Effect of the structure of 1- and 3-methylpyrimidin-4-ones on the rate of nucleophilic substitution of the 2-methylsylfanyl group

Article abstract of DOI:10.1023/B:RUJO.0000034918.26019.44

Rate constants for substitution of the 2-methylsulfanyl group in 1- and 3-methyl-2-methylsulfanyl-pyrimidin-4-ones and their 5-fluoro analogs were measured in the reaction with butylamine, alkaline hydrolysis, and methanolysis. The rate of substitution in 1-methyl isomers having a zwitterionic structure is greater by a factor of ～2 than the rate of substitution in 3-methyl isomers with conjugated double bonds in the ring. The presence of a fluorine atom in position 5 accelerates nucleophilic substitution in 1-methyl isomers, while 5-fluoro-3-methyl-2-methylsulfanylpyrimidin-4-ones react at a lower rate than their 5-unsubstituted analogs. According to the NMR data, the reactions involve formation of a tetrahedral intermediate. Anchimeric effect of the methyl group on N¹ hampers attack by basic reagent on the C⁶ atom.

Full text of DOI:10.1023/B:RUJO.0000034918.26019.44

Russian Journal of Organic Chemistry, Vol. 40, No. 1, 2004, pp. 104-113. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 1, 2004,
pp. 113-122.
Original Russian Text Copyright Ó 2004 by Kheifets, Gindin, Nikolova.
Effect of the Structure of 1- and 3-Methylpyrimidin-4-ones
on the Rate of Nucleophilic Substitution
of the 2-Methylsylfanyl Group
G. M. Kheifets1, V. A. Gindin2, and T. A. Nikolova1
1 Institute of Experimental Medicine, Russian Academy of Medical Sciences,
ul. Akad. Pavlova 12, St. Petersburg, 197376 Russia
2
St. Petersburg State University, St. Petersburg, Russia
Received March 18, 2003
Abstract—Rate constants for substitution of the 2-methylsulfanyl group in 1- and 3-methyl-2-methylsulfanyl-
pyrimidin-4-ones and their 5-fluoro analogs were measured in the reaction with butylamine, alkaline hydrolysis, and
methanolysis. The rate of substitution in 1-methyl isomers having a zwitterionic structure is greater by a factor of ~2
than the rate of substitution in 3-methyl isomers with conjugated double bonds in the ring. The presence of a
fluorine atom in position 5 accelerates nucleophilic substitution in 1-methyl isomers, while 5-fluoro-3-methyl-2-
methylsulfanylpyrimidin-4-ones react at a lower rate than their 5-unsubstituted analogs. According to the NMR
data, the reactions involve formation of a tetrahedral intermediate. Anchimeric effect of the methyl group on N1
hampers attack by basic reagent on the C6 atom.
Comparison of properties of the isomeric products
formed by replacement of hydrogen on the N1 and N3
atoms of pyrimidinones or pyrimidinethiones by various
groups or sugar residues attracts persistent interest of
researchers. This concerns their stability [1], structure
and conformation [2], fragmentation under electron im-
pact [1, 3], physical properties [4], behavior under condi-
tions of radiolysis [5] and electrolysis [6], chemical reac-
tivity [7, 8], and biological activity [9]. Interest in biologi-
cal activity of 1- and 3-isomers arises to a considerable
extent from the fact that in natural bases glycosyl group
is attached to N1. Factors responsible for such a selec-
tive glycosylation still remain unclear [10]. The NH acid-
ity of uracils (pyrimidine-2,4-diones) constitutes an im-
portant problem from the viewpoint of both chemistry and
biology. Biological aspects of this problem include H-bond-
ing [11] and activity of enzymes for which uracils are
substrates [12, 13].
R = H, Me; X = H,AlkS,AlkO,AlkNH;Y= H, F.
mers B are more stable (by ~8–11 kcal/mol). This is con-
sistent with the known transformation of 1-methyl-
pyrimidin-4-one A (R = Me, X = Y = H) into 3-methyl
isomer B (R = Me, X = Y = H) on heating above 150°C
[15]. According to the 13C NMR data [16], zwitterionic
structure of 1-methylpyrimidin-4-ones A (R = Me) pre-
dominates in solution. Presumably, this is the reason why
potentially tautomeric compounds in organic solvents
(where stabilization of the zwitterionic structure via
solvation is weak) exist mainly as structures B (R =
H) [16].
Unlike pyrimidin-2-ones and uracils, replacement of
hydrogen at the nitrogen atom in pyrimidin-4-ones and
fused systems containing a pyrimidin-4-one moiety leads
to isomers A and B, which formally differ from each other
by arrangement of double bonds in the ring:
Up to now, no unambiguous interpretation was pro-
posed for the different reactivities of isomers A and B.
