Recyclization of ethyl 4-hydroxy-2-thioxohexa-hydropyrimidine-5-carboxy- lates into 5-acyl-5,6-dihydro-2-thiouracils

Full text of DOI:10.1007/s10593-009-0321-8

Chemistry of Heterocyclic Compounds, Vol. 45, No. 6, 2009
LETTERS TO THE EDITOR
RECYCLIZATION OF ETHYL
4-HYDROXY-2-THIOXOHEXA-
HYDROPYRIMIDINE-5-CARBOXY-
LATES INTO 5-ACYL-5,6-DIHYDRO-
2-THIOURACILS
A. D. Shutalev1* and N. S. Zhukova1
Keywords: 5-acyl-5,6-dihydro-2-thiouracils, 5-acyl-2-thioxohexahydropyrimidin-4-ones, esters of
4-hydroxy-2-thioxohexahydropyriimidine-5-carboxylic acids, recyclization.
We have observed previously that 5-acyl-4-hydroxyhexahydropyrimidine-2-thiones 1 under the
influence of bases (NaH, NaOH) in dry acetonitrile underwent rearrangement, proceeding with clevage of the
C-4–C-5 to give N-acyl-N'-(β-oxoalkyl)thioureas [1]. In a continuation of this investigation it seemed advisable
to study the behavior of esters of 4-hydroxy-2-thioxohexahydropyrimidine-5-carboxylic acids with respect to
bases. In this paper we present preliminary results of the study of the reaction of the previously described
hydroxypyrimidines 2a,b [2,3] with sodium hydride.
We have shown, that unlike compounds 1, pyrimidine 2a under the influence of an equivalent amount of
NaH in anhydrous acetonitrile at room temperature in one day was converted not into the thioureide 3a but
instead underwent recyclization to form 5-benzoyl-5,6-dihydro-2-thiouracil (4). The latter was isolated in 91%
yield after neutralization of the reaction mixture with acetic acid with subsequent removal of the solvent in
vacuum, treatment of the solid residue with water and filtration of the product. Evidently the recyclization of
compound 2a occurs via the intermediate formation of its acyclic isomer, oxoalkylthiourea, 7a.
Conversion of the hydroxypyrimidine 2b (a mixture of 5R*,6R*- and 5S*,6R*-diastereomers in a 65:35
ratio) under the influence of an equivalent amount of sodium hydride occurred analogously (acetonitrile, 20°C).
In this case a product was obtained in 85% yield as a mixture of dihydrothiouracil 5 (cis diastereomer) and the
Z- and E-isomers of the enol forms of 6 in the ratio 60:30:10 respectively. We have shown that this ratio is not
changed when the hydroxypyrimidine 2b with a different isomer composition [(5R*,6R*):(5S*,6R*) = 92:8] was
used and also on recrystallization of the product.
_______
* To whom correspondence should be addressed, e-mail: shutalev@orc.ru.
1 M. V. Lomonosov Moscow State Academy of Fine Chemical Technology, Moscow 119571, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, 929-931, June, 2009. Original article
submitted April 29, 2009.
0009-3122/09/4506-0745©2009 Springer Science+Business Media, Inc.
745

