Synthesis of ethyl 5-acetyl-1-R-4-aryl-6-hydroxy-6-methyl-2-oxopiperidine- 3-carboxylates

Article abstract of DOI:10.1007/s10593-013-1212-6

The reaction of arylidene acetylacetones and ethoxycarbonylacetamides in the presence of triethyl-amine was found to lead to the formation of ethyl 5-acetyl-1-R-4-aryl-6-hydroxy-6-methyl-2-oxo-piperidine-3-carboxylates.

Full text of DOI:10.1007/s10593-013-1212-6

Chemistry of Heterocyclic Compounds, Vol. 48, No. 12, March, 2013 (Russian Original Vol. 48, No. 12, December, 2012)
SYNTHESIS OF ETHYL 5-ACETYL-1-R-4-ARYL-6-HYDROXY-
6-METHYL-2-OXOPIPERIDINE-3-CARBOXYLATES
M. S. Sargsyan1, S. S. Hayotsyan1*, A. Kh. Khachatryan1, A. E. Badasyan1,
G. A. Panosyan2, and S. G. Kon'kova1
The reaction of arylidene acetylacetones and ethoxycarbonylacetamides in the presence of triethyl-
amine was found to lead to the formation of ethyl 5-acetyl-1-R-4-aryl-6-hydroxy-6-methyl-2-oxo-
piperidine-3-carboxylates.
Keywords: arylidene acetylacetone, ethoxycarbonylacetamide, piperidine, heterocyclization.
The amide group is an important component of many biologically active compounds, therefore the
development of new methods for the synthesis of compounds containing this pharmacophoric group attracts a
definite interest. In this regard, we have recently shown that a room temperature reaction of secondary amides of
acetoacetic acid 1 with arylidene acetylacetone 2 in the presence of base gave only the amide 4 among the three
possible ketone products 4-6 [1] (Scheme 1). Under these conditions, the nucleophilicity of the acetyl fragment
methyl group at the α-position to the amide group of adduct 3 exceeded the nucleophilicity of the remaining two
acetyl groups, so that the cyclization proceeded through pathway a.
Similar behavior was observed by Gein and coworkers, who studied the reaction of aldehydes and
amides of acetoacetic acid, leading to the formation of carbocycles containing two amide groups [2].
In order to exclude the possibility of carbocyclization (pathway a) in the above-mentioned reaction and
to direct it towards heterocyclization (pathway b), ethoxycarbonylacetamides 7a-c were used instead of
acetoacetamides 1 (Scheme 2). These experiments showed that the reaction also proceeded at room temperature
in the presence of triethylamine, while the intermediate adducts 8a-e underwent intramolecular
heterocyclization (pathway b) to give ethyl 5-acetyl-1-R-4-aryl-6-hydroxy-6-methyl-2-oxopiperidine-3-carb-
oxylates 9a-e in 27-90% yields.
_______
*To whom correspondence should be addressed, e-mail: sargis@hayotsyan.com.
1Institute of Organic Chemistry of the Scientific Technological Center of Organic and Pharmaceutical
Chemistry, National Academy of Sciences of the Republic of Armenia, 26 Azatutyan Ave., Yerevan 0014,
Armenia.
2Molecular Structure Research Center of the Scientific Technological Center of Organic and Pharmaceutical
Chemistry, National Academy of Sciences of the Republic of Armenia, 26 Azatutyan Ave., Yerevan 0014,
Armenia; e-mail: henry@nsrc.am.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1928-1931. Original article
submitted May 3, 2012.
0009-3122/13/4812-1805©2013 Springer Science+Business Media New York
1805

