Mannich synthesis of 3-amino-1-aryl-2-(4-chlorophenyl)-propan-1-ones

Full text of DOI:10.1134/S1070428009120173

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 12, pp. 1853–1855. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © G.A. Gevorgyan, A.P. Avakyan, N.K. Gasparyan, G.A. Panosyan, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45,
No. 12, pp. 1854–1856.
SHORT
COMMUNICATIONS
Mannich Synthesis of 3-Amino-1-aryl-2-(4-chlorophenyl)-
propan-1-ones
G. A. Gevorgyana, A. P. Avakyana, N. K. Gasparyana, and G. A. Panosyanb
a Scientific and Technological Center of Organic and Pharmaceutical Chemistry, National Academy of Sciences of Armenia
Mndzhoyan Institute of Fine Organic Chemistry, pr. Azatutyan 26, Erevan, 375014 Armenia
e-mail: gyulgev@gmail.com
b Molecular Structure Research Center, National Academy of Sciences of Armenia, Erevan, Armenia
Received September 17, 2008
DOI: 10.1134/S1070428009120173
β-Amino ketones (Mannich bases) are potential
biologically active compounds [1, 2]. In continuation
of our previous studies [3–5] we have synthesized
a new series of β-amino ketones, 3-amino-1-aryl-2-(4-
chlorophenyl)propan-1-ones II–IX by aminomethyla-
tion of 4-substituted 4-chlorobenzyl phenyl ketones I
with paraformaldehyde and various amines, in particu-
lar azepane, 4-(3-chlorophenyl)piperazine, 4-(2-fluoro-
phenyl)piperazine, 4-ethylpiperazine, and 4-(2-furyl-
carbonyl)piperazine. The best yields were obtained by
carrying out the reaction at pH 8–9. For example, the
yields of compound II in the condensation of
4-chlorobenzyl 4-methoxyphenyl ketone with azepane
(as hydrochloride) and paraformaldehyde in ethanol
(or dioxane) were as follows: 67% at pH 8–9, 22% at
pH 4, and 5% at pH 1. β-Amino ketones II–IX were
converted into the corresponding hydrochlorides X–
XVII with a view to examine their biological activity.
Initial ketones I were prepared by Friedel–Crafts
acylation of the corresponding substituted benzenes
with 4-chlorophenylacetyl chloride.
Compounds II–IX were isolated as colorless crys-
talline substances which were insoluble in water. They
showed in the IR spectra carbonyl absorption band in
the region 1660–1680 cm–1. Hydrochlorides X–XVII
were water-soluble crystalline substances.
3-Amino-1-aryl-2-(4-chlorophenyl)propan-1-ones
II–IX and their hydrochlorides X–XVII (general
procedure). A mixture of 0.1 mol of substituted phenyl
4-chlorobenzyl ketone I, 3.6 g (0.12 mol) of paraform-
aldehyde, and 0.12 mol of the corresponding amine in
80 ml of ethanol was heated for 8–10 h. The solvent
was distilled off, the residue was dissolved in water,
and the solution was acidified to pH 1–2 with 10%
hydrochloric acid and extracted with diethyl ether or
benzene to remove unreacted ketone. The aqueous
phase was adjusted to pH 8–9 by adding 40% aqueous
sodium hydroxide and extracted with diethyl ether or
benzene (3×100 ml). The combined extracts were
dried over anhydrous sodium sulfate, the solvent was
distilled off, and the precipitate was filtered off and
recrystallized from ethanol. Compounds II–IX thus
O
O
O
CH2O, XYNH
EtOH
NXY
NXY·HCl
HCl, Et2O
R
R
R
Cl
Cl
Cl
I
II–IX
X–XVII
II–V, X–XIII, XYN = azepan-1-yl; VI, XIV, XYN = 4-(3-chlorophenyl)piperazin-1-yl; VII, XV, XYN = 4-(2-fluorophenyl)piperazin-
1-yl; VIII, XVI, XYN = 4-ethylpiperazin-1-yl; IX, XVII, XYN = 4-(furan-2-ylcarbonyl)piperazin-1-yl; II, VI, VII, X, XIV, XV,
R =MeO; III, VIII, IX, XI, XVI, XVII, R = EtO; IV, XII, R = Me; V, XIII, R = sec-butyl.
