Aromatization with dearylation on Hantzsch cyclocondensation of 4-(dimethylamino)benzaldehyde, cyclohexane-1,3-diones, and some 1,3-[N,C]dinucleophiles

Article abstract of DOI:10.1007/s10593-009-0250-6

The Hantzsch three-component cyclization of 4-(dimethylamino)benzaldehyde, cyclohexane-1,3-diones, and some 1,3-[N,C]-dinucleophiles (5-amino-3-methyl-1- phenylpyrazole, 3,5-dimethoxyaniline, and 4-amino-1,3-dimethylpyrimidine-2,6- dione) proceeds in boil

Full text of DOI:10.1007/s10593-009-0250-6

Chemistry of Heterocyclic Compounds, Vol. 45, No. 2, 2009
AROMATIZATION WITH DEARYLATION
ON HANTZSCH CYCLOCONDENSATION
OF 4-(DIMETHYLAMINO)BENZALDEHYDE,
CYCLOHEXANE-1,3-DIONES, AND SOME
1,3-[N,C]DINUCLEOPHILES
I. B. Dzvinchuk1*, N. A. Tolmachova1, A. N. Chernega1, and M. O. Lozinskii1
The Hantzsch three-component cyclization of 4-(dimethylamino)benzaldehyde, cyclohexane-1,3-diones,
and some 1,3-[N,C]-dinucleophiles (5-amino-3-methyl-1-phenylpyrazole, 3,5-dimethoxyaniline, and
4-amino-1,3-dimethylpyrimidine-2,6-dione) proceeds in boiling acetic acid with the splitting off
N,N-dimethylaniline and the formation of polycondensed heterocyclic sytems with a γ-unsubstituted
pyridine ring (pyrazolo[3,4-b]quinoline, acridine, and pyrimido[4,5-b]quinoline).
Keywords: acridines, pyrazolo[3,4-b]quinolines, pyrimido[4,5-b]quinolines, aromatization, dearylation,
Hantzsch reaction.
The Hantzsch pyridine synthesis, including pyridines condensed with other rings, consists of two stages,
the formation of the 1,4-dihydropyridine ring and its subsequent oxidation [1-5]. The method has been improved
in practical organic chemistry during 125 years and has been changed in principle when obtaining compounds
with a γ-unsubstituted pyridine ring, since the classical scheme using formaldehyde gives unsatisfactory results
[6].
It was established primarily that formaldehyde may be replaced by other aldehydes. Thus, 1,4-di-
hydropyridines obtained from some aliphatic aldehydes [6-10], polyfluorobenzaldehydes [11], and
4-(dimethylamino)benzaldehyde (1) [12], are aromatized with the splitting off the substituent in the γ-position
by the action of certain oxidizing agents, sodium cyanide, and electrophilic reagents.
Secondly, procedures were proposed for conversion of the two-stage synthesis into one stage. For
example, 1,4-dihydropyridines obtained from antipyrine-4-carbaldehyde, are aromatized with the splitting off
antipyrine even under the conditions of formation (20oC, 18 h), although the initial aldehyde must first be
converted into the more reactive chloropyridinium salt [13]. We have found that the aldehyde 1 mentioned
above is more convenient for that purpose. On carrying out the reaction involving it in boiling acetic acid
(120oC, 2 h), as shown in the synthesis of derivatives of acridine [14], pyrazolo[3,4-b]pyridine [15], and
_______
* To whom correspondence should be addressed, e-mail: Rostov@bpci.kiev.ua.
1Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 244-251, February, 2009. Original
article submitted November 9, 2007.
194
0009-3122/09/4502-0194©2009 Springer Science+Business Media, Inc.