The structure of esters 9a-e was established using IR, 1H NMR, 13C NMR, and DEPT spectroscopy. We
should note that no carbocyclization products, formed by nucleophilic attack of the acetyl group of adducts 8a-e
(pathway c), were found in the reaction mixtures. The absence of such products was clearly related to the low
electrophilicity of the ethoxycarbonyl group.
Scheme 1
O
O
R1
O
Me
O
Me
Me
NHR
O
O
Piperidine
a
R1
Me
+
EtOH, 20°C
O
Me
NHR
b
Me
O
1
2
c
3
c
b
a
O
R1
O
O
R1
O
O
O
R1
O
O
Me
NHR Me
Me
Me
Me
NHR
Me
Me
O
N
R
HO
HO
OH
6
4
5
Scheme 2
O
O
O
O
R1
O
O
R1
O
EtO
NHR
Me
Me
NHR
OEt
7a–c
Et3N
EtO
Me
Me
+
EtOH
20°C
O
Me
O
O
N
OH
b
c
R1
R
9a–e
Me
8a–e
O
2a–c
2 a R1 = Ph, b R1 = 4-O2NC6H4, c R1 = 4-Me2NC6H4; 7 a R = 2-MeC6H4, b R = 2,4-Me2C6H3, c R = Bn;
9 a R = 2-MeC6H4, R1 = Ph; b R = 2,4-Me2C6H3, R1 = Ph; c R = Bn, R1 = Ph;
d R = 2,4-Me2C6H3, R1 = 4-O2NC6H4; e R = 2-MeC6H4, R1 = 4-Me2NC6H4
Thus, in the present work, we studied the reaction of arylidene acetylacetones and ethoxycarbonyl-
acetamides in the presence of triethylamine. A convenient method has been developed for the synthesis of
heterocyclization products of the starting compounds, namely, esters of 1,4-disubstituted 5-acetyl-6-hydroxy-
6-methyl-2-oxopiperidine-3-carboxylic acid.
EXPERIMENTAL
The IR spectra were recorded on a Specord 75 IR spectrometer for vaseline mulls. The 1H and 13C NMR
spectra were recorded on a Varian Mercury 300 spectrometer (300 and 75 MHz, respectively) in 1:3 DMSO-d6–
CCl4 with TMS as internal standard. The elemental analysis was carried out on a Korshun-Klimova instrument
1806

