An efficient synthesis of new fluorinated uracil derivatives.

Article abstract of DOI:10.1039/b300796k

A series of potentially biologically active fluorinated uracil derivatives has been prepared in three steps from oxazolines and fluorinated nitriles with good chemical yields.

Full text of DOI:10.1039/b300796k

An efficient synthesis of new fluorinated uracil derivatives†
Santos Fustero,* Esther Salavert, Juan F. Sanz-Cervera, Julio Piera and Amparo Asensio
Departamento de Química Orgánica, Universidad de Valencia, E-46100 Burjassot, Spain.
E-mail: Santos.Fustero@uv.es; Fax: +34 963 544 339; Tel: +34 963 544 279
Received (in Cambridge, UK) 20th January 2003, Accepted 12th February 2003
First published as an Advance Article on the web 27th February 2003
A series of potentially biologically active fluorinated uracil
derivatives has been prepared in three steps from oxazolines
and fluorinated nitriles with good chemical yields.
aromatic fluorinated nitriles were commercially available, only
one of the aliphatic nitriles (5d, perfluorooctanenitrile) could be
purchased. For that reason, 5a,5 5b,5,6 and 5c6 were prepared
with previously described procedures.
2
Because of the essential role that nucleic acids play in metabolic
processes, much emphasis has been placed on the design of
antimetabolites with a similar structure. For instance, analogs of
nucleosides have been successfully used as antineoplasic and
antiviral agents.1 The structures can be modified to affect the
base ring, the sugar, or both. Thus far, most research in this area
has focused on the preparation of nucleosides or their
derivatives with pyrimidinic bases, and particularly uracils with
fluorinated groups in position 5 or 6 of the ring (see structure 1
below). While compounds in which the substituent appears on
C-5 have found applications as antitumoral agents,2 those in
which it appears on C-6 act mostly as herbicides, insecticides,
and acaricides.3 An important example of the former is
5-fluorouracil 2, which displays potent anticarcinogenic activ-
ity.1
First, 2-alkyl-D -oxazolines 4 were treated with 1 equiv. of
LDA at 278 °C to afford their enolates. These were then
condensed with different fluorinated nitriles 5, which after
hydrolysis† gave a variety of chiral and achiral oxazolin-
protected b-enamino acids 6 in yields ranging from 60 to 93%
(Scheme 1 and Table 1).‡§
Next, the condensation of the protected, fluorinated b-
enamino acids 6 with either phosgene or triphosgene7¶ yielded
a mixture of isomeric oxazolopyrimidinones 7 and 8 in yields
ranging from 70 to 95% (Scheme 1 and Table 2). In all cases, the
pyrimidinone derivatives 8 were the predominant products of
the condensation reaction. In more than half of the cases, both
oxazolopyrimidinones 7§ and 8§ were isolated and purified, but
in some instances only 8 was isolated (entries 2, 3, 5, 6, and
9).The results of an assay with a non-fluorinated compound
(entry 11, Table 2) seem to indicate that the outcome of this
reaction is not dependent on whether the starting oxazoline b-
enamino acid is fluorinated or not.
Because of the structural similarities between isomeric
compounds 7 and 8, their structural elucidation was only
possible through X-ray diffraction analysis. The results for
Table 1 Results for the reaction between oxazolines 4 and nitriles 5
Yield
In this paper, we describe a convenient and efficient synthetic
strategy for the preparation of new C-6 fluoroalkylated N-3
a
Entry
4
5
R1
R2
RF
Product (%)b
2
alkylated pyrimidin-2,4-diones 3 from 2-alquil-D -oxazolines 4
1
2
3
4
5
6
7
8
9
4a
4a
4a
4a
4b
4c
4c
4a
4a
4a
4c
5a
5b
5c
5d
5a
5a
5b
5e
5f
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
CF2(b-C10H7) 6a
CF2(a-C10H7) 6b
CF2C6H5
84
80
70
60
76
74
65
70
93
70
72
and fluorinated nitriles 5.
In our synthesis we used two commercial oxazolines, namely
6c
6d
2
2
2-methyl-D -oxazoline (4a) and 2-ethyl-D -oxazoline (4b), as
(CF2)6CF3
2
well as (R)-2-methyl-4-phenyl-D -oxazoline (4c) (Scheme 1).
CF2(b-C10H7) 6e
C6H5 CF2(b-C10H7) 6f
This last compound, although not yet commercially available,
can be easily prepared following methods described in the
literature.4 In addition, both aromatic and aliphatic fluorinated
nitriles 5 were also used as starting materials. While all the
C6H5 CF2(a-C10H7) 6g
H
H
H
2,4-F2C6H3
p-CF3C6H4
p-FC6H4
6h
6i
6j
10
11
a
5g
5g
C6H5 p-FC6H4
6k
† Electronic supplementary information (ESI) available: general procedures
for the preparation of compounds 3, 6, 7, 8 and 9. See http://www.rsc.org/
suppdata/cc/b3/b300796k/
b-C10H7 = b-naphtyl; a-C10H7 = a-naphtyl. b Yields for purified prod-
ucts.
Scheme 1 Synthetic sequence for the preparation of fluorinated uracil derivatives 3.
CHEM. COMMUN., 2003, 844–845 This journal is © The Royal Society of Chemistry 2003
844

