Synthesis and acylation of 4-Chloroalkyl-3,4-dihydropyrimidin-2(1H)-ones

Article abstract of DOI:10.5560/ZNB.2012-0182

4-Chloroalkyl-3,4-dihydropyrimidin-2(1H)-ones are useful multifunctional 3,4-dihydropyrimidine building blocks with low molecular weight and sufficient solubility, which may be modified selectively by substituents in different positions. Here we propose a

Full text of DOI:10.5560/ZNB.2012-0182

Synthesis and Acylation of 4-Chloroalkyl-3,4-dihydropyrimidin-2(1H)-
ones
Maksim A. Kolosov, Olesia G. Kulyk, Muataz Al-Ogaili, and Valeriy D. Orlov
Department of Organic Chemistry, V. N. Karazin Kharkiv National University, Svobody sq., 4,
61022, Kharkiv, Ukraine
Reprint requests to Dr. Maksim A. Kolosov. Fax: +38 (057) 705-12-36.
E-mail: kolosov@univer.kharkov.ua
Z. Naturforsch. 2012, 67b, 921 – 924 / DOI: 10.5560/ZNB.2012-0182
Received July 4, 2012
4-Chloroalkyl-3,4-dihydropyrimidin-2(1H)-ones are useful multifunctional 3,4-dihydropyrimidine
building blocks with low molecular weight and sufficient solubility, which may be modified selec-
tively by substituents in different positions. Here we propose a simple one-pot protocol for the synthe-
sis of these compounds, which is based on the use of common reagents viz. urea, chloroaliphatic alde-
hydes and 3-ketoesters. Acylation of 4-chloroalkyl-3,4-dihydropyrimidin-2(1H)-ones by carboxylic
acid anhydrides leads to 3-acyl derivatives.
Key words: 3,4-Dihydropyrimidin-2(1H)-ones, Biginelli Reaction, Chloroaliphatic Aldehydes,
One-pot Synthesis, Acylation
NH2
NH2
Me
O
Introduction
Me
OEt
+
O
NH2
O
N
pathway A
O
O
H
Biginelli compounds (namely, the derivatives
OEt
of
5-alkoxycarbonyl-4-aryl-3,4-dihydropyrimidin-
2(1H)-ones) are readily available heterocycles [1 – 3].
This fact has caused a tremendous number of pub-
lications in this area [3]. In contrast, promising
multifunctional compounds, such as 4-chloroalkyl
derivatives of 3,4-dihydropyrimidin-2(1H)-ones, are
rather poorly known [4 – 8].
For example, the most usual pathways of 4-chlo-
romethyl-5-ethoxycarbonyl-6-methyl-3,4-dihydropy-
rimidin-2(1H)-one synthesis consist of two-step
[4, 5] (pathway A, Scheme 1) or one-step proto-
cols (pathway B, Scheme 1) [6], but necessarily
involve the use of 1,2-dichloroethyl ethyl ether.
So, the use of other chloroaliphatic aldehydes
or their derivatives is limited and still remains
unexplored.
Cl
Cl
OEt
Cl
Cl
OEt
Me
Cl
OEt
O
+
NH2
O
HN
OEt
1a
pathway B
O
NH2
O
O
N
H
Me
Scheme 1. Known pathways for the synthesis of 4-chloro-
methyl-5-ethoxycarbonyl-6-methyl-3,4-dihydropyrimidin-
2(1H)-one (1a).
Here we report a simple and cheap protocol for the
one-pot synthesis of 5-alkoxycarbonyl-4-chloroalkyl- Results and Discussion
6-methyl-3,4-dihydropyrimidin-2(1H)-ones starting
from very common reagents, namely aliphatic alde-
The most common reagents for the synthesis of
hydes, urea and acetoacetic esters, and discuss their Biginelli compounds are solvent/catalyst systems such
acylation.
as ethanol/HCl [9], glacial HOAc [9], DMF/TMSCl
c
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M. A. Kolosov et al. · 4-Chloroalkyl-3,4-dihydropyrimidin-2(1H)-ones
Cl
Cl
(CH2)
O
n
Cl
(CH2)
n
Cl
O
(CH2)
n
O
(CH2)
n
R
O
OR
HOAc/HCl
- 5 oC
(RCO)2O,
Δ
HN
OEt
NH2
N
OEt
HN
OR
O
O
+
O
NH2
N
H
Me
O
O
N
H
Me
Me
O
N
H
Me
O
1a,b
1a-c
3a-c
R = Me (a, b), n-Pr (c); n = 1 (a, c), 2 (b)
R = OEt (a, b), OBn (c);
n = 1 (a, c), 2 (b)
Scheme 4. Acylation of 4-chloroalkyl-3,4-dihydropyrimidin-
2(1H)-ones 1a, b.
