Synthesis of 5-(2-hydroxybenzoyl)-1,3-disubstituted uracils

Article abstract of DOI:10.1055/s-0033-1338932

A new synthesis of novel nucleoside analogues is reported. These 5-(2-hydroxybenzoyl)-1,3-disubstituted uracils have been prepared by the coupling of chromone-3-carboxylic acid with carbodiimides, leading to 3-chromone-N-acylureas, which underwent organocatalyzed N-cyclization and chromone ring opening. In the case of ditolylcarbodiimide, the corresponding uracil was obtained by a one-pot, uncatalyzed reaction with chromone-3- carboxylic acid. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1338932

LETTER
▌1147
lSetyternthesis of 5-(2-Hydroxybenzoyl)-1,3-Disubstituted Uracils
5-(2-Hydroxybenzoyl)-1,3-Disubstituted Uracils
Oualid Talhi, Diana C. G. A. Pinto, Artur M. S. Silva*
Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
Fax +351(234)370084; E-mail: artur.silva@ua.pt
Received: 20.02.2013; Accepted after revision: 19.03.2013
tene in acetic acid gives 6-methyl-1,3-disubstituted ura-
cils in good to excellent yields.8a The Baylis–Hillman
reaction has been applied in the synthesis of substituted
uracils through a multistep procedure.8c Interesting results
Abstract: A new synthesis of novel nucleoside analogues is report-
ed. These 5-(2-hydroxybenzoyl)-1,3-disubstituted uracils have
been prepared by the coupling of chromone-3-carboxylic acid with
carbodiimides, leading to 3-chromone-N-acylureas, which under-
went organocatalyzed N-cyclization and chromone ring opening. In were achieved by the microwave activation of metal car-
the case of ditolylcarbodiimide, the corresponding uracil was ob-
tained by a one-pot, uncatalyzed reaction with chromone-3-carbox-
ylic acid.
bene complexes, in particular, in the synthesis of uracil
derivatives, through the reaction of alkynyl alkoxy car-
bene complexes with ureas.8b The synthesis of 1,3-disub-
Key words: chromone derivatives, nucleoside analogues, uracil
analogues, organic synthesis, 2D NMR
stituted uracils was also accomplished in good yields by
the amino-selenenylation of α,β-unsaturated esters and
cyclization with isocyanates, followed by oxidation–elim-
ination of the phenylseleno group.8d
One of the four nucleobases in ribonucleic acid is uracil
Because uracil derivatives exhibit a wide range of biolog-
(U), a naturally occurring pyrimidine derivative that is
ical potential in drug discovery and development, devel-
part of several pharmacologically important molecules
oping reliable synthetic routes for their synthesis remains
(Figure 1). A large and growing body of literature has
of interest. In the present investigation, we describe a sim-
documented investigations on diverse multistage proto-
ple synthetic access to 5-(hydroxybenzoyl)-1,3-disubsti-
cols to prepare 1,3-disubstituted uracils emphasizing their
tuted uracil compounds 4a–c through ring transformation
potent anti-HIV activity.1 The uracil heteronucleus has
of chromone-3-carboxylic acid (1) upon reaction with car-
found further biological applications, and compounds
bodiimides 2a–c. This greener approach avoids multistep
containing this moiety display antiviral,2 anticancer,3 and
procedures and obviates laborious purification steps re-
antimicrobial4 activities, cytotoxicity to cancer cells,5 and
sulting from multicomponent approaches.