compounds 7h and 8k indicated that, whereas compound 7h
displayed a fluorinated oxazolo[3,2-c]pyrimidone structure, 8k
was an oxazolo[3,2-a]pyrimidone.∑
Finally, 7 and 8 underwent an oxazoline ring-opening
reaction with several nucleophiles under either basic (Method
A) or acidic (Method B) conditions, to give compounds 3§
(Scheme 1 and Table 3) in good to excellent yields.8,9.**
It is worth noting that uracil 3 was obtained as the only
reaction product regardless of whether compound 7, 8 or a
mixture thereof were used. In all examples, the ring-opening
reaction in acidic medium was faster (0.5–2 h) and produced
better yields (80–98%) than the corresponding reactions under
basic conditions (5–7 h; 72–80%).
To confirm the validity of our approach as a general method
of introducing a nucleophile into these systems, we attempted
the incorporation of the cyclic amine t-butyl 1-piperazine-
carboxylate†† (Scheme 2). Thus, 7g and 8g reacted with of N-
BOC-piperazine at 100 °C for 24 h, to yield the desired
compound 9 § in 80% yield, proving the validity of our
approach.
Scheme 2 Preparation of compound 9.
In summary, we have developed a straightforward synthesis
of new fluorinated uracil derivatives 3 from oxazolines 4 and
fluorinated nitriles 5 in only three steps and with good chemical
yields. The ring-opening reaction of intermediate oxazolopyr-
imidinones 7 and 8 by a number of different nucleophiles allows
the preparation of a variety of interesting analogues with
potential biological activity.
We thank the Ministerio de Ciencia y Tecnología of Spain for
financial support (PPQ2000–0824). E.S. and J.P. thank the
Generalitat Valenciana and the Ministerio de Educación y
Cultura of Spain, respectively, for predoctoral fellowships.
Table 2 Results for the reaction of compounds 6 with triphosgene
Notes and references
‡ These compounds appeared exclusively in the enamino form.
§ Compounds 3, 6, 7, 8 and 9 showed spectroscopic (1H, 19F, 13C-NMR)
and HRMS data in agreement with their structures.
¶ In our synthesis, substituting phosgene for triphosgene did not affect the
yields; thus, since triphosgene is easier to handle, we used one molar
equivalent of triphosgene in each reaction. An excess of triphosgene did not
influence the yields and proportion of the products.
Yield
(%)c
Isolated
products
b
Entrya
R2
RF
7/8d
1
2
3
4
5
6
7
8
9
H
H
H
H
H
(R)-Ph
H
H
CF2(b-C10H7)
CF2(a-C10H7)
CF2C6H5
80
82
72
70
85
90
95
89
82
87
79
30/70
10/90
5/95
7a, 8a
8b
8c
7d + 8de
8e
(CF2)6CF3
10/90
20/80
10/90
35/65
30/70
35/65
30/70
30/70
CF2(b-C10H7)
CF2(b-C10H7)
2,4-F2C6H3
p-CF3C6H4
p-FC6H4
8f
∑ Full details of the X-ray structures of 7h and 8k will be published in a full
account of this work.
7g, 8g
7h, 8h
8i
7j, 8j
7k, 8k
** It is noteworthy that when treated with a base (e.g. aq. K2CO3/dioxane),
those compounds 3 in which Nu = Cl revert to a mixture 7 + 8 in
