The Synthesis of Adamantane Ring Containing Benzimidazole, Benzoxazole, and Imidazo[4,5-e]benzoxazole Derivatives from 3-Aminophenol

Article abstract of DOI:10.1002/jhet.3062

Adamantane derivatives containing heterocycles such as benzimidazoles, benzoxazoles, and fused imidazo[4,5-e]benzoxazoles were synthesized from 3-aminophenol. The route started with amidation of adamantane-1-carboxylic acid chloride with 3-aminophenol fur

Full text of DOI:10.1002/jhet.3062

Month 2017
The Synthesis of Adamantane Ring Containing Benzimidazole,
Benzoxazole, and Imidazo[4,5-e]benzoxazole Derivatives from
3-Aminophenol
a
Marina Soselia,
Irina Geibel,b Davit Zurabishvili,a and Shota Samsoniyaa
*
aFaculty of Exact and Natural Sciences, Ivane Javakhishvili Tbilisi State University, I. Chavchavadze Avenue 3, 0179
Tbilisi, Georgia
bInstitut für Chemie, Universität Oldenburg, Carl-von-Ossietzky-Street 9-11, 26111 Oldenburg, Germany
*
E-mail: marina.soselia@tsu.ge
Received July 30, 2017
DOI 10.1002/jhet.3062
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
Adamantane derivatives containing heterocycles such as benzimidazoles, benzoxazoles, and fused
imidazo[4,5-e]benzoxazoles were synthesized from 3-aminophenol. The route started with amidation of
adamantane-1-carboxylic acid chloride with 3-aminophenol furnishing N-(3-hydroxyphenyl)adamantane-
1-carboxamide. Subsequent nitration gave three regioisomers. After reduction of the nitro groups, the respec-
tive aniline derivatives were used in the formation of benzimidazole and benzoxazole rings. The cyclization
of the 2-substituted benzoxazole ring was performed using two methods: via condensation of N-(2-amino-3-
hydroxyphenyl)adamantane-1-carboxamide with carbonitriles in the presence of a Lewis acid or via Cu(II)-
catalyzed oxidative coupling of aminophenol with aromatic aldehydes. The benzimidazole ring formed by
acid-catalyzed cyclization of N-(2-amino-5-hydroxyphenyl)adamantane-1-carboxamide was then converted
to a tricyclic system after three synthetic steps.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
many other properties [7]. For example, amino
adamantanes like rimantadine and amantadine (Fig. 1)
were among the first drugs that were used for the
treatment and prevention of viral diseases by inhibition of
the influenza proteins, thereby preventing the release of
infectious viral nucleic acids into the cell. Furthermore,
bromantane and kemantane act as psychoanaleptics,
restoring functional activity of the nervous and immune
systems and thus enhancing physical and mental
functions. Midantane (amantadine hydrochloride), for
instance, is effective for treatment of neurodegenerative
disorders like Parkinson’s disease, Alzheimer’s disease, or
disseminated sclerosis [8,9]. Recently, adamantane was
identified as a key subunit in some synthetic cannabinoid
designer drugs like APICA (SDB-001), an indole-based
adamantane performing as a potent cannabinoid receptor
agonist [10].
Benzo-fused nitrogen and oxygen-containing heterocycles
such as benzimidazoles [1–3] and benzoxazoles [4,5] are
distinguished by a broad spectrum of high bioactivity,
and therefore, they are interesting compounds for
medicinal chemistry. These important pharmacophores are
contained in
a vast number of biologically active
compounds that are used in agriculture and medicine.
Novel-fused tricyclic compounds like 8H-imidazo[4,5-e]
[1,3]benzoxazole are also of great interest, and their
MPGES-1 enzyme selective inhibitor properties were
patented [6]. Diseases associated with hormonal, nervous,
and immune system disorders are usually cured by
membranotropic drugs such as adamantane-containing
medicaments. The main features based on an adamantane
moiety are the low toxicity and the variety of biological
activities, including anti-viral, immunotropic, psychotropic,
anti-cancer, analgesic, anticonvulsant, detoxifying, and
The adamantane moiety, besides of its wide range of
biological activity, is featured with properties improving
© 2017 Wiley Periodicals, Inc.

M. Soselia, I. Geibel, D. Zurabishvili, and S. Samsoniya
Vol 000
adamantane-containing heterocycles. We wish to report
herein on the preparation of benzimidazoles,
benzoxazoles, and fused imidazo[4,5-e]benzoxazoles
from 3-aminophenol.
RESULTS AND DISCUSSION
Our approach to synthesize the benzoxazoles 7a–j
started with the conversion of 1-adamantane carboxylic
acid to the corresponding acid chloride and the reaction
of this intermediate product with 3-aminophenol giving
N-(3-hydroxyphenyl)adamantane-1-carboxamide (1) in 80%
yield according to a known procedure (Scheme 1) [17].
The subsequent nitration with 65% nitric acid in acetic
acid furnished three regioisomers, the ortho-isomers 2a
(3%) and 2b (40%) as well as the para-isomer 2c (30%),
which were separated by column chromatography.
Reduction of the nitro groups of 2b and 2c afforded
aminoamides 3b (91%) and 3c (95%). The aminophenol
moiety of 3b was utilized for cyclization to the
benzoxazoles 7a–j using two methods with yields up to
76% (Table 1). Initially, the Cu(II)-catalyzed, oxidative
coupling reactions [18] of 3b with acetic anhydride 4 (7a,
entry 1) and diverse aldehydes 5 (7b–g, entries 2–7) were
investigated. While the yields of the reaction with acetic
anhydride (entry 1, 7a, 16%), 4-methoxybenzaldehyde 5f
(entry 7, 7g, 15%) and 3,4-dimethoxybenzaldehyde 5c
(entry 4, 7d, 7%) were low, the results with benzaldehyde
5a (entry 2, 7b, 50%), with 4-isopropylbenzaldehyde 5b
(Entry 3, 7c, 32%) and the 4-bromo-substituted
benzaldehyde 5e (entry 6, 7f, 39%) as well as with
Figure 1. Selected examples of biologically active adamantane
derivatives.
the biological characteristics of the medication enhancing
the drug’s prolonged action and at the same time reducing
toxicity and side negative effects [11]. Introducing the
bulky, high lipophilic adamantane ring system into the
compound provokes an increase of its lipophilicity and
stability and improves its pharmacokinetics. Therefore,
interaction of the lipophilic adamantane with the lipid
layer of cell membranes enhances the permeability and
thus facilitates the drug’s ability to penetrate into the
cells [12].
Considering the unique properties of adamantanyl
moieties, there are already many biological studies of
adamantane-containing benzimidazoles that revealed anti-
virus [13], anti-obesity [14], anti-tumor [15], anti-allergy,
and anti-asthma [16] activities. However, compounds of
benzoxazoles as well as tricyclic ring systems involving
an adamantane motif are insufficiently investigated.