pyrido[2,3-d]pyrimidine [16], the formation of a 1,4-dihydropyridine ring and its aromatization are combined in
one process, which in spite of the data of [5], proceeds not with retention of the 4-(dimethylamino)phenyl
substituent, but with selective spitting off N,N-dimethylaniline.
In the latter synthetic procedure, available, stable, and low toxicity starting materials are used, and the
desired products are isolated easily from the reaction mixture, and in high yield. With the aim of broadening the
scope of the method the three-component interaction of aldehyde 1, cyclohexane-1,3-dione 2a,b and some
1,3-[N,C]dinucleophiles, aminopyrazole 3, dimethoxyaniline 4, and aminopyrimidinedione 5 has been studied
for the first time in the present work.
We found that the interaction of reactants 1, 2, and 3-5 in boiling acetic acid proceeds through
1,4-dihydropyridine-containing compounds of the type of 6-8, which are aromatized with splitting off
dimethylaniline and the formation of derivatives of pyrazolo[3,4-b]quinoline 9, acridine 10, and pyrimido-
[4,5-b]quinoline 11 respectively.
Reaction by the given scheme (method A) is complete in 2 h, and the N,N-dimethylaniline formed in it
does not interfere in the isolation of the desired products. Products 9 and 11 were isolated in yields of 76-94%
on diluting the reaction mixtures with water, and acridines 10 in 75-82% yield after removing the acetic acid and
washing.
Me2N
O
R
R
+
Me
O
Me
HO
O
CHO
1
2a,b
N
N
N
N
O
–2H2
O
–2H2
OMe
Ph
NH2
NH2
–2H2O
MeO
Me
3
5
NH2
Ar
4
Me
O
O
O
O
O
Ar
H
H
Ar H
Me
N
Me
N
R
R
R
N
N
H
6a,b
O
N
O
N
N
R
R
R
H
H
Ph
Me
Me
8a,b
7a,b
–PhNMe2
–PhNMe2
–PhNMe2
Me
H
O
O
H
O
O
H
9
O
Me
2 N
Ph
4
5
4
5
6
3
8
1
3
N
Me
O
6
7
7
8
7
6
2
3
R
R
R
2
N 1
N 9
1N
Me
N
O
N10
10a,b
8
9
4
5
R
10
R
R
Me
9a,b
11a,b
2, 6−11 a R = H, b R = Me; 6−8 Ar = 4-Me2NC6H4
The process may stop at the stage of forming compounds containing a 1,4-dihydropyridine ring. In the
three-component cyclocondensations involving dimedone 2b in 2-propanol products 6b and 7b are formed and
product 8b is formed in acetic acid at 80oC. On boiling compounds 6b-8b in acetic acid products 9b-11b
(method B) are also formed. The yields in both stages were high, however the two-stage scheme of synthesis of
these compounds has no advantage over the one-stage, since the gain in overall yield is insignificant, and the
consumptions of time and materials grow noticeably.
195

