Effect of the structure of 1- and 3-methyl-5-fluoropyrimidin-4-ones on H-D exchange in position 6 under conditions of base catalysis

Article abstract of DOI:10.1023/B:RUJO.0000034917.31926.78

Hydrogen atom in position 6 of 5-fluoro-1-methylpyrimidin-4(1H)-one and its 2-methylsulfan-yl, 2-methoxy and 2-butylamino derivatives is readily replaced by deuterium in 90% methanol-d₄ at ～20εC under conditions of base catalysis. The rate of H

Full text of DOI:10.1023/B:RUJO.0000034917.31926.78

Russian Journal of Organic Chemistry, Vol. 40, No. 1, 2004, pp. 97-103. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 1,
2004, pp. 106-112.
Original Russian Text Copyright Ó 2004 by Kheifets, Gindin, Moskvin.
Effect of the Structure of 1- and 3-Methyl-5-fluoropyrimidin-4-
ones on H–D Exchange in Position 6 under Conditions of Base
Catalysis
G. M. Kheifets1, V. A. Gindin2, and A. V. Moskvin3
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
3
St. Petersburg State Chemical and Pharmaceutical Academy, St. Petersburg, Russia
Received December 26, 2002
Abstract—Hydrogen atom in position 6 of 5-fluoro-1-methylpyrimidin-4(1H)-one and its 2-methylsulfan-yl, 2-
methoxy and 2-butylamino derivatives is readily replaced by deuterium in 90% methanol-d4 at ~20ºC under conditions
of base catalysis. The rate of H–D exchange decreases in the series H, SMe > OMe >> NHBu. Isomeric 5-fluoro-3-
methylpyrimidin-4-ones, as well as their 5-unsubstituted analogs, do not undergo H–D exchange. Ready deuterium
exchange in 5-fluoro-1-methylpyrimidin-4-ones is explained by synergistic effect of the zwitterionic structure and 5-
fluorine atom on the C6–H acidity. The gain in energy due to this effect, expressed through the enthalpy of dissociation
of the C6–H bond, is ~15 kcal/mol provided that effect of the medium is absent; the contribution of the 5-fluorine
atom is 5.3–6.0 kcal/mol.
In the preceding study [1], while measuring the rate of
alkaline methanolysis of compounds Ia, Ib, IIa, and IIb,
we have found that the 6-H signal of pyrimidinone Ib dis-
appeared from the 1H NMR spectrum immediately (in less
than 1 min) after addition of a solution of NaOD in D2O to
a solution of Ib in methanol-d4 at room temperature.
I, II, X = H, R1 = SMe (a); X = F, R1 = SMe (b), OMe (c), H (d), Et2N(CH2)2S (e), NHBu (f); X = R1 = H (g); III, X = F, R2 =
Me, R3 = H (a); X = F, R2 = H, R3 = Me (b), X = F, R2 = R3 = Me (c); X = Br, R2 = R3 = Me (d); X = Br, R2 = R3 = OMe (e);
X = Br, R2 = R3 = H (f).
In the 13C NMR spectrum of 5-fluoro-1-methyluracil
(IIIa) isolated from the reaction mixture (Scheme 1), the
C6 signal appeared as a doublet of triplets. In the IR spec-
trum of this compound, the C–H stretching vibration band
Scheme 1, H–D exchange occurs just in 2-methylsulfanyl
derivative Ib, for the rate of replacement of 6-H by deute-
rium is much greater than the rate of methoxylation and
incommensurably greater than the conversion of 5-fluoro-
2-methoxy-1-methylpyrimidine-4(1H)-one (Ic) into uracil
IIIa [1]. Insofar as no deuterium exchange was observed
with both 3-methyl isomer IIb and its protium analog Ia,
such a ready isotope exchange in compound Ib is likely to
result from synergistic effect of the structure of I and fluo-
rine atom in the 5-position.
–1
was displaced toward lower frequencies (2289 cm ; Figs.
