Synthesis and cyclizations of N-(2,3-, 3,4- and 3,5-dimethylphenyl)-β- alanines

Article abstract of DOI:10.3390/10020407

A series of 1-aryl substituted dihydro-, 5-methyldihydro- and 6-methyldihydro-2,4(1H,3H)pyrimidinediones and their 2-thio analogues were obtained by reaction of the corresponding β-alanines or α-methyl- and β-methyl-β-alanines with urea or potassium thiocyanate. The reaction of N-(2,3- and 3,5-dimethylphenyl)-α-methyl-β-alanines with ethyl acetoacetate gave 1-(2,3- or 3,5-dimethylphenyl)-2,5-dimethyl-1,4,5,6- tetrahydro-4(1H)pyridones. The combined spectral data obtained by ¹H-, ¹³C-, ¹H/¹³C (HETCOR) NMR and IR provided useful information about the structure of the products synthesized in this work.

Full text of DOI:10.3390/10020407

Molecules 2005, 10, 407-416
molecules
ISSN 1420-3049
http://www.mdpi.org
Synthesis and Cyclizations of N-(2,3-, 3,4- and 3,5-Dimethyl-
phenyl)-β-alanines
Rita Vaickelioniene 1, Vytautas Mickevicius 1 and Gema Mikulskiene 2,*
1
Department of Organic Chemistry, Kaunas University of Technology, Radvilenu pl. 19, LT-50299
Kaunas, Lithuania, Tel. (+370) 37 456 561, Fax (+370) 37 300 152
2
Institute of Biochemistry, LT-08662 Vilnius, Mokslininku 12, Lithuania, Tel. (+370) 5 272 9195,
Fax (+370) 5 272 9196
*Author to whom correspondence should be addressed; E-mail: gemam@bchi.lt
Received: 17 February 2004; in revised form: 10 October 2004 / Accepted: 13 October 2004 /
Published: 28 February 2005
Abstract: A series of 1-aryl substituted dihydro-, 5-methyldihydro- and 6-methyl-
dihydro-2,4(1H,3H)pyrimidinediones and their 2-thio analogues were obtained by
reaction of the corresponding β-alanines or α-methyl- and β-methyl-β-alanines with urea
or potassium thiocyanate. The reaction of N-(2,3- and 3,5-dimethylphenyl)-α-methyl-β-
alanines with ethyl acetoacetate gave 1-(2,3- or 3,5-dimethylphenyl)-2,5-dimethyl-
1
1,4,5,6-tetrahydro-4(1H)pyridones. The combined spectral data obtained by H-, 13C-,
1H/13C (HETCOR) NMR and IR provided useful information about the structure of the
products synthesized in this work.
Keywords: N-Aryl-β-alanines, 1-aryl substituted dihydropyrimidinedione, dihydro-
pyrimidinone-2-thione, 1,4,5,6-tetrahydropyridone, NMR spectra, IR spectra
Introduction
N-Aryl-β-alanines can be obtained in different ways. The most convenient method is the reaction
of aromatic amines with α,β-unsaturated acids, their esters and nitriles. Acidic or basic catalysts are
needed in the reactions of amines with the unsaturated acid derivatives, but the reactions of amines
with the unsaturated acids take place much easier than with the other derivatives as the acid itself acts
as a catalyst. N-Substituted β-alanines have been shown to be versatile starting materials for the

Molecules 2005, 10
408
synthesis of a variety of heterocyclic systems, for example, the pyrimidine skeleton that is commonly
found in pharmaceuticals, fungicides and herbicides. We have recently described the synthesis of N-(2-
substituted phenyl)dihydro-2,4(1H,3H) pyrimidinediones and 2-thiones with substituents at the 5- and
6-positions [1,2]. Their structures were confirmed by their NMR spectra and it was shown that most of
5- and 6-methyldihydropyrimidindiones and their 2-thio analogues formed two atropisomers due to the
restricted rotation about the N(1)-C(1’) bond. The problems of structure determination and the energetic
characteristics of this process have been discussed.
Results and Discussion
We now report the synthesis of new N-aryl-β-alanines and their cyclization products. The N-aryl-
β-alanines, N-aryl-α-methyl- and N-aryl-β-methyl-β-alanines described in this work were synthesized
from aromatic amines reacted with acrylic, methacrylic and crotonic acids and were obtained in either
the free form or as the corresponding HCl salts. Scheme 1 illustrates the approach used in the synthesis
of substituted dihydropyrimidinone and hydropyridone derivatives from N-substituted β-alanines.
