Synthesis of 1-(dihydroxypropyl)-5-substituted uracils

Article abstract of DOI:10.1016/S0040-4039(03)01872-0

Novel 1-(dihydroxypropyl)-5-substituted uracils were synthesized in the reaction of 1-(4-nitrophenyl)-5-substituted uracil derivatives with appropriate aminopropanediols under mild conditions. In the case of 3-amino-1,2-propanediol both racemic and enanti

Full text of DOI:10.1016/S0040-4039(03)01872-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7291–7293
Synthesis of 1-(dihydroxypropyl)-5-substituted uracils
Andrzej Gondela and Krzysztof Walczak*
Institute of Organic Chemistry and Technology, Silesian University of Technology, Krzywoustego 4, 44-100 Gliwice, Poland
Received 30 June 2003; revised 25 July 2003; accepted 1 August 2003
Abstract—Novel 1-(dihydroxypropyl)-5-substituted uracils were synthesized in the reaction of 1-(4-nitrophenyl)-5-substituted
uracil derivatives with appropriate aminopropanediols under mild conditions. In the case of 3-amino-1,2-propanediol both
racemic and enantiomerically enriched products were obtained. These compounds may be considered as new building blocks for
oligonucleotide synthesis.
© 2003 Elsevier Ltd. All rights reserved.
The acyclonucleosides, a group of compounds in which,
the carbohydrate moieties are acyclic chains mimicking
the sugar portion of naturally occurring nucleosides
represent an important class of biologically active
molecules.1 Several acyclonucleosides are known to
possess moderate antiviral activity (e.g. Acyclovir, (S)-
HMPA, etc.).1,2 Such analogues are of considerable
interest as monomer precursors for the generation of
antisense oligonucleotides.3 On the other hand acy-
clonucleosides possessing two hydroxyl functions can
be useful intermediates in the synthesis of 1,3-dioxolane
and 1,3-dioxane derivatives.4,5 Recently we have
demonstrated, that 1,4-dinitroimidazoles can be easily
converted into 3-(4-nitroimidazol-1-yl)-1,2-propanediols
via the so-called ‘degenerated imidazole ring transfor-
mation’.6 Currently we have focused on other hetero-
cyclic systems, which are able to undergo similar
reactions. It is known from the literature that 3-methyl-
5-nitro-1-(4%-nitrophenyl)uracil when treated with pri-
mary amines undergoes transformation into 1-alkyl
derivatives.7–9 3-Methyl-1-phenyluracil-5-carboxamide
undergoes the same reaction under forcing conditions.
In contrast, the biological activity of alkyl derivatives
of 5-nitrouracil is rather less recognized in comparison
with other uracil analogues. 5-Nitro-2%-deoxyuridine
inhibits thymidylate synthetase,10,11 and 5-nitro-1-[3-(5-
nitro-2-furan-2-yl)-acroyl]uracil exhibits antitumor
activity on leukemia P388 cells.12 An inhibition effect
on macrophage RAW 264.7 of 1-(2-hydroxy-3-
methoxypropyl)-5-nitrouracil was also reported.13
We report here a simple method for the synthesis of
5-substituted uracil propanediol derivatives. The direct
nucleophilic addition of 3-methyl-5-nitrouracil to
(hydroxymethyl)oxirane according to the method
described by Acevedo14 failed and the expected product
was obtained in low yield (Table 1, entry 1). When
Table 1. Yields and properties of 1-(dihydroxypropyl)-5-substituted uracil derivatives
No.
Product
R
R1
Yield (%)
Mp (°C)
[h]D (c 0.5, MeOH)
1
2
3
4
5
6
7
8
9
3a
3a
3b
3c
3d
3e
3f
NO2
NO2
NO2
NO2
CONH2
CONH2
CONH2
NO2
(RS)-CH2CH(OH)CH2OH
(RS)-CH2CH(OH)CH2OH
(R)-CH2CH(OH)CH2OH
(S)-CH2CH(OH)CH2OH
(RS)-CH2CH(OH)CH2OH
(R)-CH2CH(OH)CH2OH
(S)-CH2CH(OH)CH2OH
-CH(CH2OH)2
18
75
75
87
96
90
92
74
70
186–188
187–188
171–172
173–174
201–202
193–194
192–194
209–210
236–237
–
–
+50
−46
–
+55
−58
–
3g
3h
CONH2
-CH(CH2OH)2
–
Keywords: 1-(dihydroxypropyl)-5-substituted uracils; aminopropanediols; enantiomers.
