2-[3-Alkoxy-4-(hydroxy, alkoxy, acyloxy)phenyl]-2,3-dihydro-1H- benzimidazoles on the basis of vanillin and vanillal derivatives

Article abstract of DOI:10.1134/S1070363207110138

Previously unknown 2-[3-alkoxy-4-(hydroxy, alkoxy, acyloxy)phenyl]-2,3- dihydro-1H-benzimidazoles were prepared by the reaction of aldehydes of the vanillin series and their ethers and esters with 1,2-phenylenediamine in absolute methanol.

Full text of DOI:10.1134/S1070363207110138

ISSN 1070-3632, Russian Journal of General Chemistry, 2007, Vol. 77, No. 11, pp. 1924 1927.
Pleiades Publishing, Ltd., 2007.
Original Russian Text E.A. Dikusar, N.G. Kozlov, V.I. Potkin, 2007, published in Zhurnal Obshchei Khimii, 2007, Vol. 77, No. 11, pp. 1871 1875.
2-[3-Alkoxy-4-(hydroxy, alkoxy, acyloxy)phenyl]-2,3-dihydro-
1H-benzimidazoles on the Basis of Vanillin
and Vanillal Derivatives
E. A. Dikusar, N. G. Kozlov, and V. I. Potkin
Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus,
ul. Surganova 13, Minsk, 220072 Belarus
e-mail: evgen_58@mail.ru
Received April 9, 2007
Abstract Previously unknown 2-[3-alkoxy-4-(hydroxy, alkoxy, acyloxy)phenyl]-2,3-dihydro-1H-benz-
imidazoles were prepared by the reaction of aldehydes of the vanillin series and their ethers and esters with
1,2-phenylenediamine in absolute methanol.
DOI: 10.1134/S1070363207110138
Natural aldehydophenols, such as vanillin and
vanillal (3-methoxy- and 3-ethoxy-4-hydroxybenzal-
dehydes), as well as their ethers and esters are available
building blocks carrying the aromatic structural
fragment containing methoxy, ethoxy, and ester
groups. They are well suitable for purposeful syn-
thesis of various classes of biologically active com-
pounds [1 3].
roxy,
alkoxy,
acyloxy)phenyl]-2,3-dihydro-1H-
benzimidazoles containing hydroxy, ether, and ester
groups. Target 2,3-dihydro-1H-benzimidazoles IIIa
III , IVa IV were obtained by condensation of
vanillin, vanillal, or their ethers and esters I with
1,2-phenylenediamine (II) in absolute methanol under
reflux in 82 89% yields. The reactions were complete
in 0.5 h and occurred under mild conditions without
catalysts, which allowed preservation of the labile
ester group.
The aim of this work is to develop a preparative
synthesis of previously unknown 2-[3-alkoxy-4-(hyd-
CHO
H
N
RO
R1O
H2N
+
MeOH
H2O
H2N
RO
N
H
OR1
I
II
IIIa III , IVa IV
III, R = Me, R1 = H (a), Me (b), MeC(O) (c), EtC(O) (d), PrC(O) (e), Me2CHC(O) (f), Me(CH2)6C(O) (g),
Me(CH2)7C(O) (h), Me(CH2)8C(O) (i), Me(CH2)16C(O) (j), H2C=CMeC(O) (k), cyclo-C6H11C(O) (l), C6H5CH2C(O) (m),
C6H5(CH2)2C(O) (n), C6H5C(Me)HCH2C(O) (o), Z-C6H5C(H)=C(C N)C(O) (p), C6H5C(O) (q), 4-ClC6H4C(O) (r),
2,4-Cl2C6H3C(O) (s), 2,4-Cl2C6H3OCH2C(O) (t), 4-BrC6H4C(O) (u), 3-O2NC6H4C(O) (v), 3,5-(O2N)2C6H3C(O) (w),
MeO(O)C (x), EtO(O)C (y), MeO(O)C(CH2)2C(O) (z), Cl2C=CClCH2C(O) ( ); IV, R = Et, R1 = H (a), Me (b),
MeC(O) (c), EtC(O) (d), PrC(O) (e), Me2CHC(O) (f), Me2CHCH2C(O) (g), Me(CH2)4C(O) (h), Me(CH2)5C(O) (i),
Me(CH2)6C(O) (j), Me(CH2)7C(O) (k), Me(CH2)8C(O) (l), Me(CH2)11C(O) (m), Me(CH2)16C(O) (n), cyclo-C6H11C(O)
(o), C6H5(CH2)2C(O) (p), C6H5C(Me)HCH2C(O) (q), trans-C6H5C(H)=C(H)C(O) (r), Z-C6H5C(H)=C(C N)C(O) (s),
4-MeC6H4C(O) (t), 2,4-Cl2C6H3C(O) (u), 2,4-Cl2C6H3OCH2C(O) (v), 3-O2NC6H4C(O) (w), 4-O2NC6H4C(O) (x),
3,5-(O2N)2C6H3C(O) (y), MeO(O)C (z), EtO(O)C ( ), MeO(O)C(CH2)2C(O) ( ), Cl2C=CClCH2C(O) ( ).
