p-(dimethylamino)benzaldehyde modification of the Hantzsch reaction: Synthesis of 3-(1H-benzimidazol-2-yl)-5,7-dimethoxyquinolines

Article abstract of DOI:10.1007/s10593-007-0235-2

A three component cyclocondensation of p-(dimethylamino)benzaldehyde with 3,5-dimethoxyaniline and 2-phenacyl-1H-benzimidazoles gives previously unknown 2-aryl-3-(1H-benzimidazol-2-yl)-5,7-dimethoxyquinolines. The Hanztsch type reaction occurs in refluxing acetic acid and is accompanied by aromatization of the 1,4-dihydroquinolines formed through loss of N,N-dimethylaniline.

Full text of DOI:10.1007/s10593-007-0235-2

Chemistry of Heterocyclic Compounds, Vol. 43, No. 12, 2007
p-(DIMETHYLAMINO)BENZALDEHYDE
MODIFICATION OF THE HANTZSCH
REACTION: SYNTHESIS OF 3-(1H-BENZ-
IMIDAZOL-2-YL)-5,7-DIMETHOXY-
QUINOLINES
I. B. Dzvinchuk, A. N. Chernega, and M. O. Lozinskii
A three component cyclocondensation of p-(dimethylamino)benzaldehyde with 3,5-dimethoxyaniline and
2-phenacyl-1H-benzimidazoles gives previously unknown 2-aryl-3-(1H-benzimidazol-2-yl)-5,7-
dimethoxyquinolines. The Hanztsch type reaction occurs in refluxing acetic acid and is accompanied by
aromatization of the 1,4-dihydroquinolines formed through loss of N,N-dimethylaniline.
Keywords: aldehydes, anilines, benzimidazoles, quinolines, aromatization, dearylation, Hantzsch
reaction, selectivity.
The Hantzsch synthesis of pyridines usually consists of two stages: a three component cyclocondensation
of aldehydes with acetoacetic ester and ammonia (or ammonium acetate) and subsequent oxidation of the
1,4-dihydropyridines formed [1]. Exchange of acetoacetic ester for dimedone similarly gives acridine
compounds with an aromatic pyridine ring (including those not containing a substituent at position 10) but the
first stage of the reaction involving formaldehyde (or paraformaldehyde) occurs with very low selectivity and in
only 41% yield [2]. As we reported earlier [3] the same acridine compound is obtained in 85% yield by replacing
formaldehyde by p-(dimethylamino)benzaldehyde 1 in the starting three component system. In this case the
reaction of the reagents in refluxing acetic acid does not stop at the formation of the corresponding 10-aryl-1,10-
dihydroacridine but is accompanied by a previously unknown aromatization via fission of N,N-dimethylaniline.
Such a modification of the Hantzsch reaction has clear advantages: 1) the aldehyde 1 is available and, in contrast
to formaldehyde, stable on storage and readily measured out; 2) the use of an oxidant is not required; 3) the N,N-
dimethylaniline formed in the reaction has a high solubility and does not hinder the separation of the product
from the reaction mixture; 4) the process is single stage and efficient. In our opinion this variation of the
Hantzsch reaction can be efficiently used as a novel and convenient method for preparation of compounds with a
γ-unsubstituted pyridine ring which we have also demonstrated in our work on the synthesis of novel quinoline
compounds.
__________________________________________________________________________________________
Institute of Organic Chemistry, National Academy of Sciences of Ukraine Kiev 02094; e-mail:
Rostov@bpci.kiev.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1792-1798,
December, 2007. Original article submitted March 27, 2007.
0009-3122/07/4312-1519©2007 Springer Science+Business Media, Inc.
1519

