Electrophilic ipso-substitution in uracil derivatives

Article abstract of DOI:10.1007/s11172-013-0354-0

Treatment of 5-iodo-1,3,6-trimethyluracil with 50% H₂SO ₄ gives 1,3,6-trimethyluracil; with 5-bromo-1,3,6-trimethyluracil, a mixture of 1,3,6-trimethyluracil and 6-bromomethyl-1,3-dimethyluracil is obtained. 5-Chloro-1,3,6-trimethyluracil remains inert under these conditions. According to the DFT modeling of the reactions of 5-halo-1,3,6-trimethyluracils, a nucleophilic agent can abstract either Hal⁺ or the methyl proton from the carbocation formed by protonation of the starting halouracil at position 5, which accounts for the formation of two products from the 5-bromo derivative. Under similar conditions, 6-methyluracil dibromohydrin yields N-bromo-5-bromo-6-hydroxymethyluracil. Bromination or chlorination of 5-hydroxymethyl- or 5-formyl-6-methyluracils follows the ipso-substitution scheme leading to 6-methyluracil 5-halo- and 5,5-dihalohydrins.

Full text of DOI:10.1007/s11172-013-0354-0

Russian Chemical Bulletin, International Edition, Vol. 62, No. 11, pp. 2445—2453, November, 2013
2445
Electrophilic ipsoꢀsubstitution in uracil derivatives*
I. B. Chernikova, S. L. Khursan, L. V. Spirikhin, and M. S. Yunusov
Institute of Organic Chemistry, Ufa Scientific Center of the Russian Academy of Sciences,
7
1 prosp. Oktyabrya, 450054 Ufa, Russian Federation.
Fax: +7 (347) 235 6066. Eꢀmail: msyunusov@anrb.ru
Treatment of 5ꢀiodoꢀ1,3,6ꢀtrimethyluracil with 50% H SO4 gives 1,3,6ꢀtrimethyluracil;
2
with 5ꢀbromoꢀ1,3,6ꢀtrimethyluracil, a mixture of 1,3,6ꢀtrimethyluracil and 6ꢀbromomethylꢀ
1
,3ꢀdimethyluracil is obtained. 5ꢀChloroꢀ1,3,6ꢀtrimethyluracil remains inert under these conꢀ
ditions. According to the DFT modeling of the reactions of 5ꢀhaloꢀ1,3,6ꢀtrimethyluracils,
+
a nucleophilic agent can abstract either Hal or the methyl proton from the carbocation formed
by protonation of the starting halouracil at position 5, which accounts for the formation of two
products from the 5ꢀbromo derivative. Under similar conditions, 6ꢀmethyluracil dibromohydrin
yields Nꢀbromoꢀ5ꢀbromoꢀ6ꢀhydroxymethyluracil. Bromination or chlorination of 5ꢀhydrꢀ
oxymethylꢀ or 5ꢀformylꢀ6ꢀmethyluracils follows the ipsoꢀsubstitution scheme leading to
6
ꢀmethyluracil 5ꢀhaloꢀ and 5,5ꢀdihalohydrins.
Key words: substituted uracils, halogenation, ipsoꢀsubstitution.
Synthetic analogs of pyrimidine nucleosides are curꢀ
rently employed in medicine as efficient anticancer, antiꢀ
viral, and antiinflammatory drugs. Uracil derivatives subꢀ
Nꢀchlorosuccinimide (NCS) because of nonselective oxiꢀ
dative chlorination.
1
stituted at the C=C bond are well studied and used acꢀ
tively. 6ꢀMethyluracil (1) shows anabolic and anticatabolic
activity, promotes cell regeneration processes and wound
healing, and exhibits antiinflammatory, hematopoietic,
Scheme 1
2
and leukopoietic properties. 5ꢀHydroxyꢀ6ꢀmethyluracil
is an efficient stimulant of the phagocytal activity of leukoꢀ
3
cytes (thereby enhancing an organism´s immune system )
4
and inhibits peroxide oxidation of lipids.
Halogenꢀcontaining pyrimidine bases are also of inꢀ
5
6
terest. For instance, 5ꢀfluorouracil and ftorafur are used
7
in chemotherapy to treat cancers. 5ꢀIodoꢀ2´ꢀdeoxyuridine
inhibits neoplasia and has a virusꢀinhibiting effect on
the herpes virus. 5ꢀBromoꢀ3ꢀsecꢀbutylꢀ6ꢀmethyluracil
8
(
bromacil) is known to be a highly efficient herbicide.
In the present work, we studied the reactivities of halogenꢀ
containing 6ꢀmethylꢀ and 1,3,6ꢀtrimethyluracils in their
reactions with 50% H SO . Comꢀ
2
4
pounds 2—4 were obtained from 6ꢀ
methyluracil (1) as described earlier.9
Oxidative halogenation of 1,3,6ꢀtriꢀ
methyluracil (5)1 gave 5ꢀiodoꢀ (6)
and 5ꢀbromoꢀ1,3,6ꢀtrimethyluracils
0
(
5
7) (Scheme 1). For the synthesis of
ꢀchloroꢀ1,3,6ꢀtrimethyluracil (8),
compound 5 was chlorinated with
R = H (1), I (2),
Br (3), Cl (4)
Reagents and conditions: a. Me SO4 (4 equiv.), 20% NaOH
2
(
4 equiv.), 100 C, 4 h. b. KI (2 equiv.), H O (4 equiv.),
2 2
*
Dedicated to Academician of the Russian Academy of Sciences
20% H SO , 25 C, 4 h. c. KBr (4 equiv.), H O (6 equiv.),
2
4
2
2
M. P. Egorov on the occasion of his 60th birthday.
AcOH, 25 C, 4 h. d. NCS (1.25 equiv.), AcOH, 50 C, 4 h.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2445—2453, Novemer, 2013.
066ꢀ5285/13/6211ꢀ2445 © 2013 Springer Science+Business Media, Inc.
1

