Synthesis and reactions of some 5(6)-(1-adamantyl)benzimidazoles

Article abstract of DOI:10.1007/s10593-008-0136-z

4-(1-Adamantyl)-1,2-diaminobenzene, previously unreported in the literature, has been prepared and a novel series of 5(6)-(1-adamantyl) benzimidazole derivatives synthesized. Nitration, hydrogenation, and side chain reactions have been carried out.

Full text of DOI:10.1007/s10593-008-0136-z

Chemistry of Heterocyclic Compounds, Vol. 44, No. 8, 2008
SYNTHESIS AND REACTIONS OF SOME
5(6)-(1-ADAMANTYL)BENZIMIDAZOLES
D. S. Zurabishvili1, M. O. Lomidze2, Sh. A. Samsoniya1, A. Wesquet3, and U. Kazmaier3
4-(1-Adamantyl)-1,2-diaminobenzene, previously unreported in the literature, has been prepared and a
novel series of 5(6)-(1-adamantyl)benzimidazole derivatives synthesized. Nitration, hydrogenation, and
side chain reactions have been carried out.
Keywords: adamantane, benzimidazole, o-phenylenediamine, hydrogenation, hydrolysis, condensation,
nitration, cyclization.
Substances with an adamantane fragment in the molecule have a broad spectrum of biological activity
[1-3]. We have previously reported [4, 5] the synthesis and reactions of 5(6)-(1-adamantyl)benzimidazoles. The
synthesized benzimidazoles were assayed for their biocide, antihelmintic, antitumor, and anti HIV activity [6, 7]
revealing compounds with identified activity. The results obtained point to the promise of a directed synthesis of
benzimidazoles with adamantane substituents. Hence the search for novel biologically active compounds
through the synthesis of adamantane-containing benzimidazoles and a study of their physicochemical and
biological properties is a very timely scientific task.
Br
NHCOMe
NHCOMe
ZnCl2
1
It is known that the main problem in the synthesis of benzimidazoles is the preparation of the
corresponding substituted o-phenylenediamine. The aim of our work was the discovery of optimum conditions
for synthesizing adamantane-containing o-phenylenediamine. The key reagent in the synthesis of 4-(1-adaman-
tyl)-1,2-diaminobenzene (4) is 1-(4-acetamidophenyl)adamantane (1). The methods of preparing compound 1 in
the literature [8, 9] are multistage demanding the use of acetanilide in a tenfold excess and are characterized by
further technical difficulties. The authors of [8] have noted that an attempt to prepare compound 1 by treating
1-bromoadamantane with acetanilide under Friedel-Crafts catalytic conditions was unsuccessful.
__________________________________________________________________________________________
2
1Iv. Javakhishvili State University, Tbilisi 0128, Georgia; e-mail: shotasamsonia@yahoo.de. Georgia
3
State Agricultural University, Tbilisi 0131; e-mail: m.lomidze@dr.com. Saarbrucken University, Saarbrucken
66041, Germany; e-mail: u.kazmaier@mx.uni-saarland.de. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 8, pp. 1172-1182, August, 2008. Original article submitted August 31, 2006; revision submitted
March 3, 2008.
0009-3122/08/4408-0941©2008 Springer Science+Business Media, Inc.
941

1-(4-Acetamidophenyl)adamantane (1) was synthesized by the alkylation of acetanilide by 1-bromo-
adamantane in tetrachloroethane or nitrobenzene medium in the presence of zinc chloride [10]. The synthesis
was carried out at 75ºC in a single stage using an equimolar ratio of reagents.
Compound 1 melts at 197-199ºC instead of the literature figures of 164-165 [8] and 173-175ºC [9].
Nitration of the product 1 obtained by us gave the 1-(4-acetamido-3-nitrophenyl)adamantane (2) with mp
212-214ºC, in agreement with literature data [11, 12]. Hydrolysis of compound 1 gives the corresponding
aniline which additionally confirms the correctness of structure 1.
NO2
NH2
NO2
NHCOMe
1
3
2
NH2
NH2
NHCOMe
.
2HCl
NH2
5
4
4-(1-Adamantyl)-1,2-diaminobenzene (4) was prepared from compound 1 by successive nitration,
hydrolysis, and reduction. In the nitration of adamantane 1 we used 58-60% HNO3 in place of 82% HNO3 [11,
12]. Nitration using a mixture of nitric and sulfuric acids in the presence of glacial acetic acid and acetic
anhydride gave the corresponding compound 2, hydrolysis of which led to the nitroaniline 3 [11, 12] and
hydrogenation gave compound 5. The reduction of 1-(4-amino-3-nitrophenyl)adamantane (3) was carried out in
several systems including Fe–NH4Cl, Fe–HCl, and SnCl2·2H2O–ethanol. The best result was obtained by
hydrogenation using molecular hydrogen in absolute ethanol in the presence of Raney nickel. Compound 4 was
converted to the dihydrochloride due to its susceptibility to oxidation.
