Oxidative halogenation of 6-methyluracil

Article abstract of DOI:10.1007/s10593-012-1094-z

An efficient method has been developed for the preparation of halo derivatives of 6-methyluracil by employing oxidative halogenation. Elemental halogens and potassium halides were used as the halogenating agents, while NaNO₃ and H₂O₂ were used as the oxidizing agents. Iodination of 6-methyl-uracil leads to 5-iodo-6-methyluracil as the single reaction product, while bromination or chlorination lead to 5-halo-6-methyluracil, 5,5-dihalo-6-hydroxy-6-methyl-5,6-dihydrouracil, or their mixture depending on the acidity of the medium and the ratio of the substrate and reagents. Bromination of 5-chloro-6-methyluracil leads to 5-bromo-5-chloro-6-hydroxy-6-methyl-5,6-dihydrouracil, while chlorination of 6-methyl-, 5-bromo-6-methyl-, and 5-chloro-6-methyluracils using gaseous chlorine yields 5,5-dichloro-6-hydroxy-6-methyl-5,6-dihydrouracil.

Full text of DOI:10.1007/s10593-012-1094-z

Chemistry of Heterocyclic Compounds, Vol. 48, No. 7, October, 2012 (Russian Original Vol. 48, No. 7, July, 2012)
OXIDATIVE HALOGENATION OF 6-METHYLURACIL
V. G. Kasradze1*, I. B. Ignatyeva1, R. A. Khusnutdinov1, K. Yu. Suponitskii2,
M. Yu. Antipin2, and M. S. Yunusov1
An efficient method has been developed for the preparation of halo derivatives of 6-methyluracil by employing
oxidative halogenation. Elemental halogens and potassium halides were used as the halogenating agents, while
NaNO3 and H2O2 were used as the oxidizing agents. Iodination of 6-methyl-uracil leads to 5-iodo-
6-methyluracil as the single reaction product, while bromination or chlorination lead to 5-halo-6-methyluracil,
5,5-dihalo-6-hydroxy-6-methyl-5,6-dihydrouracil, or their mixture depending on the acidity of the medium and
the ratio of the substrate and reagents. Bromination of 5-chloro-6-methyluracil leads to 5-bromo-5-chloro-
6-hydroxy-6-methyl-5,6-dihydrouracil, while chlorination of 6-methyl-, 5-bromo-6-methyl-, and 5-chloro-
6-methyluracils using gaseous chlorine yields 5,5-dichloro-6-hydroxy-6-methyl-5,6-dihydrouracil.
Keywords: 5,5-dihalo-6-hydroxy-6-methyl-5,6-dihydrouracils, 5-halo-6-methyluracils, 6-methyluracil,
oxidative halogenation.
Uracil and its derivatives are found in living organisms and are used in medical practice [1-7]. We
studied 6-methyluracil, which displays a broad spectrum of physiological activity and is a component of a
number of drugs [8].
Halogenated derivatives serve as convenient intermediates for obtaining compounds with various
functional groups. Bromination of uracil with various brominating agents, namely, Br2 [9-16], N-bromo-
succinimide [17-19], and pyridine–HBr–Br2 [20] has been studied most widely. Some 5-halouracils have been
synthesized by oxidative halogenation using such oxidation agents as ammonium cerium(IV) nitrate [21],
bis(tetrabutylammonium) peroxydisulfate [22], orthoperiodic acid [23], and H2O2–chloroperoxidase [24].
Iodination of uracil derivatives was carried out using ICl [25], while chlorination was achieved with elemental
chlorine [26]. N-Iodosuccinimide [27] and N-chlorosuccinimide [28] have been used as halogenating agents.
Methods for iodination of 6-methyluracil have been developed using iodine in water, which give
5-iodo-6-methyluracil in 60-70% yield [29], while bromination of this uracil derivative has been carried out
using bromine [9, 10, 30, 31] and N-bromosuccinimide [17, 32].
We studied oxidative halogenation in a search for efficient methods for the insertion of various halogen
atoms into 6-methyluracil. This method is based on the combined action of elemental halogen or halide and a strong
oxidizing agent, such as HNO3, nitrates, KMnO4, HClO4, H2O2, CH3CO3H, HNO3–H2SO4 mixtures, etc. [33-35].
_______
*To whom correspondence should be addressed, e-mail: kasradzevg@anrb.ru.
1Institute of Organic Chemistry, Ufa Science Center, Russian Academy of Sciences, 71 Oktyabrya Ave., Ufa
450054, Russia.
2A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilova St.,
Moscow 119991, Russia; e-mail: kirshik@yahoo.com.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1095-1106, July, 2012. Original
article submitted July 5, 2011.
1018
0009-3122/12/4807-1018©2012 Springer Science+Business Media New York

O
O
I
[I]
HN
HN3
5
1
room temp.
O
N
H
Me
O
N
Me
H
2
1
TABLE 1. Synthesis Conditions and Yields of 5-Iodo-6-methyluracil (2)
Halogenating
mixture
Molar ratio of
substrate and reagents
Solvent
Time, h
Yield, %
KI–H2O2
KI–H2O2
I2–H2O2
KI–H2O2
KI–H2O2
KI–NaNO3
I2
1:1.5:3
1:1.5:3
1:1:4
1:1.5:3
1:1.5:3
1:4:4
1:1
AcOH
4
4
100
100
75
20% H2SO4
AcOH
10
10
10
20
10
40
MeOH
10
1,4-Dioxane
AcOH
10
40
THF–Н2О, 1:1
H2O
20
I2
1:1
20
The iodination of 6-methyluracil (1) was carried out with KI–H2O2, I2–H2O2, I2, and KI–NaNO3 using
various solvents (Table 1).