Consequently, there is an ongoing need to establish
synthetic methodologies for the construction of different
Scheme 1. Preparation of benzoxazoles 7a–j. Reagents and conditions: (a) 1) SOCl2, 60°C, 30 min; 2) Et3N, CH2Cl2, 23°C, 3 h. (b) 1.3 equiv HNO3,
AcOH, 23°C, 1 h; (c) Pt/C (cat.), 1 atm H2, EtOH, 23°C, 24–32 h; (d) 2.0 equiv Ac2O (4), Cu(OAc)2 · H2O (cat.), toluene, 110°C, air, 7 h; (e) 1.0 equiv
aldehyde 5a–f, Cu(OAc)2 · H2O (cat.), toluene, 110°C, air, 16–20 h; (f) 1.0 equiv carbonitrile 6a–c, ZnCl2 (cat.), PhCl, 135°C, inert atmosphere (N2), 24 h.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
The Synthesis of Adamantane Ring Containing Benzimidazole, Benzoxazole, and
Imidazo[4,5-e]benzoxazole Derivatives from 3-Aminophenol
Table 1
Scope and yields of the synthesis of products 7a–j and 11a–b.
Entry
Starting material
Acetic anhydride
Method
Product (R)
Yielda (%)
1
2
3
4
5
6
7
8
4
(d)
(e)
(e)
(e)
(e)
(e)
(e)
(f)
(f)
(f)
(g)
(g)
7a
7b
7c
7d
7e
(Me)
(Ph)
16
50
32
7
53
39
15
17
76
19
11
9
5a
5b
5c
5d
5e
5f
6a
6b
6c
5a
5f
Benzaldehyde
4-Isopropylbenzaldehyde
3,4-Dimethoxybenzaldehyde
Thiophene-2-carbaldehyde
3-Bromobenzaldehyde
4-Methoxybenzaldehyde
4-Bromobenzonitrile
Terephthalodinitrile
3-Methoxypropionitrile
Benzaldehyde
(4-iPrC6H4)
[3,4-(MeO)2C6H4]
(2-thienyl)
(3-BrC6H4)
(4-MeOC6H4)
(4-BrC6H4)
(4-NCC6H4)
(2-MeOC2H4)
(Ph)
7f
7g
7h
7i
7j
11a
11b
9
10
11
12
4-Methoxybenzaldehyde
(4-MeOC6H4)
aYields of isolated products after chromatographic purification.
thiophene-2-carbaldehyde 5d (entry 5, 7e, 53%) were
moderate, but yet preparative useful. The results could not
be significantly improved by switching the method to the
condensation of 3b with carbonitriles 6 in the presence of
the Lewis acid ZnCl2 (7h–j, entries 8–10) [19]. Only the
utilization of terephthalodinitrile 6b gave a good yield of
76% (entry 9, product 7i).
cyclization using trifluoroacetic acid in toluene
(Scheme 2). The nitration of compound 8 gave three nitro
products, 9a–c, with the mono nitrated 9a (44%) being
the main product of this reaction. After reduction of the
nitro group in 9a to the aminophenol 10 (99%),
compound 10 was coupled with aromatic aldehydes 5a
and 5f, catalyzed by Cu(OAc)2 · H2O [18], to provide
access to the tricyclic systems (Table 1, entries 11 and
12), products 11a (11%) and 11b (9%)] with an
imidazo[4,5-e]benzoxazole moiety.
While isomer 3b was applied in the synthesis of
benzoxazoles 7, isomer 3c was converted to
benzimidazole
8 in 99% yield by acid-catalyzed
Scheme 2. Preparation of benzimidazole 5 and imidazo[4,5-e]benzoxazoles 8a and 8b. Reagents and conditions: (a) CF3COOH, toluene, 110°C, 11 h;
(b) 1.0 equiv HNO3, AcOH, 23°C, 30 min; (c) Pd/C (cat.), 1 atm H2, EtOH, 23°C, 1 d; (g) 2.6 equiv aldehyde 5a or 5f, Cu(OAc)2 · H2O (cat.), toluene,
110°C, air, 9–15 h.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Soselia, I. Geibel, D. Zurabishvili, and S. Samsoniya
Vol 000
Table 2
Pa and Pi values for the renal disease treatment activity of compounds 11a–b and their structural analogs.
Renal disease treatment
Entry
Compound name
Pa
Pi
1
2
3
4
5
6
7
8
9
10
11
12
13
14
11a
11b
7-(1-Adamantyl)-2-phenyl-6H-imidazo[4,5-e]benzoxazole
7-Cyclohexyl-2-phenyl-6H-imidazo[4,5-e]benzoxazole
7-Methyl-2-phenyl-6H-imidazo[4,5-e]benzoxazole
2-Phenyl-6H-imidazo[4,5-e]benzoxazole
7-Isopropyl-2-phenyl-6H-imidazo[4,5-e]benzoxazole
2,7-Diphenyl-6H-imidazo[4,5-e]benzoxazole
0.882
0.392
0.630
0.451
0.526
0.537
0.677
0.810
0.350
0.540
0.398
0.468
0.459
0.520
0.003
0.008
0.004
0.005
0.011
0.007
0.004
0.003
0.011
0.004
0.008
0.005
0.005
0.005
7-tert-Butyl-2-phenyl-6H-imidazo[4,5-e]benzoxazole
7-(1-Adamantyl)-2-(4-methoxyphenyl)-6H-imidazo[4,5-e]benzoxazole
7-Cyclohexyl-2-(4-methoxyphenyl)-6H-imidazo[4,5-e]benzoxazole
7-Methyl-2-(4-methoxyphenyl)-6H-imidazo[4,5-e]benzoxazole
2-(4-Methoxyphenyl)-6H-imidazo[4,5-e]benzoxazole
7-Isopropyl-2-(4-methoxyphenyl)-6H-imidazo[4,5-e]benzoxazole
7-Phenyl-2-(4-methoxyphenyl)-6H-imidazo[4,5-e]benzoxazole
7-tert-Butyl-2-(4-methoxyphenyl)-6H-imidazo[4,5-e]benzoxazole
CONCLUSIONS
compounds, the high Pa values for revealed activities
were compared with the structural analogs of obtained
compounds with some functional groups on the place of
adamantyl moiety. As it was expected, replacing of
adamantyl group from the molecule in most cases
decreased its predicted activity. Molecules with methyl,
phenyl, cyclohexyl, isopropyl, and tert-butyl moiety
showed much lower Pa value than the same molecule
with adamantane. For example, Pa values for the renal
disease treatment activity of fused tricyclic compounds
are shown in Table 2.
In summary, adamantane derivatives containing
heterocycles such as benzoxazoles, benzimidazoles, and
fused imidazo[4,5-e]benzoxazoles were synthesized from
the starting material 3-aminophenol. Key steps of the
reaction sequences were the amidation of adamantane-1-
carboxylic acid chloride with 3-aminophenol, nitration
reactions followed by reduction of the nitro groups using
a palladium catalyst. The final cyclizations toward the
desired adamantane-containing heterocycles were
performed either by Cu(II)-catalyzed oxidative coupling
or by Lewis acid-catalyzed condensation reactions.
Biological activity spectra prediction.