Scheme 1
1
O
1
2
4
2
R
R
R
R
R
O
O
H3C
1
2
4
C
OH
OH
2 H2C
R
R
R
H
H
OH
OH
3
N
R
NH2
R
3
N
R
4
H3C
OH
OH
O
R
O
1a-c
CH3
O
5 a, c
2a, b
O
OH
H2C
O
1) (NH2)2CO
2) KSCN
H2C
2
1
OH
R
R
R
1
2
R
3
R
2
1
H
N
3
R
R
R
X
N
R
H
NH2
3
N
CH3
OH
R
4
R
OH
3 a-c
4
O
R
4
H3C
1) (NH2)2CO
2) KSCN
4 a-c
O
1
O
O
CH3
H3C
1) (NH2)2CO
2) KSCN
[10] a, c
[11] a, c
1
2
4
R
R
X
N
O
O
NH2
3
2
R
X
N
R
R
HCl
NH2
CH3
3
R
OH
R
2
1
[6] a-c
[7] a-c
O
X
N
R
R
R
O
CH3
H
N
4
OH
1
R
2
H3C
N
O
R
R
R
3
O
R
[8] a,c, 8b
[9] a-c
3
HCl
O
R
4
H3C
4
CH3
1
2
HCl
16 a, c
17 a, c
R
R
R
X
N
H
N
18 a, c
3
O
R
1
2
4
R
R
X
N
H
4
N
3
12 a-c
13 a-c
O
R
R
CH3
14 a-c
15 a-c
a R1 = R2 = CH3; R3 = R4 = H; b R1 = R4 = H; R2 = R3 = CH3; c R1 = R3 = H; R2 = R4 = CH3;
6, 8, 10, 12, 14, 16 X = O; 7, 9, 11, 13, 15, 17 X = S

Molecules 2005, 10
409
1-Aryldihydro-2,4(1H,3H)pyrimidindiones 12, 14, 16 and their 2-thioanalogues 13, 15, 17 were
prepared by condensation of N-aryl-β-alanines or their hydrochlorides 3-5 with urea or potassium
thiocyanate in acetic acid under reflux, followed by cyclization by hydrochloric acid of the
intermediate N-aryl-N-carbamoyl-β-alanines 6, 8, 10 and N-aryl-N-thiocarbamoyl-β-alanines 7, 9, 11
to give the more stable dihydropyrimidinediones 12, 14, 16 and their 2-thioanalogues 13, 15, 17.
The dihydropyrimidindiones and their 2-thio analogues are acid-resistant, but in basic medium they
easily cleave forming the respective salts of N-aryl-N-carbamoyl- and N-aryl-N-thiocarbamoyl-β-
alanines. Compound 14b was cleaved in 10 % sodium hydroxide solution by heating the reaction
mixture to boiling temperature. N-Carbamoyl-β-alanine 8b was separated from reaction mixture by
acidifying this solution with acetic acid. Condensation of N-(2,3-dimethylphenyl)-α-methyl-β-alanine
(4a) and N-(3,5-dimethylphenyl)-α-methyl-β-alanine (4c) with ethyl acetoacetate gave the
corresponding 1-aryl-3-ethoxycarbonyl-2,5-dimethyl-1,4,5,6-tetrahydro-4(1H)pyridones 18.
The structure of the studied compounds was investigated using 1H-, 13C-, 1H/13C (HETCOR) NMR
and IR spectroscopy. The NMR spectra were assigned unambiguously through consideration of the
1
features of H-NMR spectral characteristics, the signal intensity arguments and the additivity rules of
the 13C-NMR spectra, including DEPT 13C-NMR spectral characteristics [3,5].
The substituent increments used in this work were available in literature [3] and were obtained
during the interpretation of spectra of the respective compounds [4]. 1H/13C (HETCOR)-NMR spectra
[5] were used to assist the assignments of the studied compounds, particularly to check the
identification of the resonances of methyl groups located on the benzene and on the heterocyclic ring
as well.
The presence of characteristic splitting of the resonances was observed during the spectroscopic
analysis of compounds 12-18. The c-type compounds presented a single set of the resonances in their
1H- and 13C-NMR spectra. A double set of the resonances for the C-4 atoms was only found in
compounds 12b and 13b. Meanwhile, all a-type compounds produced NMR spectra with split
resonances. Moreover, compounds 14a and 15a showed some additional splitting of the resonances of
the C-2 and C-4 atoms. It has been suggested that such splitting of the resonances of the
aforementioned compounds possessing methyl groups in different locations was caused by the
restricted rotation of benzene and heterocyclic rings around the C(1’)-N(1) bond and the possibility of
the existence of diastereomers.
Conclusions
We have presented the synthesis of new N-aryl-β-alanines and their cyclization products. The
1
structure elucidation of the representative series of the study compounds was carried out using H-,
1
13C-, H/13C (HETCOR) NMR and IR spectroscopy. The examination in detail of the structural
features of the reported compounds was not the aim of this study and will be performed in the planned
subsequent work.

Molecules 2005, 10
410
Experimental
General
1
The H- and 13C-NMR spectra were recorded on a Jeol FX 100 (100 MHz) or Bruker DRX 500
(500 MHz) instruments; chemical shifts are reported in ppm on the δ scale with tetramethylsilane as
the internal reference. The IR spectra were measured in a Perkin-Elmer Spectrum GX FT-IR system.
Silica gel plates (Silufol UV-254) were used for analytical tlc. Spectroscopic data for the prepared
compounds is given in Table 1. Physical properties, analytical data and yields for the prepared
compounds are given in Table 2.
N-Carboxyethyl-N-(2,3- and 3,4-dimethylphenyl)-β-alanine hydrochlorides (2a,b). A solution of the
corresponding dimethylanilines 1a,b (3.03 g, 0.025 mol), water (20 mL) and acrylic acid (5.4 g, 0.075
mol) was heated with stirring for 6 h at 90-100 °C. At the end of reaction period the reaction mixture
was treated with 5 % sodium hydroxide solution (50 mL), cooled and extracted with diethyl ether (3 x
50 mL). The alkaline solution was neutralized with hydrochloric acid and extracted with diethyl ether
(3 x 50 mL). The ethereal solution dried by cooling for 1 h at -20 °C, filtered and saturated ethereal-
hydrogen chloride solution was added. The resulting precipitate was filtered off.