TABLE 1. Characteristics of the Synthesized Compounds
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield, %
(method)
mp, °С
С
Н
N
6b
C27H30N4O
C25H30N2O3
C23H28N4O3
C17H15N3O
C19H19N3O
C15H15NO3
C17H19NO3
C13H13N3O3
C15H17N3O3
75.31
76.03
73.54
73.86
67.80
67.63
73.48
73.63
74.64
74.73
69.88
70.02
71.42
71.56
60.08
62.23
6.76
7.09
7.23
7.44
6.69
6.91
5.57
5.45
6.34
6.27
5.76
5.88
6.57
6.71
5.18
5.05
13.47
13.13
6.72
6.89
13.88
13.72
15.07
15.15
13.58
13.76
5.28
5.44
4.78
4.91
16.15
16.21
223-225
96
89
77
7b
288-289.5
210-211
123-124
8b
9a
87 (A)
9b
164.5-166 (130 [17]) 94 (A), 95 (B)
10a
10b
11a
11b
151-152.5
154-155.5
186.5-188
182-183.5
75 (A)
82 (A), 85 (B)
76 (А)
62.56
62.71
5.85
5.96
14.53
14.62
92 (А), 95 (B)
TABLE 2. IR and 1H NMR Spectra of the Synthesized Compounds
Com- IR spectrum,
1Н NMR spectrum, δ, ppm (J, Hz)
pound νС=О, cm–1
6b
7b
1620
1630
0.95 and 1.02 (3Н and 3H, two s, 7-, 7-СН3); 1.91 (3H, s, 3-CH3);
1.95 and 2.15 (1Н and 1H, two d, J = 16, H-8,8); 2.51 (2H, m, Н-6,6);
2.82 (6H, s, N(CH3)2); 4.86 (1H, s, H-4);
6.61 and 7.01 (2Н and 2H, two d, J = 8.1, C6H4); 7.38 (1H, m, H-4 Ph);
7.51 (4H, m, H-2,3,5,6 Ph); 9.33 (1H, s, H-9)
0.90 and 1.00 (3Н and 3H, two s, 3-, 3-CH3);
1.95 and 2.13 (1Н and 1H, two d, J = 16.0, H-4,4);
2.31 and 2.42 (1Н and 1H, two d, J = 17.0, H-2,2); 2.75 (6H, s, N(CH3)2);
3.64 and 3.69 (3Н and 3H, two s, 6-, 8-OCH3); 5.02 (1H, s, H-9);
6.11 and 6.13 (1Н and 1H, two d, J = 2.0, H-5,7);
6.48 and 6.91 (2Н and 2H, two d, J = 9.0, C6H4); 9.20 (1H, s, H-10)
8b
1655, 1680 0.91 and 1.04 (3Н and 3H, two s, 8-, 8-СН3);
2.02 and 2.20 (1Н and 1H, two d, J = 16.0, H-9,9);
2.55 and 2.60 (1Н and 1H, two d, J = 16.0, H-7,7); 2.79 (6H, s, N(CH3)2);
3.09 (3H, s, 1-CH3); 3.44 (3H, s, 3-CH3); 4.75 (1H, s, H-5);
6.54 and 7.01 (2Н and 2H, two d, J = 8.4, C6H4); 8.94 (1H, s, H-10)
9a
9b
1680
1700
2.13 (2Н, m, Н-7,7); 2.60 (3H, s, CH3); 2.70 (2H, t, J = 6.0, H-8,8);
3.18 (2H, t, J = 6.0, H-6,6); 7.34 (1H, t, J = 7.5, H-4 Ph);
7.56 (2H, t, J = 7.8, H-3,5 Ph); 8.25 (2H, d, J = 7.5, H-2,6 Ph); 8.72 (1H, s, H-4)
1.06 (6H, s, 7-, 7-CH3); 2.61 (2H, s, H-8,8); 2.62 (3Н, s, 3-СН3);
3.12 (2H, s, H-6,6); 7.33 (1H, t, J = 7.5, H-4 Ph);
7.56 (2H, t, J = 7.8, H-3,5 Ph); 8.28 (2H, d, J = 7.5, H-2,6 Ph);
8.73 (1H, s, H-4)
10a
10b
1680
1690
2.11 (2H, m, Н-3,3); 2.67 (2H, t, J = 6.0, H-4,4); 3.12 (2H, t, J = 7.5, H-2,2);
3.91 (3H, s, 6-CH3); 3.96 (3H, s, 8-CH3); 6.62 (1H, d, J = 2.0, H-7);
6.93 (1H, d, J = 2.0, H-5); 8.76 (1H, s, H-9)
1.03 (6H, s, 3-CH3); 2.58 (2H, s, H-4,4); 3.04 (2H, s, H-2,2);
3.92 (3H, s, 6-OCH3); 3.97 (3H, s, 8-OCH3); 6.65 (1H, s, H-7);
6.96 (1H, s, H-5); 8.77 (1H, s, H-9)
11a
11b
1670, 1690, 2.11 (2H, m, Н-8,8); 2.66 (2H, t, J = 6.5, H-9,9); 3.10 (2H, t, J = 6.5, H-7,7);
1710 3.27 (3H, s, 1-CH3); 3.55 (3H, s, 3-CH3); 8.56 (1H, s, H-5)
1650, 1670, 1.05 (6H, s, 8-, 8-CH3); 2.60 (2H, s, H-9,9); 3.06 (2H, s, H-7,7);
1700 3.29 (3H, s, 1-CH3); 3.58 (3H, s, 3-CH3); 8.60 (1H, s, H-5)
196