for carbon and hydrogen and the Dumas-Pregl method for nitrogen. The melting points were determined on a
Boetius hot stage apparatus.
Reaction of Ethoxycarbonylacetamides 7a-c with Arylidene Acetylacetones 2a-c (General
Method). An equimolar mixture of acetamide 7a-c, acetylacetone 2a-c, and triethylamine was dissolved in
absolute ethanol and left at room temperature for 24-120 h. The precipitate that formed was filtered off, washed
with absolute ether, and recrystallized from absolute ethanol. No individual compound could be isolated from
the viscous mass remaining after evaporation of the filtrate of the reaction mixture.
Ethyl
5-acetyl-6-hydroxy-6-methyl-1-(2-methylphenyl)-2-oxo-4-phenylpiperidine-3-carboxylate
(9a) was obtained from acetylacetone 2a (0.56 g, 3 mmol) and acetamide 7a (0.66 g, 3 mmol) in the presence of
triethylamine (0.30 g, 3 mmol) in absolute ethanol (7 ml). Reaction time 24 h. Yield 1.10 g (90%). White
crystalline powder. Mp 178-179°С. IR spectrum, ν, cm-1: 3380 (OH), 1725 (COO), 1690 (CO), 1635 (CON).
1H NMR spectrum, δ, ppm (J, Hz): 0.98 (3H, t, J = 7.1, OCH2CH3); 1.09 (3H, s, 6-CH3); 1.90 (3H, s,
5-COCH3); 2.15 (3H, s, ArCH3); 3.53 (1H, d, J = 12.5, 3-CH); 3.73 (1H, d, J = 12.0, 5-CH); 3.92 (2H, q,
J = 7.1, OCH2CH3); 4.24 (1H, t, J = 12.3, 4-CH); 6.47 (1H, s, 6-OH); 7.18-7.35 (8H, m, H Ph, H Ar); 7.40-7.46
13
(1H, m, H Ar). C NMR spectrum, δ, ppm: 13.5 (OCH2CH3); 17.6 (ArCH3); 25.3 (6-CH3); 29.7 (5-COCH3);
38.9 (C-4); 56.9 (C-3); 59.4 (OCH2CH3); 62.5 (C-5); 84.5 (C-6); 125.6; 126.9; 127.1 (CH Ar); 127.9, 128.0
(C-2,3,5,6 Ph); 129.2; 129.7 (CH Ar), 136.7; 137.0; 138.9 (i-C Ar); 164.7; 168.1; 206.7 (CОCH3). Found, %:
C 70.12; H 6.68; N 3.54. C24H27NO5. Calculated, %: C 70.04; H 6.65; N 3.42.
Ethyl 5-acetyl-6-hydroxy-1-(2,4-dimethylphenyl)-6-methyl-2-oxo-4-phenylpiperidine-3-carboxylate
(9b) was obtained from acetylacetone 2a (0.85 g, 4.5 mmol) and acetamide 7b (1.06 g, 4.5 mmol) in the presence of
triethylamine (0.45 g, 4.5 mmol) in absolute ethanol (6 ml). Reaction time 96 h. Yield 1.00 g (52%). Fine white
crystalline powder. Mp 167-168°С. IR spectrum, ν, cm-1: 3400 (OH), 1720 (COO), 1680 (CO), 1620 (CON).
1H NMR spectrum, δ, ppm (J, Hz): 0.98 (3H, t, J = 7.1, OCH2CH3); 1.09 (3H, s, 6-CH3); 1.89 (3H, s, 5-СOCH3);
2.10 (3H, s, 2-CH3 Ar); 2.35 (3H, s, 4-CH3 Ar); 3.50 (1H, d, J = 12.5, 3-CH); 3.71 (1H, d, J = 12.0, 5-CH); 3.92 (2H,
q, J = 7.1, OCH2CH3); 4.23 (1H, t, J = 12.3, 4-CH); 6.39 (1H, s, 6-OH); 6.96-7.04 (2H, m) and 7.21-7.33 (6H, m,
H Ph, H Ar). Found, %: C 71.09; H 6.92; N 3.30. C25H29NO5. Calculated, %: C 70.90; H 6.90; N 3.31.
Ethyl 5-acetyl-1-benzyl-6-hydroxy-6-methyl-2-oxo-4-phenylpiperidine-3-carboxylate (9c) was
obtained from acetylacetone 2a (0.40, 2.17 mmol) and acetamide 7c (0.48 g, 2.17 mmol) in the presence of
triethylamine (0.22 g, 2.17 mmol) in absolute ethanol (4 ml). Reaction time 120 h. Yield 0.47 g (53%). Fine
white crystals. Mp 150-152°С. IR spectrum, ν, cm-1: 3345 (OH), 1720 (COO), 1690 (CO), 1610 (CON). 1H NMR
spectrum, δ, ppm (J, Hz): 0.99 (3H, t, J = 7.1, OCH2CH3); 1.30 (3H, s, 6-CH3); 1.87 (3H, s, 5-COCH3); 3.42
(1H, d, J = 12.7, 3-CH); 3.73 (1H, d, J = 12.1, 5-CH); 3.92 (2H, q, J = 7.1, OCH2CH3); 4.09 (1H, t, J = 12.4,
4-CH); 4.40 (1H, d, J =16.4) and 5.01 (1H, d, J = 16.4, CH2Ph); 6.48 (1H, s, 6-OH); 7.12-7.34 (10H, m, H Ph).
Found, %: C 70.61; H 6.63; N 3.43. C24H27NO5. Calculated, %: C 70.04; H 6.65; N 3.42.
Ethyl 5-acetyl-6-hydroxy-1-(2,4-dimethylphenyl)-6-methyl-4-(4-nitrophenyl)-2-oxopiperidine-3-carb-
oxylate (9d) was obtained from acetylacetone 2b (0.93 g, 4 mmol) and compound 7b (0.94 g, 4 mmol) in the
presence of triethylamine (0.40 g, 4 mmol) in absolute ethanol (10 ml). Reaction time 96 h. Yield 1.28 g (68%).
Yellowish crystalline powder. Mp 124-125°С. IR spectrum, ν, cm-1: 3390 (OH), 1705 (COO), 1675 (CO), 1620
1
(CON). H NMR spectrum, δ, ppm (J, Hz): 1.03 (3H, t, J = 7.1, OCH2CH3); 1.11 (3H, s, 6-CH3); 1.93 (3H, s,
5-СОСН3); 2.12 (3H, s, 2-CH3 Ar); 2.35 (3H, s, 4-CH3 Ar); 3.72 (1H, d, J = 12.4, 3-CH); 3.90 (1H, d, J = 12.1,
5-CH); 3.87-4.01 (2H, m, OCH2CH3); 4.41 (1H, t, J = 12.2, 4-CH); 6.47 (1H, s, 6-OH); 6.97-7.04 (2H, m) and
7.62-7.69 (2H, m, 4-O2NC6H4); 7.29 (1H, d, J = 7.8) and 8.13-8.21 (2H, m, 2,4-Me2C6H3). Found, %: C 63.95;
H 5.99; N 5.96. C25H28N2O7. Calculated, %: C 64.09; H 6.02; N 5.98.
Ethyl 5-acetyl-6-hydroxy-4-(4-dimethylaminophenyl)-6-methyl-1-(2-methylphenyl)-2-oxopiperi-
dine-3-carboxylate (9e) was obtained from acetylacetone 2c (0.92 g, 4 mmol) and acetamide 7a (0.884 g,
4 mmol) in the presence of triethylamine (0.41 g, 4 mmol) in absolute ethanol (12 ml). Reaction time 120 h.
Yield 0.48 g (27%). Fine light lemon-colored crystals. Mp 155-156°С. IR spectrum, ν, cm-1: 3400 (OH), 1735
(COO), 1700 (CO), 1640 (CON). 1H NMR spectrum, δ, ppm (J, Hz): 1.04 (3H, t, J = 7.1, OCH2CH3); 1.07 (3H,
1807