NH2
.
2HCl
N
RCOOH
NH2
R
N
H
4
6–9
6 R = 1-Ad; 7 R = o-C6H4Cl; 8 R = p-C6H4Cl; 9 R = CH2OPh
Condensation of compound 4 with carboxylic acids was carried out via heating the reagents in the ratios
1: 5 and 1: 10 in order to prepare the novel 5(6)-(1-adamantyl)benzimidazoles 6-9.
The basic properties of compound 4 were greater than o-phenylenediamine due to the electron-donor
effects of an adamantyl radical. It is known [13] that heating o-phenylenediamine with adamantane carboxylic
acid at atmospheric pressure does not lead to cyclization to a benzimidazole whereas condensation of compound
4 gave the cyclization product 6 in 97% yield under the same conditions.
Condensation of compound 4 with aromatic acids occurs at high temperature, e.g. in the case of
p-chlorobenzoic acid at 230-240ºC.
942

Benzimidazolylcarbamates are widely used in the preparation of fungicide and antihelmintic
preparations but the majority of them show embriotoxic and teratogenic properties [14]. With the aim of
decreasing the possible appearance of similar side effects we have prepared the adamantyl-substituted
benzimidazolylcarbamate 10 [15].
ClCOOMe
4
N
C
NHCOOMe
N
CaNCN
pH 3, 95-100°C
pH 12, 35-40°C
NHCOOMe
N
H
10
5(6)-(1-Adamantyl)-2-methoxycarbonylaminobenzimidazole (10) was synthesized in two stages. The
optimum conditions found for the process were: stage 1, treatment of calcium cyanamide with methyl
chloroformate at 35-40ºC and pH 12; stage 2, reaction of the N-cyanomethylcarbamate with compound 4 at
90-100ºC and pH 3. The product 10 was obtained in 49% yield.
In order to study the mobility of the methylene group protons of the 5(6)-(1-adamantyl)-2-phenoxy-
methylbenzimidazole (9) we have condensed compound 9 with benzaldehyde at 175-179ºC and obtained the
product 11 in 50% yield.
N
CH2O
PhCHO
N
H
9
O
N
N
H
11
We have further studied the nitration reaction of 5(6)-(1-adamantyl)benzimidazole (12), the synthesis of
which has been described by us before [4]. The positive inductive effect of the adamantyl radical leads to an
increase in electron density in the corresponding ortho positions, i.e. in positions 4 and 6 of the benzimidazole
ring. This explains the formation of a mixture of isomers 13 and 14 as a result of the nitration reaction.
The nitration was performed at 30-35ºC with an experimentally established optimum ratio of the
reacting components benzimidazole-HNO3-H2SO4 of 1:2:6. The yield of the nitration products 13 and 14 was
95%. Recrystallization from ethanol gave the product 14 with Rf 0.67 in 90% yield. Using column
chromatography it was possible to separate the product 13 with Rf 0.79 in 4% yield.
Hydrogenation of the mixture of nitro products 13 and 14 in the presence of Raney nickel in absolute
ethanol and subsequent treatment with HCl gave the aminobenzimidazole dihydrochloride mixture in 30% yield.
Treatment of the latter with an aqueous solution of 10% NaOH gave a mixture of the bases. Multi-crystallization
from a mixture of chloroform and hexane gave the less soluble isomer 15 with Rf 0.46.
Mass spectroscopic and elemental analytical data (Table 1) confirmed the composition of the
compounds prepared. The structure of the products was confirmed by IR, UV, and 1H NMR data. The IR spectra
of compounds 6-15 showed absorption bands for the following groups: benzimidazole N–H at
943

NO2
N
N
H
N
HNO3/H2SO4
30-35°C
14
N
H
N
12
N
H
O2N
13
1) H2 , Ni
2) HCl
N
N
10% NaOH
.
2HCl
N
H
N
H2N
H2N
H
15
3460-3100, aromatic ring (Ar) C–H at 3085-3005, and adamantane (Ad) C–H at 2980-2820 cm-1. The IR
spectrum of compound 10 showed absorption bands for the ester carbonyl group at 1700 and 1650 and C–O–C
at 1270 and 1090 cm-1. The IR spectrum of compound 11 showed absorption bands typical of a vinyl C=C group
at 1640 as well as bands corresponding to (C=)C–H at 3060 and C–O–Ph at 1230 and 1200 cm-1. Bands typical
of a C–NO2 group were seen at 1520 and 1320 and at 1525 and 1330 cm-1 respectively in the IR spectra of
compounds 13 and 14. These bands are not observed in the reduction product 15 but absorption bands
characteristic of the NH2 group appear at 3490 and 3380 cm-1.