1, 2). These data indicated that the 6-H atom in IIIa was
replaced by deuterium. According to the NMR data, in
the absence of alkali, compound Ib in D2O and CD3OD
remained unchanged as long as 3 years. In the transfor-
mation of pyrimidinone Ib into uracil IIIa according to
1070-4280/04/4001-0097Ó2004 MAIK “Nauka/ Interperiodica”

98
KHEIFETS et al.
Scheme 1.
Numerous examples of facile isotope exchange in
heteroaromatic compounds, including those containing a
pyrimidine ring, have been reported [2–6]. The exchange
process in pyrimidinones and pyrimidinediones is favored
by the presence of onium nitrogen atom [4, 5] or halogen
atom (as in 5-halouracils or 5-halouridines) [6] in the vi-
cinity of the ring carbon atom involved. Base-catalyzed
H–D exchange in the 5-halo derivatives is strongly ac-
celerated due to desolvation upon replacement of water
or methanol by DMSO [6]. In our case, i.e., with a sub-
strate which has a betaine-like structure I [7] but is not
a true onium salt, the exchange process readily occurs in
a protic medium. There are two examples of very fast
Fig. 1. Fragments of the 13C NMR spectra corresponding
to the C6 signal of 5-fluoro-1-methyluracil obtained by
methanolysis of 5-fluoro-1-methyl-2-methylpyrimidin-
4(1H)-one (Ib) (a) in a mixture of methanol-d4 and a 0.2 M
solution of NaOD in D2O and (b) in a mixture of methanol
and a 0.2 M solution of NaOH in H2O. The other frag-
ments of the spectra are identical.
>
H–D exchange in such pyrimidine derivatives at pD 6,
-
namely replacement of hydrogen by deuterium at C5 in
4,6-dihydroxypyrimidine and its mono-N-methyl deriva-
tive. However, these compounds are fairly strong acids
(pKa 5.4 and 5.75, respectively), and deuterium exchange
therein occurs during their tautomeric transformations
involving a common anion [8].
Another even more interesting aspect of the prob-
lem under study is the lack of H–D exchange at C6 in
3-methyl isomer IIb. The 2-H atom neighboring to the
N-methyl group is replaced by deuterium both in 1-me-
thyl-pyrimidin-4(1H)-one (Ig) and in isomeric 3-methyl-
pyrimidin-4(3H)-one (IIg) in D2O at 90–100°C in the
absence of a catalyst [4, 5]. These compounds, as well as
their 5-fluoro-substituted analogs Id and IId, also under-
go deuterium exchange at C2 on prolong storage in D2O
at room temperature.
Presumably, the observed relations in H–D ex-
change at C6 reflect most clearly differences in the re-
activity of 1- and 3-methylpyrimidin-4-ones, depending
on the position of the N-methyl group, which were dis-
cussed previously [1, 9, 10]. These relations attract in-
terest from the viewpoint of similarity between the ex-
change reaction and many chemical [11] and biological
[12] processes inherent to heterocycles. In additon, com-
pounds of the 5-fluoro-1-methylpyrimidin-4-one series can
be regarded as models of some N-glycosylated physi-
ologically active substances [7].
Fig. 2. IR spectra (KBr) of 5-fluoro-1-methyluracil ob-
tained from 5-fluoro-1-methyl-2-methylpyrimidin-4(1H)-
one (Ib) by (a) hydrolysis in 1 N hydrochloric acid, (b)
methanolysis in a 0.2 M solution of NaOD in 90% CD3OD,
and (c) methanolysis in a 0.2 M solution of NaOH in 90%
methanol.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 1 2004

EFFECT OF THE STRUCTURE OF 1-AND 3-METHYL-5-FLUOROPYRIMIDIN-4-ONES
99
In order to understand reasons for the different be-
haviors of isomers Ib and IIb it was necessary to eluci-
date whether deuterium exchange of 6-H occurs only
with compound Ib or this is a general property of 5-fluoro-
1-methylpyrimidin-4-one derivatives and how the substitu-
ent at C2 affects the exchange process. Table 1 contains
the rates of H–D exchange at C6 in N-methyl derivatives
of 5-fluoropyrimidin-4-one and some structurally related
compounds, which were determined by 1H NMR spec-
troscopy at ~20°C. None of the compounds given in
Table 1 exchanges hydrogen in the absence of a base.
