N- vs. S-PTC alkylation of 5-carboethoxy-2-thiouracil and its reactivity towards some nucleophilic reagents

Article abstract of DOI:10.1080/714040963

The reactivity of 5-carboethoxy-2-thiouracil (1) toward alkylation by different organohalogen compounds under phase-transfer catalysis (PTC) conditions has been investigated to give S-monoalkylated products and/or simultaneous S- and N-dialkylated product

Full text of DOI:10.1080/714040963

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Phosphorus, Sulfur, and Silicon and the Related
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N- vs. S-PTC Alkylation of 5-Carboethoxy-2-thiouracil
And Its Reactivity Towards Some Nucleophilic Reagents
a
a
a
a
a
M. A. Hassan , M. M. Mohamed , S. A. Shiba , M. K. Abou El-Regal & A. Khalil
a
Ain Shams University, Cairo, Egypt
Published online: 18 Jun 2010.
To cite this article: M. A. Hassan , M. M. Mohamed , S. A. Shiba , M. K. Abou El-Regal & A. Khalil (2003) N- vs. S-PTC
Alkylation of 5-Carboethoxy-2-thiouracil And Its Reactivity Towards Some Nucleophilic Reagents, Phosphorus, Sulfur, and
Silicon and the Related Elements, 178:11, 2497-2504, DOI: 10.1080/714040963
To link to this article: http://dx.doi.org/10.1080/714040963
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Phosphorus, Sulfur, and Silicon, 178:2497–2504, 2003
Copyright ꢀC Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500390247953
N- vs. S-PTC ALKYLATION OF 5-CARBOETHOXY-2-
THIOURACIL AND ITS REACTIVITY TOWARDS
SOME NUCLEOPHILIC REAGENTS
M. A. Hassan, M. M. Mohamed, S. A. Shiba,
M. K. Abou El-Regal, and A. Khalil
Ain Shams University, Cairo, Egypt
(
Received May 4, 2003; accepted June 24, 2003)
The reactivity of 5-carboethoxy-2-thiouracil (1) toward alkylation by
different organohalogen compounds under phase-transfer catalysis
(
PTC) conditions has been investigated to give S-monoalkylated prod-
ucts and/or simultaneous S- and N-dialkylated products. Also, nu-
cleophilic additions of methylmagnesium iodide, hydroxylamine, and
hydrazine to 5-carbethoxy-2-thiouracil (1) have been investigated. The
structures of all products have been confirmed by elemental analysis
and spectral data.
Keywords: 5-Carboethoxy-2-thiouracil; phase-transfer catalysis (PTC);
pyrimidothiazine; thiazolopyrimidine
In continuation of our interests1 and reported PTC–alkylation
−4
5−8
of some heterocyclic compounds, we study the reactivity of N-versus
S-alkylation of 5-carboethoxy-2-thiouracil under phase-transfer catal-
ysis conditions.
On the other hand, we synthesize some new 2-alkylthiouracil deriva-
tives by a versatile method that might add new biological activities to
9
10
their reported medicinal applications, recently, as antithyroids. Also,
we synthesize some new condensed pyrimidines in addition to an anal-
1
1
ogous compounds with potential medicinal interest.
RESULTS AND DISCUSSION
5
-Carboethoxy-2-thiouracil (1) exists in two major tautomeric forms,
(
A) and (B); the keto–form (A) is the predominant one. This phenomena
Address correspondence to M. A. Hassan, Chemistry Department, Faculty of Sci-
ence, King Abdulaziz University, PO Box 80203, Jeddah 21589, Saudi Arabia. E-mail:
mahassan77@yahoo.com
2
497

2
498
M. A. Hassan et al.
is confirmed by spectral data in addition to our results of PTC–
alkylation which are afforded S-monoalkylated products and/or S- and
N-dialkylated products but no O-alkylated product is obtained.
The proper applied PTC reaction conditions as a general pro-
cedure of alkylation of 5-carboethoxy-2-thiouracil (1) by haloor-
ganic compounds4
,12,13
are benzene/anhydrous potassium carbonate as
liquid/solid phases and tetrabutylammonium bromide (TBAB) as cata-
◦
lyst with continuous efficient stirring for 4-6 h at 70 C.
Treatment of 5-carboethoxy-2-thiouracil (1) with n-butyl bromide or
chloroacetonitrile in 1:3 molar ratio, respectively, under the optimized
PTC conditions afforded, exclusively, S-monoalkylation to give ethyl
2
-(n-butylthio)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (2a) or ethyl
2-[(cyanomethyl)thio]-6 oxo- 1,6-dihydropyrimidine-5-carboxylate (2b)
(
Scheme 1).
SCHEME 1