1
The H NMR spectra of compounds 6-11, 13-15 showed broadened singlet signals in the region
12.84-8.95 ppm for NH groups as well as signals in the form of singlets, doublets, double doublets, and
multiplets typical of benzimidazole and benzene rings protons at 8.28-6.85 ppm while multiplets were observed
in the region 2.17-1.70 ppm characteristic of adamantyl radical protons. In compound 7 the proton ortho to the
chlorine atom appears as a double doublet at 8.26 ppm, the two benzimidazole ring protons H-4 and H-7 as a
broadened singlet and doublet at 7.66 and 7.65 ppm, and the H-4',5',6' and H-6 are seen as a multiplet at
7.45-7.29 ppm. In compound 8 the four benzene ring protons H-3',5' and H-2',6' occur as two double doublets at
8.16 and 7.61 ppm respectively, the benzimidazole ring H-7 proton as a doublet at 7.58 ppm, and the H-4 and
H-6 signals as multiplets at 7.47-7.24 ppm (DMSO-d6). In the spectrum recorded in CDCl3 the H-6 proton
appears as a double doublet at 7.36 ppm with J6,7 = 8.6 and J6,4 = 1.2 Hz. Compound 9 shows two phenyl group
protons H-2' and H-6' as double doublets at 7.33 ppm with the remaining three phenyl group protons as a
multiplet at 7.05-7.03 ppm. The benzimidazole protons H-4, H-6, and H-7 are seen as a multiplet at 7.29-7.25
ppm respectively while the methylene group protons are observed as a singlet at 5.75 ppm. The benzimidazole
ring H-4 and H-7 protons for compound 10 appear as doublets at 7.54 and 7.48 ppm and H-6 as a double doublet
at 7.42 ppm while the three CH3 group protons occurred as a singlet at 3.93 ppm. The three benzimidazole ring
protons and ten phenyl group protons in compound 11 occur as multiplets at 7.78-7.48 and 7.46-6.99 ppm while the
vinyl group proton is seen as a broadened singlet at 6.54 ppm. In the minor nitration product 13 the H-2 proton
appears as a singlet at 8.22 ppm and the H-7 and H-4 protons as double doublets at 8.28 and 8.20 ppm respectively
with spin-spin coupling J4,7 = 1.6 Hz and so indicate that the nitro group substitutes position 6. In nitration product
14 the H-2 proton is a singlet at 8.17 ppm and the H-7 and H-6 protons are two doublets at 8.15 and 7.76 ppm with
a spin-spin coupling of J6,7 = 11 Hz inferring that the nitro group occurs in position 4. On the
944

basis of this data we can conclude that, as in the case of 5(6)-hydroxybenzimidazole [16], the nitration of 5(6)-(1-
adamantyl)benzimidazole (12) occurs principally at the benzimidazole ring 4 position to form compound 14 (in
90% yield). In compound 15 the H-2, H-4, and H-7 protons appear as singlets at 7.91, 7.53, and 6.85 ppm
respectively.
13
The C NMR spectra of compounds 6-11, 13-15 show signals typical of benzimidazole and benzene
ring carbon atoms at 95.0-161.0 ppm and four peaks characteristic of the adamantyl radical in the region
28.2-43.8 ppm, of which three signals correspond to nine carbon atoms and one signal to the carbon atom bound
to the benzimidazole. Because of the presence of two adamantyl radicals in compound 6 eight signals
characteristic of an adamantyl radical are observed at 28.2 (3C), 29.1 (3C), 35.3 (1C), 36.3 (1C), 36.5 (3C), 36.9
(3C), 41.5 (3C), and 43.8 ppm (3C). Compound 9 shows the absorption bands for the adamantyl radical (29.0, 36.3,
36.8, 43.6 ppm) together with a signal typical of a CH2 carbon atom (64.42) ppm and signals in the region 114.6-
157.6 ppm for the carbon atoms of the benzimidazole and benzene rings. Compound 10 shows the adamantyl
radical signals (28.3, 35.8, 36.1, 43.0 ppm), the CH3 group carbon peak at 53.1 ppm, and a peak at 153.8 ppm
assigned to the C=O carbonyl group carbon.
The UV absorption spectra of compounds 7, 8, 11 show absorption bands which typify benzimidazole
derivatives with λmax 204-212, 230-249, 253-265, and 301-335 nm.
