A simple and efficient one-pot synthesis of 4-alkyl-3,4-dihydropyrimidin- 2(1H)-ones

Article abstract of DOI:10.3184/174751913X13573126386313

4-Alkyl-3,4-dihydropyrimidin-2(1H)-ones possess a number of important properties in comparison with their 4-aryl analogues. We show that these compounds can be synthesised by a simple one-pot reaction of urea or thiourea, different aliphatic aldehydes (from acetaldehyde to valeraldehyde) and various dicarbonyl compounds (ethyl acetoacetate, pentane-2,4-dione, N-(4-chlorophenyl)-3-oxobutanamide, acetoacetaldehyde dimethylacetal) in refluxing DMF or HOAc without use of any catalyst. The methylation of 4-alkyl-5-C(O)R-3,4-dihydropyrimidin-2(1H)-ones leads to 1-methyl derivatives.

Full text of DOI:10.3184/174751913X13573126386313

JOURNAL OF CHEMICAL RESEARCH 2013
RESEARCH PAPER 115
FEBRUARY, 115–118
A simple and efficient one-pot synthesis of 4-alkyl-3,4-dihydropyrimidin-
2(1H)-ones
Maksim A. Kolosov*, Olesia G. Kulyk, Dmitriy A. Beloborodov and Valeriy D. Orlov
Department of Organic Chemistry, V.N. Karazin Kharkiv National University, Svobody sq., 4, 61022, Kharkiv, Ukraine
4-Alkyl-3,4-dihydropyrimidin-2(1H)-ones possess a number of important properties in comparison with their 4-aryl
analogues. We show that these compounds can be synthesised by a simple one-pot reaction of urea or thiourea, dif-
ferent aliphatic aldehydes (from acetaldehyde to valeraldehyde) and various dicarbonyl compounds (ethyl acetoac-
etate, pentane-2,4-dione, N-(4-chlorophenyl)-3-oxobutanamide, acetoacetaldehyde dimethylacetal) in refluxing DMF
or HOAc without use of any catalyst. The methylation of 4-alkyl-5-C(O)R-3,4-dihydropyrimidin-2(1H)-ones leads to
1-methyl derivatives.
Keywords: Biginelli reaction, 3,4-dihydropyrimidin-2(1H)-ones, alkylation, one-pot reaction, aliphatic aldehydes, dicarbonyl
compounds
The Biginelli reaction is an efficient three-component one-
pot protocol for 3,4-dihydropyrimidin-2(1H)-ones(thiones)
synthesis starting from ureas, aldehydes and 1,3-dicarbonyl
compounds.1–4 These compounds have a number of activities
– antiflammatory, antitumour, antiviral, insecticidal etc.3–8
Being aza-analogues of nifedipine and related calcium channel
modulators, 3,4-dihydropyrimidin-2(1H)-ones(thiones) have
been intensively explored.9–13
In comparison with their 4-aryl analogues, 4-alkyl-3,4-dihy-
dropyrimidin-2(1H)-ones have lower molecular weight, lipo-
philicity, and considerable solubility in most organic solvents.
Nevertheless, the most attention is usually paid to the synthesis
of 4-arylsubstituted 3,4-dihydropyrimidin-2(1H)-ones and,
particularly, to the application of new catalysts for Biginelli
reaction.14
EtOH–conc. HCl system for 3 h gave only 5% yield of the
target compound 1f, reflux in HOAc (2 h.) gave 29% and,
finally, reflux in DMF (3 h.) gave 40% yield of the pure
product. The use of such alcohols as n-butanol and n-pentanol
(with the purpose of increasing the reaction temperature) was
limited: on the one hand, their solubility in water was poor
and, on the other hand, the attempt to precipitate the products
with hexane resulted in impurities of the starting compounds
that were insoluble in hexane.
The optimum conditions for compounds 1i–l was reflux in
DMF for 20 min, while the compounds 1a–h, m–o needed 3 h.
of reflux in DMF with further work up (see Experimental).
Compared with their 4-aryl analogues, compounds 1a–o
have significantly better solubility in most organic solvents
and lower melting points (see Table 1).
No systematic investigation of the three-component interac-
tion of urea/thiourea, different aliphatic aldehydes and dicar-
bonyl compounds of different types has previously been carried
out nor has the general procedure of 4-alkyl-3,4-dihydropy-
rimidin-2(1H)-ones synthesis been explored. In the present
work, we have tried to rectify this omission.
We failed to synthesise a target 4-propyl-3,4-dihydropyrim-
idin-2(1H)-one starting from 1,3-cyclohexanedione as dicar-
bonile reagent, urea and propionaldehyde in refluxing DMF.