Theoretical assumptions are hardly valuable for solutions
where substrates are capable of forming hydrogen bonds,
while the available experimental data are scanty, some-
As follows from the results of quantum-chemical
calculations of tautomers A and B (R = H) [1, 14], iso-
1070-4280/04/4001-0104Ó2004 MAIK “Nauka/ Interperiodica”

EFFECT OF THE STRUCTURE OF 1- AND 3-METHYLPYRIMIDIN-4-ONES
105
Aminolysis with butylamine. The aminolysis of
compounds I–IV with butylamine was carried out at
145°C in DMSO in the absence of butylammonium salt
in order to avoid acid catalysis. The substrate-to-amine
ratio was 1:100 (pseudofirst-order conditions), and the
ratio of DMSO to butylamine was 2:1. All 2-butylamino
derivatives V–VIII were isolated and purified, and their
structure was confirmed by the NMR, UV, and IR spec-
tra. The reaction rate was monitored by spectrophotom-
etry. A sample of the mixture was diluted with an acid so
that the substrate molecule remained neutral while the
product was converted into the corresponding cation
(Fig. 1). Spectrophotometric study of the reaction of all
substrates I–IV with butylamine showed the absence of
side processes. In all cases, the conversion was quantita-
tive: the UV spectra recorded at t=t¥ corresponded to
the theoretical concentration of the final product. The
results of kinetic measurement are shown in Fig. 2. It is
seen that the difference in the rates of aminolysis of
1- and 3-methyl isomers is small. Introduction of a fluo-
rine atom into position 5 of the pyrimidine ring reduces
the rate of aminolysis of the 3-methyl isomer by a factor
of 2.
times contradictory, and mostly qualitative. Noncatalytic
H–D exchange at C2 in 1-methylpyrimidin-4-one in D2O
at 90–100°C is faster by a factor of 3 than analogous
reaction with its 3-methyl isomer [17]. Under conditions
of base catalysis, 5-fluoro-1-methylpyrimidin-4-ones
readily exchange hydrogen at C6 for deuterium, whereas
5-fluoro-3-methylpyrimidin-4-ones do not undergo H–D
exchange under the same conditions [18]. The rates of
exchange of alkylsulfanyl groups in the reactions of
1- and 3-methyl-2-methylsulfanylpyrimidin-4-ones with
2-(diethylamino)ethane-1-thiol in ethanol are similar, but
they differ by an order of magnitude for the correspond-
ing 5-fluoro derivatives [8]. Aminolysis of 3-methyl-2-
methylsulfanylpyrimidin-4-one in pure methylamine
smoothly occurs at room temperature and takes 4 days,
whereas analogous reaction with 1-methyl-2-
methylsulfanylpyrimidin-4-one requires heating for a weak
at 65°C [19]. 2-Benzylsulfanyl-1,6-dimethylpyrimidin-4-
one reacts with 2-aminoethanol (in the presence of the
corresponding ammonium salt) in boiling ethanol. The
reaction with its 3-methyl isomer occurs at 145–150°C
[20]. On the other hand, 2-ethylsulfanyl-3,5-
dimethylpyrimidin-4-one and 2-ethylsulfanyl-1,5-
dimethylpyrimidin-4-one react with 2-aminoethanol in melt
under approximately similar conditions, at 195 and 205°C,
respectively [21]. Nucleophilic substitution at position 2
in isomeric 7-methylhypoxanthine derivatives is more fac-
ile when the pyrimidine ring therein has a p-quinoid struc-
ture [22].
Alkaline hydrolysis. Products of alkaline hydroly-
sis of compounds I–IV are the corresponding uracils IX–
XII. The reaction mechanism was studied previously [23]
with 3-methyl-2-methylsulfanylpyrimidin-4-one (II) as an
example. It was found that the reaction occurs in two
steps through intermediate C (see Schemes 1 and 2).
The rate-determining step is addition of hydroxide ion to
the neutral substrate molecule.
In the present work we measured the rates of re-
placement of the 2-methylsulfanyl group in 1- and 3-me-
thyl-2-methylsulfanylpyrimidin-4-ones I and II and their
5-fluoro analogs III and IV in the reaction with buty-
lamine, alkaline hydrolysis, and methanolysis. The condi-
tions were selected in such a way that the rate-determin-
ing stage involved neutral molecule of the substrate. Here,
we took into account that the reactivities of isomers I, II
and III, IV are difficult to compare in a medium where
acid catalysis is possible: the isomers are characterized
by different basicities but cations derived therefrom have
similar structures [16].
Fig. 1. UV spectra (a) of (1) 1-methyl-2-methylsulfanylpyri-
midin-4(1H)-one and (2) 2-butylamino-1-methylpyrimidin-
4(1H)-one in 0.01 N hydrochloric acid and (b) of (1) 5-fluoro-
3-methyl-2-methylsulfanylpyrimidin-4(3H)-one and (2)
2-butylamino-5-fluoro-3-methylpyrimidin-4(3H)-one in
0.1 N hydrochloric acid.
Y= H (I,II,V,VI),Y= F (III,IV,VII,VIII).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 1 2004

106
KHEIFETS et al.