2446
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 11, November, 2013
Chernikova et al.
Scheme 2
Reagents and conditions: i. 50% H SO , 80 C, 5 h.
2
4
Heating of 5ꢀiodoꢀ1,3,6ꢀtrimethyluracil (6) in 50%
H SO at 80 C produces 1,3,6ꢀtrimethyluracil (5) in 68%
yield (Scheme 2). Apparently, its formation is due to iniꢀ
tial protonation at the double bond (intermediate A) folꢀ
lowed by abstraction of the iodonium cation with the anꢀ
ion (see Scheme 2). With 5ꢀbromoꢀ1,3,6ꢀtrimethyluracil
at the C(5) atom. In the next step of the reaction, the
carbocation is attacked by a nucleophilic agent (in our
2
4
–
model, HOSO O ). Carbocations 6a—8a can be transꢀ
2
formed into molecular products in three different ways
(I)—(III) (Scheme 3).
In pathway (III), products 6b—8b can undergo allylic reꢀ
arrangement with transfer of either the H or halogen atom.
Using our theoretical model, we also studied other posꢀ
sible transformations of the carbocation. In particular, we
assumed that the attack of the nucleophile can be preꢀ
ceded by the formation of molecular intermediates 6c—8c
(Scheme 4, reaction (IV)).
(
(
7) as a substrate, we obtained a mixture of compounds 5
40%) and 9 (41%); the latter can be formed from interꢀ
mediate B via its allylic rearrangement. The mixture was
separated by HPLC with water—acetonitrile as an eluent.
Concentration of the fraction containing compound 9 at
5
0—60 C resulted in replacement of the Br atom by the
13
+
+
hydroxy group ( C NMR data).
Abstraction of Hal (H ) from intermediates 6c—8c
with the hydrosulfate anion leads to an unstable structure
in which the C(6)—O bond dissociates with elimination of
5
ꢀHaloꢀ6ꢀmethyluracils (2—4) and 5ꢀchloroꢀ1,3,6ꢀ
trimethyluracil (8) remain inert under similar conditions.
To explain the observed trends and identify the reacꢀ
tion mechanism, we performed theoretical DFT modeling
at the level B3LYP/6ꢀ311+G(d,p)//B3LYP/6ꢀ311G(d,p)
for uracils 3, 7, and 8 and at the level B3LYP/CEPꢀ121G
for all compounds (including 6). When constructing
a theoretical model, we considered carbocations 3a and
–
HOSO O to form trimethyluracil 5 (see Scheme 4, reacꢀ
2
tion (V)) or the starting compounds 6—8 (reaction (VI)).
The changes in the enthalpies and Gibbs energies of the
model reactions are given in Table 1. One can see that G
of reaction (V) is much higher than G of reaction (VI);
i.e., the proton abstraction from intermediates 6c—8c supꢀ
presses reaction (V) completely. Therefore, the sequence
of reactions shown in Scheme 4 returns the system to the
starting reactants.
6
a—8a to be key intermediates under the chosen experiꢀ
mental conditions. These carbocations are produced by
protonation of the corresponding compounds 3 and 6—8

ipsoꢀSubstitution in uracils
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 11, November, 2013 2447
Scheme 3
Hal = I (6a,b), Br (7a,b), Cl (8a,b)
Scheme 4
Hal = I (6c), Br (7c), Cl (8c)
This theoretical model explains why uracils 2—4 yield
no ipsoꢀsubstitution products. The N—H bond intrinsic in
compounds 2—4 ensures additional stabilization of the
carbocation (Scheme 5). With 5ꢀbromoꢀ6ꢀmethyluracil (3)
as an example, we demonstrated that, apart from the aforeꢀ
mentioned reactions (I)—(III), the hydrosulfate anion easꢀ
ily abstracts the N(1)H proton (reaction (VII)) and that
the resulting imine undergoes a thermodynamically favorꢀ
able rearrangement leading to the starting uracil (reacꢀ
tion (VIII)).
Comparison of the thermodynamic parameters of reꢀ
actions (I)—(III), (VII), and (VIII) for uracil 3 (see Table 1)
reveals that the transformations shown in Scheme 5 comꢀ
pletely suppress all the other reaction pathways of carbꢀ
ocation 3a. This seems to be the case of uracils 2 and 4
as well. Therefore, according to our theoretical model,

2448
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 11, November, 2013
Chernikova et al.