N-(2,3-Dimethylphenyl)-β-alanine (3a). A solution of 2,3-dimethylaniline (1a, 30.3 g, 0.1 mol), acrylic
acid (7.2 g, 0.1 mol) and toluene (100 mL) was stirred for 24 h at 20 °C. Afterwards 5 % sodium
hydroxide (200 mL) was added to the reaction mixture and non-reacted amine was extracted with
diethyl ether (3 x 100 mL). The alkaline solution was neutralized with hydrochloric acid. The obtained
oily residue of β-alanine 3a was washed with water to give a precipitate, which was filtered off and
washed with water.
N-(3,4- and 3,5-Dimethylphenyl)-β-alanine hydrochlorides (3b,c). These compounds were synthesized
from arylamines 1b,c by the procedure described for 3a and were obtained as oily residues. These oily
residues were dissolved in diethyl ether (150 mL), dried by cooling at -20 °C for 1 h filtered and
saturated ethereal – hydrogen chloride solution was added, resulting in a precipitate, which was filtered
off.
N-(2,3- and 3,5-Dimethylphenyl)-α-methyl-β-alanines (4a,c). A solution of the 2,3-dimethylaniline
1a,c (30.3 g, 0.25 mol), methacrylic acid (23.7 g, 0.275 mol), toluene (100 mL) and hydroquinone (1
g) was heated with stirring for 24 h at 70 °C. The solution was then allowed to cool and 5 % sodium
hydroxide (200 mL) was added and non-reacted arylamine was isolated by extraction with toluene (1 x
100 mL) and diethyl ether (2 x 100 mL). The alkaline solution was neutralized with hydrochloric acid,
giving an oily residue of the α-methyl-β-alanines 4a,c, which was washed with water to give a
precipitate that was filtered and washed with water.
N-(3,4-Dimethylphenyl)-α-methyl-β-alanine hydrochloride (4b). A solution of 3,4-dimethylaniline
(1b, 30.3 g, 0.25 mol), methacrylic acid (23.7 g, 0.275 mol), toluene (100 mL) and hydroquinone (1 g)
was heated with stirring for 24 h at 70 °C. The solution was allowed to cool and 5 % sodium hydroxide

Molecules 2005, 10
411
solution (200 mL) was added and non-reacted arylamine was isolated by extraction with toluene (1 x
100 mL) and diethyl ether (2 x 100 mL). The alkaline solution was neutralized with hydrochloric acid
and extracted with diethyl ether (3 x 100 mL). To the ethereal solution saturated ethereal-hydrogen
chloride solution was added and resulting precipitate was filtered off.
N-(2,3- and 3,5-Dimethylphenyl)-β-methyl-β-alanine hydrochlorides (5a,c). A mixture of the
corresponding arylamine 1a, c (23.7 g, 0.275 mol), crotonic acid and toluene (100 mL) was refluxed
for 10 h cooled and 5 % sodium hydroxide solution (200 mL) was added. The toluene layer was
isolated, alkaline solution was extracted with diethyl ether (2 x 100 mL) and neutralized with
hydrochloric acid. The oily residue of β-methyl-β-alanines 5a,c thus obtained was washed with water,
dissolved in diethyl ether (200 mL), dried by cooling 1 h at -20 °C, filtered and saturated ethereal-
hydrogen chloride solution was added, resulting in a precipitate of the corresponding salt which was
filtered off.
N-Carbamoyl-(3,4-dimethylphenyl)-α-methyl-β-alanine (8b). A mixture of dihydropyrimidinedione
14b (2.32 g, 0.01 mol) and 10 % sodium hydroxide (20 mL) was heated up to boiling temperature,
filtered and kept at room temperature for 0.5 h. After that the mixture was acidified with 20 % acetic
acid, the residue filtered off and washed with water.
1-(2,3-, 3,4- and 3,5-dimethylphenyl)dihydro-2,4(1H, 3H)pyrimidinediones (12a-c) and 5-methyl- and
6-methyldihydro-2,4(1H,3H)pyrimidindiones (14a-c, 16a,c). A mixture of the corresponding N-aryl-β-
alanine or hydrochloride 3,4,5 (0.01 mol), urea (2.4 g, 0.02 mol) and acetic acid (10 mL) was heated
under reflux for 14 h, then concentrated hydrochloric acid (5 mL) was added and refluxing was
continued for 0.5 h. The reaction mixture was diluted with water (30 mL) and was kept in cold for
crystallization. The dihydropyrimidinedione precipitates were filtered and washed with water.
1-(2,3-, 3,4- and 3,5-Dimethyl)dihydro-4(1H,3H)pyrimidinon-2-thiones (13a-c), 5-methyl- and 6-
methyldihydro-4(1H,3H)pyrimidinon-2-thiones (15a-c, 17a,c). These compounds were obtained using
the method for preparing 1-arylsubstituted dihydropyrimidinediones 12,14,15 using potassium
thiocyanate instead of urea.
Preparation of 3-ethoxycarbonyl-1-(2,3- and 3,5-dimethylphenyl)-2,5-dimethyl-1,4,5,6-tetrahydro-
4(1H)pyridones (18a,c). A reaction mixture of the corresponding N-aryl-α-methyl-β-alanine 4 (0.05
mol) and ethyl acetoacetate (30 mL) was refluxed for 8 h then cooled down to 20 °C, suspended in 5 %
sodium carbonate solution (200 mL) and boiled. The reaction mixture was cooled down and extracted
with diethyl ether (2 x 100 mL). The ethereal solution was dried with sodium carbonate (20 g) for 30
min, filtered, solvent was evaporated in vacuo, and the residue was washed with cold diethyl ether and
hexane (10 mL).

Molecules 2005, 10
412
Table 1. Spectroscopic data of the prepared compounds
IR (KBr
tabl.)
