Synthesis of 4,n-diaryl-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydro-3- quinolinecarboxamides

Article abstract of DOI:10.1007/s10593-011-0826-9

The reaction of dimedone, N-aryl-substituted acetoacetic acid amides, aryl aldehydes, and ammonium acetate gives 4,N-diaryl-2,7,7-trimethyl-5-oxo-1,4,5,6, 7,8-hexahydro-3-quinoline carboxamides.

Full text of DOI:10.1007/s10593-011-0826-9

Chemistry of Heterocyclic Compounds, Vol. 47, No. 6, September 2011 (Russian original Vol. 47, No. 6, June, 2011)
SYNTHESIS OF 4,N-DIARYL-2,7,7-TRIMETHYL-
5-OXO-1,4,5,6,7,8-HEXAHYDRO-
3-QUINOLINECARBOXAMIDES
V. L. Gein1*, M. I. Kazantseva1, and A. A. Kurbatova1
The reaction of dimedone, N-aryl-substituted acetoacetic acid amides, aryl aldehydes, and ammonium
acetate gives 4,N-diaryl-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydro-3-quinoline carboxamides.
Keywords: aryl aldehydes, N-aryl-substituted acetoacetic acid amides, ammonium acetate, 4,N-diaryl-
2,7,7,-trimethyl-5-oxo-1,4,5,6,7,8-hexahydro-3-quinoline carboxamides, dimedone.
1,4,5,6,7,8-Hexahydro-3-quinolinecarboxamides show a broad range of biological activity [1]. A four-
component reaction of dimedone, aryl aldehyde, acetoacetanilide, and ammonium acetate has been reported in
the literature [2] describing the preparation of this type compounds.
Continuing the study of this reaction course, we report for the first time the use of N-aryl-substituted
acetoacetic acid amides. The reaction is carried out at 150–160ºC over 5–10 min in the absence of solvent and
gives the 4,N-diaryl-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydro-3-quinolinecarboxamides 1a–k in 47–87%
yield. Further oxidation products of these compounds were not observed.
The use of substituted aryl aldehydes led to higher yields of the final products 1b–e,g–j than did unsub-
stituted benzaldehyde.
R
R1
O
O
O
R1
R2
R2
CHO
N
H
O
O
NH4OAc
Me
Me
+
+
Me
Me
N
H
Me
O
N
Me
R
H
1a–k
a–e R1 = R2 = ꢀꢁ; f–j R1 = ꢀꢁ, R2 = H; ꢀ,f R = H, b,g R = 4-ꢂl, c,h R = 4-ꢃꢀꢁ, d,i R = 3-NO2, e,j R = 4-NO2; k R = R2 = ꢄ, R1 = ꢃꢀꢁ
The compounds 1a–k are appeared as light-yellow, crystalline materials soluble in DMF, DMSO and,
under heating, in ethanol but are insoluble in water.
_______________
*To whom correspondence should be addressed, e-mail: geinvl48@mail.ru.
1Perm State Pharmaceutical Academy, 2 Polevaya St., Perm 614990, Russia.
__________________________________________________________________________________________
Translated from Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 881–884, June,
2011. Original article submitted February 21, 2011.
0009-3122/11/4706-0728©2011 Springer Science+Business Media, Inc.
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ꢀ

1
The H NMR spectra of prepared compounds showed the presence of signals with chemical shifts con-
firming the heterocycle structure, viz. an H-4 proton singlet at 4.80–5.10 ppm and the heterocyclic NH proton
signal at 8.05–8.70 ppm. The IR spectra of compounds 1a–k showed stretching vibration bands for the N–H
bond in position 1 of the heterocycle at 3248–3376 cm–1. The mass spectrum of compound 1f showed a
molecular ion peak with m/z 400 [M–H]+ and fragment ions at m/z 323 [M–Ph]+ (82) and 294 [M–PhNHCH3]+
(100) which confirm the structure.