We also attempted to reproduce a method for the preparation of 5-iodo-6-methyluracil (2) using iodine
in water [29]. In contrast to the work of Konkina et al. [29], the reaction was carried out with a smaller amount
of water and the solvent was not distilled off for isolation of the product. The yield of 5-iodo-6-methyluracil
was 20%. A similar result was obtained when the reaction was carried out in 1:1 water–THF.
Iodination using KI–H2O2–AcOH was accompanied by spontaneous warming of the reaction mixture to
50-60°C, which led to intense foaming. So, the temperature of the reaction mixture was maintained at ≤25°C
during addition of the oxidizing agent. Complete conversion required 4 h and 1–KI–H2O2 molar ratio of 1:1.5:3.
This reaction gave 5-iodo-6-methyluracil (2) in quantitative yield (Table 1). Substitution of acetic acid with
20% H2SO4 also led to the formation of 5-iodo-6-methyluracil (2) in quantitative yield. Intense heat evolution
was observed upon iodination in methanol or 1,4-dioxane, thus the reaction mixture was cooled and maintained
at 20-25°C. At low substrate conversions the yield of 5-iodo-6-methyluracil (2) was 10% in both cases.
The oxidative iodination with I2–H2O2–AcOH system gave a 75% yield of 5-iodo-6-methyluracil (2)
and required 10 h, the reaction being slower than when using KI (Table 1).
The use of NaNO3 in acetic acid as an oxidant led to the formation of iodouracil 2 in 40% yield (Table 1).
The bromination of 6-methyluracil was carried out using KBr–H2O2, KBr–NaNO3, Br2, Br2–H2O2,
HBr–H2O2, and N-bromosuccinimide as brominating agents, while water, acetic acid, or 20% sulfuric acid were
used as solvents (Table 2).
Complete substrate conversion after 4 h reaction was observed using KBr–H2O2 in acetic acid as the
brominating agent, and the yield of 5-bromo-6-methyluracil (3) was 90% (Table 2). We should note that
6-methyluracil did not react with this mixture in water. The formation of 5-bromo-6-methyluracil (3) upon
bromination with KBr–NaNO3 in acetic acid was observed only 4 h after the addition of NaNO3 to a mixture of
uracil 1 and KBr, as indicated by thin-layer chromatography and by change in the reaction mixture from
colorless to light-yellow. Continuing the reaction for 20 h led to the formation of bromouracil 3 in 85% yield.
The bromination of 6-methyluracil (1) was also carried out with N-bromosuccinimide in acetic acid both
at room temperature and at 100°C (Table 2). In both cases, the yield of 5-bromo-6-methyluracil (3) was high,
but the reaction required 7 h at room temperature and only 1.5 h at 100°C.
It is known that the reaction of 6-methyluracil (1) with an equimolar amount of bromine in water led to
5-bromo-6-methyluracil (3) [13]. We have shown that the use of hydrogen peroxide in this reaction allowed a
50% reduction in the amount of bromine required. When the 1–Br2–H2O2 molar ratio was 1:0.5:1.5, the yield of
bromouracil 3 was 92% (Table 2).
1019

O
O
O
O
Br
Br
Me
Br
Cl
Me
Br
Cl
HN
HN
[Br]
[Br]
HN
HN
+
1, 2
room temp.
room temp.
N
H
3
Me
N
H
4
O
O
N
H
6
O
O
N
H
5
Me
OH
OH
TABLE 2. Reaction Conditions and Yields for Bromination of Uracils 1-3
and 5
Molar ratio of
substrate and
reagents
Reaction
product
(yield, %)
Com-
pound
Halogenating
mixture
Solvent
Time, h
KBr–H2O2
KBr–H2O2
KBr–H2O2
KBr–NaNO3
Br2–H2O2
Br2–H2O2
Br2–H2O2
NBS
1:2:4
1:2:4
1:2:4
1:4:4
1:0.5:1.5
1:1:3
1:1:3
1:1
AcOH
4
6
3 (90)
1
1
1
1
1
1
1
1*
1
1
2
2
2
3
5
5
20% H2SO4
H2O
4 (85)
6
—
AcOH
20
4
3 (85)
3 (92)
H2O
H2O
1
3 (31), 4 (63)
4 (91)
AcOH
1
AcOH
1.5
7
3 (87)
NBS
1:1
AcOH
3 (86)
HBr–H2O2
Br2
1:4:4
1:1
–
3
3 (32), 4 (44)
3 (93)
H2O
8
KBr–H2O2
KBr–H2O2
KBr–H2O2
KBr–H2O2
KBr–H2O2
1:2:4
1:4:8
1:2:4
1:2:4
1:2:4
20% H2SO4
20% H2SO4
20% H2SO4
20% H2SO4
AcOH
8
3 (67), 4 (12)
3 (31), 4 (52)
4 (60)
8
4
6
6 (84)
6
6 (25)
Tee and Bannerjee [10] noted that the reaction of 6-methyluracil (1) with a twofold excess of bromine in
water gives 5,5-dibromo-6-hydroxy-6-methyl-5,6-dihydrouracil (4), and the intermediate in this reaction is 5-bromo-
6-methyluracil (3), since the dibromohydrin 4 also forms upon bromination of the bromouracil 3 with an equimolar
amount of bromine. In our case, the formation of dibromohydrin 4 was observed along with the bromouracil 3 in the
bromination of 6-methyluracil (1) in water with the Br2–H2O2 system, when the 1–Br2–H2O2 ratio was 1:1:3 (Table
2). While the reaction in aqueous medium leads to a mixture of uracils 3 and 4, this reaction in acetic acid at the
same ratio of substrate and reagents gives only the dibromohydrin 4 in a 91% yield.