Carboethoxy Thiouracil
2499
Methylation of 5-carboethoxy-2-thiouracil (1) by methyl iodide
under the same PTC reaction conditions underwent simultaneous
S- and N-dimethylation to give ethyl 1-methyl-2-(methylthio)-6-oxo-1,6-
dihydropyrimidine-5-carboxylate (3a) (Scheme 1). Also, benzylation of
thiouracil (1) by benzyl bromide under the same optimized PTC reac-
tion conditions afforded a mixture of S-monobenzylated product, ethyl
2
-(n-benzylthio)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (2c) and
S- and N-dibenzylated product, ethyl 1-benzyl-2-(benzylthio)-6-oxo-1,6-
dihydro-pyrimidine-5-carboxylate (3b) in 1:3 yield ratio, which are
separated by column chromatography (Scheme 1). Benzylsulfanylth-
iouracil (2c) was previously14 synthesized by a multi-step procedure in
a mild yield.
On the other hand, treatment of an equimolar amounts of 5-carbo-
ethoxy-2-thiouracil (1) with 1,2-dibromoethane or 1,3-dibromopropane
under the same optimized phase-transfer catalysis conditions under-
went simultaneous S- and N-cycloalkylation to give ethyl 5-oxo-2,3-
dihydro-5H-[1,3]thiazolo[3,2-a]-pyrimidine-6-carboxylate (4a) or ethyl
6
-oxo-3,4-dihydro-2H,6H-pyrimido[2,1-b][1,3]thiazine-7-carboxylate
(
4b) respectively (Scheme 1). Also, an equimolar amounts of ethyl bro-
moacetate and 5-carboethoxy-2-thiouracil (1) under the optimized PTC
reaction conditions underwent, simultaneous, S- and N-cycloalkylation
to give ethyl 3,5-dioxo-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]-pyrimidine-
6
-carboxylate (5) (Scheme 1).
5
-Carboethoxy-2-thiouracil (1) is considered as an. α,.β-unsaturated
ester, which is reacted with excess methylmagnesium iodide in dry ether
via Michael route addition reaction to give ethyl 2-mercapto-4-methyl-
6
-oxo-1,4,5,6-tetra-hydropyrimidine 5-carboxylate (6) (Scheme 2).
Treatment of 5-caroethoxy-2-thiouracil (1) with nitrogen nucle-
ophiles such as hydroxylamine or hydrazine hydrate underwent
nucleophilic displacement of the mercapto group to give ethyl
2-hydroxylamino-6-oxo-1,6-dihydro-pyrimidine-5-carboxylate (7a) or
ethyl 2-hydrazino-6-oxo-1,6-dihydropyrimidine-5-carboxylate (7b) re-
spectively (Scheme 2).
SCHEME 2

2
500
M. A. Hassan et al.
EXPERIMENTAL
Melting points reported are uncorrected. IR spectra were recorded on
Pye-Unicam SP 2000 spectrophotometer and Maltson-1000 series FT-
IR spectrophotometer using KBr Wafer technique. The NMR spectra
were recorded by Varian Nova 500, using TMS as internal standard and
CDCl3 as solvent. The chemical shifts are recorded on δ-scale in ppm.
The mass spectra were measured by AMD 604 spectrophotometer us-
ing single focusing mass spectrometer with direct inlet at beam energy
7
0 eV. Elemental analysis was estimated by a Carlo-Erba 1106 C,H,N
analyzer. The key starting 5-carbethoxy-2-thiouracil is an Aldrich prod-
uct No. 85, 525-1 and was used without further purification.
PTC-Alkylation of 5-Carboethoxy-2-thiouracil (1)
General Procedure
To a solution of 5-carboethoxy-2-thiouracil (1) (2.0 g, 0.01 mol) in
dry benzene (50 ml), anhydrous K2CO3 (2.7 g, 0.02 mol) and tetra-
butylammonium bromide (TBAB) (0.003 mol), the organic monohalo-
gen compounds (0.03 mol), such as n-butyl bromide, chloroacetonitrile,
methyl iodide, and benzyl bromide, and organic dihalogen compounds
such as 1,2-dibromoethane and 1,3-dibromopropane or ethyl bromoac-
etate (0.01 mol) was added in round-bottom flask fitted with condenser
◦
and kept at 70 C. The reaction mixture was stirred vigorously and con-
trolled by TLC over the reaction period. At the end of the reaction, the
benzene layer was separated by filtration and the solvent was evapo-
rated, then the residue was triturated with Pet. Ether 60-80 to release
the excess of unreacted halogen compound. The residue was crystallized
from the suitable solvent to give 2–5. The K2CO3 residue was dissolved
in water (50 ml) and acidified by hydrochloric acid (15% solution) to
confirm if an acidic by-product also existed. In all cases, there is no by-
product isolated from the K2CO3 residue. The physical data and yield
%
of the products 2–5 are listed in Table I and the spectral data are
listed in Table II.
Addition of methylmagnesium iodide on 5-carboethoxy-2-thiouracil
1).
(
Formation of ethyl 2-mercapto-4-methyl-6-oxo-1,4,5,6-tetrahydro-
pyrimidine-5-carboxylate (6). To a suspension of 5-carboethoxy-2-
thiouracil (1) (2.0 g, 0.01 mol) in dry ether (50 ml), a methylmagnesium
iodide (0.05 mol) in dry ether (50 ml) was added dropwise with stir-
ring. After complete addition, the solution was refluxed on water bath
for 3 h and then poured onto cold ammonium chloride solution (40 ml,

