Bicyclic compounds obtained by the Biginelli reaction

Full text of DOI:10.1134/S1070428010040305

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 4, pp. 599–601. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © M.M. Kurbanova, 2010, published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 4, pp. 606–608.
SHORT
COMMUNICATIONS
Bicyclic Compounds Obtained by the Biginelli Reaction
M. M. Kurbanova
Baku State University, ul. Z. Khalilova 23, Baku, AZ-1073, Azerbaidjan
e-mail: kurbanova1972@rambler.ru
Received December 8, 2008
DOI: 10.1134/S1070428010040305
It was found for the first time that three-component
condensation of 2-hydroxynaphthalene-1-carbaldehyde
with ethyl acetoacetate and urea in the presence of tri-
chloroacetic acid yields ethyl 1-methyl-15-oxo-2-oxa-
14,16-diazatetracyclo[11.3.1.03.12.06.11]heptadeca-
3,5,7,9,11-pentaene-17-carboxylate [1]. While continu-
ing studies in this line, 5-bromosalicylaldehyde was
selected as substrate for the above three-component
condensation. The reaction of 5-bromosalicylaldehyde
with ethyl acetoacetate and urea in the presence of
trichloroacetic acid gave, depending on the conditions,
ethyl 4-(5-bromo-2-hydroxyphenyl)-6-methyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (I) or ethyl
4-bromo-9-methyl-11-oxo-8-oxa-10,12-diazatricyclo-
[7.3.1.02.7]trideca-2,4,6-triene-13-carboxylate (II)
(Scheme 1). Ester I was formed when the reactants
were heated for 2–4 h in boiling ethanol, whereas bi-
cyclic compound II was isolated when the reaction
mixture was heated for 7–9 h at 40°C. The progress of
the reaction was monitored by thin-layer chromatog-
raphy. The structure of compounds I and II was proved
by IR and NMR spectroscopy and X-ray diffraction
data (Fig. 1).
For comparison, three-component condensation of
5-bromosalicylaldehyde with acetylacetone and thio-
urea was examined. Under analogous conditions, the
products were 1-[4-(5-bromo-2-hydroxyphenyl)-6-
methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl]-
ethanone (III) and 1-(4-bromo-9-methyl-11-thioxo-8-
oxa-10,12-diazatricyclo[7.3.1.02.7]trideca-2,4,6-trien-
13-yl)ethanone (IV) (Scheme 2). Compounds III and
IV were isolated as crystalline substances whose struc-
ture was proved by IR and NMR spectroscopy and
X-ray analysis (Fig. 2).
A probable mechanism of formation of bicyclic
products II and IV is shown in Scheme 3.
Ethyl 4-(5-bromo-2-hydroxyphenyl)-6-methyl-2-
oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (I).
A mixture of 5.025 g (0.025 mol) of 5-bromosalicyl-
aldehyde, 4.8 ml (0.038 mol) of ethyl acetoacetate,
1.5 g (0.025 mol) of urea, and 25 mg of trichloroacetic
Scheme 1.
Br
O
OH
O
EtO
NH
CHO
Me
N
OH
O
O
O
H
+
+
I
Me
OEt
H2N
NH2
Br
H
N
O
Br
COOEt
NH
O
Me
II
599

KURBANOVA
600
Scheme 2.
Br
O
OH
S
Me
NH
CHO
Me
N
OH
O
O
S
H
+
+
III
Me
Me
H2N
NH2
Br
H
N
S
Br
COMe
NH
O
Me
IV
acid in 10 ml of ethanol was stirred for 2–4 h on
heating under reflux. The progress of the reaction was
monitored by TLC. When the reaction was complete,
the mixture was cooled to room temperature, and the
precipitate was filtered off, washed with ethanol, dried,
and recrystallized from aqueous ethanol. Yield 75%,
mp 190–191°C. IR spectrum, ν, cm–1: 3325, 1745,
5-bromosalicylaldehyde, 4.8 ml (0.038 mol) of ethyl
acetoacetate, 1.5 g (0.025 mol) of urea, and 25 mg of
trichloroacetic acid in 10 ml of ethanol was heated for
7–9 h at 40°C. After cooling, the precipitate was
filtered off and dried. Yield 55%, mp 197°C. IR spec-
trum, ν, cm–1: 3350, 1740, 1680. 1H NMR spectrum, δ,
ppm: 1.27 t (3H, CH2CH3), 2.35 s (3H, CH3), 3.27 d
(1H, CH), 4.16 q (2H, CH2O), 4.46 d (1H, CH), 6.77–
7.21 m (3H, Harom), 8.36 s (1H, NH), 8.41 s (1H, NH).
Found, %: C 47.39; H 4.27; Br 22.59; N 7.95.
C14H15BrN2O4. Calculated, %: C 47.32; H 4.22;
Br 22.53; N 7.88.
1
1660. H NMR spectrum, δ, ppm: 1.30 t (3H,
CH2CH3), 2.57 s (3H, CH3), 4.25 q (2H, CH2O), 5.70 s
(1H, CH), 7.70–7.00 m (4H, Harom), 8.00 s (1H, NH),
9.41 s (1H, NH), 10.11 s (1H, OH). Found %: C 47.36;
H 4.25; Br 22.60; N 7.91. C14H15BrN2O4. Calculated,
%: C 47.32; H 4.22; Br 22.53; N 7.88.
1-[4-(5-Bromo-2-hydroxyphenyl)-6-methyl-2-
thioxo-1,2,3,4-tetrahydropyrimidin-5-yl]ethanone
(III) was synthesized as described above for com-
pound I from 1.9 g (0.025 mol) of thiourea. Yield
Ethyl 4-bromo-9-methyl-11-oxo-8-oxa-10,12-di-
azatricyclo[7.3.1.02.7]trideca-2,4,6-triene-13-carbox-
ylate (II). A mixture of 5.025 g (0.025 mol) of
C10
C9
Br1
C16
C11
C12
Br1
C8
C9
N10
C15
O2
C7
O1
C6
C13
C7
C4
C8
C3
C11 S1
N12
O4
C13 C5
C14
C15
N3
N1
C5
C1
C2
O1
C4
O3
O2
C6
C16
C14
Fig. 1. Structure of the molecule of ethyl 4-(5-bromo-2-hy-
droxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-
5-carboxylate (I) according to the X-ray diffraction data.
Fig. 2. Structure of the molecule of 1-(4-bromo-9-methyl-11-
thioxo-8-oxa-10,12-diazatricyclo[7.3.1.02.7]trideca-2,4,6-trien-
13-yl)ethanone (IV) according to the X-ray diffraction data.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 4 2010

