Synthesis and properties of methyl hydropyrimidineacetates

Article abstract of DOI:10.1007/s10593-007-0146-2

The alkylation of 1-aryl-substituted dihydro-2,4(1H,3H)-pyrimidinediones with methyl 2-bromoacetate has been studied followed by hydrolysis and condensation of the products with o-phenylenediamine. The compounds have been identified by NMR, and IR spectro

Full text of DOI:10.1007/s10593-007-0146-2

Chemistry of Heterocyclic Compounds, Vol. 43, No. 7, 2007
SYNTHESIS AND PROPERTIES OF METHYL
HYDROPYRIMIDINEACETATES
K. Brokaite1, V. Mickevičius1, and G. Mikulskiene2
The alkylation of 1-aryl-substituted dihydro-2,4(1H,3H)-pyrimidinediones with methyl 2-bromoacetate
has been studied followed by hydrolysis and condensation of the products with o-phenylenediamine. The
compounds have been identified by NMR, and IR spectrometry and mass spectrometry. Structural
characteristics in the 1H and 13C NMR spectra of the synthesized are discussed.
Keywords: 1-aryldihydro-2,4(1H,3H)-pyrimidinedione, benzimidazoles, hydropyrimidineacetic acids,
alkylation, condensation, NMR, IR, mass spectrometry.
Pyrimidineacetic acids and their derivatives possess biological activity [1-4]. However there is no
information on the synthesis of dihydropyrimidineacetic acids. The objective of our work was the synthesis and
investigation of some chemical properties of the products of alkylation of 1-aryl-substituted dihydro-
2,4-(1H,3H)-pyrimidinediones with methyl bromoacetate.
Scheme 1
OMe
O
OH
O
O
O
N
O
N
1. NaH
2. BrCH2COOMe
H
N
N
N
HCl
2'
N
O
R
R
O
O
R
4'
6'
5'
3a-e
1a-e
2a-e
c
b
NH2
NH2
c
b
g
d
g
N
d
e
N
f
HCl
N
e
a
O
H
f
N
O
a
NH
H
b'
H
N
g'
N
+
R
N
N
+
c'
d'
N
O
R
R
N
N
H
a'
N
f'
e'
H
4a–e
5a, b, e
6c, d
a R = Ph, b R = 4-MeC6H4, c R = 2,4-Me2C6H3, d R = 2-Me-5-ClC6H3,
e R = 4-Me-3-ClC6H3
__________________________________________________________________________________________
1Kaunas Technological University, Kaunas LT-50524, Lithuania; e-mail: Vytautas.Mickevicius@ktu.lt.
2Institute of Biochemistry, Vilnius LT-08622, Lithuania; e-mail: gemam@bchi.lt. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 7, 1095-1105, July, 2007. Original article submitted March 11, 2006.
926
0009-3122/07/4307-0926©2007 Springer Science+Business Media, Inc.