The anti HIV and antitumor activities of compounds 7-9 were studied in the National Cancer Institute
(Bethesda, Maryland, USA). The anti HIV activity was determined on 60 different lines in 9 cancer tissue types.
The antitumor activity was studied to find compounds affecting the reproductive cycle of the AIDS virus.
TABLE 1. Characteristics of the Compounds Synthesized
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
M, g/mol
m/z*
С
H
N
1
2
3
C18H23NO
79.96
80.25
68.96
68.77
70.44
70.56
60.95
60.46
8.83
8.61
7.35
7.05
7.30
7.40
7.67
8.43
5.50
5.20
8.99
8.91
10.40
10.29
8.88
8.59
269.39
314.39
272.35
315.29
269
314
—
C18H22N2O3
C16H20N2O2
4
·
2HCl C16H24Cl2N2
242
(–2HCl)
284
5
6
7
8
9
C18H24N2O
C27H34N2
75.62
76.02
83.98
83.89
76.55
76.12
75.95
76.12
80.38
80.41
70.53
70.13
83.46
83.40
68.42
68.67
8.54
8.51
9.51
8.86
6.36
6.39
5.81
6.39
7.38
7.31
6.99
7.12
6.79
6.77
6.72
6.44
9.93
9.95
7.18
7.25
8.21
7.72
7.36
7.72
7.83
7.81
12.59
12.91
6.44
6.27
13.78
14.13
284.41
386.58
362.90
362.90
358.49
325.41
446.59
297.36
297.36
267.38
386
362
362
—
C23H23ClN2
C23H23ClN2
C24H26N2O
10
11
13
14
15
C19H23N3O2
C31H30N2O
C17H19N3O2
C17H19N3O2
C17H21N3
325
446
297
297
—
68.33
68.67
76.59
76.37
6.56
6.44
7.87
7.90
13.99
14.13
15.85
15.72
_______
* Values of m/z for the molecular ions [M+·] according to electron impact
mass-spectrometric data.
945

The analysis was based on the death of T-4 lymphocytes induced by the human AIDS virus. Compound 7 proved
inactive but 5(6)-(1-adamantyl)-2-(4-chlorophenyl)benzimidazole (8) and 5(6)-(1-adamantyl)-2-phenoxymethyl-
benzimidazole (9) showed weak in vitro cytostatic activity and suppressed the capability of the HIV
reproductive cycle.
The results obtained point to the promise of further, targeted synthesis of benzimidazoles with
adamantane substituents.
EXPERIMENTAL
The course of the reaction and purity of the substances was monitored by TLC on Silufol UV-254 plates
using acetone–CCl4 as eluent and revealed using iodine vapor. silica gel with particle size 100-400 µm was used
as sorbent for column chromatography. IR spectra were taken on a Specord IR-75 spectrophotometer using
1
hexachlorobutadiene or vaseline oil and UV spectra on a Specord UV-vis spectrometer using ethanol. H NMR
and 13C NMR spectra were recorded on Bruker-400, Varian UNITY-400 (400 and 100 MHz respectively)
(compounds 9 and 13) and Tesla BS 567A (100 MHz) spectrometers (compounds 1,2,4,5 and 14). The internal
standard was HMDS for compounds 1 and 2, and TMS for compounds 4-15. Mass spectra were taken on a
Ribermag 10-10-B spectrometer with electron impact ionization and electron ionization energy of 70 eV.
Melting points were measured on a Boetius apparatus with a PHMKO5 visual attachment.
1-Bromoadamantane from the Swiss company Fluka AG (CH-9470 Buchs) was used as the starting
material.