An exception is pyrimidinone Ie. In this case, a very slow
H–D exchange at C6 occurs due to autocatalysis by the
side-chain diethylamino group. We also examined the
ability of the corresponding 5-protium analogs to undergo
base-catalyzed H–D exchange. In no cases, even at an
alkali concentration of 0.2–0.3 M, introduction of deuterium
to C6 or C5 was detected. We did not examine the behavior
ofthese compounds at elevated temperature, though deu-
terium exchange for some derivatives becomes possible
under more severe conditions. For example, replacement
of 6-H (together with 2-H) by deuterium in compound Ig
Scheme 2.
1
the doublet signal from 6-H in the H NMR spectrum
and the transformation of the C6 signal from doublet to
doublet of triplets, the other signals retaining their posi-
tion and multiplicity. The rate of H–D exchange was de-
termined from the decrease in the intentsity of the 6-H
signal relative to signals of the other groups and DSS
signal (internal reference). Under conditions of base ca-
talysis, compounds containing a methylsulfanyl or methoxy
group in position 2 can undergo methoxylation followed
by transformation into the corresponding uracils [1]. These
processes were monitored by NMR spectroscopy, but
their rate was negligible as compared to the rate of deu-
terium exchange.
was observed in a buffer solution with pD = 11.8, t0.5
~
~
113 h, 70°C [3], while its 3-methyl isomer IIg undergoes
H–D exchange at C2 (but not at C6) in a 0.3 M solution
of NaOD in D2O at 90°C [5]. 5-Fluoro-1-methyluracil
(IIIa) and 5-fluorouridine exchange 6-H in 0.5 M NaOD/
D2O (t0.5 ~ 20 min, 60°C [13]; cf. Table 1).
~
As follows from the data in Table 1, appreciable ex-
change of 6-H is possible only under base catalysis. The
rate of exchange in D2O increases in the presence of
20% of DMSO. All the examined 5-fluoro-1-methyl-
pyrimidin-4-ones I were found to undergo H–D exchange,
whereas isomeric 5-fluoro-3-methylpyrimidin-4-ones II
were not. With respect to the substituent on C2, the rate
of H–D exchange decreases in the series H, SMe >
OMe >> NHBu. Strong deceleration of the process in
going to the 2-butylamino derivative may be due to ion-
ization of the exocyclic amino group in basic medium. No
H–D exchange at C6 was observed for compounds with
an aromatic character of the heteroring. In the 1H NMR
spectra of 5-fluoro-4-methoxy-2-methylsulfanylpyrimidine
(IVa) we observed slow decrease in intensity (by 95% in
Unless otherwise stated, all measurements were per-
formed in methanol-d4 after addition of NaOH in D2O.
This medium contained 90% of methanol-d4, and the
catalytic species was strongly nucleophilic trideutero-
–
methoxide ion (CD3O ). This follows from the fact that
H–D exchange at C6 in compound Ic is accompanied by
replacement of the methoxy group on C2 by CD3O
(Scheme 2).
The rates of the based-catalyzed reactions
were estimated by the pseudofirst-order rate con-
–1
stants kap (s ) and catalytic constants kcat = kap/
–
–1 –1
c(OH ) (l mol s ) which were calculated from the
initial concentrations of the base. The progress of the
reaction was monitored following the disappearance of
Scheme 3.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 1 2004

100
KHEIFETS et al.
Table 1. Hydrogen–deuterium exchange at C6 in 1-methyl- and 3-methylpyrimidin-4-one derivatives and related compounds in a
solution of NaOD in CD3OD–D2O (9:1) at (20±1)°C and enthalpies of dissociation DdH0(0) (kcal/mol) of the C6–H bond, calculated
by the PM3 semiempirical method
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kcat = kap/c(NaOD).
b
c
d
e
f
No exchange was observed over a period of several hours or tens hours.