various enzyme inhibitory activities, namely for human
Uncatalyzed nucleophilic addition of 1 to the C=N double
bond of carbodiimide 2a and 2b followed by an O→N
acyl shift, led to the isolation of 3-chromone-N-acylureas
3a and 3b (Scheme 1). The reaction proceeds upon heat-
ing to reflux in chloroform for 30 min, to give compounds
3a and 3b in 74 and 80% yields, respectively, after recrys-
tallization from the appropriate solvent.9 This first rapid
step is then followed by N-cyclization and concomitant
chromone ring opening, under organobase-catalysis using
4-pyrrolidinopyridine (4-PPy), leading to the uracil-based
products 4a and 4b (Scheme 1 and Scheme 2). To simpli-
fy the synthetic route, this second step was realized in situ
by adding 4-PPy directly to the first reaction mixture to
transform 3a and 3b into uracil derivatives 4a (64%) and
4b (51%), respectively, without their isolation as interme-
diates.10 Thus, the whole in situ two-step synthetic ap-
proach consists of a ring transformation of chromone-3-
carboxylic acid 1 into uracil 4a and 4b (Scheme 1). This
procedure could be shortened to a one-pot, uncatalyzed
reaction only when reacting the tolyl-substituted carbodi-
imide 2c with acid 1, leading to direct production of the
desired uracil derivative 4c under environmentally friend-
ly conditions, without the formation of any 3-chromone-
N-acylurea or other intermediates. In this case, the reac-
tion was accomplished by heating to reflux in chloroform
for 30 min, affording compound 4c in 77% yield after re-
crystallization from ethanol (Scheme 1).11
deoxyuridine triphosphatase, thymidine phosphorylase
and poly(ADP-ribose)polymerase-1.6 Moreover, uracil
derivatives are increasingly used in cancer treatment, for
instance 5-fluorouracil (5-FLU) is an approved drug and
one of the most potent thymidylate synthase inhibitors
(GI50 = 17.1 µM)7 (Figure 1).
H
N
H
N
O
O
2
6
5
NH
NH
F
4
O
U
O
5-FLU
Figure 1 Structure of uracil (U) and 5-fluorouracil (5-FLU)
Although extensive research has been carried out on the
synthesis of uracil derivatives, this has led to only a few
simple and convenient synthetic routes. Recent literature
reports reveal several multistage and/or chemical con-
suming methods to build the uracil nucleus and its poly-
substituted derivatives.8 A solid-phase condensation of
resin-bound unsymmetrically substituted ureas with dike-
SYNLETT 2013, 24, 1147–1149
Advanced online publication: 08.04.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338932; Art ID: ST-2013-D0163-L
© Georg Thieme Verlag Stuttgart · New York

1148
O. Talhi et al.
LETTER
ylic acid and carbodiimide derivatives to produce 3-chro-
mone-N-acylureas.12 The second step involves ring
transformation of chromone into uracil under organobase-
catalyzed reaction conditions. The whole two-step reac-
tion could be performed in a one-pot procedure without
isolation of 3-chromone-N-acylureas as intermediates.
The reaction of chromone-3-carboxylic acid with ditolyl-
carbodiimide affords the desired uracil derivative in a
green, non-catalyzed synthetic route.
R
O
O
HN
O
O
in situ, two steps
N
CHCl3, reflux, 30 min
R = Cy, i-Pr
R
COOH
O
O
1
3a,b
4-PPy (cat.)
CHCl3, reflux
30 min
+
N
R
C
R
N
R
2a–c
a R = Cy
b R = i-Pr
c R = Tol
Acknowledgment
N
O
O
one step
We would like to thank Fundação para a Ciência e a Tecnologia
(FCT, Portugal), the European Union, QREN, FEDER,
COMPETE, for funding the Organic Chemistry Research Unit
(QOPNA) (project PEst-C/QUI/UI0062/2011) and the Portuguese
National NMR Network (RNNMR). European Community’s
Seventh Framework Programme (FP7/2007-20139 under grant
agreement N° 215009) is also acknowledged for financial support.
