Supplemental data
Copper and palladium complexes with substituted pyrimidine-2-thiones and 2-thiouracils:
Syntheses, spectral characterization and X-ray crystallographic study
A.S. KUZOVLE, E.V. SAVINKINA*, V.V. CHERNYSHEV, M.S. GRIGORIEV and A.N. VOLOV
Reagents
Commercial CuCl (reagent grade), CuCl2.2H2O (for analysis), PdCl2 (ReagentPlus), KSCN (reagent
grade), HCl (reagent grade), Na2SO3 (for analysis), KOH (for analysis), β-aminopropionic acid
(premium), tosyl chloride (for preparation, purification and analysis), thiourea (for analysis),
propionic aldehyde (reagent grade), C2H5OH (95%), C2H5OC2H5 (reagent grade), hexane (reagent
grade) were used without further purification. Acetylacetone and ethyl acetoacetate were dried over
anhydrous magnesium sulfate and then double distilled under vacuum (nD20 = 1.452 and nD20 =
1.419, respectively). Benzoyl chloride was distilled under reduced pressure (nD20 = 1.554). Benzene
and acetonitrile were dried by boiling over P2O5 for 12 h, distilled over P2O5 and absolutized by
boiling over sodium metal or calcium hydride respectively under argon atmosphere (nD20 = 1.501
and nD20 = 1.344, respectively). Aqueous solution of formaldehyde (33.9%) was prepared by
dissolution of 25.33 g of paraform in 49.26 mL of water in a sealed ampule at boiling water bath for
40 h. Acetic aldehyde was prepared by decomposition of paraldehyde with sulfuric acid with
further distillation under ambient pressure into an ice-cooled receiver (nD20 = 1.331). Suspension of
sodium hydride was washed from paraffin oil with petroleum ether (pre-distilled over P2O5) and
dried by heating in vacuum.
Synthesis
Complexes [Cu(L)2Cl] (1-4 for L = L1–L4, respectively) and [Pd(L)2Cl2] (5-8 for L = L1–L4,
respectively) were prepared from the corresponding metal salts and pre-synthesized L1–L4.
Para-toluenesulfinic acid was prepared by reduction of tosyl chloride (0.16 mol) by sodium sulfite
(0.20 mol) in the presence of NaOH (0.35 mol) in aqueous medium (98 mL) with stirring at 70 °C
for 4 h followed by acidifying of isolated dry sodium sulfinate (0.11 mol) with 18.82 mL of 19%
HCl in 240 mL of water at room temperature and cooling down to 4 °C for 1 h. Yield 53%.
5-Acetyl-6-methyl-1,2,3,4-tetrahydropyrimidine-2-thione (L1)
Thiourea (0.26 mol) and formaldehyde (0.26 mol) in water (23 mL) were stirred with catalytic
quantity of barium hydroxide (0.76 mmol) for 4 h. The reaction mixture was neutralized with CO 2
and filtered. The solution was concentrated at room temperature for 1 month; the resulting
hydroxymethylthiourea was washed with icy water (3 times). Yield 48%.
Reaction of hydroxymethylthiourea (18.87 mmol) with para-toluenesulfinic acid (22.64 mmol) in
water (22 mL) for 24 h produced N-(tosylmethyl)thiourea. Yield 99%.
1
N-(tosylmethyl)thiourea (11.67 mmol) was stirred with acetylacetone (14.82 mmol) and KOH
(14.00 mmol) in ethanol (30 mL) at room temperature for 4.5 h, then para-toluenesulfonic acid
(4.20 mmol) was added, the mixture was refluxed for 1.5 h and then concentrated on a rotary
evaporator. The residue was treated with hexane (2×15 mL), hexane was decanted, the mixture was
treated with the saturated solution of NaHCO3 (15 mL) and allowed to stay for 1 d. The resulting
5-acetyl-6-methyl-1,2,3,4-tetrahydropyrimidine-2-thione was washed with water, petroleum ether
and diethyl ether. Yield 70%. MP 226 – 227 °C with decomposition.
Anal. Calcd for C7H10N2OS (%): C 49.39; H 5.92; N 16.46. Found (%): C 49.15; H 6.02; N 16.37.