The only isolated product was Hantzsch-type 3,4,6,7,9,10-
hexahydroacridine-1,8(2H,5H)-dione 2, that agreed well with
the literature20–22 (Scheme 2). Here the molecule of urea
appeared to be the source of ammonia.
We were also unable to obtain 6-unsubstituted compound 3
starting from urea, butyraldehyde and acetoacetaldehyde
dimethylacethal in refluxing DMF. In contrast to compounds
1a–o, compound 3 may be isolated in low yield (23%,
similarly to known procedure5) by refluxing of the starting
materials in glacial HOAc (Scheme 3).
Results and discussion
We have found15 that refluxing DMF seems to be efficient sol-
vent for 4-aryl-3,4-dihydropyrimidin-2(1H)-ones synthesis in
moderate yields. We continued our research and tried to extend
this general protocol for the synthesis of 4-alkylsubstituted
3,4-dihydropyrimidin-2(1H)-ones (Scheme 1).
Working up the optimal conditions for the synthesis of
4-alkyl-3,4-dihydropyrimidin-2(1H)-ones, we tested various
solvents, times of heating and catalysts. The low boiling points
of the starting aldehydes and their solubility in water and reac-
tivity of the starting dicarbonyl compounds were considered.
Compound 1f was used as the model.
Methylation of the compounds 1b,f in MeCN/KOH–H2O,
similarly to the alkylation of their 4-aryl analogues23, afforded
to 1-methyl-3,4-dihydropyrimidin-2(1H)-ones 4a,b (Scheme 4).
The proposed route to compounds 4a,b seemed to be usable
and simple, while an attempt to synthesise the compound 4b
by ternary condensation of N-methylurea, propionaldehyde
and ethyl acetoacetate in DMF gave a large quantity of
impurities and the product was difficult to isolate.
Generally, alcohols were found to be unsatisfactory solvents
for the studied reaction. Reflux of the starting materials in
Scheme 1 Synthesis of 4-Alkyl-3,4-dihydropyrimidin-2(1H)-ones 1a–o.
* Correspondent. E-mail: kolosov@univer.kharkov.ua

116 JOURNAL OF CHEMICAL RESEARCH 2013
Table 1 Yields and melting points of obtained
4-alkyl-3,4-dihydropyrimidin-2(1H)-ones 1a–o
oxygen and standart set of equipment (Khimlaborpribor, Klin).
Their results were found to be in good agreement ( 0.3%) with the
calculated values.
Compd
X
R
Alk Yield of M.p./°C M.p./°C
pure
(lit.)
4-Alkyl-6-methyl-3,4-dihydropyrimidin-2(1H)-ones(thiones)
(1a–h,m,n); general procedure
product/%
A solution of the corresponding urea (16 mmol), appropriate aliphatic
aldehyde (25 mmol) and dicarbonyl compound (16 mmol) in DMF
(5 mL) was heated under reflux for 3 h. The mixture was diluted with
EtOH (10 mL) and poured into water (250 mL). The water phase was
saturated with NaCl, extracted with EtOAc (3 × 30 mL), the extract
was dried over Na2SO4, filtered and the solvent was removed under
reduced pressure to yield crude products 1a–h,m,n which were cryst-
allised from EtOAc–hexane mixture (1:1) to give the pure compounds.
Melting points of the compounds 1a–h,m,n are given in Table 1.
5-Acetyl-4,6-dimethyl-3,4-dihydropyrimidin-2(1H)-one (1a): Pale-
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
O
O
O
O
O
O
O
O
O
O
O
O
S
Me
Me
Me
Me
OEt
OEt
OEt
OEt
Me
Et
41
42
48
35
48
40
58
42
38
77
88
89
25
38
62
186–187 186–18816
172–173 173–17516
139–140 151–15217
Pr
Bu
Me
Et
Pr
Bu
118–119
–
185–187 186–18816
178–179 179–18116
184–185184.5–18518
162–164 161–16319
NHC6H4Cl-p Me
NHC6H4Cl-p Et
NHC6H4Cl-p Pr
NHC6H4Cl-p Bu
259–260
260–262
210–211
118–120
185–186
–
–
–
–
–
1
yellow solid. H NMR (200 MHz, DMSO-D6): δ 1.07 (3H, d, J =
6.4 Hz, CH3), 2.17 (3H, s, CH3), 2.19 (3H, s, CH3), 4.15–4.25 (1H, m,
CH), 7.27 (1H, br. s, NH), 8.99 (1H, br. s, NH). 13C NMR (125 MHz,
DMSO-D6): δ 19.32, 23.61, 30.62, 46.85, 112.08, 147.48, 153.17,
194.54. IR (KBr, cm–1): ν = 1692 (C=O), 1607 (C=C). MS (EI, 70 eV):
m/z = 43(14), 153(100), 168(16) [M]+. Anal. Calcd for C8H12N2O2: C,
57.13; H, 7.19; N, 16.66. Found: C, 56.98; H, 7.20; N, 16.85%.