Scheme 2. Procedure for the synthesis of target 4-chloro-
alkyl-3,4-dihydropyrimidin-2(1H)-ones 1a–c.
[10, 11] or pure DMF [12]. Depending on the starting
The best ratio of reagents are equimolar amounts of
compounds, different systems of solvent/catalyst [13] urea and ketoester with 1.5 equivalents of aldehyde.
and ratios of reagents [9, 14, 15] may be used, but heat- Noteworthy, compounds 1 turned out to be much more
ing is needed in all cases.
soluble in alcohols and ethyl acetate than their 4-aryl
We have now found, that the optimal conditions analogs.
for the synthesis of compounds 1a–c from urea,
Acylation of compounds 1a, b with carboxylic acid
chloroaliphatic aldehydes and alkyl acetoacetates in- anhydrides occurred smoothly and led to the 3-acyl
clude glacial HOAc/dry HCl as solvent/catalyst sys- derivatives 3a–c, the spectroscopic and physical data
tem and cooling of the reaction mixture to about of which agreed well with literature data [17, 18]
−5 ◦C with prolonged stirring (see Experimental Sec- (Scheme 4).
tion, Scheme 2).
An attempt to obtain the 1-methyl derivative of com-
When alcohol/HCl or DMF were used, the products pound 1a under the conditions of phase-transfer cataly-
1 were not obtained, and only dark mixtures of poly- sis (MeI, saturated KOH-H2O, MeCN [19]) was unsuc-
mers were formed. The same was noted upon heating; cessful; this may be caused by auto-alkylation of com-
no experiments with heating were successful.
pound 1a and/or processes of its recyclization [4 – 8].
One of the important details of the improved pro-
tocol is the addition of the reagents in turns. First the
aldehyde and urea should be dissolved, then the ke-
toester should be added, and the solution should then
be saturated with dry HCl. During the saturation with
HCl a precipitate is formed, which completely dis-
solves after further gas bubbling. Taking into consider-
ation the mechanism of the acid-catalyzed Biginelli re-
action [16], an alkylidene-bis-urea 2 may be proposed
for the initial precipitate (Scheme 3).
Conclusion
We worked out a simple protocol for the synthe-
sis of 5-alkoxycarbonyl-4-chloroalkyl-6-methyl-3,4-
dihydropyrimidin-2(1H)-ones starting from the com-
mon reagents aldehydes, urea and alkyl acetoacetates.
The moderate yields of the target products are com-
pletely compensated by the availability and low cost of
the starting compounds.
Experimental Section
Chloroacetaldehyde, urea, and alkyl acetoacetates were
commercially available. 3-Chloropropanal was obtained as
described in ref. [20]. Melting points were determined using
a Kofler hot-stage apparatus. 1H NMR spectra were recorded
in [D6]DMSO at 200 MHz using a Varian Mercury VX-200
spectrometer with Si(CH3)4 as internal standard. Chemical
shifts are reported in ppm (δ scale), coupling constants are
given in Hz. Mass spectra (EI, 70 eV) were obtained us-
ing a Varian 1200L instrument using a direct probe expo-
Cl
(CH2)n
Cl
HOAc
HCl
O
(CH2)n
O
NH2
+
H2N
N
H
NH
-5 oC
O
NH2
O
NH2
n = 1, 2
2
Scheme 3. Possible scheme of the initial precipitate forma-
tion.
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M. A. Kolosov et al. · 4-Chloroalkyl-3,4-dihydropyrimidin-2(1H)-ones
923
sure method. IR spectra were recorded on KBr pellets using 5-Benzyloxycarbonyl-4-chloromethyl-6-methyl-
a Specord IR-75 spectrometer. Elemental analyses (C, H, N) 3,4-dihydropyrimidin-2(1H)-one (1c)
were performed by standard combustion procedure, their re-
Yield 6%. M. p. 210 – 211 ◦C. – IR (KBr, cm−1):
ν = 1655 (C=O), 1702 (C=O), 3116, 3376 (NH). – 1H NMR
(200 MHz, [D6]DMSO): δ = 2.20 (s, 3 H, CH3), 3.43 – 3.60
(m, 2 H, CH2Cl), 4.35 – 4.45 (m, 1 H, C(4)H), 5.10 (s, 2 H,
OCH2), 7.10 – 7.60 (m, 6 H, Ph + N(3)H), 9.20 (br. s, 1 H,
N(1)H). – MS (EI, 70 eV): m/z(%) = 245 (15) [M–Ph]+, 110
(10), 91 (100). – Anal. for C14H15ClN2O3: calcd. C 57.05,
H 5.13, N 9.50; found C 56.97, H 4.90, N 9.62.
sults were found to be in good agreement (±0.3%) with the
calculated values.
