Condensation of 2-(4-chlorophenyl)-1-(2,4-dihydroxyphenyl) ethanone with N,N-dimethylformamide dimethyl acetal: An effective approach to 3-(4-chlorophenyl)-7-methoxy-4H-chromen-4-one, N,O- and N,N-heterocycles

Article abstract of DOI:10.1007/s10593-015-1777-3

[Figure not available: see fulltext.] A convenient sequence for the preparation of 2-(4-chlorophenyl)-1-(2,4-dimetoxyphenyl)-3-(dimethylamino)prop-2-en-1-one has been developed. It has been demonstrated that the use of 1-(2,4-dihydroxyphenyl)ethanone or 1

Full text of DOI:10.1007/s10593-015-1777-3

DOI 10.1007/s10593-015-1777-3
Chemistry of Heterocyclic Compounds 2015, 51(9), 799–803
CHEMISTRY OF
HETEROCYCLIC
Condensation of 2-(4-chlorophenyl)-1-(2,4-dihydroxy-
phenyl)ethanone with N,N-dimethylformamide dimethyl acetal:
an effective approach to 3-(4-chlorophenyl)-7-methoxy-4H-chromen-4-one,
N,O- and N,N-heterocycles
Viktoriia S. Moskvina1*, Sergey V. Shilin1, Volodymir P. Khilya1
1 Kyiv National Taras Shevchenko University,
60 Volodymyrska St., Kyiv 01033, Ukraine; е-mail: v.moskvina@gmail.com
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2015, 51(9), 799–803
Submitted August 12, 2015
Accepted September 15, 2015
HO
OH
O
MeO
O
O
DMFDMA
(R = Me)
Cl
Cl
(R = H)
DMFDMA
NH2OH, Py
Cl
Me
N
OR
MeO
OMe
O
MeO
MeO
Me
NH2OH, EtOH
O
Cl
N
NH
NH2
H2N
Cl
Cl
OMe
OMe
MeO
N
N
N
R
N
H2N
A convenient sequence for the preparation of 2-(4-chlorophenyl)-1-(2,4-dimetoxyphenyl)-3-(dimethylamino)prop-2-en-1-one has been
developed. It has been demonstrated that the use of 1-(2,4-dihydroxyphenyl)ethanone or 1-(2-hydroxy-4-methoxyphenyl)ethanone in a
condensation reaction with N,N-dimethylformamide dimethyl acetal leads to their heterocyclization to give an isoflavone. Reactions of
the enamino ketone with N,O- and N,N-binucleophiles have been studied; as the result, 4,5-diarylisoxazole, 4,5-diarylpyrazoles, and
4,5-diaryl-substituted 2-aminopyrimidine have been obtained in good yields.
Keywords: deoxybenzoin, N,N-dimethylformamide dimethyl acetal, enamino ketone, 2-hydroxydeoxybenzoin, isoflavone, heterocyc-
lization.
Derivatives of 1,2-diphenylethanone (deoxybenzoin or
2-phenylacetophenone) are widely used in condensation
reactions to synthesize various heterocyclic compounds.
Moreover, 2-hydroxydeoxybenzoins are often considered
as precursors to isoflavones and, given their availability
and synthetic potential, are frequently used in flavonoid
synthesis.1
midines.2,3 In each case, the cyclization reaction proceeds
via C–C–C + N–O, C–C–C + N–N, C–C–C + N–C–N ring
formation to yield the corresponding heterocycle. The ring
formation may proceed via two possible mechanisms
differing in the order of their key steps, namely,
nucleophilic attack and amine exchange reaction, which
give two regioisomeric products.
