Three component condensation of 6-quinolylamine with aromatic aldehydes and cyclohexyl 1,3-diketones

Article abstract of DOI:10.1007/s10593-007-0120-z

A three component condensation of 6-quinolylamine with 4-bromo-or 4-methoxybenzaldehyde, and 1,3-cyclohexanedione or dimedone gave 12-(4-bromophenyl)-and 12-(4-methoxyphenyl)-9,9-dimethyl-8,9,10,12-tetrahydro- 7H-benzo[b][4,7]phenanthrolin-11-ones. The re

Full text of DOI:10.1007/s10593-007-0120-z

Chemistry of Heterocyclic Compounds, Vol. 43, No. 6, 2007
THREE COMPONENT CONDENSATION
OF 6-QUINOLYLAMINE WITH AROMATIC
ALDEHYDES AND CYCLOHEXYL 1,3-DIKETONES
N. G. Kozlov1, K. N. Gusak1, and A. V. Tkachev2
A three component condensation of 6-quinolylamine with 4-bromo-or 4-methoxybenzaldehyde, and
1,3-cyclohexanedione or dimedone gave 12-(4-bromophenyl)- and 12-(4-methoxyphenyl)-9,9-dimethyl-
8,9,10,12-tetrahydro-7H-benzo[b][4,7]phenanthrolin-11-ones. The reaction intermediates obtained
were N-arylmethylene-6-quinolylamines, 2-arylmethylenebis(1,3-cyclohexanediones), 3-(6-quinolyl-
amino)-2-cyclohexenone, and 5,5-dimethyl-3-(6-quinolylamino)-2-cyclohexenone.
Keywords: arylaldehydes, arylmethylene-6-quinolylamines, 2-arylmethylenebis(1,3-cyclohexane-
diones), 12-aryl-8,9,10,12-tetrahydro-7H-benzo[b][4,7]phenanthrolin-11-ones, dimedone, 6-quinolyl-
amine, 3-(6-quinolylamino)-2-cyclohexenone, 1,3-cyclohexanedione
Up to this time various multi component reactions have been widely used in synthetic organic chemistry,
including the chemistry of heterocyclic compounds [1, 2]. Such reactions include the three component
condensation of aromatic amines with aldehydes and CH-acids and were the basis of novel methodology
developed by us for the synthesis of polycondensed nitrogen containing heterocycles of the aza- and
diazaphenanthrene series [3-6], which are of promise as light sensitive materials, luminophores, and bioactive
material with a broad range of action [7-9].
With the object of preparing novel 4,7-phenanthrolines we have studied in this work the condensation of
6-quinolylamine 1 with the substituted benzaldehydes 2a,b and the cyclic β-diketones 1,3-cyclohexanedione 3a
and 5,5-dimethyl-1,3-cyclohexanedione (dimedone) 3b.
The reactions were carried out by heating an equimolar mixture of reagents in n-butanol. Thanks to the
high reactivity of the β-dicarbonyl compound its reaction with the amine and aldehyde in alcoholic medium
occurs in the absence of a catalyst, the role of which is fulfilled by the proton of the dissociated enol form of the
β-diketone. On the basis of previous investigations [4, 5] we proposed that the final products of the cascade of
heterocyclization are the 8-aryl-7,8,9,10,11,12-hexahydrobenzo[a][4,7]phenanthrolin-11-ones A, these being
formed via reaction of the 6-quinolylamine 1 with arylaldehydes with separation of the Schiff bases 5a,b,
addition of a molecule of 1,3-diketone to the C=N bond of the azomethine, and the following cyclocondensation
1
of the product B. However, on the basis of the H NMR spectroscopic data (Table 1) we have shown that the
reaction results selectively in the structures formed (which are isomeric with A) and these are the 12-aryl-
8,9,10,12-tetrahydro-7H-benzo[b][4,7]phenanthrolin-11-ones 4a,b.
__________________________________________________________________________________________
1Institute of Physico-Organic Chemistry, National Academy of Sciences of Belarus, Minsk 220072;
e mail: loc@ifoch.bas-net.by. 2N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of
the Russian Academy of Sciences, Novosibirsk 630090; e-mail: atkachev@nioch.nsc.ru. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No 6, pp. 877-885, June, 2007. Original article submitted January 28,
2005.
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0009-3122/07/4306-740©2007 Springer Science+Business Media, Inc.