* Corresponding author. Tel.: +4832-237-1792; fax: +4832-2372094; e-mail: walczak@polsl.gliwice.pl
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01872-0

7292
A. Gondela, K. Walczak / Tetrahedron Letters 44 (2003) 7291–7293
order to obtain 1-(2,3-dihydroxypropyl)-3-methyl-5-
substituted uracils the reaction of the appropriate uracil
1a or 1b with 4-aminomethyl-2,2-dimethyl-1,3-diox-
olane 4 was performed (Scheme 2). Application of the
same conditions (as above) gave intermediate products
1-(2,2-dimethyl-[1,3]-dioxolan-4-ylmethyl)-3-methyl-5-
nitrouracil17 5a and 1-(2,2-dimethyl-[1,3]-dioxolan-4-
ylmethyl)-3-methyluracil-5-carboxamide19
5b
in
satisfactory yields (68% and 86%, respectively). Cleav-
age of the dioxolane ring using 80% aq. acetic acid gave
3a or 3d in almost quantitative yield (>92%).
Scheme 1.
In conclusion, two parallel methods have been used for
the syntheses of 1-(dihydroxypropyl)-5-substituted
uracil derivatives. We have obtained both racemic and
enantiomerically enriched products in all the reactions
studied. We believe that the acyclonucleosides described
will be of interest, both as synthetic intermediates and
propane-2,3-diol monomers, having non-hydrogen
bonded bases in oligonucleotide synthesis.20–23
3-methyl-1-(4-nitrophenyl)uracil7 1a and ( )-3-amino-
1,2-propanediol were refluxed in anhydrous ethanol for
6 h, 1-(2,3-dihydroxypropyl)-3-methyl-5-nitrouracil 3a
was isolated in 75% yield (after column purification and
crystallization from methanol) (Scheme 1, Table 1,
entry 2).
In order to avoid racemization during the reaction, the
experiments in which we applied pure enantiomers (R
or S) of 3-amino-1,2-propanediol were performed in
anhydrous DMF at room temperature. After 4–5 h, the
corresponding products 3b and 3c were obtained in
satisfactory yields (entries 3, 4).15
References
1. Garg, R.; Gupta, S. P.; Gao, H.; Babu, M. S.; Debnath,
A. K.; Hansch, C. Chem. Rev. 1999, 99, 3525–3601.
2. Abushanab, E. In Nucleosides and Nucleotides as Antitu-
mor and Antiviral Agents; Chu, C. K.; Baker, D. C., Eds.;
Plenum Press: New York, 1993; pp. 159–171.
3. Seeberger, P. H.; Caruthers, M. H. In Applied Antisense
Oligonucleotide Technology; Stein, C. D.; Krieg, A. M.,
Eds.; Modified Oligonucleotides as Antisense Therapeutics;
Wiley-Liss: New York, 1998; Chapter 3, pp. 51–72.
4. Efimtseva, E. V.; Mikhailov, S. N.; Meshkov, S.; Hanka-
maki, T.; Oivanen, M.; Lonberg, H. J. Chem. Soc.,
Perkin Trans. 1 1995, 1409–1415.
3-Methyl-(4-nitrophenyl)uracil-5-carboxamide 1b was
prepared from 1-(4-nitrophenyl)-5-cyanouracil16 by N-3
methylation with methyl iodide followed by partial
hydrolysis of the cyano group.17
Compound 1b reacted smoothly with 3-amino-1,2-
propanediol (RS, R or S) and gave the desired products
3d–f in excellent yields (entries 5–7).18 The optical
purity of a single enantiomer depended on the optical
purity of the starting 3-amino-1,2-propanediols.
According to the reaction mechanism and mild reaction
conditions racemization during synthesis can be pre-
vented. The optical purity of the obtained compounds
is not less than 94 (ee) as calculated from the enan-
tiomeric composition of the starting amino-
propanediols.
