Conversion of sterically hindered diacylated 1,2-phenylenediamines into 2-substituted benzimidazoles

Article abstract of DOI:10.1248/cpb.53.492

A series of bulky 2-substituted benzimidazoles was designed in order to find new leads for several biological targets. Formation by cyclodehydration from their monoacylated counterparts was shown to be strongly dependent upon the nature of the acyl group. In the case of a dicyclohexylmethyl group, cycllzation was only observed in a p-toluenesulfonic acid/toluene mixture from the symmetrical diacylated precursor. Analysis of the mechanism was begun starting from mixed diacylated derivatives.

Full text of DOI:10.1248/cpb.53.492

492
Chem. Pharm. Bull. 53(5) 492—497 (2005)
Vol. 53, No. 5
Conversion of Sterically Hindered Diacylated 1,2-Phenylenediamines into
2-Substituted Benzimidazoles
Julie CHARTON,* Sophie GIRAULT-MIZZI, and Christian SERGHERAERT
UMR CNRS 8525, Universite de Lille II, Institut de Biologie et Institut Pasteur de Lille; 1 rue du Professeur Calmette, B.P.
447, 59021 Lille cedex, France. Received November 22, 2004; accepted February 9, 2005
A series of bulky 2-substituted benzimidazoles was designed in order to find new leads for several biological
targets. Formation by cyclodehydration from their monoacylated counterparts was shown to be strongly depen-
dent upon the nature of the acyl group. In the case of a dicyclohexylmethyl group, cyclization was only observed
in a p-toluenesulfonic acid/toluene mixture from the symmetrical diacylated precursor. Analysis of the mecha-
nism was begun starting from mixed diacylated derivatives.
Key words benzimidazole; cyclization; mechanism
The use of 2-alkyl- and 2-aryl-substituted benzimidazoles compound 12 (Table 2). With respect to this compound, there
has grown extensively in medicinal chemistry. Antihistamine was no cyclization observed after an 8 h reflux either with
Astemizole1) and antiulcerative Omeprazole2) both constitute HCl 4 N in dioxane/MeOH 1 : 1 as solvent or with pure acetic
notable clinical examples. In addition, benzimidazole-based acid.
compounds have shown important biological activities such
Synthesis via Diacylated Precursors and Discussion
as inhibition of phosphodiesterase IV,3) antagonism of an- about the Mechanism of Cyclization Cyclization of com-
giotensin I4,5) and neuropeptide Y binding.6) A number of pound 12 was observed however in the conditions previously
routes have been developed for synthesis of 2-substituted reported for the preparation of 2-substituted benzoxazoles
benzimidazoles during last ten years. For example, lewis and benzimidazoles, when starting from the corresponding
acids have been used in liquid-7) or solid-phase8) synthesis. In symmetrical diacylated precursor by action of p-toluenesul-
our programme, we targeted sterically hindered 2-substituted
benzimidazoles.
Table 1. Yields of Conversion into Compound 1 According to Cyclodehy-
dration Conditions
Synthesis via Monoacylated Precursors The choice of
bulky substituents for synthesis purposes led us logically to
consider a two-step procedure whereby 1,2-phenylenedi-
amine was first treated with the appropriate activated car-
boxylic acid, and which then allowed, in a second stage, the
cyclodehydration of the resulting monoacylated derivative
(Chart 1).
Amongst the different coupling reagents tested, the DCC-
induced formation of symmetric anhydrides was retained for
step 1, involved in the synthesis of compounds 1—12 (Table
2), and consequently enabled formation of a series of monoa-
cylated precursors with good yield. Furthermore, for step 2,
different acidic conditions relating to cyclodehydration (pure
CH3COOH, HCl (4 N), HCl (4 N) in dioxane/MeOH 1 : 1,
CF3COOH/DCM 1 : 1),7,9—12) were compared (Table 1) for
the case of the diphenylmethyl derivative (compound 1,
Table 2). After 4 h of reflux, total conversion into the 2-sub-
stituted benzimidazole was only observed with HCl 4 N in
dioxane/MeOH 1 : 1 as solvent (entry 3, Table 1) or with pure
acetic acid (entry 1, Table 1).
Reflux time
(h)
Yield
(%)
Entry
Acid
Solvent
CH3COOH
HCl (4 N)
Dioxane/MeOH 1 : 1
Toluene
1
2
3
4
5
CH3COOH
HCl (4 N)
HCl (4 N)
pTsOH
4
8
4
8
8
100
50
100
95
CF3COOH
DCM
0
Table 2. Cyclodehydration Yields of Compounds 1—12 via Monoacylated
Intermediates
Yield
(%)
Yield
(%)
Compound
R
Compound
R
1
2
60
75
7
8
75
86
Under optimal conditions as determined previously: DCC
coupling between an appropriate carboxylic acid and 1,2-
phenylenediamine, followed by reflux of the monoacylated
derivative in pure acetic acid and final purification by thick
layer chromatography, led to the isolation of the desired com-
pounds with good yields, except for the dicyclohexylmethyl
3
4
84
63
9
95
60
10
5
6
60
74
11
12
75
0
Chart 1. Synthesis of 2-Substituted Benzimidazoles via Monoacylated In-
termediates
∗ To whom correspondence should be addressed. e-mail: jcharton@pharma.univ-lille2.fr
© 2005 Pharmaceutical Society of Japan

May 2005
493
Table 3. HPLC Conversion Ratio from Mixed Diacylated Precursors 16—
30
Conversion into Conversion
A series
derivative
(%)
into B series
derivative
(%)
Reagent
R
Rꢀ
t (h)a)
16
17
18
19
20
22
36
40
22
36
65
55
0
35
45
100
100
92
Chart 2. Synthesis of 2-Substituted Benzimidazoles via Mixed Diacylated
Precursors
0
8
With the aim of confirming the nature of the two com-
pounds obtained, each 2-benzimidazole was synthesized. The
procedure described in Chart 1 was used for compound 18B
(Table 3). In the case of compound 17B (or 23B, Table 3),
the monoacetylation was realized with propyl chloride on 2-
nitroaniline. The 2-methyl and the 2-tert-butyl analogs (re-
spectively 16B or 22B and 25B, Table 3) are commercially
available.