R1
R1
O
R1
R1
O
R
R
R
128.8
OH
142.0
54.7
NH
N
NH
N
N
N
A
5a,b
B
R1
R1
R1
R1
NH2
R
O
O
N
O
O
1
R1
OH
NH2
R1
+
R
D
2a,b
R
C
N
O
O
3a,b
R1
R1
R1
R1
OH
R
O
R
O
O
O
O
O
N
N
H
R1
R1
R1
F
R1
7a,b
9a
R1
R1
R1
R1
R1
R
O
15
10
O
R
16
O
11
9
14
13
R1
11a
8
9b
7a
NH
12
12b
4
5
OH
1
12a
NH
NH
3
2
6a
2
7
6
3
N
N
N
8
5
6a,b
E
4a,b
2, 4, 5, 7 a R = Br, b R = OMe; 3, 4, 6, 7 a R1 = H, b R1 = Me
Detailed analysis of the NMR spectra of the reaction products 4a and 4b shows that they belong to one
and the same structural type. Comparison of the experimental values of the chemical shifts of the carbon nuclei
with those calculated by an additive scheme show that for the structure A it is impossible to explain the
appearance of the signals at 107.8 (107.25) and 35.07 (34.71) ppm while in the structures 4a and 4b the C(11a)
and C(12) atoms have such shifts. On the other hand, in the case of structure A other signals should appear (see
reaction scheme) and these are, in fact not found. Analysis of the H–H and C–H spin-spin couplings allows
741

