Photochemical behaviour of 5-perfluoroalkenyl uracils

Article abstract of DOI:10.1016/j.tetlet.2004.04.187

Phototransformations of derivatives of 5-fluoroalkenyl uracils depend strongly on the fluorinated substituents. 1,3-Dimethyl-5-trifluorovinyluracil when irradiated in water with UV light (λ>300nm) gives 1,3-dimethyl-(5,6-dihydrourac-6-yl)-difluoroacetic a

Full text of DOI:10.1016/j.tetlet.2004.04.187

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5767–5769
Photochemical behaviour of 5-perfluoroalkenyl uracils
Henryk Koroniak,* Piotr Karwatka and Tomasz Cytlak
Adam Mickiewicz University, Faculty of Chemistry, Grunwalszka 6, 60-780 Poznaꢀn, Poland
Received 7 August 2003; revised 21 April 2004; accepted 30 April 2004
Available online 15 June 2004
Abstract—Phototransformations of derivatives of 5-fluoroalkenyl uracils depend strongly on the fluorinated substituents. 1,3-Di-
methyl-5-trifluorovinyluracil when irradiated in water with UV light (k > 300 nm) gives 1,3-dimethyl-(5,6-dihydrourac-6-yl)-diflu-
oroacetic acid as the only product, while the analogous 1,3-dimethyl-5-(E-pentafluoropropenyl)uracil isomerizes to its Z isomer. It is
suggested that the first transformation is thermodynamically controlled while the second one is kinetically controlled, the difference
being due to torquoselectivity.
Ó 2004 Elsevier Ltd. All rights reserved.
It is known that modified uracils with an unsaturated
exocyclic side chain in position 5 display significant
antiviral activity.1 Recently, we studied extensively
synthetic methodology to access 5-fluorinated alkenyl
uracils as well as to determine their structural proper-
ties.2 One of the reasons for our research is the potential
biological activity of fluorinated 5-alkenyl uracils. This
expectation is based on the geometrical similarity of
hydrogen and fluorine. The therapeutic properties are
attributed to the structural similarity of fluorine and
hydrogen-containing molecules (e.g., the 5-fluorouracil
analogue of uracil) to such an extent that these mole-
cules are quite often not indistinguishable by enzymes.3
In our studies we were able to synthesize a series of new
derivatives of uracil with 5-perfluoroalkenyl groups,
which along with the endocyclic 5,6 double bond, form a
diene system.2
The photochemical properties of 1,3-dimethyl-5-(triflu-
orovinyl)uracil 1 were studied, assuming that the elec-
trocyclization of the diene would be a dominant
reaction. The intermediate, a cyclobutene derivative,
O
F
O
CH3
O
F
CH3
N
N
ν
h , λ>300 nm
F
H O
2
N
O
N
CF2COOH
CH3
CH3
1
2
hν
λ>300 nm
H O
2
H O
2
O
N
O
O
O
F
OH
F
CH3
CH3
O
F
CH3
O
N
N
N
F
- HF
O
N
N
CH3
3
F
F
F
CH3
CH3
4
5
Keywords: Uracil; 5-Trifluorovinyl uracil; 5-Pentafluoropropenyl uracil; Photorearrangement.
* Corresponding author. Tel.: +48-61-8291303; fax: +48-61-8291507; e-mail: koroniak@main.amu.edu.pl
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.187