Bromination in 20% sulfuric acid using a KBr–H2O2 mixture, where the 1–KBr–H2O2 molar ratio was
1:2:4, also gave the dibromohydrin 4 as the sole reaction product (Table 2). Bromination of 6-methyluracil (1)
with 20% HBr–H2O2 was accompanied by intense heating of the reaction mixture, thus the reaction mixture was
cooled, maintaining the temperature at 20-25°C. Under these conditions, the reaction gave a mixture of uracils 3
and 4 with a predominance of the latter.
Bromination of 5-bromo-6-methyluracil (3) for 4 hours in KBr–H2O2–20% H2SO4 gave a mixture of the
starting bromide 3 and dibromohydrin 4, although under the same conditions 6-methyluracil (1) was completely
converted to the dibromohydrin 4, which was isolated in 85% yield.
We also studied the bromination of 5-iodo-6-methyluracil (2) and 5-chloro-6-methyluracil (5) under
various conditions (Table 2). The reaction of iodouracil 2 with bromine in water at 1:1 molar ratio of iodouracil
2 to Br2 proceeded to give 5-bromo-6-methyluracil (3) in 93% yield. The use of a mixture of KBr–H2O2 in 20%
sulfuric acid as the brominating agent at 1:2:4 molar ratio of 2–KBr–H2O2 was also accompanied by a complete
conversion of the substrate and gave a mixture of the uracils 3 (67%) and 4 (12%). When the amount of
brominating reagent was doubled, the yield of dibromohydrin 4 was raised to 52%. We should note that the
reaction of iodouracil 2 with KBr in sulfuric acid did not proceed in the absence of an oxidizing agent.
1020

Bromination of 5-chloro-6-methyluracil (5) using KBr–H2O2 mixture in 20% sulfuric acid at a 1:2:4
molar ratio of 5–KBr–H2O2 gave 5-bromo-5-chloro-6-hydroxy-6-methyl-5,6-dihydrouracil (6) in 84% yield
(Table 2). Partial conversion of the halo derivative 5 was observed in acetic acid for the same ratio of substrate
and reagents, and the yield of the adduct 6 was 25%.
Chlorination of 6-methyluracil (1) was carried out using KCl–H2O2 at a 1:2:4 molar ratio of 1–KCl–H2O2
both in concentrated acetic acid and sulfuric acid of various concentrations (Table 3). The reaction in 5%
sulfuric acid proceeded with low substrate conversion and the formation of chloride 5 in 25% yield. Increasing
the sulfuric acid concentration to 10% led to a complete conversion of 6-methyluracil (1) and obtaining of
chloride 5 and 5,5-dichloro-6-hydroxy-6-methyl-5,6-dihydrouracil (7) mixture. Carrying out the reaction in
50% sulfuric acid gave dichlorohydrin 7 as the single reaction product in 91% yield.
It should be noted that the reaction of 6-methyluracil (1) with KCl–H2O2 mixture did not occur in acetic
acid, which indicates an increase in the oxidative capacity of H2O2 with increasing of the medium acidity (Table 3).
Use of NaNO3 as an oxidant also did not lead to positive results.
The chlorination of 6-methyluracil (1) was studied using 36% HCl–H2O2 in different proportions as the
chlorinating reagent. The reaction of the substrate with this mixture at a 1:2:4 molar ratio of 1–HCl–H2O2 was
complete in 8 h and gave chloride 5 in 81% yield and dichlorohydrin 7 in 7% yield (Table 3). Dichlorohydrin 7
was the only product obtained at 1:6:8 molar ratio of 1–HCl–H2O2. In all cases, the use of hydrochloric acid was
accompanied by intense foaming of the reaction mixture, which began 2-4 h after addition of the oxidizing agent.
The chlorination of 6-methyluracil (1) was also carried out using gaseous chlorine (Table 3). The
reaction was carried out in various solvents, such as 98% aqueous acetic acid, water, methanol, and chloroform.
In water and acetic acid, the reaction produced the dichlorohydrin 7, while the methyl ether 8 was formed in
methanol. The reaction of 6-methyluracil (1) with chlorine dried over P2O5 in dry chloroform gave 5-chloro-
6-methyluracil (5) in 75% yield, while chlorination using moist chlorine in chloroform not subjected to drying
gave the dichlorohydrin 7 in 89% yield.
1
O
Cl2 (gas)
CHCl3 (abs.) Н2O or АсОН
Cl
Cl
Me
MeO
MeOH
NH
N
H
5
O
7
8
Dichlorohydrin 7 was the only product in the reaction of chlorine with bromouracil 3 and chlorouracil 5
in acetic acid (Table 3).
It should be noted that in contrast to the bromination of 5-chloro-6-methyluracil (5), which, as noted
above, gives 5-bromo-5-chloro-6-hydroxy-6-methyl-5,6-dihydrouracil (6), the chlorination of bromouracil 3
leads to a substitution of the bromine atom by a chlorine atom, probably due to the different orientation of the
bromine atom in the intermediate.