2,3-Dihydro-1H-benzimidazoles IIIa III , IVa
IV are colored (largely yellow) viscous glass-like or
crystalline substances soluble in benzene, chloroform,
acetone, and lower alcohols, and insoluble in water
and hexane. The compounds do not contain admix-
tures of the starting materials and need no additional
purification. The structure of 2,3-dihydro-1H-benz-
imidazoles was proved by the elemental analyses,
cryoscopic molecular weights (see table), and IR, UV,
and 1H NMR spectra. According to the 1H NMR spec-
tra, their purity is 95 1%.
1924

2-[3-ALKOXY-4-(HYDROXY, ALKOXY, ACYLOXY)PHENYL]-2,3-DIHYDRO-1H-BENZIMIDAZOLES 1925
Yields, melting points, elemental analyses, and molecular weights 2,3-dihydro-1H-benzimidazoles IIIa III and IVa
IV
Found, %
H
Calculated, %
H
M
Comp.
no.
Yield,
%
mp,
C
Formula
C
N
C
N
found calculated
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
IIIi
89
84
82
88
88
83
85
82
84
85
83
89
85
88
82
85
85
87
84
81
82
86
82
69.84 6.05 11.23 C14H14N2O2
70.69 6.48 10.65 C15H16N2O2
69.41
70.29
67.59
68.44
69.21
69.21
71.71
72.22
72.70
75.55
69.66
71.57
72.76
73.78
74.21
72.53
72.82
66.23
60.74
59.34
59.31
64.45
57.80
5.82 11.56
6.29 10.93
227.7
242.3
267.9
281.8
303.7
305.1
344.8
360.2
379.9
482.4
295.4
338.6
347.5
358.0
375.2
380.8
336.0
369.3
401.1
422.7
411.4
388.6
413.6
242.3
256.3
284.3
298.3
312.4
312.4
368.5
382.5
396.5
508.7
310.4
352.4
360.4
374.4
388.5
397.4
346.4
380.0
415.3
445.3
425.3
391.4
434.4
67.88 5.71
68.76 6.20
69.45 6.49
69.60 6.61
71.97 7.85
72.64 8.08
72.98 8.43
75.87 10.20
70.04 6.03
71.96 7.11
9.42 C16H16N2O3
8.97 C17H18N2O3
8.68 C18H20N2O3
8.74 C18H20N2O3
7.15 C22H28N2O3
6.95 C23H30N2O3
6.64 C24H32N2O3
5.16 C32H48N2O3
8.59 C18H18N2O3
7.58 C21H24N2O3
7.28 C22H20N2O3
7.01 C23H22N2O3
6.90 C24H24N2O3
5.57
6.08
6.45
6.45
7.66
7.91
8.13
9.51
5.85
6.86
5.59
5.92
6.23
9.85
9.39
9.97
9.97
7.60
7.32
7.06
5.51
9.03
7.95
7.77
7.48
7.21
IIIj
IIIk
IIIl
92 93
IIIm
IIIn
IIIo
IIIp
IIIq
IIIra
IIIsb
IIItc
IIIud
IIIv
IIIw
105 106 73.14 5.87
111 112 74.05 6.12
78 79
74.62 6.45
187 188 72.89 5.05 10.17 C24H19N3O3
4.82 10.57
148 149 73.10 5.44
166 167 66.68 6.52
193 194 61.05 3.97
146 147 59.81 4.30
180 181 59.72 4.12
7.85 C21H18N2O3
5.24
4.50
3.88
4.07
4.03
8.08
7.36
6.75
6.29
6.59
7.06 C21H17ClN2O3
6.25 C21H16Cl2N2O3
5.94 C22H18Cl2N2O4
6.30 C21H17BrN2O3
202 203 64.87 4.51 10.52 C21H17N3O5
4.38 10.74
3.70 12.84
246
58.07 3.93 12.39 C21H16N4O7
(decomp.)
