An efficient synthesis of 1-substituted uracil ring systems and their thio analogues

Article abstract of DOI:10.1055/s-2005-917114

A facile and simple regioselective synthesis of uracils and their thio analogues has been achieved by cyclocondensation of a common precursor, diazadienium iodide 1, and isothiocyanates 2a,b. The key step in this synthetic process is the preparation of 4-

Full text of DOI:10.1055/s-2005-917114

LETTER
2805
An Efficient Synthesis of 1-Substituted Uracil Ring Systems and Their Thio
Analogues
S
ynthesis of 1-Sub
é
stituted Ura
l
cil Rin
i
g
Syst
gs
Robin, Karine Julienne, Sophie Raimbault, Jean-Claude Meslin, David Deniaud*
Laboratoire de Synthèse Organique, UMR CNRS 6513, FR 2465Faculté des Sciences et des Techniques, 2, rue de la Houssinière, BP 92208,
44322 Nantes Cedex 3, France
Fax +33(2)51125402; E-mail: david.deniaud@chimie.univ-nantes.fr
Received 21 July 2005
The hetero-Diels–Alder methodology employing aza-
Abstract: A facile and simple regioselective synthesis of uracils
dienes represents a straightforward and an efficient
and their thio analogues has been achieved by cyclocondensation of
a common precursor, diazadienium iodide 1, and isothiocyanates
2a,b. The key step in this synthetic process is the preparation of 4-
approach to nitrogen-containing six-membered hetero-
cycles.8 In the course of our ongoing research, we recently
methylsulfanylpyrimidine-2-thiones 3a,b, which after further elab- reported that the cyclisation of the azadiene salt 1 with
oration gave the expected uracil analogues 4a,b–8a,b.
glycosylisothiocyanates, in the presence of a base, is a
very convenient method for the preparation of nucleo-
sides.9 We present here a methodology for the preparation
of 1-substituted uracil ring systems and their thio- and
dithio analogues based on [4+2] cyclocondensation
followed by nucleophilic substitution on the obtained
methylsulfanylpyrimidinethiones (Scheme 1). Indeed,
alkylsulfanylpyrimidines are useful intermediates in the
synthesis of highly substituted uracil analogues by nu-
cleophilic substitution reactions.10 With the aim of
investigating the synthesis of uracil derivatives, it would
be interesting to develop a simple process involving
heterocyclic ring formation from methyl or phenylisothio-
cyanate 2a,b and, a common precursor, diazadienium
iodide 1 (Scheme 1).
Key words: cycloadditions, uracil analogues, pyrimidine, sulfur,
heterocycles
Substituted uracils and their thio analogues represent an
important class of organic molecules that have attracted a
great deal of attention in synthetic organic chemistry as
well as in medicinal chemistry because of their antiviral
and anticancer activities.1 Particularly, thioxo derivatives
have shown a diverse range of biological properties such
as hyperthyroidism, anticarcinogenic, cardiovascular and
antihypertensive activities.2 Among uracil ring systems,
DABOs, HEPT and its analogues have been reported to be
active as inhibitors of HIV-1 reverse transcriptase.3 Nu-
merous methods for the synthesis of a wide variety of
uracil derivatives have been described in the literature in-
volving multi-step reactions either via rearrangements,4
ring synthesis,5 or regioselective 1-alkylation of uracil.
The most general pyrimidine-2,4-diones and their thioxo
derivatives synthesis involves the combination of a 1,3-di-
carbonyl component with a N–C–N fragment, such as
urea, thiourea, amidine and their analogues.6 On the other
hand, 1-substituted uracils can be prepared via reaction of
primary amines with 3-ethoxyacryloylisocyanate which
offers a method particularly suitable for complex amines.7
The biological properties of uracils and their thio ana-
logues prompted us to investigate the new and general
synthesis of these heterocycles (4–8).
