Novel transformation of 5-cyanouracil derivatives

Article abstract of DOI:10.1016/j.tetlet.2004.09.008

5-Cyano-1-(dihydroxypropyl)-3-methyluracils were synthesized in the reaction of 1-(4-nitrophenyl)-5-cyano-3-methyluracil with appropriate aminodiols. In the aprotic solvents, the reaction proceeds according to the ANRORC type mechanism. In protic solvents the products of Dimroth rearrangement were isolated.

Full text of DOI:10.1016/j.tetlet.2004.09.008

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8007–8009
Novel transformation of 5-cyanouracil derivatives
*
´
Andrzej Gondela, Rafał Gabanski and Krzysztof Walczak
Department of Organic Chemistry, Biochemistry and Biotechnology, Silesian University of Technology,
Krzywoustego 4, 44-100 Gliwice, Poland
Received 31 May 2004; revised 24 August 2004; accepted 2 September 2004
Available online 18 September 2004
Abstract—5-Cyano-1-(dihydroxypropyl)-3-methyluracils were synthesized in the reaction of 1-(4-nitrophenyl)-5-cyano-3-methylura-
cil with appropriate aminodiols. In the aprotic solvents, the reaction proceeds according to the ANRORC type mechanism. In protic
solvents the products of Dimroth rearrangement were isolated.
Ó 2004 Elsevier Ltd. All rights reserved.
Recently we have demonstrated, that 1,3-disubstituted
uracil derivatives possessing an electron-withdrawing
group such as a nitro or carbamoyl group at the 5-posi-
tion can be easily converted into the appropriate 1-
(dihydroxypropyl)-5-substituted uracils when reacted
with aminodiols.1 These compounds can be considered
as potential building blocks in oligonucleotides synthe-
sis. This reaction occurred by an ANRORC mechanism
(Attack of Nucleophile, Ring Opening, Ring Closure).2,3
Investigating the scope and limitations of this transfor-
mation on series of uracil derivatives we examined the
reaction of 5-cyano-1,3-disubstituted uracils with appro-
priate functionalized amino compounds. It is known
that 5-cyano-3-methyl-1-phenyluracil when treated with
primary amines undergoes transformation into 6-amino-
3-methyl-1-phenyl-5-(N-substituted-iminomethyl)uracil,
as a result of a Dimroth type rearrangement.4,5
phenyl)uracil.8 Methylation at N3 was carried out in
DMSO solution using methyl iodide in the presence of
anhydrous potassium carbonate.9
When 1 was treated with 1-amino-2-hydroxypropane 2a
in anhydrous ethanol at room temperature the expected
product of the Dimroth rearrangement, namely 6-amino-
3-methyl-5-(N-2-hydroxypropyl)iminomethyl)-1-(4-nitro-
phenyl)uracil 3 was obtained in 51% yield (Scheme 1).10
Application of anhydrous DMF as a solvent changed
the course of the reaction. When 1 was reacted with
2equiv of 2a at room temperature, the appearance of
the characteristic yellow coloured 4-nitroaniline was
observed. From the reaction mixture the desired 5-
cyano-1-(2-hydroxypropyl)-3-methyluracil 4a was iso-
lated in 86% yield (Scheme 2, Table 1, entry 1).11 Under
the same conditions 1 was treated with several amino
derivatives 2b–e yielding 4b–e in satisfactory yields
(entries 2–5). The structures of all the synthesized com-
pounds were confirmed by NMR spectroscopy and ele-
mental analyses. The structure of 4c was also established
by X-ray analysis (Fig. 1).12
We report here a novel method for the preparation of N
1-alkylated 5-cyanouracil derivatives. The crucial influ-
ence of a solvent on the direction of this reaction is also
considered. The starting 5-cyano-3-methyl-1-(4-nitro-
phenyl)uracil 1 was prepared according to the method
described by Wolfbeis.6 Condensation of (cyanoacet-
yl)urea with 4-nitroaniline and triethoxymethane in
DMSO solution affords (2Z)-N-(aminocarbonyl)-2-
cyano-3-(4-nitrophenylamino)acrylamide.7 The acryl-
amide derivative underwent thermal cyclocondensation
in boiling 1,2-dichlorobenzene giving 5-cyano-1-(4-nitro-
To establish the influence of solvent on the reaction out-
come, the reaction of 1 with 2a was repeated in 2-
hydroxypropane and t-butanol. In such conditions a
mixture of the Dimroth type rearrangement product 3
and ANRORC product 4a was obtained in molar ratios
of 3:1 to 4:1, respectively (total yield 90%). The opposite
ratio (1:5) of rearrangement/ANRORC products was
obtained when the reaction was carried out in DMF
containing 10% (volume) of water (total yield 96%). This
clearly confirms the influence of solvent type on reaction
direction. Based on these results we postulate that after
Keywords: 1-(Dihydroxypropyl)-5-cyanouracils; Aminopropanediols;
Enantiomers.
