S-Aminoalkylation of 6-hydroxy-2-thiouracils
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 5, May, 2021
947
2
-{[2-(Diethylamino)ethyl]sulfanyl}-6-hydroxy-5-[(2RS)-
21.95 (CH CH CH ); 22.20 (С(4)H , piperidine); 22.67 (С(3)H
3 2 2 2 2
pentan-2-yl]pyrimidin-4(3H)-one, hydrochloride (1e). The yield
and С(5)H , piperidine); 23.88 (SCH CH ); 29.34 (СH); 36.02
2 2 2
was 1.30 g (57%), colorless crystals, m.p. 243.0—243.6 °C (de-
(CH CH CH ); 51.03 (SCH CH ); 54.04 (С(2)H and С(6)H ,
3
2
2
2
2
2
2
comp.). τ = 5.04 min. R 0.08 (EtOAc—C H —Et N, 12 : 3 : 1
piperidine); 57.03 (C(6), pyrimidine); 105.64 (С(5), pyrimidine);
R
f
6
14
3
1
(
v/v)). Н NMR (D O), δ: 0.95 (t, 3 H, CH CH СH , J = 7.4 Hz);
157.50 (С(4), pyrimidine); 166.81 (С(2), pyrimidine). MS,
2
3
2
2
+
1
.27 (d, 3 H, CH CH, J = 7.0 Hz); 1.29—1.35 (m, 2 H,
found: m/z 326.1897 [M + H] ; calculated for С16H28N O S:
3
3
2
CH CH СH ); 1.58—1.65 (m, 2 H, CH CH СH ); 3.05—3.11
M + H = 326.1898.
3
2
2
3
2
2
(
m, 7 H, N(CH CH ) and CH); 3.47—3.53 (m, 5 H, N(CH CH )
Aminoalkylation of 6-hydroxy-5-[2-(methylsulfanyl)ethyl]-
2-thioxo-2,3-dihydropyrimidin-4(1H)-one (2c) was carried out
similarly to aminoalkylation of compound 2a, using compound
2
3 2
2
3 2
+
and N H); 3.61 (br.s, 4 H, SCH CH ); 4.30 (br.s, 1 H, OH);
2
2
1
3
4
.81 (br.s, 1 H, NH). C NMR (DMSO-d ), δ: 14.68
6
i
(
(
(
CH CH СH ); 18.86 (CH CH); 21.98 (CH CH СH ); 25.62
2c (1.5 g, 7.87 mmol) in anhydrous Pr OH (25 mL), the corre-
3
2
2
3
3
2
2
SCH ); 29.39 (N(CH CH ) ); 36.89 (CH CH СH ); 44.31
sponding hydrochloride 3c•HCl or 3d•HCl (7.21 mmol) in
2
2
3 2
3
2
2
i
CH); 52.31 (SCH CH ); 57.69 (N(CH CH ) ); 65.02 (C(6),
anhydrous Pr OH (10 mL), Na (0.18 g, 7.87 mmol) in anhydrous
2
2
2
3 2
i
pyrimidine); 105.73 (С(5), pyrimidine); 157.32 (С(4), pyrimid-
Pr OH (40 mL). The solvent was evaporated to dryness under
ine); 167.71 (С(2), pyrimidine). MS, found: m/z 314.1897
reduced pressure, the residue was recrystallized from acetone.
6-Hydroxy-5-[2-(methylsulfanyl)ethyl]-2-{[2-(pyrrolidin-1-
yl)ethyl]sulfanyl}pyrimidin-4(3H)-one, hydrochloride (4a). The
yield was 1.07 g (44%), yellowish crystals, m.p. 236.8—237.2 °C
+
[
M + H] ; calculated for С15H28N O S: M = 314.1899.