It is known that enamino ketones can be used for the
preparation of substituted isoxazoles, pyrazoles, and pyri-
In the context of our ongoing interest in the synthetic
potential of enamino ketones, we set out to explore the use
0009-3122/15/5109-0799©2015 Springer Science+Business Media New York
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Chemistry of Heterocyclic Compounds 2015, 51(9), 799–803
of 1,2-diphenylethanones as key intermediates in the
ethanone (1a) with dimethyl sulfate in acetone in the
presence of K2CO3 in a 91% yield. Subsequent reaction of
compound 1c with DMFDMA gave 2-(4-chlorophenyl)-
1-(2,4-dimethoxyphenyl)-3-(dimethylamino)prop-2-en-1-one
(3) in 94% yield (Scheme 2). Previously, DMFDMA has
been used to obtain enamino ketones with o-OSO2Ph group
(yields up to 58%)6 and o-OBn group (yield 70%).7
To introduce pharmacologically significant hetero-
cyclic moieties of pyrazole, aminopyrimidine, and
isoxazole, we then used the enamino ketone 3 in the
cyclization reactions with N,N- and N,O-binucleophiles –
hydrazine, N-methylhydrazine, guanidine, and hydroxyl-
amine. Heating compound 3 with a small excess (1.2 equiv)
of NH2NH2·H2O, N-methylhydrazine, or NH2OH·HCl in
an ethanol solution gave the corresponding pyrazoles 4a,b
and isoxazole 5, respectively, in high yields (Scheme 2).
Initially, the dimethylamino group of compound 3 is
substituted via addition–elimination.8 The subsequent
cyclization leads to the corresponding target 4,5-diaryl-
pyrazoles and 4,5-diarylisoxazole.
synthesis of 2-(4-chlorophenyl)-1-(2,4-dimethoxyphenyl)-
3-(dimethylamino)prop-2-en-1-one.
We discovered that, unexpectedly, the reaction of
2-(4-chlorophenyl)-1-(2,4-dihydroxyphenyl)ethanone (1a)
with N,N-dimethylformamide dimethyl acetal (DMFDMA,
3 equiv) results only in the formation of 3-(4-chlorophenyl)-
7-methoxy-4H-chromen-4-one (2) in a 75% yield. When
2-(4-chlorophenyl)-1-(2-hydroxy-4-methoxyphenyl)ethanone
(1b) was used, isoflavone 2 was obtained in a 92% yield
(Scheme 1). It must be noted that the use of equimolar
reagent quantities also resulted in compound 2, but with
lower yields (52%). It was reported previously that the use
of DMFDMA in reactions with deoxybenzoin leads to
hydroxyisoflavones, but under different conditions, i.e.,
refluxing in benzene for 4 h with reagent molar ratio 1 : 0.2.4
In our case (reflux for 20–30 min, reagent ratio 1 : 1–3 equiv),
the heterocyclization was accompanied by methylation of
the hydroxyl group to give 7-methoxyisoflavone 2. Thus,
this synthetic method can be successfully used for an
efficient one-step synthesis of 3-aryl-7-methoxy-4H-
chromen-4-ones.
It should be noted that similar 4,5-diaryl-substituted
pyrazoles and isoxazoles have been previously obtained via
isoflavone recyclization reactions under the action of
hydrazines and NH2OH, resulting usually in mixtures of
regioisomeric products, i.e., pyrazoles and isoxazoles, and
corresponding 2-aminochromones and 5-aminoisoxazo-
les.9,10 In our case, the only products were compounds 4
and 5, as is evidenced by NMR data. For example, the
Scheme 1
1
signals of pyrazole protons in the H NMR spectra of
compounds 4a,b are located at 7.63 and 7.66 ppm,
respectively, fully in accordance with the literature data.9
The peak of the isoxazole proton of compound 5 is
observed at 8.78 ppm, which confirms the formation of the
said product, since for its regioisomer the corresponding
signal would have been observed in the weaker field region
(9.4–9.8 ppm).10
To confirm the structure of compound 5, we have
carried out the counter synthesis starting with 7-methoxy-
isoflavone 2. The reaction of compound 2 with NH2OH·HCl
