Unusual reaction of thiomalonamide with 5,5-dimethyl-2- phenylaminomethylidene-1,3-cyclohexanedione

Full text of DOI:10.1007/s10593-013-1176-6

Chemistry of Heterocyclic Compounds, Vol. 48, No. 10, January, 2013 (Russian Original Vol. 48, No. 10, October, 2012)
UNUSUAL REACTION OF THIOMALONAMIDE
WITH 5,5-DIMETHYL-2-PHENYLAMINOMETHYLIDENE-
1,3-CYCLOHEXANEDIONE
V. V. Dotsenko1* and S. G. Krivokolysko1
Keywords:
enaminodicarbonyl
compounds,
pyrimidine-5-carboxamides,
thiomalonamide,
heterocyclization, 1H-13C HMBC spectra.
β-Enaminocarbonyl compounds are commonly used in heterocyclic synthesis as convenient and readily
available 1,3-dielectrophile 3C synthones [1, 2]. In previous work [3], we showed that the reaction of 5,5-di-
methyl-2-phenylaminomethylidenecyclohexane-1,3-dione (1) with cyanothioacetamide gives the quinoline
derivative 2. We established that the reaction of thiomalonamide 3 with dimedone derivative 1 yields
6-thioxopyrimidine-5-carboxamide 4 instead of the expected 3-carbamoyl analog of quinoline 2. Alkylation of
carboxamide 4 with benzyl chloride gives benzyl derivative 5.
1
The structures of carboxamides 4 and 5 were supported by IR, H-NMR, and 13C-NMR spectroscopy,
HPLC/MS, elemental analysis, and the results of a 1H-13C HMBC NMR experiment for carboxamide 4 (Fig. 1).
The 1H NMR spectrum of carboxamide 4 shows signals for two amide groups and one methylene group, as well
as singlets for protons H-4 and NH. The HPLC/MS shows a peak [M+H]+- with m/z 213.6. Atom H-4 in the
pyrimidine ring in the 1H-13C HMBC spectrum gives four correlation peaks: δ-8.78/127.1 (H-4/C-5), 8.78/159.6
(H-4/C-2), 8.78/163.7 (H-4/5-CONH2), and 8.78/179.7 ppm (H-4/C-6). The CH2 group protons give two cross
peaks: δ-3.69/159.6 (CH2/C-2) and 3.69/167.8 ppm (CH2/CO). The finding of cross peaks at δ 7.17/41.1
O
NHPh
O
CN
S
CN
S
+
Me
Me
Me
Me
H2N
O
N
H
1
2
O
S
O
S
O
S
NH2
N
PhCH2Cl
NH2
Ph
KOH
EtOH
N
NH2
1
+
N
H
N
H2N
3
NH2
O
NH2
O
4
5
_______
*To whom correspondence should be addressed, e-mail: victor_dotsenko@bigmir.net.
1"ChemEx" Laboratory, Vladimir Dal' East Ukrainian National University, 20-A Molodyozhnyi Kv., Lugansk
91034, Ukraine.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1680-1682, October, 2012.
Original article submitted September 12, 2012.
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0009-3122/13/4810-1568©2013 Springer Science+Business Media New York