Table 1. Characteristics of the Compounds Synthesized.
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Rf*
mp, °С*2
Yield, %
C
H
N
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
5a
5b
5e
6c
6d
C13H14N2O4
C14H16N2O4
C15H18N2O4
C14H15ClN2O4
C14H15ClN2O4
C12H12N2O4
C13H14N2O4
C14H16N2O4
C13H13ClN2O4
C13H13ClN2O4
C18H16N4O2
C19H18N4O2
C20H20N4O2
C19H17ClN4O2
C19H17ClN4O2
C15H15N3
59.54
59.16
60.86
60.66
62.06
62.43
54.11
53.89
54.11
54.35
58.06
58.21
59.54
59.21
60.86
60.57
52.62
52.23
52.62
52.37
67.49
67.62
68.25
68.59
68.95
68.88
61.88
61.55
61.88
61.73
75.92
75.82
5.38
5.46
5.84
5.48
6.25
5.99
4.87
4.63
4.87
4.53
4.87
4.75
5.38
5.03
5.84
5.49
4.42
4.34
4.42
4.17
5.03
5.36
5.43
5.46
5.79
5.43
4.65
4.36
4.65
4.60
6.37
6.30
10.68
10.34
10.14
10.39
9.65
9.58
9.02
8.96
9.02
9.31
11.29
11.13
10.68
10.57
10.14
10.32
9.44
9.28
9.44
9.31
17.49
17.55
16.76
16.49
16.08
16.30
15.19
15.11
15.19
15.36
17.71
17.56
110-111
108-109
120-121
97-98
40
55
30
66
92
38
72
51
56
64
21
43
38
42
30
11
11
14
23
24
101-102
149-150
202-203
165 (dec.)
184-185
143-144
230 (dec.)
245-246
193-194
128-129
159 (dec.)
Resin
0.41
0.46
0.55
0.59
0.52
0.64
0.62
0.73
0.23
0.2
C16H17N3
76.46
76.63
67.25
67.33
71.43
71.21
65.48
65.43
6.82
6.56
5.64
5.43
6.18
5.98
5.35
5.05
16.72
16.59
14.70
14.89
19.27
19.16
18.03
18.31
Resin
C16H16ClN3
C26H26N6O
145 (dec.)
151-152
149-150
C25H23ClN6O
_______
* Acetone–hexane, 1:1
*2 Solvents: toluene (compounds 2a,b,d,e) and 2-propanol (compound 2c).
We have established that the reaction of 1-aryl-substituted dihydro-2,4(1H,3H)-pyrimidinediones 1a-e
with methyl bromoacetate in DMF in the presence of sodium hydroxide occurred uniquely to give the products
of N-alkylation – methyl 2-[3-aryl-2,6-dioxohexahydro-1-pyrimidyl]acetates 2a-e, separated from the reaction
mixture by dilution with water and ice. The dihydropyrimidineacetic acids 3a-e were prepared by boiling the
corresponding esters 2a-e in 10% hydrochloric acid with subsequent cooling of the reaction mixture to 4°C.
The possibility of synthesis of benzimidazole system by the Phillips method from the carboxylic acids
and o-phenylenediamine was explored. On investigating the products of the condensation of the methyl esters
2a-e with o-phenylenediamine in 4M hydrochloric acid it appeared that two products were formed in each
reaction – 1-aryl-3-(1H-benzimidazolylmethyl)dihydropyrimidine-2,4(1H,3H)-diones 4a-e and products of the
decompo-sition of the hydropyrimidine ring – N-aryl-N-[2-(1H-benzimidazol-2-yl]amines 5a,b,e, or N-[2-(1H)-
benzimidazol-2-yl)ethyl]-N′-(1H-benzimidazol-2-yl)-disubstituted phenylureas 6c,d (Table 1). It is probable
927