1-(4-Acetamidophenyl)adamantane (1) was prepared by method [10] in 80% yield with mp 197-199ºC
(ethanol); Rf 0.38 (acetone–CCl4, 1:3). IR spectrum (thin film), ν, cm-1: 3295, 3180, 3100 (NH), 3050 (C–H Ar),
2980-2850 (Ad), 1650 (C=O). 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 7.76 (1H, s, NH); 7.37, 7.20 (4H, dd,
3
3
4
4
AA'BB', C6H4, J2,3 = J5,6 = 8.7, J2,6 = J3,5 = 3.3); 2.06 (3H, s, CH3); 2.05-1.69 (15H, m, Ad). 13C NMR
spectrum (CDCl3), δ, ppm: 24.2, 28.8, 35.8, 36.7, 43.1, 119.9, 125.2, 135.3, 147.5, 168.4
1-(4-Acetamido-3-nitrophenyl)adamantane (2). A nitrating mixture prepared from 59% HNO3 (20 ml,
380 mmol) and 95% H2SO4 (105 ml, 1860 mmol) was added dropwise to a cooled mixture of the amide 1 (50 g,
190 mmol), glacial acetic acid (100 ml), and acetic anhydride (40 ml). The mixture was stirred at room
temperature for 12 h and poured into iced water. The precipitate was filtered off, washed with water to neutral
reaction, and dried to give lemon colored crystals (52.2 g, 90%) with mp 212-214ºC (benzene–ethanol) and
Rf 0.81 (acetone–CCl4, 1: 3). IR spectrum (thin film), ν, cm-1: 3350 (NH), 3090, 3030 (C–H Ar), 2980-2840
1
(Ad), 1700 (C=O), 1580, 1330 (C–NO2). H NMR spectrum (CDCl3), δ, ppm (J, Hz): 10.13 (1H, s, NH); 8.58
3
4
3
4
(1H, d, J5,6 = 8.8, H-5); 8.07 (1H, d, J2,6 = 2.4, H-2); 7.59 (1H, dd, J6,5 = 8.8, J6,2 = 2.4, H-6); 2.21 (3H, s,
13
CH3); 2.06-1.71 (15H, m, Ad). C NMR spectrum (CDCl3), δ, ppm: 25.3, 28.6, 35.9, 36.4, 42.7, 121.7, 122.0,
132.3, 132.8, 136.4, 147.1, 168.4.
1-(4-Amino-3-nitrophenyl)adamantane (3). Yield 89%; mp 224-226ºC (benzene–ethanol, 1:1), (mp
218-219 [11] and 222-224ºC [12]).
4-(1-Adamantyl)-1,2-diaminobenzene Dihydrochloride (4). A solution of compound 3 (10.57 g,
39 mmol) in absolute ethanol (100 ml) was hydrogenated over 12 h at 18ºC (730 mm Hg) in the presence of Raney
nickel. The mixture was filtered and the filtrate was treated with ethanol saturated with HCl to pH 1. The mixture
was held for 1 day and white crystals were precipitated with dry ether, filtered off, washed with ether, and dried.
Yield 12 g (98%); mp 258-260 (ethanol–ether) and 266-267ºC (ethanol). The dihydrochloride 4·2HCl
was treated with a 10% solution of NaOH to give the 4-(1-adamantyl)-1,2-diaminobenzene 4 as white crystals with
mp 135-137ºC, unstable in air. Rf 0.42 (acetone–CCl4, 1:3). IR spectrum (thin film), ν, cm-1: 3400, 3290, 3230,
1625 (NH2), 3040 (C–H Ar), 2990-2850 (Ad), 1275 (C–N). UV spectrum (EtOH), λmax, (log ε): 211 (4.28).
1H NMR spectrum (CD3OD), δ, ppm (J, Hz): 7.67-7.57 (3H, m, C6H5); 5.27 (4H, s, 2 NH2); 2.20-1.80 (15H, m, Ad).
946

1-(4-Acetamido-3-aminophenyl)adamantane (5). A solution of nitroamide 2 (2.62 g, 8 mmol) in
absolute ethanol (80 ml) was hydrogenated using molecular hydrogen at 21ºC for 6 h (736 mm Hg) in the
presence of Raney nickel. The precipitate was filtered off, dissolved in benzene, and the solution was evaporated
to give 1.92 g (81%) of crystals with mp 228-230ºC (benzene–ethanol) and Rf 0.61 (acetone–CCl4, 1:1). IR
spectrum (thin film), ν, cm-1: 3380, 3310, 3220 (NH2), 3160, 3110 (NH), 3040 (C–H Ar), 2980-2840 (C–H Ad),
1650 (C=O). 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 8.89 (1H, br. s, NH); 7.16 (1H, d, 3J5,6 = 8.2, H-5);
4
3
4
6.83 (1H, d, J2,6 = 2.1, H-2); 6.64 (1H, dd, J6,5 = 8.2, J6,2 = 2.1, H-6); 3.18 (2H, s, NH2); 2.09 (3H, s, CH3);
2.07-1.80 (15H, m, Ad).
