Reaction of Halogenated Uracils with KI

Article abstract of DOI:10.1007/s10600-017-2218-6

Treatment of 5-iodo-1,3,6-trimethyluracil or 5-bromo-1,3,6-trimethyluracil with H₂SO₄ (5%) in the presence of an excess of KI at 80°C for 5 h produced 1,3,6-trimethyluracil as the only product. Analogous treatment of N-bromo-6-iodomethyluracil gave a mixture with 5-bromo-6-iodomethyluracil as the main constituent. The reaction with an excess of KI in MeOH at 50°C formed 5-bromo-6-hydroxymethyluracil, N(1)-iodo-5-bromo-6-hydroxymethyluracil, N(3)-iodo-5-bromo-6-iodomethyluracil, and 5-bromo-6-iodomethyluracil depending on the reaction time.

Full text of DOI:10.1007/s10600-017-2218-6

DOI 10.1007/s10600-017-2218-6
Chemistry of Natural Compounds, Vol. 53, No. 6, November, 2017
REACTION OF HALOGENATED URACILS WITH KI
*
I. B. Chernikova, L. V. Spirikhin,
M. F. Abdullin, and M. S. Yunusov
Treatment of 5-iodo-1,3,6-trimethyluracil or 5-bromo-1,3,6-trimethyluracil with H SO (5%) in the presence
2
4
of an excess of KI at 80°C for 5 h produced 1,3,6-trimethyluracil as the only product. Analogous treatment
of N-bromo-6-iodomethyluracil gave a mixture with 5-bromo-6-iodomethyluracil as the main constituent.
The reaction with an excess of KI in MeOH at 50°C formed 5-bromo-6-hydroxymethyluracil, N(1)-iodo-5-
bromo-6-hydroxymethyluracil, N(3)-iodo-5-bromo-6-iodomethyluracil, and 5-bromo-6-iodomethyluracil
depending on the reaction time.
Keywords: bromo- and iodo-derivatives of methyluracils.
Halogenated uracils are important components in drug design [1–4]. They are formed in the human body in various
inflammations [5, 6]. Therefore, the development of synthetic methods for halogenated uracils, their conversions under
various conditions, and the study of the mechanisms of these conversions are highly critical problems.
Previously, oxidative halogenation of 6-methyluracil derivatives was shown to be effective and several of their
conversions were studied [7]. Thus, treatment of 5-iodo-1,3,6-trimethyluracil with H SO (50%) at 80°C gave
2
4
1,3,6-trimethyluracil although 5-bromo-1,3,6-trimethyluracil formed a mixture of 1,3,6-trimethyluracil and 6-bromomethyl-
1,3-dimethyluracil. However, 5-chloro-1,3,6-trimethyluracil did not react. The reaction with 5,5-dibromo-6-hydroxy-6-methyl-
5,6-dihydrouracil under analogous conditions gave N-bromo-5-bromo-6-hydroxymethyluracil [8]. Herein, it is demonstrated
that treatment of 5-bromo-5-chloro-6-hydroxy-6-methyl-5,6-dihydrouracil (1) with H SO (50%) at 80°C formed 5-chloro-6-
2
4
bromomethyluracil (2). Refluxing 2 in aqueous MeCN for 2 h produced 3 with a 6-hydroxymethyl group (Scheme 1). Under
the same conditions, 5-bromo-5-fluoro-6-hydroxy-5,6-dihydrouracil converted in good yield into 5-fluorouracil whereas
5-chloro-5-fluoro-6-hydroxy-5,6-dihydrouracil turned out to be inert [9].
O
O
O
Br
Cl
Cl
Cl
HN
HN
HN
a
b
CH
3
O
N
H
O
N
H
O
N
H
CH OH
2
CH Br
2
OH
1
3
2
a. 50% H SO , 80ꢀC, 5 h; b. MeCN–H O 1:1, reflux, 2 h
2
4
2
Scheme 1
It was also demonstrated that 1,3,6-trimethyluracil (6) was formed as the only product from treatment of 5-iodo- (4)
or 5-bromo-1,3,6-trimethyluracil (5) with H SO (5%) in the presence of an excess of KI at 80°C for 5 h (Scheme 2). These
2
4
reactions without KI returned starting 4 and 5. The corresponding 5-chloro-derivative was unreactive.