s, 6-CH3); 1.90 (3H, s, 5-СОСН3); 2.14 (3H, s, ArCH3); 2.94 (6H, s, N(CH3)2); 3.39 (1H, d, J = 12.6, 3-CH);
3.63 (1H, d, J = 12.0, 5-CH); 3.88-4.00 (2H, m, OCH2CH3); 4.11 (1H, t, J = 12.3, 4-CH); 6.37 (1H, s, 6-OH);
6.54-6.65 (2H, m) and 7.05-7.14 (2H, m, 4-Me2NC6H4); 7.18-7.24 (3H, m) and 7.40-7.16 (1H, m, 2-MeC6H4).
13C NMR spectrum, δ, ppm: 13.6 (OCH2CH3); 17.5 (ArCH3); 25.3 (6-CH3); 29.5 (COCH3); 38.4 (C-4); 39.7
(2C, N(CH3)2); 57.3 (C-3); 59.6 (OCH2CH3); 62.9 (C-5); 84.5 (C-6); 111.8 (2CH Ar); 125.5 (CH Ar); 125.7
(i-C Ar); 126.9 (CH Ar)); 128.3 (2CH Ar); 129.2; 129.5 (CH Ar); 136.4; 137.1; 148.9 (i-C Ar); 164.8; 168.0;
207.0 (CОCH3). Found, %: C 68.85; H 7.15; N 6.20. C26H32N2O5. Calculated, %: C 69.01; H 7.13; N 6.19.
REFERENCES
1.
2.
M. S. Sargsyan, S. S. Hayotsyan, A. Kh. Khachatryan, A. E. Badasyan, and S. G. Kon'kova, Khim. Zh.
Armenii, 65, 1469 (2012).
V. L. Gein, E. V. Levandovskaya, N. V. Nosova, N. V. Antonova, E. V. Voronina, M. I. Vakhrin, and
A. P. Krivenko, Pharm. Chem. J., 41, 643 (2007).
1808