5-Alkoxycarbonyl-4-chloroalkyl-6-methyl-3,4-dihydro-
pyrimidin-2(1H)-ones 1a–c. General procedure
To
a solution of 2.00 g (0.033 mol) of urea in
15 mL of glacial HOAc 0.05 mol of the appropriate
chloroaliphatic aldehyde (50% water solution in the case of
2-chloroacetaldehyde) was added. Then 0.033 mol of an ap-
propriate alkyl acetoacetate was added, and the mixture was
cooled to –10 ◦C (ice/NaCl bath). The mixture was saturated
with dry HCl at −5 ◦C (heating takes place) with vigorous
stirring. The process of saturation took 4 – 5 h, and the mix-
ture turned pale yellow. It was allowed to react for about
12 – 20 h, and under cooling the pH of the mixture was ad-
justed to neutral by addition of conc. aqueous Na2CO3 solu-
tion (about 250 mL). The formed precipitate was filtered off,
washed with water and 70% aqueous methanol to remove
unreacted ketoester. Work-up of the mother liquor did not
lead to the isolation of additional portions of the target com-
pounds. Compounds 1a–c can be crystallized from acetone
or an EtOAc-hexane (1 : 1) mixture.
3-Acyl-4-chloroalkyl-5-ethoxycarbonyl-6-methyl-3,4-
dihydropyrimidin-2(1H)-ones 3a–c.
General procedure
A mixture of of compound 1 (2.6 mmol) with the appro-
priate carboxylic acid anhydride (40 mmol) was stirred at
150 ◦C for 3 h. The mixture was cooled, poured into water
and allowed to mix for 6 – 12 h. The precipitate of compound
3 was filtered off and washed with water. Compounds 3a–c
can be recrystallized from EtOH.
3-Acetyl-4-chloromethyl-5-ethoxycarbonyl-6-methyl-
3,4-dihydropyrimidin-2(1H)-one (3a)
Yield 75%. M. p. 152 – 153 ◦C. – IR (KBr, cm−1):
ν = 1662 (C=O), 1702 (C=O), 2978, 3163, 3269 (NH). –
1H NMR (200 MHz, [D6]DMSO): δ = 1.20 (t, J = 7.0, 3 H,
CH2CH3), 2.23 (s, 3 H, CH3), 2.42 (s, 3 H, CH3), 3.55 – 3.75
(m, 2 H, CH2Cl), 4.12 (q, J = 7.0, 2 H, CH2CH3), 5.62 (t,
J = 4.7, 2 H, C(4)H), 10.11 (br. s, 1 H, N(1)H). – MS (EI,
70 eV): m/z(%) = 229 (10) [M–OEt]+, 225 (15), 183 (100),
155 (40), 137 (30). – Anal. for C11H15ClN2O4: calcd. C
48.10, H 5.50, N 10.20; found C 47.95, H 5.43, N 9.98.
4-Chloromethyl-5-ethoxycarbonyl-6-methyl-
3,4-dihydropyrimidin-2(1H)-one (1a)
Yield 32%. M. p. 176 – 177 ◦C (lit. [4]: m. p.
176.5 – 177 ◦C). – IR (KBr, cm−1): ν = 1672 (C=O), 1735
(C=O), 2929, 3123, 3216 (NH). – 1H NMR (200 MHz,
[D6]DMSO): δ = 1.19 (t, J = 7.0, 3 H, CH2CH3), 2.17 (s,
3 H, CH3), 3.45 – 3.64 (m, 2 H, CH2Cl), 4.07 (q, J = 7.0,
2 H, CH2CH3), 4.30 – 4.45 (m, 1 H, C(4)H), 7.43 (br. s,
1 H, N(3)H), 9.18 (br. s, 1 H, N(1)H). – MS (EI, 70 eV):
m/z(%) = 183 (100) [M–CH2Cl]+, 155 (35), 137 (40). –
Anal. for C9H13ClN2O3: calcd. C 46.46, H 5.63, N 12.04;
found C 46.70, H 5.87, N 11.85.