The starting diazadienium iodide 1 was obtained in two
steps in good yield by sulfhydration of 3-dimethylami-
noacrylonitrile followed by methylation of the vinylthio-
amide intermediate.9,11 Iodide 1 reacted with phenyl or
methylisothiocyanate to give methylsulfanylthiouracils
3a and 3b, respectively, in good yields. The probable
mechanism for the formation of pyrimidinethiones 3a,b is
outlined in Scheme 2. It is assumed that the reaction of
diazadienium iodide 1 with isothiocyanates 2a,b involves
a regioselective [4+2] cycloaddition reaction leading to an
intermediate, which, in the presence of triethylamine,
undergoes elimination of dimethylamine yielding uracil
analogues 3a,b.12
S
4a,b X = S, Y =S
5a,b X = S, Y =O
7a,b X = O, Y =S
8a,b X = O, Y =O
H
1
, HI
HN
N
S
R
N
SMe
3a,b
X
R
N
Y
+
N
N
N
C
S
2a,b
R
R = Ph (a) or Me (b)
uracil, thio and dithio analogues
Scheme 1
SYNLETT 2005, No. 18, pp 2805–2807
0
3
.1
1
.2
0
0
5
Advanced online publication: 10.10.2005
DOI: 10.1055/s-2005-917114; Art ID: G23305ST
© Georg Thieme Verlag Stuttgart · New York

2806
A. Robin et al.
LETTER
H
N
literature we never observed oxidation of the methyl-
sulfide to sulfoxide or sulfone, and methylthiouracils 6a,b
were obtained with good yield (Scheme 3).16 Of course,
derivative 6a could be obtained in one step from phenyl-
isocyanate but our goal was to develop a general strategy
for the synthesis of pyrimidine-2-thiones. Furthermore,
isothiocyanates are more commercially available and less
toxic than isocyanate derivatives. For example, since the
Bhopal tragedy in 1984, it is not possible to purchase
methylisocyanate for the synthesis of compound 6b in one
step.
S
S
NH
S
R
SMe
C
N
iii
(– HI)
N
R
+
N
N
HI,
1
2a,b
(– Me2NH)
N SMe
i, ii
S
CN
N
R
The treatment of compounds 6a,b with hydrogen sulfide
or alcoholic potassium hydroxide resulted in good yields
of 4-thiouracils 7a,b and 8a,b derivatives, respectively
(Scheme 3). The structural assignments of products 7 and
8 were based on analytical data and spectral evidence.17
3a,b
N
Scheme 2 Reagents and conditions: (i) H2S, py–Et3N, 48h, r.t.,
79%; (ii) MeI, THF, 18 h, r.t., 96%; (iii) Et3N, CH2Cl2, 6 h, r.t. for 3a,
70%, 4 h, r.t. for 3b, 69%.
Thus, simple and elegant protocols for the synthesis of 1-
N-substituted uracil ring systems and their thio analogues
have been developed starting from the 4-methylsulfanyl-
pyrimidine-2-thiones 3a,b. The process is applicable to
various isothiocyanates, and extensions of these reactions
are currently under investigation in our laboratory.
The reactivity of the methylsulfanyl group of 3a,b to-
wards displacement by O- and S-nucleophiles makes it an
attractive alternative for the preparation of N-substituted
(thio)uracils.13 Thus, treatment of pyrimidine-2-thiones
3a,b with gaseous H2S under basic conditions for two
hours at room temperature provided the desired di-
thiouracils 4a,b by addition–elimination sequence and
loss of methanethiol (Scheme 3). In the same way,
methylsulfanyl derivatives 3a,b were easily transformed
to 2-thiouracils 5a,b by treatment with a 1 M solution of
KOH in ethanol at reflux for four hours.
Acknowledgment
The authors are grateful to the French Ministry of Education and the
CNRS for financial support.
References
H
N
H
N
S
R
N
SMe
S
R
S
S
R
O
i
ii
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N
N
N
3a,b
4a,b
5a,b
dithiouracil
2-thiouracil
iii
H
H
N
O
R
N
SMe
O
N
O
O
R
S
iv
v
N
N
N
R
8a,b
6a,b
7a,b
4-thiouracil
uracil
Scheme 3 Reagents and conditions: (i) H2S, py–Et3N, 2 h, r.t., 70%
for 4a, 75% for 4b; (ii) KOH/EtOH 1 M, 4 h, 100 °C then HCl 6 M,
0.5 h, r.t., 76% for 5a, 98% for 5b; (iii) Oxone®, wet Al2O3, CH2Cl2,
48 h, r.t., 73% for 6a, 78% for 6b; (iv) H2S, py–Et3N, 2 h, r.t., 76%
for 7a, 64% for 7b; (v) KOH/EtOH 1 M, 4 h, 100 °C then HCl 6 M,
0.5 h, r.t., 70% for 8a, 74% for 8b.