The rate of exchange was too high to be measured.
In a solution of NaOD in DMSO-d6–D2O (1 : 5).
In a solution of Et3N in D2O.
t
0.5 < 16 s.
-
g
In a CD3OD–D2O mixture (9:1) in the absence of a base, 80% of 6-H was replaced by deuterium in 90 days, and 50%
of 2-methoxy derivative Ic was formed [1].
h In a buffer solution with pD = 11.2 at 70°C, kap ~ 1.6 ´ 10–6 s–1 [3].
~
i
The resulting 2-methoxy derivative IIb (R = OCH3) [1] contained no deuterium.
j
No exchange of 6-H was observed in a 0.3 M solution of NaOD in D2O at 90°C [5].
k
In a solution of NaOD in DMSO-d6.
l
t
0.5 (s) at 38°C (data of [6]).
m Only replacement of the 4-methoxy group by CD3O was observed (94% in 7 h).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 1 2004

EFFECT OF THE STRUCTURE OF 1-AND 3-METHYL-5-FLUOROPYRIMIDIN-4-ONES
101
Table 2. Chemical shifts of C6 in the 13C NMR spectra of 1- and
3-methyl-5-fluoropyrimidin-4-onesIand IIand 1-methylpyrimidin-
4-onea
7 h) only of the methoxy group signal (d 4.06 ppm), while
the other signals (including that from 6-H) did not change
their position and intensity and the signal from methanol
increased in intensity. These data suggest replacement
of the 4-methoxy group by CD3O (with formation of com-
pound IVb) under conditions of base catalysis, as shown
in Scheme 3.
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Unlike 1- and 3-methyl-5-fluorouracils which give rise
to an appreciable amount of the corresponding anions
under the H–D exchange conditions, 5-fluoro-1,3-
dimethyluracil (IIIc) exchanges 6-H by deuterium fairly
readily, though the exchange rate is considerably lower
than in 5-fluoro-1-methylpyrimidin-4-ones Ib and Ie.
These data indicate that the absence of deuterium ex-
change of 6-H in 5-fluoro-3-methyl isomers II cannot be
explained in terms of spatial arrangement of the N-me-
thyl group with respect to the C6 atom.
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The difference in the chemical shifts d of 6-H in 5-fluoro derivatives
of 1-methyl and 3-methyl isomers is +(0.02–0.11) ppm, and for the
5-protium analogs, –(0.13–0.45) ppm [7].
Assuming that H–D exchange in the series of 5-fluoro
derivatives I involves formation of partially saturated in-
termediate A which then eliminates CD3OH molecule,
there are no factors preventing formation of an analo-
gous intermediate from isomers II. Moreover, anchimeric
effect of the methyl group, which hinders the exchange
process, could be expected just for 1-methyl isomers I.
Cushley et al. [13] previously proposed a mechanism for
H–D exchange at C6 in 5-fluorouracil derivatives, which
involved addition at the C5–C6 bond. This mechanism was
later ruled out [6]. An alternative path of the exchange
includes direct deprotonation at C6 by the action of a base
to give intermediate anion; however, in this case isomers
I and II should be characterized by different kinetic or
thermodynamic acidities. Although quasi-p-quinoid iso-
mers I are contributed mainly by the zwitterionic struc-
ture while the contribution of ionic structure to quasi-o-
quinoid isomers II is equal to zero (due to small volume
of the Y1 molecular orbital) [7], different CH acidities of
isomers I and II do not directly follow from their struc-
ture. According to the NMR data, the shielding param-
eters of C6 and 6-H in isomers I and II are very similar
(Table 2). The gas-phase enthalpies of dissociation of the
C6–H bond (DdH0) at 0 K, calculated by the PM3 method
with no regard to effect of the medium (Table 1), indicate
that proton abstraction from C6 in compounds I requires
a smaller energy (by about ~15 kcal/mol) as compared to
structures II. Within the series of compounds with the
same structure (I or II), the presence of a fluorine atom
in position 5 gives an energy gain (in the C6–H bond dis-
sociation energy) of 5.4–6.4 kcal/mol (see Table 1). The
enthalpies of dissociation of the C6–H bond in 1,3-di-
methyluracils having acceptor substituents in position 5
show a satisfactory correlation with the rates of base-
catalyzed H–D exchange at C6 in DMSO-d6:
ln k = 71.8 – 0.22DdH0(0) (kcal/mol); r = 0.999.