O
O
X
a
H C N
3
H C N
3
O
N
CH
O
N
CH
CH
CH
3
3
X = I or Br
3
3
4, 5
6
a. KI (5 equiv.), 5% H SO , 80ꢀC, 5 h
4
Scheme22
Ufa Institute of Chemistry, Russian Academy of Sciences, 71 Prosp. Oktyabrya, Ufa, 450054, e-mail:
inna.b.chernikova@yandex.ru. Translated from Khimiya Prirodnykh Soedinenii, No. 6, November–December, 2017,
pp. 968–971. Original article submitted February 27, 2017.
©
1140
0009-3130/17/5306-1140 2017 Springer Science+Business Media New York

The reaction mechanism probably involved initial protonation of C-5 and formation of a carbonium ion on C-6
–
followed by cleavage of a halo cation X by I to release I (X = I) or IBr (X = Br).
2
The reactions of previously reported [8] N-bromo-5-bromo-6-hydroxymethyluracil (7) with KI under various conditions
seemed interesting. Treatment of 7 with a two-fold excess of KI in MeOH at 50°C for 4 h (Scheme 3) formed two products in
a 3:1 ratio (determined from integrated intensities in PMR spectra).
O
O
O
Br
Br
CH OH
Br
CH OH
a
HN
HN
HN
+
O
N
Br
O
N
H
O
N
I
CH OH
2
2
2
7
9
8
c
O
O
b
Br
CH I
IN
8
Br
+
HN
O
N
H
2
O
N
H
CH I
2
11
10
a. KI (2 equiv.), MeOH, 50ꢀC, 4 h; b. KI (2 equiv.), MeOH, 50ꢀC, 1-2 h; c. KI (5 equiv.), 5% H SO , 80ꢀC, 5 h
2
4
Scheme 3
The PMR spectrum of the main product had H-1:H-3:H-7 resonances with integrated intensities of 1:1:2.
1
13
The H– C HMBC NMR spectrum indicated all these protons gave cross peaks with the C-5 resonance (92.25 ppm); proton
H-1, with the resonance of C-7 (59.67 ppm). Resonances of the N-1 and N-3 protons were located at 10.53 and 11.50 ppm,
15
1
respectively. N– H correlation spectra showed that these two protons correlated to resonances for N-1 at 134.80 and N-3 at
13
156.13 ppm. The C NMR spectrum had resonances that coincided accurately up to 0.4–0.5 ppm with the resonances of
starting 7 [8]. Thus, the main reaction product had the structure 5-bromo-6-hydroxymethyluracil (8).
13
A second minor product gave C NMR resonances that were significantly different from those of 7, i.e., C-7 ꢁꢂ = 17;
15
C-6 ꢁꢂ = 10, and C-5 ꢁꢂ = 8 ppm. The N NMR spectrum with full proton suppression gave two weak resonances at ꢂ 137.68
15
and 156.87 ppm for N-1 and N-3. The N NMR spectrum recorded in inept mode was missing the resonance at 137.68 ppm.
1
13
This suggested that the proton on this atom was replaced. The H– C HMBC spectrum showed that H-3 coupled with C-5
(100.29 ppm) and C-4 (159.80 ppm).
The electrospray ionization (ESI) mass spectrum in negative-ion mode of the reaction product had two strong peaks
–
with m/z 329/331 of approximately equal intensity that corresponded to the ion [M – 17] that formed by loss of hydroxyl
radical from the parent ion. The peak was doubled because of the Br atom. The mass showed that the N(1) substituent was an
15
I atom, as shown above. This confirmed the N NMR spectral data recorded in inept mode. Therefore, the second product
had the structure N(1)-iodo-5-bromo-6-hydroxymethyluracil (9). The mass spectrum of the product had a triplet of peaks for
–
[M – OH] for an impurity of starting 7 with m/z 281:283:285 in a 0.5:1:0.4 ratio that corresponded to a compound with two
Br atoms.
Shortening the reaction time to 1 and 2 h produced 10 in addition to 8 (main product from the reaction for 2 h).
Compound 10 had a C-7 I atom (main product of the reaction for 1 h). This was confirmed by a characteristic resonance for
13
the –CH I group in the C NMR spectrum at –1.52 ppm (Scheme 3b).
2
Compound 10 was assumed to have an I atom on N-3 because of the appearance in negative-ion ESI mass spectra of
10 of a doublet of peaks with m/z 329/331. Its loss from the molecular ion was responsible for the formation of this ion
–
13
[M – I] with m/z 329/331. An analysis of C NMR spectra of all synthesized compounds suggested that the N-3 I atom had
little effect on the chemical shifts of the uracil core, in contrast to an N-1 I atom.