We began with the fact that one of the methods of preparing 1,4-dihydropyridines is based on a three
component [1+3+2] cyclocondensation of aldehydes with β-aminocrotonic ester and acetoacetic ester [4]. This
method can be extended by varying the nature of the reaction components, in particular was use of
5-aminopyrazoles and dimedone for synthesis of pyrazoloquinolines [5]. For the first time we have used a
similar reaction of aldehyde 1 with 3,5-dimethoxyaniline 2 as the 1,3-[N,C]-dinucleophilic component and the
2-phenacyl-1H-benzimidazoles 3a-g as the methylene carbonyl component. It was found that the three
component cyclocondensation of aldehydes, anilines, and methyl ketones to form quinolines (known as the so
called Bayer reaction) occurs such that the starting aldehyde introduces its substituent into the 2 position of the
target product [6].
We have found that the reactions of the reagents 1-3 occur regioselectively in refluxing acetic acid via a
Hanztsch reaction. However, they do not stop at the formation of the expected compounds 4a-g which contain a
1,4-dihydropyridine fragment but undergo subsequent aromatization with fission of N,N-dimethylaniline to give
the previously unknown 4-unsubstituted 2-aryl-3-(1H-benzimidazol-2-yl)-5,7-dimethoxyquinolines 5a-g. The
products with an isomeric 2-unsubstituted quinoline structure 6a-g were not detected (their formation would
have been possible if the process occurred via a Bayer reaction scheme).
NMe2
MeO
H
N
HOAc,
120°C,
2 h
OMe
+
+
N
O
H2N
Ar
CHO
1
3a-g
2
Me2N
H
Me
O
– PhNMe2
H
OMe
N
N
N
H
Ar
H
4a-g
N
N
MeO
5
6
8
7'
H
N
4
N
OMe
OMe
6'
5'
7
Ar
3
MeO
N
N1
6a-g
2
4'
Ar
5a-g
3–6 a Ar = Ph, b Ar = 4-MeOC6H4, c Ar = 4-MeC6H4, d Ar = 3,4,5-(MeO)3C6H2,
e Ar = 4-BrC6H4, f Ar = 3-O2NC6H4, g Ar = 4-O2NC6H4
The reaction is not markedly complicated by side processes (e.g. reaction of aldehyde 1 with the target
material which have a reactive nucleophilic center) and is complete after 2 h. The products were separated from
the reaction mixtures by dilution with water in 72-94% yields.
1520

MeO
Me
N
Me2NCH(OMe)2
Me I
OMe
5a
– MeOH,
N
N
– Me2NCHO
Ph
7
MeO
Me
N
OMe
+
N
N
_
I
Ph
Me
8
The structure of compound 5a was confirmed by methylation at the benzimidazole nitrogen atom and
subsequent quaternization of product 7 with methyl iodide to give the salt 8. In contrast to the remaining
synthesized compounds we have been able to grow crystals suitable for X-ray analysis from this salt. The overall
view of cation 8 and its basic geometric parameters are given in Figure 1. Both bicyclic systems N(1)N(2)C(1-7) and
N(3)C(8-16) are planar (the deviation of the atoms from the mean square planes not exceeding 0.007 and 0.026 Å).
The dihedral angle between these systems is 65.6º. The benzene ring C(19-24) is twisted by 39.4º relative to the
N(3)C(8-16) plane. The N(1) and N(2) atoms have a planar trigonal configured bonds (sum of valence angles at these
atoms 360.0 and 359.9º). Evidently it is position 4 and not 2 which is unsubstituted in the quinoline ring of
cation 8. This conclusion also extends to compounds 7 and 5a since the chemical changes occurring in them only
alter the immediate surroundings of the nitrogen atoms in the molecules.
The composition and structure of all of the synthesized compounds were confirmed through elemental
analysis (Table 1) and from their 1H NMR spectra (Table 2).
TABLE 1. Characteristics of the Compounds Synthesized
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
Yield, %
С
Н
N
5a
5b
5c
5d
5e
5f
5g
7
C24H19N3O2
C25H21N3O3
C25H21N3O2
C27H25N3O5
C24H18BrN3O2
C24H18N4O4
C24H18N4O4
C25H21N3O2
C26H24IN3O2
75.48
75.57
72.79
72.98
75.78
75.93
68.65
68.78
62.49
62.62
67.47
67.60
67.49
67.60
75.79
75.93
4.89
5.02
5.01
5.14
5.44
5.35
5.25
5.34
3.81
3.94
4.18
4.25
4.15
4.25
5.21
5.35
10.89
11.02
10.03
10.21
10.47
10.63
8.74
8.91
8.97
9.13
13.07
13.14
13.09
13.14
10.48
10.63
300-301.5
319-320.5
311-312.5
233-235
88
75
87
86
92
72
94
91
81
287.5-289
272.5-274
276.5-278
198.5-200
273-276 (dec.)
8
58.05
58.11
4.26
4.50
7.69
7.82
1521