Obviously, the ease of isotope exchange in 5-fluoro-
1-methylpyrimidin-4-ones I, in contrast to their 3-methyl
isomers II, is explained primarily by their different struc-
ture in the initial state, which becomes crucial at the ex-
change moment.
In keeping with the mechanism proposed for H–D
exchange at C6 in 5-halouridines [6], the reaction with 5-
fluoro-1,3-dimethyluracil (IIIc) involves proton abstrac-
tion from C6 with formation of intermediate anion B which
is stabilized due to electron-withdrawing effect of the
neighboring positively charged nitrogen atom.
The H–D exchange at C6 in 5-fluoro-1-methyl-
pyrimidin-4-ones I may occur through intermediate car-
banion C whose formation requires no additional energy
for charge separation. Anion C is stabilized by the posi-
tive charge on the nitrogen atom, as well as by resonance
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 1 2004

102
KHEIFETS et al.
delocalization of electron density on the reaction center.
The presence of a fluorine atom in position 5 provides an
additional stabilizing effect. According to the 13C NMR
data, deshielding effect (DdC) of fluorine atom in position
5 of 1- and 3-methylpyrimidin-4-ones on C5 is equal to 36
ppm, while the C6 atom is shielded by 15–18 ppm [7];
these values are very consistent with the chemical shifts
of carbon nuclei in vinyl fluoride which may be regarded
as a model of the FC5C6 fragment in pyrimidin-4-ones I.
The corresponding DdC values for vinyl fluoride are 25
and –59.2 ppm (relative to ethylene) [14]. There are no
factors favoring “internal” stabilization of intermediate
anion derived from 5-fluoro-3-methylpyrimidin-4-ones II;
here, the thermodynamic barrier is the main reason for
the absence of H–D exchange at C6. This barrier (~15
kcal/mol) is so high that solvation of the neutral molecule
and/or carbanion cannot reduce it to a sufficient extent.
A different pattern is observed with 5-bromo- (IIId) and
5-methoxy-1,3-dimethyluracils (IIIe) for which the
DDdH0(0) values relative to 5-unsubstituted 1,3-di-
methyluracil (IIIf) are –8 and –3 kcal/mol, respectively.
All these compounds readily exchange 6-H by deuterium
in DMSO-d6 in the presence of NaOD [6]. 1-Methyl
derivatives Id and Ig are characterized by a DDdH0(0)
value of –5.93 kcal/mol, and the half-conversion period
The kinetic experiments were performed in NMR
ampules.Asample was dissolved in a required volume of
methanol-d4, and the initial spectrum was recorded rela-
tive to DSS. A solution of NaOD in D2O was then added
(it was prepared in such a way that the resulting solution
contained 90% of methanol-d4). A concentrated (2.5 M)
solution of NaOD was prepared by dissolution of metal-
lic sodium in D2O, and its concentration was determined
by titration.After addition of NaOD solution, the ampule
was shaken, and this moment was taken as initial (the
time elapsed from the moment of addition of the base to
recording of the first spectrum did not exceed 1 min).
The rate of H–D exchange was determined from the
decrease in the 6-H signal intensity, taking into account
the intensities of signals from unexchangeable protons.
The rate constants were determined by the graphical
method from the semilog plots of the intensity ratio be-
tween the 6-H and DSS signals versus time. The site of
H–D exchange was checked each time by the 13C NMR
spectra: replacement of 6-H by D was accompanied by
conversion of the doublet C6 signal into a doublet of trip-
lets, while the other carbon signals did not change their
position and multiplicity.