The rate of conversion of mixed diacylated 1,2-phenylene-
diamines 16—30 into the corresponding 2-substituted benz-
imidazoles of the A and/or B series was strongly dependent
upon the nature of the acyl substituents and the transforma-
tion was generally complete after 12 to 80 h as shown by
HPLC (Table 3).
Conversion of dicyclohexylmethyl acyl compound to the
expected 2-benzimidazole 12 (dicyclohexylmethyl deriva-
tive) decreased gradually as the size of the opposing alkyl
group increased (compounds 16—18) and there was very lit-
tle or no conversion in the case of an aromatic moiety (com-
pounds 19, 20). The same trend was observed when a mono-
cyclohexylmethyl group opposed a diphenylmethyl group
(compound 26) demonstrating thereby that the steric factor
has no critical influence. The diphenylmethyl group was also
preferentially converted into expected 2-benzimidazole 1 ir-
respective of the opposing alkyl or alicyclic group and a
maximum of conversion was achieved in the case of the tert-
butyl group (compounds 22—26). Its association with a less
bulky aromatic group, such as the benzyl compound 27, led
to a balanced conversion. This balance was also observed
when a phenyl ring associated with a cyclohexyl group was
opposed by an alicyclic group whether associated or not to a
phenyl group (compounds 29, 30).
In the last two cases (compounds 29, 30), monoacylated
derivatives corresponding to the hydrolysis of each amide
bond and their cyclized counterparts appeared gradually in
both HPLC and mass spectrometry. For compound 29, they
were identified by comparison with compounds 29A, 29B,
31 and 32 synthesized independently. HPLC signals for
monoacylated intermediates were in good correlation with
both conversion percentages related to their cyclized counter-
parts and with completion times (Chart 3, Figs. 1, 2).
21
22
23
24
25
26
27
28
29
30
22
12
12
24
24
24
12
12
80
35
100
88
68
75
93
74
45
100
40
46
100
12
32
25
7
26
55
100
60
54
a) Time to reach 100% of conversion.
fonic acid in toluene at reflux.13) In the case of benzoxazole
formation it was demonstrated that cyclization proceeds
through an initial ester hydrolysis with intermediate forma-
tion of phenol, requiring the adjacent amido group.14)
Though no such hypothesis for a mechanism has been re-
ported for the case of benzimidazole formation.
Absence of cyclization when starting from the mono dicy-
clohexylmethyl derivative effectively eliminated the step in-
volved in phenol formation as described for the benzoxazole
series. Therefore, we analyzed the mechanism of cyclization
by studying the transformation of a series of mixed diacy-
lated materials, comprising either a dicyclohexylmethyl or a
diphenylmethyl group and a variety of alkyl, alicyclic, aryl
groups, as well as two compounds with a cyclohexylphenyl-
methyl group (Table 3). Mixed diacylated compounds were
synthesized in two consecutive steps, according to the proce-
dure described in Chart 2, and were then brought to reflux in
a p-toluenesulfonic acid/toluene (0.2 M) mixture. After re-
moval of acidic by-products by washing the reaction mixture
with a sodium bicarbonate solution, a typical mixture of de-
rivatives 16A—30A and 16B—30B corresponding to each
substituent alternately introduced at the 2-position was ob-
tained and analyzed by HPLC and mass spectrometry.
For compounds 16—28, no monoacylated intermediate
was detected. So far as compounds 16—21 are concerned,
these observations are consistent with the absence of cycliza-
tion accounted for the dicyclohexylmethyl monoacylated
starting material. In this case, the formation of the corre-
sponding 2-benzimidazoles can be explained by an alternate

494
Vol. 53, No. 5
amide-assisted hydrolysis with a conversion mixture depen- amide-assisted phosphinic ester hydrolysis, it is the oxygen
dent on the nature of the associated group Rꢀ. A mechanistic rather than the nitrogen atom of the amide which serves as
rationale for the conversion of mixed diacylated 1,2-phenyl- the nucleophilic center.15) In the present case, intramolecular
enediamines to benzimidazoles is proposed in Chart 4.
attack of the amide oxygen on the carbon atom of the adja-
In the previous case as described for an acid-catalyzed cent protonated amide of mixed diacylated 1,2-phenylenedi-
amines 33 might afford two 1,2-dihydro-benzo[1,3,6]oxadi-
azepine intermediates 33ꢀ and 33ꢁ. These intermediates may
then rearrange to the benzimidazoles 33A and 33B respec-
Fig. 1. HPLC Spectrum of the Reaction Mixture for the Formation of
Chart 3. Proposed Mechanism for the Formation of Compounds 29A and
Compounds 29A and 29B from Compound 29 (Mixture of Diastereoiso-
29B
Fig. 2. MALDI-TOF Spectrum of the Reaction Mixture for the Formation of Compounds 29A and 29B
Reaction time: 48 h.
Chart 4. Proposed Mechanism for the Formation of 2-Substituted Benzimidazoles

May 2005
495
Chart 5. Proposed Mechanism for the Formation of Benzimidazoles 23A and B from the Compound 23
(tR) were obtained at flow rates of 1 ml/min using different methods: a gradi-
ent run from 100% eluant A to 100% eluant B in 7 min 30 s for method A, in
10 min for method B and in 30 min for method C.
General Procedure for Synthesis of Benzimidazoles 2—4, 6, 8—11
and 18B To a solution of the appropriate acid (1 eq) in DMF (0.25 M) were
tively. A similar mechanism has been proposed for the con-
version of N,O-diacylated-2-aminophenols to benzoxa-
zoles.14)
Rate of conversion of mixed diacylated 1,2-phenylenedi-
amines to 2-substituted benzimidazoles is strongly dependent added a solution of DCC in DCM (0.5 eq), DIEA (1.1 eq) and o-phenylene-
diamine (0.4 eq). After stirring for 12 h at room temperature, the mixture
was filtered and the solvent evaporated. The residue was diluted with DCM,
washed with aqueuous NaHCO3 5%, dried over MgSO4, concentrated and
purified by TLC (CH2Cl2/MeOH 9.8 : 0.2, 9.5 : 0.5 or 9.9 : 0.1) to give the
upon the nature of the acyl substituents which improve or de-
crease the stabilization of one of the 1,2-dihydro-benzo-
[1,3,6]oxadiazepine intermediates. For example, when a
diphenylmethyl group is involved, the intermediates 23ꢀ,
leading to the 2-diphenylmethyl-benzimidazole, is better sta-
bilized than the intermediate 23ꢁ (Chart 5). This is consistent
with the percentage observed for the formation of com-
pounds 23A and B (Table 3).