It is known that in the presence of acid, dibromohydrin 4 reacts with bromide ions to give 5-bromo-
6-methyluracil (3) and Br2 [16]. We attempted to reproduce this reaction with dichlorohydrin 7. However,
dichlorohydrin 7 did not react with potassium chloride in 5% sulfuric acid either at room temperature or at
reflux, probably due to the high electron affinity of the chlorine atom.
O
Cl
KCl–H2O2
HN
Cl
1
5
(in 50% H2SO4)
H2SO4–H2O
Me
OH
O
N
H
7
1021

TABLE 3. Reaction Conditions and Product Yields for Chlorination of
Uracils 1, 3, and 5*
Molar ratio of
substrate and
reagents
Reaction
product
(yield, %)
Com- Halogenating
Solvent
Time, h
pound
mixture
1
1
1
1
1
1
1
1
1
1
1
3
5
KCl–H2O2
KCl–H2O2
KCl–H2O2
KCl–H2O2
KCl–NaNO3
HCl–H2O2
HCl–H2O2
Cl2
1:2:4
1:2:4
1:2:4
1:2:4
1:4:4
1:2:4
1:6:8
5% H2SO4
10% H2SO4
50% H2SO4
AcOH
AcOH
—
8
8
8
8
8
8
8
2
2
2
2
2
2
5 (25)
5 (64), 7 (12)
7 (91)
—
—
5 (81), 7 (7)
7 (93)
5 (75)
7 (89)
7 (84)
8 (85)
7 (83)
7 (89)
—
CHCl3*2
AcOH
H2O
Cl2
Cl2
Cl2
MeOH
AcOH
AcOH
Cl2
Cl2
_______
*Reactions were carried out at room temperature.
*2Dried CHCl3 and Cl2 were used.
The structure of dichlorohydrin 7 was confirmed by X-ray diffraction structural analysis. The symmetry-
independent part of the unit cell contains one molecule (Fig. 1). The six-membered ring has an ordinary "half-
chair" conformation. An extensive hydrogen bond system exists in the crystal due to the presence of acidic
protons and strong proton acceptors. The molecules are connected in parallel layers by N–H···O and O–H···O
bonds, while short Cl···Cl and Cl···O contacts connect these layers into a three-dimensional framework. It is also
interesting to note that an empirical hydrogen bonding rule [36] is realized in this structure postulating that the
strongest proton acceptor (the C(4)=O(2) group) forms a bond with the strongest electron donor (O(3)–H(3)).
The resultant very strong hydrogen bond causes a marked lengthening of the C(4)=O(2) bond (1.2294(12) Å vs.
the length of the C(1)=O(1) bond, 1.2030(13) Å).
Fig. 1. A general view of dichlorohydrin 7 molecule with representation of the atoms as 50% probability
thermal ellipsoids.
Thus, oxidative halogenation is an efficient method for the preparation of 5-halo-6-methyluracils and
5,5-dihalo-6-hydroxy-6-methyl-5,6-dihydrouracils. Oxidative chlorination requires a stronger oxidizing agent
and, in some cases, enhanced acidity of the medium. Dichlorohydrins are also formed in good yield upon
chlorination using gaseous chlorine in water or acetic acid.
1022

EXPERIMENTAL
The IR spectra were recorded on a Shimadzu Prestige-21 IR spectrometer in vaseline mull. The 1H and
13C NMR spectra were recorded on a Bruker AM-300 spectrometer at 300 and 75 MHz, respectively, in DMSO-
d6 with TMS as internal standard. The chemical ionization mass spectra were recorded on a Shimadzu LCMS-
2010 EV instrument at atmospheric pressure with recording of the positive ions. The elemental analysis was
carried out on a EURO-3000 instrument. The melting points were determined in a glass capillary. The thin-layer
chromatography was carried out on Chemapol Silufol plates with 9:1 chloroform–methanol as the eluent and
development with iodine vapor.
5-Iodo-6-methyluracil (2). A. 36% H2O2 (0.45 ml, 4.8 mmol) was added dropwise to a mixture of
6-methyluracil (1) (0.20 g, 1.6 mmol) and KI (0.39 g, 2.4 mmol) in acetic acid (2 ml), maintaining the
temperature of the reaction mixture at 20-25°C. The mixture was stirred for 4 h. During this time, the color of
the mixture turned from dark-blue to light-brown. Then, 20% aqueous Na2S2O3 (5 ml) was added until the
mixture became completely colorless. The precipitate was filtered off, washed with water, dried at 60°C, and
recrystallized from ethanol to give iodouracil 2. Yield 0.40 g (100%).
B. 36% H2O2 (0.45 ml, 4.8 mmol) was added dropwise to a mixture of 6-methyluracil (1) (0.20 g,
1.6 mmol) and KI (0.39 g, 2.4 mmol) in 20% sulfuric acid (2 ml) at room temperature and stirred for 4 h. During
this time, the color of the reaction mixture turned from dark-brown to light-gray. The reaction mixture was
treated as in method A to give iodouracil 2. Yield 0.40 g (100%).
C. 36% H2O2 (0.60 ml, 6.4 mmol) was added dropwise to a mixture of 6-methyluracil (1) (0.20 g,
1.6 mmol) and I2 (0.20 g, 1.6 mmol) in acetic acid (2 ml) at 20-25°C and stirred for 10 h. The mixture was
treated as in method A to give iodouracil 2. Yield 0.30 g (75%).