The dominant product from the reaction of 7 with a five-fold excess of KI in H SO (5%) at 80°C for 5 h was
2
4
13
5-bromo-6-iodomethyluracil (11) (Scheme 3c). Its structure was confirmed by PMR and C NMR spectral data. The negative-
–
ion ESI mass spectrum of 11 showed a doublet of peaks with m/z 329/331 that were apparently due to the [M – H] ion. Minor
products were obviously compounds with a C-6 hydroxymethyl, a C-5 Br atom, and an N-1 or N-3 I atom.
An analysis of negative-ion mass spectra of the uracil derivatives indicated that the C-7 substituent (OH, Br, I) (2, 3,
7, 9–11) and a halogen on one of the N atoms (Br or I; 7, 9–11) led under ESI conditions to the loss of the C-7 substituent.
H atom was lost if the N atom did not have a halogen (2, 3, 11).
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EXPERIMENTAL
13
15
PMR, C NMR, and N NMR spectra were recorded on a pulsed Bruker Avance-III 500 MHz spectrometer at
1
13
13
operating frequency 500.13 MHz for H and 125.47 MHz for C. Chemical shifts in PMR and C NMR spectra were given
in ppm with solvent resonances as standards. Chemical shifts in N NMR were obtained in F -projection of H– N HMBC
15
1
15
1
spectra and were adjusted to the ammonia scale. 2D spectra were recorded using standard multi-pulse sequences in standard
modes of the instrument software. Mass spectra were obtained on an LCMS-2010 EV quadrupole liquid chromatograph–
mass-spectrometer (Shimadzu) in negative-ion mode with ESI. Melting points were determined in glass capillaries.
Starting compounds 1 [7], 4 [8], 5 [8], and 7 [8] were synthesized by the previously published methods. Physicochemical
characteristics agreed with known data.
5-Chloro-6-bromomethyluracil (2). A suspension of 1 (0.27 g, 1 mmol) in H O (1.40 mL) at 80°C was treated
2
dropwise with H SO (98%, 1.30 mL, 25.5 mmol) and stirred at this temperature for 5 h. The resulting precipitate was filtered
2
4
off, rinsed with distilled H O until neutral, and dried at 60°C to afford white crystals of 2 (0.13 g, 52%), mp 250–252°C
2
1
(EtOH). Í NMR spectrum (500 MHz, DMSO-d , ꢂ, ppm): 3.35 (2H, s, Í-7), 10.80 (1H, s, H-1), 11.50 (1H, s, H-3).
C NMR spectrum (125 MHz, DMSO-d , ꢂ, ppm): 24.82 (t, C-7), 105.50 (s, C-5), 147.97 (s, C-2), 149.95 (s, C-6), 160.12 (s,
C-4). Mass spectrum, ESI, m/z (I , %): [Ì – Í] 237 (71), 239 (100), 241 (29).
6
13
6
–
rel
5-Chloro-6-hydroxymethyluracil (3). A suspension of 2 (0.24 g, 1 mmol) in aqueous MeCN (4 mL, MeCN–H O,
2
1:1) was stirred and refluxed for 2 h. The resulting precipitate was filtered off, rinsed with distilled H O, and dried at 60°C to
2
1
afford white crystals of 3 (0.21 g, 95%), mp 237–239°C (EtOH). Í NMR spectrum (500 MHz, DMSO-d , ꢂ, ppm, J/Hz):
4.05 (2H, d, J = 3.5, Í-7), 4.35 (1H, br.s, ÎÍ), 10.70 (1H, s, H-1), 11.50 (1H, s, H-3). C NMR spectrum (125 MHz,
6
13
DMSO-d , ꢂ, ppm): 57.58 (t, C-7), 102.70 (s, C-5), 149.25 (C-2), 151.25 (C-6), 160.66 (C-4). C H ClN O . Mass spectrum,
6
5
5
2 3
–
ESI, m/z (I , %): [Ì – Í] 175 (76), 177 (24).
rel
Reaction of 5-Iodo-1,3,6-trimethyluracil (4), 5-Bromo-1,3,6-trimethyluracil (5), or N-Bromo-5-bromo-6-
hydroxymethyluracil (7) with KI in H SO (5%) (General Method). A suspension of 4, 5, or 7 (1 mmol) and KI (0.83 g,
2
4
5 mmol) in H O (1.88 mL) at 80°C was treated dropwise with H SO (98%, 0.05 mL, 1 mmol), stirred for 5 h at that temperature,
2
2
4
cooled, treated with Na S O ·5H O solution (10%), and extracted with CHCl . The combined extracts were washed with
2
2
3
2
3
distilled H O, dried over Na SO , and evaporated to produce 6 (0.10 g, 68% yield from 4 and 0.10 g, 65% from 5).