Table 1. The enthalpies of activation (H ) and reaction
Scheme 5

(
 H) and the Gibbs energies of activation (G ) and reꢀ
action ( G) (kcal mol ) for the competitive transformaꢀ
r
–
1
r
tion pathways of carbocations 3a and 6a—8a (calculated
at the B3LYP/6ꢀ311+G(d,p)//B3LYP/6ꢀ311G(d,p) level)
Reactiona Uracil H
G
rH
rG
I
3
6
7
7
8
8
3
6
7
7
8
8
3
6
7
7
8
8
6
7
7
8
8
6
7
7
8
8
6
7
7
8
8
3
3
—
—
—
—
—
—
—
—
—
—
17.9
8.0
18.8
6.0
b
b
b
b
b
b
b
b
23.0
17.8
32.2
26.0
–16.0
–3.7
–10.5
–6.3
–13.4
–8.6
–3.9
5.2
–0.6
2.5
–1.7
0.7
–1.7
0.3
–3.7
–1.6
–5.3
9.7
22.7
21.5
33.9
31.2
–2.0
–10.9
–2.6
–11.8
–3.3
0.9
24.4
16.1
32.3
24.1
–15.0
–5.1
–8.6
–7.2
–11.7
–9.5
–1.9
5.0
2.3
2.5
0.8
0.6
12.0
18.2
10.6
15.6
8.9
–6.0
6.1
5.5
—
—
II
III
–3.1
0.8
–1.4
–0.6
–3.3
–2.4
1.2
5.0
3.6
3.8
2.9
3.0
—
—
—
—
—
—
—
—
—
13.3
13.8
14.7
13.8
12.8
12.1
17.4
18.8
20.1
17.9
19.1
16.8
—
—
—
—
—
—
—
—
—
tion shows the pseudoaxial orientation of the Br atom. In
the twistꢀconformation of intermediate 7b, the C(5) and
C(6) atoms deviate from the plane of the pyrimidine ring.
–
We modeled attacks of HOSO O on the C(5)H atom
2
(
reverse), the halogen atom (ipso), and the H atom of the
C(6)Me group (side) (see Scheme 3). The first pathway
(II) involves deprotonation of 7a, thus recovering the startꢀ
ing uracil 7. The second pathway (I) is actually a model of
ipsoꢀsubstitution in uracil 7. The third pathway (III) inꢀ
volves a "side" reaction leading to uracil 9 through interꢀ
mediate 5ꢀbromoꢀ1,3ꢀdimethylꢀ6ꢀmethylidenedihydroꢀ
pyrimidineꢀ2,4(1H,3H)ꢀdione (7b). We localized the tranꢀ
sition states for reactions (II) and (III) (see Fig. 1), while
the scan of the potential energy surface (PES) of the
ipsoꢀsubstitution reaction revealed a monotonically (as
with a Morse curve) increasing energy of the system as the
Br atom moves away from 7a to form a couple of molecuꢀ
b
b
IV
V
b
b
b
b
17.8
15.2
–17.2
–26.8
–17.7
–27.2
–18.4
2.0
b
b
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
VI
lar products (uracil 5 and HOSO OBr). Similar strucꢀ
2
b
b
tures, transition states, and PES profile were found in the
–
reactions of carbocations 6a and 8a with HOSO O .
2
The probability of each competitive pathway in the
VII
VIII
transformation of carbocations 6a—8a was estimated from
–16.9
–17.1

the Gibbs energies of activation G (see Table 1) calcuꢀ
a
lated by subtracting the sum of G of the carbocation and
hydrosulfate anion from the Gibbs energy of the transition
state (for ipsoꢀsubstitution, the total Gibbs energy of the
molecular products). The calculated and experimental data
For the designations of the reactions, see Schemes 3—5.
Calculated at the B3LYP/CEPꢀ121G level.
b

uracils 2—4 are inert under the chosen experimental conꢀ
ditions, while their N(1),N(3)ꢀdimethylated derivatives
are in good agreement. For instance, G (ipso) for uracil 6

is lower than G (side); i.e., the formation of intermediate
(
(
6—8) can be involved in competitive reactions (I)—(III)
see Scheme 3). The structures of all reactants, intermediꢀ
6b is thermodynamically less favorable than the abstracꢀ
tion of the I atom. In the case of uracil 7, the calculations
at both levels predict close Gibbs energies of the ipso and
side pathways. Therefore, both transformations will occur
simultaneously, yielding uracils 5 and 9 in comparable
amounts. Finally, when the uracil molecule contains the
Cl atom in position 5, the calculated G and H values
in the abstraction of this atom from carbocation 8a are
substantially higher than those for Brꢀ and Iꢀcontaining
structures 6a and 7a; i.e., ipsoꢀsubstitution in uracil 8 seems
ates, and final products of these reactions were optimized
at the levels B3LYP/6ꢀ311+G(d,p)//B3LYP/6ꢀ311G(d,p)
and B3LYP/CEPꢀ121G.
The optimized structures of 5ꢀbromoꢀ1,3,6ꢀtrimethylꢀ
uracil (7), the key intermediates, and the transition states
are shown in Fig. 1 as examples. Carbocation 7a adopts
a distorted halfꢀchair conformation; the torsion angle
N(1)—C(6)—C(5)—C(4) is 19.8. This stable conformaꢀ