5-Acetyl-4-ethyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one (1b):
Me
OEt
Et
Et
S
143–144 142–14319
S
NHC6H4Cl-p Et
220–223
–
1
Experimental
Pale-yellow solid. H NMR (200 MHz, DMSO-D6): δ 0.78 (3H, t,
J = 7.7 Hz, CH3), 1.25–1.45 (2H, m, CH2), 2.15 (3H, s, CH3), 2.17
(3H, s, CH3), 3.95–4.15 (1H, m, CH), 7.37 (1H, br. s, NH), 8.91 (1H,
br. s, NH). 13C NMR (125 MHz, DMSO-D6): δ 9.25, 19.32, 30.01,
30.66, 52.10, 110.64, 147.92, 153.34, 194.73. IR (KBr, cm–1): ν =
1707 (C=O), 1681 (C=O), 1615 (C=C). MS (EI, 70 eV): m/z = 68(90),
110(100), 154(90), 183(35) [M+1]+. Anal. Calcd for C9H14N2O2: C,
59.32; H, 7.74; N, 15.37. Found: C, 59.23; H, 7.65; N 15.50%.
5-Acetyl-6-methyl-4-propyl-3,4-dihydropyrimidin-2(1H)-one (1c):
Aliphatic aldehydes, ureas, dicarbonyl compounds, acetoacetaldehyde
dimethylacethal and methyl iodide were commercially available.
Melting points were determined using Koffler hot stage apparatus. 1H
NMR spectra were recorded in DMSO-d6 at 200 MHz using Varian
Mercury VX-200 spectrometer with Si(CH3)4 as internal standard.
13C NMR spectra were recorded in DMSO-d6 at 125 MHz using
Bruker Avance DRX 500 spectrometer with Si(CH3)4 as internal
standard. Chemical shifts are reported in ppm (δ-scale), coupling
constants for 1H NMR spectra (3J) are given in Hz. Mass-spectra (EI,
70 eV) were obtained using Varian 1200L instrument using direct
probe exposure method. IR spectra were recorded using Specord
IR-75 spectrometer on KBr pellets. Elemental analyses (N) were
performed by the Dumas method, using a Dumas–Pregl–Korshun set
of equipment (Khimlaborpribor, Klin). Elemental analyses (C, H)
were performed using combustion procedure in low flow rate of
1
Pale-yellow solid. H NMR (200 MHz, DMSO-D6): δ 0.82 (3H, t,
J = 6.7 Hz, CH3), 1.15–1.37 (4H, m, 2CH2), 2.15 (3H, s, CH3), 2.16
(3H, s, CH3), 4.00–4.15 (1H, m, CH), 7.39 (1H, br. s, NH), 8.92 (1H,
br. s, NH). 13C NMR (125 MHz, DMSO-D6): δ 14.26, 17.70, 19.33,
30.68, 39.40, 50.55, 111.18, 147.85, 153.32, 194.59. IR (KBr, cm–1):
ν = 1701 (C=O), 1679 (C=O), 1609 (C=C). MS (EI, 70 eV): m/z =
110(18), 153(100), 196(6) [M]+. Anal. Calcd for C10H16N2O2: C,
61.20; H, 8.22; N, 14.27. Found: C, 61.08; H, 8.26; N, 14.38%.
5-Acetyl-4-butyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one (1d):
1
Pale-yellow solid. H NMR (200 MHz, DMSO-D6): δ 0.82 (3H, t,
J = 6.7 Hz, CH3), 1.05–1.45 (6H, m, 3CH2), 2.15 (3H, s, CH3), 2.16
(3H, s, CH3), 4.00–4.15 (1H, m, CH), 7.38 (1H, br. s, NH), 8.90 (1H,
br. s, NH). 13C NMR (125 MHz, DMSO-D6): δ 14.47, 19.33, 22.51,
26.64, 30.63, 36.83, 50.76, 111.20, 147.79, 153.29, 194.51. IR (KBr,
cm–1): ν = 1720 (C=O), 1626 (C=C). MS (EI, 70 eV): m/z = 68(100),
110(55), 153(85), 195(5), 210(5) [M]+. Anal. Calcd for C11H18N2O2:
C, 62.83; H, 8.63; N, 13.32. Found: C, 63.02; H, 8.60; N, 13.45%.