D. 36% H2O2 (0.45 ml, 4.8 mmol) was added dropwise to a mixture of 6-methyluracil (1) (0.20 g,
1.6 mmol) and KI (0.39 g, 2.4 mmol) in methanol (2 ml) or 1,4-dioxane (2 ml) at 20-25°C and stirred for 10 h.
During this time, the color of the reaction mixture turned from brown to pale-yellow. The reaction mixture was
treated as in method A to give iodouracil 2. Yield 0.04 g (10%).
E. A mixture of 6-methyluracil (1) (0.50 g, 4 mmol), KI (2.65 g, 16 mmol), and NaNO3 (1.36 g,
16 mmol) in acetic acid (20 ml) was stirred for 20 h at room temperature. During this time, the color of the
reaction mixture turned from dark-blue to dark-yellow. The reaction mixture was treated as in method A to give
iodouracil 2. Yield 0.40 g (40%).
F. A mixture of 6-methyluracil (1) (0.20 g, 1.6 mmol) and I2 (0.40 g, 1.6 mmol) in water (or 1:1 THF–
water) (5 ml) was stirred for 40 h (10 h in the case of 1:1 THF–water) and then treated as in method A to give
iodouracil 2. Yield 0.08 (20%).
Iodouracil (2): Mp 255-257 °С (decomp., EtOH) (mp 262-265°С (Н2О) [29]). IR spectrum, ν, cm-1: 584,
1
13
669 (C–I). H NMR spectrum, δ, ppm: 2.27 (3H, s, CH3); 11.26 (2H, br. s, 1,3-NH). С NMR spectrum, δ, ppm:
24.0 (CH3); 71.6 (C-5); 150.9 (C-2); 154.8 (C-6); 161.7 (C-4). Mass spectrum, m/z (Irel, %): 253 [M+H]+ (14), 127
(100). Found, %: C 23.80; H 1.98; I 50.40; N 11.11. C5H5IN2O2. Calculated, %: C 23.83; H 2.00; I 50.36; N 11.12.
Bromination of 6-Methyluracil (1). A. 36% H2O2 (0.60 ml, 6.4 mmol) was added dropwise to a
mixture of 6-methyluracil (1) (0.20 g, 1.6 mmol) and KBr (0.38 g, 3.2 mmol) in acetic acid (2 ml) and stirred at
room temperature for 4 h. Then, 10% aqueous Na2S2O3 (5 ml) was added to the resultant light-yellow
suspension until it turned colorless. The precipitate formed was filtered off, washed with water, dried at 60°C,
and recrystallized from ethanol to give 5-bromo-6-methyluracil (3). Yield 0.29 g (90%).
B. 36% H2O2 (0.60 ml, 6.4 mmol) was added dropwise to a mixture of 6-methyluracil (1) (0.20 g,
1.6 mmol) and KBr (0.38 g, 3.2 mmol) in 20% sulfuric acid (2 ml) and stirred for 6 h at room temperature. The
reaction proceeds with foaming. The precipitate formed was filtered off, washed with water, and dried at 60°C
to give 5,5-dibromo-6-hydroxy-6-methyl-5,6-dihydrouracil (4). Yield 0.41 g (85%).
C. A mixture of 6-methyluracil (1) (5.0 g, 40 mmol), KBr (19.0 g, 160 mmol), and NaNO3 (13.6 g,
160 mmol) in acetic acid (150 ml) was stirred at room temperature for 20 h. Then, 10% aqueous Na2S2O3 (30 ml)
1023

was added to the light-yellow suspension until it became completely colorless. The reaction mixture was treated
as in method A to give bromouracil 3. Yield 7.0 g (85%).
D. Bromine (0.044 ml, 0.8 mmol) was added dropwise to a solution of 6-methyluracil (1) (0.20 g,
1.6 mmol) in water (2 ml) and H2O2 (0.360 ml, 2.4 mmol) at room temperature and stirred for 4 h. During this
time, the reaction mixture turns completely colorless. The precipitate formed was filtered off, washed with
water, and dried at 60°C to give uracil 3. Yield 0.30 g (92%).
E. Bromine (0.096 ml, 1.76 mmol) was added dropwise to a mixture of 6-methyluracil (1) (0.20 g,
1.6 mmol) and 36% H2O2 (0.45 ml, 4.8 mmol) in water (2 ml) at room temperature and stirred for 1 h. The
reaction mixture was treated as in method A to give a mixture of products 3 and 4, which was separated by
fractional crystallization from water. The yield of bromouracil 3 was 0.10 g (31%), while the yield of
dibromohydrin 4 was 0.30 g (63%).
F. Bromine (0.096 ml, 1.76 mmol) was added dropwise to a mixture of 6-methyluracil (1) (0.2 g,
1.6 mmol) and 36% H2O2 (0.45 ml, 4.8 mmol) in acetic acid (2 ml) at room temperature and stirred for 1 h. The
reaction mixture was treated as in method A to give dibromohydrin 4. Yield 0.43 g (91%).
G. 6-Methyluracil (1) (0.30 g, 2.4 mmol) was dissolved in acetic acid (6 ml) and acetic anhydride
(0.30 ml) at 100°C, and N-bromosuccinimide (0.43 g, 2.4 mmol) was added in small portions. The mixture was
stirred for 1.5 h at 100°C. The precipitate formed was filtered off, washed with dichloromethane until complete
removal of acetic acid, and dried at 60°C to give bromouracil 3. Yield 0.42 g (87%).