5768
H. Koroniak et al. / Tetrahedron Letters 45 (2004) 5767–5769
O
F
O
F
CH3
O
F
CH3
O
CF3
N
N
h , λ>300 nm
ν
CF3
F
H O
2
N
N
CH3
CH3
6
7
O
F
CH3
N
CF3
O
N
F
CH3
8
was expected to undergo further transformations.
Moreover the presence of fluorine atoms in the cyclo-
butene moiety should stabilize its structure.4a Surpris-
well-known reaction, we believe that in this case tor-
quoselectivity10 seems to be an important and domi-
nating factor. It seems that in the ring opening of the
intermediate cyclobutene 8, among the two substituents
–CF3 and –F responsible for the isomerization, the
fluorine being an efficient p-electron donor will prefer-
entially rotate outward, forcing the CF3 group to rotate
inward. As a result formal trans–cis isomerization is
observed. It is just another experimental example sup-
porting the torquoselectivity prediction based on com-
putational calculations.10
ingly, during irradiation5 of
1
with UV light
(k > 300 nm) in water, we isolated 1,3-dimethyl-(5,6-di-
hydrourac-6-yl)-difluoroacetic acid 2, as the only stable
product.6 Irradiation of the same substrate 1 with higher
energy light (k ¼ 254 nm) led to cleavage of the C(5)–
C(trifluorovinyl) bond and gave 1,3-dimethyluracil as
the sole product.
The mechanism of these transformations seems to in-
volve a Michael type addition–elimination reaction after
the photochemical electrocyclization. The more stable
keto 5 versus enol 4 tautomer then reacts with a nucleo-
phile (water) leading to the most thermodynamically
stable product––a derivative of difluoroacetic acid 2. In
the case of irradiation with higher energy light (low-
pressure mercury lamp, k ¼ 254 nm) simple cleavage of
a C–C bond occurs.
References and notes
1. (a) De Clerq, E.; Descamps, J.; De Somer, P.; Barr, P. J.;
Jones, A. S.; Walker, R. T. Proc. Natl. Sci. U.S.A. 1979, 76,
2947–2951; (b) Jones, A. S.; Rahim, S. G.; Walker, R. T.
J. Med. Chem. 1981, 24, 759–760; (c) Coe, P. L.; Harnden,
M. R.; Jones, A. S.; Noble, S. A.; Walker, R. T. J. Med.
Chem. 1982, 25, 1329–1334; (d) De Clerq, E.; Desgranges,
C.; Herdewijn, P.; Sim, I. S.; Jones, A. S.; McLean, M. J.;
Walker, R. T. J. Med. Chem. 1986, 29, 213–217.
2. (a) Koroniak, H.; Fiedorow, P.; Pluskota, D.; Karwatka,
P.; Abboud, K. A. J. Mol. Struct. 1994, 323, 215–221; (b)
Koroniak, H.; Karwatka, P.; Pluskota, D.; Fiedorow, P.;
Jankowski, J. J. Fluorine Chem. 1995, 71, 135–137.
It would appear that the final product 2 is formed via the
labile intermediate 3, the structure of which we were not
able to determine experimentally. We suggest that the
keto 5–enol 4 equilibrium should favour the keto tau-
tomer 5, which can sometimes be reversed.4 On the basis
of DFT calculations, however, keto form 5 is 0.4 kcal/
mol (1.7 kJ/mol) more stable than the enol form 4.7
3. Welch, J.; Eswarakrishan, S. Fluorine in Bioorganic
Chemistry; John Wiley and Sons, 1991.
4. (a) Lemal, D. M. Acc. Chem. Res. 2001, 34, 662–671; (b)
Lindner, P. E.; Correa, R. A.; Gino, J.; Lemal, D. M.
J. Am. Chem. Soc. 1996, 118, 2556–2563; (c) Lindner,
P. E.; Lemal, D. M. J. Org. Chem. 1996, 61, 5109–5115.
5. Photoirradiations were carried out in a water cooled
reactor with an immersed medium pressure mercury lamp
using a 1 mm Pyrex filter which provided UV light with
k > 300 nm. The phototransformations were followed by
HPLC analysis. The concentration of the irradiated water
solutions of 1, 6 and 7 was in the range of 10ꢀ3 M (usually
1 mM), due to the solubility of the starting material.
6. Pure 2 was isolated from the irradiated solution of 1. After
1.5 h irradiation of 1, the solvent (water) was removed in
vacuo. The solid precipitate was collected and showed to
consist of 2 and unreacted traces of 1. After column
chromatography (to remove unreacted 1) and recrystalli-
zation, samples of pure 2 (purity checked by HPLC,
reverse phase C-18 column) were submitted for analysis.
These findings are in contrast to the photochemical
transformations
of
1,3-dimethyl-5-(E-pentafluoro-
propenyl)uracil. It is surprising, that in this case only
E–Z isomerization was observed. No traces of inter-
mediates analogous to 4 or 5 were found in the reaction
mixture. The irradiation of a water solution of 6 led to a
photostationary state involving equilibration with 1,3-
dimethyl-5-(Z-pentafluoropropenyl)uracil 7, where the
more sterically congested 7 is the major product (HPLC
ratio 6/7 ¼ 1:1.54).9 Irradiation of 7 as the starting
material also led to the identical photostationary state.
This experimental observation suggests that the uni-
molecular transformation is much faster than the
bimolecular nucleophilic reaction with molecules of
solvent (water), as observed in the case of 1. Although
trans–cis photochemically induced isomerization is a
1
Yield (isolated) 55%. H NMR, (DMSO-d6, in ppm in d
scale downfield from TMS), 2.60 (br m, 2H, C5–H2), 2.96