IR (Nujol) (cm–1): 3275, 3187, 3136 ( (NH)), 1612 ((С=О), (С=С)), 1592 (thioamide II: δ(NH),
ν(C–N)), 1187 (thioamide III: δ(NH)), 780 (thioamide V: δ(NH)).
1
H NMR (DMSO-d6) (ppm): 2.15 (3H, s, CH3), 2.17 (3H, s, CH3C=O), 3.94 (1H, s, N–CH2), 9.06
(1H, s, N(3)H), 9.92 (1H, s, N(1)H).
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C NMR (DMSO-d6) (ppm): 17.80 (CH3) 30.12 (CH3, CH3C=O), 41.29 (C(4)), 105.77 (C(6)),
144.03 (C(5)), 175.68 (C(2)), 194.81 (C=O in Ac).
Ethyl 4,6-dimethyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (L2)
To a solution of acetic aldehyde (33.40 mmol) in water (45 mL) para-toluenesulfinic acid
(33.40 mmol) and thiourea (33.40 mmol) were added; N-(1-tosylethyl)thiourea formed in 24 h.
Yield 89%.
N-(1-tosylethyl)thiourea (8.01 mmol) was stirred with ethyl acetoacetate (10.18 mmol) and KOH
(9.62 mmol) in ethanol (40 mL) at room temperature for 5.5 h, then para-toluenesulfonic acid
(2.88 mmol) was added, the mixture was refluxed for 1 h and concentrated on a rotary evaporator.
The residue was treated with hexane (2×10 mL), hexane was decanted, the mixture was treated with
the saturated solution of NaHCO3 (10 mL) and allowed to stay for 1 d. The resulting ethyl
4,6-dimethyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate was washed with water,
petroleum ether and diethyl ether. Yield 84%. MP 193–194 °C with decomposition.
Anal. Calcd for C9H14N2O2S (%): C 50.45; H 6.59; N 13.07. Found (%): C 50.81; H 6.88; N 13.11.
IR (Nujol) (cm–1): 3315, 3181, 3120 ( (NH)), 1660 ((С=О), (С=С)), 1584 (thioamide II: δ(NH),
ν(C–N)), 1195 (thioamide III: δ(NH)), 1143, 1127, 776 (skeleton vibrations of the pyrimidinethione
ring).
1
H NMR (DMSO-d6) (ppm): 1.09 (3H, d, J = 6.29 Hz, CH3C(4)H), 1.19 (3H, t, J = 7.11 Hz,
CH3CH2O), 2.19 (3H, s, CH3C(6)), 4.02–4.16 (2H and 1H, m, overlapping of 1H signals of CH2 in
OCH2CH3 and C(4)H), 9.19 (1H, s, N(3)H), 10.12 (1H, s, N(1)H).
1
H NMR (CD3CN-d3) (ppm): 1.19 (3H, d, J = 5.83 Hz, CH3C(4)H), 1.24 (3H, t, J = 7.13 Hz,
CH3CH2O), 2.23 (3H, s, CH3C(6)), 4.14 (2H, m, OCH2CH3), 4.28 (1H, m, C(4)H), 7.44 (1H, s,
N(3)H), 8.16 (1H, s, N(1)H).
13
C NMR (DMSO-d6) (ppm): 14.18 (CH3, CH3C(4)H), 17.10 (CH3, CH3CH2O), 22.74 (CH3,
CH3C(6)), 46.69 (C(4)), 59.50 (CH2, CH3CH2O), 101.93 (C(6)), 144.72 (C(5)), 165.12 (COOEt),
174.67 (C(2)).
2
13
C NMR (CD3CN-d3) (ppm): 14.40 (CH3, CH3C(4)H), 17.90 (CH3, CH3CH2O), 22.78 (CH3,
CH3C(6)), 48.50 (C(4)), 60.87 (CH2, CH3CH2O), 104.31 (C(6)), 144.87 (C(5)), 166.40 (COOEt),
176.88 (C(2)).
cis-5-Acetyl-6-ethyl-5,6-dihydro-2-thiouracil (L3)
To a solution of propionic aldehyde (20.12 mmol) in water (45 mL) para-toluenesulfinic acid
(20.12 mmol) and thiourea (20.12 mmol) were added; N-(1-tosylpropyl)thiourea formed in 24 h.