N
CHCl3, reflux, 30 min
only when R = Tol
R
OH
O
4a–c
Scheme 1 Synthesis of 5-(2-hydroxybenzoyl)-1,3-disubstituted ura-
cils 4a–c
References and Notes
All compounds were characterized by extensive NMR
spectroscopic analysis (1H, 13C, HSQC and HMBC spec-
tra). These data allowed a distinction between the chro-
mone (3a and 3b) and the uracil (4a and 4b) rings. The
vinylic protons (H-2)/carbons (C-2) of chromones 3a and
3b appear at δ = 8.07–8.08/154.2 ppm, whereas those of
H-6/C-6 of uracils 4a, 4b and 4c appear at δ = 7.69–
7.94/142.5–147.4 ppm, due to the influence of the neigh-
boring electronegative oxygen or nitrogen. Other impor-
tant features that may help to differentiate between these
two types of compounds are the resonances of the NH pro-
tons of compounds 3a and 3b, assigned as a broad signal
or doublet (due to the coupling with the cyclohexyl tertia-
ry proton) at δ = 6.49–6.74 ppm; and the OH protons of
compounds 4a–c, appearing as a singlet at δ = 11.71–
11.79 ppm, due to strong deshielding resulting from an in-
tramolecular hydrogen bond established with the carbonyl
group.
(1) (a) Maruyama, T.; Kozai, S.; Yamasaki, T.; Witvrouw, M.;
Pannecouque, C.; Balzarini, J.; Snoeck, R.; Andrei, G.; De
Clercq, E. Antiviral Chem. Chemother. 2003, 14, 271.
(b) Maruyama, T.; Kozai, S.; Demizu, Y.; Witvrouw, M.;
Pannecouque, C.; Balzarini, J.; Snoeck, R.; Andrei, G.; De
Clercq, E. Nucleic Acids Symp. Ser. 2004, 48, 3.
(c) Maruyama, T.; Kozai, S.; Demizu, Y.; Witvrouw, M.;
Pannecouque, C.; Balzarini, J.; Snoecks, R.; Andrei, G.; De
Clercq, E. Chem. Pharm. Bull. 2006, 54, 325.
(d) Maruyama, T.; Demizu, Y.; Kozai, S.; Witvrouw, M.;
Pannecouque, C.; Balzarini, J.; Snoecks, R.; Andrei, G.; De
Clercq, E. Nucleosides, Nucleotides Nucleic Acids 2007, 26,
1553.
(2) Isono, Y.; Sakakibara, N.; Ordonez, P.; Hamasaki, T.; Baba,
M.; Ikejiri, M.; Maruyama, T. Antiviral Chem. Chemother.
2011, 22, 57.
(3) Torrence, P. F.; Huang, G. F.; Edwards, M. W.; Bhooshan,
B.; Descamps, J.; De Clercq, E. J. Med. Chem. 1979, 22,
316.
(4) McCormick, J. E.; McElhinney, R. S. J. Chem. Soc., Perkin
Trans. 1 1985, 93.
(5) (a) Prachayasittikul, S.; Sornsongkhram, N.; Pingaew, R.;
Worachartcheewan, A.; Ruchirawat, S.; Prachayasittikul, V.
Molecules 2009, 14, 2768. (b) Istanbullu, H.; Zupko, I.;
Alptuzun, V.; Erciyas, E. Turk. J. Chem. 2012, 36, 583.
In summary, we have developed a novel and facile syn-
thetic route to 5-(2-hydroxybenzoyl)-1,3-disubstituted
uracil derivatives. The protocol involves, in the first step,
coupling of commercially available chromone-3-carbox-
R
O
O
O
O
H
N
N
C
N
H
O
O
R
O
N
R
O
R
3
R
N
R
N
H
O
O
O
O
O
R
R
N
N
N
N
R
R
OH
O
O
O
O
O
O
4
H
Scheme 2 Proposed mechanism for the formation of 5-(2-hydroxybenzoyl)-1,3-disubstituted uracils 4a–c
Synlett 2013, 24, 1147–1149
© Georg Thieme Verlag Stuttgart · New York

LETTER
5-(2-Hydroxybenzoyl)-1,3-Disubstituted Uracils
1149
(6) (a) Copik, A.; Suwinski, J.; Walczak, K.; Bronikowska, J.;
Czuba, Z.; Król, W. Nucleosides, Nucleotides Nucleic Acids
2002, 21, 377. (b) Miyakoshi, H.; Miyahara, S.; Yokogawa,
T.; Endoh, K.; Muto, T.; Yano, W.; Wakasa, T.; Ueno, H.;
Chong, K. T.; Taguchi, J.; Nomura, M.; Takao, Y.; Fujioka,
A.; Hashimoto, A.; Itou, K.; Yamamura, K.; Shuto, S.;
Nagasawa, H.; Fukuoka, M. J. Med. Chem. 2012, 55, 6427.