1H-NMR (solvent)
13C-NMR (solvent)
(d6-DMSO) 2.35 (s, 3H, 2’-CH3Ar),
2.45 (s, 3H, 3’-CH3Ar), 2.30-2.65
(m, 4H, CH2CO), 3.65-3.95 (m, 4H,
CH2NCH2), 7.30-7.90 (m, 3H, Ar),
11.14 (bs, 2H, COOH).
(d6-DMSO) 2.30 (s, 6H, 3’,4’-
CH3Ar), 2.44-2.80 (m, 4H, CH2CO),
3.66-3.98 (m, 4H, CH2NCH2), 7.40-
7.70 (m, 3H, Ar), 10.60 (bs, 2H,
COOH).
2a
2b
–
–
–
–
(d6-acetone) 1.98 (s, 3H, 2’-CH3Ar),
2.18 (s, 3H, 3’-CH3Ar), 2.50-2.72
(m, 2H, CH2CO), 3.32-3.51 (m, 2H,
NCH2), 6.40-7.10 (m, 3H, Ar).
(d6-DMSO) δ: 2.29 (s, 6H, 3’,4’-
CH3Ar), 2.74-3.45 (m, 2H, CH2CO),
3.40-3.62 (m, 2H, NCH2), 7.45-7.60
(m, 3H, Ar), 9.66 (bs, 1H, COOH).
(d6-DMSO) 2.30 (s, 6H, 3’,5’-
CH3Ar), 2.70-2.95 (m, 2H, CH2CO),
3.34-3.60 (m, 2H, NCH2), 7.02-7.25
(m, 3H, Ar), 10.25 (bs, 1H, COOH).
(d6-acetone) 1.24 (d, J = 6.9 Hz, 3H,
CH CH3), 2.02 (s, 3H, 2’-CH3Ar),
2.21 (s, 3H, 3’-CH3Ar), ), 2.65-3.06
(m, 1H, CH), 3.13-3.60 (m, 2H,
NCH2), 6.50-7.10 (m, 3H, Ar).
(d6-DMSO) 1.29 (d, J = 6.9 Hz, 3H,
CH CH3), 2.28 (s, 6H, 3’,4’-CH3Ar),
2.75-3.10 (m, 1H, CH), 3.16-3.65 (m,
2H, NCH2), 7.25-7.50 (m, 3H, Ar),
10.66 (bs, 1H, COOH).
3a
3b
3c
–
–
–
–
–
–
4a
4b
4c
–
–
–
–
–
(CDCl3) 1.25 (d, J = 7.02 Hz, 3H,
CHCH3), 2.23 (s, 6H, 3’,5’-CH3Ar),
2.74-2.90 (m, 1H, CH), 3.14-3.27 (m, 120.22 (Ar-C-4’), 139.01 (Ar-C-3’,5’), 147.44
2H, CH2N), 6.25-6.45 (m, 3H, Ar),
7.5 (bs, 1H, COOH).
(CDCl3) 14.84 (CHCH3), 21.47 (3’,5’-CH3Ar),
39.23 (CH), 47.09 (CH2), 111.39 (Ar-C-2’,6’),
(Ar-C-1’), 181.17 (CO).
(d6-DMSO) 1.36 (d, J = 6.5 Hz, 3H,
CH CH3), 2.34 (s, 3H, 2’-CH3Ar),
2.37 (s, 3H, 3’-CH3Ar), 2.60-3.25
(m, 2H, CH2CO), 3.65-4.15 (m, H,
CH), 7.45-7.65 (m, 3H, Ar), 10.67
(bs, 1H, COOH).
(d6-DMSO) 1.35 (d, J = 6.6 Hz, 3H,
CH CH3), 2.36 (s, 6H, 3’,5’-CH3Ar),
2.50-3.15 (m, 2H, CH2CO), 3.65-
4.10 (m, 1H, CH), 7.02-7.32 (m, 3H,
Ar), 10.70 (bs, 1H, COOH).
5a
5c
–
–
–
–

Molecules 2005, 10
413
Table 1. Cont.
(d6-DMSO) 14.58 (5-CH3), 18.84 (4’-CH3), 19.35 3328.16 (NH),
(d6-DMSO) 1.01 (d, J = 7.0 Hz, 3H,
CHCH3), 2.31 (s, 6H, 3’, 4’-CH3Ar), (3’-CH3), 38.33 (C-5), 51.23 (C-6), 125.16 (Ar-C- 1692.11 (C=O),
2.37-2.56 (m, 1H, CHCO), 3.58-3.79 6’), 128.80 (Ar-C-2’), 130.33 (Ar-C-5’), 134.83 1631.71 (C=O).
8b
(m, 2H, CH2N), 6.99-7.23 (m, 3H,
Ar), 12.20 (bs, 1H, NH).
(Ar-C-4’), 137.37, (Ar-C-3’), 139.90 (Ar-C-1’),
157.41 (C-2), 175.93 (C-4).
(d6-DMSO) 2.01 (s, 3H, 2’-CH3Ar), (d6-DMSO) 13.81 (2’-CH3), 19.92 (3’-CH3), 30.98 3191.75 (NH),
2.21 (s, 3H, 3’-CH3Ar), 2.60-2.89
(m, 2H, CH2CO), 3.40-3.82 (m, 2H,
CH2N), 7.07-7.19 (m, 3H, Ar), 10.32 (Ar-C-3’), 140.79 (Ar-C-1’), 151.70, 151.78 (C-
(C-5), 44.69 (C-6), 124.68 (Ar-C-6’), 125.94 (Ar- 1719.25 (C=O),
C-5’), 128.63 (C-4’), 134.01 (Ar-C-2’), 137.38 1689.35 (C=O).