Yield 92%.
N-(1-tosylpropyl)thiourea (6.68 mmol) was stirred with ethyl acetoacetate (8.01 mmol) and NaH
(7.68 mmol) in acetonitrile (21 mL) at room temperature for 6 h, then the mixture was concentrated
on a rotary evaporator in a cooled water bath. The residue was treated with hexane (2×10 mL),
hexane was decanted, the mixture was treated with the saturated solution of NaHCO3 (10 mL) and
allowed to stay for 1 d. The resulting ethyl 6-ethyl-4-hydroxy-4-methyl-2thioxohexahydropyrimidine-5-carboxylate was washed with icy water, petroleum ether and diethyl
ether. Yield 85%.
Addition of absolutized acetonitrile (8 mL) to a mixture of dry ethyl 6-ethyl-4-hydroxy-4-methyl-2thioxohexahydropyrimidine-5-carboxylate (2.55 mmol) and NaH (2.55 mmol) resulted in vigorous
evolution of a gas and formation of a solution with small quantity of a precipitate, which increased
after stirring the mixture at room temperature for 1 d. Then acetic acid (0.11 mL) was added; the
mixture was stirred for 30 min and concentrated on a rotary evaporator using cool water bath (to
avoid decomposition and transformations of the product). The residue was treated with water
(1.5 mL) and allowed to stay in a refrigerator for 40 min. The resulting cis-5-acetyl-6-ethyl-5,6dihydro-2-thiouracil was filtered off, washed with icy water and petroleum ether. Powder of the
compound represented the mixture of three isomers (NMR analysis): cis-5-acetyl-6-ethyl-5,6dihydro-2-thiouracil, (Z)-5-(1-hydroxyethylidene)- 6-ethyl-5,6-dihydro-2-thiouracil and (E)-5-(1hydroxyethylidene)- 6-ethyl-5,6-dihydro-2-thiouracil. Yield 75%. MP 176–178 °C with
decomposition.
Anal. Calcd for C8H12N2O2S (%): C 47.98; H 6.04; N 13.99. Found (%): C 46.83; H 5.95; N 14.15.
IR (Nujol) (cm–1): 3182, 3121 ( (NH)), 1645, 1590 (NH-C(S)-NH-C(O) and (С=О), CH3C=O),
1283 (thioamide III: δ(NH)).
1
H NMR (DMSO-d6) (ppm) for cis-5-acetyl-6-ethyl-5,6-dihydro-2-thiouracil: 0.86 (3Н, t, J =
7.37 Hz, CH3CH2), 1.35-1.60 (2H, m, overlapping of 1H signal of CH2 in CH3CH2 and that from
other isomers), 2.24 (3H, s, CH3C=O), 3.77 (1H, m, C(6)H), 3.80 (1H, d, J = 3.95 Hz,C(5)H), 9.78
(1H, d, J = 2.59 Hz N(1)H), 11.24 (1 H, s, N(3)H).
1
H NMR (DMSO-d6) (ppm) for (Z)-5-(1-hydroxyethylidene)- 6-ethyl-5,6-dihydro-2-thiouracil: 0.80
(3Н, t, J = 7.41 Hz, CH3CH2), 1.35-1.60 (2H, m, overlapping of 1H signal of CH2 in CH3CH2 and
that from other isomers), 2.00 (3H, s, CH3COH), 4.17 (1H, d t, J = 5.37, 4.21 Hz, C(6)H), 9.77 (1H,
s, N(1)H), 11.03 (1H, s, N(3)H), 14.00 (1 H, s, OH).
1
H NMR (DMSO-d6) (ppm) for (E)-5-(1-hydroxyethylidene)- 6-ethyl-5,6-dihydro-2-thiouracil:
0.78 (3Н, t, J = 7.45 Hz, CH3CH2), 1.35-1.60 (2H, m, overlapping of 1H signal of CH2 in CH3CH2
3
and that from other isomers), 2.34 (3H, s, CH3COH), 4.28 (1H, d t, J = 4.97, 4.21 Hz, C(6)H), 9.47
(1H, s, N(1)H), 10.24 (1H, s, N(3)H).