Table 1. Apparent (kap) and catalytic (kOH) rate constants for
hydrolysis of 1- and 3-methyl-2-methylsulfanylpyrimidin-4-ones
Iand II and 5-fluoro-1-methyl-2-methylsulfanylpyrimidin-4(1H)-
one (III), 60°C, I = 0.5 M
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methyl-2-methylsulfanylpyrimidin-4(1H)-one (III), and (4)
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Table 2. Apparent rate constants for hydrolysis of 1- and 3-
methyl-2-methylsulfanylpyrimidin-4-ones I and II and 5-fluoro-
1-methyl-2-methylsulfanylpyrimidin-4(1H)-one (III) in
a 0.145 N aqueous solution of sodium hydroxide at 45–70°C
(I = 0.5 M) and parameters of the Arrhenius equation
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substrate, 1.1 ´ 10 , butylamine, 1.1 ´ 10 ;kap ´ 10 , s :19.6
(I), 11.4 (II), 20.9 (III), 5.49 (IV).
Scheme 1.
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Tables 1 and 2 contain the apparent rate constants
for hydrolysis of compounds I–III, depending on the al-
kali concentration and temperature. The process strictly
follows the first-order kinetics. The catalytic second-or-
der rate constants kOH were determined from the slope
of the linear dependence of log kap on the activity of hy-
droxide ions (aOH), and the thermodynamic parameters
were estimated from the log kap-1/T relation. According
to the data in Tables 1 and 2, the rate of alkaline hydroly-
sis of 1-methyl isomer I is more than twice as high as
that found for 3-methyl isomer II. Introduction of a fluo-
rine atom into position 5of the pyrimidine ring only slightly
increases the reaction rate. The absence of side processes
in the hydrolysis of compounds I–III is confirmed by al-
most quantitative yields of the corresponding uracils,
which were calculated from the UV spectra, and by simi-
larity of the spectral patterns observed for the reaction
mixture (Fig. 3; d, e) and an artificial mixture consisting
of the substrate and the product (Fig. 3; a, b). A different
pattern was found for 5-fluoro-3-methyl-2-methylsulfanyl-
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pyrimidin-4-one (IV) (Fig. 3; c, f). Unlike artificial mix-
tures, the absorption intensity at l 292 nm (correspond-
ing to absorption maximum of the hydrolysis product) in
the spectra of the reaction mixtures decreases with time,
and the final spectrum (at t = t¥) corresponds to the spec-
trum of 5-fluoro-3-methyluracil (XII) anion formed in an
amount of 60% of the theoretical value.Analogous trans-
formation was observed for the UV spectrum of IV in a
0.1 N alkali solution kept for a long time at room tem-
perature. Increase in the intensity of high-frequency ab-
sorption in the initial period cannot be attributed to
methanethiolate ion, for such absorption was not observed
in the hydrolysis of pyrimidinones I–III; moreover, the
contribution of the entire theoretical amount of
methanethiol to the above absorption could be no more
than 30%.*
* UV spectrum of methanethiolate ion in H2O: lmax = 238.5 nm, e =
5045±200 l mol–1 cm .
–1
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 1 2004

EFFECTOFTHE STRUCTURE OF 1-AND 3-METHYLPYRIMIDIN-4-ONES
107
Fig. 3. UV spectra of (a–c) mixtures of pyrimidin-4-ones II–IV and uracils X–XII in 0.01 N NaOH and (d–f) reaction mixtures obtained
from substrates II–IV in 0.1 N NaOH: (a) a mixture of 3-methyl-2-methylsulfanylpyrimidin-4(3H)-one (II) and 3-methyluracil (X);
fraction of II, %: (1) 100, (2) 80, (3) 60, (4) 40, (5) 20, (6) 0; (b) a mixture of 5-fluoro-1-methyl-2-methylsulfanylpyrimidin-4(1H)-one
(III) and 5-fluoro-1-methyluracil (XI); fraction of III, %: (1) 100, (2) 90, (3) 70, (4) 50, (5) 30, (6) 10, (7) 0; (c) a mixture of 5-fluoro-3-
methyl-2-methylsulfanylpyrimidin-4(3H)-one (IV) and 5-fluoro-3-methyluracil (XII); fraction of IV, %: (1) 100, (2) 75, (3) 50, (4) 25,
(5) 0; (d) 3-methyl-2-methylsulfanylpyrimidin-4(1H)-one (II); reaction time t, min: (1) 0, (2) 7, (3) 30, (4) 40, (5) 100, (6) t¥;
(e) 5-fluoro-1-methyl-2-methylsulfanylpyrimidin-4(1H)-one (III); t, min: (1) 0, (2) 5, (3) 15, (4) 30, (5) 60, (6) 90, (7) 150, (8) 240,
(9) 330, (10) 450, (11) t¥; (f) 5-fluoro-3-methyl-2-methylsulfanylpyrimidin-4(3H)-one (IV); t, min: (1) 0, (2) 5, (3) 15, (4) 35, (5) 65,
(6) 100, (7) 150, (8) 180, (9) 270, (10) t¥.