Thus we have developed a method for the synthesis of 5-acyl-5,6-dihydro-2-thiouracils based on the
recyclization of readily available esters of 4-hydroxy-2-thioxohexahydropyrimidine-5-carboxylic acids under
the influence of sodium hydride. The recyclization described is of a general nature which will be the basis of our
future studies. It should be noted that 5-acyl-5,6-dihydrothiouracils and their 2-oxoanalogs have been a difficult
class of heterocyclic compounds to obtain until now. The only previously described example of this class was
obtained by the reaction of phorone with chlorosulfonyl isocyanate [4].
EtO
R1
O
EtO
R1
O
EtO
R1
HN
O
R
O
R
NaH
R
O
NaH
OH
HN
NH2
HN
NH
NH
S
S
S
2a,b
3a,b
7a,b
R1 = H
R1 = Et
Me
O
OH
HO
HN
Ph
Me
HN
Me
HN
O
Et
O
O
Et
O
Et
O
+
+
NH
HN
NH
NH
NH
S
S
S
S
5
Z-6
E-6
4
2, 3, 7 a R = Ph, R1 = H; b R = Me, R1 = Et
IR spectra of nujol mulls were recorded with a Bruker Equinox 55/s Fourier spectrophotometer. 1H and
13C NMR spectra of DMSO-d6 solutions were recorded with Bruker DPX 300 spectrometer (300 and 75 MHz
1
respectively). The standards were the central signal of the residual protons of the solvent, δ 2.50 ppm (for H)
and the central signal of the C atom of the solvent, δ = 39.50 ppm (for 13C).
5-Benzoyl-5,6-dihydro-2-thiouracil (4). Yield 90.6%; mp 243.5-244°C (dec., ethanol). IR spectrum, ν,
cm-1: 3179 (w), 3107 (w, NH), 1693 (w, C=O in PhC=O), 1674 (w), 1597(w), 1580 [m, NH–C(S)–NH–C(O)];
706 cm-1 (w, δCH in Ph). 1H NMR spectrum, δ, ppm (J, Hz): 11.30 (1H, d, 4JN(3)H,N(1)H = 1.4, H-3); 9.72 (1H, ddd,
3
4
3JN(1)H,Ha-6 =3.3, JN(1)H,Hb-6 = 3.0, JN(1)H,N(3)H = 1.4, H-1); 8.02-8.07 (2H, m, H-2 and H-6 in Ph); 7.66-7.72 (1H,
3
3
m, H-4 in Ph); 7.51-7.59 (2H, m, H-3 and H-5 in Ph); 4.97 (1H, dd, JH-5, Hb-6 = 8.0, JH-5, Ha-6 =6.2, H-5); 3.68
2
3
3
2
3
(1H, ddd, JHa-6,Hb-6 = 13.7, JHa-6,H-5 = 6.2, JHa-6,N(1H) = 3.3, Ha-6); 3.63 (1H, ddd, JHa-6,Hb-6 = 13.7, JHb-6,H-5 = 8.0,
3JHb-6,N(1H) = 3.0, Hb-6). 13C NMR spectrum, δ ppm): 194.98 (C=O in PhC=O); 178.48 (C-2); 165.24 (C-4); 135.48
(C-1 in Ph); 133.95 (C-4 in Ph); 129.04 (C-2 and C-6 in Ph); 128.76 (C-3 and C-5 in Ph); 46.59 (C-5); 41.03 (C-6).
Found, %: C 56.20; H 4.27; N 11.99. C11H10N2O2S. Calculated, %: C 56.40; H 4.30; N 11.96.
cis-5-Acetyl-6-ethyl-5,6-dihydro-2-thiouracil (5), Z-6-ethyl-5-(1-hydroxyethylidene)-5,6-dihydro-
2-thiouracil (Z-6), and E-6-ethyl-5-(1-hydroxyethylidene)-5,6-dihydro-2-thiouracil (E-6) (a 60:30:10
mixture). Yield 84.7%; mp 176-177.5°C (ethanol). IR spectrum, ν, cm-1: 3178 (w), 3126 (s, NH), 1642 (w) 1590
1
[w, NH–C(S)–NH–C(O) and C=O in Ac]. H NMR, δ, ppm (J, Hz): dihydrothiouracil 5 – 11.27 (1H, d,
3
4
3
4J N(1)H,N(3)H = 1.5, H-3); 9.81 (1H, dd, JN(1)H,H-6 = 3.9, JN(1)H,N(3)H = 1.5, H-1); 3.82 (1H, d, JH-5,H-6 = 3.9, H-5);
746

3
3
3
3
3.77 (1H, ddt, JH-6,CHa = 7.2, JH-6,CHb = 5.4, JH-6,H-5 = JH-6,N(1)H =3.9, H-6); 2.24 (3H, s, CH3 in Ac);
1.30-1.60(2H, signal overlap with signals of analogous protons in other isomers, CH2 in Et); 0.86 (3H, t,
3J = 7.4, CH3 in Et); dihydrothiouracil Z-6 – 14.01 (1H, s, OH); 11.06 (1H, d, 4JN(3)H,N(1)H = 1.7, H-3); 9.79 (1H, dd,
3JN(1)H, H-6 = 4.0, 4JN(1)H,N(3)H = 1.7, H-1); 4.17 (1H, dt, 3JH-6,CHa = 3JH-6,CHb = 5.5, 3JH-6,N(1)H = 4.0, H-6); 2.00 (3H, s,
CH3–C=); 1.30-1.60 (2H, m, signals overlapping with signals of analogous protons for other isomers, CH2 in
Et); 0.79 (3H, t, 3J =7.3, CH3 in Et); dihydrothiouracil E-6 – 10.28 (1H, d, 4JN(3)H,N(1)H = 1.7, H-3); 9.49 (1H, dd,
4
3
3
3
3JN(1)H,H-6 =4.4, JN(3)H,N(1)H = 1.7, H-1); 4.28 (1H, dt, JH-6,CHa = JH-6,CHb = 6.0, JH-6,N(1)H = 4.4, H-6); 2.33 (3H,
CH3–C=); 1.30-1.60 (2H, signal overlap with signals of analogous protons of other isomers, CH2 in Et); 0.77
(3H, t, 3J = 7.3, CH3 in Et). 13C NMR spectra, δ, ppm: dihydrothiouracil, 5 – 201.98 (C=O in Ac); 177.45 (C-2);
164.34 (C-4); 56.90 (C-5); 52.33 (C-6); 29.07 (CH3 in Ac); 26.12 (CH2 in Et); 9.55 (CH3 in Et);
dihydrothiouracil Z-6 – 176.94 (C-2); 174.28 (C–OH); 167.12 (C-4); 95.29 (C-5); 52.21 (C-6); 30.48 (CH2 in
Et); 18.43 (CH3–C=); 8.45 (CH3 in Et); dihydrothiouracil E-6 – 177.12 (C-2); 166.40 (C–OH); 162.66 (C-4);
98.87 (C-5); 51.42 (C-6); 28.77 (CH2 in Et); 19.64 (CH3 in CH3–C=); 9.25 (CH3 in Et). Found, %: C 47.81;
H 6.32; N 13.68. C8H12N2O2S. Calculated, %: C 47.98; H 6.04; N 13.99.
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