2,5(6)-Di(1-adamantyl)benzimidazole (6). A mixture of compound 4 (1 g, 3.17 mmol) and adamantane
carboxylic acid (5.4 g, 30 mmol) was heated at 195-200ºC for 2 h. The mixture was cooled, poured into iced
water, and treated with a 10% solution of NaOH to pH 10. The precipitate was held in a basic medium until full
conversion of excess acid to AdCOONa. The precipitate was then filtered, washed with water to neutral pH and
dried. Yield 1.19 g (96%); mp 272-275ºC, crystals melting and again melting at 282-284ºC (chloroform–
hexane), Rf 0.44 (acetone–CCl4, 1:1). IR spectrum (thin film), ν, cm-1: 3200-3100 (NH), 3040 (C–H Ar), 2980-
2840 (Ad). Hydrochloride mp 335-336ºC (ethanol). 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 8.95 (1H, br. s,
3
4
NH); 7.73-7.33 (2H, m, H-4,7); 7.28 (1H, dd, J6,7 = 8.4, J6,4 = 1.2, H-6); 2.17-2.05 (12H, m, Ad); 2.02-1.91
13
(6H, m, Ad); 1.85-1.74 (12H, m, Ad). C NMR spectrum (CDCl3), δ, ppm: 28.2, 29.1, 35.3, 36.3, 36.5, 36.9,
41.5, 43.8, 119.6, 122.8, 126.9, 140.2, 142.5, 146.0, 161.8.
5(6)-(1-Adamantyl)-2-(2-chlorophenyl)benzimidazole (7). A mixture of the diamine dihydrochloride
4 (3.15 g, 10 mmol) and o-chlorobenzoic acid (7.85 g, 50 mmol) was heated for 2 h at 170-180ºC. The mixture
was cooled, iced water was added, and the product was treated with 10% aqueous NaOH solution to pH 10. The
precipitate was filtered off, washed initially with 10% NaOH and then water to neutral reaction, and dried. The
yield of dry product was 3.35 g (93%). Recrystallization from a mixture of ethanol and water gave creamish
colored crystals (2.6 g, 72%). Column chromatography using chloroform eluent gave white crystals with mp
284-285ºC (chloroform–hexane), Rf 0.84 (acetone–CCl4, 1:1). IR spectrum (thin film), ν, cm-1: 3400 (NH), 3050
(C–H Ar), 2980-2840 (Ad), 790, 750 (C–Cl). UV spectrum (EtOH), λmax, nm (log ε): 211 (4.68), 246 (4.22), 301
(4.25). 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 10.12 (1H, br. s, NH); 8.26 (1H, dd, 3J3',4' = 8.5, 4J3',5' = 4.3,
H-3'); 7.66 (1H, br. s, H-4); 7.65 (1H, d, 3J7,6 = 9.3, H-7); 7.45-7.29 (4H, m, H-4',5',6',6); 2.16-2.07 (3H, m, Ad);
2.01-1.89 (6H, m, Ad); 1.86-1.71 (6H, m, Ad). 13C NMR spectrum (CDCl3), δ, ppm: 29.0, 36.5, 36.8, 43.6,
100.0, 114.8, 121.7, 127.1, 127.5, 130.7, 131.3, 131.4, 132.2, 147.9, 148.0.
5(6)-(1-Adamantyl)-2-(4-chlorophenyl)benzimidazole (8). A mixture of the diamine dihydrochloride
4 (3.15 g, 10 mmol) and p-chlorobenzoic acid (7.85 g, 50 mmol) was heated for 2 h at 230-240ºC. The mixture
was cooled, iced water was added and the product was treated with 10% NaOH solution to pH 10. The
precipitate was filtered off, washed with 10% NaOH and water to neutral reaction, and dried. Yield of dry
product 3.32 g (91%). Recrystallization from a mixture of ethanol and water gave creamish colored crystals
(2.9 g, 80%). Column chromatography with chloroform eluent gave white crystals with mp 173-175ºC
(chloroform–hexane), Rf 0.91 (acetone–CCl4, 1:1). IR spectrum (thin film), ν, cm-1: 3460 (NH), 3150 (C–H Ar),
2980-2840 (Ad), 820, 780 (C–Cl). UV spectrum (EtOH), λmax, nm (log ε): 204 (4.62), 230 (4.2), 249 (4.09), 314
1
(4.28), 328 sh (4.19). H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 12.84 (1H, s, NH); 8.16 (2H, dd,
3J3',2' = 3J5',6' = 8.5, 4J3',5' = 2.0, H-3',5'); 7.61 (2H, dd, 3J2',3' = 3J6',5' = 8.5, 4J2',6' = 2.0, H-2',6'); 7.58 (1H, d, 3J7,6 = 8.6,
13
H-7); 7.47-7.24 (2H, m, H-6,4); 2.12-2.04 (3H, m, Ad); 1.98-1.91 (6H, m, Ad); 1.81-1.71 (6H, m, Ad). C NMR
spectrum (DMSO-d6), δ, ppm: 28.4, 35.7, 36.2, 43.0, 106.9, 110.6, 114.6, 118.3, 119.3, 127.9, 129.0, 135.0, 143.8,
149.8.