3
2
2
-{[2-(Dimethylamino)ethyl]sulfanyl}-6-hydroxy-5-[(2RS)-
pentan-2-yl]pyrimidin-4(3H)-one, hydrochloride (1f). The yield
was 1.86 g (76%), colorless crystals, m.p. 241.4—241.9 °C (de-
(decomp.). τR = 3.32 min. R 0.09 (EtOAc—C H —Et N,
f
6
14
3
1
comp.). τ = 5.69 min. R 0.05 (EtOAc—C H —Et N, 12 : 3 : 1
12 : 3 : 1 (v/v)). Н NMR (D O), δ: 1.71—1.81 (m, 2 H, C(4)H ,
R
f
6
14
3
2
2
1
(
1
v/v)). Н NMR (D O), δ: 0.82 (t, 3 H, CH CH СH , J = 7.3 Hz);
pyrrolidine); 2.00 (m, 2 H, C(3)H , pyrrolidine); 2.12 (s, 3 H,
2
2
3
2
2
.15 (d, 3 H, CH CH, J = 7.0 Hz); 1.17—1.25 (m, 2 H,
CH ); 2.61—2.65 (m, 4 H, CH SCH CH (at С(5) of pyrimid-
3
3 3 2 2
+
CH CH СH ); 1.44—1.50 (m, 2 H, CH CH СH ); 2.87—2.95
ine)); 2.75 (s, 1 H, N H); 3.17—3.25 (m, 2 H, C(2)H , pyrrol-
2
3
2
2
3
2
2
(
m, 7 H, N(CH ) and CH); 3.56 (br.s, 5 H, SCH CH and
idine); 3.60 (dt, 4 H, SCH CH , J = 46.1 Hz, J = 6.0 Hz);
3
2
2
2
2 2 1 2
+
13
N H); 4.83 (br.s, 2 H, NH and OH). C NMR (DMSO-d ), δ:
3.73—3.78 (m, 2 H, C(5)H , pyrrolidine); 4.71 (br.s, 2 H,
2
6
1
3
1
2
(
4.64 (CH CH СH ); 18.64 (CH CH); 21.95 (CH CH СH );
NH and OH). С NMR (D O), δ: 15.52 (CH ); 22.24 (С(3)H
3
2
2
3
3
2
2
2 3 2
5.55 (SCH ); 29.35 (N(CH ) ); 36.86 (CH CH СH ); 44.27
and С(4)H , pyrrolidine); 23.92 (CH SCH CH (at С(5)
2 3 2 2
2
3 2
3
2
2
CH); 57.59 (SCH CH ); 65.11 (C(6), pyrimidine); 105.76 (С(5),
of pyrimidine)); 25.13 (SCH ); 32.75 (С(2)H and С(5)H2,
2
2
2 2
pyrimidine); 157.31 (С(4), pyrimidine); 167.43 (С(2), pyrimid-
pyrrolidine); 54.83 (SCH ); 99.82 (С(5), pyrimidine); 158.63
2
+
ine). MS, found: m/z 286.1584 [M + H] ; calculated for
(С(4) and C(6), pyrimidine); 167.51 (С(2), pyrimidine). MS,
+
С13H24N O S: M + H = 286.1586.
found: m/z 316.1576 [M + H] ; calculated for С13H22N O S :
3
2
3
2 2
6
-Hydroxy-5-[(2RS)-pentan-2-yl]-2-{[2-(pyrrolidin-1-yl)-
M + H = 316.1579.
ethyl]sulfanyl}pyrimidin-4(3H)-one, hydrochloride (1g). The yield
6-Hydroxy-5-[2-(methylsulfanyl)ethyl]-2-{[2-(piperidin-1-
yl)ethyl]sulfanyl}pyrimidin-4(3H)-one, hydrochloride (4b). The
yield was 0.70 g (28%), yellowish crystals, m.p. 227.7—228.3 °C
was 1.12 g (46%), colorless crystals, m.p. 241.0—241.6 °C (de-
comp.). τ = 4.90 min. R 0.15 (EtOAc—C H —Et N, 12 : 3 : 1
R
f
6
14
3
1
(
1
2
(
(
v/v)). Н NMR (D O), δ: 0.83 (t, 3 H, CH CH CH , J = 7.4 Hz);
(decomp.). τR = 3.35 min. R 0.15 (EtOAc—C H —Et N,
2
3
2
2
f 6 14 3
1
.13—1.23 (m, 5 H, CH CH and CH CH CH ); 1.45—1.50 (m,
12 : 3 : 1 (v/v)). Н NMR (D O), δ: 1.41—1.51 (m, 2 H, С(4)H ,
2 2
3
3
2
2
H, CH CH CH ); 2.01 (br.s, 2 H, С(3)H , pyrrolidine); 2.15
piperidine); 1.71—1.82 (m, 4 H, С(3)H and С(5)H , piperidine);
3
2
2
2
2 2