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Synthesis 2000, 695. (e) Landreau, C.; Deniaud, D.;
Reliquet, A.; Reliquet, F.; Meslin, J. C. J. Heterocycl. Chem.
2001, 38, 93.
In order to expand the versatility of these processes and to
introduce diversity in the target uracils accessible from
methylsulfanylpyrimidinethiones 3a,b, we set out to in-
vestigate the conversion of their thiocarbonyl to carbonyl
functionality. The different reagents used for this transfor-
mation have been met with varying degrees of success,
each having different limitations and giving different side
reactions.14 The most efficient method for achieving 6a,b
involved the use of Oxone® and wet alumina in dichlo-
romethane.15 In contrast to the method developed in the
(6) (a) Joule, J. A.; Mills, K. In Heterocyclic Chemistry, 4th ed.;
Mead, O., Ed.; Blackwell Science: Oxford, 2000.
(b) Stanovnik, B.; Svete, J. Chem. Rev. 2004, 104, 2433.
Synlett 2005, No. 18, 2805–2807 © Thieme Stuttgart · New York

LETTER
Synthesis of 1-Substituted Uracil Ring Systems
2807
(7) Hronowski, L. J. J.; Szarek, W. A. Can. J. Chem. 1985, 63,
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(14) (a) Masuda, R.; Hojo, M.; Ichii, T.; Sasano, S.; Kobayashi,
T.; Kuroda, C. Tetrahedron Lett. 1991, 32, 1195.
(b) Mohammadpoor-Baltork, I.; Khodaei, M. M.; Nikoofar,
K. Tetrahedron Lett. 2003, 44, 591.
(15) (a) Mohammadpoor-Baltork, I.; Sadeghi, M. M.;
Esmayilpour, K. Phosphorus, Sulfur Silicon Relat. Elem.
2003, 178, 61. (b) Greenhalgh, R. P. Synlett 1992, 235.
(16) Methylthiouracils 6.
(8) (a) Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P.
Tetrahedron 2002, 58, 379. (b) Abbiati, G.; Cirrincione de
Carvalho, A.; Rossi, E. Tetrahedron 2003, 59, 7397.
(c) Mohan, C.; Kumar, V.; Mahajan, M. P. Tetrahedron Lett.
2004, 45, 6075. (d) Jayakumar, S.; Singh, P.; Mahajan, M.
P. Tetrahedron 2004, 60, 4315. (e) Landreau, C.; Deniaud,
D.; Meslin, J. C. J. Org. Chem. 2003, 68, 4912.
(f) Landreau, C.; Deniaud, D.; Reliquet, A.; Meslin, J. C.
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(9) Pearson, M. S. M.; Robin, A.; Bourgougnon, N.; Meslin, J.
C.; Deniaud, D. J. Org. Chem. 2003, 68, 8583.
Oxone® (1.23 g, 2.0 mmol) and wet alumina (1.0 g) were
added to a solution of methylsulfanylpyrimidinethiones (1.0
mmol) in CH2Cl2 (15 mL). The reaction mixture was stirred
at r.t. for 48 h. Then, the inorganic salts were removed by
filtration and the filtrate was concentrated under vacuum.
The residue was purified by chromatography on silica gel
(CH2Cl2–PE–Et3N, 90:7:3).
(10) Herrera, A.; Martinez-Alvarez, R.; Ramiro, P. Tetrahedron
2003, 59, 7331.
(11) (a) Robin, A.; Meslin, J. C.; Deniaud, D. Synthesis 2004,
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Tetrahedron Lett. 2004, 45, 9557.