IIIx
IIIy
IIIz
81
81
84
81
88
90
88
84
87
88
86
87
84
86
85
85
81
82
87
87
84
88
83
64.20 5.45
65.22 5.90
64.35 5.83
52.61 3.20
70.43 6.51 10.54 C15H16N2O2
71.46 6.98 10.03 C16H18N2O2
68.77 6.29
69.59 6.63
70.26 6.80
70.12 6.91
70.83 7.24
71.60 7.54
72.03 7.85
72.51 8.08
73.12 8.29
73.39 8.58
74.74 9.14
76.10 9.96
72.47 7.39
9.01 C16H16N2O4
8.54 C17H18N2O4
7.62 C19H20N2O5
6.35 C18H15Cl3N2O3
63.99
64.96
64.05
52.26
70.29
71.09
68.44
69.21
69.92
69.92
70.57
71.16
71.71
72.22
72.70
73.14
74.30
75.82
72.11
74.21
74.60
74.59
72.98
5.37
5.77
5.66
3.65
6.29 10.93
6.71 10.36
9.33
8.91
7.86
6.77
289.6
300.8
344.2
398.6
248.9
261.3
287.7
298.6
315.0
318.5
326.4
339.1
346.8
360.2
383.7
394.8
438.6
502.6
349.0
379.3
388.4
369.9
395.2
300.3
314.3
356.4
413.7
256.3
270.3
298.3
312.4
326.4
326.4
340.4
354.4
368.5
382.5
396.5
410.6
452.6
522.8
366.5
388.5
402.5
386.4
411.5
e
III
IVa
IVb
IVc
IVd
IVe
IVf
IVg
IVh
IVi
IVj
IVk
IVl
IVm
IVn
IVo
IVp
IVq
IVr
IVs
9.05 C17H18N2O3
8.65 C18H20N2O3
8.16 C19H22N2O3
8.24 C19H22N2O3
7.93 C20H24N2O3
7.45 C21H26N2O3
7.21 C22H28N2O3
7.04 C23H30N2O3
6.85 C24H32N2O3
6.67 C25H34N2O3
5.85 C28H40N2O3
5.06 C33H50N2O3
7.20 C22H26N2O3
7.03 C24H24N2O3
6.52 C25H26N2O3
6.96 C24H22N2O3
9.98 C25H21N3O3
6.08
6.45
6.79
6.79
7.11
7.39
7.66
7.91
8.13
8.35
8.91
9.64
7.15
6.23
6.51
5.74
9.39
8.97
8.58
8.58
8.23
7.90
7.60
7.32
7.06
6.82
6.19
5.36
7.64
7.21
6.96
7.25
74 75
96 97
121 122 74.63 6.45
85 86 74.98 6.64
178 179 74.96 5.95
180 181 73.31 5.36
5.14 10.21
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 11 2007

1926
DIKUSAR et al.
Formula
Table (Contd.)
Found, %
H
Calculated, %
H
M
Comp.
no.
Yield,
%
mp,
C
C
N
C
N
found calculated
IVt
82
86
81
84
85
87
156 157 74.07 6.13
200 201 61.84 4.20
152 153 60.53 4.54
198 199 65.02 4.83 10.05 C22H19N3O5
210 211 64.80 4.57 10.10 C22H19N3O5
7.01 C23H22N2O3
6.08 C22H18Cl2N2O3
5.70 C23H20Cl2N2O4
73.78
61.55
60.14
64.69
64.69
58.67
5.92
4.23
4.39
4.72 10.36
4.72 10.36
4.03 12.44
7.48
6.53
6.10
364.2
409.8
442.3
384.6
388.4
325.1
374.4
429.3
459.3
405.4
405.4
450.4
IVuf
IVvg
IVw
IVx
IVy
250
58.93 4.25 12.23 C22H18N4O7
(decomp.)