The enthalpies of dissociation of the C6–H bond in
pyrimidine derivatives DdH0(0) were calculated (accord-
ing to the Hess law) as the heat effect of the reaction
t
0.5 (corresponding to replacement of 50% of 6-H by D)
~
in 90% methanol-d4 in a buffer solution with pD ~11.8 is
2 min at 21°C (Id) and 113 h at 70°C (Ig) [3]. Kurinovich
and Lee [15] showed a leveling effect of solvation on the
calculated enthalpies of protolytic dissociation of the N1–
H and N3–H bonds in uracil, which attained 8 kcal/mol in
going from an inert solvent to aqueous medium. For 5-
fluoro-1-methylpyrimidin-4-ones I, the calculated values
of DDdH0(0) = DdH0(0)(Ib or Ic) – DdH0(0)(Id) are –3.2
and –0.8 kcal/mol, respectively, though the rates of H–D
exchange in 90% methanol-d4 differ by factors of 2 and
15 (Table 1). The observed inversion may be interpreted
in terms of different effects of solvation of the neutral
molecules and/or carbanions derived therefrom.
–
AH g A + H+ using the equation DdH0(0) =
–
DdH0(0)(A ) + DdH0(0)(H+) – DdH0(0) (AH), where
–
DdH0(0)(AH), DdH0(0)(A ), and DdH0(0)(H+) are the
standard gas-phase enthalpies of formation (at 0 K) of
the corresponding pyrimidin-4-one derivatives, their an-
ions, and a proton, which were calculated by the PM3
semiempirical method with the aid of GAMESS software
package [16]; DdH0(0) (H+) = 353.58 kcal/mol.
The procedures for the preparation of compounds
used in this work and their properties were reported in
[1, 7].Asample of 5-fluoro-1,3-dimethyluracil, mp 131–
134°C [17], was kindly provided by E.P. Studentsov.
EXPERIMENTAL
5-Fluoro-1-methyluracil. 5-Fluoro-1-methyl-2-
methylsulfanylpyrimidin-4(1H)-one (Ib), 0.11 mmol, was
dissolved in 5.8 ml of 90% methanol containing 0.22 mmol
of sodium hydroxide, and the mixture was left to stand
for 5 days at room temperature. The mixture was then
neutralized with hydrochloric acid (without separation of
crystal), the precipitate was filtered off, and the filtrate
was evaporated to obtain an additional amount of the prod-
uct. Overall yield 90%. The product was purified by re-
crystallization from water. mp 261°C; published data [18]:
1
The H and 13C NMR spectra were recorded on a
Bruker DPX-300 spectrometer at 300 and 75.47 MHz,
respectively. Samples were examined as 0.01–0.030 M
solutions which were placed in 5-mm NMR ampules
(while recording the 13C NMR spectra from dilute solu-
tions, the number of scans attained 6000–7000). The
chemical shifts (ppm) and signal intensities were mea-
sured relative to DSS. The IR spectra were measured on
a Bruker IFS-88 spectrometer in KBr.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 1 2004

EFFECT OF THE STRUCTURE OF 1-AND 3-METHYL-5-FLUOROPYRIMIDIN-4-ONES
103
mp 263–264°C. UV spectrum, lmax (log e): 0.1 N HCl:
274 (3.92); 0.1 N NaOH: 271 (3.80).
11. Shatenshtein, A.I., Izotopnyi obmen i zameshchenie
vodoroda v organicheskikh soedineniyakh (Isotope Ex-
change and Replacement of Hydrogen in Organic Com-
pounds), Moscow:Akad. Nauk SSSR, 1960; Bologa, M. and
Gard, E., Stud. Cercet. Chim., 1971, vol. 19, p. 1329; Chem.
Abstr., 1972, vol. 76, p. 98563; Zoltewicz, J.A. and Smith,
C.L., J. Am. Chem. Soc., 1966, vol. 88, p. 4766.
[6-2H]-5-Fluoro-1-methyluracil was synthesized
by a similar procedure using methanol-d4 and NaOD in
D2O.
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