These findings suggest that, when the rate of hy-
drolysis of pyrimidinone IV is comparable with the rate
of formation of 5-fluoro-3-methyluracil, an additional re-
action product accumulates in the mixture. This product
is then converted into one or more nonabsorbing species,
i.e., those lacking specific absorption. According to the
data of [24], unsubstituted uracil is fairly stable on heat-
ing in alkali, whereas 5-fluorouracil undergoes slow de-
composition to give a nonabsorbing product (or products;
t0.5 = 50 h at 80°C in 0.2 N NaOH). Presumably, this
transformation is the result of attack by hydroxide ion on
the ring C6 atom, elimination of hydrogen fluoride, and
intermediate formation of barbituric acid; the pyrimidine
ring in the latter is cleaved under these conditions. The
formation of 1-methylbarbituric acid on heating of
5-bromo-3-methyluracil in alkali is explained in a similar
way, and its low yield is attributed to slow decomposition
to a nonabsorbing product [25]. In order to estimate the
contribution of such transformations of 5-fluoro-3-
methyluracil (XII) in the hydrolysis of pyrimidinone IV,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 1 2004

108
KHEIFETS et al.
Table 3. Apparent rate constants for decomposition of
1-methyluracil (IX), 3-methyluracil (X), 5-fluoro-1-methyluracil
(XI), and 5-fluoro-3-methyluracil (XII) in aqueous alkali at 80°C
(substrate concentration c = 7´10–5 M, I = 0.5 M)a
when no fluorine atom is present in position 5, and it may
play the role of a “depot” in the transformation of
pyrimidinone II into 3-methyluracil.As shown below, at-
tack by a base on C6 of the pyrimidine ring is really pos-
sible.
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Methanolysis of pyrimidin-4-ones I–IV. Unlike
aqueous alkali, pyrimidinone IV is quantitative converted
into 5-fluoro-3-methyluracil (XII) at room temperature
in a methanolic solution of sodium hydroxide containing
10–15% of water (Fig. 4). According to the data of UV
spectroscopy, the reaction involves an intermediate prod-
uct whose rate of formation is greater by a factor of 35–
40 than the rate of its subsequent transformation into uracil
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=
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b The spectrum did not change over a period of 5 days.
Table 4. Apparent rate constants for decomposition of barbitu-
ric (XIII), 1-methylbarbituric (XIV), and 1,3-dimethylbarbituric
acids (XV) in aqueous alkali at 80°C
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XII (at a substrate concentration of 10 to 10 M). This
intermediate was also detected by TLC analysis of the
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an analogous behavior. As follows from the NMR data,
2-methylsulfanylpyrimidinones I–IV are rapidly converted
into 2-methoxy derivatives XVI–XIX which then give rise
to the corresponding uracils. The different rates of the
first and second reaction stages allowed us to isolate 2-
methoxy derivatives XVI–XIX in preparative experiments
which were carried out both in the presence of 10–15%
of water and in the absence of it. Below are given the
half-conversion periods for the transformation of com-
pounds I–IV into 2-methoxy derivatives XVI–XIX in 90%
CD3OD containing 2 equiv of NaOD at 20°C (initial sub-
strate concentration 0.11 M).
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The ionic strength was maintained constant at 0.5 M.
we measured the lifetimes of uracils IX–XII and barbi-
turic acids XIII–XV (Tables 3, 4). Comparison of the
data in Tables 1–4 and those reported in [24] shows that
the rate of decomposition of N-methyl-substituted uracils
IX–XII is much greater than the rate of decomposition
of 5-unsubstituted uracil and 5-fluotouracil and that
1-methylbarbituric acid XIV is converted into a nonab-
sorbing product at a rate exceeding the rate of conver-
sion of 5-fluoro-3-methyluracil (XII) by a factor of 12–15.
Therefore, the low yield of uracil XII cannot be the re-
sult of its direct transformation into 1-methylbarbituric acid
XIV during the hydrolysis of pyrimidinone IV. This means
that the contribution of the IV > XII > XIV path (if it
exists) is small (Scheme 2). Probably, a part of
pyrimidinone IV is transformed into a nonabsorbing prod-
uct at a rate comparable with the rate of formation of
uracil XII via attack by hydroxide ion at the C6 atom,
followed by elimination of HF from intermediate D (see
Scheme 2). Isomeric 1-methylpyrimidinone III is quanti-
tatively converted into 5-fluoro-1-methyluracil (Fig. 3, e).