*
Corresponding author. Tel.: +48 32 237 1792; fax: +48 32 237
2094; e-mail: walczak@polsl.gliwice.pl
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.008

8008
A. Gondela et al. / Tetrahedron Letters 45 (2004) 8007–8009
O
N
H
O
N
H3C
O
H3C
O
CN
OH
CH3
N
N
N
OH
CH3
+
H2N
NH2
EtOH
2a
3
1
NO2
NO2
Scheme 1.
O
N
O
H3C
O
CN
N
H3C
CN
N
+
H2N R
DMF
O
N
R
2a - e
4a - e
1
NO2
Scheme 2.
Table 1. Yields and melting points of 1-(substituted)-5-cyanouracils
Entry Product
R
Yield Mp
(%)
Figure 1. Crystal structure of 4c. Displacement ellipsoids are drawn at
the 50% probability level.
(°C)
1
2
3
4
4a
4b
4c
4d
–CH2CH(OH)CH3 86
(R,S)-CH2CH(OH)CH2OH 6–0115510
108–109
latter more susceptible to attack by the amine nitrogen
atom (Scheme 3, path a) and leads to the product of
the Dimroth rearrangement. In an aprotic solvent, the
attack of the nitrogen atom of the nucleophile occurs
on the carbonyl carbon atom giving the ANRORC prod-
uct (Scheme 3, path b). In conclusion a method for the
synthesis of 5-cyano-1-hydroxyalkyl or dihydroxyalkyl-
uracil derivatives has been described. These compounds
possessing two functional groups (cyano and hydroxyl)
may be useful intermediates in the synthesis of other
uracil derivatives. They can also be considered as poten-
tial building blocks in the synthesis of modified
oligonucleotides.
(R)-CH2CH(OH)CH2OH*
–CH(CH2OH)2
69
64
147–149
175–177
O
5
4e
75
168–169
O
*
½aŠD þ 54 (c 1, MeOH).
addition of the nucleophile (amino derivative) to C6 of
the uracil ring and ring opening, in protic solvents, addi-
tion of a proton to the nitrile nitrogen atom makes the
O
H
C
O
N
H
H3C
N
NHR
H3C
O
R
Path a
N
N
C
N
In protic solvents
O
NH
NH2
H+
O
N
H3C
O
CN
N
NO2
H2N R
NO2
3
O
CN
H3C
N
O
NO2
H3C
O
CN
_
HN
NH
p-NO -C H NH
2
2
6
4
N
O
R
1
N
R
4
Path b
In aprotic solvents
NO2
Scheme 3.

A. Gondela et al. / Tetrahedron Letters 45 (2004) 8007–8009
8009
H-10b), 3.70–3.78 (m, 1H, H-20), 4.65 (d, 1H, J = 4.8Hz,
OH), 6.74 (br s, 1H, NH2), 7.58 (d, 2H, J = 9.0Hz, Ar),
8.39 (s, 1H, CH@N), 8.41 (d, 2H, J = 9.0Hz, Ar), 11.19
(br s, 1H, NH2). 13C NMR (DMSO): d (ppm) 20.98, 27.09,
64.03, 65.94, 85.67, 125.08 (2C), 131.53 (2C), 140.02,
147.90, 149.88, 154.10, 158.47, 161.80. EIMS (m/z) = 347
[M+].
References and notes
1. Gondela, A.; Walczak, K. Tetrahedron Lett. 2003, 44,
7291–7293.
2. Terier, F. Nucleophilic Aromatic Displacement; VCH
Publishers: Cambridge, 1991; pp 402–424.
3. Barczynski, P.; Van der Plas, H. J. Org. Chem. 1982, 47,
1077–1079.
4. Hirota, K.; Sajiki, H.; Kitade, Y.; Maki, Y. Chem. Pharm.
Bull. 1989, 37, 2008–2011.