H. N-bromosuccinimide (0.43 g, 2.4 mmol) was added in small portions with stirring to a mixture of
6-methyluracil (1) (0.30 g, 2.4 mmol) in acetic acid (6 ml) and acetic anhydride (0.30 ml) and stirred at room
temperature for 7 h. The reaction mixture was treated as in method G to give bromouracil 3. Yield 0.41 g (86%).
I. 36% H2O2 (0.75 ml, 8 mmol) was added dropwise to a solution of 6-methyluracil (1) (0.25 g, 2 mmol)
in 20% hydrobromic acid (2 ml, 8 mmol) at 20-25°C and stirred for 3 h. During this time, the reaction mixture
turned from orange to light-yellow. Treatment by analogy to the method A gave a mixture of bromouracil 3 and
dibromohydrin 4, which was separated by fractional crystallization from water to give 0.13 g (32%)
bromouracil 3 and 0.27 g (44%) dibromohydrin 4.
5-Bromo-6-methyluracil (3). Mp 237-239°С (decomp., EtOH). IR spectrum, ν, cm-1: 597, 678 (C–Br). 1H
NMR spectrum, δ, ppm: 2.20 (3H, s, CH3); 11.37 (2H, br. s, 1,3-NH). 13С NMR spectrum, δ, ppm: 19.6 (CH3); 95.1
(C-5); 150.3 (C-2); 151.5 (C-6); 160.1 (C-4). Mass spectrum, m/z (Irel, %): 205 [M+H]+ (100), 127 (36). Found, %:
C 29.29; H 2.44; Br 39.02; N 13.66. C5H5BrN2O2. Calculated, %: C 29.29; H 2.46; Br 38.98; N 13.66.
5,5-Dibromo-6-hydroxy-6-methyl-5,6-dihydrouracil (4). Mp 214-216 °С (decomp., EtOH) (darkens at
200°С, mp 232-234 °С (acetone–ligroin) [10]). 1H NMR spectrum, δ, ppm: 2.18 (3H, s, CH3); 6.54 (1H, s, ОН);
11.27 (1H, s, 1-NH); 11.35 (1H, s, 3-NH). 13С NMR spectrum, δ, ppm: 23.6 (CH3); 66.3 (C-5); 83.9 (C-6); 151.0
(C-4); 164.2 (C-2). Found, %: C 19.67; H 2.25; Br 53.24; N 9.25. C5H6Br2N2O3. Calculated, %: C 19.89;
H 2.00; Br 52.93; N 9.28.
Bromination of 5-Bromo-6-methyluracil (3). 36% H2O2 (0.37 ml, 4 mmol) was added dropwise to a
mixture of 5-bromo-6-methyluracil (3) (0.20 g, 1 mmol) and KBr (0.24 g, 2 mmol) in 20% sulfuric acid (2 ml).
The reaction mixture was stirred for 4 h at room temperature. The mixture foamed and the color turned from
bright-yellow to colorless. The precipitate formed was filtered off, washed with water, and dried at 60°C to give
5,5-dibromo-6-hydroxy-6-methyl-5,6-dihydrouracil (4). Yield 0.17 g (60%).
Bromination of 5-Iodo-6-methyluracil (2). A. Bromine (0.05 ml, 1 mmol) was added dropwise to a
mixture of 5-iodo-6-methyluracil (2) (0.25 g, 1 mmol) in water (3 ml) at room temperature and stirred for 8 h.
During this time, the reaction mixture turned from dark-brown to light-gray. Then, 10% aqueous Na2S2O3 (5 ml)
was added to the resultant suspension until it became completely colorless. The precipitate formed was filtered
off, washed with water, and dried at 60°C to give 5-bromo-6-methyluracil (3). Yield 0.19 g (93%).
B. 36% H2O2 (0.37 ml, 4 mmol) was added dropwise to a mixture of 5-iodo-6-methyluracil (2) (0.25 g,
1 mmol) and potassium bromide (0.24 g, 2 mmol) in 20% sulfuric acid (3 ml) at room temperature and stirred
for 8 h. During this time, the reaction mixture turned from orange-brown to mustard-colored. Treatment of the
1024

reaction mixture by analogy to method A gave a mixture of products 3 and 4, which was separated by fractional
crystallization from water to give 0.14 g (67%) bromouracil (3) and 0.03 g (12%) dibromohydrin 4.
C. 36% H2O2 (0.75 ml, 8 mmol) was added dropwise to a mixture of 5-iodo-6-methyluracil (2) (0.25 g,
1 mmol) and potassium bromide (0.48 g, 4 mmol) in 20% sulfuric acid (3 ml) at room temperature and stirred
for 8 h. During this time, the reaction mixture turned from orange to brown. Treatment by analogy to method A
gave a mixture of products 3 and 4, which was separated by fractional crystallization from water to give 0.06 g
(31%) bromouracil 3 and 0.16 g (52%) dibromohydrin 4.
Chlorination of 6-Methyluracil (1). A. 36% H2O2 (0.6 ml, 6.4 mmol) was added dropwise to a mixture
of 6-methyluracil (1) (0.20 g, 1.6 mmol) and potassium chloride (0.24 g, 3.2 mmol) in 5% sulfuric acid (2 ml) at
room temperature and stirred for 8 h. The reaction proceeds with foam formation. The precipitate formed was
filtered off, washed with water, dried at 60°C, and recrystallized from ethanol to give 5-chloro-6-methyluracil
(5). Yield 0.06 g (25%).