ipsoꢀSubstitution in uracils
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 11, November, 2013 2449
O
Br
O
O
Br
Br
1.213
1.197
N
1.210
C
C
1.905
1.990
2.020
N
C
C
O
C
C
1
.461
1.516
1.486
1.515
.487
N
C
C
C
C
C
1
1
.360
C
C
C
C
N
N
O
1.501
1.488
N
1.340
O
1
.389
1.303
1.401
C
C
C
C
C
C
7
7a
7b
O
C
O
S
C
C
1.407
O
1.317
O
N
O
O
N
C
O
1
.514
С
C
.493
C
1.314
1
.325
1.491
1.340
C
1.519
1
C
1.439
Br
2
.004
O
S
1
.452 1.227
C
N
Br
1
.956
1.511
C
N
C
1.500
O
O
C
1.204
C
1
.202
O
O
TS(reverse)
imag = 202i cm–1
TS(side)
imag = 992i cm–1
Fig. 1. B3LYP/6ꢀ311G(d,p)ꢀoptimized structures of 5ꢀbromoꢀ1,3,6ꢀtrimethyluracil (7), carbocation 7a, and intermediate 7b and the
transition states (TS) in the proton transfer from carbocation 7a to the hydrosulfate anion. The interatomic distances are quoted in
ångströms; imag is the only imaginary frequency for the TS.
to be unlikely, which was confirmed experimentally. It
should also be noted that, as expected, all carbocations
Scheme 6
6
a—8a easily undergo reversible deprotonation (reverse
pathway). Obviously, this pathway makes no contribution
to the ratio of the irreversible consumption pathways of
uracils 6—8, only affecting the rate and time of the whole
reaction.
Other examples of successful ipsoꢀsubstitution in
5
5
ꢀsubstituted 6ꢀmethyluracils include halogenation of
ꢀhydroxymethylꢀ6ꢀmethyluracil (11) and 5ꢀformylꢀ6ꢀ
methyluracil (12) prepared according to known proceꢀ
dures.11
Compound 11 was brominated with KBr—H O in
2
2
AcOH or 20% H SO . Under these conditions, the conꢀ
2
4
version of uracil 11 was incomplete; the reaction gave
bromouracil 3 in AcOH or dibromouracil 13 in 20% H SO
2
4
(
Scheme 6). In this reaction, two alternative pathways of
ipsoꢀsubstitution are possible: the key carbocation can be
+
stabilized by elimination of CH OH (i) or by the formaꢀ
2
tion of a fourꢀmembered oxetane ring followed by its deꢀ
composition (ii) (see Scheme 6).
DFT modeling of these mechanisms of ipsoꢀsubstituꢀ
tion in hydroxymethyluracil 11 revealed a transition state
only for pathway (i) (Fig. 2). In the case of pathway (ii),
Reagents and conditions: a. KBr (4 equiv.), H O (6 equiv.),
2
2
AcOH, 25 C, 4 h. b. KBr (4 equiv.), H O2 (6 equiv.), 20%
2
H SO , 25 C, 4 h.
2
4

2450
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 11, November, 2013
Chernikova et al.
Scheme 8
C
O
1.273
0
.996
2
.406
C
Br
C
1
1.853
N
.903
C
1.480
Reagents and conditions: a. Br (2 equiv.), AcOH, 25 C, 6 h.
2
1.221
b. KBr (4 equiv.), H O (6 equiv.), 20% H SO , 25 C, 4 h.
C
2
2
2
4
O
N
C
O
Scheme 9
Fig. 2. Transition state in the ipsoꢀsubstitution reaction with
= 177i cm–1, G

=
uracil 11 (B3LYP/6ꢀ311G(d,p), 
imag
–
1
=
14.0 kcal mol ).
the PES profile, first, has a substantially higher energy
and, second, shows characteristic breakpoints indicative
of an orbital symmetry disturbance during the transformaꢀ
tions under discussion. Hence, our theoretical analysis
provides evidence for the simpler pathway (i) of ipsoꢀsubꢀ
stitution in hydroxymethyluracil 11.
Reagents and conditions: i. 50% H SO , 80 C, 5 h.
2
4
The presence of two bromine atoms in compound 15
was revealed by elemental analysis and confirmed by mass
spectrometry in the negative ion mode. The mass specꢀ
Reactions of 5ꢀformyluracil 12 with molecular haloꢀ
gens also follow the ipsoꢀsubstitution pattern. Chlorinaꢀ
tion with dried Cl in anhydrous CHCl gives 5ꢀchloroꢀ6ꢀ
2
3
–
trum shows the peaks of the ion [M – OH] with m/z
methyluracil (4), while the use of moist Cl in nonꢀdried
2
(
Irel (%)) 281 (50), 283 (100), and 285 (50), which is
CHCl leads to 5,5ꢀdichloroꢀ6ꢀhydroxyꢀ6ꢀmethyldihydroꢀ
3
1
2
characteristic of fragments containing two Br atoms.
uracil (14) (Scheme 7).
13
The C NMR spectrum consists of five signals. The sigꢀ
nals at  59.90 and 92.62 are due to the CH OH group and
the C(5) atom of the uracil ring, respectively. The other
2
Scheme 7
three signals at  150—160 were assigned using an HMBC
1
experiment. The H NMR spectrum shows a signal at