IVz
IV
IV
83
81
82
81
65.28 5.96
66.06 6.19
65.00 6.18
53.42 3.97
8.63 C17H18N2O4
8.12 C18H20N2O4
7.28 C20H22N2O5
6.20 C19H17Cl3N2O3
64.96
65.84
64.85
53.36
5.77
6.14
5.99
4.01
8.91
8.53
7.56
6.55
305.4
314.8
360.3
409.6
314.3
328.4
370.4
427.7
h
IV
a
b
c
Found Cl, %: 9.04. Calculated Cl, %: 9.31; Found Cl, %: 16.88. Calculated Cl, %: 17.07; Found Cl, %: 15.70. Calculated Cl, %:
d
e
f
15.92; Found Br, %: 18.36. Calculated Br, %: 18.79; Found Cl, %: 25.34. Calculated Cl, %: 25.71; Found Cl, %: 16.10.
Calculated Cl, %: 16.52; Found Cl, %: 15.08. Calculated Cl, %: 15.44; Found Cl, %: 24.61. Calculated Cl, %: 24.87.
g
h
The IR spectra of 2,3-dihydro-1H-benzimidazoles
IIIa III , IVa IV contain absorption bands of the
The 2,3-hydro-1H-benzimidazoles are unstable
compounds quickly darkening on exposure to sunlight
and air oxygen due to tarring. Apparently, first oxida-
tive dehydration occurs to form 1H-benzimidazoles
which undergo further transformations. In the IR s
pectra of the samples of 2,3-dihydro-1H-benzimida-
zoles IIIa III , IVa IV , handled for 1 2 days at
20 25 C, we observed appearance and gradual growth
1
following bonds, cm : N H, 3420 3140; C Harom
,
3100 3000, 870 740; C Halk, 2990 2870; C=O,
1770 1740 (IIIc III , IVc IV ); C Carom, 1600
1
1370 cm ; and C O, 1280 1000. The presence of
C N groups in compounds IIIp, IVs is confirmed by
the observation of an absorption band at 2225
1
1
2224 cm . The presence of NO2 groups in com-
of the characteristic band at 1625 1622 cm related
1
pounds IIIw, IIIv, IVv IVy is confirmed by the ob-
to C=N absorption. At the same time, the H NMR
servation of characteristic IR bands at 1541 1525 and
spectra showed gradual decrease in the intensity of
the C(2)H proton signal at 8.45 8.55 ppm. These facts
provide evidence for the above suggestions. Com-
pounds IIIa III , IVa IV can be handled for a long
time in sealed ampules under argon in the absence of
light and at temperatures below 5 C.
1
1349 1343 cm .
The UV spectra of 2,3-dihydro-1H-benzimidazoles
IIIa III , IVa IV show absorption bands with
(log ) at 238 nm (3.95) and 292 nm (4.00), assmigax-
nable to the 2-[3-alkoxy-4-(hydroxy, alkoxy, acyloxy)-
phenyl]-2,4-dihydro-1H-benzimidazole fragments. In
As known, aldehydes react with primary amines to
form azomethines [4]. Among the reaction products
of the vanillin and vanillal derivatives with 1,2-
phenylenediamine (II), no corresponding azomethines
were found. To explain this fact we carried out quan-
tum-chemical calculations of the heats of formation
(Hf) of 2-[3-alkoxy-4-(hydroxy, alkoxy, acyloxy)-
phenyl]-2,3-dihydro-1H-benzimidazoles IIIa, IIId,
IIIq, IVb, IVc, IV and their isomeric azomethines,
(E)-[3-alkoxy-4(hydroxy, alkoxy, acyloxy)phenyl-
methylene](2-aminophenyl)amines Va, Vd, Vq, VIb,
VIc, VI .