1
H NMR (CD3CN-d3) (ppm) for cis-5-acetyl-6-ethyl-5,6-dihydro-2-thiouracil: 0.94 (3Н, t, J =
7.37 Hz, CH3CH2), 1.50-1.70 (2H, m, overlapping of 1H signal of CH2 in CH3CH2 and that from
other isomer), 2.27 (3H, s, CH3C=O), 3.86 (1H, m, C(6)H), 4.21 (1H, m, C(5)H), 7.98 (1H, s,
overlapping of 1H signal of N(1)H and that from other isomers), 9.13 (1 H, s, N(3)H).
1
H NMR (CD3CN-d3) (ppm) for (Z)-5-(1-hydroxyethylidene)- 6-ethyl-5,6-dihydro-2-thiouracil:
0.88 (3Н, t, J = 7.41 Hz, CH3CH2), 1.50-1.70 (2H, m, overlapping of 1H signal of CH2 in CH3CH2
and that from other isomer), 2.00 (3H, s, CH3COH), 4.15 (1H, m, C(6)H), 7.98 (1H, s, overlapping
of 1H signal of N(1)H and that from other isomers), 8.86 (1H, s, N(3)H), 13.70 (1H, s, OH).
13
C NMR (DMSO-d6) (ppm) for cis-5-acetyl-6-ethyl-5,6-dihydro-2-thiouracil: 9.44 (CH3,
CH3CH2), 26.08 (CH2, CH3CH2), 28.96 (CH3, CH3C=O), 52.32 (C(6)), 56.89 (C(5)), 164.21 (C(4)),
177.45 (C(2)), 201.78 (C=O, CH3C=O).
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C NMR (DMSO-d6) (ppm) for (Z)-5-(1-hydroxyethylidene)- 6-ethyl-5,6-dihydro-2-thiouracil:
8.37 (CH3, CH3CH2), 18.35 (CH3, CH3COH), 30.40 (CH2, CH3CH2), 52.20 (C(6)), 95.28 (C(5)),
167.04 (C(4)), 174.15 (COH), 176.94 (C(2)).
13
C NMR (DMSO-d6) (ppm) for (E)-5-(1-hydroxyethylidene)- 6-ethyl-5,6-dihydro-2-thiouracil:
9.16 (CH3, CH3CH2), 19.78 (CH3, CH3COH), 28.72 (CH2, CH3CH2), 51.44 (C(6)), 98.62 (C(5)),
162.54 (C(4)), 166.35 (COH), 177.11 (C(2)).
13
C NMR (CD3CN-d3) (ppm) for cis-5-acetyl-6-ethyl-5,6-dihydro-2-thiouracil: 9.94 (CH3,
CH3CH2), 27.22 (CH2, CH3CH2), 29.59 (CH3, CH3C=O), 54.22 (C(6)), 58.19 (C(5)), 164.71 (C(4)),
179.29 (C(2)), 202.13 (C=O, CH3C=O).
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C NMR (CD3CN-d3) (ppm) for (Z)-5-(1-hydroxyethylidene)- 6-ethyl-5,6-dihydro-2-thiouracil:
9.06 (CH3, CH3CH2), 18.91 (CH3, CH3COH), 31.56 (CH2, CH3CH2), 54.11 (C(6)), 96.42 (C(5)),
167.77 (C(4)), 174.08 (COH), 178.90 (C(2)).
5,6-Dihydro-2-thiouracil (L4)
Synthesis of 5,6-dihydro-2-thiouracil from β-aminopropionic acid ethyl ester was realized by the
really elegant way and detailed described by Gaspert and Scaric [15]. However, this method is not
suitable for β-aminopropionic acid.
On the base of this approach we suggested a new method for the synthesis of 5,6-dihydro-2thiouracil starting from β-aminopropionic acid (Scheme 2). Base catalyzed reaction of
β-aminopropionic acid (14) with benzoylisothiocyanate (13), obtained from benzoyl chloride (12),
gave N-benzoyl-N’-(2-carboxyethyl)thiourea (15), which was then used for acid catalyzed
intramolecular cyclization, producing 5,6-dihydro-2-thiouracil (L4).