4.31 for the methylene protons of the CH OH group.
2
The HMBC spectrum reveals cross peaks of this sigꢀ
nal with those for the carbon atoms at  92.62 (C(5))
and 153.23 (C(6)). Therefore, the signals at  150.38 and
1
60.44 most likely relate to the C(2) and C(4) atoms,
respectively.
1
The H NMR spectrum contains two other signals of
half intensity for the NH protons ( 10.70 and 11.50). To
Reagents and conditions: a. Cl (dry), CHCl (anhydrous), 25 C,
2
3
2
h. b. Cl (moist), CHCl (nonꢀdried), 25 C, 2 h.
2 3
15
1
confirm this assignment, we recorded N— H correlaꢀ
Bromination of compound 12 with two equivalents of
Br in AcOH affords 5ꢀbromoꢀ6ꢀmethyluracil (3) in 54%
yield, the conversion of the substrate being incomplete.
tion spectra. In the HSQC spectrum, the signal at  10.70
H
2
shows a cross peak with the signal at N 133.83 and the
signal at H 11.50 shows a cross peak with the signal at
N 155.31. At the same time, the HMBC spectrum reꢀ
Oxidative bromination in 20% H SO gives 5,5ꢀdibromoꢀ
2
4
6
(
ꢀhydroxyꢀ6ꢀmethyldihydrouracil (13) in 88% yield
Scheme 8)*.
Compound 13 reacts with 50% H SO4 to form
veals a correlation between the signal at  133.83 and the
N
signal for the protons of the CH OH group. Therefore, the
2
2
signals at N 133.83 and 155.31 can be assigned to the
Nꢀbromoꢀ5ꢀbromoꢀ6ꢀhydroxymethyluracil
Scheme 9).
(15)
N(1) and N(3) atoms, respectively. The signals at  10.70
H
(
and 11.50 relate to the N(1)H and N(3)H protons, respecꢀ
tively. The integral intensity of 0.5 H for either of the latter
signals suggests that the Br and H atoms at N(1) and N(3)
*
The mechanisms of these reactions are being investigated.