1
the H NMR spectra of 2,3-dihydro-1H-benzimida-
zoles IIIa III , IVb, the signals of MeO group
appear as singlets at 3.85 3.92 ppm. In the spectra
of compounds IVa IV , the EtO group gives a triplet
at 1.35 1.70 ppm (Me) and a quartet at 4.00
4.40 ppm (CH2). The signals of aromatic protons of
2,3-dihydro-1H-benzimidazoles IIIa III , IVa IV
are in the range
6.50 8.35 ppm. The signals of
methylidene protons at C(2) appear as a characteristic
singlet at 8.45 8.55 ppm.
1
The IR, UV, and H NMR spectra of 2,3-dihydro-
The quantum-chemical calculations were carried
out by the semiempirical MNDO PM3 method with
full optimization of interatomic distances and bond
and dihedral angles, using GAMESS [5]. The follow-
1H-benzimidazoles IIIa III , IVa IV
evidence for the presence of the corresponding frag-
ments of ester groups.
provide
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 11 2007

2-[3-ALKOXY-4-(HYDROXY, ALKOXY, ACYLOXY)PHENYL]-2,3-DIHYDRO-1H-BENZIMIDAZOLES 1927
2-[3-Alkoxy-4-(hydroxy, alkoxy, acyloxy)phenyl-
2,3-dihydro-1H-benzimidazoles IIIa III , IVa
IV (general procedure). A solution of 5 mmol of
aldehyde of the vanillin series I and 5 mmol of 1,2-
phenylenediamine (II) in 30 ml of methanol was re-
fluxed for 0.5 h under argon. The solution was filtered
while hot through a folded filter paper, cooled, and
left for 10 15 h at 5 C. The crystals of compounds
IIIj, IIIm IIIv, IVm, IVn, IVp IVy were filtered off
on a glass frit, washed with a little methanol, and
dried in a vacuum. The other 2,3-dihydro-1H-benz-
imidazoles IIIa IIIi, IIIk, IIIl, IIIx IIIz, IVa IVl,
IVo, IVz IV were obtained as viscous glass-like
compounds by removing methanol in a vacuum
(1 mm Hg, T 30 35 C).
NH2
N
H
C
RO
OR1
Va, Vd, Vq, VIb, VIc, VI
1
ing Hf values (kcal mol ) of 2,3-dihydro-1H-benz-
imidazoles were obtained (the Hf values for the iso-
meric (E)-azomethines are given in brackets): 25.5
(IIIa) [ 12.9 (Va)]; 65.2 (IIId) [ 54.8 (Vd)]; 24.6
(IIIq) [ 13.6 (Vq)]; 20.5 (IVb) [ 10.5 (VIb)]; 65.8
(IVc) [ 55.2 (VIc)]; 109.5 (IV ) [ 97.8 (VI )].
Hence, 2,3-dihydro-1H-benzimidazoles IIIa, IIId,
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1
IIIq, IVb, IVc, IV are 10.0 12.1 kcal mol
thermodynamically more stable than the correspond-
ing isomeric (E)-azomethines Va, Vd, Vq, VI b, VIc,
VI . This fact explains the formation of 2,3-dihydro-
benzimidazoles IIIa III , IVa IV , rather than
azomethines in the reactions of aldehydes I with
1,2-phenylenediamine (II) under conditions of ther-
modynamic equilibrium [4].
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EXPERIMENTAL
The IR spectra were recorded on a Nicolet Protege-
460 Fourier spectrometer in thin layer or in KBr. The
UV spectra were obtained on a Varian Cary-300 UV-
4
Vis spectrophotometer for 1 10 M methanol solu-
tions. The 1H NMR spectra were taken on a Tesla BS-
587A (100 MHz) spectrometer for 5% CDCl3 solu-
tions against internal TMS. Elemental analysis was
performed on an Elementar Vario EL-III C,H,N,O,S-
analyzer, determination error 0.1%. The molecular
weights (M) were measured by cryoscopy in benzene.
Vanillin and vanillal esters I were obtained by the
procedures in [6 9]. 1,2-Phenylenediamine of analytic
grade was used, purity 98%, mp 102 103 C.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 11 2007