EXPERIMENTAL
The IR spectra were recorded on a Specord M-80 spectrometer using vaseline oil. 1H NMR spectra were
taken on a Bruker DRX500 instrument (500 MHz) using DMSO-d6 with TMS as internal standard. Mass spectra
were recorded on an Agilent 7890A/5975C chromato mass spectrometer with ionization energy 70 eV.
Preparation of the 3-Quinolinecarboxamides 1a–k (General Method). A mixture of dimedone
(0.01 mol), the corresponding benzaldehyde (0.01 mol), the N-aryl-substituted acetoacetic acid amide
(0.01 mol), and ammonium acetate (0.01 mol) was held with stirring for 5–10 min at 150–160ºC until gas
evolution ceased and the reaction mixture solidified. After cooling, the residue was treated with ethanol and the
crystals produced were filtered off.
2,7,7-Trimethyl-5-oxo-4-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic Acid 2,4-Dimethylphe-
nylamide (1a). Yield 2.0 g (48%); mp 243–245ºC (ethanol). IR spectrum, ꢀ, cm–1: 1632 (C=O), 1688 (CON),
3076 (NH), 3248 (NH). 1H NMR spectrum, ꢁ, ppm (J, Hz): 0.89 (3ꢄ, s, 7-ꢂꢄ3); 1.02 (3ꢄ, s, 7-ꢂꢄ3); 1.85 (3ꢄ, s,
2-ꢂꢄ3); 1.98 (1ꢄ, d, J = 16.2, ꢄa-8); 2.06, 2.20 (6ꢄ, two s, 2',4'-ꢂꢄ3); 2.14 (1ꢄ, d, J = 16.2, ꢄb-8); 2.30 (1ꢄ, d,
J = 16.9, ꢄa-6); 2.40 (1ꢄ, d, J = 16.9, ꢄb-6); 4.90 (1ꢄ, s, ꢄ-4); 6.80–7.30 (8H, m, H Ar); 8.61 (1ꢄ, s, NH); 8.90
(1ꢄ, s, NH). Found, %: ꢂ 78.47; H 7.32; N 6.89. ꢂ27ꢄ30N2O2 . Calculated, %: ꢂ 78.23; H 7.29; N 6.76.
4-(4-Chlorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic Acid 2,4-Di-
methylphenylamide (1b). Yield 3.9 g (87%); mp 242–244ºC (ethanol). IR spectrum, ꢀ, cm–1: 1640 (C=O),
1
1680 (CON), 3072 (NH), 3248 (NH). H NMR spectrum, ꢁ, ppm (J, Hz): 0.85 (3ꢄ, s, 7-ꢂꢄ3); 1.03 (3ꢄ, s,
7-ꢂꢄ3); 1.85 (3ꢄ, s, 2-ꢂꢄ3); 1.98 (1ꢄ, d, J = 16.0, ꢄa-8); 2.14, 2.20 (6ꢄ, two s, 2',4'-ꢂꢄ3); 2.15 (1ꢄ, d,
J = 16.0, ꢄb-8); 2.29 (1ꢄ, d, J = 17.0, ꢄa-6); 2.39 (1ꢄ, d, J = 17.0, ꢄb-6); 4.95 (1ꢄ, s, ꢄ-4); 6.85–7.40 (7H, m,
H Ar); 8.68 (1ꢄ, s, NH); 9.49 (1ꢄ, s, NH). Found, %: ꢂ 72.32; H 6.56; N 6.15. ꢂ27ꢄ29ClN2O2 . Calculated, %:
ꢂ 72.23; H 6.51; N 6.24.