5. Cadet, G.; Chan, Ch. S.; Daniel, R. Y.; Davis, C. P.;
Guiadeen, D.; Rodriguez, G.; Thomas, T.; Walcott, S.;
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czak, K. Eur. J. Org. Chem. 2003, 1080–1084.
7. Hirota, K.; Kitade, Y.; Sajiki, H.; Maki, Y. Tetrahedron
Lett. 1986, 27, 3263–3266.
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Soc., Perkin Trans. 1 1990, 367–373.
9. Senda, S.; Hirota, K.; Notani, J. Chem. Pharm. Bull.
1972, 20, 1389–1396.
Under the same conditions, 1a or 1b treated with
symmetrical 2-amino-1,3-propanediol gave the desired
products 3g,h in satisfactory yields (entries 8, 9). In
10. Washtien, W. L.; Santi, D. V. J. Med. Chem. 1982, 25,
1252–1255.
11. Trusule, M.; Kupce, E.; Augustane, I.; Verovskii, N. V.;
Lukevics, E.; Baumane, L.; Gavars, R.; Stradins, J. Khim.
Geterocycl. Soedin. 1991, 12, 1687–1694.
12. Kranz, P.; Lee, C. S.; Gero, A. M.; O’Sullivan, W. J.
Biochem. Pharmacol. 1989, 38, 3785–3789.
13. Copik, A.; Suwinski, J.; Walczak, K.; Bronikowska, J.;
Czuba, Z.; Kro´l, W. Nucleosides, Nucloetides Nucleic
Acids 2002, 21, 377–383.
14. Acevedo, O. L.; Andrews, R. S. Tetrahedron Lett. 1996,
37, 3931–3934.
15. Synthesis of 1-(dihydroxypropyl)-3-methyl-5-substituted
uracils (general procedure): To a solution of (R)-(+)-3-
Scheme 2.

A. Gondela, K. Walczak / Tetrahedron Letters 44 (2003) 7291–7293
7293
amino-1,2-propanediol 2 (1.1 mmol) in anhydrous DMF
(10 ml) 1a or 1b was added (1 mmol) in one portion while
stirring. The resulting yellow-reddish solution was stirred
until the substrate had been consumed and then concen-
trated under reduced pressure. The oily residue was
purified on a silica gel column using methanol–chloro-
form mixture (1:9) as eluent.
63.56, 68.62, 103.44, 150.50, 150.75, 162.52, 163.26. Anal.
calcd for C9H13N3O5 (243.22): %C, 44.44; %H, 5.40; %N,
17.28. Found: %C, 44.46; %H, 5.61; %N, 16.97.
19. Synthesis of 1-(2,2-dimethyl-[1,3]-dioxolane-4-ylmethyl)-
3-methyl-5-substituted uracils (general procedure): To the
solution of 4-aminomethyl-2,2-dimethyl-[1,3]-dioxolane 4
(1.1 mmol) in anhydrous DMF (10 ml) 1a or 1b was
added (1 mmol) in one portion while stirring. The result-
ing yellow-reddish solution was stirred until the substrate
had been consumed and then concentrated under reduced
pressure. The oily residue was crystallized from methanol.
5a: Yield 68%; mp 167–168°C; 1H NMR, (CDCl3): l
(ppm)=1.34 (3H, s, CH3), 1.46 (3H, s, CH3), 3.41 (3H, s,
N-CH3), 3.73 (1H, dd, J=9.0 Hz, 5.7 Hz, H-5a%), 3.84
(1H, dd, J=13.8 Hz, 7.2 Hz, CH2a), 4.16 (1H, dd, J=9.0
Hz, 6.6 Hz, H-5%b), 4.28 (1H, dd, J=13.8 Hz, 2.7 Hz,
CH2b), 4.40–4.50 (1H, m, H-4%), 8.81 (1H, s, H-6). 13C
NMR, (CDCl3), l (ppm)=24.78, 26.66, 28.93, 52.54,
66.11, 72.88, 110.47, 124.96, 147.64, 149.88, 154.24. Anal.
calcd for C11H15N3O6 (285.3): %C, 46.32; %H, 5.30; %N,
14.73. Found: %C, 46.37; %H, 5.01; %N, 14.67.
3b:
(R)-(+)-1-(2,3-dihydroxypropyl)-3-methyl-5-nitrou-
racil: 1H NMR, (DMSO-d6): l (ppm)=3.22 (s, 3H, CH3),
3.27–3.48 (m, 2H, H-3a%,b), 3.64–3.71 (m, 2H, H-1a%, H-2),
4.21 (d, 1H, J=10.8 Hz, H-1%b), 4.78 (t, 1H, J=5.7 Hz,
OH-3%), 5.13 (d, 1H, J=5.1 Hz, OH-2%), 9.12 (s, 1H, H-6).