(c) Murray, P. E.; McNally, V. A.; Lockyer, S. D.; Williams,
K. J.; Stratford, I. J.; Jaffar, M.; Freeman, S. Bioorg. Med.
Chem. 2002, 10, 525.
(7) Steinhagen, H.; Gerisch, M.; Mittendorf, J.; Schlemmer, K.
H.; Albrecht, B. Bioorg. Med. Chem. Lett. 2002, 12, 3187.
(8) (a) Wahhab, A.; Leban, J. Tetrahedron Lett. 2000, 41, 1487.
(b) Spinella, A.; Caruso, T.; Pastore, U.; Ricart, S. J.
Organomet. Chem. 2003, 684, 266. (c) Lee, C. G.;
for 30 min. After complete consumption of 1, and formation
of 3a or 3b (TLC), 4-PPy (0.04 g, 0.05 equiv) was added to
the reaction mixture, which was then heated to reflux for a
further 30 min. The solvent was then evaporated to dryness
and the resulting resinous solid was recrystallized from
EtOH to afford compound 4a or 4b.
1,3-Dicyclohexyl-5-(2-hydroxybenzoyl)pyrimidine-
2,4(1H,3H)-dione 4a: Yield: 1.342 g (64%); white solid;
mp 80 °C. 1H NMR (300 MHz, CDCl3): δ = 1.07–2.04 and
2.35–2.48 (m, 20 H, CH2-cyclohexyl), 4.46–4.58 (m, 1 H,
H-1′), 4.84 (tt, J = 12.2, 3.7 Hz, 1 H, H-1′′), 6.85–6.91 (m,
1 H, H-5′′′′), 6.97–7.02 (m, 1 H, H-3′′′′), 7.44–7.53 (m, 2 H,
H-4′′′′, H-6′′′′), 7.71 (s, 1 H, H-6), 11.77 (s, 1 H, 2′′′′-OH).
13C NMR (75 MHz, CDCl3): δ = 24.9, 25.1, 25.5, 26.1, 28.2
and 32.0 (CH2-cyclohexyl), 54.7 (C-1′′), 56.3 (C-1′), 113.0
(C-5), 118.0 (C-3′′′′), 118.5 (C-5′′′′), 119.3 (C-1′′′′), 132.5
(C-6′′′′), 136.5 (C-4′′′′), 143.0 (C-6), 150.3 and 159.8 (C-2,
C-4), 162.4 (C-2′′′′), 195.4 (C-1′′′). MS (ESI+): m/z = 397
[C23H28N2O4 + H]+. Anal. Calcd for C, 69.67; H, 7.12; N,
7.07. Found: C, 69.65; H, 7.11; N, 7.05.
Gowrisankar, S.; Kim, J. N. Bull. Korean Chem. Soc. 2005,
26, 481. (d) Jian, C.; Xian, H. Synth. Commun. 2009, 39,
205.
(9) Synthesis of N,N-Disubstituted (Carbamoyl)-4-oxo-4H-
chromene-3-carboxamide 3a and 3b: Chromone-3-
carboxylic acid 1 (1 g, 5.26 mmol) was added to the
appropriate carbodiimide 2 (5.26 mmol, 1 equiv) in CHCl3
(20 mL) and the reaction mixture was heated to reflux for 30
min. The solvent was evaporated to dryness and the resulting
resinous solid was recrystallized from EtOH to afford
compound 3a. In the case of 3b, the recrystallization solvent
was a mixture of light petroleum and EtOAc (5:1).