This may be due to the fact that the rate of hydrolysis
considerably exceeds the rate of HF elimination and/or
due to anchimeric effect of the 1-methyl group, which
hinders attack on C6 by a base in side reaction. Attack by
hydroxide ion or water on the C6 atom in 3-methyl-2-
methylsulfanylpyrimidin-4-one (II) to give tetrahedral
complex like D is also possible; however, the latter is stable
Scheme 2.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 1 2004

EFFECTOFTHE STRUCTURE OF 1-AND 3-METHYLPYRIMIDIN-4-ONES
109
Compound no. I II III IV
t0.5, min 4.0 7.6 2.8 11.0
These data indicate approximately the same differ-
ence in the reactivities of 1- and 3-methyl isomers I–IV
as that observed in the aminolysis with butylamine and
alkaline hydrolysis (see above). The rate of methanolysis
was measured by 1H NMR spectroscopy, following varia-
tion in the intensity of signals from the S- and N-methyl
groups, as well as from the ring protons. Deviation in the
t
0.5 values determined with the use of the above param-
eters did not exceed 5%. When the reaction was com-
plete, 13C NMR spectra were recorded. They contained
signals typical of pure compounds XVI–XIX. The 6-H
signal of pyrimidinone III cannot be used in the determi-
nation of the reaction rate, for the 6-H proton is instanta-
neously replaced by deuterium at an alkali concentration
of 0.2 M (cf. [18]). A very fast deuterium exchange at
C6 was also observed with 2-methoxy derivative XVIII
in the same medium. In this case, the intensity of the
2-MeO signal (d 4.0 ppm) decreased exponentially, while
the 1-Me signal (d 3.55 ppm) did not change its position
and intensity; simultaneously, the signal from methanol
(d 3.38 ppm) increased in intensity.Addition of 1 equiv of
a 5.8 M solution of NaOCD3 to a solution of compound
Fig. 4. UV spectra of the reaction mixture in the methanolysis
of 5-fluoro-3-methyl-2-methylsulfanylpyrimidin-4(3H)-one
(IV) in alcoholic (86% of methanol) alkali at 20°C after (1) 0,
(2) 4.2, (3) 24, (4) 192, and (5) 408 h; cNaOH = 0.1 M; cIV = 8.4 ´
–5
10 M.
1
approaches the rate of methoxylation of substrate III,
t0.5 » 2.2 min. Presumably, this is not an accidental coin-
cidence, for the exchange process undoubtedly involves
XVIII in DMSO-d6 led to appearance in the H NMR
spectrum of a quartet signal from hydroxy proton at
d 4.10 ppm, J(CH3–OH) = 4.0 Hz. We can conclude that
H–D exchange at C6 [18] in pyrimidinone XVIIIa is ac-
companied by replacement of the 2-methoxy group by
CD3O. The rate of replacement of the 2-methoxy group
–
attack by CD3O ion on the C2 atom in XVIIIa, forma-
tion of tetrahedral complex E, and elimination of
methoxide ion in excess methanol-d4 (Scheme 3).
–1
increases as the alkali concentration rises [kap (s ) =
Table 5. Proton and carbon chemical shifts (d and dC, ppm) in
the NMR spectra of 2-methoxy-3-methylpyrimidin-4-one (XVII)
and products of addition of 1 equiv of sodium methoxide
(adducts I and J) in DMSO-d6.
–0.001 + 0.0099cNaOH (M); r = 0.99]; at an alkali concen-
tration of 0.2 M, the rate of methoxy group exchange
Scheme 3.
3DUDPHWHUꢀ & ꢀ
ꢊꢄ0HWKR[\ꢄꢈꢄPHWK\OS\ULPLGLQꢄꢆꢄRQHꢀꢏ;9,,ꢐꢀ
ꢍꢅꢂꢋ ꢀ ꢌꢅꢌꢁ ꢀ ꢈꢅꢊꢌꢀ ꢈꢅꢇꢋꢀ
& ꢀ
& ꢀ
& ꢀ 10Hꢀ 20Hꢀ
Gꢁ
ꢀꢀ
ꢀꢀ
ꢁꢋꢌꢅꢆꢀ ꢁꢍꢁꢅꢇꢀ ꢁꢂꢌꢅꢌꢀ ꢁꢋꢁꢅꢇꢀ ꢊꢌꢅꢆꢀ ꢋꢍꢅꢂꢀ
G ꢀ
$GGXFWꢀ,ꢀ
ꢋꢅꢁꢍ ꢀ ꢌꢅꢈꢆ ꢀ ꢈꢅꢂꢍꢀ ꢈꢅꢁꢋꢀ
Gꢀ
ꢀꢀ
ꢀꢀ
ꢇꢇꢅꢋꢀ ꢁꢍꢋꢅꢇꢀ ꢇꢋꢅꢇꢀ ꢁꢋꢋꢅꢍꢀ ꢊꢍꢅꢍꢀ ꢆꢉꢅꢍꢀ
G ꢀ
Scheme 4.
$GGXFWꢀ-ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Gꢀ
G ꢀ
ꢀꢀ
ꢀꢀ
ꢁꢍꢁꢅꢁꢀ ꢁꢍꢌꢅꢊꢀ
ꢋꢇꢅꢇꢀ ꢈꢍꢅꢆꢀ ꢋꢋꢅꢇ ꢀ
a
ꢀ
J5,6 = 6.5 Hz.
b J5,6 = 6.0 Hz.
c Obscured by the signal of adduct I.
d 2-MeO group.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 1 2004

110
KHEIFETS et al.
equilibrium involves three kinds of adduct I molecules,
i.e., those containing (1) two methoxy groups, (2) one
methoxy and one trideuteromethoxy group, and (3) two
trideuteromethoxy groups. The 13C NMR spectra of the
final reaction mixture contain weak signals from the sub-
strate and new signals belonging to complex I (Table 5).