928

929

that the reaction occurs in two directions. The first direction is the condensation of o-phenylenediamine with the
esters 2 to give compounds 4a-e. The second direction of the reaction is that the nucleophile diamine attacks the
4-CO group of the heterocycle with subsequent opening of the heterocycle to form the benzimidazole fragment
(compounds 6c,d) with subsequent hydrolysis of the amide to give compounds with the structures 5a,b,e.
The structures of the compounds synthesized were confirmed by IR, mass spectrometry, and 1H and 13C
NMR spectroscopy (Table 2) with assignment of the signals on the basis of general rules of additivity of
substituents and published spectral data of model compounds [5-9].
13
With the necessity to assign spectral lines we used the APT C NMR method [5, 6]. The investigation
compounds are divided to for classes according the characteristic features of their structural fragments. The
substituent R in all the compounds synthesized has the form of a benzene ring with varying degrees of
substitution. The spectral lines of the carbon atoms of the benzene ring for compounds 2a-e and 4a-e in their 13H
NMR spectra were identified on the basis of the refined in the given word increments (Ci = 12.05, Co = -1.32, Cm
= 2.06, and Cp = -0.54 ppm) of the influence of the substituent in the pyrimidine ring [8], in the case of
compounds 5a,b,e the refined influence of the fragment NHCH2CH2 [5-7] (Ci = 19.97, Co = -16.41, Cm = 0.43,
and Cp = -12.69 ppm), but in compounds 6c-d by comparison with related fragments in model compounds [9].
The character of the substitution on the benzene ring has an important effect on the structural characteristics and
properties of the compound. With no substituent on the benzene ring (compounds 2a-5a) or with p- or
1
m-substituents (compounds 2b-5b and 2e-5e) the aliphatic hydrogen atoms appear in the H NMR spectra as
triplets (Table 3, Fig., 4b), while hydrogen atoms of the NCH2C= fragment are observed as a sharp singlet.
Substituent in the o-position (compounds 2c-4c, 2d-4d) hinder rotation about the C(1)-N bond, as a consequence
of which the hydrogen atoms in the NCH2 fragment appear as an AB spin-spin multiplet in the ABX2 spin-spin
system (Fig., 4c). The hydrogen atoms in the NCH2C= fragment appear as an AB spin-spin multiplet. In the 13
C
NMR spectra of compounds with an o-substituent in the benzene ring, no specific changes in the chemical shifts
of the carbon atoms of the pyrimidinedione ring were observed.
Table 3. 13C NMR Spectral Data for Compounds 2a-d
Carbon
atoms
Chemical shifts (acetone-d6), δ, ppm
2b 2c
2а
2d
С-1
144.55
127.18
130.56
127.96
130.56
127.18
154.13
142.04
127.11
131.08
137.67
131.08
127.11
154.14
140.78
137.28
133.17
139.14
144.38
136.90
133.93
C-2
C-3
C-4
129.02 or 129.48
132.93
C-5
128.63 or 129.24
128.63 or 129.24
153.67
C-6
129.02 or 129.48
153.63
C-2'
C-4'
170.59 or 170.85
33.21
170.61 or 170.80
33.23
170.66 or 170.99
33.32
170.56 or 170.87
33.24
C-5'
C-6'
45.78
45.90
45.76
45.54
NCH2
COO
CH2C
OO
43.12
43.11
43.01
43.02
170.59 or 170.85
53.31
170.61 or 170.80
53.29
170.66 or 170.99
170.56 or 170.87
OCH3
2-CH3
4-CH3
53.28
18.83
21.96
53.33
18.45
21.92
930

1
The characteristics of the H NMR spectra of compounds 2a-e are the singlet for the COOCH3 group at
13
3.6 ppm and correspondingly in the C NMR spectra carbon resonances at 170 and 53 ppm. The structures of
1
compounds 3a-e were confirmed by the broad singlet at 11.3 ppm in the H NMR spectra. The presence of the
characteristic benzimidazole multiplets in the aromatic proton region [10-12] and a broad singlet at 12.2 ppm in
1
13
the H NMR spectrum indicate the formation of compounds of type 4a-e. In the C NMR spectra the presence
ppm
ppm
ppm
Fig. Aliphatic proton parts of the 1H NMR spectra of compounds 4b,c and 6c.
931