In conclusion, formation of bulky 2-substituted benzimi-
dazoles from their monoacylated counterparts depends
highly upon the nature of the acyl group. In the case of a
diphenylmethyl group, cyclization can be observed with an
appropriate choice of acidic media and completion times are
in the same range as those reported for less bulky, symmetri-
cal diacylated compounds.13) Conversely, in the case of a di-
cyclohexylmethyl group, cyclization can be only achieved in
a p-toluenesulfonic acid/toluene (0.2 M) mixture, starting
from a diacylated precursor. It was observed that the mecha-
expected monoacylated compound. This latter was diluted in pure acetic
acid (0.2 M). Following reflux of the mixture for 5 h, the solvent was evapo-
rated, the residue diluted in DCM, washed with aqueous NaHCO3 5%, dried
over MgSO4 and concentrated. The expected benzimidazole was obtained
after trituration in a Et2O/pentane mixture or purification by TLC.
General Procedure for Synthesis of Benzimidazoles 1 and 7 To a so-
lution of the appropriate acid (1 eq) in DCM (0.2 M) was added thionyl chlo-
ride (2.5 eq). Following reflux of the mixture for 1.5 h, the solvent and the
excess of SOCl2 were evaporated. The residue was diluted with THF (0.3 M)
and this solution was added to a solution of 2-nitroaniline (1.5 eq) and pyri-
dine (5 eq) in THF (0.3 M). After stirring for 5 h at room temperature, the
solvent was evaporated. The residue was diluted in DCM, washed with
aqueous KHSO4 5%, aqueous NaHCO3 5% and saturated aqueous NaCl.
The organic layer was dried over MgSO4, concentrated and the residue puri-
fied by trituration in Et2O to give the expected monoacylated compound.
This latter was diluted in pure acetic acid (0.2 M) in presence of iron (2 eq).
Following reflux of the mixture for 8 h, the solvent was evaporated, the
residue diluted with DCM, washed with aqueous NaHCO3 5%, dried over
nism of cyclization starting from mixed diacylated precursors MgSO4 and concentrated. The expected benzimidazole was obtained after
purification by TLC.
General Procedure for Synthesis of Benzimidazoles 5 and 17B To a
solution of 2-nitroaniline (255 mg, 1.85 mmol, 1 eq) and pyridine (0.74 ml,
9.25 mmol, 5 eq) in dry DCM (5 ml) was added respectively 4-biphenylcar-
was not unique and was directly related to the nature of the
acyl groups. In addition to the potential synthetic utility of
the conversion described herein, the present study has also
provided some mechanistic rationales for the conversion of
mixed diacylated 1,2-phenylenediamines to benzimidazoles
under acidic conditions.
bonyl chloride (216 mg, 2.22 mmol, 1.2 eq) or propyl chloride (194 ml,
2.22 mmol, 1.2 eq). After stirring for 12 h at room temperature, the mixture
was washed with aqueous 5% KHSO4, aqueous 5% NaHCO3 and saturated
aqueous NaCl. The organic layer was dried over MgSO4 and concentrated.
The residue was diluted in pure acetic acid (10 ml) in presence of iron
(305 mg, 5.55 mmol, 3 eq). Following reflux of the mixture for 2 h, the sol-
vent was evaporated, the residue diluted with DCM, washed with aqueous
NaHCO3 5%, dried over MgSO4, concentrated and purified by TLC to give
expected compound.
Experimental
All reactions were monitored using thin-layer chromatography carried out
on 0.2 mm E. Merck silica gel plates (60F-254) using UV light as visualiz-
ing agent. 1H- and 13C-NMR spectra were measured in DMSO-d6 using a
Brücker 300 MHz spectrometer. Mass spectra were recorded on a Maldi
mass spectrometer (Maldi-MS). Chromatography was carried out using sil-
ica gel 60 (230—400 mesh ASTM) from Macherey-Nagel. Thick-layer
chromatography (TLC) was performed using silica gel from Merck and the
compounds were extracted from silica gel using the following solvent sys-
tem: CH2Cl2/MeOH 80 : 20. The melting point (mp) of the benzimidazoles
was determined on a Büchi 535 capillary mp apparatus and were uncor-
rected. The purity of the final compounds was verified by high performance
liquid chromatography (PHPLC) with a C18 Xterra or TSK-GEL column. An-
alytical HPLC was performed on a Shimadzu system equipped with a UV
detector set at 254 nm. Compounds were dissolved in MeOH and injected
through a 50 ml loop. The following eluant systems were used: A (H2O/TFA
100 : 0.05) and B (CH3CN/H2O/TFA 80 : 20 : 0.05). HPLC retention times
2-Benzhydryl-1H-benzoimidazole (1, 22—28A, 20B or 28B) (Tables 2,
3) A white solid (100 mg, 41%). mp 210—212 °C. Solvent for TLC: cy-
clohexane/AcOEt 7 : 3. Rf (cyclohexane/AcOEt 7 : 3): 0.45. tR (C18 Xterra,
1
method B): 5.35 min, PHPLC: 99%. H-NMR d: 12.31 (1H, s, NH), 7.40—
7.11 (14H, m, ArH), 5.74 (1H, s, CH). 13C-NMR d: 156.1, 142.3, 129.5,
129.3, 122.7, 121.9, 119.4, 112.0, 51.6. Maldi-MS m/z: 285 [MꢁH]ꢁ.
2-Benzyl-1H-benzoimidazole (2, 19B or 27B) (Tables 2, 3) A white
solid (100 mg, 38%). mp 179—180 °C. Purified by trituration. Rf (CH2Cl2/
MeOH 9.5 : 0.5): 0.45. tR (C18 Xterra, method B): 4.30 min, PHPLC: 99%.
1H-NMR d: 12.27 (1H, s, NH), 7.52—7.10 (9H, m, ArH), 4.17 (2H, s, CH2).