in pyridine proceeded as a nucleophilic attack of NH2OH at
C-2 and C-4 atoms with opening of the pyran-4-one ring
and resulted in a mixture of 4,5-diarylisoxazole 6 as the
We assume that the chroman-4-one system is formed as
a result of C-formylation of the methylene group followed
by cyclization. The hydroxyl group methylation occurs due
to the presence of a strong base MeO– formed in situ
during the reaction, which is consistent with literature
data.5
2-(4-Chlorophenyl)-1-(2,4-dimetoxyphenyl)ethanone (1c)
is the most convenient precursor to the desired enamino
ketone 3, as it eliminates the possibility of cyclization to
isoflavone. We obtained compound 1c by a complete
methylation of 2-(4-chlorophenyl)-1-(2,4-dihydroxyphenyl)-
Scheme 2
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Chemistry of Heterocyclic Compounds 2015, 51(9), 799–803
Scheme 3
major product and trace amounts of 3,4-diarylisoxazole 7,
which were separated by crystallization (Scheme 3). The
1H NMR signal of the isoxazole proton of compound 6 is
located at 8.78 ppm, which corresponds to a similar signal
of compound 5; the OH signal is observed at 9.87 ppm and
disappears when D2O is added. The chemical shift of the
methylamino)prop-2-en-1-one
into
heterocyclization
reaction with 1,2-N,N-, 1,2-N,O-, and 1,3-N,N-binucleo-
philes gave new pyrazole, isoxazole, and pyrimidine deri-
vatives, respectively. In comparison to a classic method,
isoflavone recyclization, the described approach gives
higher yields of products and higher regioselectivity.
1
phenol OH group in the H NMR spectrum measured in
CDCl3 can be used to reliably distinguish isoxazole
regioisomers (6 and 7).10 The H atom of the hydroxyl
group in the regioisomer 7 forms an intramolecular hydro-
gen bond of chelate type with the isoxazole ring N atom
and is expected to resonate at 9.0–9.6 ppm. Conversely, the
analogous H atom of OH group in regioisomer 6 cannot
form such a hydrogen bond and is expected to appear at a
higher field (6.5–7.0 ppm). The OH group signal of
compound 6 is observed at 6.44 ppm and disappears when
D2O is added, confirming the formation of the particular
regioisomer.
As an additional proof, an alkylation reaction of 2-[4-(4-
chlorophenyl)isoxazol-5-yl]-5-methoxyphenol (6) was carried
out. Treatment of compound 6 with MeI in acetone with
K2CO3 as a base resulted in the formation of compound 5 in a
84% yield; all physicochemical properties of compound 5
obtained by two different pathways were identical.
Experimental
1
1H and 13C, as well as H–13C HSQC NMR spectra
were recorded on a Mercury-400 spectrometer (400 and
100 MHz, respectively). The TMS signal was used as an
internal standard. Mass spectra were recorded on an
Agilent 1100 LC/MSD instrument using atmospheric
pressure chemical ionization. Elemental analyses were
performed using a Perkin-Elmer CHN Analyzer. Melting
points were determined using a Kofler type Leica Galen III
micro hot stage microscope. All solvents used were
purified and dried by standard procedures. Reaction
progress and identity of obtained compounds were
monitored by TLC on Merck 60 F254 silica gel plates using
CH2Cl2–MeOH mixtures as eluents.
2-(4-Chlorophenyl)-1-(2,4-dihydroxyphenyl)ethanone (1a)
was prepared as described previously.11
We have demonstrated in our previous work8 that
reaction of enamino ketones with guanidine carbonate
proceeds smoothly when refluxing the reaction mixture in
DMF with K2CO3 as a base. Reaction of compound 3 with
guanidine carbonate under the described conditions (DMF/
K2CO3) was complete in 2.5 h, giving the 4,5-diaryl-
substituted 2-aminopyrimidine 8 in 97% yield (Scheme 4).