Estimation of
possible biological activity for the synthesized
compounds was made on the basis of a PASS (prediction
of activity spectra for substances) prediction results by
ParmaExpert software. The PASS program predicts the
pharmacological effects of a molecule based on the
analysis of structure–activity relationship for the training
set of database including about 300.000 thoroughly
selected data records about structure and biological
activity of organic compounds [20]. Activity spectrum of
a compound is estimated as probable active (Pa) or
probable inactive (Pi), and their value varies from 0.000
to 1.000. Only activities with Pa > Pi are considered as
possible for a particular compound. The average accuracy
of a prediction is reported to be as high as 95% [21].
According to the predicted results, amides 1, 2a–c, and
3b–c revealed high activity (Pa > 0.7) as anti-viral agents
against picornavirus and influenza. The benzoxazoles
7a–j gave good results as 5-hydroxytryptamine release
inhibitors while benzimidazoles 8, 9a–c and 10 as kidney
function stimulants. Compounds 11a–b shown Pa > 0.8
on renal disease treatment activity. Furthermore, among
the wide spectrum of predicted activities for synthesized
EXPERIMENTAL
Preparative column chromatography was carried out
using Merck SiO2 (35–70 μm, type 60 Å) with hexanes
and ethyl acetate (EtOAc) as eluents. TLC was performed
on aluminum plates coated with SiO2 F254.
1H- and
13C-NMR spectra were recorded on Bruker Avance DRX
500 instruments. Multiplicities of carbon signals were
determined with DEPT experiments. MS and HRMS
spectra were obtained with a Finnigan MAT95 (EI) and a
Waters Q-TOF Premier (ESI, pos. mode) spectrometer. IR
spectra were recorded on
a
Bruker Tensor 27
spectrometer equipped with a “GoldenGate” diamond
ATR unit. Elemental analyses were measured with a Euro
EA-CHNS instrument from HEKAtech. Melting points of
crystalline compounds were determined on a Gallenkamp
Melting Point apparatus and are uncorrected.
Reagents and starting materials were purchased from
common commercial suppliers and used without further
purification. Solvents were purified and dried following
standard procedures. Compound 1 was synthesized
according to a literature procedure [16].
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
The Synthesis of Adamantane Ring Containing Benzimidazole, Benzoxazole, and
Imidazo[4,5-e]benzoxazole Derivatives from 3-Aminophenol
Preparation of compounds 2a–c. HNO3 (65%, 7 mL,
15 mmol) was added dropwise within 15 min to a cold
suspension (ice-water bath) of compound 1 (2.99 g,
11.0 mmol) in acetic acid (15 mL), and the reaction
mixture was stirred at ambient temperature for 1 h.
Subsequently, the suspension was poured into ice
(200 mL), and the yellow participate formed was
collected by filtration and washed with water
(3 × 100 mL). The crude product was purified by column
chromatography (SiO2, hexanes/EtOAc 3:1) to yield the
isomer 2a (104 mg, 0.33 mmol, 3%, Rf = 0.85) in
the first fraction. Secondly, compound 2b (1.39 g,
5.13 mmol, 40%, Rf = 0.80) and as the third fraction
isomer 2c (1.05 g, 3.32 mmol, 30%, Rf = 0.71) was
Preparation of compounds 3b and 3c. The catalyst (5%
Pt, 1% Fe, on charcoal, 100 mg) was added to a solution of
nitro compound 2b or 2c (0.78 g, 2.37 mmol) in EtOH
(25 mL). The reaction mixture was degased and then
stirred at ambient temperature for 24 h under an
atmosphere of hydrogen (1 atm). Then the catalyst was
removed by filtration, and the solvent was removed in
vacuo. The crude product was recrystallized from
chloroform (10 mL) to give the aminoamides 3b and 3c.
N-(4-Amino-3-hydroxyphenyl)adamantane-1-carboxamide
(3b). Yield: 0.64 g (2.24 mmol, 91%); white-gray solid,
mp 200–202°C. IR (ATR): 3356, 3326, 3291, 3899, 2850,
1
1646, 1619, 1544 cmÀ1. H NMR (methanol-d4): δ 1.73–
1.81 (m, 6H, Ad), 1.92–1.96 (m, 6H, Ad), 2.02–2.06 (m,
3H, Ad), 6.63–6.72 (m, 2H, 2 Ar), 6.98 (d, J = 1.9 Hz,
1H, Ar) ppm. 13C{1H} NMR (methanol-d4): δ 30.16
(3 CH), 38.01 (3 CH2), 40.53 (3 CH2), 42.81 (C), 111.24
(CH), 115.46 (CH), 117.44 (CH), 131.64 (C), 133.66 (C),
146.75 (C), 179.57 (C) ppm. MS (ESI): m/z (%) = 287.2
(100) [M + H]+. HRMS (ESI): m/z [M + H] + calcd for
isolated.
N-(3-Hydroxy-2-nitrophenyl)adamantane-1-carboxamide
(2a). This compound was obtained as a red solid, mp
155–157°C. IR (ATR): 3351, 2912, 2850, 1695, 1611,
1
1579 cmÀ1; H NMR (DMSO-d6): δ 1.60–1.76 (m, 6H,
Ad), 1.77–1.96 (m, 6H, Ad), 1.96–2.05 (m, 3H, Ad),
6.81 (d, J = 7,9 Hz, 1H, Ar), 6.90 (d, J = 8.2 Hz, 1H,
Ar), 7.33 (t, J = 8.2 Hz, 1H, Ar), 9.27 (s, 1H, OH), 10.86
(s, 1H, NH) ppm; 13C{1H} NMR (DMSO-d6): δ 27.56
(3 CH), 36.00 (3 CH2), 38.22 (3 CH2), 40.39 (C), 114.30
(CH), 117.31 (CH), 131.31 (CH), 131.63 (C), 135.96 (C),
150.37 (C), 176.03 (C) ppm. MS (ESI): m/z (%) = 339.1
(100) [M + Na]+. Anal. Calcd for C17H20N2O4: C, 64.54;
C17H23N2O2: 287.1760; found: 287.1747.
N-(2-Amino-5-hydroxyphenyl)adamantane-1-carboxamide
(3c). Yield: 0.67 g (2.34 mmol, 95%); white-gray solid,
mp 180–182°C. IR (ATR): 3312, 3006, 2906, 2850,
1
1629 cmÀ1. H NMR (methanol-d4): δ 1.78–1.84 (m, 6H,
Ad), 1.98–2.03 (m, 6H, Ad), 2.04–2.09 (m, 3H, Ad),
6.55 (dd, J = 8.5 Hz, J = 2.7 Hz, 1H, Ar), 6.69
(d, J = 2.6 Hz, 1H, Ar), 6.75 (d, J = 8.5 Hz, 1H, Ar), 7.90
(s, 1H, NH) ppm. 13C{1H} NMR (methanol-d4): δ 29.70
(3 CH), 37.56 (3 CH2), 40.24 (3 CH2), 42.47 (C), 113.68
(CH), 114.98 (CH), 120.51 (CH), 127.55 (C), 134.69 (C),
151.79 (C), 179.47 (C) ppm. MS (ESI): m/z (%) = 309.2
(100) [M + Na]+. Anal. Calcd for C17H22N2O2: C, 71.30;
H, 6.37; N, 8.86. Found: C, 64.03; H, 6.83; N, 8.34.