13C-NMR d: 154.4, 138.5, 129.6, 129.3, 127.4, 122.5, 121.8, 119.2, 111.8,
35.8. Maldi-MS m/z: 209 [MꢁH]ꢁ.

496
Vol. 53, No. 5
2-Cyclohexylmethyl-1H-benzoimidazole (3, 26B or 30B) (Tables 2, 3) 1 eq) and para-toluenesulfonic acid (135 mg, 0.72 mmol, 2 eq) in toluene
A white solid (115 mg, 64%). mp 202—205 °C. Purified by trituration. Rf
(3.5 ml) was stirred for 24 h at reflux. Then the solvent was evaporated and
the residue was diluted with DCM (20 ml), washed with aqueuous NaHCO3
(CH2Cl2/MeOH 9.5 : 0.5): 0.45. tR (C18 Xterra, method B): 4.89 min, PHPLC
:
99%. 1H-NMR d: 7.49—7.44 (2H, m, ArH), 7.14—7.10 (2H, m, ArH), 2.69 5%, dried over MgSO4, concentrated and purified by TLC (CH2Cl2/MeOH
(2H, d, Jꢂ7.1 Hz, CH2), 1.69—1.16 (11H, m, CHꢁCH2 cyclohexyl). 13C- 9.6 : 0.4) to give compound 12. A white solid (68 mg, 65%). mp 205—
NMR d: 154.9, 121.7, 118.8, 111.5, 48.3, 37.1, 34.2, 33.5, 26.5. Maldi-MS 207 °C. Rf (CH2Cl2/MeOH 9.6 : 0.4): 0.5. tR (TSK-GEL, method B):
1
m/z: 215 [MꢁH]ꢁ.
6.44 min, PHPLC: 99%. H-NMR d: 12.16 (1H, s, NH), 7.68 (1H, m, ArH),
2-(Cyclopentylphenylmethyl)-1H-benzoimidazole (4 or 29B) (Tables 2, 7.55 (1H, m, ArH), 7.25 (2H, m, ArH), 2.69 (1H, t, Jꢂ7.5 Hz, CH), 2.09
3) A white solid (150 mg, 35%). mp 208—210 °C. Solvent for TLC:
CH2Cl2/MeOH/NH4OH 9.8 : 0.8 : 0.1. Rf (CH2Cl2/MeOH/NH4OH 9.8 : 0.2 :
(2H, m, CH), 1.93—0.85 (20H, m, H cyclohexyl). 13C-NMR d: 176.3,
156.9, 121.9, 121.4, 118.9, 111.5, 57.4, 51.8, 32.2, 31.6, 30.1, 30.0, 26.9.
0.1): 0.55. tR (TSK-GEL, method B): 5.60 min, PHPLC: 99%. 1H-NMR d: Maldi-MS m/z: 297 [MꢁH]ꢁ.
12.26 (1H, s, NH), 7.50—7.31 (4H, m, ArH), 7.26 (2H, m, ArH), 7.16 (1H,
m, ArH), 7.07 (1H, m, ArH), 3.85 (1H, d, Jꢂ11.2 Hz, CH), 2.85 (1H, m,
CH), 1.64—1.42 (6H, m, CH2 cyclopentyl), 1.10 (2H, m, CH2 cyclopentyl).
13C-NMR d: 157.8, 142.9, 129.2, 128.9, 127.4, 122.3, 121.7, 119.2, 111.7,
52.5, 44.6, 32.2, 25.6, 25.5. Maldi-MS m/z: 277 [MꢁH]ꢁ.
Monoacylated Precursors (13—15) To a solution of dicyclohexyl-
acetic, diphenylacetic or cyclohexylphenylacetic acid (10 mmol, 1 eq) in
DMF (40 ml) were added a solution of DCC 1 M in DCM (5 ml, 5 mmol,
0.5 eq), DIEA (1.8 ml, 11 mmol, 1.1 eq) and o-phenylenediamine (433 mg,
4 mmol, 0.4 eq). After stirring for 12 h at room temperature, the mixture was
2-Biphenyl-4-yl-1H-benzoimidazole (5) (Table 2)
(299 mg, 60%). mp 178—180 °C. Solvent for TLC: CH2Cl2/MeOH/NH4OH washed with aqueuous NaHCO3 5%, dried over MgSO4, concentrated and
9.8 : 0.1 : 0.1. Rf (CH2Cl2/MeOH/NH4OH 9.9 : 0.1 : 0.1): 0.40. tR (C18 purified by TLC (CH2Cl2/MeOH 9.8 : 0.2, 9.5 : 0.5 or 9.9 : 0.1 respectively)
Xterra, method B): 6.16 min, PHPLC: 99%. 1H-NMR d: 8.27 (2H, d, to give respectively compound 13, 14 or 15.
A white solid filtered and the solvent evaporated. The residue was diluted with DCM,
Jꢂ8.4 Hz, ArH benzimidazole), 7.87 (2H, d, Jꢂ8.4 Hz, ArH benzimida-
zole), 7.78 (2H, d, Jꢂ7.2 Hz, ArH biphenyl), 7.62 (2H, m, ArH biphenyl),
7.51 (2H, t, Jꢂ7.1 Hz, ArH biphenyl), 7.41 (1H, m, ArH biphenyl), 7.24—
N-(2-Aminophenyl)-2,2-dicyclohexylacetamide (13) (Chart 2)
A
white solid (378 mg, 30%). Rf (CH2Cl2/MeOH 9.8 : 0.2): 0.65. tR (C18
Xterra, method B): 7.31 min, PHPLC: 99%.1H-NMR d: 9.11 (1H, s, NH), 7.07
7.18 (2H, m, ArH biphenyl). 13C-NMR d: 151.8, 142.1, 140.1, 129.9, 128.7, (1H, m, ArH), 6.88 (1H, m, ArH), 6.70 (1H, m, ArH), 6.53 (1H, m, ArH),
128.0, 127.9, 127.5, 122.9, 115.3. Maldi-MS m/z: 271 [MꢁH]ꢁ.
2-Biphenyl-2-yl-1H-benzoimidazole (6) (Table 2)
4.71 (2H, s, NH2), 2.09 (1H, t, Jꢂ7.2 Hz, CH), 1.68 (12H, m, CHꢁCH2),
A
white solid 1.10 (10H, m, CH2). Maldi-MS m/z: 315 [MꢁH]ꢁ.
(140 mg, 33%). mp 212—213 °C. Solvent for TLC: CH2Cl2/MeOH 9.7 : 0.3.