In addition, we also observed signals which were assigned
to complex J arising from attack by methoxide ion on C6
in substrate XVII. According to the NMR data, analo-
gous transformations occur with 5-fluoro-2-methoxy-3-
methylpyrimidine-4(3H)-one (XIX) on addition of an
equivalent amount of sodium methoxide to a solution of
XIX in DMSO-d6.
Fig. 5. Variation of the intensity of the methoxy group signal
with time in the 1H NMR spectrum of 2-methoxy-3-
methylpyrimidin-4(1H)-one (XVII) in DMSO-d6 after addi-
tion of one equivalent of (1) sodium methoxide and (2) sodium
trideuteromethoxide.
EXPERIMENTAL
The 1H and 13C NMR spectra were measured on a
Bruker DPX-300 spectrometer operating at 300 MHz for
1H 300 and 75.47 MHz for 13C. The UV spectra were
recorded on SF-16, SF-8, and Hitachi 356 spectropho-
tometers. The IR spectra were obtained on an IKS-24
instrument. pH values were measured using a model 673
pH meter at 60.0±0.1°C in a cell equipped with an agar
bridge filled with a solution of KCl. The pH meter was
preliminarily calibrated against standard buffer solutions
at 60°C (phosphate buffer, pH 6.84; borate buffer, pH
8.96). The pH values were measured before and after
kinetic experiment, the deviation did not exceed 0.05 pH
units. In experiments performed below 80°C, a water
thermostat was used, and in experiments performed at
145°C, a glycerol thermostat.
We previously detected by the kinetic method for-
mation of a tetrahedral intermediate in the alkaline hy-
drolysis of pyrimidinone II; it was also shown that its
formation is the rate-determining stage [23]. In the present
work we made an attempt to obtain spectroscopic proofs
for the existence of intermediate I by prolonging its life-
time under conditions excluding its decomposition into the
hydrolysis products (Scheme 4). After addition of an
equivalent amount of sodium methoxide in DMSO-d6 to
substrate XVII, all its signals in the 1H NMR spectrum
decreased in intensity. Simultaneously, new signals ap-
peared in the spectrum (Table 5), and their intensity at-
tained 90% in several days at room temperature. A simi-
lar pattern was observed in a 1 : 1 mixture of dioxane-d8
and DMSO-d6. In analogous experiments with sodium
trideuteromethoxide, the intensity of the MeO signal of
substrate XVII (d 3.95 ppm) almost instantaneously fell
down to ~10% and it no longer changed (Fig. 5). Here,
the overall intensity of the unresolved signals from the
methoxy group in complex I and methoxide ion also re-
mained unchanged (it corresponded to one equivalent).
The intensities of signals from the other groups changed
exponentially, regardless of whether CH3ONa or CD3ONa
was added.
Kinetic study of the aminolysis of pyrimidinones
I–IV with butylamine. Butylamine, 1.1 ml (11 mmol),
was added to a solution of 0.11 mmol of compound I–IV
in 2.2 ml of DMSO. A 165-ml sample of the mixture was
kept at (145.0±0.1)°C. A2:1 mixture of DMSO with bu-
tylamine (as reference solution) was kept under the same
conditions.After cooling, the contents of the ampule were
washed off with hydrochloric acid into a volumetric flask,
and the solution was adjusted to a spectrophotometric
concentration (0.01 M for compounds I and II and 0.1 M
for compounds III and IV) by addition of hydrochloric
acid. The rate of the aminolysis was monitored following
the disappearance of UV absorption at l 298 nm for
compound II, 312 nm for IV, and 240 nm for I and III.
The plot of log[D0/(Dt – D¥)] versus time was linear up
to 3t0.5.
Interpretation of the above findings is not difficult, if
we take into account that one equivalent of NaOCD3
participates in the reaction and that OCH3–OCD3 ex-
change is a fast process while the equilibrium shifts to-
ward tetrahedral complex I slowly. Also, a steric isotope
effect is observed upon elimination of methoxy or
drideuteromethoxy group from complex I [26]. Here, the
Butylamine of analytical grade was dried over so-
dium hydroxide and distilled over a fresh portion of so-
dium hydroxide through a column; a fraction with bp 78°C,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 1 2004

EFFECTOFTHE STRUCTURE OF 1-AND 3-METHYLPYRIMIDIN-4-ONES
111
nD20 = 1.405, was collected. Dimethyl sulfoxide of chemi-
cally pure grade was purified over zeolites and distilled; a
fraction with bp 85–87°C (25 mm) was collected; the
concentration of water in DMSO was checked by H
NMR spectroscopy.
tions were placed in ampules which were sealed and kept
at 80°C. Reference solutions were kept under the same
conditions. The rate of decomposition was determined
1
from the decrease in the optical density at l = lmax
.