Ethyl 4,6-dimethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carbo-
xylate (1e): Pale-yellow solid. 1H NMR (200 MHz, DMSO-D6): δ 1.07
(3H, d, J = 6.2 Hz, CH3), 1.17 (3H, t, J = 7.3 Hz, CH3), 2.13 (3H, s,
CH3), 3.9–4.2 (3H, m, CH + CH2), 7.20 (1H, br. s, NH), 8.97 (1H, br.
s, NH). 13C NMR (125 MHz, DMSO-D6): δ 14.71, 18.15, 23.87, 46.79,
59.55, 101.00, 148.20, 153.05, 165.84. IR (KBr, cm–1): ν = 1706
(C=O), 1655 (C=O). MS (EI, 70 eV): m/z = 110(15), 137 (25),
155(80), 183(100), 198(5) [M]+. Anal. Calcd for C9H14N2O3: C, 54.53;
H, 7.12; N, 14.13. Found: C, 54.51; H, 7.01; N, 14.30%.
Scheme 2 Synthesis of 9-ethyl-3,4,6,7,9,10-
hexahydroacridine-1,8(2H,5H)-dione 2.
Ethyl 4-ethyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-car-
1
boxylate (1f): Pale-yellow solid. H NMR (200 MHz, DMSO-D6):
Scheme 3 Synthesis of compound 3.
δ 0.76 (3H, t, J = 7.6 Hz, CH3), 1.16 (3H, t, J = 7.0 Hz, CH3), 1.30–
1.50 (2H, m, CH2), 2.14 (3H, s, CH3), 3.90–4.16 (3H, m, CH + CH2),
7.27 (1H, br. s, NH), 8.91 (1H, br. s, NH). 13C NMR (125 MHz,
DMSO-D6): δ 8.96, 14.70, 18.20, 30.12, 51.86, 59.51, 99.30, 148.85,
153.35, 166.00. IR (KBr, cm–1): ν = 1724 (C=O), 1674 (C=O), 1644
(C=C). MS(EI, 70eV):m/z=137(15), 155(34), 183(100), 212(5) [M]+.
Anal. Calcd for C10H16N2O3: C, 56.59; H, 7.60; N, 13.20. Found: C,
56.65; H, 7.70; N, 13.34%.
Ethyl6-methyl-2-oxo-4-propyl-1,2,3,4-tetrahydropyrimidine-5-car-
1
boxylate (1g): Pale-yellow solid. H NMR (200 MHz, DMSO-D6):
δ 0.82 (3H, t, J = 6.7 Hz, CH3), 1.16 (3H, t, J = 6.95 Hz, CH3), 1.15–
1.50 (4H, m, 2CH2), 2.14 (3H, s, CH3), 3.95–4.15 (3H, m, CH + CH2),
7.29 (1H, br. s, NH), 8.90 (1H, br. s, NH). 13C NMR (125 MHz,
DMSO-D6): δ 14.24, 14.71, 17.50, 18.18, 39.52, 50.31, 59.52, 99.94,
Scheme 4 Alkylation of compounds 1b,f.

JOURNAL OF CHEMICAL RESEARCH 2013 117
148.72, 153.30, 165.93. IR (KBr, cm–1): ν = 1715 (C=O), 1668 (C=O).
MS (EI, 70 eV): m/z = 110(75), 137(80), 155(100), 184 (95),
227(25) [M+1]+. Anal. Calcd for C11H18N2O3: C, 58.39; H, 8.02; N,
12.38. Found: C, 58.35; H, 7.91; N, 12.51%.
CH), 7.16 (1H, br. s, NH), 7.31 (2H, d, J = 8.5 Hz, ArH), 7.63 (2H, d,
J = 8.5 Hz, ArH) 8.51 (1H, br. s, NH), 9.68 (1H, br. s, NH). IR (KBr,
cm–1): ν = 1718 (C=O), 1670 (C=O), 1492 (C=C). 13C NMR
(125 MHz, DMSO-D6): δ 14.65, 17.60, 22.74, 26.41, 37.40, 52.07,
106.14, 121.78, 127.22, 129.07, 139.00, 139.29, 153.86, 166.59. MS
(EI, 70 eV): m/z = 137(80), 195(85), 264(100), 321(5) [M]+. Anal.
Calcd for C16H20ClN3O2: C, 59.72; H, 6.26; N, 13.06. Found: C, 60.08;
H, 6.56; N, 13.03%.