4-(4-Methoxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic Acid 2,4-Di-
methylphenylamide (1c). Yield 3.2 g (73%); mp 233–235ºC (ethanol). IR spectrum, ꢀ, cm–1: 1632 (C=O), 1688
1
(CON), 3048 (NH), 3026 (NH). H NMR spectrum, ꢁ, ppm (J, Hz): 0.89 (3ꢄ, s, 7-ꢂꢄ3); 1.02 (3ꢄ, s, 7-ꢂꢄ3);
1.85 (3ꢄ, s, 2-ꢂꢄ3); 1.97 (1ꢄ, d, J = 16.1, ꢄa-8); 2.05, 2.20 (6ꢄ, two s, 2',4'-ꢂꢄ3); 2.14 (1ꢄ, d,
J = 16.1, ꢄb-8); 2.27 (1ꢄ, d, J = 16.9, ꢄa-6); 2.38 (1ꢄ, d, J = 16.9, ꢄb-6); 3.70 (3ꢄ, s, ꢃCH3); 4.90 (1ꢄ, s,
ꢄ-4); 6.70–7.20 (7H, m, H Ar); 8.10 (1ꢄ, s, NH); 8.30 (1ꢄ, s, NH). Found, %: ꢂ 75.72; H 7.24; N 6.28.
ꢂ28ꢄ32N2O3. Calculated, %: ꢂ 75.65; H 7.26; N 6.30.
2,7,7-Trimethyl-4-(3-nitrophenyl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic Acid 2,4-Di-
methylphenylamide (1d). Yield 3.2 g (70%); mp 234–236ºC (ethanol). IR spectrum, ꢀ, cm–1: 1638 (C=O), 1688
(CON), 3070 (NH), 3248 (NH). 1H NMR spectrum, ꢁ, ppm (J, Hz): 0.89 (3ꢄ, s, 7-ꢂꢄ3); 1.02 (3ꢄ, s, 7-ꢂꢄ3); 1.85
(3ꢄ, s, 2-ꢂꢄ3 ); 1.99 (1ꢄ, d, J = 16.1, ꢄa-8); 2.08, 2.20 (6ꢄ, two s, 2',4'-ꢂꢄ3); 2.17 (1ꢄ, d, J = 16.1, ꢄb-8); 2.34
(1ꢄ, d, J = 17.0, ꢄa-6); 2.43 (1ꢄ, d, J = 17.0, ꢄb-6); 5.10 (1ꢄ, s, ꢄ-4); 6.85–7.20 (7H, m, H Ar); 8.05 (1ꢄ, s, NH);
8.80 (1ꢄ, s, NH). Found, %: ꢂ 70.65; H 6.38; N 9.05. ꢂ27ꢄ29N3O4 . Calculated, %: ꢂ 70.57; H 6.36; N 9.14.
2,7,7-Trimethyl-4-(4-nitrophenyl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic Acid 2,4-Di-
methylphenylamide (1e). Yield 3.35 g (73%); mp 171–173ºC (ethanol). IR spectrum, ꢀ, cm–1: 1642 (C=O),
1
1680 (CON), 3088 (NH), 3288 (NH). H NMR spectrum, ꢁ, ppm (J, Hz): 0.89 (3ꢄ, s, 7-ꢂꢄ3); 1.03 (3ꢄ, s,
7-ꢂꢄ3); 1.85 (3ꢄ, s, 2-ꢂꢄ3); 2.13, 2.20 (6ꢄ, two s, 2',4'-ꢂꢄ3); 1.98 (1ꢄ, d, J = 16.1, ꢄa-8); 2.16 (1ꢄ, d,
J = 16.1, ꢄb-8); 2.32 (1ꢄ, d, J = 16.8, ꢄa-6); 2.41 (1ꢄ, d, J = 16.8, ꢄb-6); 5.10 (1ꢄ, s, ꢄ-4); 6.85–7.53 (7H, m,
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H Ar); 8.10 (1ꢄ, s, NH); 8.80 (1ꢄ, s, NH). Found, %: ꢂ 70.37; H 6.40; N 9.05. ꢂ27ꢄ29N3O4 . Calculated, %:
ꢂ 70.57; H 6.36; N 9.14.