br.s, 2 H, С(4)H , pyrrolidine); 2.92—2.98 (m, 1 H, СH); 3.17
2.11 (s, 3 H, CH ); 2.60—2.65 (m, 4 H, CH SCH CH (at С(5)
3 3 2 2
2
+
+
br.s, 2 H, С(2)H , pyrrolidine); 3.35 (s, 1 H, N H); 3.56 (dt, 4 H,
of pyrimidine)); 2.71 (s, 1 H, N H); 3.01—3.06 (m, 2 H, С(2)H ,
2
2
SCH CH , J = 37.9 Hz, J = 6.8 Hz); 3.73 (br.s, 2 H, С(5)H ,
piperidine); 3.47 (dt, 4 H, 2 CH (SCH CH , J = 27.8 Hz,
2 2 2 1
2
2
1
2
2
13
pyrrolidine), 4.55 (br.s, 1 H, OH); 4.71 (br.s, 1 H, NH). С NMR
J = 6.3 Hz); 3.64—3.71 (m, 2 H, С(6)H , piperidine); 4.57 (br.s,
2
2
1
3
(
(
(
5
D O), δ: 14.63 (CH CH CH ); 18.82 (CH CH); 21.94
2 H, NH and OH). С NMR (D O), δ: 15.52 (CH ); 22.24
2 3
2
3
2
2
3
CH CH CH ); 22.56 (С(3)H and С(4)H , pyrrolidine); 26.64
(С(4)H , piperidine); 22.87 (С(3)H and С(5)H , piperidine);
3
2
2
2
2
2
2
2
SCH ); 29.35 (СH); 36.82 (CH CH CH ); 52.21 (SCH CH );
23.91 (CH SCH CH (at С(5) of pyrimidine)); 32.74 (SCH ),
3 2 2 2
2
3
2
2
2
2
4.93 (С(2)H and С(5)H , pyrrolidine); 56.02 (C(6), pyrimid-
54.81 (С(2)H and С(6)H , piperidine); 56.79 (SCH CH ); 99.77
2
2
2 2 2 2
ine); 105.71 (С(5), pyrimidine); 157.43 (С(4), pyrimidine);
(С(5), pyrimidine); 158.63 (С(4) and C(6), pyrimidine); 167.51
+
+
1
67.57 (С(2), pyrimidine). МS, found: m/z 312.1740 [M + H] ;
(С(2), pyrimidine). MS, found: m/z 330.1304 [M + H] ; calcu-
calculated for С16H28N O S: M + H = 312.1742.
lated for С14H24N O S : M + H = 330.1306.
3
2
3 2 2
6
-Hydroxy-5-[(2RS)-pentan-2-yl]-2-{[2-(piperidin-1-yl)-
ethyl]sulfanyl}pyrimidin-4(3H)-one, hydrochloride (1h). The yield
was 1.73 g (69%), colorless crystals, m.p. 236.2—236.9 °C (de-
comp.). τ = 4.73 min. R 0.25 (EtOAc—C H —Et N, 12 : 3 : 1
This work was financially supported by the Russian
Science Foundation (Project No. 19-13-00123), using the
park of analytical instruments of the Center for Collective
Use (CCU) of the N. D. Zelinsky Institute of Organic
Chemistry of the Russian Academy of Sciences and N. N.
Vorozhtsov Novosibirsk Institute of Organic Chemistry of
the Siberian Branch of the RAS.
R
f
6
14
3
1
(
v/v)). Н NMR (D O), δ: 0.83 (t, 3 H, CH CH CH , J = 7.2 Hz);
2 3 2 2
1
2
.16—1.20 (m, 5 H, CH CH and CH CH CH ); 1.45—1.50 (m,
3 3 2 2
H, CH CH CH ); 1.73—1.80 (m, 4 H, С(3) and С(5), piper-
3
2
2
idine); 1.94—1.98 (m, 2 H, С(4)H , piperidine); 2.93—3.01 (m,
2
+
3
4
H, СH and С(2)H , piperidine); 3.35 (s, 1 H, N H); 3.46 (dt,
2
This work does not involve human participants and
animal subjects.
H, SCH CH , J = 37.9 Hz, J = 6.8 Hz); 3.63 (br.s, 2 H,
2
2
1
2
С(6)H , piperidine), 4.59 (br.s, 1 H, OH); 4.77 (br.s, 1 H, NH).
2
1
3
С NMR (D O), δ: 14.64 (CH CH CH ); 18.05 (CH CH);
The authors declare no competing interest.
2
3
2
2
3