742

743

ready identification of the signal for atom C(12a) (115.69 and 116.82 ppm in 4a and 4b respectively) for which
long range spin spin coupling cross peaks with the methine hydrogen atoms at δ 5.83 and 5.74 and amino
protons at 9.74 and 9.79 ppm are observed in the C-H correlation spectrum. Hence the cross peaks can be
explained by geminal and vicinal interaction in the structures 4a,b. In the case of the alternative structure A
interaction with the methine proton would not be possible:
R1
R1
R
R
R1
R1
O
O
H
H
H
N
N
H
N
N
4a,b
A
The structure of compounds 4a,b was also confirmed from IR and mass-spectrometric data. The IR
spectra shown characteristic stretching bands for the NH and CO groups at 3290-3195 and 1625-1580 cm-1. The
stretching of the alkyl and cycloaliphatic CH bonds occurred at 2960-2870 and the aromatic CH bonds at
3060-3030 cm-1. The IR spectrum of compound 4b shows a band for the C–O–C fragment at 1230 cm-1.
The mass spectra of the benzophenanthrolinones 4a,b show molecular ion peaks [M]+ (Irel 14-18%). The
strongest ion peak (100%) is seen for the [M-C6H4R]+ peak (m/z 249 for compound 4a and 277 for compound
4b). Rather strong peaks are also seen in the spectra at m/z 193 (25-28%) which correspond to elimination from
the [M-C6H4R]+ ion of the fragment CH2CH2CO for compound 4a and (CH3)2CHCH2CO for the dimethyl
derivative 4b.
The benzo[b]-annelated products 4a,b can be considered as formed via the heterocyclization of the
enaminohydroxy ketone C, formed through hydramine fission of amino diketone B to 6-quinolylamine and
2-arylmethylene-1,3-cyclohexanedione D, and then addition of the latter to 6-quinolylamine at the carbon atom
of great electron density which occurs at position 5 of the quinoline ring [10].
In the three component mixture of reagents the 2-arylmethylene-1,3-cyclohexanedione D can be directly
formed from aldehyde 2a,b and cyclohexanedione 3a,b and further reaction with the 6-quinolylamine 1 occurs
as shown in the mechanism above.
In addition, it is possible for an initial reaction of 6-quinolylamine 1 with 1,3-cyclohexanedione 3a,b to
form 3-(6-quinolylamino)-2-cyclohexenone 6a,b. The aldehyde 2a,b then adds to the double bond of the
cyclohexenone fragment of enamino ketone 6a,b. The intermediate E formed is a substituted benzyl alcohol and
can condense with a molecule of aromatic compound similarly to the occurrence in the case of the acid catalyzed
reaction of arenes with aldehydes [11]. The condensation of amino alcohol E takes place via the aromatic part of
the molecule itself and occurs at the electron rich 5 position of the quinoline ring to form the products 4a,b.
In order to clear up the possible stages of formation of the benzophenanthroline ring we carried out
consecutive reactions of each of the reagents of the three component mixture with the two others. Condensation
of 6-quinolylamine with para-bromo- and para-methoxybenzaldehydes 2a,b in an aliphatic alcohol gave the
pure arylmethylene-6-quinolylamines 5a,b. Heating the azomethines 5a,b with 1,3-cyclohexanedione 3a or
dimedone 3b in n-butanol readily gave the target compounds 4a,b.
Refluxing the 6-quinolylamine 1 with 1,3-cyclohexanedione 3a or dimedone 3b in butanol gave the
cyclohexenones 6a and 6b. However these compounds do not react in the free state with the third arylaldehyde
component 2a,b.
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Despite the use of equimolar amounts of regents the reaction of aldehydes 2a,b with 1,3-diketones 3a,b
in an aliphatic alcohol gave the 2-arylmethylenebis(1,3-cyclohexanediones) 7a,b instead of the expected
2-arylmethylene-1,3-cyclohexanediones D. The formation of the bis-1,3-diketones 7a,b is none the less
unexpected since it is known [12, 13] that 1,3-cyclohexanedione and dimedone are used for the quantitative
determination and qualitative identification of aldehydes as the bis-1,3-dicarbonyl derivatives. When heated with
6-quinolylamine 1 in n-butanol the bisdiketones 7a,b form the target benzo[b][4.7]phenanthrolinones 4a,b. It is
likely that the intermediate F loses a molecule of 1,3-cyclohexanedione to form the amino ketoenol E,
cyclocondensation of which then gives the phenanthroline 4a,b. In the process of transforming the amino
diketone F to the amino alcohol E it is suggested that the water involved in hydrating the starting molecule is
that present in the alcohol solution. In aqueous alcoholic medium hydrolytic fission of bisdiketone 7a,b is
possible to give the 2-arylmethylene-1,3-cyclohexanedione D and this then reacts with the 6-quinolyl-amine 1 as
described in the scheme above to form the benzo[b]phenanthrolines 4a,b.
Since all three variants of the first stage of the three component condensation are feasible, the obtained
intermediate N-arylmethylene-6-quinolylamines 5a,b and 2-arylmethylenebis(1,3-cyclohexanediones) 7a,b can
form the final products 4a,b in subsequent reactions, and the hetarylaminocyclohexenones 6a,b can take part in
the process of forming the phenanthrolines 4a,b in situ it is impossible to make an unambiguous choice amongst
the three reaction routes. However, independently of the order of reaction of the reagents in the three component
mixture, the condensation of 6-quinolylamine with aromatic aldehydes and cyclic 1,3-diketones occurs in a
single vessel to give a high yield of the target compounds selectively and thus forms the basis for considering
this reaction as a high efficiency method for preparing inaccessible annelated 4,7-phenanthroline derivatives.
EXPERIMENTAL
1H and 13C NMR spectra were recorded on a Bruker DRX-500 spectrometer (500 and 125 MHz
respectively) using DMSO-d6 [(c = 30 mg/ml) for compounds 4a,b and 6a,b, internal standard DMSO-d6 solvent
(δC 39.50, δH 2.50 ppm) ] or chloroform-d (for compounds 7a,b with TMS as internal standard.
Assignment of the signals was carried out using 13C NMR Spectra recorded in the J- modulation regime
(noise decoupling from protons, opposite phase for signals of atom with even and odd numbers of associated
protons tuned to the constant J = 135 Hz) in single resonance mode and also for two dimensional spectra as: 1)
homonuclear 1H-1H correlations; 2) heteronuclear 13C-1H correlations for direct spin spin coupling (J = 135 Hz),
and 3) heteronuclear 13C-1H correlation for long range spin spin coupling (J = 10 Hz).
IR spectra were taken on a Nicolet Protégé-460 Fourier spectrometer. Mass spectra were recorded on a
Finnigan MAT Incos 50 instrument with electron ionization energy 70 eV. Compound melting points were
determined on a Koffler block.
N-Arylmethylene-6-quinolylamines 5a,b were prepared by method [4].
12-(p-Bromophenyl)- and 12-(p-Methoxyphenyl)-9,9-dimethyl-8,9,10,12-tetrahydro-7H-benzo[b]-
[4,7]phenanthrolin-11-ones (4a,b). A solution of amine 1 (1.44 g, 10 mmol), the corresponding aldehyde 2a or
2b (10 mmol), and 1,3-cyclohexanedione 3a (for compound 4a) or dimedone 3b (for compound 4b) (10 mmol)
in n-butanol (30 ml) was refluxed for 3 h. The precipitated product was filtered off and crystallized from a
mixture of ethanol and benzene (3:1).
Compound 4a. Yield 84%; mp 335-336ºC. Found, %: C 65.09; H 4.27; Br 19.52; N 6.59. C22H17BrN2O.
Calculated, %: C 65.19; H 4.20; Br 19.75; N 6.91.
Compound 4b. Yield 79%; mp 312-313ºC. Found, %: C 77.94; H 6.07; N7 .18. C25H24N2O2. Calculated,
%: C 78.13; H 6.25; N 7.29.
Condensation of N-Arylmethylene-6-quinolylamines 5a,b with 1,3-Diketones 3a,b. A solution of the
azomethine 5a or 5b (5 mmol), 1,3-cyclohexanedione 3a (for compound 5a) or dimedone 3b (for compound 5b)
745