The present work shows that 2-methoxydeoxybenzoins
are the optimal parent compounds for the synthesis of
enamino ketones from deoxybenzoins; it was discovered
that the reaction of DMFDMA with 2-hydroxydeoxy-
benzoins gives 3-aryl-7-methoxychromones with high
yields. Introducing 2-aryl-1-(2,4-dimethoxyphenyl)-3-(di-
2-(4-Chlorophenyl)-1-(2-hydroxy-4-methoxyphenyl)-
ethanone (1b). Dry K2CO3 (2.76 g, 0.02 mol) was added to
a mixture of compound 1a (2.62 g, 0.01 mol) and dimethyl
sulfate (1.04 ml, 0.011 mol) in anhydrous acetone (20 ml)
at room temperature. The mixture was heated to reflux for
2 h, and the progress was monitored by TLC (visualization
with FeCl3). The solution was cooled, treated with water
(100 ml), and acidified with 36% HCl to pH 5–6. The
precipitate was filtered off, washed with cold water, and
recrystallized from MeOH. Yield 2.58 g (94%), mp 85–86°С.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 3.83 (3H,
s, OCH3); 4.28 (2H, s, COCH2); 6.4 (1H, s, H-3); 6.46 (1H,
d, J = 9.2, Н-5); 7.27 (4Н, s, Н-2',3',5',6'); 7.91 (1H, d,
J = 9.21, Н-6); 12.47 (1H, s, OH). 13C NMR spectrum
(DMSO-d6), δ, ppm: 44.9 (COCH2); 56.2 (OCH3); 103.1
(C-3); 107.8 (C-5); 113.4 (C-1); 128.6 (C-3',5' Ar); 129.8
(C-2',6'); 131.4 (C-1'); 131.9 (C-6); 133.6 (C-4'); 165.1
(C-2); 166.8 (C-4); 203.7 (C=O). Mass spectrum, m/z
(Irel, %): 277 [M+H]+ (100). Found, %: С 64.94; Н 4.52.
C15H13СlO3. Calculated, %: C 65.11; H 4.74.
Scheme 4
2-(4-Chlorophenyl)-1-(2,4-dimethoxyphenyl)ethanone
(1c). Dry K2CO3 (4.14 g, 0.03 mol) was added to a mixture
801

Chemistry of Heterocyclic Compounds 2015, 51(9), 799–803
of compound 1a (2.62 g, 0.01 mol) and dimethyl sulfate
dimethoxyphenyl)-1-methyl-1H-pyrazole (4b) (General
method). Hydrazine hydrate (0.06 ml, 0.0012 mol) or
methylhydrazine (0.05 ml, 0.0012 mol) was added to a
mixture of compound 3 (0.34 g, 0.001 mol) in anhydrous
EtOH (10 ml). The solution was refluxed with stirring for 2–
3 h. After completion of the reaction, the mixture was
cooled to room temperature. The solvent was evaporated,
and the residue was recrystallized from EtOH.
(2.37 ml, 0.025 mol) in anhydrous acetone (20 ml) at room
temperature. The mixture was heated to reflux for 3 h, and
the progress was monitored by TLC. The solution was
cooled, treated with water (100 ml), and acidified with 36%
HCl to pH 5–6. The precipitate was filtered off, washed
with cold water, and recrystallized from MeOH. Yield 2.64 g
(91%), mp 70–71°С. 1H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 3.84 (3H, s, 4-OCH3); 3.92 (3H, s,
2-OCH3); 4.18 (2H, s, COCH2); 6.52 (1H, d, J= 9.2, Н-5);
6.55 (1H, s, H-3); 7.15 (2Н, d, J= 8.8, Н-3',5'); 7.25 (2Н, d,
J = 8.8, Н-2',6'); 7.63 (1H, d, J= 9.2, Н-6). 13C NMR
spectrum (DMSO-d6), δ, ppm: 44.3 (COCH2); 55.9
(2,4-OCH3); 97.6 (C-3); 106.4 (C-5); 113.7 (C-1); 128.4
(C-3',5'); 129.7 (C-2',6'); 131.2 (C-1'); 132.3 (C-6); 133.9
(C-4'); 162.4 (C-2); 166.8 (C-4); 202.4 (C=O). Mass
spectrum, m/z (Irel, %): 291 [M+H]+ (100). Found, %:
С 65.93; Н 5.04. C16H15СlO3. Calculated, %: C 66.10;
H 5.20.