5(6)-(1-Adamantyl)-2-phenoxymethylbenzimidazole (9). A mixture of the diamine dihydrochloride 4
(1.55 g, 4.92 mmol) and phenoxyacetic acid (3.8 g, 25 mmol) was heated for 3 h at 140-145ºC. The mixture was
cooled and 10% NaOH solution was added to pH 10. The precipitate was held in alkaline medium for
conversion of the excess acid to the sodium salt. The principitate was filtred off, washed with water to neutral
947

reaction. Yield 1.75 g (99%); mp 223-224ºC (methanol), Rf 0.69 (acetone–CCl4, 1:1). IR spectrum (thin film),
ν, cm-1: 3250-3100 (NH), 3040 (C–H Ar), 2960-2840 (C–H Ad), 1230, 1040 (C–O–C). 1H NMR spectrum (CDCl3),
3
3
4
δ, ppm (J, Hz): 7.50 (1H, br. s, NH); 7.33 (2H, dd, J2',3' = J6',5' = 8.8, J2',6' = 1.6, H-2',6'); 7.29-7.25 (3H, m,
13
H-4,6,7); 7.05-7.03 (3H, m, C6H5); 5.75 (2H, s, CH2); 2.17-1.71 (15H, m, Ad). C NMR spectrum (CDCl3), δ,
ppm: 29.0, 36.3, 36.8, 43.6, 64.2, 114.6, 120.3, 121.8, 129.7, 144.0, 150.0, 157.6.
5(6)-(1-Adamantyl)-2-(methoxycarbonylamino)benzimidazole (10). KOH solution (10%, 25 ml) was
added to technical 38% CaNCN (8.4 g, 3.2 g, 40 mmol). The mixture was cooled and methyl chloroformate
(3.78 g, 40 mmol) was added dropwise with stirring. The mixture was stirred for 30 min at pH 12 and 35-40ºC,
filtered, and the precipitate was washed with distilled water (10 ml). The filtrate and water wash were poured
into a round bottomed flask, acidified with conc. HCl to pH 3, and compound 4 (4.8 g, 20 mmol) was added
portionwise. The mixture was heated for 3 h at 95-100°C, periodically conc. HCl was added to keep pH 3. The
mixture was then cooled, filtered, and the precipitate was washed with hot water, acetone, and ether, and dried.
Yield 3.16 g (49%). For purification it was converted to the hydrochloride and then again to the base,
mp > 330ºC with decomposition (chloroform). Hydrochloride mp > 350ºC with decomposition. Rf 0.81
(acetone–CCl4, 1:1). IR spectrum (thin film), ν, cm-1: 3380 (NH), 3070, 3020 (C–H Ar), 2980-2830 (C–H Ad),
1
4
1700, 1650 (C=O), 1275, 1090 (C–O–C). H NMR spectrum (CDCl3), δ, ppm (J, Hz): 7.54 (1H, d, J4,6 = 1.5,
H-4); 7.48 (1H, d, 3J7,6 = 8.5, H-7); 7.42 (1H, dd, 3J6,7 = 8.5, 4J6,4 = 1.5, H-6); 6.05 (2H, br. s, 2 NH); 3.93 (3H, s,
CH3); 2.17-2.09 (3H, m, Ad); 1.96-1.88 (6H, m, Ad); 1.86-1.72 (6H, m, Ad). 13C NMR spectrum (DMSO-d6), δ,
ppm: 28.3, 35.8, 36.1, 43.0, 53.1, 99.4, 109.0, 112.7, 120.3, 138.7, 139.8, 146.4, 153.8.
5(6)-(1-Adamantyl)-2-(1-phenoxy-2-phenylvinyl)benzimidazole (11). A mixture of compound 9
(0.5 g, 1.4 mmol) and benzaldehyde (4 ml, 39 mmol) was heated for 5 h at 175-179ºC. The mixture was cooled,
dissolved in ether (50 ml), and treated with saturated NaHCO3 solution. The ether was washed with water to
neutral reaction, dried over Na2SO4, and evaporated. The residue was washed with hexane and then
recrystallized from hexane. Yield 0.32 g (50%); mp 246-248ºC (hexane), Rf 0.63 (acetone–CCl4, 1:1).