Rf (CH2Cl2/MeOH 9.7 : 0.3): 0.40. tR (C18 Xterra, method B): 5.06 min,
N-(2-Aminophenyl)-2,2-diphenylacetamide (14) (Chart 2) A white
solid (751 mg, 62%). Rf (CH2Cl2/MeOH 9.8 : 0.2): 0.50. tR (TSK GEL,
PHPLC: 99%. 1H-NMR d: 12.07 (1H, s, NH), 7.72—7.69 (1H, m, ArH), method A): 4.94 min, PHPLC: 99%. 1H-NMR d: 9.60 (1H, s, NH), 7.40—7.23
7.63—7.48 (4H, m, ArH), 7.33—7.25 (1H, m, ArH), 7.24—7.10 (7H, m, (10H, m, ArH phenyl), 7.18 (1H, dd, Jꢂ1.4, 7.9 Hz, ArH), 7.18—7.12 (1H,
ArH). 13C-NMR d: 152.9, 144.3, 141.8, 140.9, 135.4, 131.9, 131.3, 131.0, td, Jꢂ1.5, 7.9 Hz, ArH), 6.71 (1H, dd, Jꢂ1.4, 8.0 Hz, ArH), 6.54 (1H, td,
130.7, 129.6, 128.9, 128.2, 127.9, 122.9, 122.1, 119.7, 112.1. Maldi-MS Jꢂ1.5, 7.4 Hz, ArH), 4.78 (2H, s, NH2). Maldi-MS m/z: 303 [MꢁH]ꢁ.
m/z: 271 [MꢁH]ꢁ.
N-(2-Aminophenyl)-2-cyclohexyl-2-phenylacetamide (15) (Chart 2)
2-(4-Propylphenyl)-1H-benzoimidazole (7) (Table 2) A white solid A white solid (519 mg, 42%). Rf (CH2Cl2/MeOH 9.9 : 0.1): 0.50. tR (TSK
(310 mg, 25%). mp 197—198 °C. Solvent for TLC: CH2Cl2/MeOH 9.6 : 0.4.
GEL, method B): 6.82 min, PHPLC: 99%. 1H-NMR d: 9.30 (1H, s, NH),
Rf (CH2Cl2/MeOH 9.6 : 0.4): 0.50. tR (C18 Xterra, method B): 5.65 min,
7.33—7.30 (2H, m, ArH), 7.26—7.21 (2H, m, ArH), 7.18—7.12 (1H, m,
1
PHPLC: 99%. H-NMR d: 12.74 (1H, s, NH), 8.01 (2H, m, ArH), 7.54 (2H, ArH), 7.02 (1H, m, ArH), 6.80 (1H, m, ArH), 6.60 (1H, m, ArH), 6.43 (1H,
m, ArH), 7.27 (2H, m, ArH), 7.11 (2H, m, ArH), 2.53 (2H, t, Jꢂ7.3 Hz,
m, ArH), 4.60 (2H, s, NH2), 3.31 (1H, d, Jꢂ10.7 Hz, CH), 1.95—1.00 (11H,
CH2), 1.56 (2H, m, CH2), 0.83 (3H, t, Jꢂ7.3 Hz, CH3). 13C-NMR d: 152.3, m, H cyclohexyl). Maldi-MS m/z: 309 [MꢁH]ꢁ.
145.0, 129.7, 128.6, 127.2, 123.1, 122.4, 119.5, 112.0, 37.9, 26.4, 14.5.
Diacylated Derivatives (16—20, 22—30) To a solution of appropriate
acid (1.1 eq) in dry DCM (0.25 M) were added DIEA (2 eq), PyBrop (1.3 eq)
Maldi-MS m/z: 237 [MꢁH]ꢁ.
2-(1-Phenylethyl)-1H-benzoimidazole (8) (Table 2) A white solid and compound 13, 14 or 15 (1 eq). After stirring for 12 h at room tempera-
(200 mg, 63%). mp 197—199 °C. Purified by trituration. Rf (CH2Cl2/MeOH ture, the mixture was washed with aqueuous NaHCO3 5%, dried over
1
9.7 : 0.3): 0.40. tR (C18 Xterra, method B): 4.28 min, PHPLC: 99%. H-NMR MgSO4, concentrated and purified by TLC (CH2Cl2/MeOH) to give expected
d: 12.18 (1H, s, NH), 7.57—7.07 (9H, m, ArH), 4.37 (1H, q, Jꢂ7.2 Hz,
CH), 1.69 (3H, d, Jꢂ7.2 Hz, CH3). 13C-NMR d: 158.2, 144.5, 129.3, 128.2,
127.4, 122.5, 121.7, 119.2, 111.8, 40.2, 21.3. Maldi-MS m/z: 223 [MꢁH]ꢁ.
compound.
N-(2-Acetylaminophenyl)-2,2-dicyclohexylacetamide (16) (Chart 2,
Table 3) A white solid (152 mg, 21%). Solvent for TLC: CH2Cl2/MeOH
2-(9H-Fluoren-9-yl)-1H-benzoimidazole (9) (Table 2) A white solid 9.9 : 0.1. Rf (CH2Cl2/MeOH 9.6 : 0.4): 0.55. tR (TSK GEL, method B):
(100 mg, 60%). mp ꢃ225 °C. Solvent for TLC: CH2Cl2/MeOH 9.5 : 0.5. Rf 8.87 min, PHPLC: 99%. 1H-NMR d: 9.22 (1H, s, NH), 9.21 (1H, s, NH),
(CH2Cl2/MeOH 9.5 : 0.5): 0.50. tR (C18 Xterra, method B): 5.36 min, PHPLC
:
7.34—7.25 (2H, m, ArH), 7.08—7.04 (2H, m, ArH), 3.19 (3H, s, CH3), 1.95
1
99%. H-NMR d: 12.16 (1H, s, NH), 7.96 (2H, m, ArH), 7.52—7.42 (5H, (1H, m, CH), 1.58—1.54 (12H, m, H cyclohexyl), 1.62—0.83 (10H, m, H
m, ArH), 7.35—7.28 (3H, m, ArH), 7.11—7.08 (2H, m, ArH), 5.53 (1H, s, cyclohexyl). Maldi-MS m/z: 357 [MꢁH]ꢁ.
CH), 3.17 (2H, m, CH2), 2.90 (2H, m, CH2). 13C-NMR d: 158.8, 143.9,
136.5, 136.2, 135.2, 129.8, 129.6, 126.6, 126.5, 122.4, 121.7, 119.2, 111.7,
48.4, 35.2, 34.5, 29.2. Maldi-MS m/z: 283 [MꢁH]ꢁ.