Ethyl 4-butyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-car-
1
boxylate (1h): Pale-yellow solid. H NMR (200 MHz, DMSO-D6):
δ 0.82 (3H, t, J = 6.7 Hz, CH3), 1.16 (3H, t, J = 6.95 Hz, CH3), 1.1–
1.44 (6H, m, 3CH2), 2.14 (3H, s, CH3), 3.95–4.15 (3H, m, CH + CH2),
7.30 (1H, br. s, NH), 8.91 (1H, br. s, NH). 13C NMR (125 MHz,
DMSO-D6): δ 14.40, 14.70, 18.18, 22.41, 26.40, 36.90, 50.53, 59.51,
99.95, 148.70, 153.31, 165.94. IR (KBr, cm–1): ν = 1726 (C=O), 1707
(C=O), 1652 (C=C). MS (EI, 70 eV): m/z = 137(25), 155(35),
183(100), 195(5), 241(5) [M+1]+. Anal. Calcd for C12H20N2O3: C,
59.98; H, 8.39; N, 11.66. Found: C, 60.09; H, 8.63; N, 11.43%.
5-Acetyl-4-ethyl-6-methyl-3,4-dihydropyrimid-2(1H)-thione (1m):
N-(4-chlorophenyl)-4-ethyl-6-methyl-2-thioxo-1,2,3,4-tetrahydro-
1
pyrimidine-5-carboxamide (1o): Yellow solid. H NMR (200 MHz,
DMSO-D6): δ 0.81 (3H, t, J = 7.0 Hz, CH3), 1.27–1.54 (2H, m, CH2),
1.94 (3H, s, CH3), 4.13–4.27 (1H, m, CH), 7.31 (2H, d, J = 8.5 Hz,
ArH), 7.63 (2H, d, J = 8.5 Hz, ArH), 8.99 (1H, br. s, NH), 9.75 (1H,
br. s, NH), 9.82 (1H, br. s, NH). IR (KBr, cm–1): ν = 1682 (C=O), 1493
(C=C). 13C NMR (125 MHz, DMSO-D6): δ 8.55, 16.87, 29.80, 53.36,
107.10, 121.72, 127.36, 128.96, 136.50, 138.52, 166.01, 175.34. MS
(EI, 70 eV): m/z = 127(95), 153(100), 183(85), 280(80), 309(10) [M]+.
Anal. Calcd for C14H16ClN3OS: C, 54.28; H, 5.21; N, 13.56. Found: C,
54.15; H, 5.34; N, 13.34%.
1
Pale-yellow solid. H NMR (200 MHz, DMSO-D6): δ 0.76 (3H, t,
J = 7.3 Hz, CH3), 1.25–1.45 (2H, m, CH2), 2.20 (3H, s, CH3), 2.22
(3H, s, CH3), 4.04–4.19 (1H, m, CH), 9.30 (1H, br. s, NH), 10.05 (1H,
br. s, NH). IR (KBr, cm–1): ν = 1610 (C=C). 13C NMR (125 MHz,
DMSO-D6): δ 8.90, 18.63, 29.56, 30.75, 52.29, 111.23, 144.60,
174.41, 195.35. MS (EI, 70eV): m/z = 43(10), 169(100), 198(20)
[M]+. Anal. Calcd for C9H14N2OS: C, 54.52; H, 7.12; N, 14.13. Found:
C, 54.59; H, 6.87; N, 13.90%.
Ethyl 4-ethyl-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-
carboxylate (1n): Pale-yellow solid. 1H NMR (200 MHz, DMSO-D6):
δ 0.76 (3H, t, J = 7.6 Hz, CH3), 1.16 (3H, t, J = 7.0 Hz, CH3), 1.30–
1.50 (2H, m, CH2), 2.19 (3H, s, CH3), 3.98–4.15 (3H, m, CH + CH2),
9.20 (1H, br. s, NH), 10.06 (1H, br. s, NH). IR (KBr, cm–1): ν = 1708
(C=O), 1578 (C=C). 13C NMR (125 MHz, DMSO-D6): δ 8.66, 14.65,
17.59, 29.72, 52.16, 59.92, 100.56, 145.82, 165.74, 175.58. MS (EI,
70 eV): m/z = 171(30), 199(100), 228(10) [M]+. Anal. Calcd for
C10H16N2O2S: C, 52.61; H, 7.06; N, 12.27. Found: C, 52.49; H, 6.95;
N, 12.01%.