ipsoꢀSubstitution in uracils
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 11, November, 2013 2451
experience rapid exchange on the NMR time scale and
that their positions are interchangeable.
To sum up, this study demonstrated that electrophilic
ipsoꢀsubstitution is quite characteristic of 5ꢀsubstituted
uracils.
All calculations were performed on a supercomputing clusꢀ
ter of the Joint Use Center of the Institute of Organic Chemistry
(
Ufa Scientific Center of the Russian Academy of Sciences).
ꢀIodoꢀ1,3,6ꢀtrimethyluracil (6). A 36% solution of H O
5
2
2
(
2.40 mL, 26 mmol) was added dropwise to a solution of 1,3,6ꢀ
trimethyluracil (5) (1.00 g, 6.50 mmol) and KI (2.16 g, 13 mmol)
in 20% H SO (10 mL), while maintaining the reaction temꢀ
2
4
Experimental
perature within 20—25 C. The reaction mixture was stirred for
h; its color changed from dark blue to light brown. A 20% soluꢀ
4
1
H and 13C NMR spectra were recorded on a Bruker AMꢀ300
tion of Na2S2O3 (15 mL) was added until complete decoloration
was achieved. The precipitate that formed was filtered off, washed
with water, dried at 60 C, and recrystallized from EtOH. Yield
spectrometer (300 and 75 MHz, respectively). 15N NMR spectra
were recorded on a Bruker Avance III 500 instrument (50.68
MHz). The signals of the solvents (DMSOꢀd or CDCl ) served
as the internal standards. The signals in the H and C NMR
spectra were assigned using the spectra simulated with the ACD
program package.
Mass spectra (ESI) were measured on an LCMSꢀ2010 EV
quadrupole liquid chromatographꢀmass spectrometer (Shimꢀ
adzu). Solutions of samples in methanol/water were infused into
the instrument through a syringe (flow rate 50 L min– , acetoꢀ
nitrile—water (1 : 1) as an eluent). The capillary potentials were
.5 (positive ion mode) and –3.5 kV (negative ion mode). The
interface capillary temperature was 250 C (capillary voltage
5 to –25 V). Nitrogen was used as a nebulizing gas (flow rate
.5 L min ). The voltage applied to highꢀfrequency lenses
Qꢀarray) was 5 to –5 V. Column chromatography was carꢀ
ried out on a Waters Breeze instrument (a Luna C18 column,
50 × 4.6 mm, particle size 5 m, flow rate 1 mL min–
,
1
.70 g (94%), light creamꢀcolored crystals, m.p. 122—124 C
6
1
3
13
(
(
decomp.) (cf. Ref. 22: m.p. 152—153 C (naphtha)). Found
%): C, 30.12; H, 3.00; N, 10.05; I, 45.50. C H N O I. Calcuꢀ
7
9
2
2
1
lated (%): C, 30.02; H, 3.24; N, 10.00; I, 45.31. H NMR
(
(
CDCl ), : 2.65 (s, 3 H, MeC(6)); 3.41 (s, 3 H, MeN(1)); 3.51
s, 3 H, MeN(3)). C NMR (CDCl ), : 25.75 (CH C(6));
3 3
3
13
2
1
9.83 (MeN(3)); 34.07 (MeN(1)); 74.00 (C(5)); 151.59 (C(2));
52.76 (C(6)); 159.68 (C(4)).
1
5
ꢀBromoꢀ1,3,6ꢀtrimethyluracil (7). A 36% solution of H O
2 2
(3.60 mL, 39 mmol) was added dropwise to a solution of 1,3,6ꢀtriꢀ
4
methyluracil (5) (1.00 g, 6.50 mmol) and KBr (3.09 g, 26 mmol)
in AcOH (5 mL). The reaction mixture was stirred at room
temperature for 4 h and concentrated. Then distilled water
2
1
(
–
1
(10 mL) was added, and the product was extracted with CHCl3.
The combined extracts were washed with water, dried with
Na SO , and concentrated. The residue was recrystallized from
1
2
4
2
EtOH. Yield 1.39 g (92%), light yellow crystals, m.p. 134—136 C
decomp.) (cf. Ref. 23: m.p. 138 C (MeOH)). Found (%):
C, 36.00; H, 3.60; N, 12.16; Br, 34.12. C H N O Br. Calcuꢀ
MeCN—H O (1 : 1) as an eluent). Elemental analysis was carꢀ
ried out on a EUROꢀ3000 instrument. Melting points were deꢀ
termined in glass capillaries.
2
(
7
9
2
2
1
lated (%): C, 36.07; H, 3.89; N, 12.02; Br, 34.28. H NMR
Quantum chemical calculations were performed with the
Gaussianꢀ09 (Revision C.1) program.1 Primary processing and
visualization of the results obtained were accomplished with the
ChemCraft program.14 The geometrical parameters of uracils
and their derivatives were fully optimized, and the force conꢀ
stants were calculated, using the hybrid electron density funcꢀ
(
(
CDCl ), : 2.52 (s, 3 H, MeC(6)); 3.39 (s, 3 H, MeN(1)); 3.49
s, 3 H, MeN(3)). C NMR (CDCl ), : 20.42 (CH C(6));
3 3
3
3
13
2
1
9.22 (MeN(3)); 33.29 (MeN(1)); 97.79 (C(5)); 149.86 (C(2));
51.06 (C(6)); 158.55 (C(4)).
5
ꢀChloroꢀ1,3,6ꢀtrimethyluracil (8). NꢀChlorosuccinimide
1.09 g, 8.13 mmol) was added in portions at 50 C to a solution
of 1,3,6ꢀtrimethyluracil (5) (1.00 g, 6.50 mmol) in AcOH
10 mL). The reaction mixture was stirred at 50 C for 4 h and
(
tional B3LYP1
5,16
and the basis set 6ꢀ311G(d,p). The total
17
energies were calculated in a single computational run for each
optimized state with the diffuse basis set 6ꢀ311+G(d,p). Since
the above basis sets are unsuitable for iodineꢀcontaining comꢀ
pounds, the B3LYP/CEPꢀ121G approximation was also used to
fully optimize the structures of all compounds and calculate their
total energies and force constants (CEPꢀ121G is a triple splitꢀ
(
concentrated. Then distilled water (10 mL) was added, and the
product was extracted with CHCl . The combined extracts were
3
washed with water, dried with Na SO , and concentrated. The
2
4
residue was recrystallized from EtOH. Yield 0.93 g (76%), white
crystals, m.p. 95—97 C (decomp.) (cf. Ref. 23: m.p. 151 C
1
8,19
valence basis set with the effective core potential).
The enꢀ
(
MeOH)). Found (%): C, 44.38; H, 4.50; N, 14.90; Cl, 18.50.
ergy minima on the PES corresponding to the above structures
were determined by the absence of negative eigenvalues of the
diagonalized Hessian; the presence of only one negative (imagiꢀ
nary) frequency served as a criterion for a saddle point on the
PES. The thermodynamic potentials (the enthalpy H and the
Gibbs energy G) of the compounds and the transition states
were calculated by the equation
C H N O Cl. Calculated (%): C, 44.58; H, 4.81; N, 14.85;
7
9
2
2
1
Cl, 18.80. H NMR (CDCl ), : 2.41 (s, 3 H, MeC(6)); 3.35 (s, 3 H,
MeN(1)); 3.45 (s, 3 H, MeN(3)). C NMR (CDCl ), : 17.63
3
13
3
(
CH C(6)); 29.13 (MeN(3)); 33.05 (MeN(1)); 107.68 (C(5));
3
1
48.36 (C(2)); 151.05 (C(6)); 158.72 (C(4)).
Reaction of 5ꢀiodoꢀ1,3,6ꢀtrimethyluracil (6) with 50% H SO .
2
4
Sulfuric acid (98%, 0.6 mL, 12 mmol) was added dropwise at
8
0
0 C to a suspension of 5ꢀiodoꢀ1,3,6ꢀtrimethyluracil (6) (0.2 g,
.70 mmol) in water (0.7 mL). The reaction mixture was stirred
H (G) = Etot + ZPE + TCH (TC ),
G
where Etot is the total energy of the compound, ZPE is the enꢀ
ergy of zeroꢀpoint vibrations, and TC is the thermal correction
to the enthalpy or the Gibbs energy (this correction was calcuꢀ
lated for the experimental temperature T = 353 K). The effect of
the solvent (water) was considered using the IEFPCM continual
model.2
at 80 C for 5 h and diluted with distilled water (10 mL). The
product was extracted with CHCl . The combined extracts were
3
washed with water, dried with Na SO , and concentrated. The
2
4
residue was recrystallized from EtOH. The yield of 1,3,6ꢀtriꢀ
methyluracil (5) was 0.07 g (68%), white crystals, m.p. 114—116 C.
Found (%): C, 54.48; H, 6.37; N, 18.25. C H N O . Calcuꢀ
0,21
7
10
2
2