N-[2-(2,2-Dicyclohexylacetylamino)phenyl]propionamide (17) (Chart
2, Table 3) A white solid (115 mg, 20%). Solvent for TLC: CH2Cl2/MeOH
9.7 : 0.3. Rf (CH2Cl2/MeOH 9.8 : 0.8): 0.20. tR (Xterra, method B): 9.36 min,
PHPLC: 90%. 1H-NMR d: 9.36 (1H, s, NH), 9.21 (1H, s, NH), 7.46—7.43
(1H, m, ArH), 7.34—7.31 (1H, m, ArH), 7.15—7.08 (2H, m, ArH), 2.24
2-(Cyclohexylphenylmethyl)-1H-benzoimidazole (10 or 29A, 30A)
(Tables 2, 3) A white solid (120 mg, 21%). mp 195—197 °C. Solvent for
TLC: CH2Cl2/MeOH 9.7 : 0.3. Rf (CH2Cl2/MeOH 9.8 : 0.2): 0.45. tR (TSK- (2H, q, Jꢂ7.5 Hz, CH2), 2.00 (1H, t, Jꢂ7.0 Hz, CH), 1.65—1.61 (12H, m, H
GEL, method B): 5.06 min, PHPLC: 99%. 1H-NMR d: 12.18 (1H, s, NH), cyclohexyl), 1.19—0.93 (12H, m, H cyclohexyl and 3H, t, Jꢂ7.5 Hz, CH3).
7.53 (1H, m, ArH), 7.45 (1H, m, ArH), 7.37 (1H, m, ArH), 7.25 (2H, m,
Maldi-MS m/z: 371 [MꢁH]ꢁ.
ArH), 7.17 (1H, m, ArH), 7.07 (2H, m, ArH), 3.80 (1H, d, Jꢂ10.7 Hz, CH),
N-[2-(2,2-Dicyclohexylacetylamino)phenyl]butyramide (18) (Chart 2,
2.29 (1H, m, CH), 1.58—0.91 (10H, m, CH2 cyclohexyl). 13C-NMR d: Table 3) A white solid (120 mg, 18%). Solvent for TLC: CH2Cl2/MeOH
157.2, 144.2, 141.7, 134.7, 129.2, 129.1, 127.4, 122.3, 121.7, 119.2, 53.3,
9.7 : 0.3. Rf (CH2Cl2/MeOH 9.8 : 0.2): 0.30. tR (Xterra, method B): 9.87 min,
41.9, 32.3, 31.6, 29.8, 26.8, 26.4. Maldi-MS m/z: 291 [MꢁH]ꢁ.
PHPLC: 90%. H-NMR d: 10.40 (1H, s, NH), 10.35 (1H, s, NH), 7.53—7.50
1
2-(1,2,3,4-Tetrahydronaphthalen-2-yl)-1H-benzoimidazole (11) (Table (1H, m, ArH), 7.43—7.39 (1H, m, ArH), 7.05—7.02 (2H, m, ArH), 2.26
2) A white solid (140 mg, 53%). mp ꢃ225 °C. Purified by trituration. Rf (2H, q, Jꢂ7.4 Hz, CH2), 2.18 (1H, t, Jꢂ7.3 Hz, CH), 1.74—1.49 (16H, m, H
(CH2Cl2/MeOH 9.5 : 0.5): 0.45. tR (C18 Xterra, method B): 5.06 min, PHPLC
:
cyclohexylꢁCH2), 1.19—0.95 (8H, m, H cyclohexyl), 0.86 (3H, t, Jꢂ
1
99%. H-NMR d: 7.55 (1H, m, ArH), 7.43 (1H, m, ArH), 7.24—7.10 (6H,
m, ArH), 3.32 (3H, m, CHꢁCH2), 3.17 (2H, m, CH2), 2.90 (2H, m, CH2).
13C-NMR d: 158.8, 143.9, 136.5, 136.2, 135.2, 129.8, 129.6, 126.6, 126.5,
7.4 Hz, CH3). Maldi-MS m/z: 385 [MꢁH]ꢁ.
2,2-Dicyclohexyl-N-(2-phenylacetylaminophenyl)acetamide (19)
(Chart 2, Table 3) A white solid (171 mg, 25%). Solvent for TLC:
122.4, 121.7, 119.2, 111.7, 48.4, 35.2, 34.5, 29.2. Maldi-MS m/z: 249 CH2Cl2/MeOH 9.8 : 0.2. Rf (CH2Cl2/MeOH 9.8 : 0.2): 0.60. tR (Xterra,
[MꢁH]ꢁ.
2-Dicyclohexylmethyl-1H-benzoimidazole (12, 16—21A or 21B) (Ta-
bles 2, 3) A solution of diacylated compound 16 (130 mg, 0.36 mmol,
method B): 10.22 min, PHPLC: 94%. 1H-NMR d: 9.60 (1H, s, NH), 9.17 (1H,
s, NH), 7.46—7.39 (2H, m, ArH), 7.30—7.20 (5H, m, ArH), 7.13—7.11
(2H, m, ArH), 3.59 (2H, s, CH2), 1.87 (1H, t, Jꢂ7.5 Hz, CH), 1.65—0.90

May 2005
497
(22H, m, H cyclohexyl). Maldi-MS m/z: 433 [MꢁH]ꢁ.
ArH), 3.17—3.12 (1H, m, CH), 3.10—3.04 (1H, m, CH), 1.98—0.93 (20H,
m, H cyclohexylꢁH cyclopentyl). Maldi-MS m/z: 495 [MꢁH]ꢁ.
2-Cyclohexyl-N-[2-(2-cyclohexylacetylamino)phenyl]-2-phenylac-
etamide (30) (Chart 2, Table 3) A white solid (160 mg, 49%). Solvent for
TLC: CH2Cl2/MeOH 9.9 : 0.1. Rf (CH2Cl2/MeOH 9.8 : 0.2): 0.65. tR (TSK-
GEL, method B): 10.39 min, PHPLC: 99%. 1H-NMR d: 9.66 (1H, s, NH),
9.09 (1H, s, NH), 7.45—7.29 (7H, m, ArH), 7.13—7.12 (2H, m, ArH),
3.31—3.24 (3H, m, CHꢁCH2), 2.09—0.96 (22H, m, H cyclohexyl). Maldi-
MS m/z: 433 [MꢁH]ꢁ.