N-(3-Hydroxy-4-nitrophenyl)adamantane-1-carboxamide
(2b). This compound was obtained as a yellow solid, mp
192–194°C. IR (ATR): 3434, 2904, 2849, 1686, 1628,
1
1589 cmÀ1. H NMR (DMSO-d6): δ 1.66–1.78 (m, 6H,
Ad), 1.87–1.97 (m, 6H, Ad), 1.90–2.12 (m, 3H, Ad),
7.27 (d, J = 9.1 Hz, 1H, Ar), 7.75 (s, 1H, Ar), 7.94
(d, J = 9.2 Hz, 1H, Ar), 9.54 (s, 1H, OH), 10.85 (s, 1H,
NH) ppm. 13C{1H} NMR (DMSO-d6): δ 27.55 (3 CH),
35.85 (3 CH2), 37.88 (3 CH2), 41.37 (C), 108.03 (CH),
111.21 (CH), 126.06 (CH), 130.40 (C), 146.36 (C),
154.15 (C), 176.79 (C) ppm. MS (ESI): m/z (%) = 339.2
(100) [M + Na]+. Anal. Calcd for C17H20N2O4: C, 64.54;
H, 7.74; N, 9.78. Found: C, 71.26; H, 7.78; N, 9.55.
N-(2-Methylbenzoxazol-6-yl)adamantane-1-carboxamide
(7a). A mixture of compound 3b (92 mg, 0.30 mmol),
Cu(OAc)2 · H2O (19 mg, 0.10 mmol) and acetic
anhydride 4 (61 mg, 0.60 mmol) in glacial acetic acid
(2 mL) was heated to reflux at 118°C for 7 h.
Subsequently, the solvent was removed in vacuo, and the
residue was purified by column chromatography (SiO2,
hexanes/EtOAc 2:1) to give the title compound 7a
(15 mg, 0.05 mmol, 16%, Rf = 0.30) as pink crystals, mp
235–237°C. IR (ATR): 3261, 2900, 2849, 1644, 1623,
H, 6.37; N, 8.86. Found: C, 64.63; H, 6.41; N, 8.61.
N-(5-Hydroxy-2-nitrophenyl)adamantane-1-carboxamide
(2c). This compound was isolated as a dark yellow solid,
mp 280–285°C. IR (ATR): 3094, 2920, 2851, 1660, 1598,
1
1559 cmÀ1. H NMR (DMSO-d6): δ 1.64–1.80 (m, 6H,
1582, 1527 cmÀ1 1H NMR (CDCl3): δ 1.60–2.09
.
Ad), 1.85–1.97 (m, 6H, Ad), 2.01–2.06 (m, 3H, Ad),
6.62 (dd, J = 9.2 Hz, J = 2.2, 1H, Ar), 7.98
(d, J = 2.1 Hz, 1H, Ar), 8.08 (d, J = 9.3 Hz, 1H, Ar),
10.57 (s, 1H, OH), 11.17 (s, 1H, NH) ppm. 13C{1H}
NMR (DMSO-d6): δ 27.58 (3 CH), 35.93 (3 CH2), 38.42
(3 CH2), 41.69 (C), 107.27 (CH), 111.40 (CH), 128.55
(CH), 129.74 (C), 137.05 (C), 164.39 (C), 176.32 (C)
ppm. MS (ESI): m/z (%) = 339.2 (100) [M + Na]+. Anal.
Calcd for C17H20N2O4: C, 64.54; H, 6.37; N, 8.86.
Found: C, 64.36; H, 6.62; N, 8.90.
(m, 15H, Ad), 2.81 (s, 3H, CH3), 7.07 (dd, J = 8.5 Hz,
J = 2.1 Hz, 1H, Ar), 7.43 (s, 1H, NH), 7.53
(d, J = 8.5 Hz, 1H, Ar), 8.17 (d, J = 2.0 Hz, 1H, Ar)
ppm. 13C{1H} NMR (CDCl3): δ 14.65 (CH3), 28.30
(3 CH), 36.59 (3 CH2), 39.46 (3 CH2), 41.73 (C), 103.09
(CH), 116.54 (CH), 119.07 (CH), 135.28 (C), 138.06 (C),
151.49 (C), 164.13 (C), 176.21 (C) ppm. MS (ESI): m/z
(%) = 333.1 (100) [M + Na]+. HRMS (ESI): m/z calcd
+
333.1579 (for C19H22N2NaO2 ); found 333.1576
[M + Na]+.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Soselia, I. Geibel, D. Zurabishvili, and S. Samsoniya
Vol 000
Benzoxazoles 7b–g: general procedure A. A mixture of
compound 3b (1.0 equiv), Cu(OAc)2 · H2O (0.4 equiv)
and an aldehyde 5a–f (1.0 equiv) in absolute toluene
(10 L/mol 3b) was heated to reflux for 16–20 h using a
Dean-Stark trap. Upon completion of the reaction
(monitored by TLC), the solvent was removed in vacuo,
and the residue was purified by column chromatography
to give the final products 7b–g (Table 1, entries 2–7).
N-(2-Phenylbenzoxazol-6-yl)adamantane-1-carboxamide
N-[2-(3,4-Dimethoxyphenyl)benzoxazol-6-yl]adamantane-1-
carboxamide (7d). According to GPA, the reaction of 3b
(100 mg, 0.35 mmol), Cu(OAc)2 · H2O (30 mg,
0.15 mmol), and 3,4-dimethoxybenzaldehyde 5c (58 mg,
0.35 mmol) in absolute toluene (30 mL) was heated to
reflux for 20 h to give the title compound 7d (10 mg,
0.02 mmol, 7%, Rf = 0.25) after column chromatography
(SiO2, hexanes/EtOAc 2:1) as colorless crystals, mp 140–
145°C. IR (ATR): 3259, 2902, 2850, 1650, 1620 cmÀ1
.
1H NMR (CDCl3): δ 1.56–2.13 (m, 15H, Ad), 3.97
(s, 3H, OCH3), 4.02 (s, 3H, OCH3), 6.99 (d, J = 8.4 Hz,
1H, Ar), 7.11 (dd, J = 8.5 Hz, J = 1.9 Hz, 1H, Ar), 7.45
(s, 1H, NH), 7.63 (d, J = 8.5 Hz, 1H, Ar), 7.73
(d, J = 1.8 Hz, 1H, Ar), 7.83 (dd, J = 8.3 Hz, J = 1.9 Hz,
1H, Ar), 8.27 (d, J = 1.8 Hz, 1H, Ar) ppm. 13C{1H}
NMR (CDCl3): δ 28.27 (3 CH), 36.57 (3 CH2), 39.44
(3 CH2), 41.75 (C), 56.20 (CH3), 56.29 (CH3), 103.12
(CH), 110.04 (CH), 111.18 (CH), 116.89 (CH), 119.30
(CH), 119.96 (C), 121.23 (CH), 135.50 (C), 138.75 (C),
149.39 (C), 151.26 (C), 152.05 (C), 163.54 (C), 176.21
(C) ppm. MS (EI, 70 eV): m/z (%) = 432.6 (100), 135.1
(100), 93.1 (14) [M]+. HRMS (EI, 70 eV): m/z calcd
(7b).