H. Koroniak et al. / Tetrahedron Letters 45 (2004) 5767–5769
5769
(s, 3H, N3–CH3), 3.00 (s, 3H, N1–CH3), 4.10 (m, 1H, C6–
H). 19F NMR, (DMSO-d6, in ppm in u scale upfield from
9. The 19F NMR spectra of fluorinated alkenes are of great
importance for determining their structure. The coupling
2
3
3
CFCl3) 105.2 (1F, dd, JF–F ¼ 243Hz, JF–H ¼ 8:5 Hz),
constants, JF–F of fluorine atoms at the C@C bond have
2
3
3
109.7 (1F, dd, JF–F ¼ 243Hz, JF–H ¼ 18 Hz); LSIMS in
negative mode showed the [MꢀH]ꢀ ion at m=z (relative
intensity) ¼ 235 (50).
useful analytical value. Generally Jtrans F–F ꢂ 120–150 Hz,
3
while Jcis F–F ꢂ 10–45 Hz. In our case: 6: 19F NMR,
(CDCl3, in ppm in u scale upfield from CFCl3), 67.4 (3F,
3
4
7. In the case of molecules containing fluorine only ab initio
and DFT computational methods give reliable data
concerning thermodynamic stability.8 In our case
B3LYP/6-31Gꢁ calculations were used to determine the
equilibrium 4 versus 5. The calculated, very small,
DGo ¼ 0:4 kcal/mol for the keto–enol equilibrium is sur-
prising, however, the presence of fluorine atoms should
significantly stabilize the enol form 4.4
dd, C@CFCF3, JCF –F ¼ 11 Hz, JCF –F ¼ 21 Hz), 135.0
3
3
3
4
(1F, dq, CF@CFCF3, Jtrans F–F ¼ 139 Hz, JCF –F
¼
3
3
21 Hz), 164.0 (1F, dq, CF@CFCF3, Jtrans F–F ¼ 139 Hz,
4JCF –F ¼ 11 Hz); 7: 19F NMR, (CDCl3, in ppm in u scale
3
3
upfield from CFCl3), 66.4 (3F, dd, C@CFCF3, JCF –F
¼
3
4
13Hz, JCF –F ¼ 8 Hz), 111.1 (1F, m, CF@CFCF3), 148.1
3
3
4
(1F, dq, CF@CFCF3, Jcis F–F ¼ 10 Hz, JCF –F ¼ 13Hz).
3
At photostationary state the ratio 6/7 1:1.4 (based on
NMR integration).
8. Houk, K. N.; Beno, B. R.; Nendel, M.; Black, K.; Yoo, H.
Y.; Wilsey, S.; Lee, J. K. J. Mol. Struct. (THEOCHEM)
1997, 398, 169–179.
10. Dolbier, W. R., Jr.; Koroniak, H.; Houk, K. N.; Sheu, C.
Acc. Chem. Res. 1996, 29, 471–477.