Spectroscopic data of compound 6a: IR (KBr): n = 1664,
1614, 1493, 1287 cm–1. 1H NMR (200 MHz, CDCl3):
d = 2.52 (s, 3 H, CH3S), 6.22 (d, 1 H, 3J = 7.0 Hz, CH-5),
7.28 (m, 6 H, 5 × CHar and CH-6). 13C NMR (50 MHz,
CDCl3): d = 13.0 (CH3S), 103.7 (CH-5), 126.1 (2 × CHar),
128.7 (CHar), 129.5 (2 × CHar), 140.3 (Car), 144.0 (CH-6),
153.9 (CO), 178.6 (C-4). Mp 156–158 °C. HRMS (ESI+):
m/z calcd for C11H10N2OSNa [M + Na]+: 241.0412; found:
241.0410.
(12) Methylsulfanylpyrimidinethiones 3.
Isothiocyanate (2.2 mmol) was added to a solution of
diazadienium iodide 1 (272 mg, 1.0 mmol) in CH2Cl2 (10
mL). After 15 min, Et3N (300 mL, 2.2 mmol) was added and
the reaction mixture was stirred at r.t. over a period of 4 h for
3a and 4 h for 3b. Then, the organic mixture was washed
twice with H2O, dried over MgSO4 and concentrated under
vacuum. The residue was purified by chromatography on
silica gel (CH2Cl2–PE–Et3N, 50:47:3).
Spectroscopic data of compound 3a: IR (KBr): n = 1605,
1589, 1481, 1405, 1323, 1175 cm–1. 1H NMR (200 MHz,
CDCl3): d = 2.66 (s, 3 H, CH3S), 6.60 (d, 1 H, 3J = 7.0 Hz,
CH-5), 7.40 (m, 5 H, 5 × CHar), 7.43 (d, 1 H, 3J = 7.0 Hz,
CH-6). 13C NMR (50 MHz, CDCl3): d = 13.2 (CH3S), 107.7
(CH-5), 126.6 (2 × CHar), 129.3 (CHar), 129.9 (2 × CHar),
144.0 (2 C, CH-6 and Car), 173.4 (C-4), 182.0 (CS). Mp 173–
175 °C. HRMS (ESI+): m/z calcd for C11H10N2S2Na [M +
Na]+: 257.0183; found: 257.0182.
(17) Spectroscopic data of compound 7b: IR (KBr): n = 1742,
1734, 1719, 1630, 1325, 1109 cm–1. 1H NMR (400 MHz,
DMSO-d6): d = 3.25 (s, 3 H, CH3N), 6.22 (d, 1 H, 3J = 6.8
Hz, CH-5), 7.53 (d, 1 H, 3J = 6.8 Hz, CH-6). 13C NMR (50
MHz, DMSO-d6): d = 36.0 (CH3N), 111.7 (CH-5), 142.4
(CH-6), 148.8 (CO), 190.1 (CS). Mp 193–196 °C. HRMS
(ESI+): m/z calcd for C5H6N2SONa [M + Na]+: 165.0099;
found: 165.0098.
Spectroscopic data of compound 8b: IR (KBr): n = 1695,
1423, 1379, 1331. 1H NMR (400 MHz, DMSO-d6): d = 3.21
(s, 3 H, CH3N), 5.51 (d, 1 H, 3J = 8.0 Hz, CH-5), 7.60 (d, 1
H, 3J = 8.0 Hz, CH-6). 13C NMR (50 MHz, DMSO-d6):
d = 34.4 (CH3N), 99.7 (CH-5), 145.6 (CH-6), 150.5 (CO-2),
163.1 (CO-4). Mp 229–234 °C. HRMS (ESI+): m/z calcd for
C5H6N2O2Na [M + Na]+: 149.0327; found: 149.0325.
(13) (a) Hori, M.; Kataoka, T.; Shimizu, H.; Imai, E.; Yokomoto,
M.; Ando, Y. Synthesis 1987, 278. (b) Tea-Gokou, C.;
Pradère, J. P.; Bujoli, B.; Quiniou, H.; Toupet, L. Bull. Soc.
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Synlett 2005, No. 18, 2805–2807 © Thieme Stuttgart · New York