C21
C22
C20
C23
C26
C19
C8
N3
C17
C24
C4
C7
C13
C12
C3
N2
C5
C6
C14
C9
O1
C1
C11
C2 N1
C10
C15
C16
C25
O2
C18
Fig. 1. Overall view of the compound 8 cation. Basic bond lengths (l) and valence angles (ω).
l: (N(1)–C(1) 1.334(2), N(1)–C(2) 1.386(2), N(2)–C(1) 1.335(2), N(2)–C(3) 1.384(2), N(3)–C(8) 1.318(2),
N(3)–C(12) 1.362(2) Å; ω: C(1)N(1)C(2) 108.4(1), C(1)N(2)C(3) 108.7(1), С(8)N(3)С(12) 119.7(2) deg.
The similarity of structure for compounds 5a-g follows from the fact that the chemical shifts of
identically placed protons in their bicyclic fragments have very small differences whose dependence can be fully
related to the change in the nature of the Ar substituent. In particular, the singlet signal for the quinoline ring H-4
appears clearly at 8.64-8.81 ppm, shifted to lower fields with a systematic change from electron-donor to
electron-acceptor aryl R substituent.
Hence the limits of the Hantzsch reaction in the synthesis of compounds with an aromatic
γ-unsubstituted pyridine ring can be overcome by exchanging formaldehyde for p-(dimethyl-
amino)benzaldehyde. Such a reaction modification has quite a widespread usage and is particularly suitable for
preparing the previously unknown 4-unsubstituted 3-(1H-benzimidazol-2-yl)-5,7-dimethoxyquinolines.
EXPERIMENTAL
Monitoring of the reaction course and purity of the synthesized compounds was carried out by TLC on
1
Silufol UV-254 plates using the solvent system benzene–ethanol (9:1) and revealed using UV light. H NMR
Spectra for the compounds were recorded on a Varian VXR-300 spectrometer (300 MHz) using DMSO-d6
solvent and TMS as standard. Before determination of elemental analysis and spectroscopic investigation the
compounds were dried for 5 h at 145ºC (crystals of salt 8 were dried at 20-25ºC for X-ray analysis).
X-ray Structural Investigation of Compound 8 Single Crystal which was grown from ethanol and
had dimensions 0.30×0.30×0.45 mm was carried out at room temperature on a Bruker Apex II automatic
diffractometer (MoKα radiation, λ = 0.71069 Å, θmax = 35º, -29 ≤ h ≤ 33, -17 ≤ k ≤ 14, -35 ≤ l ≤ 19). In all
25,150 reflections were collected (9941 independent reflections, Rint = 0.023). Crystals of compound 8 are
monoclinic with a = 20.739(2), b = 10.8940(8), c = 22.033(2) Å, β = 91.84(1)º, V = 4975.3(7) Å3, M = 545.4,
1522