´
11. Synthesis of 1-alkyl-5-cyano-3-cyanouracils 4a–e (general
procedure): To the solution of amine 2a–e (2mmol) in
anhydrous DMF (10mL), 5-cyano-3-methyl-1-(4-nitro-
phenyl)uracil 1 was added while stirring. The resulting
deep red solution was stirred until the starting uracil had
disappeared (3–12h). The solvent was evaporated under
reduced pressure and the residue was purified by chroma-
tography over silica gel using a mixture of ethyl acetate/n-
hexane (1:1) as eluent. 4-Nitroaniline was eluted first
followed by the 1-alkyl-5-cyano-3-methyluracil derivative.
Compound 4a: 5-Cyano-1-(2-hydroxypropyl)-3-methyl-
5. Hirota, K.; Kitade, Y.; Sajiki, H.; Maki, Y. J. Chem. Soc.,
Perkin Trans. 1 1990, 367–373.
6. Wolfbeis, O. S. Liebigs Ann. Chem. 1982, 182–185.
7. (2Z)-N-(Aminocarbonyl)-2-cyano-3-(4-nitrophenylamino)-
acrylamide: To a solution of cyanoacetylurea (5.0g,
39.4mmol) in DMSO (50mL), ethyl orthoformate
(6.5mL, 39.5mmol) and 4-nitroaniline (6.0g, 44mmol)
were added. The reaction mixture was stirred in an oil
bath at 50–60°C for 24h, then poured into aq methanol
(MeOH–H2O, 1:1, 50mL). The precipitated solid was
filtered off and recrystallized from acetic acid. Yield 7.7g
uracil 1H NMR (DMSO):
d (ppm) 1.09 (d, 3H,
J = 6.0Hz, CH3), 3.19 (s, 3H, N–CH3), 3.48 (dd, 1H,
J = 13.2Hz, 9.2Hz, CH2–Ha), 3.89 – 3.93 (m, 2H, CH2–
Hb, H-20), 5.01 (d, 1H, J = 4.8Hz, OH), 8.58 (s, 1H, H-6).
13C NMR (DMSO): (ppm) 20.28, 27.93, 56.83, 63.32,
86.11, 114.46, 150.03, 153.67, 159.91. EIMS (m/z) = 209
[M+ ].
1
(77%); mp 206–208°C, H NMR (DMSO): d (ppm) 7.28
(br s, 1H, NH2), 7.72 (d, 2H, J = 9.3Hz, Ar), 7.85 (br s,
1H, NH2), 8.26 (d, 2H, J = 9.3Hz, Ar), 8.77 (d, 1H,
J = 12.9Hz, @CH), 10.23 (s, 1H, NH), 10.86 (d, 1H,
J = 12.9Hz, NH–Ph). 13C NMR (DMSO): d (ppm)
115.10, 117.77 (2C), 82.55, 125.12 (2C), 143.04, 145.60,
149.54, 153.93, 164.69.
Compound 4b: (R,S) 5-Cyano-1-(2,3-dihydroxypropyl)-3-
1
methyluracil H NMR (DMSO): d (ppm) 3.19 (s, 3H, N
–CH3), 3.29–3.47 (m, 2H, H-30a, H-3b0 ), 3.51 (dd, 1H,
J = 13.5, 9.3Hz, H-10a), 3.67–3.77 (m, 1H, H-20), 4.10(dd,
1H, J = 13.5Hz, 3.3Hz, H-10b), 4.76 (t, 1H, J = 5.4Hz, 30-
OH), 5.09 (d, 1H, J = 5.7Hz, 20-OH), 8.57 (s, 1H, H-6).
13C NMR (DMSO): d (ppm) 28.64, 54.30, 64.16, 68.87,
86.66, 115.18, 150.63, 154.58, 160.60. Anal. Calcd for
C9H11N3O4 (225.23): %C, 47.99; %H, 4.92; %N, 18.66.
Found: %C, 48.05; %H, 5.02; %N, 18.36. EIMS
(m/z) = 225 [M+].
8. 5-Cyano-1-(4-nitrophenyl)uracil: (2Z)-N-(Aminocarbon-
yl)-2-cyano-3-(4-nitrophenylamino)acrylamide
(5.0g,
18.2mmol) was refluxed in 1,2-dichlorobenzene (120mL)
until TLC (ethyl acetate–n-hexane, 1:1 v/v) indicated
absence of substrate (approx 3h). After cooling to room
temperature, a precipitate formed. The solid was filtered
off, rinsed with n-hexane and recrystallized from MeOH.