of the benzimidazole fragment is confirmed by a group of lines characteristically broadened because of exchange
processes - the lines are sometimes lost in the background (compounds 4b,c) and also a signal at 150 ppm,
assigned to the atom C-a.
It is characteristic of compounds 5a,b,e, products of decomposition of the hydropyrimidine ring, that a
1
second signal for NH at 5.5 ppm in the H NMR spectrum appears, sometimes observed as a triplet because of
spin-spin interaction with the protons of the CH2 group, and the presence of the CH2CH2, fragment in which the
difference of chemical shifts is 0.5 ppm less than in the corresponding fragment of the pyrimidinedione ring, and
the absence of the lines of the carbon in the carbonyl groups at 150 and 169 ppm in the 13C NMR spectrum.
On decomposition of the hydropyrimidine ring in compounds with o-substitution in the benzene ring,
stable compounds 6c,d are formed in which there are two benzimidazole units. The structures of compounds
6c,d are confirmed by the presence of two broad singlets of the NH of the benzimidazole fragments at 12.2 and
1
the singlet of the NH group at 6.2 ppm in the H NMR spectra. The presence of a doublet at 4.4 ppm indicates
the existence of the NHCH2C= unit. The presence of a fast exchange process of molecules of compounds in the
solutions 6c,d is indicated by the broad the multiplets of the fragment NCH2CH2C= (Fig. 6c), while in the
1
absence of exchange a resolution of the multiplets is observed (Fig. 4c,b). Careful integration of the H NMR
spectra of compounds 6c,d confirmed the presence of the required number of protons and the fragments
mentioned above.
Table 4. 13C NMR Spectral Data for Compounds 4a-e
Carbon
atoms
Chemical shifts (DMSO-d6), δ, ppm
4b 4c 4d
4а
142.33
4e
141.26
С-1
C-2
C-3
139.82
125.11
129.12
138.59
142.23
134.79
132.14
125.21
128.67
135.04
131.16
125.68
132.76
or 133.16
C-4
C-5
126.00
128.67
135.32
129.12
136.85
127.29
or 127.54
132.76
or 133.16
126.95
130.31
131.08
123.87
or 127.29
C-6
125.21
125.11
126.95
127.29
or 127.29
or 127.54
C-2'
151.04
151.07
151.09
150.96
150.99
or 152.24
or 152.23
or 151.78
or 151.79
or 152.26
C-4'
169.50
31.33
43.55
38.44
169.53
31.33
43.65
38.42
169.64
31.44
43.58
38.23
169.57
31.35
43.34
38.28
169.49
31.26
43.51
38.52
C-5'
C-6'
NCH2C=
С-a
151.04
151.07
151.09
150.96
150.99
or 152.24
or 152.23
or 151.78
or 151.79
or 152.26
C-b
C-c
118.36
Not observed
121.36
114.69
121.40
118.30
118.33
121.10
121.10
121.16
or 121.68
or 121.83
or 121.78
C-d
121.10
121.36
121.40
121.10
121.16
or 121.68
or 121.83
or 121.78
C-e
111.04
134.16
143.04
Not observed
Not observed
Not observed. Not observed
17.32
111.15
111.09
134.20
143.05
16.91
111.11
134.26
143.22
C-f
C-g
Not observed
2-CH3
4-CH3
20.50
20.54
19.11
932

The presence of lines at 156, 153, an 152 ppm in the 13C NMR spectra of compounds 6c,d indicates the
existence of the NCONH fragment, and correspondingly the C-a and C′-a atoms of the benzimidazole unit. The
lines at 47, 27, and 38 ppm are unambiguously assigned to the carbon atoms of the fragments NCH2CH2,
NCH2CH2, and CONHCH2C= respectively.
For comparison (Tables 3 and 4) of the chemical shifts of the corresponding fragments of compounds
2a-e and 4a-e it should be noted that in the spectra of compounds 2a-e, recorded in acetone-d6, a weak field shift
of the lines of the aliphatic and aromatic carbon atoms by 2 ppm was observed in the 13C NMR spectra.
Table 5. 13C NMR Spectral Data for Compounds 5a,b,c
Carbon
atoms
Chemical shifts (DMSO-d6), δ, ppm
5а
5b
5e
С-1
148.47
112.09
128.93
115.81
128.93
112.09
41.41
146.22
147.99
C-2
C-3
112.28
129.37
111.29 or 111.80
133.64
C-4
124.20
121.44
C-5
C-6
129.37
112.28
131.39
111.29 or 111.80
41.39
NHCH2CH2
NHCH2CH2
С-a
41.72
28.58
153.16
118.12
28.61
153.22
28.50
153.05
C-b
118.29
118.20
C-c
C-d
121.39 or 121.44
121.39 or 121.44
110.73
121.15 or 121.29
121.15 or 121.29
110.83
121.01 or 121.10
121.01 or 121.10
110.54
C-e
C-f
134.21
134.45
134.32
C-g
143.31
142.41
143.18
2-CH3
4-CH3
20.05
18.46
Table 6. 13C NMR Spectral Data for Compounds 6c,d
Chemical shifts (DMSO-d6), δ, ppm.
Carbon atoms
6c
6d
С-1
137.11 or 137.26
141.54
135.90
130.58
129.41
127.67
132.60
156.32
38.28
C-2
137.11 or 137.26
131.94
C-3
C-4
136.37
C-5
127.73
C-6
129.36
NCONH
NHCH2C=
NCH2CH2C=
NCH2CH2C=
С-a / C-a'
C-b / C-b'
C-c / C-c'
C-d / C-d'
C-e/ C-e'
C-f / C-f'
C-g / C-g'
2-CH3
156.65
38.75
47.25
27.88
47.44
27.88
152.48 or 153.40
114.69 or 114.80
121.25 or 121.32
121.25 or 121.32
114.69 or 114.80
138.87
152.44 or 153.41
118.33 or 118.42
121.30 or 121.37
121.30 or 121.37
110.75 or 110.83
134.23 or 134.56
143.33 or 143.63
16.91
138.87
17.26
4-CH3
20.60
933