2
2
4
The physicochemical characteristics agreed with known data [8]. Compound 7 (0.27 g) was obtained as a mixture and
a yellow amorphous powder, the main component of which was 5-bromo-6-iodomethyluracil (11).
1
5-Bromo-6-iodimethyluracil (11). Í NMR spectrum (500 MHz, DMSO-d , ꢂ, ppm): 4.09 (2H, s, H-7), 11.44 (1Í,
6
13
s, H-1), 11.52 (1H, s, H-3). C NMR spectrum (125 MHz, DMSO-d , ꢂ, ppm): –1.44 (t, C-7), 95.57 (s, C-5), 150.14 (s, C-2),
152.11 (s, C-6), 160.54 (s, C-4). Mass spectrum, ESI, m/z (I , %): [Ì – Í] 329 (99), 331 (100).
6
–
rel
Reaction of N-Bromo-5-bromo-6-hydroxymethyluracil (7) with KI for 1, 2, and 4 h (General Method).
A mixture of 7 (0.3 g, 1 mmol) and KI (0.33 g, 2 mmol) in MeOH (2 mL) was stirred at 50°C for 1, 2, and 4 h and cooled.
The precipitate was filtered off, rinsed with distilled H O and Me CO, and dried at 60°C to afford a mixture of 8 and 9 as
2
2
a yellow amorphous powder (0.23 g, 3:1 ratio) if the reaction was carried out for 4 h; a mixture of 8 and 10 (0.33 g, 1:2 ratio),
for 1 h; and a mixture of 8 and 10 (0.36 g, 3:1 ratio), for 2 h.
1
5-Bromo-6-hydroxymethyluracil (8). Í NMR spectrum (500 MHz, DMSO-d , ꢂ, ppm): 4.00 (1H, br.s, ÎÍ), 4.30
6
13
(2H, s, H-7), 10.54 (1Í, s, H-1), 11.50 (1H, s, H-3). C NMR spectrum (125 MHz, DMSO-d , ꢂ, ppm): 59.67 (t, C-7), 92.25 (s,
C-5), 150.12 (s, C-2), 152.83 (s, C-6), 159.94 (s, C-4). N NMR spectrum (50.58 MHz, DMSO-d , ꢂ, ppm): 134.80 (N-1), 156.13
6
15
6
(N-3).
1
N(1)-Iodo-5-bromo-6-hydroxymethyluracil (9). Í NMR spectrum (500 MHz, DMSO-d , ꢂ, ppm): 4.00 (1H, br.s,
6
13
ÎÍ), 4.50 (2H, s, H-7), 11.72 (1H, s, H-3). C NMR spectrum (125 MHz, DMSO-d , ꢂ, ppm): 42.89 (t, C-7), 100.29 (s, C-5),
149.90 (s, C-2), 142.00 (s, C-6), 159.80 (s, C-4). N NMR spectrum (50.58 MHz, DMSO-d , ꢂ, ppm): 137.68 (N-1), 156.87
(N-3). Mass spectrum, ESI, m/z (I , %): [Ì – ÎÍ] 329 (99), 331 (100).
6
15
6
–
rel
1
N(3)-Iodo-5-bromo-6-iodomethyluracil (10). Í NMR spectrum (500 MHz, DMSO-d , ꢂ, ppm): 4.17 (2H, s,
6
13
H-7), 10.50 (1H, s, H-1). C NMR spectrum (125 MHz, DMSO-d , ꢂ, ppm): –1.52 (t, C-7), 94.88 (s, C-5), 150.00 (s, C-2),
151.73 (s, C-6), 159.88 (s, C-4). Mass spectrum, ESI, m/z (I , %): [Ì – I] 329 (99), 331 (100).
6
–
rel
1142

ACKNOWLEDGMENT
The work was performed according to the plan of scientific research at Ufa Institute of Chemistry, RAS, on the topic
Synthesis of Biologically Active Heterocyclic and Terpenoid Compounds (State registration No. AAAA-A17-117011910025-6).
Information technology support used RFBR Grant 13-00-14056. The spectral studies were performed using equipment at the
Khimiya Joint Use Center, UfIC, RAS.
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