B. 36% H2O2 (0.60 ml, 6.4 mmol) was added dropwise to a mixture of 6-methyluracil (1) (0.20 g,
1.6 mmol) and potassium chloride (0.24 g, 3.2 mmol) in 10% sulfuric acid (2 ml) at room temperature and
stirred for 8 h. The reaction proceeds with foam formation. Treatment of the reaction mixture by analogy to
method A gave a mixture of the chlorouracil 5 and 5,5-dichloro-6-hydroxy-6-methyl-5,6-dihydrouracil (7),
which was separated by fractional crystallization from water to give 0.16 g (64%) chlorouracil 5 and 0.04 g
(12%) dichlorohydrin 7.
C. 36% H2O2 (0.60 ml, 6.4 mmol) was added dropwise to a mixture of 6-methyluracil (1) (0.20 g, 1.6 mmol)
and potassium chloride (0.24 g, 3.2 mmol) in 50% sulfuric acid (2 ml) at room temperature and stirred for 8 h. The
reaction proceeds with foam formation. The reaction mixture was maintained for 12 h at 5°C. The precipitate formed
was filtered off, washed with water (3 ml), and dried at 60°C to give dichlorohydrin 7. Yield 0.30 g (91%).
D. 36% H2O2 (0.74 ml, 8 mmol) was added dropwise to a mixture of 6-methyluracil (1) (0.25 g,
2 mmol) in concentrated hydrochloric acid (0.30 ml, 4 mmol) and water (0.70 ml) at room temperature and
stirred for 8 h. The reaction proceeds with foam formation. The precipitate formed was filtered off, washed with
water, dried at 60°C to give 5-chloro-6-methyluracil (5). The filtrate was evaporated in vacuum until a
precipitate formed, cooled, and filtered. The precipitate was dried at 60°C to give a mixture of chlorouracil 5
and dichlorohydrin 7, which was separated by fractional crystallization from water to give 0.26 g (81%)
chlorouracil 5 and 0.03 g (7%) dichlorohydrin 7.
E. 36% H2O2 (3.20 ml, 32 mmol) was added dropwise to a mixture of 6-methyluracil (1) (0.50 g,
4 mmol) in concentrated hydrochloric acid (2 ml, 24 mmol) at room temperature and stirred for 8 h. The
reaction proceeds with foam formation. The mixture was treated by analogy to method C to give the
dichlorohydrin 7. Yield 0.80 g (93%).
F. Gaseous chlorine dried over P2O5 was passed through a solution of 6-methyluracil (1) (0.20 g,
1.6 mmol) in dry chloroform (5 ml) for 30 min, and the solution was stirred at room temperature for an
additional 2 h. The solution was evaporated under vacuum to dryness. The precipitate was washed with
dichloromethane and dried at 60°C to give the chlorouracil 5. Yield 0.20 g (75%).
G. Gaseous chlorine was passed through a solution of 6-methyluracil (1) (0.20 g, 1.6 mmol) in acetic
acid (5 ml) for 30 min, and the resultant yellow-green reaction mixture was stirred at room temperature for an
additional 2 h. Treatment by analogy to method F gave the dichlorohydrin 7. Yield 0.30 g (89%).
H. Gaseous chlorine was passed through a solution of 6-methyluracil (1) (0.20 g, 1.6 mmol) in H2O
(5 ml) for 30 min. The resultant yellow-green reaction mixture was stirred at room temperature for an additional
2 h. Treatment by analogy to method F gave the dichlorohydrin 7. Yield 0.28 g (84%).
I. Gaseous chlorine was passed through a solution of 6-methyluracil (1) (0.20 g, 1.6 mmol) in methanol (5
ml) for 30 min. The resultant yellow-green mixture was stirred at room temperature for an additional 2 h. Treatment
by analogy to method F gave 5,5-dichloro-6-methoxy-6-methyl-5,6-dihydrouracil (8). Yield 0.31 g (85%).
5-Chloro-6-methyluracil (5). Mp 303–305°С (decomp., EtOH). IR spectrum, ν, cm-1: 621, 696 (C–Cl).
1H NMR, δ, ppm: 2.16 (3H, s, CH3); 10.83 (1H, s, 1-NH); 11.21 (1H, s, 3-NH). 13С NMR spectrum, δ, ppm:
1025

17.0 (CH3); 104.7 (C-5); 149.7 (C-2); 150.1 (C-6); 159.9 (C-4). Mass spectrum, m/z (Irel, %): 161 [M+H]+ (100),
137 (11). Found, %: C 37.38; H 3.11; Cl 22.12; N 17.44. C5H5ClN2O2. Calculated, %: C 37.40; H 3.14;
Cl 22.08; N 17.45.
1
5,5-Dichloro-6-hydroxy-6-methyl-5,6-dihydrouracil (7). Mp 285-287°С (decomp., EtOH). H NMR
spectrum, δ, ppm: 1.70 (3H, s, CH3); 6.54 (1H, s, ОН); 8.80 (1H, s, 1-NH); 10.90 (1H, s, 3-NH). 13С NMR
spectrum, δ, ppm: 21.2 (CH3); 84.1 (C-5); 85.0 (C-6); 150.9 (C-4); 163.5 (C-2). Found, %: C 27.80; H 2.71;
Cl 33.12; N 12.92. C5H6Cl2N2O3. Calculated, %: C 28.19; H 2.84; Cl 33.29; N 13.15.