4-(4-Chlorophenyl)-5-(2,4-dimethoxyphenyl)-1H-pyra-
1
zole (4a). Yield 0.29 g (93%), mp 145–146°С. H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 3.82 (6H, s,
2,4-OCH3); 6.56 (1H, d, J = 7.6, Н-5); 6.57 (1H, s, Н-3);
7.10 (2Н, d, J= 8.4, Н-3',5'); 7.12 (2Н, d, J= 8.4, Н-2',6');
7.18 (1H, d, J= 7.6, Н-6); 7.63 (1Н, s, СН pyrazole); 12.77
(1Н, s, NH). 13C NMR spectrum (DMSO-d6), δ, ppm: 56.4
(2,4-OCH3); 98.6 (C-3); 107.4 (C-5); 112.4 (C-1); 118.2
(C pyrazole); 128.6 (C-3',5'); 129.4 (C-2',6'); 133.6 (C-6);
132.8 (CH pyrazole); 133.2 (C-1'); 134.3 (C-4'); 143.6
(C pyrazole); 158.7 (C-2); 161.9 (C-4). Mass spectrum,
m/z (Irel, %): 315 [M+H]+ (100). Found, %: С 64.63;
Н 4.62; N 8.74. C17H15СlN2О2. Calculated, %: C 64.87;
H 4.80; N 8.90.
3-(4-Chlorophenyl)-7-methoxy-4H-chromen-4-one (2).
A mixture of compound 1a (2.62 g, 0.01 mol) or 1b (2.76 g,
0.01 mol) and DMFDMA (2.65 ml, 0.02 mol) was stirred
for 30 min under reflux. After completion of the reaction,
the mixture was cooled to room temperature. The solvent
was evaporated, and the residue was recrystallized from
MeOH. Yield 1.94 g (75%) if obtained from compound 1a;
2.62 g (92%) if obtained from compound 1b, mp 197–
4-(4-Chlorophenyl)-5-(2,4-dimethoxyphenyl)-1-methyl-
1H-pyrazole (4b). Yield 0.28 g (87%), mp 149–150°С.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 3.78 (6H,
s, 2,4-OCH3); 3.91 (3H, s, CH3N); 6.54 (1H, d, J= 7.6,
Н-5); 6.59 (1H, s, Н-3); 7.12 (2Н, d, J= 8.4, Н-3',5'); 7.16
(2Н, d, J = 8.4, Н-2',6'); 7.21 (1H, d, J= 7.6, Н-6); 7.66
(1Н, s, СН pyrazole). 13C NMR spectrum (DMSO-d6),
δ, ppm: 38.9 (NCH3); 55.8 (2,4-OCH3); 98.4 (C-3); 107.2
(C-5); 111.8 (C-1); 119.6 (C pyrazole); 128.8 (C-3',5');
129.6 (C-2',6'); 132.3 (C-6); 133.9 (C-4'); 134.5 (C-1');
137.1 (CH pyrazole); 139.4 (C pyrazole), 158.6 (C-2);
161.4 (C-4). Mass spectrum, m/z (Irel, %): 329 [M+H]+
(100). Found, %: С 65.59; Н 5.03; N 8.24. C18H17СlN2О2.
Calculated: C 65.75; H 5.21; N 8.52.
4-(4-Chlorophenyl)-5-(2,4-dimethoxyphenyl)isoxazole
(5). I. Hydroxylamine hydrochloride (0.08 g, 0.0012 mol)
was added to a mixture of compound 3 (0.34 g, 0.0010 mol) in
anhydrous EtOH (10 ml), and the solution was refluxed
with stirring for 3 h. After completion of the reaction, the
mixture was cooled to room temperature. The solvent was
evaporated, and the residue was recrystallized from EtOH.