According to general procedure A (GPA), the
reaction of 3b (143 mg, 0.50 mmol), Cu(OAc)2 · H2O
(40 mg, 0.20 mmol) and benzaldehyde 5a (53 mg,
0.50 mmol) in absolute toluene (50 mL) was heated to
reflux for 16 h to give the title compound 7b (93 mg,
0.25 mmol, 50%, Rf
=
0.25) after column
chromatography (SiO2, hexanes/EtOAc 4:1) as pale beige
crystals, mp 196–198°C. IR (ATR): 3433, 3901, 2819,
1
1665, 1620, 1556, 1523, 1481 cmÀ1. H NMR (CDCl3):
δ 1.71–1.79 (m, 6H, Ad), 1.95–1.99 (m, 6H, Ad),
2.08–2.11 (m, 3H, Ad), 7.11–7.19 (m, 1H, Ar), 7.44–7.54
(m, 3H, Ar), 7.58 (s, 1H, NH), 7.62 (d, J = 8.4 Hz, 1H,
Ar), 8.20 (dd, J = 6.7, J = 3.0 Hz, 2H, Ar), 8.28
(d, J = 2.1 Hz, 1H, Ar) ppm. 13C{1H} NMR (CDCl3): δ
28.19 (3 CH), 36.47 (3 CH2), 39.31 (3 CH2), 41.67 (C),
103.21 (CH), 117.12 (CH), 119.57 (CH), 127.20 (C),
127.52 (CH), 128.96 (2 CH), 131.44 (2 CH), 135.82 (C),
138.51 (C), 151.20 (C), 163.29 (C), 176.28 (C) ppm. MS
(ESI): m/z (%) = 395.1 (100) [M + Na+]. HRMS (ESI):
+
432.2049 (for C26H28N2O4 ); found 432.2036 [M]+.
N-[2-(2-Thienyl)benzoxazol-6-yl]adamantane-1-
carboxamide (7e). According to GPA, the reaction of 3b
(100 mg, 0.35 mmol), Cu(OAc)2 · H2O (30 mg,
0.15 mmol), and thiophene-2-carbaldehyde 5d (39 mg,
0.35 mmol) in absolute toluene (30 mL) was heated to
reflux for 17 h to give the title compound 7e (70 mg,
0.18 mmol, 53%, Rf = 0.70) after column chromatography
(SiO2, hexanes/EtOAc 2:1) as orange crystals, mp
203–205°C. IR (ATR): 3440, 3070, 2909, 2849, 1659,
1618, 1575 cmÀ1. 1H NMR (CDCl3): δ 1.72–1.79 (m, 6H,
Ad), 1.95–1.99 (m, 6H, Ad), 2.12–2.08 (m, 3H, Ad), 7.13
(dd, J = 8.5 Hz, J = 1.9 Hz, 1H, Ar), 7.16 (dd, J = 4.8 Hz,
J = 3.9 Hz, 1H, thienyl), 7.52 (m, 2H, thienyl; NH), 7.59
(d, J = 8.5 Hz, 1H, Ar), 7.83–7.89 (m, 1H, thienyl), 8.24
(d, J = 1.8 Hz, 1H, Ar) ppm. 13C{1H} NMR (CDCl3): δ
28.22 (3 CH), 36.51 (3 CH2), 39.36 (3 CH2), 41.71 (C),
103.06 (CH), 117.15 (CH), 119.40 (CH), 128.35 (CH),
129.72 (C), 129.87 (CH), 130.15 (CH), 135.82 (C),
138.41 (C), 150.94 (C), 159.33 (C), 176.24 (C) ppm. MS
(EI, 70 eV): m/z (%) = 378.5 (70) 135.0 (100), 78.9 (23)
[M]+. HRMS (EI, 70 eV): m/z calcd 378.1402 (for
C22H22N2O2S+); found 378.1395 [M]+.
+
m/z calcd 373.1916 (for C24H25N2O2 ); found 373.1908
[M + H]+.
N-[2-(4-Isopropylphenyl)benzoxazol-6-yl]adamantane-1-
carboxamide (7c). According to GPA, the reaction of 3b
(100 mg, 0.35 mmol), Cu(OAc)2 · H2O (30 mg,
0.15 mmol) and 4-isopropylbenzaldehyde 5b (52 mg,
0.35 mmol) in absolute toluene (30 mL) was heated to
reflux for 16 h to give the title compound 7c (46 mg,
0.11 mmol, 32%, Rf
=
0.68) after column
chromatography (SiO2, hexanes/EtOAc 3:1) as colorless
crystals, mp 225–226°C. IR (ATR): 3434, 2906, 2851,
1620, 1565, 1485 cmÀ1 1H NMR (CDCl3): δ 1.30
.
(d, J = 6.8 Hz, 6H, 2 CH3), 1.69–1.86 (m, 6H, Ad),
1.98–2.02 (m, 6H, Ad), 2.07–2.17 (m, 3H, Ad), 2.99
(p, J = 6.8 Hz, 1H, CH), 7.12 (dd, J = 8.5 Hz,
J = 2.2 Hz, 1H, Ar), 7.37 (d, J = 8.4 Hz, 2H, Ar), 7.45
(s, 1H, NH), 7.64 (d, J = 8.5 Hz, 1H, Ar), 8.15
(d, J = 8.3 Hz, 2H, Ar), 8.28 (d, J = 2.2 Hz, 1H, Ar)
ppm. 13C{1H} NMR (CDCl3): δ 23.84 (2 CH3), 28.23
(3 CH), 34.34 (CH), 36.52 (3 CH2), 39.36 (3 CH2), 41.69
(C), 103.20 (CH), 116.99 (CH), 119.44 (CH), 124.80 (C),
127.13 (2 CH), 127.67 (2 CH), 135.62 (C), 138.65 (C),
151.16 (C), 152.83 (C), 163.59 (C), 176.25 (C) ppm. MS
(EI, 70 eV): m/z (%) = 414.3 (30), 135.1 (100), 83.9 (75)
[M]+. HRMS (EI, 70 eV): m/z calcd 414.2307 (for
C27H30N2O2+); found 414.2301 [M]+.