2,7,7-Trimethyl-5-oxo-4-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic Acid 2-Methylphe-
nylamide (1f). Yield 1.9 g (47%); mp 254–256ºC (ethanol). IR spectrum, ꢀ, cm–1: 1632 (C=O), 1692 (CON),
3068 (NH), 3248 (NH). 1H NMR spectrum, ꢁ, ppm (J, Hz): 0.89 (3ꢄ, s, 7-ꢂꢄ3); 1.03 (3ꢄ, s, 7-ꢂꢄ3); 1.85 (3ꢄ,
s, 2-ꢂꢄ3); 1.98 (1ꢄ, d, J = 16.2, ꢄa-8); 2.06 (3ꢄ, s 2'-ꢂꢄ3); 2.15 (1ꢄ, d, J = 16.2, ꢄb-8); 2.30 (1ꢄ, d, J = 16.9,
ꢄa-6); 2.39 (1ꢄ, d, J = 16.9, ꢄb-6); 4.90 (1ꢄ, s, ꢄ-4); 7.00–7.25 (9H, m, H Ar); 8.65 (1ꢄ, s, NH); 8.85 (1ꢄ, s,
NH). Mass spectrum, m/z (Irel, %): 400 [ꢀ–ꢄ]+ (37), 323 [ꢀ–Ph]+ (82), 294 [ꢀ–PhNHꢂꢄ3]+ (42). Found, %:
ꢂ 77.88; H 7.22; N 6.85. ꢂ26ꢄ28N2O2. Calculated, %: ꢂ 77.97; H 7.05; N 6.99.
4-(4-Chlorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic Acid 2-Met-
hylphenylamide (1g). Yield 3.7 g (72%); mp 248–250ºC (ethanol). IR spectrum, ꢀ, cm–1: 1632 (C=O), 1692
1
(CON), 3176 (NH), 3376 (NH). H NMR spectrum, ꢁ, ppm (J, Hz): 0.89 (3ꢄ, s, 7-ꢂꢄ3); 1.03 (3ꢄ, s,
7-ꢂꢄ3); 1.87 (3ꢄ, s, 2-ꢂꢄ3); 1.98 (1ꢄ, d, J = 16.0, ꢄa-8); 2.06 (3ꢄ, s, 2'-ꢂꢄ3); 2.15 (1ꢄ, d, J = 16.0, ꢄb-8); 2.29
(1ꢄ, d, J = 16.7, ꢄa-6); 2.39 (1ꢄ, d, J = 16.7, ꢄb-6); 4.98 (1ꢄ, s, ꢄ-4); 7.00–7.25 (8H, m, H Ar); 8.70 (1ꢄ, s,
NH); 9.00 (1ꢄ, s, NH). Found, %: ꢂ 71.68; H 6.32; N 6.49. ꢂ26ꢄ27ClN2O2 . Calculated, %: ꢂ 71.80; H 6.26;
N 6.44.
4-(4-Methoxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic Acid 2-Met-
hylphenylamide (1h). Yield 3.4 g (79%); mp 218–220ºC (ethanol). IR spectrum, ꢀ, cm–1: 1632 (C=O), 1690
(CON), 3184 (NH), 3296 (NH). 1H NMR spectrum, ꢁ, ppm (J, Hz): 0.89 (3ꢄ, s, 7-ꢂꢄ3); 1.02 (3ꢄ, s, 7-ꢂꢄ3); 1.86
(3ꢄ, s, 2-ꢂꢄ3); 1.97 (1ꢄ, d, J = 16.0, ꢄa-8); 2.12 (3ꢄ, s, 2'-ꢂꢄ3); 2.14 (1ꢄ, d, J = 16.0, ꢄb-8); 2.28 (1ꢄ, d,
J = 16.8, ꢄa-6); 2.38 (1ꢄ, d, J = 16.8, ꢄb-6); 4.90 (1ꢄ, s, ꢄ-4); 7.00–7.18 (8H, m, H Ar); 8.60 (1ꢄ, s, NH); 8.80
(1ꢄ, s, NH). Found, %: ꢂ 75.28; H 6.93; N 6.69. ꢂ27ꢄ30N2O3. Calculated, %: ꢂ 75.32; H 7.02; N 6.51.