13C NMR, (DMSO): l (ppm)=28.15, 53.45, 63.37, 68.24,
124.00, 149.48, 149.53, 154.35. Anal. calcd for
C8H11N3O6 (245.2): %C, 39.39; %H, 4.52; %N, 17.14.
Found: %C, 39.30; %H, 4.52; %N, 16.95.
16. Wolfbeis, O. S. Liebigs Ann. Chem. 1982, 182–185.
17. 1b. 3-Methyl-(4-nitrophenyl)uracil-5-carboxamide: To the
suspension of 1-(4-nitrophenyl)-5-cyanouracil16 (9.0 g, 33
mmol) in water (0.6 ml, 33 mmol), concd sulphuric acid
(41 ml, 98%) was added. The reaction mixture was stirred
at 50°C for 3 h and then poured onto crushed ice (210 g).
The precipitated solid was filtered off, rinsed with water
and finally with methanol and crystallized from acetone.
5b: Yield 86%; mp 199–200°C; 1H NMR, (DMSO): l
(ppm)=1.25 (s, 3H, CH3), 1.33 (s, 3H, CH3), 3.25 (s, 3H,
N-CH3), 3.68 (dd, 1H, J=8.6 Hz, 5.6 Hz, H-5a%), 3.94–
4.14 (m, 3H, CH2a, CH2b, H-5%b), 4.29 (m, 1H, H-4%), 7.56
(bd, 1H, J=3.5 Hz, NH2), 8.19 (bd, 1H, J=3.5 Hz,
NH2), 8.47 (s, 1H, H-6). 13C NMR, (DMSO): l (ppm)=
25.16, 26.44, 28.02, 51.21, 65.82, 73.03, 103.94, 108.94,
150.17, 150.65, 162.32, 162.96.
1
Yield 9.5 g (98%); mp 286–288°C. H NMR, (DMSO): l
(ppm)=3.28 (s, 3H, CH3), 7.22 (bd, 1H, J=3 Hz, NH2),
7.81 (d, 2H, J=9.3 Hz, Ar), 8.22 (bd, 1H, J=3 Hz,
NH2), 8.37 (s, 1H, H-6), 8.38 (d, 2H, J=9.3 Hz, Ar).
18. 3e: (R)-(+)-1-(2,3-dihydroxypropyl)-3-methyluracil-5-car-
boxamide: 1H NMR, (DMSO): l (ppm)=3.23 (s, 3H,
Me), 3.28–3.47(m, 2H, H-3%), 3.59 (dd, 1H, J=13.2 Hz,
20. Kool, E. T. Acc. Chem. Res. 2002, 35, 936–943.
21. Loakes, D. Nucleic Acids Res. 2001, 29, 2437–2447.
22. Kool, E. T. Biopolymers 1998, 48, 3–17.
23. Berger, M.; Wu, Y.; Ogawa, A. K.; McMinn, D. L.;
Schultz, P. G.; Romesberg, F. E. Nucleic Acids Res. 2000,
28, 2911–2914.
9.3 Hz, H-1%), 3.65–3.76 (m, 1H, H-2%), 4.16 (dd, 1H,
a
J=13.2 Hz, 2.7 Hz, H-1b% ), 4.74 (t, 1H, J=5.7 Hz,
3%-OH), 5.04 (d, 1H, J=5.4 Hz, 2%-OH), 7.53 (d, 1H,
J=3.6 Hz, NH), 8.22 (s, 1H, J=3.6 Hz, NH), 8.41 (s,
1H, H-6). 13C NMR, (DMSO): l (ppm)=27.84, 53.17,