2-Methyl-1H-benzoimidazole (16B or 22B) (Table 3) A white solid
(commercially available). mp 175—179 °C. Rf (CH2Cl2/MeOH 9 : 1): 0.45.
tR (TSK-GEL, method A): 2.60 min, PHPLC: 100%. 1H-NMR d: 12.16 (1H, s,
NH), 7.50—7.36 (2H, m, ArH), 7.12—7.06 (2H, m, ArH), 2.47 (3H, s,
CH3). 13C-NMR d: 158.3, 121.5, 118.6, 111.0, 15.2. Maldi-MS m/z: 133
[MꢁH]ꢁ.
2,2-Dicyclohexyl-N-(2-diphenylacetylaminophenyl)acetamide (20)
(Chart 2, Table 3) A white solid (160 mg, 44%). Solvent for TLC:
CH2Cl2/MeOH 9.9 : 0.1. Rf (CH2Cl2): 0.55. tR (TSK-GEL, method B):
11.38 min, PHPLC: 95%. 1H-NMR d: 9.97 (1H, s, NH), 9.12 (1H, s, NH),
7.53—7.46 (2H, m, ArH), 7.39—7.23 (10H, m, ArH), 7.19—7.13 (2H, m,
ArH), 5.06 (1H, s, CH), 1.83 (1H, t, Jꢂ7.0 Hz, CH), 1.59—0.90 (22H, m, H
cyclohexyl). Maldi-MS m/z: 509 [MꢁH]ꢁ.
2,2-Dicyclohexyl-N-[2-(2,2-dicyclohexylacetylamino)phenyl]acetamide
(21) (Chart 2, Table 3) To a solution of o-phenylenediamine (130 mg,
1.21 mmol, 2.4 eq) in DCM (15 ml) were added dicyclohexylacetic acid
(650 mg, 2.9 mmol, 1 eq), PyBrop (1.35 g, 2.9 mmol, 2.4 eq) and DIEA
(0.63 ml, 3.63 mmol, 3 eq). After stirring for 12 h at room temperature, the
mixture was washed with aqueuous NaHCO3 5%, dried over MgSO4, con-
centrated and purified by TLC (CH2Cl2/MeOH 9.8 : 0.2) to give compound
21. A white solid (600 mg, 95%). Rf (CH2Cl2/MeOH 9.8 : 0.4): 0.7. tR (TSK-
GEL, method C): 31.8 min, PHPLC: 94%. 1H-NMR d: 9.41 (2H, s, NH),
7.60—7.54 (2H, m, ArH), 7.14—7.11 (2H, m, ArH), 1.98—1.93 (2H, m,
CH), 1.75—0.93 (44H, m, H cyclohexyl). Maldi-MS m/z: 521 [MꢁH]ꢁ.
N-(2-Acetylaminophenyl)-2,2-diphenylacetamide (22) (Chart 2, Table
3) A white solid (120 mg, 49%). Solvent for TLC: CH2Cl2/MeOH 9.8 : 0.2.
Rf (CH2Cl2/MeOH 9.5 : 0.5): 0.50. tR (TSK-GEL, method A): 5.43 min,
PHPLC: 99%. 1H-NMR d: 9.52 (1H, s, NH), 9.34 (1H, s, NH), 7.58—7.54
(1H, m, ArH), 7.39—7.32 (9H, m, ArH), 7.29—7.24 (2H, m, ArH), 7.17—
7.13 (2H, m, ArH), 5.24 (1H, s, CH), 1.90 (3H, s, CH3). Maldi-MS m/z: 335
[MꢁH]ꢁ.
2-Ethyl-1H-benzoimidazole (17B or 23B) (Table 3) A white solid
(68 mg, 25%). mp 145—147 °C. Solvent for TLC: cyclohexane/AcOEt 5 : 5.
Rf (CH2Cl2/MeOH 9 : 1): 0.45. tR (TSK-GEL, method A): 2.81 min, PHPLC
:
99%. 1H-NMR d: 12.15 (1H, s, NH), 7.48—7.41 (2H, m, ArH), 7.13—7.07
(2H, m, ArH), 2.82 (2H, q, Jꢂ7.6 Hz, CH2), 1.31 (3H, t, Jꢂ7.6 Hz, CH3).
13C-NMR d: 156.7, 121.6, 115.0, 22.6, 12.8. Maldi-MS m/z: 147 [MꢁH]ꢁ.
2-Propyl-1H-benzoimidazole (18B or 24B) (Table 3) A white solid
(90 mg, 30%). mp 153—154 °C. Solvent for TLC: CH2Cl2/MeOH 9.3 : 0.7.
Rf (CH2Cl2/MeOH 9.3 : 0.7): 0.50. tR (C18 Xterra, method B): 3.77 min,
PHPLC: 99%. 1H-NMR d: 12.14 (1H, s, NH), 7.47—7.38 (2H, m, ArH),
7.10—7.06 (2H, m, ArH), 2.75 (2H, t, Jꢂ7.4 Hz, CH2), 1.82—1.70 (2H, m,
CH2), 0.91 (3H, t, Jꢂ7.4 Hz, CH3). 13C-NMR d: 155.8, 122.1, 121.6, 118.9,
111.5, 31.4, 21.8, 14.6. Maldi-MS m/z: 161 [MꢁH]ꢁ.
N-(2-Diphenylacetylaminophenyl)propionamide (23) (Chart 2, Table
3) A white solid (83 mg, 25%). Solvent for TLC: CH2Cl2/MeOH 9.8 : 0.2.
Rf (CH2Cl2/MeOH 9.5 : 0.5): 0.40, tR (TSK-GEL, method A): 5.86 min,
PHPLC: 99%. 1H-NMR d: 9.59 (1H, s, NH), 9.22 (1H, s, NH), 7.54—7.51
(1H, m, ArH), 7.42—7.28 (9H, m, ArH), 7.26—7.24 (2H, m, ArH), 7.17—
7.14 (2H, m, ArH), 5.22 (1H, s, CH), 2.17 (2H, q, Jꢂ7.5 Hz, CH2), 0.96
(3H, t, Jꢂ7.5 Hz, CH3). Maldi-MS m/z: 359 [MꢁH]ꢁ.