3-Acetyl-4-(2-chloroethyl)-5-ethoxycarbonyl-6-methyl-
3,4-dihydropyrimidin-2(1H)-one (3b)
Yield 59%. M. p. 176 – 177 ◦C. – IR (KBr, cm−1):
ν = 1642 (C=O), 1702 (C=O), 3183, 3263 (NH). – 1H
NMR (200 MHz, [D6]DMSO): δ = 1.20 (t, J = 7.0, 3 H,
CH2CH3), 1.78 – 2.00 (m, 2 H, CH2CH2Cl), 2.21 (s, 3 H,
CH3), 2.37 (s, 3 H, CH3), 3.45 (t, J = 6.8, 2 H, CH2Cl),
4.00 – 4.20 (m, 2 H, CH2CH3), 3.55 – 3.75 (m, 2 H, CH2Cl),
5.50 (t, J = 6.6, 1 H, C(4)H), 10.10 (br. s, 1 H, N(1)H). –
MS (EI, 70 eV): m/z(%) = 225 (15) [M–CH2CH2Cl]+, 183
(100), 137 (45). – Anal. for C12H17ClN2O4: calcd. C 49.92,
H 5.93, N 9.70; found C 50.08, H 5.90, N 9.82.
4-(2-Chloroethyl)-5-ethoxycarbonyl-6-methyl-
3,4-dihydropyrimidin-2(1H)-one (1b)
Yield 20%. M. p. 187 – 188 ◦C. – IR (KBr, cm−1):
ν = 1642 (C=O), 1708 (C=O), 3116, 3229 (NH). – 1H
NMR (200 MHz, [D6]DMSO): δ = 1.17 (t, J = 7.0, 3 H,
CH2CH3), 1.65 – 1.95 (m, 2 H, CH2CH2Cl), 2.17 (s, 3
H, CH3), 3.61 (t, J = 6.0, 2 H, CH2Cl), 3.90 – 4.15 (m, 2
H, CH2CH3), 4.13 – 4.30 (m, 1 H, C(4)H), 7.52 (br. s, 1
H, N(3)H), 9.09 (br. s, 1 H, N(1)H). – MS (EI, 70 eV):
m/z(%) = 201 (10) [M–OEt]+, 183 (100), 155 (70), 137
3-Butyryl-4-chloromethyl-5-ethoxycarbonyl-6-methyl-
3,4-dihydropyrimidin-2(1H)-one (3c)
Yield 52%. M. p. 112 – 113 ◦C. – IR (KBr, cm−1):
(60). – Anal. for C10H15ClN2O3: calcd. C 48.69, H 6.13, ν = 1668 (C=O), 1705 (C=O), 3103, 3149 (NH). – 1H
N 11.36; found C 46.51, H 5.98, N 11.08.
NMR (200 MHz, [D6]DMSO): δ = 0.86 (t, J = 7.0, 3 H,
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924
M. A. Kolosov et al. · 4-Chloroalkyl-3,4-dihydropyrimidin-2(1H)-ones
(CH2)2CH3), 1.21 (t, J = 7.0, 3 H, CH2CH3), 1.40 – 1.70 Acknowledgement
(m, 2 H, CH2CH2CH3), 2.23 (s, 3 H, CH3), 2.58 – 2.78 (m,
1 H, CH2C2C3), 2.83 – 3.03 (m, 1 H, CH2C2C3), 3.55 – 3.75
The work was supported by V. N. Karazin Kharkiv
(m, 2 H, CH2Cl), 4.12 (q, J = 7.0, 2 H, CH2CH3), 5.62 National University (grant 811/22 – 11). We also thank V.
(t, J = 4.4, 1 H, C(4)H), 10.12 (br. s, 1 H, N(1)H). – MS V. Vashchenko, E. V. Vashchenko, V. I. Musatov (STC
(EI, 70 eV): m/z(%) = 257 (10) [M–EtO]+, 253 (15) [M– “Institute for Single Crystals” NAS of Ukraine), L. V.
CH2Cl]+, 183 (100). – Anal. for C13H19ClN2O4: calcd. C Vasilenko (V. N. Karazin Kharkiv National University) and
51.57, H 6.33, N 9.25; found C 51.58, H 6.30, N 9.00.
Enamine Ltd. for spectroscopic measurements.
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