1853

GEVORGYAN et al.
1854
obtained were dissolved in ether, and a solution of
hydrogen chloride in diethyl ether was slowly added
dropwise until pH 1. The precipitate was filtered off,
washed with anhydrous diethyl ether, and recrystal-
lized from anhydrous acetone. We thus isolated hydro-
chlorides X–XVII.
6.9 Hz); 1.46 br and 1.57 br (4H each, C6H12Ν); 2.58–
2.66 m [4H, Ν(CH2)2]; 2.72 d.d (1H, CH2, Ј = 12.8,
5.4 Hz); 3.33 d.d (1H, CH2, Ј = 12.8, 8.6 Hz); 4.08 q
(2H, OCH2, Ј = 6.9 Hz); 4.81 d.d (1H, CH, Ј = 8.6, Ј =
5.4 Hz); 6.87 m and 7.92 m (2H each, C6H4O); 7.22 m
and 7.30 m (2H each, C6H4Cl). Found, %: C 71.68;
H 7.35; Ν 3.71. C23H28ClΝO2. Calculated, %: C 71.58;
H 7.31; Ν 3.63.
3-(Azepan-1-yl)-2-(4-chlorophenyl)-1-(4-ethoxy-
phenyl)propan-1-one hydrochloride (XI). mp 164–
166°C. Found, %: Cl 8.34; Ν 3.35. C23H28ClΝO2·HCl.
Calculated, %: Cl 8.41; Ν 3.32.
3-(Azepan-1-yl)-2-(4-chlorophenyl)-1-(4-methyl-
phenyl)propan-1-one (IV). Yield 62%, mp 97–99°C,
Rf 0.58. IR spectrum: ν 1672 cm–1 (C=O). Found, %:
C 74.36; H 7.34; Ν 3.88. C22H26ClΝO. Calculated, %:
C 74.24; H 7.36; Ν 3.94.
3-(Azepan-1-yl)-2-(4-chlorophenyl)-1-(4-methoxy-
phenyl)propan-1-one (II). a. A mixture of 24.6 g
(0.1 mol) of 4-chlorobenzyl 4-methoxyphenyl ketone,
3.6 g (0.12 mol) of paraformaldehyde, and 11.9 g
(0.12 mol) of hexamethyleneimine in 80 ml of ethanol
was heated for 8 h. The mixture was then treated
according to the general procedure described above.
Yield 24.9 g (67%), mp 99–101°C, Rf 0.62. IR spec-
trum: ν 1664 cm–1 (C=O). Found, %: C 71.15; H 7.08;
Ν 3.74. C22H26ClΝO2. Calculated, %: C 71.05; H 7.05;
Ν 3.77.
3-(Azepan-1-yl)-2-(4-chlorophenyl)-1-(4-methyl-
phenyl)propan-1-one hydrochloride (XII). mp 154–
157°C. Found, %: Cl 9.14; Ν 3.51. C22H26ClΝO·HCl.
Calculated, %: Cl 9.05; Ν 3.57.
3-(Azepan-1-yl)-1-(4-sec-butylphenyl)-2-(4-
chlorophenyl)propan-1-one (V). Yield 56%, mp 103–
104°C, Rf 0.61. IR spectrum: ν 1672 cm–1 (C=O).
Found, %: C 75.51; H 8.17; Ν 3.44. C25H32ClΝO. Cal-
culated, %: C 75.45; H 8.10; Ν 3.52.
b. A mixture of 24.6 g (0.1 mol) of 4-chlorobenzyl
4-methoxyphenyl ketone, 3.6 g (0.12 mol) of para-
formaldehyde, and 16.3 g (0.12 mol) of hexamethyl-
eneimine hydrochloride in 80 ml of ethanol was heated
for 10 h. The solvent was distilled off, the residue was
dissolved in water, and 10% hydrochloric acid was
added to the solution until pH 1. The mixture was then
treated acording to the general procedure. Yield 8.2 g
(22%), mp 99–101°C, Rf 0.62.
c. Hydrochloric acid was added dropwise to a mix-
ture of 24.6 g (0.1 mol) of 4-chlorobenzyl 4-methoxy-
phenyl ketone, 3.6 g (0.12 mol) of paraformaldehyde,
and 16.3 g (0.12 mol) of hexamethyleneimine hydro-
chloride in 80 ml of dioxane until pH 1. The mixture
was heated for 10 h, The solvent was distilled off, the
residue was dissolved in water, and the product was
isolated according to the general procedure. Yield 1.9 g
(5%), mp 99–101°C, Rf 0.62.