IR spectrum (thin film), ν, cm-1: 3280 (NH), 3060, 3040 (C–H Ar), 2950, 2895, 2840 (C–H Ad), 1640 (C=C),
1
1230, 1200 (C–O–Ph). UV spectrum, λmax, nm (log ε): 208 (4.67), 265 (4.15), 332 (4.49). H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 9.23 (1H, br. s, NH); 7.78-7.48 (3H, m, C6H5); 7.46-7.19 (7H, m, C6H5); 7.19-6.99 (3H, m,
C6H5); 6.54 (1H, s, =CH); 2.17-2.05 (3H, m, Ad); 2.04-1.86 (6H, m, Ad); 1.83-1.73 (6H, m, Ad). 13C NMR spectrum
(CDCl3), δ, ppm: 29.0, 36.7, 36.8, 43.6, 115.2, 123.0, 128.5, 128.7, 129.8, 130.2, 133.3, 133.6, 144.0, 159.2
5(6)-(1-Adamantyl)-6(5)-nitrobenzimidazole (13) and 5(6)-(1-Adamantyl)-4(7)-nitrobenzimidazole
(14). A nitrating mixture prepared from 59% HNO3 (0.25 ml, 3 mmol) and conc. H2SO4 (0.5 ml, 9 mmol) was
added dropwise with stirring and cooling to 5(6)-(1-adamantyl)benzimidazole (12) (0.39 g, 1.5 mmol). The
mixture was stirred for 4 h at 30-35ºC and poured into iced water. The precipitate was filtered off, washed with
water to neutral reaction, and dried. Yield of the mixture of the two isomers 13 and 14 0.44 g (95%).
Recrystallization from ethanol gave compound 14 (0.41 g, 90%) with mp 242-244ºC (ethanol), Rf 0.67 (acetone–
CCl4, 1:1). Compound 13 remained in the filtrate. The ethanol was evaporated to dryness and the residue was
column chromatographed using chloroform eluent to give the nitro product 13 (0.018 g, 3.98%) with mp
333-335ºC (chloroform–hexane), Rf 0.79 (acetone–CCl4, 1:1). Compound 13. IR spectrum (thin film), ν, cm-1:
3300-2700 (NH), 3085, 3025 (C–H Ar), 2950, 2900, 2845 (C–H Ad), 1525, 1330 (C–NO2). 1H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 8.28 (1H, d, 4J7,4 = 1.6, H-7); 8.22 (1H, s, H-2); 8.20 (1H, d, 4J4,7 = 1.6, H-4); 2.17-1.70
13
(15H, m, Ad). C NMR spectrum (CDCl3), δ, ppm: 28.8, 36.5, 43.5, 94.4, 117.4, 118.6, 124.7, 134.0, 141.5,
142.4. Compound 14. IR spectrum (thin film), ν, cm-1: 3390 (NH), 3100, 3040 (C–H Ar), 2980-2840 (C–H
Ad), 1520, 1320 (C–NO2). 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 10.6 (1H, br. s, NH); 8.17 (1H, s, H-2);
8.15 (1H, d, 3J7,6 = 11, H-7); 7.76 (1H, d, 3J6,7 = 11, H-6); 2.14-1.70 (15H, m, Ad).
5(6)-(1-Adamantyl)-6(5)aminobenzimidazole (15). A solution of the mixture of nitro products 13 and
14 (1.12 g, 3.7 mmol) in absolute ethanol (80 ml) was hydrogenated for 4 h at 20ºC (729 mm Hg) in the
presence of Raney nickel. The mixture was filtered and ethanol was added saturated with HCl to pH 1. The
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product was held for 1 day and crystals were precipitated with dry ether, washed with ether, and dried. Yield
0.38 g (30%); mp > 350ºC. The dihydrochloride was treated with 10% NaOH solution to liberate the products as
their free bases to give a mixture of the aminobenzimidazoles (0.27 g) with mp 230-235ºC. After repeated
recrystallizations the less soluble isomer 15 was obtained; mp 254-256ºC, the melt crystallizing and again
melting at 264-266ºC (chloroform–hexane), Rf 0.46 (acetone–CCl4, 1:1). IR spectrum (thin film), ν, cm-1: 3490,
3380 (NH2), 3120 (NH), 3075, 3020 (C–H Ar), 2960, 2910, 2850 (C–H Ad), 1625 (NH deformation). 1H NMR
spectrum (CDCl3), δ, ppm: 7.91 (1H, s, H-2); 7.53 (1H, s, H-4); 6.85 (1H, s, H-7); 4.22 (2H, br. s, NH2);
13
2.17-2.09 (9H, m,Ad); 1.83-1.75 (6H, m, Ad). C NMR spectrum (DMSO-d6), δ, ppm: 28.4, 36.3, 39.9, 99.4,
113.0, 129.0, 130.6, 133.4, 139.3, 142.8.
The authors express their thanks to the Georgian Ministry of Education and Science (Project No. 94),
the Georgian Science Fund (grant no. GNSF/ST07/4-181), and the German Research Society (DFG) for
financial support and we also express our thanks to the German Department for Academic Exchange (DAAD)
for supporting the collaboration and program exchange between the Iv. Dzhavakhishvili State University, Tbilisi
and the Saarland University (Germany).
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