Kinetic study of the methanolysis of pyrimidin-
4-ones I–IV. Experiments were performed in NMR
ampules. A required amount of the substrate was dis-
solved in methanol-d4 to a concentration of 0.11 M. The
initial spectrum was recorded relative to DSS as internal
standard. A solution of 2 equiv of NaOD in D2O was
then added so that the final solution contained 90% of
methanol-d4. After addition of NaOD/D2O, the ampule
was shaken, and this moment was assumed to be the
initial one (no more than 1 min elapsed until the first spec-
trum was recorded). The rate of the methanolysis was
determined from the variation of intensities of signals from
the ring protons, as well as from the NMe and SMe groups,
relative to the DSS signal intensity.
Kinetic study of the alkaline hydrolysis of 1- and
3-methyl-2-methylsulfanylpyrimidin-4-ones I and II
and their fluorinated analogs III and IV. The kinetic
measurements were performed by spectrophotometry at
60.0±0.1°C. For determination of the thermodynamic
parameters, the measurements were performed at 40–
70°C. Quartz cells with ground caps were filled with a
solution of alkali (3 ml) and were maintained at a con-
stant temperature (using a water thermostat). A concen-
trated substrate solution, 5 ml, was added to a final con-
centration of 8.7´10–5 M for 1-methyl isomers or 4.9´
–4
10 M for 3-methyl isomers. The concentration of alkali
solutions was checked by titration. The ionic strength was
maintained at 0.5 M by adding a required amount of NaCl.
The rate of hydrolysis was determined from decrease in
the UV absorption intensity at l 233, 308, and 235 nm for
compounds I–III, respectively. The analytical wave-
lengths were selected in such a way that the absorption
of the hydrolysis products be minimal. All experiments
were performed until the optical density no longer
changed; this final value was taken as D?. The apparent
rate constants kap were calculated by the formula:
Sodium metoxide and sodium trideuteromethoxide
were prepared by removal of methanol or methanol-d4
from the corresponding solutions on heating under reduced
pressure. The dry residue (which was preliminarily kept
in a vacuum desiccator over calcium chloride) was dis-
persed in DMSO-d6 until saturation, and the undissolved
material was separated by centrifugation. The concen-
tration of sodium methoxide (trideuteromethoxide) in the
supernatant was determined by titration.
The synthesis and properties of 1- and 3-methyl-2-
methylsulfanylpyrimidin-4-ones I and II, their 5-fluoro
analogs III and IV, and 1- and 2-butylamino-3-
methylpyrimidin-4-ones V and VI were reported by us
previously [16]. Methyluracils IX–XII were synthesized
by acid hydrolysis of the corresponding 2-methylsulfanyl-
pyrimidin-4-ones: 1-methyluracil (IX), mp 231–232°C
(from water); published data [28]: mp 231°C; 3-methyl-
uracil (X), mp 179°C (from ethanol); published data [28]:
mp 179°C; 5-fluoro-1-methyluracil (XI), mp 257–258°C
(from water); published data [29]: mp 263–264°C;
5-fluoro-3-methyluracil (XII), mp 194°C (from 50% etha-
nol); published data [29]: mp 190–191°C. 1-Methylbar-
bituric acid (XIV) was obtained by condensation of
N-methylurea with diethyl malonate, mp 131–132°C (from
ethanol); published data [30: mp 132°C. 1,3-Dimethyl-
barbituric acid (XV) was synthesized by condensation of
N,N '-dimethylurea with diethyl malonate, mp 123°C (from
benzene); published data [30]: mp 123°C. Barbituric acid
of analytical grade had mp 245°C (from water).
kap = [ln D0/(Dt – D¥)]/t.
Only those kap values were taken into consideration,
for which the spread did not exceed 5%. The time de-
pendence of log D0 – log (Dt – D¥) was linear up to 5t0.5,
which confirmed pseudofirst-order of the reaction. The
catalytic second-order rate constants kOH were deter-
mined from the slope of the linear plot of logkap versus
activity of hydroxide ions aOH, which was calculated by
the equation pOH = pKw – pH. The value Kw = 9.619 ´
10–14 (60°C, NaCl solution) was taken from [27]. pH val-
ues at 60°C were measured with the aid of a glass elec-
trode.
Kinetic study of the decomposition of barbitu-
ric acids XIII–XV in 0.1–1.0 M solutions of alkali.
Experiments were performed in a similar way at 80°C.
The rate of decomposition was estimated from the de-
crease in the UV absorption intensity at l 260 nm.