2452
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 11, November, 2013
Chernikova et al.
lated (%): C, 54.54; H, 6.54; N, 18.17. 1H NMR (CDCl ),
perature for 2 h and evaporated to dryness in vacuo. The residue
was washed with CH Cl and dried at 60 C. The yield of 5,5ꢀdiꢀ
3

: 2.21 (s, 3 H, MeC(6)); 3.29 (s, 3 H, MeN(1)); 3.39 (s, 3 H,
2
2
1
3
MeN(3)); 5.59 (s, 1 H, CH). C NMR (CDCl ), : 19.73
chloroꢀ6ꢀhydroxyꢀ6ꢀmethyldihydrouracil (14) was 0.22 g (80%).
3
9
(
CH C(6)); 27.37 (MeN(3)); 31.23 (MeN(1)); 100.52 (C(5));
Its physicochemical characteristics agree with the literature data.
3
1
51.32 (C(2)); 152.07 (C(6)); 161.93 (C(4)).
Reaction of 5ꢀbromoꢀ1,3,6ꢀtrimethyluracil (7) with 50%
Bromination of 5ꢀformylꢀ6ꢀmethyluracil (12). A. Bromine
(0.14 mL, 2.60 mmol) was added dropwise to a suspension of
5ꢀformylꢀ6ꢀmethyluracil (12) (0.20 g, 1.30 mmol) in AcOH
(2 mL). The reaction mixture was stirred at room temperature
for 6 h. The precipitate that formed was filtered off, washed with
water, dried at 60 C, and recrystallized from EtOH. The yield of
5ꢀbromoꢀ6ꢀmethyluracil (3) was 0.14 g (54%). Its physicochemiꢀ
H SO . Sulfuric acid (98%, 0.73 mL, 14.70 mmol) was added
2
4
dropwise at 80 C to a suspension of 5ꢀbromoꢀ1,3,6ꢀtrimethꢀ
yluracil (7) (0.2 g, 0.86 mmol) in water (0.8 mL). The reaction
mixture was stirred at 80 C for 5 h and diluted with distilled
water (10 mL). The products were extracted with CHCl . The
combined extracts were washed with water, dried with Na SO ,
3
9
cal characteristics agree with the literature data. The starting
2
4
and concentrated. The resulting mixture of 1,3,6ꢀtrimethyluracil
5) and 6ꢀbromomethyluracil (9) was separated by HPLC with
compound 12 was recovered from the filtrate.
(
B. A 36% solution of H O (0.72 mL, 7.8 mmol) was added
2
2
MeCN—H O (1 : 1) as an eluent. The yields of compounds 5
dropwise to a suspension of 5ꢀformylꢀ6ꢀmethyluracil (12) (0.20 g,
2
and 9 were 40 and 41%, respectively. Concentration of the fracꢀ
tion containing compound 9 under reduced pressure at 50—60 C
resulted in replacement of the Br atom by the OH, producing
1.30 mmol) and KBr (0.60 g, 5.2 mmol) in 20% H SO (2 mL).
2
4
The reaction mixture was stirred at room temperature for 4 h.
The precipitate that formed was filtered off, washed with water,
dried at 60 C, and recrystallized from EtOH. The yield of 5,5ꢀdiꢀ
bromoꢀ6ꢀhydroxyꢀ6ꢀmethyldihydrouracil (13) was 0.34 g (88%).
6
ꢀhydroxymethyluracil (10).
ꢀBromomethylꢀ1,3ꢀdimethyluracil (9). 13C NMR (CDCl ),
6
3
9