1
TABLE 2. H NMR Spectroscopic Characteristics of the Synthesized
Compounds
Com-
pound
Chemical shifts, δ, ppm, (J, Hz)
5a
3.97 (3H, s, 5-CH3O); 4.02 (3H, s, 7-CH3O); 6.77 (1H, d, J = 1.8, H-6);
7.12 (1H, d, J = 1.8, H-8); 7.16-7.19 (2H, m, H-5',6'); 7.33 (3H, m, 3HPh-m,-p);
7.40 (1H, m, H-7'); 7.46-7.48 (2H, m, 2 HPh-o); 7.61-7.63 (1H, m, H-4');
8.70 (1H, s, H-4); 12.40 (1H, s, NH*)
5b
5c
5d
5e
5f
5g
7
3.74 (3H, s, CH3OAr); 3.96 (3H, s, 5-CH3O); 4.00 (3H, s, 7-CH3O);
6.72 (1H, d, J = 1.8, H-6); 6.85 and 7.46 (2 × 2H, two d, J = 8.4, 4HAr);
7.08 (1H, d, J = 1.8, H-8); 7.16-7.19 (2H, m, H-5',6'); 7.42 (1H, m, H-7');
7.61-7.64 (1H, m, H-4'); 8.64 (1H, s, H-4); 12.24 (1H, s, NH)
2.28 (3H, s, CH3); 3.96 (3H, s, 5-CH3O); 4.00 (3H, s, 7-CH3O); 6.74 (1H, d,
J = 1.8, H-6); 7.09 and 7.39 (2 × 2H, two d, J = 8.7, 4HAr); 7.08 (1H, d, J = 1.8, H-8);
7.16-7.19 (2H, m, H-5',6'); 7.41 (1H, m, H-7'); 7.61 (1H, m, H-4');
8.65 (1H, s, H-4); 12.38 (1H, s, NH)
3.45 (6H, s, 2CH3OAr-m); 3.65 (3H, s, CH3OAr-p); 3.98 (3H, s, 5-CH3O);
4.00 (3H, s, 7-CH3O); 6.75 (1H, d, J = 1.8, H-6); 6.78 (2H, s, 2HAr);
7.11 (1H, d, J = 1.8, H-8); 7.20–7.23 (2H, m, H-5',6'); 7.43-7.46 (1H, m, H-7');
7.65-7.68 (1H, m, H-4'); 8.64 (1H, s, H-4); 12.45 (1H, s, NH)
3.97 (3H, s, 5-CH3O); 4.02 (3H, s, 7-CH3O); 6.78 (1H, d, J = 2.1, H-6);
7.12 (1H, d, J = 2.1, H-8); 7.17–7.22 (2H, m, H-5',6'); 7.39 and 7.52 (2 × 2H, two d,
J = 8.7, 4HAr); 7.43–7.46 (1H, m, H-7'); 7.60-7.63 (1H, m, H-4'); 8.72 (1H, s, H-4);
12.51 (1H, s, NH)
3.97 (3H, s, 5-CH3O); 4.04 (3H, s, 7-CH3O); 6.80 (1H, d, J = 2.1, H-6);
7.15-7.18 (3H, m, H-8 + H-5',6'); 7.41 (1H, d, J = 7.2, H-7'); 7.52-7.56 (2H, m,
H-4' + HAr-5); 7.66 (1H, d, J = 7.2, HAr-6); 8.20 (1H, d, J = 7.5, HAr-4);
8.42 (1H, s, HAr-2); 8.81 (1H, s, H-4); 12.64 (1H, s, NH)
3.97 (3H, s, 5-CH3O); 4.04 (3H, s, 7-CH3O); 6.80 (1H, d, J = 2.1, H-6);
7.11 (1H, d, J = 2.1, H-8); 7.15-7.23 (2H, m, H-5',6'); 7.44 (1H, d, J = 7.2, H-7');
7.55 (1H, d, J = 7.2, H-4'); 7.67 and 8.15 (2 × 2H, two d, J = 9.0, 4HAr);
8.81 (1H, s, H-4); 12.74 (1H, s, NH)
3.10 (3H, s, NCH3); 3.98 (3H, s, 5-CH3O); 4.00 (3H, s, 7-CH3O);
6.78 (1H, d, J = 1.8, H-6); 7.15 (1H, d, J = 1.8, H-8); 7.25-7.37 (5H, m,
H-5',6' + 3HPh-m,-p); 7.42–7.44 (3H, m, H-7' + 2HPh-o); 7.69–7.72 (1H, m, H-4');
8.62 (1H, s, H-4)
8
3.70 (6H, s, 2NCH3); 4.02 (3H, s, 5-CH3O); 4.03 (3H, s, 7-CH3O);
6.90 (1H, d, J = 1.8, H-6); 7.27 (1H, d, J = 1.8, H-8); 7.33 (2H, t, J = 7.8, 2HPh-m);
7.40-7.46 (3H, m, 3HPh-o,p); 7.71–7.75 (2H, m, H-5',6'); 8.02–8.07 (2H, m, H-4',7');
9.08 (1H, s, H-4)
_______
* Undergoes deuterium exchange.
Z = 8, dcalc = 1.46 g/cm3, µ = 13.16 cm-1, F(000) = 2192, space group C2/c (N 15). The structure was solved by a
direct method and refined by least squares analysis in a full matrix anisotropic approximation using the
CRYSTALS program package [7]. 6001 reflections were used in the refinement with I > 3σ(I) (294 refinement
parameters, number of reflections per parameter 20.4). All of the hydrogen atoms (with the exception of the
water solvate molecules) were revealed in electron density difference synthesis and included in the refinement
with fixed positions and thermal parameters. The Chebyshev [8] weighting scheme was used in the refinement
with the five parameters 1.03, 1.09, 1.07, 0.38, and 0.27. The final divergence factor values were R = 0.029 and
Rw = 0.031, GOOF = 1.086. The residual electron density from Fourier synthesis was 0.53 and 0.83 e/Å3. The
full set of X-ray data for compound 8 has been placed in the Cambridge structural database (CCDC 631876).
1523