Potassium thiocyanate (0.48 mol), pre-dried at 110 °C for 10 h, was refluxed with benzoyl chloride
(0.40 mol) in absolutized benzene (100 mL) under stirring for 6 h. A precipitate was filtered off,
benzene was removed on a rotary evaporator, and the resulting liquid benzoyl isothiocyanate was
distilled in vacuum (BP 128°C, nD20 = 1.635). Yield 60%.
4
Refluxing benzoyl isothiocyanate (44.9 mmol), β-aminopropionic acid (44.90 mmol) and KOH
(4.90 mmol) in absolutized acetonitrile (75 mL) for 2.5 h resulted in formation of a yellowish
solution. The reaction mixture was concentrated on a rotary evaporator. The residue was treated
with hexane (3×15 mL), hexane was decanted, and the product was crystallized from the C 2H5OH–
H2O (2:1) mixture. It was allowed to stay for 1 h and cooled. The precipitate of N-benzoyl-N’-(2carboxyethyl)thiourea was filtered off and washed with petroleum ether. Yield 47%. MP 149–
150 °C.
Anal. Calcd for C11H12N2O3S (%): C 52.37; H 4.79; N 11.10. Found (%): C 52.88; H 4.88; N 11.19.
IR (Nujol) (cm–1): 3233, 3173 ( (NH)), 1718 ((С=О) in COOH), 1671 (amide I: (С=О)), 1600,
1568 (planar vibration of benzene ring), 1533, 1520 (thioamide II + amide II: δ(NH), ν(CN)).
1
H NMR (DMSO-d6) (ppm): 2.65 (2H, t, J = 6.50 Hz, C(3)H2 in C(3)H2C(2)H2COOH), 3.83 (2H, dd,
J = 6.50 Hz, C(2)H2 in C(3)H2C(2)H2COOH), 7.51 (2H, m, meta-H atoms in phenyl), 7.63 (1H, m,
para-H atom in phenyl), 7.91 (2H, m, ortho-H atoms in phenyl), 11.03 (1H, t, J = 5.35 Hz, N(3)H),
11.31 (1H, s, N(1)H).
13
C NMR (DMSO-d6) (ppm): 32.28 (C(3)H2 in C(3)H2C(2)H2COOH), 40.59 (C(2)H2 in
C(3)H2C(2)H2COOH), 128.37 (C(3) in phenyl), 128.49 (C(2) in phenyl), 132.20 (C(4) in phenyl),
132.93 (C(1) in phenyl), 168.03 (C=O), 172.89 (C(2)), 180.25 (COOH).
Refluxing N-benzoyl-N’-(2-carboxyethyl)thiourea (4.46 mol) in 5% HCl (250 mL) for 1.5 h
followed by cooling and evaporating on a rotor evaporator, treatment of the residue with ethanol
(20 mL) (to dissolve all the residue) and diethyl ether (50 mL) (to remove benzoic acid, which is
high soluble in ether) and cooling in a refrigerator produced the pure residue of 5,6-dihydro-2thiouracil, which was filtered off and washed with cold diethyl ether. Yield 58%. MP 232–233°C
with decomposition.
Anal. Calcd for C4H6N2OS (%): C 36.91; H 4.64; N 21.52. Found (%): C 37.32; H 4.73; N 21.51.
IR (Nujol) (cm–1): 3189, 3122 ( (NH)), 1721 (amide I: (С=О)), 1586 (thioamide II + amide
II: δ(NH), ν(C–N)), 1165, 1154 (amide III and thioamide III : δ(NH)), 813, 777 (skeleton vibrations
of the dihydrothiouracil ring).
1
H NMR (DMSO-d6) (ppm): 2.51 (2H, t, J = 7.11 Hz, C(6)H2), 3.35 (2H, d t, J = 7.12 Hz, J =
2.90 Hz, C(5)H2), 9.56 (1H, s, N(1)H), 10.89 (1H, s, N(3)H).
13
C NMR (DMSO-d6) (ppm): 29.18 (C(6)H2), 38.27 (C(5)H2), 167.41 (C(4)), 179.05 (C(2)).
5
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