOWLEDGMENTS
The authors express their gratitude to N.K. Sama-
renko for performing elemental analysis.
10. Reichardt, C., Solvents and Solvent Effects in Organic
Chemistry, Weinheim: VCH, 1988, 2nd ed.
11. Bershtein, I.Ya. and Kaminskii, Yu.L., Spektrofoto-
metricheskii analiz v organicheskoi khimii (Spectro-
photometric Analysis in Organic Chemistry), Lenin-
grad: Khimiya, 1986.
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