9-Ethyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione (2): A
solution of urea (0.4 g, 6.67 mmol), propionaldehyde (0.6 g, 10.3 mmol)
and 1,3-cyclohexanedione (0.75 g, 6.69 mmol) in DMF (5 mL) was
heated under reflux during 3 h. The mixture was diluted with EtOH
(10 mL) and poured into water (250 mL). Water phase was saturated
with NaCl, extracted with EtOAc (3 × 30 mL), extract as dried over
Na2SO4, filtered and solvent was removed under reduced pressure
to give 0.11 g of product 2. Yield of pure product 15%. Colourless
1
crystals, m.p. 275–277 °C (lit.22 262–264 °C). H NMR (200 MHz,
DMSO-D6): δ 0.56 (3H, t, J = 7.0 Hz, CH3), 1.05–1.25 (2H, m, CH2),
1.65–2.00 (4H, m, 2CH2), 2.05–2.30 (4H, m, 2CH2), 2.30–2.47 (4H,
m, 2CH2), 3.81 (1H, t, J = 4.8 Hz, CH), 9.12 (1H, br. s, NH). 13C NMR
(125 MHz, DMSO-D6): δ 9.57, 21.71, 26.98, 27.64, 27.86, 37.57,
111.73, 152.92, 195.80. IR (KBr, cm–1): ν = 3290 (N–H), 1599 (C=O),
1478 (C=C). MS (EI, 70eV): m/z = 160(20), 216(100), 245(5) [M+1]+.
Anal. Calcd for C15H19NO2: C, 73.44; H, 7.81; N, 5.71. Found: C,
73.25; H, 8.07; N, 5.84%.
4-Alkyl-6-methyl-3,4-dihydropyrimidin-2-oxo(thioxo)-5-(N-4-chloro-
phenyl)carboxamides (1i-l,o); general procedure
A solution of urea or thiourea (6.67 mmol), appropriate aliphatic alde-
hyde (10 mmol), N-(4-chlorophenyl)acetoacetamide (0.016 mol) and
DMF (0.4 mL) was heated under reflux for 20 min. The mixture was
cooled and diluted with 70% aqueous MeOH (4 mL). The precipitate
was filtered off, air-dried and crystallised from 70 % aqueous MeOH
to give pure compounds. Melting points of the compounds 1i–l,o are
given in Table 1.
N-(4-chlorophenyl)-4,6-dimethyl-2-oxo-1,2,3,4-tetrahydropyrimi-
dine-5-carboxamide (1i): Yellow solid. 1H NMR (200 MHz, DMSO-
D6): δ 1.12 (3H, d, J = 2.92 Hz, CH3), 1.92 (3H, s, CH3), 4.17–4.33
(1H, m, CH), 7.07 (1H, br. s, NH), 7.31 (2H, d, J = 8.5 Hz, ArH), 7.63
(2H, d, J = 8.5 Hz, ArH), 8.55 (1H, br. s, NH), 9.66 (1H, br. s, NH).
IR (KBr, cm–1): ν = 1698 (C=O), 1595 (C=O), 1491 (C=C). MS (EI,
70eV): m/z = 127(100), 153(30), 279(30) [M]+. Anal. Calcd for
C13H14ClN3O2: C, 55.82; H, 5.04; N, 15.02. Found: C, 56.01; H, 4.77;
N, 14.97%.
5-Acetyl-4-propyl-3,4-dihydropyrimidin-2(1H)-one (3): A solution
of urea (10 mmol, 0.60 g), butyraldehyde (15 mmol, 1.35 mL) and
acetoacetaldehyde dimethylacethal (10 mmol, 1.32 mL) in glacial
HOAc (8 mL) was heated under reflux during 1 h. The mixture was
cooled, poured into water (160 mL) and neutralised with saturated
solution of Na2CO3. Water phase was saturated with NaCl, extracted
with EtOAc (3 × 30 mL), extract was dried over Na2SO4, filtered and
solvent was removed under reduced pressure to yield oil-like crude
product 3, which was further recrystallised from EtOAc–hexane
mixture (1:1) to give pure compound 3 (0.38 g, yield of pure product
1
23%). Pale-yellow solid, m.p. 195–196 °C. H NMR (200 MHz,
DMSO-D6): δ 0.81 (3H, t, J = 7.00 Hz, CH3), 1.05–1.40 (4H, m,
2CH2), 2.12 (3H, s, CH3), 4.07–4.2 (1H, m, CH), 7.22 (1H, br. s, NH),
7.33 (1H, d, J = 5.8 Hz, C(6)H), 9.02 (1H, br. d, J = 5.8 Hz, NH). IR
(KBr, cm–1): ν = 2929 (=C-H), 1701 (C=O), 1672 (C=O), 1618 (C=C).