12a
12b
12c
13a
(bs, 1H, NH).
2), 170.54, 170.63 (C-4).
(d6-DMSO) 2.21 (s, 6H, 3’4’-
CH3Ar), 2.72 (t, J = 6.7 Hz, 2H,
CH2CO), 3.76 (t, J = 6.7 Hz, 2H,
CH2N), 7.00-7.18 (m, 3H, Ar), 10.26 (Ar-C-3’), 139.68 (Ar-C-1’), 152.04 (C-2),
(bs, 1H, NH).
(d6-DMSO) 2.26 (s, 6H, 3’,5’-
CH3Ar), 2.67 (t, J = 6.7 Hz, 3H,
CH2CO), 3.76 (t, J = 6.7 Hz, 2H,
CH2N), 6.87-6.93 (m, 3H, Ar), 10.32 151.98 (C-2), 170.50, (C-4).
(s, 1H, NH).
(d6-DMSO) 2.07 (s, 3H, 2’-CH3Ar),
2.27 (s, 3H, 3-CH3Ar), 2.78-2.92 (m, (C-5), 47.91 (C-6), 124.46 (Ar-C-6’), 126.27 (Ar- 1702.01 (C=O),
2H, CH2CO), 3.66-4.00 (m, 2H, C-5’), 129.09 (Ar-C-4’), 133.08 (Ar-C-2’), 137.56 1213.70
CH2N), 7.05-7.16 (m, 3H, Ar), 11.22 (Ar-C-3’), 143.78 (Ar-C-1’), 166.74, 166.84 (C-
(d6-DMSO) 18.75 (4’-CH3), 19.28 (3’-CH3), 31.03 3221.93 (NH),
(C-5), 44.66 (C-6), 122.60 (Ar-C-6’), 126.39 (Ar- 1737.02 (C=O),
C-2’), 129.45 (Ar-C-5’), 133.86 (Ar-C-4’), 136.37 1689.56 (C=O).
170.41, 170.50 (C-4).
(d6-DMSO) 20.73 (3’,5’-CH3), 31.01 (C-5), 44.59 3207.49 (NH),
(C-6), 122.98 (Ar-C-2’, Ar-C-6’), 127.26 (C-4’),
137.64 (Ar-C-3’, Ar-C-5’), 141.86 (Ar-C-1’),
1727.61 (C=O),
1690.82 (C=O).
(d6-DMSO) 13.79 (2’-CH3), 19.26 (3’-CH3), 30.20 3184.28 (NH),
(>N−CS−N< ).
(bs, 1H, NH).
4), 178.44, 178.57 (C-2).
(d6-DMSO) 2.20 (s, 6H, 3’,4’-
CH3Ar), 2.78 (t, J = 6.9 Hz, 2H,
CH2CO), 3.85 (t, J = 6.9 Hz, 2H,
CH2N), 7.00-7.22 (m, 3H, Ar), 11.13 C-4’), 136.89 (Ar-C-3’), 142.80 (Ar-C-1’),
(bs, 1H, NH).
(d6-DMSO) 18.88 (4’-CH3), 19.26 (3’-CH3),
30.32, 31.02 (C-5), 48.85 (C-6), 124.03 (Ar-C-6’), 1717.41 (C=O),
127.53 (Ar-C-2’), 129.85 (Ar-C-5’), 135.47 (Ar-
3176.11 (NH),
1209.38
(>N−CS−N< ).
13b
13c
166.74, 166.83 (C-4), 179.14(C-2).
(d6-DMSO) 2.28 (s, 6H, 3’,5’-
CH3Ar), 2.78 (t, J = 6.9 Hz, 2H,
CH2CO), 3.85 (t, J = 6.9 Hz, 2H,
(d6-DMSO) 20.67 (3’,5’-CH3), 30.32 (C-5), 48.76 3186.44 (NH),
(C-6), 124.32 (Ar-C-2’, Ar-C-6’), 128.80 (Ar-C- 1736.13 (C=O),
4’), 138.16 (Ar-C-3’, Ar-C-5’), 144.94 (Ar-C-1’), 1219.63
CH2N), 6.85-7.00 (m, 3H, Ar), 11.20 166.84 (C-4), 179.00 (C-2).
(bs, 1H, NH).
(>N−CS−N< ).
(d6-DMSO) 1.12, 1.15 (2d, J = 6.8
Hz, 3H, 5-CH3), 2.04, 2.08 (2s, 3H,
2’-CH3Ar), 2.26 (s, 3H, 3’-CH3Ar),
(d6-DMSO) 12.01, 12.65 (5-CH3), 13.84 (2’-CH3), 3244.38 (NH),
19.86 19.95 (3’-CH3), 34.80 (C-5), 51.01, 51.10
(C-6), 124.18, 125.14 (Ar-C-6’), 125.13, 126.08
1732.98 (C=O),
1694.97 (C=O).
2.80-2.99 (m, 1H, CHCO), 3.38-3.64 (Ar-C-5’), 128.51, 128.76 (Ar-C-4’), 133.87,
14a
14b
(m, 2H, CH2N), 7.05-7.20 (m, 3H,
Ar), 10.29, 10.30 (2bs, 1H, NH).
134.22 (Ar-C-2’), 137.34, 137.38 (Ar-C-3’),
140.67 (Ar-C-1’), 151.83, 151.92, 152.65 (C-2),
173.08, 173.17, 173.27, 173.36 (C-4).