TABLE 3. Main Bond Lengths (l) and Valence Angles (ω) of the
Compound 9 Molecule
Bond
N(1)–C(1)
l, Å
Angle
ω, deg
1.340(2)
1.336(2)
1.367(2)
1.390(2)
1.312(2)
1.428(2)
1.408(2)
C(5)N(1)C(1)
C(1)N(2)N(3)
N(2)N(3)C(10)
N(3)C(10)C(2)
C(10)C(2)C(1)
C(2)C(1)N(2)
114.66(13)
110.19(12)
107.15(12)
110.80(13)
107.15(12)
106.89(13)
N(1)–C(5)
N(2)–C(1)
N(2)–N(3)
C(10)–N(3)
C(10)–C(2)
C(2)–C(1)
Note that all the synthesized compounds were previously unknown, although as is evident, they are
easily formed from fairly accessible reactants. The data of [17] on the synthesis of compound 9b on fusing
dimedone with aminoformylpyrazole 12 do not correspond to actuality, since its characteristics (melting point
and parameters of 1H NMR spectra) are clearly different from those found by us.
Me
CHO
N
9b
2b
+
N
NH2
Ph
12
The structure of compound 9b was established by us by the X-ray structural method (Figs. 1 and 2,
Table 3). The central heterocyclic fragment N(1)C(1-5) is planar (maximum mean-square deviation of atoms
was only 0.007 Å) and the pyrazole ring N(2)N(3)C(1)C(2)C(10) also planar (maximum mean-square deviation
0.003 Å) lies in practically the same plane (corresponding dihedral angle 0.99o). The dihedral angle between the
pyrazole ring N(1)N(2)C(1)C(2)C(10) and the phenyl ring C(14)–C(19) was 9.5°. The C(4)–C(9) ring is
nonplanar and has a half-chair conformation with a flattened fragment C(9)C(4)C(5) (corresponding modified
Cremer-Pople parameters [18] are S = 0.75, ψ = 13.00o, θ = 35.88o).
Fig. 1. General shape of the compound 9b molecule.
197

The composition and structure of all the compounds were also confirmed by data of elemental analysis
(Table 1), IR spectra, and 1H NMR spectra (Table 2). In particular in the 1H NMR spectrum of compound 9b the
chemical shifts of the gem-dimethyl grouping (1.06 ppm) and the 3-CH3 group (2.62 ppm) differ sharply, while
according to the data of [17] all three methyl groups are displayed as one nine-proton singlet (2.5 ppm). The
diastereotopic CH3 groups and the protons of the CH2 group of compounds 6b, 7b, and 8b resonate as in their
known analogs of the pyrazolo[3,4-b]quinoline type [19].
Fig. 2. Fragment of the crystal packing of compound 9b.
A method of synthesis based on the use of 4-(dimethylamino)benzaldehyde in the Hantzsch reaction has
enabled previously unknown partially hydrogenated derivatives of pyrazolo[3,4-b]quinolines, acridines, and
pyrimido[4,5-b]quinolines, containing a γ-unsubstituted pyridine ring to be obtained easily.
EXPERIMENTAL
A check on the progress of reactions and the purity of the compounds synthesized was carried out by
TLC on Silufol UV-254 plates in the solvent system benzene–ethanol, 9:1, visualizing in UV light. The IR
1
spectra of compounds were recorded on a UR-20 instrument in KBr disks. The H NMR spectra were obtained
on a Bruker Avance DRX 500 instrument (500 MHz) in DMSO-d6, standard was TMS.
X-Ray structural investigation of a monocrystal of size 0.25×0.31×0.43 mm, grown from a solution
of compound 9b in ethanol was carried out at room temperature on an Enraf–Nonius CAD-4 automatic four-
circle diffractometer (CuKα radiation, λ = 1.54178 Å, 2θ/ω scanning, θmax = 70o, sphere segment –13 ≤ h ≤ 12,
0 ≤ k ≤ 15, 0 ≤ l ≤13). Overall 2929 reflections were collected of which 2217 are symmetrically independent
(Rint = 0.01). Crystals of 9b were monoclinic, a = 11.238(2), b = 12.584(2), c = 11.787(2) Å, β = 108.88(2)°,
V = 1577.15(11) Å3, M = 305.38, Z = 4, dcalc = 1.29 g/cm3, µ = 6.093 cm-1, F(000) = 649.70, space group
P21/n (N 15-17). The structure was solved by the direct method and refined by the least squares method (MNK)
in a full-matrix anisotropic approximation using the CRYSTALS set of programs [20]. In the refinement 2217
reflections with I > 3σ(I) were used (209 parameters refined, number of reflections per parameter 10.6). The
hydrogen atoms were placed geometrically and included in the refinement with fixed thermal and positional
198