1
5,5-Dichloro-6-methoxy-6-methyl-5,6-dihydrouracil (8). Mp 200-202°С (decomp., EtOH). H NMR
spectrum, δ, ppm: 1.57 (3H, s, CH3); 3.19 (3H, s, ОCH3); 9.12 (1H, s, 1-NH); 11.08 (1H, s, 3-NH). 13С NMR
spectrum, δ, ppm: 16.0 (CH3); 50.5 (OCH3); 83.9 (C-5); 88.2 (C-6); 150.6 (C-4); 163.1 (C-2). Found, %:
C 31.59; H 3.47; Cl 31.52; N 12.03. C6H8Cl2N2O3. Calculated, %: C 31.74; H 3.55; Cl 31.23; N 12.34.
5-Bromo-5-chloro-6-hydroxy-6-methyl-5,6-dihydrouracil (6). A. 36% H2O2 (0.46 ml, 5.0 mmol) was
added dropwise to a mixture of 5-chloro-6-methyluracil (5) (0.20 g, 1.25 mmol) and potassium bromide (0.30
g, 2.50 mmol) in 20% sulfuric acid (2 ml) and stirred for 6 h at room temperature. During this time, the mixture
turned from orange to pale-yellow. The reaction proceeds with foam formation. The precipitate formed was
filtered off, washed with water, and dried at 60°C to give dihydrouracil 6. Yield 0.27 g (84%).
B. 36% H2O2 (0.46 ml, 5.00 mmol) was added dropwise to a mixture of 5-chloro-6-methyluracil (5)
(0.20 g, 1.25 mmol) and potassium bromide (0.30 g, 2.50 mmol) in acetic acid (2 ml) at room temperature at
room temperature and stirred for 6 h. During this time, the mixture turned from bright-yellow to pale-yellow.
The solvent was evaporated in vacuum. The precipitate formed was filtered off, washed with water, and dried at
1
60°C to give the dihydrouracil 6. Yield 0.10 g (25%); mp 187-188°С (decomp., EtOH). H NMR spectrum, δ,
ppm: 2.20 (3H, s, CH3); 5.70 (1H, s, ОН); 11.20 (1Н, s, 1-NH); 11.40 (1H, s, 3-NH). 13С NMR spectrum, δ,
ppm: 23.7 (CH3); 74.9 (C-5); 84.0 (C-6); 159.8 (C-4); 164.2 (C-2). Calculated, %: C 22.93; H 2.30; Br 31.15; Cl
13.63; N 11.00. C5H6BrClN2O3. Found, %: C 23.33; H 2.35; Br 31.03; Cl 13.77; N 10.88.
Chlorination of 5-Bromo-6-methyluracil (3). Gaseous chlorine was passed through a solution of
5-bromo-6-methyluracil (3) (0.20 g, 1 mmol) in acetic acid (5 ml) for 30 min. The resultant yellow-green
mixture was stirred at room temperature for additional 2 h. The solution was evaporated to dryness in vacuum.
The precipitate was washed with dichloromethane and dried at 60°C to give the dichlorohydrin 7. Yield 0.17 g
(83%).
Chlorination of 5-Chloro-6-methyluracil (5). Gaseous chlorine was passed through a solution of
5-chloro-6-methyluracil (5) (0.20 g, 1.25 mmol) in acetic acid (5 ml) for 30 min. The resultant yellow-green
mixture was stirred at room temperature for additional 2 h. The solution was evaporated to dryness in vacuum. The
precipitate was washed with dichloromethane and dried at 60°C to give the dichlorohydrin 7. Yield 0.23 g (89%).
X-ray Diffraction Structural Study of 5,5-Dichloro-6-hydroxy-6-methyl-5,6-dihydrouracil (7).
Unit cell parameters for the colorless triclinic crystals of dichlorohydrin 7, C5H6Cl2N2O3 (M 213.02) at 100 K:
a 6.5765(3), b 6.7588(3), c 9.4623(5) Å, α 81.2610(10), β 88.1270(10), γ 74.6370(10)°, V 400.84(3) Å3,
space group P-1, Z 2, dcalc 1.765 g/cm3. The experimental set of 5106 reflections was obtained on a Bruker
Smart APEX2 CCD diffractometer using λMoKα radiation, θmax 30° with a 0.26×0.23×0.19-mm monocrystal.
The reflection intensity set was treated with the SAINT and SADABS programs in the APEX2 software
package [37]. The structure was solved by the direct method and refined anisotropically by the full-matrix least-
squares method for the non-hydrogen atoms relative to F2hkl. The hydrogen atoms were placed in geometrically
calculated positions except for the hydrogen atoms bound to the oxygen and nitrogen atoms. Then, the O–H
distance was normalized to 0.85Å and the N–H distance normalized to 0.90 Å. The positions of the hydrogen
atoms were refined using the "horse-and-rider" model. A set of 2326 independent reflections was used for the
refinement (Rint = 0.0155). The crystallographic refinement converged at wR2 = 0.0653 (R1 = 0.0245 for 2094
reflections with I > 2σ(I)). All the calculations were carried out using the SHELXTL program set [38].
1026

The complete crystallographic data have been deposited at the Cambridge Crystallographic Data Center
(deposit CCDC 82859).
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