(CDCl3) 1.31 (d, J = 7.0 Hz, 3H, 5-
CH3), 2.26 (s, 6H, 3’,4’-CH3Ar),
2.73-3.00 (m, 1H, CH), 3.51-4.05 (m,
2H, CH2N), 7.03-7.40 (m, 3H, Ar),
7.81 (s, 1H, NH).
–
–
(d6-DMSO) 1.12 (d, J = 7.0 Hz, 3H,
5-CH3), 2.26 (s, 6H, 3’,5’-CH3Ar),
(d6-DMSO) 12.16 (5-CH3), 20.74 (3’,5’-CH3),
3201.75 (NH),
34.89 (C-5), 50.88 (C-6), 122.88 (Ar-C-2’, Ar-C- 1724.34 (C=O),
6’), 127.22 (Ar-C-4’), 137.66 (Ar-C-3’, Ar-C-5’), 1682.58 (C=O).
141.81 (Ar-C-1’), 151.97 (C-2), 173.17, (C-4).
14c 2.74-2.92 (m, 3H, CH2CO), 3.50-
3.75 (m, 2H, CH2N), 6.86, 6.93 (2s,
3H, Ar), 10.30 (bs, 1H, NH).

Molecules 2005, 10
414
Table 1. Cont.
(d6-DMSO) 11.86, 12.05 (5-CH3), 13.85 (2’-CH3), 3177.51 (NH),
(d6-DMSO) 1.15 (d, J = 6.9 Hz. 3H,
5-CH3), 2.05, 2.09 (2s, 3H, 2’-
CH3Ar), 2.26, 2.27 (2s, 3H, 3’-
CH3Ar), 2.98-3.20 (m, 1H, CHCO),
19.78, 19.86 (3’-CH3), 33.93, 34.06 (C-5), 53.77,
53.84 (C-6), 124.16, 124,72 (Ar-C-6’), 126.20,
126.43 (Ar-C-5’), 129.04, 129.15 (Ar-C-4’),
133.04, 133.24 (Ar-C-2’), 137.56 (Ar-C-3’),
143.65 (Ar-C-1’), 169.62, 169.71, 169.84, 169.93
(C-4), 178.31, 178.44, 178.66 (C-2).
1701.97 (C=O),
1210.30
(>N−CS−N< ).
15a
3.65-3.90 (m, 2H, CH2N), 7.00-7.16
(m, 3H, Ar), 11.19, 11.23 (2s, 1H,
NH).
(d6-DMSO) 1.16 (d, J = 6.9 Hz, 3H,
5-CH3), 2.27 (s, 6H, 3’,4’-CH3Ar),
(d6-DMSO) 11.95 (5-CH3), 18.89 (4’-CH3), 19.26 3174.29 (NH),
(3’-CH3), 34.17 (C-5), 54.67 (C-6), 123.99 (C-6’), 1703.01 (C=O),
2.91-3.07 (m, 1H, CHCO), 3.72-3.91 127.46 (Ar-C-2’), 129.85 (Ar-C-5’), 135.46 (Ar-
1211.74
15b
(m, 2H, CH2N), 7.00-7.26 (m, 3H,
Ar), 11.24 (s, 1H, NH).
C-4’), 136.93 (Ar-C-3’), 142.70 (Ar-C-1’), 169.84 (>N−CS−N< ).
(C-4), 179.02 (C-2).
(d6-DMSO) 1.14 (d, J = +6.9 Hz, 3H, (d6-DMSO) 11.92, 14.74 (5-CH3), 20.67, 20.74
5-CH3), 2.33 (s, 6H, 3’,5’-CH3Ar), (3’,5’-CH3), 34.17 (C-5), 54.60 (C-6),
3252.42 (NH),
1730.95 (C=O)
15c 2.88-3.17 (m, 3H, CHCO), 3.69-3.99 124.28,124.87 (Ar-C-2’, Ar-C-6’), 128.77, 129.38 1207.11
(m, 2H, CH2N), 6.85-7.00 (2s, 3H,
Ar), 11.20 (s, 1H, NH).
(C-4’), 138.18, 139.06 (Ar-C-3’, Ar-C-5’), 144.84 (>N−CS−N< ).
(Ar-C-1’), 169.83 (C-4), 178.93 (C-2).
(d6-DMSO) 0.99, 1.17 (2d, J = 5.0
Hz, J = 5.1 Hz, 6-CH3), 2.04, 2.09
(2s, 3H, 2’-CH3Ar), 2.27 (s, 3H, 3’-
(d6-DMSO) 13.78, 14.50 (2’-CH3), 18.17, 18.70
(6-CH3), 19.96 19.98 (3’-CH3), 37.64, 38.16 (C-
5), 50.18, 51.23 (C-6), 125.24, 125,43 (Ar-C-6’),
3185.92 (NH),
1714.33 (C=O),
1678.05 (C=O).
16a CH3Ar), 2.40-3.15 (m, 2H, CH2CO), 125.99, 127.26 (A-C-5’), 128.62, 128.89 (Ar-C-
3.60-4.10 (m, 1H, CHN), 6.95-7.20
(m, 3H, Ar), 10.37 (2bs, 1H, NH).
4’), 134.20,135.42 (Ar-C-2’), 137.16, 137,76 (Ar-
C-3’), 138,81, 139.16 (Ar-C-1’), 151.16, 151.37
(C-2), 169, 94 (C-4).