N-[2-(3-Bromophenyl)benzoxazol-6-yl]adamantane-1-
carboxamide (7f). According to GPA the reaction of 3b
(100 mg, 0.35 mmol), Cu(OAc)2 · H2O (30 mg,
0.15 mmol), and 3-bromobenzaldehyde 5e (65 mg,
0.35 mmol) in absolute toluene (30 mL) was heated to
reflux for 16 h to give the title compound 7f (61 mg,
0.14 mmol, 39%, Rf
=
0.50) after column
chromatography (SiO2, hexanes/EtOAc 3:1) as beige
crystals, mp 216–218°C. IR (ATR): 3437, 2902, 2849,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
The Synthesis of Adamantane Ring Containing Benzimidazole, Benzoxazole, and
Imidazo[4,5-e]benzoxazole Derivatives from 3-Aminophenol
1674, 1621, 1571, 1530, 1492 cmÀ1. 1H NMR (CDCl3): δ
1.74–1.82 (m, 6H, Ad), 2.00–2.01 (m, 6H, Ad), 2.12–2.14
(m, 3H, Ad), 7.15 (dd, J = 8.4 Hz, J = 2.2 Hz, 1H, Ar), 7.39
(t, J = 7.9 Hz, 1H, Ar), 7.48 (s, 1H, NH), 7.60–7.69
(m, 2H, Ar), 8.15 (d, J = 7.8 Hz, 1H, Ar), 8.31
(d, J = 2.1 Hz, 1H, Ar), 8.38 (d, J = 1.9 Hz, 1H, Ar)
ppm. 13C{1H} NMR (CDCl3): δ 28.26 (3 CH), 36.54
(3 CH2), 39.41 (3 CH2), 41.78 (C), 103.17 (CH), 117.28
(CH), 119.91 (CH), 123.12 (C), 126.05 (CH), 129.03 (C),
130.43 (CH), 130.57 (CH), 134.36 (CH), 136.24 (C),
138.35 (C), 151.36 (C), 161.78 (C), 176.28 (C) ppm.
HRMS (EI, 70 eV): m/z calcd 450.0943 (for
Ar), 8.08 (d, J = 8.7 Hz, 1H, Ar), 8.30 (d, J = 2.1 Hz,
1H, Ar) ppm. 13C{1H} NMR (CDCl3): δ 28.27 (3 CH),
36.55 (3 CH2), 39.43 (3 CH2), 41.78 (C), 103.18 (CH),
117.21 (CH), 119.79 (CH), 126.21 (C), 128.99 (2 CH),
132.36 (2 CH), 136.09 (C), 138.47 (C), 151.34 (C),
162.48 (C), 176.30 (C) ppm. HRMS (EI, 70 eV): m/z
+
calcd 450.0943 (for C24H23BrN2O2 ); found 450.0950
[M]+.
N-[2-(4-Cyanophenyl)benzoxazol-6-yl]adamantane-1-
carboxamide (7i). According to GPB, the reaction of 3b
(70 mg, 0.24 mmol), ZnCl2 (10 mg, 0.07 mmol), and
terephthalodinitrile 6b (31 mg, 0.24 mmol) in PhCl
(3 mL) was heated to reflux for 24 h to give the title
compound 7i (37 mg, 0.09 mmol, 76%, Rf = 0.33) after
column chromatography (SiO2, hexanes/EtOAc 3:1) as
colorless crystals, mp > 340°C. IR (ATR): 3429, 2907,
+
C24H23BrN2O2 ); found 450.0933 [M]+.
N-[2-(4-Methoxyphenyl)benzoxazol-6-yl]adamantane-1-
carboxamide (7g). According to GPA, the reaction of 3b
(72 mg, 0.25 mmol), Cu(OAc)2 · H2O (20 mg,
0.10 mmol), and 4-methoxybenzaldehyde 5f (34 mg,
0.25 mmol) in absolute toluene (20 mL) was heated to
reflux for 20 h to give the title compound 7g (15 mg,
1
2852, 2228, 1669, 1622, 1527 cmÀ1. H NMR (CDCl3):
δ 1.75–1.82 (m, 6H, Ad), 1.99–2.03 (m, 6H, Ad),
2.09–2.15 (m, 3H, Ad), 7.15 (dd, J = 8.7 Hz, J = 2.1 Hz,
1H, Ar), 7.52 (s, 1H, NH), 7.68 (d, J = 8.5 Hz, 1H, Ar),
7.80 (d, J = 8.0 Hz, 2H, Ar), 8.32 (d, J = 8.4 Hz, 2H,
Ar), 8.37 (d, J = 2.1 Hz, 1H, Ar) ppm. 13C{1H} NMR
(CDCl3): δ 28.24 (3 CH), 36.53 (3 CH2), 39.42 (3 CH2),
41.83 (C), 103.14 (CH), 114.63 (C), 117.51 (CH), 118.38
(C), 120.29 (CH), 127.91 (2 CH), 131.24 (C), 132.81
(2 CH), 136.78 (C), 138.27 (C), 151.55 (C), 161.21 (C),
176.37 (C) ppm. MS (EI, 70 eV): m/z (%) = 397.2 (35),
135.1 (100) [M]+. HRMS (EI, 70 eV): m/z calcd
0.04 mmol, 15%, Rf
=
0.25) after column
chromatography (SiO2, hexanes/EtOAc 3:1) as pale beige
crystals, mp 235–239°C. IR (ATR): 3262, 2898, 2850,
.
1644, 1620 cmÀ1 1H NMR (CDCl3): δ 1.74–1.84
(m, 6H, Ad), 2.00–2.04 (m, 6H, Ad), 2.11–2.13 (m, 3H,
Ad), 3.89 (s, 3H, OCH3), 6.98–7.07 (m, 2H, Ar), 7.11
(dd, J = 8.5 Hz, J = 2.1 Hz, 1H, Ar), 7.45 (s, 1H, NH),
7.61 (d, J = 8.5 Hz, 1H, Ar), 8.11–8.21 (m, 2H, Ar), 8.24
(d, J = 1.9 Hz, 1H, Ar) ppm. 13C{1H} NMR (CDCl3): δ
28.32 (3 CH), 36.61 (3 CH2), 39.48 (3 CH2), 41.77 (C),
55.60 (CH3), 103.18 (CH), 114.52 (2 CH), 116.88 (CH),
119.30 (CH), 119.92 (C), 129.41 (2 CH), 135.43 (C),
138.86 (C), 151.24 (C), 162.42 (C), 163.58 (C), 176.19
(C) ppm. MS (EI, 70 eV): m/z (%) = 402.01 (90) 135.01
(100), 93.3 (44), 79.3 (42) [M]+. HRMS (EI, 70 eV): m/z
calcd 402.1943 (for C25H26N2O+3); found 402.1945 [M]+.
+
397.1790 (for C25H23N3O2 ); found 397.1789 [M]+.
N-[2-(2-Methoxyethyl)benzoxazol-6-yl]adamantane-1-
carboxamide (7j). According to GPB, the reaction of 3b
(70 mg, 0.24 mmol), ZnCl2 (10 mg, 0.07 mmol), and
3-methoxypropionitrile 6c (20 mg, 0.24 mmol) in PhCl
(3 mL) was heated to reflux for 24 h to give the title
compound 7j (16 mg, 0.05 mmol, 19%, Rf = 0.15) after
column chromatography (SiO2, hexanes/EtOAc 2:1) as
colorless crystals, mp 175–177°C. IR (ATR): 3259, 2900,
Benzoxazoles 7h–j: general procedure B. A mixture of
compound 3b (1.0 equiv), ZnCl2 (0.3 equiv) and a
carbonitrile (1.0 equiv) in PhCl (12 L/mol 3b) was heated
to reflux under an atmosphere of nitrogen at 135°C for
24 h. Subsequently, the solvent was removed in vacuo
and the residue was purified by column chromatography
to give the products 7h–j (Table 1, entries 8–10).