parameters. The weight scheme of Chebyshev [21] was used in the refinement with parameters 2.68, 2.93, 2.56,
0.813, and 0.574. The final values of the divergence factors R = 0.041 and Rw = 0.046, GOOF = 0.990. The
residual electon density from the Fourier difference series was -0.19 and 0.17 e/Å3. Calculation of absorption in
the crystal was carried out with the aid of the azimuthal scanning method of [22]. The complete set of X-ray
structural data for compound 9b has been deposited in the Cambridge structural data bank (CCDC 664295).
4-[4-(Dimethylamino)phenyl]-3,7,7-trimethyl-1-phenyl-1,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-b]-
quinolin-5-one (6b). A solution of compounds 1 (2.98 g, 20 mmol), 2b (2.8 g, 20 mmol), and 3 (3.46 g,
20 mmol) in 2-propanol (7.5 ml) was maintained for 72 h at 15-20oC. The solid which separated was filtered off,
washed with 2-propanol, and with hexane. Analytically pure product 6b (4.1 g) was obtained.
9-[4-(Dimethylamino)phenyl]-6,8-dimethoxy-3,3-dimethyl-3,4,9,10-tetrahydroacridin-1(2H)-one
(7b). A mixture of compounds 1 (0.298 g, 2 mmol), 2b (0.28 g, 2 mmol), and 4 (0.306 g, 2 mmol) in 2-propanol
(2 ml) was maintained at 75oC for 30 min. The cooled mass was filtered, the solid washed with 2-propanol, with
hexane, and analytically pure product 7b (0.723 g) was obtained.
5-[4-(Dimethylamino)phenyl]-1,3,8,8-tetramethyl-5,8,9,10-tetrahydropyrimido[4,5-b]quinoline-
2,4,6(1H,3H,7H)-trione (8b). A mixture of compounds 1 (1.49 g, 10 mmol), 2b (1.4 g, 10 mmol), and 5
(1.55 g, 10 mmol) in glacial acetic acid (6 ml) was maintained at 80oC for 4 h. The cooled mass was filtered, the
solid washed with 2-propanol, crystallized from pyridine, and product 8b (2.5 g) was obtained.
3,7,7-Trimethyl-1-phenyl-1,6,7,8-tetrahydro-5H-pyrazolo[3,4-b]quinolin-5-one (9b). A. A mixture
of compounds 1 (0.596 g, 4 mmol), 2b (0.56 g, 4 mmol), and 3 (0.692 g, 4 mmol) in glacial acetic acid (4 ml)
was maintained for 2 h at 120oC. The boiling reaction mixture was diluted with water (4 ml) with stirring. The
cooled mass was filtered, the solid washed with a mixture of 2-propanol−water 1:1, crystallized from a mixture
of pyridine−water, 1:1, and product 9b (1.149 g) was obtained.
Product 9a was obtained analogously from compounds 1, 2a (0.56 g, 5 mmol), and compound 3.
B. A mixture of compound 6b (1.7 g, 4 mmol) and glacial acetic acid (4 ml) was maintained at 120°C
for 2 h. The product was isolated as in method A, and compound 9b (1.163 g) was obtained, which, according to
data of TLC and mp, was identical to a sample obtained by method A.
6,8-Dimethoxy-3,3-dimethyl-3,4-dihydroacridin-1(2H)-one (10b). A. A mixture of compounds 1
(0.596 g, 4 mmol), 2b (0.7 g, 5 mmol), and 4 (0.765 g, 5 mmol) in glacial acetic acid (4 ml) was maintained at
120oC for 2 h. The acetic acid was evaporated at the vacuum of a water-jet pump. The residue was dissolved
with heating in acetone (4 ml). The hot solution was diluted with 20% aqueous ammonia solution (4 ml) and
water (4 ml). The cooled mass was filtered, the solid washed with a mixture of 2-propanol–water, 1:2,
crystallized from ethanol–water, 2 : 1, and product 10b (0.934 g) was obtained.
Product 10a was obtained analogously from compounds 1, 2a, and 4.
B. Product 10b was obtained from compound 7b by method B given for compound 9b and isolated as
given above for method A.
1,3,8,8-Tetramethyl-8,9-dihydropyrimido[4,5-b]quinoline-2,4,6(1H,3H,7H)-trione (11b). A.
A
mixture of compounds 1 (0.596 g, 4 mmol), 2b (0.56 g, 4 mmol), and 5 (0.620 g, 4 mmol) in glacial acetic acid
(4 ml) was maintained at 120oC for 2 h. The boiling reaction mixture was diluted with water (4 ml) with stirring.
The cooled mass was filtered, the solid washed with a mixture of 2-propanol–water 1:1, crystallized from
2-propanol, and product 11b (1.058 g) was obtained.
Product 11a was obtained analogously from compounds 1, 2a, and 5.
B. Product 11b was obtained from compound 8b by method B given for compound 9b.
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