Yield 0.28 g (90%), mp 77–78°С. 1H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 3.54 (3H, s, 2-OCH3); 3.86
(3H, s, 4-OCH3); 6.61 (1H, d, J= 7.6, Н-5); 6.63 (1H, s,
Н-3); 7.30 (4Н, s, Н-2',3',5',6'); 7.34 (1H, d, J= 7.6, Н-6);
8.78 (1Н, s, СН isoxazole). 13C NMR spectrum (DMSO-d6),
δ, ppm: 55.6 (4-OCH3); 56.8 (2-OCH3); 98.7 (C-3); 100.4
(C isoxazole); 106.6 (C-1); 107.3 (C-5); 127.1 (C-6); 128.6
(C-2',6' Ar); 129.4 (C-3',5' Ar); 134.4 (C-4' Ar); 135.1
(C-1'); 152.4 (CH isoxazole); 158.2 (C isoxazole); 159.4
(C-2); 161.7 (C-4). Mass spectrum, m/z (Irel, %): 316
[M+H]+ (100). Found, %: С 64.44; Н 4.21; N 4.19.
C17H14СlNО3. Calculated, %: C 64.67; H 4.47; N 4.44.
II. Dry K2CO3 (0.83 g, 0.006 mol) was added to a
mixture of compound 6 (1.00 g, 0.0033 mol) and methyl
iodide (0.23 ml, 0.0036 mol) in anhydrous acetone (5 ml)
at room temperature. The mixture was heated to reflux for
1
198°С. H NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
3.92 (3H, s, OCH3); 7.00 (1H, d, J= 7.6, Н-6); 7.02 (1H, s,
H-8); 7.40 (2Н, d, J = 8.4, Н-2',6'); 7.60 (2Н, d, J = 8.4,
Н-3',5'); 8.04 (1H, d, J = 7.6, Н-5); 8.31 (1Н, s, Н-2).
13C NMR spectrum (DMSO-d6), δ, ppm: 55.6 (OCH3);
100.4 (C-8); 114.6 (C-6); 118.3 (C-4a); 122.9 (C-3); 127.9
(C-5); 128.5 (C-1'); 129.32 (C-3',5'); 130.4 (C-2',6'); 134.8
(C-4'); 153.7 (C-2); 158.8 (C-8a); 166.9 (C-7); 178.4
(C=O). Mass spectrum, m/z (Irel, %): 287 [M+H]+ (100).
Found, %: С 66.87; Н 3.65. C16H11СlO3. Calculated, %:
C 67.03; H 3.87.
2-(4-Chlorophenyl)-1-(2,4-dimethoxyphenyl)-3-(di-
methylamino)prop-2-en-1-one (3). A mixture of com-
pound 1c (2.9 g, 0.01 mol) and DMFDMA (2.65 ml,
0.02 mol) was stirred for 2 h under reflux. After completion
of the reaction, the mixture was cooled to room tempe-
rature. The solvent was evaporated, and the residue was
recrystallized from EtOH. Yield 3.26 g (94%), mp 141–142°С.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 2.71 (6Н,
s, N(CH3)2); 3.70 (3H, s, 4-OCH3); 3.80 (3H, s, 2-OCH3);
6.43 (1H, s, Н-3); 6.46 (1H, d, J= 7.6, Н-5); 7.01 (1H, d,
J = 7.6, Н-6); 7.07 (2Н, d, J = 8.4, Н-2',6'); 7.1 (1H, s,
CHN(CH3)2); 7.23 (2Н, d, J = 8.4, Н-3',5'). 13C NMR
spectrum (DMSO-d6), δ, ppm: 46.6 (N(CH3)2); 55.4
(2,4-OCH3); 102.3 (C-3); 111.9 (C=CHN(CH3)2); 112.6
(C-6); 119.4 (C-1); 128.2 (C-6); 128.6 (C-3',5'); 130.1
(2C); 133.4; 136.7; 154.5; 162.7; 168.2; 196.4. Mass
spectrum, m/z (Irel, %): 346 [M+H]+ (100). Found, %:
С 65.78; Н 5.64; N 3.92. C19H20СlNО3. Calculated, %:
C 65.99; H 5.83; N 4.05.