3-(Azepan-1-yl)-1-(4-sec-butylphenyl)-2-(4-
chlorophenyl)propan-1-one hydrochloride (XIII).
mp 140–142°C. Found, %: Cl 8.26; Ν 3.24.
C25H32ClΝO·HCl. Calculated, %: Cl 8.18; Ν 3.22.
2-(4-Chlorophenyl)-3-[4-(3-chlorophenyl)pi-
perazin-1-yl]-1-(4-methoxyphenyl)propan-1-one
(VI). Yield 58%, mp 138–140°C, Rf 0.64. IR spectrum:
1
ν 1670 cm–1 (C=O). H NMR spectrum, δ, ppm:
2.61 d.d (1H, CH2, Ј = 12.5, 5.3 Hz); 2.62 m [4H,
CH2Ν(CH2)2]; 3.08 t [4H, C6H4Ν(CH2)2, Ј = 5.1 Hz];
3.28 d.d (1H, CH2, Ј = 12.5, 8.5 Hz); 3.84 s (3H,
OCH3); 4.96 d.d (1H, CH, Ј = 8.5, 5.3 Hz); 6.66–
6.73 m (2H), 6.77 t (1H, Ј = 2.2 Hz), and 7.09 t (1H,
Ј = 8.1 Hz) (C6H4Cl-3); 6.90 m and 7.97 m (2H each,
C6H4OCH3); 7.23 m and 7.33 m (2H each, C6H4Cl-4).
Found, %: C 66.61; H 5.52; Ν 6.04. C26H26Cl2Ν2O2.
Calculated, %: C 66.53; H 5.58; Ν 5.97.
2-(4-Chlorophenyl)-3-[4-(3-chlorophenyl)pi-
perazin-1-yl]-1-(4-methoxyphenyl)propan-1-one
hydrochloride (XIV). mp 177–179°C. Found, %:
Cl 13.15; Ν 5.09. C26H26Cl2Ν2O2·HCl. Calculated, %:
Cl 13.10; Ν 5.17.
3-(Azepan-1-yl)-2-(4-chlorophenyl)-1-(4-methoxy-
phenyl)propan-1-one hydrochloride (X). mp 158–
1
159°C. H NMR spectrum, δ, ppm: 1.62 m (2H),
1.78 m (4H), and 1.98 m (2H, C6H12Ν); 2.91–3.10 m
and 3.26–3.34 m [2H each, Ν(CH2)]; 3.22 m and
4.07 m (1H each, ΝCH2); 3.84 s (3H, OCH3); 6.05 d.d
(1H, CH, Ј = 7.3, 3.6 Hz); 6.95 m and 8.03 m (2H
each, CH3OC6H4); 7.28 m and 7.44 m (2H each,
ClC6H4); 12.05 br.s (1H, HCl). Found, %: C 71.15;
H 7.08; Ν 3.74. C22H26ClΝO2 ·HCl. Calculated, %:
C 71.05; H 7.05; Ν 3.77.
3-(Azepan-1-yl)-2-(4-chlorophenyl)-1-(4-ethoxy-
phenyl)propan-1-one (III). Yield 70%, mp 105–
107°C, Rf 0.63. IR spectrum: ν 1670 cm–1 (C=O).
1H NMR spectrum, δ, ppm: 1.41 t (3H, CH3, Ј =
2-(4-Chlorophenyl)-3-[4-(2-fluorophenyl)pipera-
zin-1-yl]-1-(4-methoxyphenyl)propan-1-one (VII).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 12 2009

MANNICH SYNTHESIS OF 3-AMINO-1-ARYL-2-(4-CHLOROPHENYL)PROPAN-1-ONES
1855
Yield 55%, mp 79–82°C, Rf 0.63. IR spectrum:
(IX). Yield 63%, mp 124–126°C, Rf 0.59. IR spectrum:
1
ν 1666 cm–1 (C=O). H NMR spectrum, δ, ppm:
ν 1662 cm–1 (C=O). Found, %: C 66.97; H 5.74;
Ν 5.93. C26H27ClΝ2O2. Calculated, %: C 66.88;
H 5.83; Ν 6.00.