Kinetic study of the decomposition of 1- and
3-methyl uracils IX and X and their 5-fluoro ana-
logs XI and XII. Solutions of methyluracils with a con-
2-Butylamino-5-fluoro-1-methylpyrimidin-4
(1H)-one (VII). A mixture of 1.15 mmol of 5-fluoro-1-
–5
centration of 7 ´ 10 M in 0.09 and 0.41 M alkali solu-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 1 2004

112
KHEIFETS et al.
methyl-2-methylsulfanylpyrimidin-4(1H)-one and
11.5 mmol of butylamine was heated for 4 h at 145–150°C
under argon in a sealed ampule. Excess butylamine was
distilled off under reduced pressure, and the residue
was recrystallized from water. Yield 29%, mp 156°C. IR
spectrum: nNH 3420, 3250 cm . H NMR spectrum
(DMSO-d6), d, ppm: 7.73 d (1H, 6-H), 6.97 s (1H, NH),
3.29 c (3H, NCH3). 13C NMR spectrum (DMSO-d6),
dC, ppm: 152.1 s (C2), 162.6 d (C4), 142.65 d (C5), 128.6 d
(C6), 37.8 s (NCH3), 19.6 s and 13.8 s (Bu). UV spec-
trum: 0.1 N HCl: lmax 276 nm (log e = 3.74); 0.1 N NaOH:
lmax 275.5 nm (log e = 3.56). Found, %: N 21.0.
C9H14FN3O. Calculated, %: N 21.1.
(1H, 6-H), 6.24 d (1H, 5-H), 4.05 s (3H, OCH3), 3.41 s
(3H, NCH3). 13C NMR spectrum (D2O), dC, ppm: 168.3 s
(C4), 160.8 s (C2), 155.7 s (C6), 109.9 s (C5), 59.1 s
(OCH3), 30.9 s (NCH3).
5-Fluoro-2-methoxy-1-methylpyrimidin-4(1H)-
one (XVIII). Yield 71%, mp 178–180°C. 1H NMR spec-
trum (D2O), d, ppm: 7.84 d (1H, 6-H), 4.00 s (3H, OCH3),
3.52 s (3H, NCH3). 13C NMR spectrum (D2O), dC, ppm:
168.2 d (C4), 156.0 s (C2), 144.6 d (C5), 131.5 d (C6),
57.0 s (OCH3), 38.2 s (NCH3). Found, %: C 45.4; H 4.4;
N 17.45. C6H7FN2O2. Calculated, %: C 45.6; H 4.4; N 17.7.
1
–1
5-Fluoro-2-methoxy-3-methylpyrimidin-4(3H)-
one (XIX). Yield 81%, mp 125–127°C. 1H NMR spec-
trum (CDCl3), d, ppm: 7.6 d (1H, 6-H), 4.07 s (3H, OCH3),
3.44 s (3H, NCH3). 13C NMR spectrum (CDCl3), dC,
ppm: 156.35 d (C4), 152.9 s (C2), 146.1 d (C5), 133.7 d
(C6), 55.8 s (OCH3), 28.4 s (NCH3). Found, %: C 45.6;
H 4.9; N 17.5. C6H7FN2O2. Calculated, %: C 45.6; H 4.4;
N 17.7.
2-Butylamino-5-fluoro-3-methylpyrimidin-
4(3H)-one (VIII) was synthesized as described above
for 1-methyl isomer VII; the mixture was heated for 18 h.
Yield 27%, mp 113–115°C (from cyclohexane). IR spec-
–1
trum: nNH 3334 cm . 1H NMR spectrum (DMSO-d6),
d, ppm: 7.73 s (1H, 6-H), 7.05 s (1H, NH), 3.24 s (3H,
NCH3). 13C NMR spectrum (DMSO-d6), dC, ppm: 151.4
s (C2); 155.4 d (C4); 142.3 d (C5); 136.80 d (C6); 31.8 s
(NCH3); 30.8 s, 28.0 s, 19.65 s, and 13.8 s (Bu). UV
spectrum: 0.1 N HCl: lmax 269.5 nm (log e = 3.55); 0.1 N
NaOH: lmax 300 nm (loge = 3.78). Found, %: N 21.1.
C9H14FN3O. Calculated, %: N 21.1.
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1- and 3-Methyl-2-methoxypyrimidin-4-ones
and their 5-fluoro analogs (general procedure). To
a solution of 2.2 mmol of pyrimidinone I–IV in 15 ml of
methanol we added 4.4 mmol of sodium (as a 2.8 M so-
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2-Methoxy-1-methylpyrimidin-4(1H)-one
1
(XVI). Yield 75%, mp 144–145°C. H NMR spectrum
(CD3OD), d, ppm: 7.67 d (1H, 6-H), 6.05 d (1H, 5-H),
4.01 s (3H, OCH3), 3.55 s (3H, NCH3). 13C NMR spec-
trum (CD3OD), dC, ppm: 175.9 s (C4), 159.5 s (C2), 147.3 s
(C6), 108.3 s (C5), 59.2 s (OCH3), 38.8 s (NCH3). Found,
%: C 51.2; H 5.4; N 19.8. C6H8N2O2. Calculated, %:C 51.4;
H 5.7; N 20.0.
2-Methoxy-3-methylpyrimidin-4(3H)-one
(XVII). Yield 80%, mp 92–95°C; published data [31]:
mp 92–95°C. 1H NMR spectrum (D2O), d, ppm: 7.80 d
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 1 2004

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