1
Yield 4.54g (94%); mp 266–268°C, H NMR (DMSO): d
Compound 4d: 5-Cyano-1-(1,3-dihydroxy-2-propyl)-3-
methyluracil 1H NMR (DMSO): d (ppm) 3.21 (s, 3H,
N–CH3), 3.59–3.75 (m, 4H, CH2-100, CH2-30), 4.52–4.60
(m, 1H, H-20), 4.98 (t, 2H, J = 5.7Hz, OH-10, OH-30), 8.63
(s, 1H, H-6). 13C NMR (DMSO): d (ppm) 28.15, 58.63 (C-
10, C-30), 62.03 (C-20), 86.63, 114.60, 150.46, 151.25,
159.51. Anal. Calcd for C9H11N3O4, (M = 225.23): %C,
47.99; %H, 4.92; %N, 18.66. Found: %C, 47.91; %H, 4.73;
%N, 18.31.
(ppm) 7.80(d, 2H, J = 9.0Hz, Ar), 8.38 (d, 2H, J = 9.0Hz,
Ar), 8.87 (s, 1H, H-6), 12.28 (br s, 1H, NH). 13C NMR
(DMSO): d (ppm) 89.29, 113.99, 124.37, 128.55, 142.93,
147.23, 148.90, 153.83, 160.43.
9. 5-Cyano-3-methyl-1-(4-nitrophenyl)uracil 1: To a suspen-
sion of anhydrous potassium carbonate (0.65g, 5.0mmol)
in anhydrous DMSO (15mL), 5-cyano-1-(4-nitrophen-
yl)uracil was added (1.96g, 9.2mmol). The suspension was
stirred for 30min and methyl iodide (0.6mL, 10mmol) was
added drop wise. After 4h, TLC (ethyl acetate–n-hexane,
1:1 v/v) indicated absence of substrate, the reaction
mixture was poured onto crushed ice (60g) and neutral-
ized with aq 5% HCl. The solid formed was filtered off,
washed with water and n-hexane. The crude product
(1.95g) was recrystallized from a mixture of MeOH and
acetone (1:1). Yield 1.55g (74%); mp 209–210°C (lit. mp
201–203°C),4 1H NMR (DMSO): d (ppm) 3.24 (s, 3H,
Me), 7.78 (d, 2H, J = 9.0Hz, Ar), 8.39 (d, 2H, J = 9.0Hz,
Ar), 8.91 (s, 1H, H-6). 13C NMR (DMSO): d (ppm) 28.11,
88.57, 113.92, 124.39 (2C), 128.51 (2C), 143.28, 147.27,
149.29, 151.99, 159.59.
Compound 4e: 5-Cyano-1-(2,2-dimethyl-[1,3]dioxolane-4-
1
ylmethyl)-3-methyluracil H NMR (CDCl3): d (ppm) 1.35
(s, 3H, CH3), 1.46 (s, 3H, CH3), 3.38 (s, 3H, N–CH3),
3.67–3.80(m, 2H, H-1 a0 , H-30a), 4.15 (dd, 1H, J = 9.0Hz,
6.9Hz, H-30b), 4.23 (dd, 1H, J = 14.1, 2.7Hz, H-10b),
4.35–4.44 (m, 1H, H-20), 7.97 (s, 1H, H-6). 13C NMR
(CDCl3): d (ppm) 24.95, 26.77, 28.76, 52.42, 66.24, 73.22,
89.25, 110.54, 113.23, 150.31, 151.26, 159.27.
12. Crystallographic data for 4c, has been deposited with
Cambridge Crystallographic Data Centre as supplemen-
tary publication number CCDC 240048. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_
request/cif, by e-mailing data_request@ccdc.cam.ac.uk, or
by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44 1223 336033.
10. 6-Amino-3-methyl-5-(N-(2-hydroxypropyl)iminomethyl)-
1-(4-nitrophenyl)uracil 3 1H NMR (DMSO): d (ppm) 1.05
(d, 3H, J = 6.3Hz, 30-CH3), 3.16 (s, 3H, N–CH3), 3.35 (dd,
1H, J = 6.3, 12.3Hz, H-10a), 3.43 (dd, 1H, J = 4.8, 12.3Hz,