N-Cyclohexyl-N-(cyclohexylcarbamoyl)-4-oxo-4H-
chromene-3-carboxamide (3a): Yield: 1.550 g (74%);
white solid; mp 185 °C. 1H NMR (300 MHz, CDCl3): δ =
0.87–2.01 (m, 20 H, CH2-cyclohexyl), 3.40–3.53 (m, 1 H,
H-1′′′), 4.19 (tt, J = 11.7, 3.8 Hz, 1 H, H-1′′), 6.49 (d, J =
7.2 Hz, 1 H, 4′-NH), 7.42–7.53 (m, 2 H, H-6, H-8), 7.73
(ddd, J = 8.7, 7.1, 1.7 Hz, 1 H, H-7), 8.07 (s, 1 H, H-2), 8.22
(dd, J = 8.0, 1.7 Hz, 1 H, H-5). 13C NMR (75 MHz, CDCl3):
δ = 24.4, 25.19, 25.26, 26.0, 30.7 and 32.1 (CH2-
1,3-Diisopropyl-5-(2-hydroxybenzoyl)pyrimidine-
2,4(1H,3H)-dione 4b: Yield: 0.846 g (51%); white solid;
mp 128 °C. 1H NMR (300 MHz, CDCl3): δ = 1.39 (d, J =
6.8 Hz, 6 H, 2′-CH3), 1.51 (d, J = 6.9 Hz, 6 H, 2′′-CH3), 4.95
(sept, J = 6.8 Hz, 1 H, H-1′), 5.24 (sept, J = 6.9 Hz, 1 H, H-
1′′), 6.89 (ddd, J = 8.2, 7.2, 1.2 Hz, 1 H, H-5′′′′), 7.00–7.04
(m, 1 H, H-3′′′′), 7.47–7.54 (m, 2 H, H-4′′′′, H-6′′′′), 7.69 (s,
1 H, H-6), 11.79 (s, 1 H, 2′′′′-OH). 13C NMR (75 MHz,
CDCl3): δ = 19.1 (2′′-CH3), 21.5 (2′-CH3), 46.6 (C-1′′), 48.8
(C-1′), 113.5 (C-5), 118.3 (C-3′′′′), 118.6 (C-5′′′′), 119.4
(C-1′′′′), 132.6 (C-6′′′′), 136.8 (C-4′′′′), 142.5 (C-6), 150.2
and 159.9 (C-2, C-4), 162.7 (C-2′′′′), 195.5 (C-1′′′). MS
(ESI+): m/z = 339 [C17H20N2O4 + Na]+. Anal. Calcd for C,
64.54; H, 6.37; N, 8.86. Found: C, 64.56; H, 6.40; N, 8.90.
(11) Synthetic Procedure for 1,3-Ditolyl-5-(2-hydroxy-
benzoyl)pyrimidine-2,4(1H,3H)-dione (4c): Chromone-3-
carboxylic acid 1 (1 g, 5.26 mmol) was added to
ditolylcarbodiimide 2c (1.17 g, 5.26 mmol, 1 equiv) in
chloroform (20 mL) and the reaction mixture was heated to
reflux for 30 min. The solvent was then evaporated to
dryness and the resulting resinous solid was recrystallized
from ethanol to afford 4c. Yield: 1.682 g (77%); yellowish
white solid; mp 224 °C. 1H NMR (300 MHz, CDCl3): δ =
2.39 and 2.40 (s, 6 H, 4′/4′′-CH3, tolyl), 6.88 (ddd, J = 8.1,
7.2, 1.0 Hz, 1 H, H-5′′′′), 7.00 (dd, J = 8.4, 1.0 Hz, 1 H,
H-3′′′′), 7.17–7.20 (m, 8 H, H-2′/2′′,6′/6′′ and H-3′/3′′,5′/5′′),
7.48 (ddd, J = 8.4, 7.2, 1.6 Hz, 1 H, 4′′′′), 7.66 (dd, J = 8.1,
1.6 Hz, 1 H, H-6′′′′), 7.94 (s, 1 H, H-6), 11.71 (s, 1 H, 2′′′′-
OH). 13C NMR (75 MHz, CDCl3): δ = 21.1 and 21.2 (4′/4′′-
CH3,), 114.3 (C-5), 118.1 (C-3′′′′), 118.8 (C-5′′′′), 119.3
(C-1′′′′), 126.0 and 127.8 (C-2′/2′′,6′/6′′), 130.0 and 130.2
(C-3′/3′′,5′/5′′), 131.6 (C-1′′), 132.8 (C-6′′′′), 135.8 (C-1′),
136.9 (C-4′′′′), 139.0 and 139.6 (C-4′/4′′), 147.4 (C-6), 150.3
and 160.0 (C-2, C-4), 162.7 (C-2′′′′), 194.6 (C-1′′′). MS
(ESI+): m/z = 435 [C25H20N2O4 + Na]+. Anal. Calcd for C,
72.80; H, 4.89; N, 6.79. Found: C, 72.85; H, 4.91; N, 6.79.