2-tert-Butyl-1H-benzoimidazole (25B) (Table 3) A violet solid (com-
mercially available). mp ꢃ250 °C. Rf (CH2Cl2/MeOH 9.3 : 0.7): 0.10. tR
1
(TSK-GEL, method A): 3.18 min, PHPLC: 100%. H-NMR d: 12.08 (1H, s,
NH), 7.54—7.39 (2H, m, ArH), 7.13—7.08 (2H, m, ArH), 1.37 (9H, s,
CH3). 13C-NMR d: 162.7, 122.0, 121.3, 118.9, 111.4, 29.9. Maldi-MS m/z:
175 [MꢁH]ꢁ.
N-(2-Diphenylacetylaminophenyl)butyramide (24) (Chart 2, Table 3)
A white solid (154 mg, 61%). Solvent for TLC: CH2Cl2/MeOH 9.8 : 0.2. Rf
Acknowledgments Thanks are due to Dr. Steve Brooks for proof read-
ing, Gérard Montagne for NMR spectra and Hervé Drobecq for MALDI-MS
experiments. Julie Charton was a recipient of research fellowship from the
Ministère de l’Education Nationale et de la Recherche, France.
(CH2Cl2/MeOH 9.8 : 0.2): 0.45. tR (TSK-GEL, method B): 7.74 min, PHPLC
:
1
99%. H-NMR d: 9.64 (1H, s, NH), 9.21 (1H, s, NH), 7.52—7.49 (1H, m,
ArH), 7.43—7.30 (9H, m, ArH), 7.27—7.22 (2H, m, ArH), 7.17—7.13 (2H,
m, ArH), 5.19 (1H, s, CH), 2.11 (2H, t, Jꢂ7.3 Hz, CH2), 1.49—1.40 (2H, m,
CH2), 0.83 (2H, t, Jꢂ7.3 Hz, CH3). Maldi-MS m/z: 373 [MꢁH]ꢁ.
N-(2-Diphenylacetylaminophenyl)-2,2-dimethylpropionamide (25)
(Chart 2, Table 3) A white solid (160 mg, 61%). Solvent for TLC:
CH2Cl2/MeOH 9.8 : 0.2. Rf (CH2Cl2/MeOH 9.8 : 0.2): 0.55. tR (TSK-GEL,
method B): 8.32 min, PHPLC: 99%. 1H-NMR d: 10.12 (1H, s, NH), 8.73 (1H,
s, NH), 7.37—7.13 (14H, m, ArH), 5.20 (1H, s, CH), 0.93 (9H, s, CH3).
Maldi-MS m/z: 387 [MꢁH]ꢁ.
References
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dron Lett., 45, 313—316 (2004).
9) Safronov A. I., Traven V. F., Zh. Org. Khim., 29, 1853—1858 (1993).
10) Ogata M., Yoshimura T., Fujii H., Ito Y., Katsuki T., Synlett., 1993,
728—730 (1993).
11) Nestor J. J. Jr., Horner B. L., Ho T. L., Jones G. H., McRae G. I., Vick-
ery B. H., J. Med. Chem., 27, 320—325 (1984).
N-[2-(2-Cyclohexylacetylamino)phenyl]-2,2-diphenylacetamide (26)
(Chart 2, Table 3) A white solid (135 mg, 45%). Solvent for TLC:
CH2Cl2/MeOH 9.9 : 0.1. Rf (CH2Cl2/MeOH 9.8 : 0.2): 0.50. tR (TSK-GEL,
1
method B): 8.80 min, PHPLC: 99%. H-NMR d: 9.67 (1H, s, NH), 9.21 (1H,
s, NH), 7.51—7.16 (14H, m, ArH), 5.16 (1H, s, CH), 3.33 (2H, d, Jꢂ9.2 Hz,
CH2), 1.95—0.95 (11H, m, H cyclohexyl). Maldi-MS m/z: 427 [MꢁH]ꢁ.
2,2-Diphenyl-N-(2-phenylacetylaminophenyl)acetamide (27) (Chart 2,
Table 3) A white solid (520 mg, 47%). Solvent for TLC: CH2Cl2/MeOH
9.9 : 0.1. Rf (CH2Cl2/MeOH 9.9 : 0.1): 0.45. tR (TSK-GEL, method B):
8.44 min, PHPLC: 95%. 1H-NMR d: 9.61 (1H, s, NH), 9.53 (1H, s, NH),
7.54—7.51 (1H, m, ArH), 7.45—7.41 (1H, m, ArH), 7.35—7.22 (15H, m,
ArH), 7.16—7.13 (2H, m, ArH), 5.15 (1H, s, CH), 3.59 (2H, s, CH2). Maldi-
MS m/z: 421 [MꢁH]ꢁ.
N-(2-Diphenylacetylaminophenyl)-2,2-diphenylacetamide (28) (Chart
2, Table 3) A white solid (590 mg, 64%). Solvent for TLC: CH2Cl2/MeOH
9.8 : 0.2. Rf (CH2Cl2/MeOH 9.8 : 0.2): 0.70. tR (TSK-GEL, method B):
9.21 min, PHPLC: 99%. 1H-NMR d: 9.74 (2H, s, NH), 7.52—7.49 (2H, m,
ArH), 7.33—7.23 (20H, m, ArH), 7.18—7.15 (2H, m, ArH), 5.07 (2H, s,
CH). Maldi-MS m/z: 497 [MꢁH]ꢁ.
12) Balboni G., Guerrini R., Salvadori S., Bianchi C., Rizzi D., Bryant S.
D., Lazarus L. H., J. Med. Chem., 45, 713—720 (2002).
13) DeLuca M. R., Kerwin S. M., Tetrahedron, 53, 457—464 (1997).
14) DeLuca M. R., Taraporewala I. B., Kerwin S. M., Heterocycles, 51,
979—982 (1999).
2-Cyclohexyl-N-[2-(2-cyclopentyl-2-phenylacetylamino)phenyl]-2-
phenylacetamide (29) (Chart 2, Table 3) A white solid (100 mg, 22%).
Solvent for TLC: CH2Cl2/MeOH 9.9 : 0.1. Rf (CH2Cl2/MeOH 9.8 : 0.2): 0.70.
1
15) Reiter L. A., Jones B. P., J. Org. Chem., 62, 2808—2812 (1997).
tR (TSK-GEL, method B): 11.37 min, PHPLC: 93%. H-NMR d: 9.59 (1H, s,
NH), 9.47 (1H, s, NH), 7.44—7.24 (12H, m, ArH), 7.13—7.09 (2H, m,