2.61 d.d (1H, CH2, Ј = 12.5, 8.5 Hz); 2.59–2.69 m [4H,
CH2Ν(CH2)2]; 2.96 t [4H, C6H4Ν(CH2)2, Ј = 5.0 Hz];
3.29 d.d (1H, CH2, Ј = 12.5, 8.5 Hz); 3.84 s (3H,
OCH3); 4.94 d.d (1H, CH, Ј = 8.5, 5.3 Hz); 6.80–
7.00 m (4H, C6H4F); 6.90 m and 7.97 m (2H each,
C6H4OCH3); 7.29 m and 7.33 m (2H each, C6H4Cl).
Found, %: C 69.05; H 5.80; Ν 6.14. C26H26ClFΝ2O2.
Calculated, %: C 68.94; H 5.79; Ν 6.18.
2-(4-Chlorophenyl)-1-(4-ethoxyphenyl)-3-[4-
(furan-2-ylcarbonyl)piperazin-1-yl]propan-1-one
hydrochloride (XVII). mp 138–141°C. Found, %:
Cl 13.25; Ν 5.26. C26H27ClΝ2O2·HCl. Calculated, %:
Cl 13.16; Ν 5.1.
The IR spectra were measured on Specord 75IR
2-(4-Chlorophenyl)-3-[4-(2-fluorophenyl)pipera-
zin-1-yl]-1-(4-methoxyphenyl)propan-1-one hydro-
chloride (XV). mp 177–178°C. Found, %: Cl 13.58;
Ν 5.37. C26H26ClFΝ2O2·HCl. Calculated, %: Cl 13.51;
Ν 5.33.
1
and Nexus FT-IR spectrometers. The H NMR spectra
were recorded on a Varian Mercury-300 instrument
using DMSO-d6 as solvent. Thin-layer chromatog-
raphy was performed on Silufol UV-254 plates using
butan-1-ol–ethanol–acetic acid–water (8:2:1:3) as
eluent; development with iodine vapor.
2-(4-Chlorophenyl)-1-(4-ethoxyphenyl)-3-(4-
ethylpiperazin-1-yl)propan-1-one (VIII). Yield 59%,
mp 120–122°C, Rf 0.62. IR spectrum: ν 1672 cm–1
REFERENCES
1
(C=O). H NMR spectrum, δ, ppm: 0.99 t (3H,
CH3CH2Ν, Ј = 7.2 Hz); 1.41 t (3H, CH3CH2O, Ј =
7.0 Hz); 2.26 q (2H, CH3CH2Ν, Ј = 7.2 Hz); 2.27 m
and 2.45 m (4H each, C4H8Ν2); 2.52 d.d (1H, CH2, Ј =
12.5, 5.1 Hz); 3.21 d.d (1H, CH2, Ј = 12.5, 8.5 Hz);
4.08 q (2H, CH3CH2O, Ј = 7.0 Hz); 4.85 d.d (1H, CH,
Ј = 8.5, 5.1 Hz); 6.86 m and 7.92 m (2H each,
C6H4OEt); 7.21 m and 7.29 m (2H each, C6H4Cl).
Found, %: C 68.98; H 7.27; Ν 7.03. C23H29ClΝ2O2.
Calculated, %: C 68.90; H 7.29; Ν 6.99.
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2-(4-Chlorophenyl)-1-(4-ethoxyphenyl)-3-(4-
ethylpiperazin-1-yl)propan-1-one hydrochloride
(XVI). mp 182–184°C. Found, %: Cl 15.07; Ν 5.86.
C23H29ClΝ2O2·HCl. Calculated, %: Cl 14.99; Ν 5.91.
4. Gevorgyan, G.A., Gasparyan, N.K., Tumajyan, H.E.,
Hamazaspyan, G.S., and Panosyan, G.A., Electronic J.
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Khim.-Farm. Zh., 2005, vol. 39, no. 7, p. 26.
2-(4-Chlorophenyl)-1-(4-ethoxyphenyl)-3-[4-
(furan-2-ylcarbonyl)piperazin-1-yl]propan-1-one
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 12 2009