Synthesis of 4-(4-chlorophenyl)-5-(2,4-dimethoxy-
phenyl)-1H-pyrazole (4a) and 4-(4-chlorophenyl)-5-(2,4-
802

Chemistry of Heterocyclic Compounds 2015, 51(9), 799–803
3 h, and the progress of the reaction was monitored by TLC
guanidinium carbonate (0.22 g, 0.0012 mol) in anhydrous
DMF (10 ml) at room temperature. The mixture was heated
to reflux for 2.5 h, and the progress was monitored by
TLC. The solution was cooled, diluted with cold water
(50 ml), and acidified with 36% HCl to pH 5–6. The precipi-
tate was filtered off, washed with cold water, and recrystal-
(visualization with FeCl3). The solution was cooled, diluted
with water (100 ml), and acidified with 36% HCl to pH
5–6. The precipitate was filtered off, washed with cold
water, and recrystallized from i-PrOH. Yield 0.98 g (84%).
2-[4-(4-Chlorophenyl)isoxazol-5-yl]-5-methoxyphenol
(6). Hydroxylamine hydrochloride (0.15 g, 0.0021 mol)
was added to a solution of compound 2 (0.20 g, 0.0007 mol)
in anhydrous pyridine (5 ml), and the solution was refluxed
with stirring for 3 h. Progress of the reaction was
monitored by TLC (CH2Cl2–MeOH, 7:3). Two spots were
observed with different Rf values: the spot with Rf 0.08 did
not give a dark-green color with an alcoholic solution of
FeCl3, the spot with Rf 0.39 gave a dark-green color with
an alcoholic solution of FeCl3. After completion of the
reaction, the reaction mixture was poured into water
(100 ml), and the precipitate containing product 6 and trace
amounts of compound 7 was filtered and crystallized from
MeOH. Yield of product 6 0.17 g (81%), mp 165–167°С.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 3.78 (3H,
s, 5-OCH3); 6.46 (1H, d, J = 7.6, Н-4); 6.48 (1H, s, Н-6);
7.20 (1H, d, J = 7.6, Н-3); 7.28 (2Н, d, J = 8.2, Н-3',5');
7.35 (2Н, d, J = 8.2, Н-2',6'), 8.78 (1Н, s, СН isoxazole);
1
lized from MeOH. Yield 0.32 g (97%), mp 140–141°С. H
NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 3.28 (3H, s,
2-OCH3); 3.82 (3H, s, 4-OCH3); 6.38 (1H, s, Н-3); 6.61
(1H, d, J = 8.4, Н-5); 7.09 (2Н, d, J = 7.2, Н-3',5'); 7.27
(2Н, d, J = 7.2, Н-2',6'); 7.39 (1H, d, J= 8.4, Н-6); 8.53
(1Н, s, СН pyrimidine); 8.55 (2Н, br. s, NH2). 13C NMR
spectrum (DMSO-d6), δ, ppm: 55.6 (4-OCH3); 56.2
(2-OCH3); 99.3 (C-3); 107.4 (C-5); 117.6 (C-1); 122.3
(C pyrimidine); 128.8 (C-2',6'); 129.4 (C-3',5'); 132.4
(C-6); 134.6 (C-4'); 135.1 (C-1'); 149.6 (CH pyrimidine);
158.6 (C-2); 159.4 (C pyrimidine); 161.8 (C-4); 163.3
(C pyrimidine). Mass spectrum, m/z (Irel, %): 342 [M+H]+
(100). Found, %: С 63.04; Н 4.51; N 12.06. C18H16СlN3О2.
Calculated, %: C 63.25; H 4.72; N 12.29.
References
1
9.87 (1Н, s, ОН). H NMR spectrum (DMSO-d6 + D2O),
1. Science of Synthesis: Houben-Weyl Methods of Molecular
Transformations. Category 2. Hetarenes and Related Ring
Systems. Volume 14. Six-membered Hetarenes with One
Chalcogen, Thomas E. J., Ed.; Georg-Thieme-Verlag:
Stuttgart, 2003, 347 p.