proportions similar to those when they were obtained from 8.
†† We chose this compound not only because it would allow for
introduction of other groups after N-BOC deprotection, but also because
analogous systems are present in several pharmaceutically significant
compounds, for example Ketanserine (see ref. 9), a 5-HT2 serotonin
antagonist drug, and Zopiclone, a recently discovered ansiolytic drug which
acts as a benzodiazepine receptor agonist (see ref. 10).
H
(R)-Ph
H
10
11f
p-FC6H4
p-CH3C6H4
a In all cases, R1 = H, except in entry 5, where R1 = CH3. b b-C10H7 = b-
naphtyl; a-C10H7 = a-naphtyl. c Yield of 7 + 8 crude mixture. d Proportion
7/8 in the crude reaction mixture, as determined through 1H and/or 19F NMR
analysis. e The separation of this mixture was not possible. f Non-
fluorinated derivative.
1 Nucleosides and Nucleotides as Antitumor and Antiviral Agents, ed. C.
K. Chu and D. C.Baker, Plenum Press, New York, 1993.
2 S. Ozaki, Med. Res. Rev., 1996, 16, 51–86.
Table 3 Results for the ring-opening reaction of pyrimidinones 7 and/or 8
with nucleophiles. Synthesis of uracils 3
3 As examples, see: T. Yoshimoto and S. Yuzuru, Eur. Pat. Appl. N°
1122244 A1, 2001; G. Theodoridis and S. Crawford (FMC Corporation,
USA) N° 6277847 B1, 2001; V. Kamesweran, (American Cyanamid
Co. USA) N° 6191275 B1, 2001; K. Yagi, K. Akimoto, N. Mimori, T.
Miyake, M. Kudo, K. Arai and S. Ishii, Pest Manag. Sci., 2000, 56,
65–73.
4 K. Kamata, I. Agata and A. I. Meyers, J. Org. Chem., 1998, 63,
3113–3116.
5 C. C. Kotoris, M.-J. Chen and S. Taylor, J. Org. Chem., 1998, 63,
8052–8057.
6 W. J. Middleton and E. M. Bingham, J. Org. Chem., 1980, 45,
2883–2887.
7 For a review see: L. Cotarca, P. Delogu, A. Nardelli and V. Sunji,
Synthesis, 1996, 553–576.
8 R. Lis, T. K. Morgan, A. J. Marisca, R. P. Gómez, J. M. Lind, D. D.
Davey and G. B. Philips and M.E. Sullivan, J. Med. Chem., 1990, 33,
2883–2891; C. Agami, L. Dechoux, L. Hamon and M. Melaimi, J. Org.
Chem., 2000, 65, 6666–6669 and references cited therein.
9 J. L. Herndon, A. Ismaiel, P. Ingher, M. Teitle and R. A. Glennon, J.
Med. Chem., 1992, 35, 4903–4910.
Entrya R2
RF
Nu
Methodb Yield (%)c
3
1
2
3
4
5
H
H
H
H
H
CF2(b-C10H7) Cl
B
98
80
96
72
95
92
75
91
78
72
78
92
75
80
3a
3b
3c
3d
3e
3f
3g
3h
3i
CF2(a-C10H7) OMe
A
B
A
B
CF2C6H5
Cl
OH
(CF2)6CF3
CF2(b-C10H7) Cl
6
7
8
9
10
11
12
13
14
(R)-Ph CF2(a-C10H7) Cl
Bd
A
B
H
H
H
H
H
2,4-F2C6H3
2,4-F2C6H3
p-CF3C6H4
p-CF3C6H4
p-FC6H4
OH
Cl
OMe
OH
OEt
Cl
A
A
A
Bd
A
B
3j
3k
3m
3n
3o
(R)-Ph p-FC6H4
H
H
p-CH3C6H4
p-CH3C6H4
OAc
Cl
a In all cases, R1 = H, except in entry 5, where R1 = CH3. b Method A:
RONa/ROH, THF, reflux. Method B: HCl/dioxane, THF, rt. c Yield of
purified product. d At 50 °C.
10 S. Noble, H. Langtry and H. M. Lamb, Drugs, 1998, 55, 277–302.
CHEM. COMMUN., 2003, 844–845
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