(d6-DMSO) 1.16 (d, J = 6.6 Hz, 3H,
6-CH3), 2.27 (s, 6H, 3’,5’-CH3Ar),
(d6-DMSO) 18.48 (6-CH3), 20.69 (3’,5’-CH3),
3205.99 (NH),
37.76 (C-5), 51.31 (C-6), 125.02 (Ar-C-2’, Ar-C- 1728.28 (C=O),
6’), 128.10 (Ar-C-4’), 137.91 (Ar-C-3’, Ar-C-5’), 1690.29 (C=O).
16c 2.37-3.15 (m, 3H, CH2CO), 3.90-
4.10 (m, 1H, CHN), 6.93 (s, 3H, Ar), 140.51 (Ar-C-1’), 151.29 (C-2), 169.95 (C-4).
10.35 (bs, 1H, NH).
(d6-DMSO) 1.01, 1.18 (2d, J = 6.7
Hz, 3H, 6-CH3), 2.07 (s, 3H, 3’-
CH3Ar), 2.26, 2.28 (2s, 3H, 2’-
(d6-DMSO) 13.78, 15.00 (2’-CH3), 17.52 18.01
(6-CH3), 19.88 (3’-CH3), 36.90, 37.37, 37.62 (C-
5), 53.69, 55.12 (C-6), 124.73, 125.60 (Ar-C-6’),
3221.61 (NH),
1702.49 (C=O),
1209.98
CH3Ar), 2.50-3.25 (m, 2H, CH2CO), 126.41, 126.50 (Ar-C-5’), 129.00, 129.20 (Ar-C-
(>N−CS−N< ).
17a
17c
3.80-4.25 (m, 1H, CHN), 6.99-7.20
(m, 3H, Ar), 11.27, 11.32 (2s, 1H,
NH).
4’), 133.18, 134.54 (Ar-C-2’), 137.32, 137.86 (Ar-
C-3’), 142.01, 142.15 (Ar-C-1’), 166.35, 166.51
(C-4), 177.92, 178.05 (C-2).
(d6-DMSO) 1.23 (d, J = 6.7 Hz, 3H,
6-CH3), 2.34 (s, 6H, 3’,5’-CH3Ar),
2.45-3.30 (m, 3H, CH2CO), 3.96-
4.12 (m, 1H, CHN), 6.96, 7.04 (2s,
3H, Ar), 11.29 (s, 1H, NH.
(d6-DMSO) 17.63 (6-CH3), 20.66 (3’,5’-CH3),
36.90 (C-5), 55.18 (C-6), 125.01, 125.39 (Ar-C-
2’, Ar-C-6’), 129.07 (Ar-C-4’), 138.20 (Ar-C-3’,
3219.94 (NH),
1734.70 (C=O),
1220.85
Ar-C-5’), 143.62 (Ar-C-1’), 166.34, 166.43 (C-4), (>N−CS−N< ).
177.96 (C-2).

Molecules 2005, 10
415
Table 1. Cont.
(CDCl3) 1.24 (d, J = 6.8 Hz. 3H, 5-
CH3), 1.39 (t, J = 7.1 Hz, 3H,
(CDCl3) 12.88, 13.19 (5-CH3), 14.41
1663.80 (C=O),
1249.25
(COOCH2CH3), 14.21, 14.25 (2’-CH3), 19.17,
COOCH2CH3), 1.96, 1.98 (2s, 3H, 2- 19.33 (2-CH3), 20.36, 20.43 (3’-CH3), 60.49
CH3), 2.19, 2.25 (2s, 3H, 2’-CH3Ar), (COOCH2CH3), 106.02 (C-3), 38.40, 38.49 (C-5),
(C−O−).
2.33, 2.34 (2s, 3H, 3’-CH3), 2.60-
2.82 (m, 1H, CHCO), 3.42-3.70 (m,
2H, CH2N), 4.30 (k, J = 7.1 Hz,
COOCH2CH3), 6.90-7.30 (m, 3H,
Ar).
57.08, 57.28 (C-6), 124,44, 125.15 (Ar-C-6’),
127.00, 127.08 (Ar-C-5’), 130.11, 130.17 (Ar-C-
4’), 133.64, 133.70 (Ar-C-2’), 139.20, 139.25 (Ar-
C-3’), 142.75, 142.81 (Ar-C-1’), 163.47, 163.61
(C-2), 167.99, 168.03 (COOCH2CH3), 190.25,
190.36 (C-4).
18a
(CDCl3) 1.18 (d, J = 6.9 Hz. 3H, 5-
CH3), 1.34 (t, J = 7.1 Hz, 3H,
COOCH2CH3), 2.00 (s, 3H, 2-CH3),
2.34 (s, 6H, 3’,5’-Ar), 2.54-2.73 (m,
1H, CHCO), 3.53-3.83 (m, 3H,
CH2N), 4.28 (k, J = 7.1 Hz, 2H,
COOCH2CH3), 6.77, 6.99 (2s, 3H,
Ar).
(CDCl3) 12.99 (5-CH3), 14.39 (COOCH2CH3),
19.74 (2-CH3), 21.20 (3’,5’-CH3), 38.75 (C-5),
1726.31 (C=O),
1258.74
58.06, (C-6), 60.53 (COOCH2CH3), 106.70 (C-3), (C−O−).
124.11 (Ar-C-2’, C-6’), 129.75 (C-4’), 139.87 (C-
3’,C-5’), 144.05 (Ar-C-1’), 162.54 (C-2), 168.06
(COOCH2CH3), 190.52 (C-4).