(CONH/CH2), 7.17/167.8 (C(O)NH/C-2), 7.61/167.81 (CONH/C-2), and 7.86/127.08 ppm (CONH/C-5) permit
unequivocal assignment of the amide group signals in the 1H and 13C NMR spectra.
In conclusion, we should note that this reaction demonstrates a fundamentally new approach to the
construction of the pyrimidine ring and opens new possibilities for the preparation of functionally substituted
pyrimidines. The mechanism of this reaction, optimization of its conditions, limitations, and scope of
application will be covered in future studies.
The IR spectra were recorded on a Thermo Nicolet AVATAR 370 spectrophotometer for KBr pellets.
1
13
1
The H NMR, C NMR, and H-13C HMBC spectra were recorded on a Bruker Avance II 400 spectrometer at
1
400 MHz for the H nuclei and 100 MHz for the 13C-nuclei in ~1:1 CCl4–DMSO-d6 with TMS as internal
standard. The HPLC/MS analysis was carried out on a Shimadzu LC-10AD liquid chromatograph with a
Shimadzu-SP D-10A UV-Vis (254 nm) detector, and Sedex 75 ELSD combined with a PE SCIEX API 150EX
mass spectrometer using ES-API ionization. The elemental analysis was carried out on a Carlo-Erba 1106
Elemental Analyzer. The melting points were determined on a Koffler hot stage and not corrected. The purity of
the products was checked by thin-layer chromatography on Silufol UV-254 plates with 1:1 acetone–hexane as
the eluent and visualization by iodine vapor and UV radiation. 2-Anilinomethylene-5,5-dimethyl-1,3-cyclo-
hexanedione (1) [3] and thiomalonamide 3 [4] were obtained according to reported procedures.
8.78
O
156.2
159.6
H
163.7
7.86, 9.49
NH2
N
O
H
3.69
41.1
127.1
N
H
S
H
179.7
14.36
H2N
7.17, 7.61
167.8
Fig. 1. Observed correlations in the 1H-13C HMBC spectrum of carboxamide 4.
2-Carbamoylmethyl-6-thioxo-1,6-dihydropyrimidine-5-carboxamide (4). Thiomalonamide 3 (4.00 g,
33.9 mmol) and enaminodiketone 1 (8.24 g, 33.9 mmol) were put into a 100-ml beaker, and 96% ethanol (50
ml) was added. Potassium hydroxide (3.80 g, 67.9 mmol) was added to the obtained suspension with vigorous
stirring. The starting reagents dissolved, and a precipitate of the product 4 potassium salt formed after about 30
min. The reaction mixture was stirred for 6 h, maintained for ~16 h at 25°C, and, then, an excess of concentrated
hydrochloric acid (10 ml) was added with stirring. Note: H2S is liberated! The mixture was stirred for 2 h. The
precipitate was filtered off and washed with ethanol, water, and acetone. The sample obtained contained a trace
of starting enaminodiketone 1. In order to obtain an analytically pure sample, the crude product was heated at
reflux in acetone for 0.5 h or recrystallized from DMF. Yield 1.90 g (53%). Yellow powder; decomp. temp.
245-250°С. IR spectrum, , cm-1: 3391, 3188, 3075 (N–H), 1660, 1650 (C=O). 1Н NMR spectrum, , ppm: 3.69
(2Н, s, 2-СН2); 7.17 (1Н, br. s) and 7.61 (1Н, br. s, СН2СONH2); 7.86 (1Н, br. s) and 9.49 (1Н, br. s,
5-СONH2); 8.78 (1H, s, Н-4); 14.36 (1Н, br. s, NH). 13C NMR spectrum, , ppm: 40.9 (CH2CONH2); 127.2
(C-5); 156.2 (С-4); 159.5 (С-2); 163.9 (5-CONH2); 167.8 (CH2CONH2); 180.1 (C-6). Mass spectrum, m/z:
213.6 [M+H]+, 425.5 [2M+H]+. Found, %: C 39.50; H 3.93; N 26.62. C7H8N4O2S. Calculated, %: C 39.62;
H 3.80; N 26.40.
4-Benzylsulfanyl-2-carbamoylmethylpyrimidine-5-carboxamide (5). A 10% aqueous potassium
hydroxide solution (2.40 ml, 4.7 mmol) was added with stirring to a suspension of thioxopyrimidine 4 (1.00 g,
4.7 mmol) in ethanol (20 ml) cooled to 5-7°C. After 2 min, benzyl chloride (0.54 ml, 4.7 mmol) dissolved in
ethanol (5 ml) was added dropwise to the solution obtained. The reaction mixture was stirred at this temperature
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for 2 h and, after ~16 h, diluted with an equal volume of water. The precipitate was filtered off and
recrystallized from ethanol. Yield 0.53 g (37%). White powder; mp 205-208°С. IR spectrum, , cm-1: 3366,
1
3191, 3085 (N–H), 1661 (C=O). Н NMR spectrum, , ppm: 3.38 (2Н, br. s, SCH2); 3.74 (2Н, s, 2-СН2); 6.85
(1Н, br. s) and 7.11 (1Н, br. s, СН2СONH2); 7.17-7.28 (3Н, m, Н Ph); 7.40-7.44 (3H, m, H Ph, 5-CONHА); 7.98
(1Н, br. s, 5-СONHВ); 8.69 (1H, s, Н-4). Mass spectrum, m/z: 303.8 [M+H]+, 605.7 [2M+H]+. Found, %:
C 55.48; H 4.83; N 18.70. C14H14N4O2S. Calculated, %: C 55.62; H 4.67; N 18.53.
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