13C NMR (125 MHz, DMSO-D6): δ 14.32, 17.24, 24.92, 49.52,
114.20, 139.63, 152.87, 193.51. MS (EI, 70 eV): m/z = 43(15),
139(100), 182(5) [M]+. Anal. Calcd for C9H14N2O2: C, 59.32; H, 7.74;
N, 15.37. Found: C, 59.26; H, 8.00; N, 15.01%.
1,6-Dimethyl-4-ethyl-3,4-dihydropyrimidin-2(1H)-ones (4a,b): A
mixture of corresponding compound 1 (2.8 mmol), methyl iodide
(16 mmol, 1.05 mL) and saturated water solution of KOH (1.5 mL) in
acetonitrile (9 mL) was heated under reflux during 1 h. The mixture
was poured into brine (50 mL), water phase was extracted with EtOAc
(4 x 30 mL), extract was dried over Na2SO4, filtered and solvent
was removed under reduced pressure to yield pure corresponding
compound 4.
5-Acetyl-4-ethyl-1,6-dimethyl-3,4-dihydropyrimidin-2(1H)-one
(4a): Pale-yellow solid, yield 71% (pure product), m.p. 109–111 °C.
1H NMR (200 MHz, DMSO-D6): δ 0.77 (3H, t, J = 7.7 Hz, CH3),
1.25–1.42 (2H, m, CH2), 2.18 (3H, s, CH3), 2.29 (3H, s, CH3), 3.02
(3H, s, NCH3), 3.90–4.00 (1H, m, CH), 7.60 (1H, br. d, J = 4.0 Hz,
NH). 13C NMR (125 MHz, DMSO-D6): δ 9.46, 17.10, 29.59, 30.16,
30.54, 51.20, 113.74, 148.94, 154.01, 196.11. IR (KBr, cm–1): ν =
1699 (C=O), 1659 (C=O), 1592 (C=C). MS (EI, 70 eV): m/z = 43(25),
167(100), 196(5) [M]+. Anal. Calcd for C10H16N2O2: C, 61.20; H, 8.22;
N, 14.27. Found: C, 60.99; H, 7.95; N, 13.98%.
N-(4-chlorophenyl)-4-ethyl-6-methyl-2-oxo-1,2,3,4-tetrahydro-
1
pyrimidine-5-carboxamide (1j): Yellow solid. H NMR (200 MHz,
DMSO-D6): δ 0.81 (3H, t, J = 7.0 Hz, CH3), 1.27–1.60 (2H, m, CH2),
1.92 (3H, s, CH3), 4.13–4.27 (1H, m, CH), 7.10 (1H, br. s, NH), 7.31
(2H, d, J = 8.5 Hz, ArH), 7.61 (2H, d, J = 8.5 Hz, ArH), 8.48 (1H,
br. s, NH), 9.66 (1H, br. s, NH). IR (KBr, cm–1): ν = 1675 (C=O), 1635
(C=O), 1589 (C=C). MS (EI, 70 eV): m/z = 127(60), 167(100),
264(25), 293(5) [M]+. Anal. Calcd for C14H16ClN3O2: C, 57.24; H,
5.49; N, 14.30. Found: C, 57.43; H, 5.44; N, 14.50%.
N-(4-chlorophenyl)-6-methyl-2-oxo-4-propyl-1,2,3,4-tetrahydro-
1
pyrimidine-5-carboxamide (1k): Yellow solid. H NMR (200 MHz,
DMSO-D6): δ 0.81 (3H, t, J = 7.0 Hz, CH3), 1.05–1.46 (4H, m, 2CH2),
1.92 (3H, s, CH3), 4.10–4.27 (1H, m, CH), 7.17 (1H, br. s, NH), 7.30
(2H, d, J = 8.5 Hz, ArH), 7.62 (2H, d, J = 8.5 Hz, ArH), 8.50 (1H, br.
s, NH), 9.66 (1H, br. s, NH). IR (KBr, cm–1): ν = 1697 (C=O), 1675
(C=O), 1490 (C=C). 13C NMR (125 MHz, DMSO-D6): δ 14.33, 14.40,
17.41, 40.96, 51.79, 106.00, 121.61, 127.04, 128.89, 138.84, 139.11,
153.60, 166.42. MS (EI, 70 eV): m/z = 137(100), 181(90), 264(95),
307(5) [M]+. Anal. Calcd for C15H18ClN3O2: C, 58.54; H, 5.89; N,
13.65. Found: C, 58.65; H, 6.02; N, 13.90%.
4-Butyl-N-(4-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-
1
pyrimidine-5-carboxamide (1l): Yellow solid. H NMR (200 MHz,
DMSO-D6): δ 0.82 (3H, t, J = 6.71 Hz, CH3), 1.19–1.38 (4H, m,
Ethyl 4-ethyl-1,6-dimethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-
2CH2), 1.40–1.50 (2H, m, CH2), 1.96 (3H, s, CH3), 4.20–4.25 (1H, m,
carboxylate (4b): Pale-yellow solid, yield 78% (pure product), m.p.