BICYCLIC COMPOUNDS OBTAINED BY THE BIGINELLI REACTION
601
Scheme 3.
X
O
O
X
H2N
NH
O
+
Me
NH
R
+
H2N
NH2
OH
Me
R
OH
CHO
H2N
X
X
CHO
O
NH
H2N
O
CH2COR
Me
Me
R
Br
Br
Br
OH
HO
NH
NH
CH2COR
NH
X
Br
X
COR
NH
O
O
Me
Me
X = O, S; R = Me, OEt.
75%, mp 175°C. IR spectrum, ν, cm–1: 3345, 1665.
1H NMR spectrum, δ, ppm: 1.90 s (3H, CH3), 2.47 s
(3H, CH3), 5.57 s (1H, CH), 7.10 s (1H, NH), 7.36–
7.45 m (4H, Harom), 8.14 s (1H, NH), 9.50 s (1H, OH).
Found, %: C 45.80; H 3.77; Br 23.40; N 8.30; S 9.45.
C13H13BrN2O2S. Calculated, %: C 45.74; H 3.81;
Br 23.46; N 8.21; S 9.38.
groups were localized by the Fourier difference syn-
theses, and their positions were refined in isotropic
approximation with fixed positional and thermal
parameters. The positions of the other hydrogen atoms
were calculated on the basis of geometry considera-
tions and were refined in isotropic approximation with
fixed positional and thermal parameters. All calcula-
tions were performed using SHELXTL PLUS and
SADABS software packages [2, 3]. The complete sets
of crystallographic data for compounds I and IV were
deposited to the Cambridge Crystallographic Data
Centre (entry nos. CCDC 694407 and CCDC 707349).
1-(4-Bromo-9-methyl-11-thioxo-8-oxa-10,12-di-
azatricyclo[7.3.1.02.7]trideca-2,4,6-trien-13-yl)ethan-
one (IV) was synthesized as described above for com-
pound II from 1.9 g (0.025 mol) of thiorea. Yield 55%,
mp 187–188°C. IR spectrum, ν, cm–1: 3350, 1670.
1H NMR spectrum, δ, ppm: 1.79 s (3H, CH3), 2.31 s
(3H, CH3), 3.33 d (1H, CH), 4.59 d (1H, CH), 6.84–
7.20 m (3H, Harom), 8.97 s (1H, NH), 9.12 s (1H, NH).
Found, %: C 45.78; H 3.79; Br 23.42; N 8.27; S 9.44.
C13H13BrN2O2S. Calculated, %: C 45.74; H 3.81;
Br 23.46; N 8.21; S 9.38.
1
The H NMR spectra were recorded at 25°C from
solutions in DMSO-d6 on a Bruker-300 spectrometer
operating at 300 MHz. The IR spectra were obtained
on a Specord 75IR instrument from samples dispersed
in mineral oil. The progress of reactions and the purity
of products were monitored by TLC.
X-Ray diffraction study. Single crystals of com-
pounds I and IV suitable for X-ray analysis were ob-
tained by double recrystallization from ethanol. The
X-ray diffraction data were acquired on a Bruker
APEX II CCD diffractometer (100 K, λMoKα irradia-
tion, graphite monochromator, φ- and ω-scanning,
2θmax = 56°). The structures were solved by the direct
method and were refined by the least-squares proce-
dure in anisotropic approximation for non-hydrogen
atoms. Hydrogen atoms in the hydroxy and amino
REFERENCES
1. Kurbanova, M.M., Azerb. Khim. Zh., 2008, no. 3, p. 195.
2. Sheldrick, G.M., SHELXTL, v. 6.12. Structure Determina-
tion Software Suite, Madison, WI, USA: Bruker AXS,
2001.
3. Sheldrick, G.M., SADABS, v. 2.03, Bruker Siemens Area
Detector Absorption Correction Program, Madison, WI,
USA: Bruker AXS, 2003.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 4 2010