: 26.71 (BrCH C(6)); 27.48 (MeN(3)); 30.98 (MeN(1)); 102.44
Its physicochemical characteristics agree with the literature data.
2
(
C(5)); 151.36 (C(2)); 156.75 (C(6)); 161.60 (C(4)).
ꢀHydroxymethylꢀ1,3ꢀdimethyluracil (10). Yield 0.06 g (40%).
Found (%): C, 49.03; H, 5.65; N, 16.88. C H N O . Calcuꢀ
Reaction of 5,5ꢀdibromoꢀ6ꢀhydroxyꢀ6ꢀmethyldihydrouracil
6
(13) with 50% H SO . Sulfuric acid (98%, 1.40 mL, 27 mmol)
2
4
was added dropwise at 80 C to a suspension of 5,5ꢀdibromoꢀ6ꢀ
hydroxyꢀ6ꢀmethyldihydrouracil (13) (0.5 g, 1.65 mmol) in water
(1.50 mL). The reaction mixture was stirred at 80 C for 5 h. The
precipitate that formed was washed with water to a neutral reacꢀ
tion and dried. The yield of Nꢀbromoꢀ5ꢀbromoꢀ6ꢀhydroxyꢀ
methyluracil (15) was 0.2 g (40%), yellow powder, m.p.
323—325 C (decomp.). Found (%): C, 20.18; H, 1.14; N, 9.49;
Br, 56.14. C H N O Br . Calculated (%): C, 20.02; H, 1.34;
7
10
2
3
lated (%): C, 49.41; H, 5.92; N, 16.46. 1H NMR (CDCl ),

4

3
: 2.61 (t, 1 H, OH); 3.35 (s, 3 H, MeN(1)); 3.45 (s, 3 H, MeN(3));
13
.50 (d, 2 H, CH ); 5.90 (s, 1 H, CH). C NMR (CDCl ),
2
3
: 28.05 (MeN(3)); 30.86 (MeN(1)); 60.93 (CH OH); 99.74 (C(5));
2
1
52.16 (C(2)); 152.97 (C(6)); 162.93 (C(4)).
Bromination of 5ꢀhydroxymethylꢀ6ꢀmethyluracil (11). A. A 36%
solution of H O (0.71 mL, 7.68 mmol) was added dropwise to
2
2
5
4
2
3
2
1
a suspension of 5ꢀhydroxymethylꢀ6ꢀmethyluracil (11) (0.20 g,
.28 mmol) and KBr (0.60 g, 5.12 mmol) in AcOH (2 mL). The
N, 9.34; Br, 53.29. H NMR (DMSOꢀd ), : 2.50 (s, 1 H, OH);
6
1
4.31 (s, 2 H, CH ); 10.70 (s, 0.5 H, N(1)H); 11.50 (s, 0.5 H,
2
1
3
reaction mixture was stirred at room temperature for 4 h. The
precipitate that formed was filtered off, washed with water, dried
at 60 C, and recrystallized from EtOH. The yield of 5ꢀbromoꢀ6ꢀ
methyluracil (3) was 0.14 g (55%). Its physicochemical characꢀ
N(3)H). C NMR (DMSOꢀd ), : 59.90 (CH OH); 92.62
(C(5)); 150.38 (C(2)); 153.23 (C(6)); 160.44 (C(4)). N NMR
6
2
15
(DMSOꢀd ), : 133.83 (N(1)); 155.31 (N(3)). MS (ESI), m/z
6
–
(Irel (%)): 281 [M – OH] (50), 283 (100), 285 (50).
9
teristics agree with the literature data. The starting compound 11
was recovered from the filtrate.
This work was financially supported by the Federal
Target Program "Scientific and ScientificꢀPedagogical
Personnel of the Innovative Russia in 2011—2013" (State
Contract No. 14.740.11.0367), the Council on Grants at
the President of the Russian Federation (State Support
Program for Leading Scientific Schools of the Russian
Federation, Grant NShꢀ7014.2012.3), and the Division of
Chemistry and Materials Sciences of the Russian Academy
of Sciences (Basic Research Program in 2013, OKhꢀ01).
B. A 36% solution of H O (0.71 mL, 7.68 mmol) was added
2
2
dropwise to a suspension of 5ꢀhydroxymethylꢀ6ꢀmethyluracil
11) (0.20 g, 1.28 mmol) and KBr (0.60 g, 5.12 mmol) in 20%
H SO (2 mL). The reaction mixture was stirred at room temꢀ
(
2
4
perature for 4 h, which was accompanied by vigorous foaming.
The precipitate that formed was filtered off, washed with water,
dried at 60 C, and recrystallized from EtOH. The yield of 5,5ꢀdiꢀ
bromoꢀ6ꢀhydroxyꢀ6ꢀmethyldihydrouracil (13) was 0.25 g (65%).
Its physicochemical characteristics agree with the literature data.9
The starting compound 11 was recovered from the filtrate.
Chlorination of 5ꢀformylꢀ6ꢀmethyluracil (12). A. Chlorine gas
dried over P O was passed for 30 min through a suspension of
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5
5
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in revised form October 3, 2013