3-(1H-Benzimidazol-2-yl)-5,7-dimethoxy-2-phenylquinoline (5a). A mixture of aldehyde 1 (0.164 g,
1.1 mmol), aniline 2 (0.229 g, 1.5 mmol), and 2-phenacyl-1H-benzimidazole 3a (0.236 g, 1 mmol) in glacial
acetic acid (2 ml) was held at 120ºC for 2 h. The refluxing solution was stirred and diluted with water (4 ml).
After cooling, the precipitate was filtered off and washed with a mixture of 2-propanol and water (1:1). Yield
0.338 g. The product was recrystallized from a mixture of pyridine and water (4:1).
Compounds 5b-g were prepared similarly from 1, 2, and 3b-g.
5,7-Dimethoxy-3-(1H-1-methylbenzimidazol-2-yl)-2-phenylquinoline (7). A mixture of compound 5a
(0.381 g, 1 mmol), DMF dimethylacetal (1 ml), and anhydrous pyridine (1 ml) was held at 105-110ºC for 6 h.
Water (3 ml) was added with stirring. After cooling, the precipitate was filtered off and washed with a mixture of
2-propanol and water (1:1) to give the product in an analytically pure state (0.361 g).
2-(5,7-Dimethoxy-2-phenylquinolin-3-yl)-1,3-dimethyl-3H-benzimidazol-1-ium Iodide (8).
A
mixture of compound 7 (0.198 g, 0.5 mmol), methyl iodide (1.2 ml, 20 mmol), and anhydrous acetonitrile (2 ml)
was heated on a bath at 70-75ºC for 12 h. The reaction mixture was treated with toluene (5 ml), refluxed with
stirring, the low boiling components removed, and filtered hot. The precipitate on the filter was washed with
refluxing toluene and with diethyl ether after cooling. Crystallization from a mixture of ethanol and water (3:1)
gave 0.21 g of the product.
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