(12) The described method allowed the synthesis of only 1,3-
disubstituted uracil derivatives, and depends upon the range
of carbodiimide derivatives and chromone-3-carboxylic
acids available.
cyclohexyl), 49.7 (C-1′′′), 55.7 (C-1′′), 118.3 (C-8), 123.9
(C-3), 124.1 (C-10), 125.9 (C-6, C-5), 134.5 (C-7), 153.2
(C-3′), 154.2 (C-2), 156.1 (C-9), 162.3 (C-1′), 175.4 (C-4).
MS (ESI+): m/z = 419 [C23H28N2O4 + Na]+. Anal. Calcd for
C, 69.67; H, 7.12; N, 7.07. Found: C, 69.69; H, 7.14; N, 7.07.
N-Isopropyl-N-(isopropylcarbamoyl)-4-oxo-4H-
chromene-3-carboxamide (3b): Yield: 1.324 g (80%);
white solid; mp 137–138 °C. 1H NMR (300 MHz, CDCl3):
δ = 0.99 (d, J = 6.6 Hz, 6 H, 2′′′-CH3), 1.42 (d, J = 6.8 Hz,
6 H, 2′′-CH3), 3.72–3.89 (m, 1 H, H-1′′′), 4.50 (sept, J =
6.8 Hz, 1 H, H-1′′), 6.74 (br s, 1 H, 4′-NH), 7.42–7.54 (m,
2 H, H-6, H-8), 7.74 (ddd, J = 8.6, 7.1, 1.7 Hz, 1 H, H-7),
8.08 (s, 1 H, H-2), 8.23 (dd, J = 8.0, 1.7 Hz, 1 H, H-5). 13
C
NMR (75 MHz, CDCl3): δ = 20.7 (2′′-CH3), 21.9 (2′′′-CH3),
42.8 (C-1′′′), 48.8 (C-1′′), 118.3 (C-8), 124.1 (C-3), 124.2
(C-10), 126.0 (C-6, C-5), 134.5 (C-7), 153.2 (C-3′), 154.2
(C-2), 156.1 (C-9), 163.4 (C-1′), 175.1 (C-4). MS (ESI+):
m/z = 339 [C17H20N2O4 + Na]+. Anal. Calcd for C, 64.54; H,
6.37; N, 8.86. Found: C, 64.51; H, 6.34; N, 8.84.
(10) Synthesis of 1,3-Disubstituted-5-(2-hydroxybenzoyl)-
pyrimidine-2,4(1H,3H)-dione 4a and 4b: Chromone-3-
carboxylic acid 1 (1 g, 5.26 mmol) was added to the
appropriate carbodiimide 2a–b (5.26 mmol, 1 equiv) in
CHCl3 (20 mL). The reaction mixture was heated to reflux
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1147–1149

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.