1
2849, 1644, 1618, 1526 cmÀ1. H NMR (DMSO-d6): δ
1.70–1.74 (m, 6H, Ad), 1.90–1.95 (m, 6H, Ad),
2.01–2.05 (m, 3H, Ad), 3.15 (t, J = 6.3 Hz, 2H, CH2),
3.26 (s, 3H, OCH3), 3.79 (t, J = 6.4 Hz, 2H, OCH2), 7.51
(dd, J = 8.6 Hz, J = 1.9 Hz, 1H, Ar), 7.56 (d, J = 8.6 Hz,
1H, Ar), 8.11 (d, J = 1.8 Hz, 1H, Ar) 9.26 (s, 1H, NH)
ppm. 13C{1H} NMR (DMSO-d6): δ 27.63 (3 CH), 28.65
(CH2), 35.97 (3 CH2), 38.24 (3 CH2), 40.94 (C), 57.86
(CH3), 68.43 (CH2), 102.24 (CH), 117.09 (CH), 118.43
(CH), 136.37 (C), 136.57 (C), 150.09 (C), 164.31 (C),
176.01 (C) ppm. MS (EI, 70 eV): m/z (%) = 354.2 (15),
135.1 (100) [M]+. HRMS (EI, 70 eV): m/z calcd
N-[2-(4-Bromophenyl)benzoxazol-6-yl]adamantane-1-
carboxamide (7h).
According to general procedure B
(GPB), the reaction of 3b (70 mg, 0.24 mmol), ZnCl2
(10 mg, 0.07 mmol), and 4-bromobenzonitrile 6a (44 mg,
0.24 mmol) in PhCl (3 mL) was heated to reflux for 24 h
to give the title compound 7h (19 mg, 0.04 mmol, 17%,
Rf
=
0.60) after column chromatography (SiO2,
+
354.1943 (for C21H26N2O3 ); found 354.1942 [M]+.
hexanes/EtOAc 3:1) as colorless crystals, mp 180–182°C.
1
IR (ATR): 3434, 2910, 2851, 1674, 1619, 1520 cmÀ1. H
2-(1-Adamantyl)-5-hydroxybenzimidazole
(8).
NMR (CDCl3): δ 1.76–1.82 (m, 6H, Ad), 1.93–2.04
(m, 6H, Ad), 2.07–2.15 (m, 3H, Ad), 7.11 (dd, J = 8.7 Hz,
J = 2.1 Hz, 1H, Ar), 7.49 (s, 1H, NH), 7.59–7.73 (m, 4H,
Trifluoroacetic acid (0.10 mL, 1.30 mmol) was added to
a stirred solution of compound 3c (54 mg, 0.20 mmol) in
toluene (5 mL). The reaction mixture was heated to
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Soselia, I. Geibel, D. Zurabishvili, and S. Samsoniya
Vol 000
reflux for 11 h, and the formed precipitate was collected by
filtration, washed with toluene, and dried. The crude
product was purified by recrystallization from chloroform
(5 mL) to give the titled compound 8 (50 mg,
0.19 mmol, 99%) as a gray-white solid, mp. 220–222°C.
IR (ATR): 2912, 2856, 2280, 1778, 1663, 1638,
(CDCl3): δ 1.75–1.96 (m, 6H, Ad), 2.04–2.32 (m, 9H,
Ad), 8.78 (s, 1H, Ar), 10.38 (s, 1H, NH), 12.16 (s, 1H,
OH) ppm. 13C{1H} NMR (CDCl3): δ 28.06 (3 CH),
35.98 (C), 36.35 (3 CH2), 41.07 (3 CH2), 124.57 (CH),
132.11 (C), 134.62(C), 135.81(C), 149.59 (C) ppm. MS
(ESI): m/z (%) = 359.2 (95), 301.2 (100) [M + H]+.
HRMS (ESI): m/z calcd 359.1355 (for C17H19N4O5)+;
found 359.1353 [M + H]+.
1
1503 cmÀ1. H NMR (methanol-d4): δ 1.75–1.93 (m, 6H,
Ad), 2.14 (s, 9H, Ad), 6.95–7.04 (m, 2H, 2 Ar), 7.48
(d, J = 8.6 Hz, 1H, Ar) ppm. 13C{1H} NMR (methanol-
d4): δ 29.16 (3 CH), 36.57 (C), 36.87 (3 CH2), 40.93
(3 CH2), 99.16 (CH), 115.27 (CH), 117.07 (CH), 125.51
(C), 133.38 (C), 158.05 (C), 160.45 (C) ppm. MS (ESI):
m/z (%) = 269.2 (100) [M + H]+. HRMS (ESI): m/z calcd
269.1654 (for C17H21N2O+); found 269.1655 [M + H]+.
2-(1-Adamantyl)-4-amino-5-hydroxybenzimidazole (10).
Pd/C (10% w/w, 140 mg) was added to a solution of nitro
compound 9a (575 mg, 1.80 mmol) in EtOH (60 mL).
The reaction mixture was degased and then stirred under
an atmosphere of hydrogen (1 atm) at room temperature
for 24 h. Then the catalyst was removed by filtration, and
the solvent was removed in vacuo. The title compound 7
(450 mg, 1.6 mmol, 87%) was isolated as a brown solid,
mp 185.190°C without further purification. IR (ATR):
Preparation of compounds 9a–c. To a cold (ice-water
bath) suspension of benzimidazole 8 (1.24 g, 4.60 mmol)
in glacial acetic acid (10 mL) nitric acid (65%, 0.2 mL,
4.60 mmol) was added dropwise within 5 min. The
reaction mixture was stirred at ambient temperature for
15 min and then diluted with water (10 mL). The yellow
precipitate formed was collected by filtration, washed
with water and dried. The crude product was purified by
column chromatography (SiO2, hexanes/EtOAc 3:1) to
yield the compound 9a (0.64 g, 2.02 mmol, 44%,
Rf = 0.49) in the first fraction. Secondly, compound 9b
(114 mg, 0.46 mmol, 10%, Rf = 0.32) and the third
fraction the dinitro product 9c (49 mg, 0.14 mmol, 3%,
Rf = 0.15) was isolated.
.
3402, 3308, 2910, 1665, 1639 cmÀ1 1H NMR
(methanol-d4): δ 1.55–2.32 (m, 15H, Ad), 3.27 (s, 3H,
NH2, NH) 6.67 (d, J = 2.9 Hz, 2H, 2 Ar) ppm. 13C{1H}
NMR (DMSO-d6): δ 27.71 (3 CH), 34.83 (C), 38.13
(3 CH2), 40.80 (3 CH2), 101.23 (C), 111.77 (CH), 123.09
(C), 137.59 (C), 159.52 (2 C) ppm. MS (EI, 70 eV): m/z
(%) = 283.1 (100), 226 (10) [M]+. HRMS (EI, 70 eV):
m/z calcd 283.1685 (for C17H21N3O+); found 283.1683
[M]+.