2,7,7-Trimethyl-4-(3-nitrophenyl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic Acid 2-Met-
hylphenylamide (1i). Yield 2.9 g (66%); mp 228–230ºC (ethanol). IR spectrum, ꢀ, cm–1: 1644 (C=O), 1688
1
(CON), 3080 (NH), 3168 (NH). H NMR spectrum, ꢁ, ppm (J, Hz): 0.90 (3ꢄ, s, 7-ꢂꢄ3); 1.04 (3ꢄ, s,
7-ꢂꢄ3); 1.86 (3ꢄ, s, 2-ꢂꢄ3); 1.90 (1ꢄ, d, J = 15.7, ꢄa-8); 2.00 (1ꢄ, d, J = 15.7, ꢄb-8); 2.14 (3ꢄ, s, 2'-ꢂꢄ3); 2.34
(1ꢄ, d, J = 16.9, ꢄa-6); 2.44 (1ꢄ, d, J = 16.9, ꢄb-6); 5.10 (1ꢄ, s, ꢄ-4); 7.00–7.70 (8H, m, H Ar); 8.10 (1ꢄ, s,
NH); 8.90 (1ꢄ, s, NH). Found, %: ꢂ 70.17; H 6.03; N 9.49. ꢂ26ꢄ27N3O4. Calculated, %: ꢂ 70.10; H 6.11;
N 9.43.
2,7,7-Trimethyl-4-(4-nitrophenyl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic Acid 2-Met-
hylphenylamide (1j). Yield 3.2 g (73%); mp 237–239ºC (ethanol). IR spectrum, ꢀ, cm–1: 1600 (C=O), 1672
1
(CON), 3184 (NH), 3384 (NH). H NMR spectrum, ꢁ, ppm (J, Hz): 0.85 (3ꢄ, s, 7-ꢂꢄ3); 1.02 (3ꢄ, s,
7-ꢂꢄ3); 1.87 (3ꢄ, s, 2-ꢂꢄ3); 1.99 (1ꢄ, d, J = 16.1, ꢄa-8); 2.14 (3ꢄ, s, 2'-ꢂꢄ3); 2.16 (1ꢄ, d, J = 16.1, ꢄb-8); 2.32
(1ꢄ, d, J = 16.8, ꢄa-6); 2.42 (1ꢄ, d, J = 16.8, ꢄb-6); 5.10 (1ꢄ, s, ꢄ-4); 7.00–7.50 (8H, m, H Ar); 8.10 (1ꢄ, s,
NH); 9.10 (1ꢄ, s, NH). Found, %: ꢂ 69.97; H 6.09; N 9.47. ꢂ26ꢄ27N3O4. Calculated, %: ꢂ 70.10; H 6.11;
N 9.43.
2,7,7-Trimethyl-5-oxo-4-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic Acid 2-Methoxyphe-
nylamide (1k). Yield 2.3 g (55%); mp 180–182ºC (ethanol). IR spectrum, ꢀ, cm–1: 1632 (C=O), 1692 (CON),
3078 (NH), 3248 (NH). 1H NMR spectrum, ꢁ, ppm (J, Hz): 0.89 (3ꢄ, s, 7-ꢂꢄ3); 1.03 (3ꢄ, s, 7-ꢂꢄ3); 1.85 (3ꢄ,
s, 2-ꢂꢄ3); 1.98 (1ꢄ, d, J = 16.2, ꢄa-8); 2.16 (1ꢄ, d, J = 16.2, ꢄb-8); 2.26 (1ꢄ, d, J = 16.9, ꢄa-6); 2.39 (1ꢄ, d,
J = 16.9, ꢄb-6); 3.70 (3ꢄ, s, ꢃꢂꢄ3); 4.80 (1ꢄ, s, ꢄ-4); 6.80–7.40 (9H, m, H Ar); 8.05 (1ꢄ, s, NH); 8.90 (1ꢄ, s,
NH). Mass spectrum, m/z (Irel, %): 416 [ꢀ–ꢄ]+ (19), 339 [ꢀ–Ph]+ (32), 294 [ꢀ–PhNHꢃꢂꢄ3]+ (42). Found, %:
ꢂ 75.07; H 6.73; N 6.65. ꢂ26ꢄ28N2O3. Calculated, %: ꢂ 74.98; H 6.78; N 6.73.
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