18c
Table 2. The physical, analytical and yield data of the studied compounds
Elemental analysis data
(Calculated / Found) %
M. p., ºC;
Molecular
Formula
Yield, %
(Solv.*)
C
H
N
2a
2b
3a
3b
3c
4a
4b
4c
5a
5c
8b
12a
12b
12c
168-195
194-195
101-102
151-158
186-187
100-101
185-186
129-130
166-167
170-172
184-186
204-206
179-181
179-180
C14H19NO4·HCl 55.71 / 55.48 6.69 / 6.58
C14H19NO4·HCl 55.71 / 55.41 6.69 / 6.42
4.64 / 4.32
4.64 / 4.79
7.25 / 7.14
6.10 / 6.34
6.10 / 6.26
6.76 / 6.92
5.75 / 5.49
6.76 / 6.36
5.75 / 5.36
5.75 / 5.61
62.7
54.9
25.7
26.7
37.5
38.0
34.1
58.3
66.7
69.6
75.4
57.6
41.4
29.4
C11H15NO2
68.37 / 68.24 7.82 / 7.68
C11H15NO2·HCl 57.51 / 57.29 7.03 / 7.31
C11H15NO2·HCl 57.51 / 57.28 7.03 / 7.29
C12H17NO2
C12H17NO2·HCl 59.14 / 59.02 7.46 / 7.64
C12H17NO2 69.54 / 69.22 8.27 / 8.11
69.54 / 69.67 8.27 / 8.35
C12H17NO2·HCl 59.14 / 58.98 7.46 / 7.31
C12H17NO2·HCl 59.14 / 58.96 7.46 / 7.28
C13H18N2O3
C12H14N2O2
C12H14N2O2
C12H14N2O2
62.38 / 62.16 7.25 / 7.38 11.19 / 11.32
66.04 / 65.89 6.47 / 6.64 12.84 / 12.66
66.04 / 66.24 6.47 / 6.31 12.84 / 12.61
66.04 / 66.31 6.47 / 6.67 12.84 / 12.65
13a
13b
13c
14a
242-244
247-249
263-264
196-197
C12H14N2OS
C12H14N2OS
C12H14N2OS
C13H16N2O2
61.51 / 61.32 6.02 / 5.84 11.96 / 11.72
61.51 / 61.44 6.02 / 5.87 11.96 / 11.79
61.51 / 61.39 6.02 / 5.79 11.96 / 11.75
67.22 / 67.05 6.94 / 6.77 12.06 / 12.27
51.3
50.9
60.5
60.3

Molecules 2005, 10
416
Table 2. Cont.
14b
14c
15a
15b
15c
135-136
155-156
187-188
188-190
206-208
C13H16N2O2
C13H16N2O2
C13H16N2OS
C13H16N2OS
C13H16N2OS
C13H16N2O2
C13H16N2O2
C13H16N2OS
C13H16N2OS
C18H23NO3
C18H23NO3
67.22 / 67.41 6.94 / 6.78 12.06 / 12.20
67.22 / 67.38 6.94 / 6.81 12.06 / 12.34
62.87 / 62.69 6.49 / 6.65 11.28 / 11.47
62.87 / 62.64 6.49 / 6.35 11.28 / 11.41
62.87 / 62.69 6.49 / 6.62 11.28 / 11.05
67.22 / 67.32 6.94 / 6.75 12.06 / 12.32
67.22 / 67.07 6.94 / 6.72 12.06 / 12.28
62.87 / 62.45 6.49 / 6.58 11.28 / 11.11
62.87 / 62.45 6.49 / 6.31 11.28 / 11.40
78.3
33.2
39.5
38.7
47.8
31.4
38.4
26.6
38.5
17.0
6.6
16a 214 -216
16c
181-182
17a 224 -226
17c
18a
18c
254-255
109-110
111-112
71.73 / 71.55 7.69 / 7.49
71.73 / 71.46 7.69 / 7.82
4.65 / 4.41
4.65 / 4.47
*Solvents for crystallization: 2a,b, 3b,c, 4b, 5a,c – acetic acid, rest – ethanol.
References
1. Baltrusis, R.; Mickevicius, V.; Bylinskaite, J.; Zolotojabko, R.; Liepins, E. Synthesis and structure
of 6-methyl-1-(2-R-phenyl)dihydro-2,4(1H,3H)pyrimidinedione derivatives. Khim. Geterotsikl.
Soedin. 1990, 8, 1096-1106.
2. Mickevicius, V.; Baltrusis, R.; Bylinskaite, J.; Liepins, E.; Zolotojabko, R. Synthesis and structure
of 5-methyl-1-(2-R- phenyl)-dihydro-2,4(1H,3H)pyrimidinediones and its 2-thio analogues. Khim.
Geterotsikl. Soedin. 1991, 9, 1240-1247.
3. Kalinowski, H. O.; Berger, S.; Braun S. 13C-NMR-Spektroskopie. Georg Thieme Verlag: Stuttgart,
New York, 1984; pp. 97-99, 141, 228, 283-286.
4. Beresneviciute, K.; Beresnevicius, Z.; Mikulskiene, G.; Kihlberg, J.; Broddefalk J. 13C-NMR
study of dihydropyrimidinedione and dihydropyrimidine-2-thione derivatives. J. Magn. Reson.
Chem. 1997, 35, 553-555.
5. Duddeck, H.; Dietrich, W.; Tóth, G. Structure Elucidation by Modern NMR; Steinkopff:
Darmstadt; Springer: New York, 1998; pp. 10-14, 23-29.
Sample Availability: Available from the authors with the exception of 6-11.
© 2005 by MDPI (http:www.mdpi.org). Reproduction is permitted for noncommercial purposes.