(5 mmol) in n-butanol (20 ml) was refluxed for 2.5 h. The 4,7-phenanthroline reaction products 4a,b were
separated as described above. Yield of compound 4a 83% and of compound 4b 80%.
3-(6-Quinolylamino)- and 5,5-Dimethyl-3-(6-quinolylamino)-2-cyclohexenones (6a,b). A solution of
6-quinolylamine 1 (1.44 g, 10 mmol) and 1,3-cyclohexanedione 3a or dimedone 3b (10 mmol) in n-butanol or
ethanol (20 ml) was refluxed for 2 h. After cooling, the reaction mixture the solvent was evaporated and the oily
residue treated with ether, triturating with a glass rod. The precipitated compound 6b was filtered off and
crystallized from ethanol-benzene (1:1). In the case of the non crystallizing compound 6a the ether was decanted
and the residue was dried in air.
1
Compound 6a. Yield 70%, oily material. H NMR spectrum, δ, ppm (J, Hz): 1.98 (2H, m, CH2); 2.28
(2H, m, CH2); 5.49 (1H, s, CH=); 7.42 (1H, dd, 3J = 8.1, 4J = 4.0, H-3); 7.56 (1H, d, 3J = 8.1, H-4); 7.70 (1H, s,
3
3
3
H-5); 7.97 (1H, d, J = 8.8, H-7); 8.30 (1H, d, J = 8.8, H-8); 8.76 (1H, d, J = 4.0, H-2); 9.10 (1H, s, NH).
Found, %: C 75.49; H 5.71; N 11.57. C15H14N2O. Calculated, %: C 75.63; H 5.88; N 11.76.
Compound 6b. Yield 78%; mp 211-212ºC. 1H NMR spectrum, δ, ppm (J, Hz): 1.08 (6H, s, 2 CH3); 2.10
(2H, s, CH2); 2.45 (2H, s, CH2); 3.32 (3H, s, OCH3); 5.58 (1H, s, CH=); 7.49 (1H, dd, J = 8.5, J = 4.1, H-3);
7.60 (1H, d, J = 8.4, H-4); 7.73 (1H, s, H-5); 8.00 (d, J = 8.9, H-7); 8.34 (1H, d, J = 8.9, H-8); 8.80 (1H, d,
3J = 4.6, H-2); 9.09 (1H, s, NH). Found, %: C 76.51; H 6.62; N 10.33. C17H18N2O. Calculated, %: C 76.69;
H 6.77; N 10.53.
3
4
3
3
3
2-(p-Bromophenyl)methylenebis(1,3-cyclohexanedione) (7a) and 2-(p-Methoxyphenyl)methylene-
bis(5,5-dimethyl-1,3-cyclohexanedione (7b). A solution of aldehyde 2a or 2b (10 mmol) and
1,3-cyclohexanedione 3a (for compound 7a) or dimedone 3b (for compound 7b) (10 mmol) in 1-butanol (20 ml)
was refluxed for 0.5 h. The solid produced after cooling was separated and recrystallized from ethanol.
1
Compound 7a. Yield 90%; mp 240-241ºC. H NMR spectrum, δ, ppm (J, Hz): 2.0 (4H, m, CH2); 2.28
3
3
(4H, m, CH2); 2.57 (4H, m, CH2); 4.88 (1H, s, CH); 7.02 (2H, d, J =7.4, Harom,); 7.28 (2H, d, J = 7.4, Harom.),
11.90 (2H, br. s, OH).
1
Compound 7b. Yield 94%; mp 221-222ºC. H NMR spectrum, δ, ppm (J, Hz): 1.15 (6H, s, CH3); 1.26
(6H, s, CH3); 2.40 (8H, m, CH2); 3.78 (3H, s, OCH3); 5.48 (1H, s, CH); 6.75 (2H, d, 3J = 7.1, Harom.); 6.97 (2H, d,
3J = 7.1, Harom.); 11.88 (2H, br. s, OH).
Condensation of 2-arylmethylenebis(1,3-cyclohexanediones) 7a,b with 6-Quinolylamine (1). A
solution of bisketone 7a or 7b (5 mmol) and amine 1 (5 mmol) in butanol (20 ml) was refluxed for 2 h. The
reaction products 4a,b were separated as described above. Yield of compound 4a 77% and phenanthroline 4b
80%.
This work was carried out with the support of the Belarus-Russian Science Fund for Basic Research
(grant X04P-017).
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