118 JOURNAL OF CHEMICAL RESEARCH 2013
1
T.V. Olah, J.D. Ellis, A. Barrish, K. Kassahun, P. Leppert, D. Nagarathnam
and C. Forray, J. Med. Chem., 2000, 43, 2703.
X.-F. Zhu and D.-Q. Shi, J. Heterocycl. Chem., 2011, 48, 572.
R.H. Tale, A.H. Rodge, G.D. Hatnapure and A.P. Keche, Bioorg. Med.
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A. Dondoni and A. Massi, Mol. Diversity, 2003, 6, 261.
G. Zigeuner, C. Knopp and H. Blaschke, Monats. Chem., 1976, 107, 587.
100–101 °C. H NMR (200 MHz, DMSO-D6): δ 0.76 (3H, t, J =
7.7 Hz, CH3), 1.17 (3H, t, J = 7.7 Hz, CH3), 1.27–1.46 (2H, m, CH2),
2.38 (3H, s, CH3), 3.03 (3H, s, NCH3), 3.87–4.03 (1H, m, CH), 4.00–
4.15 (2H, m, OCH2), 7.51 (1H, br. d, J = 4.0 Hz, NH). 13C NMR
(125 MHz, DMSO-D6): δ 9.33, 14.65, 16.38, 29.58, 30.08, 50.64,
59.77, 103.05, 150.68, 154.06, 166.17. IR (KBr, cm–1): ν = 1689
(C=O), 1624 (C=C). MS (EI, 70 eV): m/z = 151(50), 169(55),
197(100), 226(5) [M]+. Anal. Calcd for C11H18N2O3: C, 58.39; H, 8.02;
N, 12.38. Found: C, 57.98; H, 7.86; N, 12.40%.
6
7
8
9
10 Ye.L. Khanina, D.Kh. Mutsenietse and G.Ya. Duburs, Chem. Heterocycl.
Comp., 1984, 20, 431.
11 K.S. Atwal, G.C. Rovnyak, B.C. O’Reilly and J. Schwartz, J. Org. Chem.,
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12 J.J. Vanden Eynde, N. Audiart, V. Canonne, S. Michel and Van Haverbeke,
We thank V.V. Vashchenko, E.V. Vashchenko, V.I. Musatov
(STC “Instituute for Single Crystalls” NAS of Ukraine) and
Enamine Ltd. for spectral measurements.
Heterocycles, 1997, 45, 1967.
13 S.V. Ryabukhin, A.S. Plaskon, E.N. Ostapchuk, D.M. Volochnyuk and
A.A. Tolmachev, Synthesis, 2007, 3, 0417.
14 M.A. Kolosov, V.D. Orlov, D.A. Beloborodov and V.V. Dotsenko, Mol.
Diversity, 2009, 13, 5.
Received 7 September 2012; accepted 30 December 2012
Paper 1201501 doi: 10.3184/174751913X13573126386313
Published online: 13 February 2013
15 M.A. Kolosov, V.D. Orlov, V.V. Vashchenko, S.V. Shishkina and
O.V. Shishkin, Collect. Czech. Chem. Commun., 2007, 72, 1219.
16 M. Wang, H. Jiang and Z. Wang, J. Chem. Res., 2005, 691.
17 H. Xu and Y.-G. Wang, J. Chem. Res. (S), 2003, 377.
18 A.D. Shutalev and N.V. Sivova, Chem. Heterocycl. Comp., 1998, 34, 848.
19 A. Mobinikhaledi, N. Forughifar, J.A. Safari and E. Amini, J. Heterocycl.
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20 A.A. Bakibayev and V.D. Filimonov, Zh. Org. Khim., 1991, 27, 854.
21 N.N. Tonkikh, A. Strakovs and M.V. Petrova, Chem. Heterocycl. Comp.,
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22 S. Chandrasekhar, Y.S. Rao, L. Sreelakshmi, B. Mahipal and C.R. Reddy,
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23 Ye.L. Khanina, M.B. Andaburskaya, G.Ya. Duburs and R.M. Zolotoyabko,
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