EXPERIMENTAL
13
1H and C NMR spectra were recorded with TMS as internal standard on a Varian Unity Inova (300
and 75 MHz respectively) spectrometer. IR spectra of KBr disks were recorded on a Perkin-Elmer Bx FT-IR
instrument. Mass spectra were recorded on a Waters ZQ 2000 instrument, with 15 eV ionizing voltage.
Monitoring of the course of reaction and purity of the compounds synthesized was via TLC using Silufol
UV-254, with development with UV light or iodine vapor.
Methyl [3-aryl-2,6-dioxotetrarylpyrimidin-1-(2H)-yl]acetates (2a-e) (General Method). A 60%
suspension of sodium hydroxide in paraffin (2.40 g, 60 mmol) was added to dry DMF (100 ml) with stirring.
The corresponding 1-aryldihydro-2,4-pyrimidinedione 1a-e (50 mmol) dissolved in dry DMF (50 ml) was added
to the suspension in 10 min with stirring. The mixture was maintained at 50°C and stirring was continued until
evolution of hydrogen ceased (~45 min). The mixture was cooled to 5-10°C, 2-bromomethyl acetate (14.2 ml,
150 mmol), dissolved in dry DMF (20 ml), was added dropwise over 10 min. The temperature of the mixture
was increased to 50-60°C, stirring was continued for 30 min, the mixture was cooled to 20°C and the mixture
was poured into a mixture of ice and water (~500 ml). The crystals of compounds 2a-e were filtered off, washed
with water, dried and recrystallized from the relevant solvent.
[3-Aryl-2,6-dioxohexahydropyrimidin-1-(2H)-yl]acetic Acids 3a-e (General Method). A solution of
2 mmol of the corresponding ester 2a-e in 10% hydrochloric acid (12 ml) was boiled for 2 h, cooled, and the
precipitated compound 3a-e was filtered off, washed with water, and dried. The solid was twice dissolved in 5%
Na2CO3 solution, filtered, and precipitated with 5% hydrochloric acid.
3-(1H-Benzimidazol-2-ylmethyl)-1-aryldihydropyrimidine-2,4(1H,3H)-diones 4a-e, N-aryl-N-[2-(1H-
benzimidazol-2-yl)ethyl]amines, 5a,b,e, and N-arylN-[2-(1H-benzimidazol-2-yl)ethyl]-N′-(1H-benz-
imidazol-2-ylmethyl)urea, 6c,d (General Method). A solution of 4 mmol of the corresponding ester 2a-e and
o-phenylenediamine (1.30 g, 12 mmol) in 4M hydrochloric acid (12 ml) was boiled for 16 h, cooled, and
neutralized 25% ammonia to pH 8-9. The precipitate was filtered off and purified by column chromatography
with 1:1 acetone–hexane as eluent.
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