δ, ppm (J, Hz): 3.78 (3H, s, 5-OCH3); 6.46 (1H, d, J = 7.6,
Н-4); 6.48 (1H, s, Н-6); 7.20 (1H, d, J = 7.6, Н-3); 7.28
(2Н, d, J = 8.2, Н-3',5'); 7.35 (2Н, d, J = 8.2, Н-2',6'), 8.78
(1Н, s, СН isoxazole). 1H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 3.75 (3H, s, 5-OCH3); 6.38 (1H, d, J = 7.6, Н-4);
6.44 (1Н, s, 1-ОН); 6.49 (1H, s, Н-6); 7.10 (1H, d, J = 7.6,
Н-3); 7.22 (2Н, d, J = 8.4, Н-2',6'); 7.29 (2Н, d, J = 8.4,
2. Abdulla, R. F.; Brinkmeyer, R. S. Tetrahedron 1979, 35,
1675.
3. Elassar, A.-Z. A.; El-Khair, A. A. Tetrahedron 2003, 59,
8463.
1
Н-3',5'); 8.34 (1Н, s, СН isoxazole). H NMR spectrum
4. Pelter, A.; Foot, S. Synthesis 1976, 326.
(CDCl3+D2O), δ, ppm (J, Hz): 3.75 (3H, s, 5-OCH3); 6.38
(1H, d, J = 7.6, Н-4); 6.49 (1H, s, Н-6); 7.10 (1H, d,
J = 7.6, Н-3); 7.22 (2Н, d, J = 8.4, Н-2',6'); 7.29 (2Н, d,
J = 8.4, Н-3',5'); 8.34 (1Н, s, СН isoxazole). 13C NMR
spectrum (DMSO-d6), δ, ppm: 55.9 (OCH3); 100.6 (C isox-
azole); 104.4 (C-6); 107.6 (C-4); 108.5 (C-2); 127.3 (C-3);
128.7 (C-2',6'); 129.6 (C-3',5'); 134.2 (C-4'); 134.9 (C-1');
152.6 (CH isoxazole); 154.8 (C-1); 159.1 (C isoxazole);
163.4 (C-4). Mass spectrum, m/z (Irel, %): 302 [M+H]+ (100).
Found, %: С 63.43; Н 3.92; N 4.36. C16H12СlNО3.
Calculated, %: C 63.69; H 4.01; N 4.64.
5. Pinto, J. C.; Fryer, R. I. J. Heterocycl. Chem. 1993, 30, 939.
6. Olivera, R.; SanMartin, R.; Churruca F., Domínguez, E.
J. Org. Chem. 2002, 67, 7215.
7. Lee, H. K.; Yun, E.; Min, J. H.; Yoon K. S.; Chong D.-H.;
Lee, S. Synth. Commun. 2012, 42, 1890.
8. Moskvina, V. S.; Khilya, V. P.; Turov, O. V.; Groth, U. M.
Synthesis 2009, 1279.
9. Khilya, V. P.; Kupchevskaya, I. P.; Grishko, L. G. In Nitrogen-
containing Heterocycles and Alkaloids; Kartsev, V. G.;
Tolstikov, G. A., Eds.; Iridium Press: Moscow, 2001, Vol. 1,
564.
10. Khilya, V. P.; Ishchenko, V. V. Chem. Heterocycl. Compd.
2002, 38, 883. [Khim. Geterotsikl. Soedin. 2002, 1019.]
11. Pivovarenko, V. G.; Khilya, V. P.; Vasil'ev, S. A. Chem. Nat.
Compd. 1989, 25, 542. [Khim. Prirod. Soedin. 1989, 639.]
5-(4-Chlorophenyl)-4-(2,4-dimethoxyphenyl)pyrimi-
din-2-amine (8). Dry K2CO3 (0.14 g, 0.001 mol) was
added to a mixture of compound 3 (0.34 g, 0.001 mol) and
803