Carboethoxy Thiouracil
TABLE I Physical Data of Compounds 2–7
2501
Elemental analysis
calcd./found
◦
Comp.
no.
m.p. C
Solvent of
cryston (yield %)
Mol. form.
(m. wt.)
(color)
C
H
N
2
2
2
3
3
4
4
5
6
7
7
a
b
c
128–130
Pet.ether
(48)
Ethanol
(58)
Pet.ether
(12)
Pet.ether
(71)
Pet.ether
(42)
Ethanol
(76)
Benzene
(62)
Ethanol
(53)
C11H16N2O3S
(256.32)
C9H9N3O3S
(239.25)
C14H14N2O3S
(290.34)
C9H12N2O3S
(228.26)
C21H21N2O3S
(381.45)
C9H10N2O3S
(226.24)
C10H12N2O3S
(240.27)
C9H8N2O4S
(240.23)
51.50
51.27
45.14
45.06
57.87
57.75
47.31
47.43
66.14
66.08
47.79
47.62
49.94
49.78
44.99
44.84
44.44
44.31
42.21
42.08
42.42
42.33
6.24
6.08
3.76
3.65
4.82
4.74
5.26
5.33
5.51
5.54
4.42
4.37
4.99
4.93
3.33
3.27
5.56
5.48
4.52
4.50
5.05
4.93
10.92
10.85
17.55
17.64
9.64
(
white)
170–172
pale yellow)
88–90
(
(
(
(
white)
9.55
a
b
a
b
97–99
pale yellow)
107–108
12.27
12.16
7.35
(
white)
7.50
174–176
pale yellow)
108–110
12.38
12.35
11.65
11.57
11.67
11.33
12.96
12.84
21.11
21.15
28.28
28.35
(
yellow)
218
(
red)
138–140
Benzene
(67)
Ethanol
(85)
Ethanol
(81)
C8H12N2O3S
(216.25)
C7H9N3O4
(199)
C7H10N4O3
(198)
(
white)
256
a
b
(
(
yellow)
230
yellow)
3
0% solution). The organic layer was separated, dried with anhydrous
Na2SO4, and the solvent was evaporated. The solid residue was crys-
tallized to give methylcarboethoxypyrimidine (6). The results are listed
in Tables I and II.
Reaction of hydroxylamine with 5-carboethoxy-2-thiouracil (1).
Formation of ethyl 2-hydroxylamino-6-oxo-1,6-dihydropyrimidine-5-
carboxylate (7a). A solution of thiouracil (1) (2.0 g, 0.01 mol) and hy-
droxylamine hydrochloride (0.8 g, 0.011 mol) in pyridine (30 ml) was
refluxed for 3 h and then poured onto crushed ice (100 g). The solid
product was filtered off, dried, and crystallized from ethanol to give hy-
droxylaminopyrimidine (7a) as yellow crystals. The results are listed
in Tables I and II.
Reaction of hydrazine hydrate with 5-carboethoxy-2-thiouracil (1).
Formation of ethyl 2-(hydrazino)-6-oxo-1,6-dihydropyrimidine-5-carbo-
xylate (7b). A solution of thiouracil (1) (2.0 g, 0.01 mol) and hy-
drazine hydrate (0.012 mol) in ethanol (50 ml) was refluxed for 4 h.
The solution was concentrated and the solid product, which was

2
502

2503

2
504
M. A. Hassan et al.
separated after cooling, was filtered off and recrystallized from ethanol
to give hydrazinopyrimidine (7b) as yellow crystals. The results are
listed in Tables I and II.
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