7-(1-Adamantyl)-2-phenyl-6H-imidazo[4,5-e]benzoxazole
(11a).
A mixture of amino alcohol 10 (50 mg,
0.14 mmol), Cu(OAc)2 · H2O (40 mg, 0.20 mmol) and
benzaldehyde 5a (162 mg, 0.37 mmol) in toluene
(30 mL) was heated to reflux for 9 h. Subsequently, the
solvent was removed in vacuo, and the residue was
2-(1-Adamantyl)-5-hydroxy-4-nitrobenzimidazole (9a).
This compound was obtained as yellow crystals, mp
188–187°C. IR (ATR): 3435, 3016, 2906, 2854, 1626,
1
1601, 1509, 1489 cmÀ1. H NMR (CDCl3): δ 1.80–1.88
purified
by
column
chromatography
(SiO2,
(m, 6H, Ad), 2.10–2.19 (m, 9H, Ad), 6.96 (d, J = 8.7 Hz,
1H, Ar), 7.93 (d, J = 8.6 Hz, 1H, Ar), 10.16 (br, s, 1H,
NH), 10.82 (s, 1H, OH) ppm. 13C{1H} NMR (CDCl3): δ
28.21 (3 CH), 35.51 (C), 36.49 (3 CH2), 41.38 (3 CH2),
112.90 (CH), 120.81 (C), 128.19 (C), 130.58 (CH),
137.86 (C), 153.74 (C), 162.58 (C) ppm. MS (ESI): m/z
hexanes/EtOAc 2:1) to give the title compound 11a
(7 mg, 0.02 mmol, 11%, Rf = 0.45) as beige crystals, mp
303–306°C. IR (ATR): 2901, 2849, 1553 1530 cmÀ1
.
1H NMR (CDCl3): δ 1.78–1.88 (m, 6H, Ad), 2.11–2.22
(m, 9H, Ad), 7.47 (d, J = 8.7 Hz, 1H, Ar), 7.49–7.57
(m, 3H, Ar), 7.66 (br. s, 1H, Ar), 8.27 (dd, J = 6.7 Hz,
J = 3.0 Hz, 2H, Ar) ppm. 13C{1H} NMR (CDCl3): δ
28.43 (3 CH), 35.64 (C), 36.71 (3 CH2), 41.66 (3 CH2),
104.94 (CH), 127.51 (2 CH), 127.61 (C), 129.09 (3 CH),
131.38 (CH), 148.05 (C), 161.91 (C), 162.79 (C) ppm.
MS (EI, 70 eV): m/z (%) = 369.2 (100), 312.1 (17) [M]+.
HRMS (EI, 70 eV): m/z calcd 369.1841 (for
C24H23N3O+); found 369.1833 [M]+.
(%)
= 314.2 (100) [M +
H]+. Anal. Calcd for
C17H19N3O3: C, 65.16; H, 6.11; N, 13.41. Found: C,
65.22; H, 6.19; N, 13.54.
2-(1-Adamantyl)-5-hydroxy-6-nitrobenzimidazole (9b).
This compound was obtained as a yellow solid, mp
258–260°C. IR (ATR):3311, 2919, 2850, 1640, 1600,
1
1551 cmÀ1. H NMR (CDCl3): δ 1.80–1.87 (m, 6H, Ad),
2.03–2.15 (m, 9H, Ad), 7.09 (s, 1H, Ar), 8.38 (s, 1H,
Ar), 10.67 (s, 1H, NH) ppm. 13C{1H} NMR (CDCl3): δ
28.19 (3 CH), 35.92 (C), 36.51 (3 CH2), 41.19 (3 CH2),
130.46 (C), 152.16 (C) ppm. MS (ESI): m/z (%) = 314.1
7-(Adamantyl)-2-(4-methoxyphenyl)-6H-imidazo[4,5-e]
benzoxazole (11b). A mixture of amino alcohol 10 (50 mg,
0.14 mmol), Cu(OAc)2 · H2O (40 mg, 0.20 mmol) and
4-methoxybenzaldehyde 5f (50 mg, 0.37 mmol) in
toluene (30 mL) was heated to reflux for 15 h.
Subsequently, the solvent was removed in vacuo, and the
residue was purified by column chromatography (SiO2,
hexanes/EtOAc 3:1) to give the title compound 11b
(100) [M + H]+. HRMS (ESI): m/z calcd 314.1505 (for
C17H20N3O3)+; found 314.1511 [M + H]+.
2-(1-Adamantyl)-5-hydroxy-4,6-dinitrobenzimidazole (9c).
This compound as a dark yellow solid, mp 133–135°C. IR
1
(ATR): 3850, 2905, 2852, 1641, 1515 cmÀ1. H NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
The Synthesis of Adamantane Ring Containing Benzimidazole, Benzoxazole, and
Imidazo[4,5-e]benzoxazole Derivatives from 3-Aminophenol
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(12 mg, 0.03 mmol, 9%, Rf = 0.25) as beige crystals, mp
293–296°C. IR (ATR): 3072, 3003, 2903, 2847, 1610,
.
1529, 1498 cmÀ1 1H NMR (CDCl3): δ 1.78–1.88
(m, 6H, Ad), 2.10–2.24 (m, 9H, Ad), 3.90 (s, 3H,
CH3O), 6.95–7.09 (m, 2H, Ar), 7.46 (d, J = 8.6 Hz, 1H,
Ar), 7.66 (s, 1H, Ar), 8.27–8.12 (m, 2H, Ar) ppm.
13C{1H} NMR (CDCl3): δ 28.42 (3 CH), 35.62 (C),
36.69 (3 CH2), 41.62 (3 CH2), 55.61 (CH3), 104.87
(2 CH), 114.56 (2 CH), 120.16 (C), 129.25 (2 CH),
147.90 (2 C), 161.83 (2 C), 162.32 (C), 162.97 (2 C)
ppm. MS (EI, 70 eV): m/z (%) = 399.1 (100), 342.1 (58),
171.2 (25) [M]+. HRMS (EI, 70 eV): m/z calcd 399.1947
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3516.
+
(for C25H25N3O2 ); found 399.1948 [M]+.
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FUNDING INFORMATION
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This work was supported by DAAD (Deutscher
Akademischer Austauschdienst) PhD students’ research
scholarship (Code № A/12/80704) and Shota Rustaveli
National Science Foundation Grant № YS/30/6-420/14
for young scientists.
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Acknowledgments. The authors are very grateful to Prof. Dr.
Jens Christoffers and to his research group and the Carl von
Ossietzky University of Oldenburg, where the synthetic work
was carried out.
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SUPPORTING INFORMATION
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Additional Supporting Information may be found online
in the supporting information tab for this article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet